Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[N+:12]([O-])([OH:14])=[O:13].C(=O)([O-])O.[Na+]>>[N+:12]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][C:5]=1[OH:9])([O-:14])=[O:13]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 7.5 g of 3-trifluoromethylphenol, 9 ml of 70% nitric acid was added dropwise at room temperature and the reaction mixture was stirred for one hour. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate twice. The combined organic layers washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.56 g of 2-nitro-5-trifluoromethylphenol.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH3:18][O:19][CH2:20][C:21](N(OC)C)=[O:22]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:21](=[O:22])[CH2:20][O:19][CH3:18])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COCC(=O)N(C)OC
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COCC(=O)c1ccc(OC)cc1C(=O)O

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 2,N-dimethoxy-N-methylacetamide. It is used in crude form in the following reaction.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH2:17][C:16]=3[CH:26]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)C(C)C)(C)C.[CH3:36][C:37]1([CH3:40])[O:39][CH2:38]1>CO>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[CH2:22][CH2:21]4)[CH2:17][C:16]=3[CH:26]=2)=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: CC1(C)CO1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCNCC2)O3)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(O)CN1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine hydrochloride (100 mg) and N,N-diisopropylethylamine (46 μl) in methanol (5 mL) is stirred for 10 min at room temperature. 1,1-Dimethyloxirane (34 μl) is added and the resulting mixture is heated to 45° C. After the conversion is complete, the solvents are evaporated in vacuo and the crude product is used for the next step without further purification. LC (method 1): tR=1.09 min; Mass spectrum (ESI+): m/z=430 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:13][CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].C(C1(NC(=O)OC(C)(C)C)CC1)=O>>[NH2:3][C:4]1([CH:5]([OH:12])[C:6]([NH:8][CH:9]2[CH2:10][CH2:11]2)=[O:7])[CH2:14][CH2:13]1
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Agent: CC(C)(C)OC(=O)NC1(C=O)CC1
Agent: Cl
Product: NC1(C(O)C(=O)NC2CC2)CC1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, starting with tert-butyl 1-formylcyclopropylcarbamate in the third step (A3).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([OH:17])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:44]4[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3cc(O)ccc3c2n1CC(C)(C)O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCc1nc2cnc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c2n1CC(C)(C)O
Reaction time: 16 h
Yield: 63.4 %

Procedure:
2-(Ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (3.31 g, 10.5 mmol), triphenylphosphine (3.43 g, 13.1 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (2.64 g, 13.1 mmol) were slurried in THF (105 mL), and cooled with an ice/water bath. Diisopropyl azodicarboxylate (2.58 mL, 13.1 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred for 16 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 1-28% CMA in chloroform) to afford 3.32 g of tert-butyl 4-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate as a tan foam.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccncc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (46 mg, 62%), MS (ISP) m/z=296.5 [(M+H)+], mp 290° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available pyridine-4-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: I[C:2]1[C:3]([CH3:20])=[C:4]([CH:12]=[C:13]([CH3:19])[C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27]([NH2:29])[CH3:28].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:27]([NH:29][C:2]1[C:3]([CH3:20])=[C:4]([CH:12]=[C:13]([CH3:19])[C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH3:28]
Reactant: COC(=O)c1c(C)cc(C(=O)OC(C)(C)C)c(C)c1I
Reactant: CCN
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCNc1c(C)c(C(=O)OC(C)(C)C)cc(C)c1C(=O)OC
Temperature: 95 °C
Reaction time: 19 h
Yield: 67 %

