Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][CH:24]=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C([O-])(=O)C.[Na+].[I:30]Cl>C(O)(=O)C.O>[I:30][C:24]1[CH:23]=[N:22][N:15]2[C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([CH3:1])[CH:3]=3)=[N:13][C:14]=12
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3nccc3n2)ccc1C(F)(F)F
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a stirred solution of 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (2.12 g, 6.14 mmol) in acetic acid (15 ml) was added at room temperature sodium acetate (0.57 g, 6.95 mmol) and drop wise a solution of iodine monochloride (1.13 g, 6.96 mmol) in acetic acid (3.5 ml). The reaction mixture was stirred at room temperature for 16 h, diluted slowly with water (up to 100 ml), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 3-iodo-5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (2.44 g, 84%) as a yellow solid. MS (EI) 471.0 [(M)+]; mp 160° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:19])[NH:6][CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH2:8][CH:9]=[CH2:10].[CH2:20]([O:22][CH2:23]Cl)[CH3:21]>O1CCCC1>[CH3:3][O:4][C:5](=[O:19])[N:6]([CH:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[CH2:8][CH:9]=[CH2:10])[CH2:23][O:22][CH2:20][CH3:21]
Reactant: CCOCCl
Reactant: C=CCC(Cc1ccc(Cl)cc1)NC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(Cc1ccc(Cl)cc1)N(COCC)C(=O)OC
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A suspension of 10.0 g of sodium hydride (80% in mineral oil, 333 mmol) in dry tetrahydrofuran [THF] is heated at reflux under argon. A solution of 60.5 g (238 mmol) of [1-(4-chloro-benzyl)-but-3-enyl]-carbamic acid methyl ester [McCarty F J, Rosenstock P D, Paolini J P, Micucci D D, Ashton L, Bennetts W W, J. Med. Chem, 1968, 11(3),534] in 50 ml of dry THF is added dropwise thereto in the course of 1 hour. The mixture is then boiled under reflux for 2 hours until the evolution of gas subsides. The mixture is cooled to 0° C. and chloromethyl ethyl ether is added dropwise in such a manner that the reaction temperature does not exceed 5° C. The mixture is then heated slowly to 25° C. and stirred for 12 hours to complete the reaction. Excess sodium hydride is destroyed carefully with 1 ml of water before more water is added. The phases are separated and the aqueous phase is extracted again with tert-butyl methyl ether. The combined organic phases are washed with brine, dried over sodium sulfate, and concentrated by evaporation. The crude product is distilled at 0.1 mbar and has a boiling range of 120-125° C. TLC: ethyl acetate/hexane (1:6) Rf =0.34, FD-MS: M+ =311 (313).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:23][CH2:24][CH2:25]Br>ClCCl.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:16]#[N:17])[CH2:25][CH2:24][CH2:23]2)=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: COc1cc(CC#N)ccc1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C2(C#N)CCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.1 %

Procedure:
To a solution of 2-(4-(benzyloxy)-3-methoxyphenyl)acetonitrile (3.1 g, 12.24 mmol) in dichloromethane (30 mL) was added sodium hydroxide (30 mL, 50% aqueous solution, 367 mmol), TBAB (0.99 g, 3.06 mmol) and then with 1,3-dibromopropane (2 mL, 19.58 mmol). The reaction was stirred at room temperature for 72 hours. The layers were separated, organic layer was dried (MgSO4) and concentrated. Purification by flash chromatography (silica gel, 5-25% EtOAc/hexane) afforded 1-(4-(benzyloxy)-3-methoxyphenyl)cyclobutanecarbonitrile (1.8 g, 50%). MS (ESI) m/z 294 (M+H)+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:26])([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:34])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.94 ml of DBU and then 1.54 ml of benzyl bromide are added at RT to a solution of 3 g of 6-(tert-butoxycarbonylamino)hexanoic acid in 60 ml of DCM and the mixture is stirred for 24 hours at RT. It is concentrated under vacuum, the residue is taken up with 100 ml of water and extracted with AcOEt, the organic phase is washed with a 5% solution of potassium carbonate, with a saturated solution of NaCl and with water and dried over sodium sulfate and the solvent is evaporated off under vacuum to give 2.8 g of the expected product, which is used as such.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1.O>CN1C(=O)CCC1>[N:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]3)[N:7]=2)[N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=12
Reactant: NC1CCC(O)CC1
Reactant: Clc1nccc(-c2cnc3ccccn23)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: OC1CCC(Nc2nccc(-c3cnc4ccccn34)n2)CC1
Temperature: 105 °C
Reaction time: 5 h
Yield: 54.7 %

