Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:30]1[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:11]([N:30]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31]1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O[C@@H]1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of anhydrous dichloromethane (35.0 mL) in a 3-necked flask with a thermometer, oxalyl chloride (1.5 mL) was added and the resulting solution was cooled to −60° C. A solution of dimethyl sulfoxide (2.6 mL) in dichloromethane (7.5 mL) was added over a period of 10 min, and then (3R)-1-tritylpyrrolidin-3-ol (5.0 g) in dichloromethane (15.0 mL) was added over a period of 10 min. The resulting solution was stirred at −60° C. for 15 min., then triethylamine (10.6 mL) was added over a period of 5 min. A white precipitate was formed. After 5 rain, the cooling bath was removed and the mixture was allowed to warm to room temperature. Water (45 mL) was added. The mixture was stirred for an additional 30 min and then extracted with dichloromethane. The organic phase was washed with 5% aqueous citric acid solution, dried over anhydrous sodium sulfate, filtered and concentrated to yield the title compound. LC-MS=243.1 (M+1).
Reaction SMILES: [C:1]([OH:18])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[NH2:20][C@H:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26].C(N(CC)CC)C.C(O)(=O)C>CC(C)=O.O>[O:18]=[C:1]([NH:26][CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]([C:27]([OH:29])=[O:28])[NH2:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Yield: 73 %

Procedure:
Following the procedure of A. Paquet Can. J. Chem. 54, 733 (1976), 353 mg. (1 mmol) of the succinimidylester of hexadecanoic acid, prepared as in example 2, was suspended in 2 ml acetone and added to a solution of 183 mg (1 mmol) L-lysine hydrochloride and 0.27 ml (ca. 2 mmol) triethylamine in 2 ml water. The reaction mixture was stirred vigorously for at least 4 h, then neutralized with acetic acid and diluted with water. The precipitate was removed by filtration and washed with water, methanol and ether. Repeated crystallizations from acetic acid/water and acetic acid gave 280 mg (73%) colourless crystals, m.p. 240°-245° C. (reported 210°-220° C.)
Reaction SMILES: [CH:1]1([C:4]2[CH:40]=[CH:39][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:19][N:18]([C:20]([C:22]5[CH:27]=[C:26]([O:28][CH2:29][C@H:30]6[CH2:34][O:33]C(C)(C)[O:31]6)[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:17]4)=[CH:12][C:11]=3[O:37][CH3:38])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>O1CCCC1>[CH:1]1([C:4]2[CH:40]=[CH:39][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:17][N:18]([C:20]([C:22]5[CH:27]=[C:26]([O:28][CH2:29][C@H:30]([OH:31])[CH2:34][OH:33])[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:19]4)=[CH:12][C:11]=3[O:37][CH3:38])=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(C2CN(C(=O)c3cc(OC[C@H]4COC(C)(C)O4)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C2CN(C(=O)c3cc(OC[C@H](O)CO)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of {{3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidin-1-yl}-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)pyridin-2-yl]-methanone prepared in (1) (0.27 g) in THF (4.0 mL) was added 1 N hydrochloric acid (2.0 mL). The reaction mixture was stirred at 60° C. for 2 hr. To the reaction mixture was added aqueous 1 N NaOH (2.0 mL) and the mixture was extracted with ethyl acetate. The solvent was removed under reduced pressure. A mixed solvent of hexane/ethyl acetate (1/1) was added to the residue. The precipitated solid was collected on a filter and dried to give the title compound (0.23 g, 93%).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][NH:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][C:4](=[O:21])[CH2:3]2.N#N.[H-].[Na+].[CH3:26]I.[NH4+].[Cl-]>CN(C=O)C.O.C(Cl)Cl>[CH3:26][N:9]1[C:10]2[C@:15]([CH3:16])([CH2:14][CH2:13][C:12](=[O:20])[CH:11]=2)[C@@H:17]2[C@H:7]([C@H:6]3[C@@:2]([CH2:19][CH2:18]2)([CH3:1])[CH2:3][C:4](=[O:21])[CH2:5]3)[CH2:8]1
Reactant: C[C@]12CC[C@H]3[C@@H](CNC4=CC(=O)CC[C@@]43C)[C@@H]1CC(=O)C2
Reactant: CI
Agent: N#N
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1C[C@H]2[C@@H]3CC(=O)C[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-azaandrost-4-ene-3,16-dione (12, R2 =H) (558 mg, 1.94 mmoles) in DMF (12 mL) was added, in a N2 atmosphere, sodium hydride (60% in mineral oil) (116 mg, 2.91 mmoles) and the mixture stirred at room temperature for 30 minutes. Methyl iodide (1.8 mL, 19.4 mmoles) was added and stirring continued for 2 hours. Saturated NH4Cl (1 mL) was added followed by methylene chloride and H2O. The organic phase was washed with H2O and brine and dried over MgSO4. Evaporation in vacuo and flash chromatography on silica gel with 4% MeOH/CHCl3 gave (13, R2 =H) as a white solid. NMR (CDCl3): δ 0.97 (s, 3H, 18-Me); 1.32 (s, 3H, 19-Me); 2.86 (s, 3H, N-CH3); 5.25 (s, 1H, 4-H).