Procedure:
1-tert-Butyl 4-methyl 3-iodo-2,5-dimethylterephthalate (300 mg, 0.769 mmol) was dissolved in dioxane (3 mL) and sparged with nitrogen for 15 minutes. XANTPHOS (18 mg, 0.031 mmol), cesium carbonate (326 mg, 1.00 mmol), ethylamine (0.1 mL) and tris(dibenzylideneacetone)dipalladium (14 mg, 0.015 mmol) were added, and the mixture was stirred in a sealed tube at 95° C. for 19 h. XANTPHOS (36 mg, 0.062 mmol), ethylamine (0.1 mL) and tris(dibenzylideneacetone)dipalladium (28 mg, 0.030 mmol) were added and the mixture was stirred in a sealed tube at 95° C. for a further 20 h. The reaction mixture was cooled to ambient temperature and was filtered through celite. The filter cake was washed with ethyl acetate, and the filtrate was concentrated to afford an orange oil which was purified by column chromatography (silica gel, 2-10% ethyl acetate in hexanes) to afford 1-tert-butyl 4-methyl 3-(ethylamino)-2,5-dimethylterephthalate (158 mg, 0.515 mmol, 67% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.08 (s, 1H), 3.91 (s, 3H), 3.83 (br s, 1H), 3.00 (q, 2H), 2.36 (s, 3H), 2.29 (s, 3H), 1.59 (s, 9H), 1.14 (t, 3H); MS (EI) for C17H25NO4: 308 (MH+).
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[O:26][C:25]([C:27]([O:29]C)=[O:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].Cl>O>[CH:1]([O:14][CH:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]2[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=2)[CH2:19][CH2:20]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)o1
Yield: 70.4 %

Procedure:
A mixture of 465 mg of methyl 5-(4-benzhydryloxypiperidin-1-ylmethyl)furan-2-carboxylate synthesized in Production Example 2, 1.7 mL of ethanol, and 3.4 mL of a 1-N sodium hydroxide aqueous solution was heated under reflux for 40 minutes. To the mixture were added 10 mL of water and 3.4 mL of 1-N hydrochloric acid, and the resulting mixture was stirred. The precipitated crystal was separated by filtration and washed with water. The resulting product was dried to give the title compound (316 mg).
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]2[C:26]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:25](Cl)[N:24]=[C:23]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:22]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCl>[CH3:8][C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][C:21]2[C:26]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:25]([O:5][CH2:4][CH2:3][OH:6])[N:24]=[C:23]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:22]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])[CH3:9]
Reactant: OCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of sodium hydroxide (2.66 g), ethylene glycol (60 mL), tetrabutylammonium bromide (1 g) and 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidin-4-yl]benzenesulfonamide (10 g) was heated to 95° C. to 100° C. and the reaction mixture was stirred for 4 hours at 95° C. to 100° C. The mixture was cooled to 25° C. followed by the addition of dichloromethane (40 mL) and de-ionized water (180 mL). The pH of the reaction mixture was adjusted to 2 to 3 with concentrated hydrochloric acid. The reaction mixture was stirred for 10 minutes and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL). Both the organic layers were combined and washed with de-ionized water (50 mL). The dichloromethane was recovered under vacuum at 40° C. to 50° C. to obtain the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][C:17]1[C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[S:20][C:21]=1[CH3:22]>C1COCC1>[CH3:22][C:21]1[S:20][C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[C:17]=1[S:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: COC(=O)c1ccccc1Sc1c(C)sc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1sc2ccccc2c1Sc1ccccc1CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium aluminum hydride (250 mg, 6.6 mmol) is added to a solution of 2-(2-methyl-benzo[b]thiophen-3-ylsulfanyl)-benzoic acid methyl ester (651 mg, 2.07 mmol) in 10 mL dry THF at 0° C. The reaction mixture is stirred for 16 hours at room temperature. The reaction is quenched with 0.5 mL water. The reaction mixture is stirred for ½ hour and 0.25 mL 15% NaOH (aq) is added. The reaction mixture is stirred for 1 hour, then 1 mL water is added and stirring is continued for another hour. The mixture is filtered, dried with MgSO4 and concentrated in vacuo to give the title compound, which is used without further purification.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[O:21])[CH2:13][CH2:12][N:11]([C:22](=[O:31])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:10][C:9]1=[O:32])=O)(C)(C)C.F[C:34](F)(F)[C:35]([OH:37])=[O:36]>C(Cl)(Cl)Cl>[C:35]([CH2:34][N:8]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14](=[O:21])[CH2:13][CH2:12][N:11]([C:22](=[O:31])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:10][C:9]1=[O:32])([OH:37])=[O:36]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cccc(NC(=O)N2CCC(=O)c3ccccc3N(C(=O)OC(C)(C)C)C(=O)C2)c1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(NC(=O)N2CCC(=O)c3ccccc3N(CC(=O)O)C(=O)C2)c1