Procedure:
A mixture of 3-(2-chloropyrimidin-4-yl)-imidazo[1,2-a]pyridine (30 mg) and 4-amino-cyclohexanol (45 mg) in NMP (1 mL) was stirred at 105° C. for 5 h. The reaction mixture was then cooled to RT and titurated with water. The resulting solid was filtered, washed with water and dried. The product was purified by ISCO using 100% DCM to 15% MeOH/DCM, and the pure fractions combined, concentrated, and titurated with EtOAc. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide 4-(4-imidazo[1,2-a]pyridin-3-yl-pyrimidin-2-ylamino)-cyclohexanol (compound 11, 22 mg).
Reaction SMILES: ClS(C1C=C(C=CC=1F)C(O)=O)(=O)=O.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([S:30](NCC)(=[O:32])=[O:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]>>[Cl:19][C:20]1[CH:28]=[C:27]([F:29])[C:26]([S:30]([NH:18][CH:15]2[CH2:17][CH2:16]2)(=[O:32])=[O:31])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: CCNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Reactant: NC1CC1
Agent: O=C(O)c1ccc(F)c(S(=O)(=O)Cl)c1
Product: O=C(O)c1cc(S(=O)(=O)NC2CC2)c(F)cc1Cl

Procedure:
1.005 g (3.6 mmol) 3-chlorosulfonyl-4-fluorobenzoic acid was added to 0.76 mL (10.9 mmol) cyclopropylamine following the general procedure in for 2-chloro-5-[(ethylamino)sulfonyl]-4-fluorobenzoic acid. Crude product was used in subsequent step without further purification
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(Cl)c1
Temperature: 105 °C
Reaction time: 0.25 h

Procedure:
1.76 g (10.0 mmol) 3-chloro-4-fluoro-1-nitro-benzene are combined with 2.614 ml (30 mmol) morpholine in 5 ml DMF and heated to 105° C. with stirring for 15 min. The reaction mixture is poured into ice water, the resulting precipitate is suction filtered, washed with water and dried at 50° C. in the drying cupboard.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[S:18][C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=O>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[S:18][C:17]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][OH:26])[CH2:21][CH2:20]4)=[N:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=CCCCCO
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCNCC4)s3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(-c3nnc(C4CCN(CCCCCO)CC4)s3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 125 mg (0.35 mmol) of 4-[5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-thiadiazol-2-yl]piperidine and 72 mg (0.70 mmol) of 5-hydroxypentanal. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: C(OC([N:8]1[CH:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=O)(C)(C)C.[ClH:22].[NH2:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28]>>[ClH:22].[ClH:22].[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:9]2[NH:8][CH:12]([C:13]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:15])[CH2:11][S:10]2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Reactant: CSCC[C@H](N)C(N)=O
Agent: Cl
Product: CSCC[C@H](NC(=O)C1CSC(c2cccnc2)N1)C(N)=O

Procedure:
N-tert-Butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid and L-methioninamide hydrochloride were used as the starting materials and treated in the same manner as in Example 4 to give [2-(3-pyridyl)thiazolidine-4-carbonyl]-L-methioninamide dihydrochloride. Melting point 131° C.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:12]=[CH:11][C:8]=1[C:9]#[N:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[C:40]([C:39]1[CH:42]=[CH:43][C:36]([O:35][CH2:34][CH2:33][CH2:32][N:22]2[CH2:23][CH2:24][CH:19]([CH2:18][CH2:17][CH2:16][O:15][C:13]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([F:6])[CH:14]=3)[CH2:20][CH2:21]2)=[CH:37][CH:38]=1)#[N:41]
Reactant: N#Cc1ccc(OCCCBr)cc1
Reactant: N#Cc1ccc(OCCCC2CCNCC2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(OCCCN2CCC(CCCOc3ccc(C#N)c(F)c3)CC2)cc1
Reaction time: 13 h
Yield: 42.3 %

Procedure:
To an N,N-dimethylformamide solution (2.0 mL) of 0.10 g of 2-fluoro-4-[3-(4-piperidinyl)propoxy]benzonitrile were sequentially added 0.10 g of potassium carbonate and 0.13 g of 4-(3-bromopropoxy)benzonitrile at room temperature, which was then stirred at the same temperature for 13 hours. Ethyl acetate, water, and toluene were added to the reaction mixture. The organic layer was separated and dried with anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; chloroform:methanol=4:1) to provide 68 mg of 4-(3-{1-[3-(4-cyanophenoxy)propyl]-4-piperidinyl}propoxy)-2-fluorobenzonitrile as white solid form.
Reaction SMILES: [Na].Cl.N[OH:4].[Cl:5][C:6]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([NH2:18])=[O:17]>CO>[Cl:5][C:6]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([NH:18][OH:4])=[O:17]
Reactant: NC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)NO