Reaction SMILES: [Cl-].[N:2]1([C:8](=[O:20])[CH2:9][N+:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.ClCC(N1CCOCC1)=O.[N:31]1C2C(=CC=CC=2)[CH:34]=[CH:33][CH:32]=1>C(#N)C>[C:32]([C:33]1[CH:34]=[C:9]([C:8]([N:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)=[O:20])[N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]=12)#[N:31]
Reactant: O=C(C[n+]1cccc2ccccc21)N1CCOCC1
Reactant: c1ccc2ncccc2c1
Agent: O=C(CCl)N1CCOCC1
Agent: [Cl-]
Solvent: CC#N
Product: N#Cc1cc(C(=O)N2CCOCC2)n2c1ccc1ccccc12
Yield: 29 %

Procedure:
1-(2-Morpholin-4-yl-2-oxo-ethyl)-quinolinium chloride: A stirred solution of 2-chloro-1-morpholin-4-yl-ethanone (1.02 g, 6.23 mmol), quinoline (700 μL, 5.91 mmol) and acetonitrile (15.0 mL) was refluxed at 96° C. for 6 h under argon. The solution was equilibrated to room temperature and the precipitate was filtered on a Buchner funnel. The solid was dried in vacuo to yield 349 mg (29%) of the title compound. 1H NMR (DMSO-d6): 9.58 (d, J=6.0 Hz, 1H), 9.42 (d, J=8.1 Hz, 1H), 8.53 (d, J=7.8 Hz, 1H), 8.44 (d, J=9.0 Hz, 1H), 8.28 (m, 2H), 8.06 (t, J=7.8 Hz, 1H), 3.82 (t, J=4.2 Hz, 2H), 3.65 (m, 4H), 3.47 (t, J=4.8 Hz, 2H).
Reaction SMILES: C([BH3-])#N.[Na+].F[C:6]1[C:14](F)=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([CH3:16])[NH:10]2.[OH2:17]>C(O)(=O)C>[OH:17][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([CH3:16])[NH:10]2
Reactant: O
Reactant: Cc1cc2c(F)c(F)ccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1Cc2c(O)cccc2N1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
750 mg of sodium cyanoborohydride are gradually added to a solution of 1 g of 4,5-difluoro-2-methylindole in 20 ml of acetic acid under argon cooled to a temperature of about 5° C. The reaction mixture is stirred at ambient temperature for 3 hours and 5 ml of water are added. The mixture is then concentrated under reduced pressure and the residue is taken up in ethyl acetate, then treated with 60 ml of a saturated sodium hydrogen carbonate solution. After stirring for 1 hour and then settling out, the organic phase is separated and the aqueous phase is extracted with 50 ml of ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with an 80/20 v/v heptane/ethyl acetate mixture. 0.37 g of 4-hydroxy-2-methylindoline is thus obtained in the form of a yellow oil, the characteristics of which are the following:
Reaction SMILES: [NH:1]1CCN[CH2:3][CH2:2]1.[CH:7]1([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.BrCC#N>>[CH:7]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([CH2:3][C:2]#[N:1])[CH2:18][CH2:19]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: C1CCC(CN2CCNCC2)CC1
Reactant: C1CNCCN1
Agent: N#CCBr
Product: N#CCN1CCN(CC2CCCCC2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Cyclohexylmethyl-piperazine piperazine (commercially available from Fluorochem Ltd) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=222.2: 1HNMR(DMSO-d6) 3.65 (s, 2H), 2.45-2.20 (m, 8H), 2.00 (d, 2H), 1.70-1.55 (m, 5H), 1.50-1.40 (m, 1H), 1.20-1.05 (m, 3H), 0.85-0.70 (m, 2H).