Procedure:
A solution of 1-tert-butyloxycarbonyl-4-(3-methylphenyl)carbamyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine (452 mg, 1.0 mmol) in chloroform (4 ml) was stirred with trifluoroacetic acid (4 ml) at room temperature for 2 hours. The mixture was evapoarted to dryness and the residue dissolved in chloroform (50 ml), washed with brine (3×40 ml), and dried (MgSO4). Filtration and evaporation of the solvent gave the product. (393 mg, 99%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[CH:14]1[C:23]2[C:18](=[C:19]([C:24]([CH3:29])([CH3:28])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1.FC1C(F)=C(C(F)(F)F)C=CC=1CN>>[CH:14]1[C:23]2[C:18](=[C:19]([C:24]([CH3:29])([CH3:28])[C:25]([NH:9][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([S:3][C:2]([F:12])([F:1])[F:13])=[CH:5][CH:6]=3)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(SC(F)(F)F)cc1
Agent: NCc1ccc(C(F)(F)F)c(F)c1F
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C)(C(=O)NCc1ccc(SC(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-[(trifluoromethyl)thio]benzylamine and 2-(5-isoquinolinyl)-2-methylpropanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/Z 405 (M+H)+; MS (ESI−) m/z 403 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.57 (s, 3H), 1.64 (s, 3H), 4.33 (d, J 6.1, 2H), 6.57 (s, 1H), 7.18 (m, 1H), 7.33 (m, 1H), 7.52 (m, 2H), 7.82 (m, 1H), 8.11 (m, 1H), 8.36 (d, J 7.8, 1H), 8.57 (m, 1H), 9.42 (s, 1H), 10.08 (s, 1H); Anal. Calcd for C21H19F3N2OS+2 HCl: C, 52.84; H, 4.43. Found: C, 52.66; H, 4.39.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[CH:14][C:15]4[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([O:26]C)=[O:25])=[CH:17][C:16]=4[CH:28]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:29]>>[ClH:29].[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[CH:14][C:15]4[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][C:16]=4[CH:28]=3)=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCCC4)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Product: O=C(O)C1=Cc2cc(-c3ccc(N4CCCC4)cc3)ccc2S(=O)(=O)CC1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To methyl 7-[4-(1-pyrrolidinyl)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (270 mg) was added 6N hydrochloric acid (30 ml), and the mixture was stirred at 70° C. for 7 hours and concentrated under reduced pressure. To the residue was added 2-propanol to give crystals, which were collected by filtration. The crystals were washed with 2-propanol and hexane to give yellow crystals of 7-[4-(1-pyrrolidinyl)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid hydrochloride (204 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].Cl>CN(C)C=O.O>[CH2:27]([O:26][C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1)OCc1ccccc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
A suspension of 6.9 g (30 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 10 g (100 mmol) of potassium bicarbonate, and 100 ml of water is stirred at room temperature and 300 ml of dimethylformamide is added followed by 6.0 ml (43 mmol) of benzyl chloroformate. The mixture is stirred at room temperature for 2 hrs and 6.0 ml of benzyl chloroformate and 6.0 g of potassium bicarbonate are added. The reaction is stirred overnight at room temperature and poured into 700 ml of ice water. The pH is adjusted to 3 with hydrochloric acid and the precipitate is filtered, washed with water, and dried to give 9.44 g of 6-[4-(benzyloxycarbonylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid after recrystallization from N,N-dimethylacetamide-methanol.
Reaction SMILES: N(C(OC)=O)=NC(OC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.[S:41]1[CH2:45][CH2:44][CH:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]O)[S:42]1>O1CCCC1.C1(C)C=CC=CC=1>[S:41]1[CH2:45][CH2:44][CH:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][N:34]2[C:30](=[O:40])[C:31]3[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33]2=[O:35])[S:42]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCCCC1CCSS1
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.6 %