Procedure:
To a solution of 1.84 g of sodium in 80 ml of methanol is added, at 50°, a solution of 1.82 g of hydroxylamine hydrochloride in 30 ml of methanol. To the suspension is added, with stirring, a solution of 5.8 g of [o-(2,6-dichloroanilino)-phenyl]-acetamide (M.P. 188°-189°) in 80 ml of methanol, and the whole subsequently refluxed for 18 hours. After cooling, the red suspension is concentrated at 40° under 11 Torr to dryness. The residue is shaken with 600 ml of water and 100 ml of ether. The aqueous phase is separated and acidified with 2 N hydrochloric acid. The suspension is extracted with 200 ml of ether, the ether solution separated, washed with water, dried over magnesium sulphate, and concentrated at 40° under 11 Torr. The residue is crystallized from ether, whereby [o-(2,6-dichloroanilino)-phenyl]-acetohydroxamic acid is obtained, M.P. 164°-165°.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][CH:29]([NH2:31])[CH3:30]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:31][CH:29]([CH3:30])[CH3:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CC(C)NC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), propan-2-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 319 (M+, 1), 304 (8), 84 (8), 73 (6), 72 (bp), 56 (7).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: ClCc1ccc(Cl)cc1
Product: O=C(O)c1cc(NCc2ccc(Cl)cc2)ccc1O
Yield: 53 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 4-chlorobenzyl chloride (630 mg, 3.91 mmole), 480 mg (53% yield) of 5-(4-chlorobenzyl)aminosalicylic acid was obtained as a white solid.: mp 227-228° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:7][CH:6]=1.[ClH:19]>[Zn].Cl[Ti](Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH:5]1[CH:6]=[CH:7][C:8](/[C:9](/[CH2:11][CH2:12][Cl:19])=[C:9](\[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=2)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:17][CH:18]=1
Reactant: Cl
Reactant: O=C(c1ccccc1)c1ccc(OCCO)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Product: OCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: 82 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
Nitrogen atmosphere was applied during the reaction. Zinc dust (1.29 g; 19.76 mmol; 2.66 equiv.) and 2-methyl-THF (14 mL) were charged to a flask and cooled to below −5° C. TiCl4 (1.1 mL; 10.03 mmol; 1.35 equiv.) was slowly added (over 20 minutes; as the addition is exothermic) to the zinc-slurry, maintaining the temperature below 0° C. The reaction mixture was heated to reflux (82° C.) and refluxed for 2 hrs. A prepared solution of both ketones (1.80 g of 4-(2-hydroxyethoxy)benzophenone (see (A) above); 7.43 mmol; 1 equiv.; 1.25 g of 3-chloropropiophenone; 7.43 mmol; 1 equiv) in 2-methyl-THF (5 mL) was slowly added to the black reaction mixture at reflux. The temperature rose to 85° C. The reaction mixture was refluxed for 2 hours. The reaction mixture was then cooled to room temperature. 4.6 mL of 1M HCl and 4.2 mL of 6 M HCl were added and the mixture stirred for 10 minutes. Then 13 mL toluene was added and the reaction mixture was stirred for 15 min. The layers were separated. The toluene layer was washed with 4 mL water and dried over MgSO4. Quantitative HPLC from toluene solution shows 38% yield and the ratio of Z/E isomers of Ospemifene 4.3/1. The toluene solution was washed with 8.5 mL conc. NaHCO3, 6 mL water and dried over MgSO4. 3.05 g of crude product was obtained after concentration on a rotavapor (bath 34° C.). Crystallization in methanol (13 mL) and water (2.5 mL) gave an oil. This solution was heated until it was a clear solution and then let to cool slowly to room temperature (crystals appeared) and then left to stand overnight at +8° C. The crystals were filtered, rinsed with 60% MeOH/water and dried. 0.787 g of light yellow solid was obtained, at 92.8% purity by HPLC (area %), and a yield of 26% (calculated as pure product).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.[H-].[Na+].F[C:11]1[CH:12]=[C:13]([CH3:20])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]>CN(C=O)C>[CH3:20][C:13]1[CH:12]=[CH:11][C:16]([N+:17]([O-:19])=[O:18])=[C:15]([CH:14]=1)[O:1][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1
Reactant: OCc1cncs1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(OCc2cncs2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
To a solution of 5-(hydroxymethyl)-1,3-thiazole (1 g, 8.68 mmol) in DMF (15 mL) was added NaH (0.413 g, 9.47 mmol) under an argon atmosphere. The reaction mixture was stirred for 20 min at 0° C. 3-Fluoro-4-nitrotoluene (1.2 g, 7.89 mmol) was added. The resulting mixture was stirred for 1 h at RT, quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with AcOEt. The organic phase was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2; hexane/AcOEt 60:40→40:60) to afford 936 mg of the title compound as an orange solid. TLC: RF=0.35 (hexane/AcOEt 1:1); HPLC: LtRet=4.26 min; LC-MS: m/z 251.2 [M+H]+.
Reaction SMILES: [C@@H]1(NCCC2(O)CCC3(OCC(C)(C)CO3)CC2)C2C(=CC=CC=2)CC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[C@@H:39]1([N:48]2[CH2:53][CH2:52][C:51]3([CH2:65][CH2:64][C:56]4(OCC(C)(C)C[O:57]4)[CH2:55][CH2:54]3)[O:50][C:49]2=[O:66])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH2:40]1>>[C@@H:39]1([N:48]2[CH2:53][CH2:52][C:51]3([CH2:54][CH2:55][C:56](=[O:57])[CH2:64][CH2:65]3)[O:50][C:49]2=[O:66])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH2:40]1
Reactant: CC1(C)COC2(CCC3(CCN([C@H]4CCc5ccccc54)C(=O)O3)CC2)OC1
Agent: CC1(C)COC2(CCC(O)(CCN[C@H]3CCc4ccccc43)CC2)OC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: O=C1CCC2(CC1)CCN([C@H]1CCc3ccccc31)C(=O)O2