Reaction SMILES: O1CCCC1.C([O:8][C:9](=[O:40])[CH:10]([NH:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH2:11][C:12]1[O:16][N:15]=[C:14]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[S:22]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)(=[O:24])=[O:23])[CH:13]=1)C.[OH-].[Li+].Cl>CO>[CH2:37]([O:36][C:34]([NH:33][CH:10]([CH2:11][C:12]1[O:16][N:15]=[C:14]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[S:22]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)(=[O:23])=[O:24])[CH:13]=1)[C:9]([OH:40])=[O:8])=[O:35])[CH:38]=[CH2:39]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2S(=O)(=O)c2cc(Cl)cc(Cl)c2)no1)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2S(=O)(=O)c2cc(Cl)cc(Cl)c2)no1)C(=O)O
Yield: 91.1 %

Procedure:
A tetrahydrofuran (1.0 mL) and methanol (0.5 mL) solution of 2-allyloxycarbonylamino-3-{3-[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-isoxazol-5-yl}-propionic acid ethyl ester (59 mg, 0.108 mmol) was stirred with 2M aqueous lithium hydroxide (0.5 mL) at room temperature for 40 minutes. The reaction was acidified to pH 1 with 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (51 mg, 91%). MS (CI) m/z 518 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3]1.[CH2:18](O)[CH2:19][OH:20]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:20]1[C:2]2([CH2:6][CH2:5][N:4]([S:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=3)(=[O:9])=[O:8])[CH2:3]2)[O:1][CH2:18][CH2:19]1
Reactant: N#Cc1ccc(S(=O)(=O)N2CCC(=O)C2)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(S(=O)(=O)N2CCC3(C2)OCCO3)cc1
Temperature: 25 °C
Yield: 95.4 %

Procedure:
4-[(3-oxo-1-pyrrolidinyl)sulfonyl]benzonitrile 23b (11.6 g, 46.3 mmol) was suspended in toluene (110 ml) and stirred at room temp. Ethylene glycol (6.2 ml, 6.9 g, 111 mmol) and para-toluene sulphonic acid monohydrate (100 mg, 0.53 mmol) were added. The reaction mixture was heated to reflux under Dean-Stark conditions and monitored by water collection and TLC (5% methanol in DCM). If necessary for the completion of the reaction (typically within 3 h), further portions of p-TSA were added. When complete the reaction mixture was washed with saturated sodium bicarbonate solution (55 ml) and water (2×55 ml). The organic layer was filtered through cotton wool and then concentrated in vacuo to approximately 50 ml or until precipitation started. Hexane (150 ml) was added and the suspension stirred at 0-5° C. for 10-20 min, filtered and washed with hexane (2×50 ml). The residue was air dried to yield 13.0 g (96%) ketal 4-(1,4-dioxa-7-azaspiro[4.4]non-7-ylsulfonyl)benzonitrile 23c. 4-(1,4-dioxa-7-azaspiro[4.4]non-7-ylsulfonyl)benzonitrile 23c was progressed according to the procedure described for example 7b which finally leads to 4-chloro-N-(4-{[3-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)-1-pyrrolidinyl]sulfonyl}benzyl)benzamide 23. M/Z APCI 566.0 (M+1), 564.2 (M−1), 1H-NMR (DMSO-d6) δ9.57 (m, 2H, H—N15), 9.42 (t, 1H, H—N5, 3J=5.92 Hz), 7.99 (d, 2H, 3J=8.65 Hz, H—C2, 3), 7.82 (d, 2H, H—C8, 9), 7.71-7.59 (m, 8H, H—C1,4,7,10,18,19,20,21), 4.62 (d, 2H, 3J=5.92 Hz, H—C6), 3.75 (m, 1H, H—C12), 3.53-3.33 (m, 2H under DMSO-H2O signal, H—C16), 3.27-3.03 (m, 6H, H—C11, 14, 17), 2.17 (m, 1H, Ha—C13), 2.04 (m, 1H, Hb—C13).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.Cl[C:14]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:18]([CH3:27])[N:17]=[N:16][C:15]=1[CH3:28]>C(OCC)(=O)C>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]2[C:14]([C:12]3[CH:11]=[CH:10][NH:9][N:8]=3)=[C:15]([CH3:28])[N:16]=[N:17][C:18]=2[CH3:27])=[CH:25][CH:24]=1