Procedure:
3.25 ml of dimethyl azodicarboxylate were added dropwise to a solution of 5.77 g of triphenylphosphine in 20 ml of tetrahydrofuran, whilst ice-cooling, and then the mixture was stirred at room temperature for 30 minutes. 3.24 g of phthalimide were then added to the reaction mixture, after which a mixture of 20 mmol of 5-(1,2-dithiolan-3-yl)pentanol (prepared as described in Preparation 1) in 30 ml of toluene and 10 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for one hour. The reaction mixture was allowed to stand overnight at room temperature, after which 1.57 g of triphenylphosphine and 0.89 ml of dimethyl azodicarboxylate were added. The resulting mixture was stirred at room temperature for 7 hours and 30 minutes. 0.88 g of phthalimide, 1.57 g of triphenylphosphine and 0.89 ml of dimethyl azodicarboxylate were then added to the reaction mixture. The reaction mixture was allowed to stand at room temperature for 4 days. At the end of this time, the solvent was removed from the reaction mixture by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1:6 and 1:4 by volume mixtures of ethyl acetate and hexane as eluent. The solvent was removed from the eluate by distillation under reduced pressure, and 30 ml of toluene were added to the residue. 1 ml of the resulting mixture was weighed, and the solvent was removed from it by distillation under reduced pressure, to give 165 mg of the title compound as an orange oil having an Rf value of 0.35 (silica gel thin layer chromatography; using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[NH:39][C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[N:32]=2)[CH2:27][CH2:26]1>>[C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:25]4[CH2:26][CH2:27][CH:28]([C:31]5[NH:39][C:34]6=[N:35][CH:36]=[CH:37][CH:38]=[C:33]6[N:32]=5)[CH2:29][CH2:30]4)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Reactant: c1cnc2[nH]c(C3CCNCC3)nc2c1
Agent: Cl
Product: c1ccc(-c2cn3ccnc3nc2-c2ccc(CN3CCC(c4nc5cccnc5[nH]4)CC3)cc2)cc1
Yield: 68.4 %

Procedure:
By reacting 150 mg (0.5 mmol) 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde with 122 mg (0.6 mmol) 2-piperidine-4-yl-3H-imidazo[4,5-b]pyridine hydrochloride salt as described in example 6.0 the desired compound (166 mg) was obtained after purification on silicagel.
Reaction SMILES: CNC(C)C[C:5]1[N:9]2[C:10]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:11]=3[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:13][CH2:14][C:8]2=[N:7][N:6]=1.C(=O)C.C([BH3-])#N.[Na+]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:10]2[N:9]3[CH:5]=[N:6][N:7]=[C:8]3[CH2:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:11]=2[CH:22]=1
Reactant: CNC(C)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nncn1-2

Procedure:
In the manner given in Example 22, 1-[2-(methylamino)-propyl]-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine is treated successively with acetaldehyde and sodium cyanoborohydride to give 1-[2-N-ethyl-N-methylamino)propyl]-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Br:11])[CH2:7][C@:6]1([C:15](=[O:16])[NH:14][C:13](=[O:17])[N:12]1[CH3:18])[CH2:5]2.[O:19]=[C:20]1[N:24]([CH2:25][C:26](O)=[O:27])[C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=2[N:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][C@@:6]3([C:15](=[O:16])[NH:14][C:13](=[O:17])[N:12]3[CH3:18])[CH2:7]2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[CH2:25][N:24]1[C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=2[N:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:20]1=[O:19]
Reactant: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1cc(N)c(Br)cc1C2
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C(=O)NC(=O)[C@]12Cc1cc(Br)c(NC(=O)Cn3c(=O)n(-c4ccccn4)c4ccccc43)cc1C2
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of (S)-5′-amino-6′-bromo-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (50 mg, 0.161 mmol, described in Intermediate 18) and (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (52 mg, 0.193 mmol, described in Intermediate 16) in DMF (1 mL) were added N,N-diisopropylethylamine (0.028 mL, 0.161 mmol), followed by PyBOP (126 mg, 0.242 mmol). The reaction mixture was heated to 40° C. for 5 h, then PyBOP (126 mg, 0.242 mmol) was added and heating was continued for 18 h. The cooled mixture was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=563 (M+1).