Procedure:
The title compound is prepared from 9-{2-[(S)-indan-1-ylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; the crude product, a mixture of the title compound and 3-[(S)-indan-1-yl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one, obtained thereafter is treated as described in Step 10 of Intermediate 2 to convert the intermediate to the title compound as well. Yield: 44% of theory; LC (method 6): tR=1.16 min; Mass spectrum (ESI+): m/z=300 [M+H]+.
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:23]=[CH:24][C:25]([C:28]([N:6]2[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]3[N:1]=[CH:2][CH:3]=[C:4]3[CH2:5]2)=[O:29])=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccnn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
To a stirred solution of 185 mg of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine in 50 ml of methylene chloride containing 2.0 ml of triethylamine is slowly added a solution of 300 mg of 4-biphenylcarbonyl chloride in 10 ml of methylene chloride at room temperature. The reaction mixture is stirred at room temperature for 16 hours and evaporated in vacuo to give a residue. The residue is extracted with chloroform, washed with water, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 250 mg of the desired product as a solid. Mass spectrum: M+H:366.
Reaction SMILES: P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)O>C(C(C)=O)C(C)C>[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Reactant: c1c[nH]cn1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CC(=O)CC(C)C
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1ccnc1
Temperature: 100 °C
Yield: 77.9 %

Procedure:
A mixture of methyl isobutyl ketone (150 ml), triphenyl phosphite (24.8 g), imidazole (10.9 g) and o-chlorophenyldiphenylmethanol (29.5 g) obtained in Example 1 (A) was heated at 100° C. for 5 hours. The reaction mixture was treated in the same manner as in Example 4 to give 26.9 g of 1-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 78%. M.P., 143°-144° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[N:1]1([C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
A solution of 21 ml (0.25 mol) of pyrrolidine in 50 ml tetrahydrofuran was added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue was purified by column chromatography. This gave 29.9 g (0.19 mol, 81% yield) of an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]=O)[CH:8]=[CH:9][C:2]1=2.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][NH:13][CH3:12])[CH:8]=[CH:9][C:2]1=2
Reactant: O=Cc1ccc2sccc2c1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1ccc2sccc2c1
Reaction time: 3 h
Yield: 89.3 %

Procedure:
Benzo[b]thiophene-5-carbaldehyde (276 mg, 1.70 mmol) was dissolved in anhydrous methanol (8.0 mL). Methylamine (0.68 mL of 33% solution in ethanol, 5.46 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a white solid and then dissolved in anhydrous methanol (10 mL). Sodium borohydride (66.0 mg, 1.75 mmol) was added and the mixture was stirred overnight at room temperature. Water (8.0 mL) was added and the solution was concentrated. Sodium hydroxide (10 mL, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×20 mL). Combined organic layers were dried over MgSO4, filtered and concentrated to afford benzo[b]thiophen-5-yl-N-methylmethanamine (269 mg, 89%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.90 (d, J=8.7 Hz, 1H), 7.79 (s, 1H), 7.71 (d, J=5.7 Hz, 1H), 7.40 (d, J=5.4 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 3.73 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][S:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:4]>[Pt]=O.C(O)C>[NH2:13][C:12]1[C:7]([S:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)CSc1ncccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: COC(=O)CSc1ncccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
A mixture of 3.0 g of 2-(methoxycarbonyl)methylthio-3-nitropyridine, 180 mg of platinum oxide, and 14 ml of ethanol was stirred at room temperature under an atmosphere of hydrogen gas for 3 hours. The gas in the atmosphere on the reaction system was placed with nitrogen gas, and the reaction mixture was filtered through Celite. The filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 2.54 g of 3-amino-2-(methoxycarbonyl)methylthiopyridine.