Reactant: Cc1nnc(C)c(-c2ccc(Cl)cc2)c1Cl
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nnc(C)c(-c2cc[nH]n2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
87 mg of sodium hydride (55% oil dispersion) was added to 5 ml of DMF. To this was added 0.14 g of pyrazole, and the mixture was stirred for 0.5 hours at room temperature. To the resultant mixture was added 0.25 g of 4-chloro-5-(4-chlorophenyl)-3,6-dimethylpyridazine, and the mixture was stirred for 3 hours on an oil bath of 80° C. To the reaction mixture was added ethyl acetate, and the mixture was washed with brine four times. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.38 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.19 g of 5-(4-chloro-phenyl)-3,6-dimethyl-4-pyrazolylpyridazine (hereinafter, described as compound (6) of the present invention.).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@@H:7]2[C@@H:11]([OH:12])[CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:8]2)=O)[CH2:3][CH2:2]1.O.C(N(CC)CC)C>O1CCCC1>[CH:1]1([NH:4][CH2:5][C@@H:7]2[C@@H:11]([OH:12])[CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(OCc1ccccc1)N1C[C@H](CNC2CC2)[C@@H](O)C1
Yield: 99 %

Procedure:
364 g of benzyl (3S,4R)-3-(N-cyclopropyl)carbamoyl-4-hydroxypyrrolidine-1-carboxylate (1.20 mol) was suspended in 1.46 L of dehydrated tetrahydrofuran. While this suspension was stirred, 3.07 L of a 1.17 M tetrahydrofuran solution of borane-tetrahydrofuran complex in (3.59 mol) was added dropwise at an internal temperature of 20 to 43° C. The mixture was stirred at an internal temperature of 41 to 46° C. for 8 hours. Subsequently, the mixture was allowed to cool under stirring and then cooled in an ice bath while kept stirred. 364 mL of water was then added dropwise at an internal temperature of 15 to 25° C. Subsequently, 726 g of triethylamine was added dropwise at an internal temperature of 16 to 18° C. The mixture was then heated and stirred for 14 hours under reflux. Subsequently, the reaction mixture was allowed to cool under stirring and concentrated under reduced pressure. To the resulting residue, 1.09 L of water was added to dissolve the solid and the solution was extracted with 2.55 L of ethyl acetate. The organic layer was washed with 1.82 L of water and extracted with 1.50 L of 2 mol/L hydrochloric acid. A 2 mol/L sodium hydroxide solution (1.67 L) was then added to the aqueous layer under stirring until pH 12. The mixture was extracted with 2.55 L of ethyl acetate and the organic layer was washed with 1.82 L of 28% brine. To this layer, 255 g of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. The resulting solid was separated by filtration and washed with 0.55 L of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure to give 345 g of a crude product of the title compound as a faint yellow oil. This product was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([CH2:13]O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][CH2:13][C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cn2cc(CO)cn2)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2cc(CCl)cn2)cc1
Reaction time: 3 h

Procedure:
To (1-(4-methoxybenzyl)-1H-pyrazol-4-yl)methanol (5.01 g, 23.0 mmol) in DCM (20 mL) was added thionyl chloride (8 mL). The reaction mixture was stirred for 3 hours and concentrated to provide the desired product (6.37 g).
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=1[O:22][CH3:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.Cl>O1CCCC1>[CH2:6]([NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([B:25]([OH:30])[OH:26])=[CH:17][C:16]=1[O:22][CH3:23])=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(Br)ccc1C(=O)NCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
n-Butyl lithium(1.6 M in hexane solution, 8.0 ml, 12.88 mmol) was added slowly to a solution of N1-benzyl-4-bromo-2-methoxybenzamide (1.65 g, 5.15 mmol) in tetrahydrofuran (40 mL) at −78° C. After 30 minutes, triisopropyl borate (1.8 mL, 7.73 mmol) was added rapidly. The reaction mixture was allowed to warm up to room temperature after 13 minutes and stirred for 16 hours. Hydrochloric acid (2.5N, 36 mL) was added and the mixture was stirred overnight. Organic solvent was removed and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give 4-[(benzylamino)carbonyl]-3-methoxyphenylboronic acid (0.675 g, 46%). 1H NMR (DMSO-d6) δ 3.90 (s, 3H), 4.51 (d, J=6.18 Hz, 2H), 7.24 (m, 1H), 7.34 (m, 4H), 7.43 (d, J=7.55 Hz, 1H), 7.59 (s, 1H), 7.69 (d, J=7.55 Hz, 1H), 8.23 (s, 2H), 8.69 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]3[N:20]=[C:21]([NH:23][C:24]([NH:26][CH2:27][CH3:28])=[O:25])[N:22]=[C:18]3[CH:17]=[C:16]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:27]([NH:26][C:24]([NH:23][C:21]1[N:22]=[C:18]2[CH:17]=[C:16]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:19]2[N:20]=1)=[O:25])[CH3:28]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(N3CCN(C(=O)OC(C)(C)C)CC3)n2n1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(N3CCNCC3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product of Step 2, 4-[2-(3-ethyl-ureido)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.52 g, 1.1 mmol) was suspended in CH2Cl2 (10 mL) Trifluoroacetic acid (5 ml) was added and the resulting solution was stirred at rt for 30 minutes. The reaction mixture was diluted with toluene and solvent was evaporated. The residue was purified by column chromatography on silica gel (0-10% MeOH in CH2Cl2 containing 1% NEt3 as eluant) to afford the target compound as a solid. MS (APCI+) 366 (M+1).
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[N+:33]([O-:35])=[O:34])[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[N+:33]([O-:35])=[O:34])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(OCCCN2CCC(O)CC2)c1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: Cc1ccc([N+](=O)[O-])c(OCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[3-(5-methyl-2-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy-1-[3-(5-methyl-2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1.[CH3:24][N:25]=[C:26]=[O:27]>O1CCCC1>[CH3:24][NH:25][C:26]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1)=[O:27]
Reactant: CN=C=O
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(N)cc2[nH]1
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc2nc(-c3ccc(OS(C)(=O)=O)cc3OC)[nH]c2c1
Reaction time: 0.25 h

Procedure:
One gram (3.0 mmol) of 5-amino-2-(2'-methoxy-4'-methanesulfonyloxy-phenyl)-benzimidazole was dissolved in 30 ml of pure tetrahydrofuran, 2.0 ml of methylisocyanate were added, and the mixture was refluxed. After 15 minutes that solvent and any excess methylisocyanate were evaporated off in vacuo, and the residue obtained was chromatographed over 250 gm of aluminium oxide (neutral) (eluant: methylene chloride with 4% ethanol).
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[N:4][CH:3]=[N:2]1.[F:10][C:11]1[CH:41]=[CH:40][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@H:25]3[CH2:29][C@@H:28]([CH2:30][C:31]4[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=4[F:39])[CH2:27][NH:26]3)=[O:24])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>>[N:1]1([CH2:6][C:7]([N:26]2[CH2:27][C@H:28]([CH2:30][C:31]3[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=3[F:39])[CH2:29][C@H:25]2[C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:41][CH:40]=3)=[CH:21][CH:20]=2)=[O:24])=[O:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2c(F)cc(F)cc2F)CN1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2c(F)cc(F)cc2F)CN1C(=O)Cn1cncn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide, gave Compound 108, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, CDCl3): δ 8.96 (s, 1H), 8.32 (s, 1H), 8.12 (s, 1H), 7.38 (d, 2H), 7.03-6.85 (m, 6H), 6.73-6.64 (m, 2H), 5.08 (d, 1H), 5.02 (d, 1H), 4.76 (d, 1H), 3.78-3.72 (m, 1H), 3.31 (t, 1H), 3.00-2.68 (m, 3H), 2.56 (dd, 1H), 1.82-1.72 (m, 1H). MS (EI) for C28H23F4N5O3 found 554 (MH+).