Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:9]#[N:10])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)CC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[C:3]([C:9]#[N:10])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: Nc1ccccc1B(O)O
Reactant: Cc1c(Br)c(C#N)nn1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: Cc1c(-c2ccccc2N)c(C#N)nn1C
Temperature: 100 °C
Yield: 58.3 %

Procedure:
Triphenylphosphine (2.4 mg, 0.09 mmol) and palladium (II) acetate (7 mg, 0.03 mmol) were added to a mixture of 4-bromo-1,5-dimethyl-1H-pyrazole-3-carbonitrile (0.600 g, 3.00 mmol), 2-aminophenylboronic acid (0.719 g, 5.25 mmol), aqueous sodium carbonate (1.8 mL of 2 M), propanol (5.25 mL) and water (1.1 mL). The reaction was heated under a nitrogen atmosphere at 100° C. for three hours and then allowed to cool to ambient temperature. The work-up procedure described in Part G of Examples 1-4 was followed. The resulting orange oil was purified by chromatography on a HORIZON HPFC system (25+M cartridge, eluting with ethyl acetate/hexane ranging in ratios from 50:50 to 75:25) to provide 371 mg of 4-(2-aminophenyl)-1,5-dimethyl-1H-pyrazole-3-carbonitrile as a pale yellow solid.
Reaction SMILES: N[C:2]1C([N+]([O-])=O)=CC=C[C:3]=1OCC1OC1.C(N)(C)(C)C.[C:21]([NH:25][CH2:26][CH:27]([OH:40])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-])=O)[C:31]=1[NH2:39])([CH3:24])([CH3:23])[CH3:22]>C(O)C>[CH3:2][C:3]1[NH:39][C:31]2[C:30]([O:29][CH2:28][CH:27]([OH:40])[CH2:26][NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:35][CH:34]=[CH:33][C:32]=2[N:36]=1
Reactant: Nc1c(OCC2CO2)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)NCC(O)COc1cccc([N+](=O)[O-])c1N
Solvent: CC(C)(C)N
Solvent: CCO
Product: Cc1nc2cccc(OCC(O)CNC(C)(C)C)c2[nH]1

Procedure:
10.5 g. of the above 1-(2-amino-3-nitrophenoxy)-2,3-epoxy-propane were stirred for 30 hours at ambient temperature with 35 g. tert.-butylamine and 100 ml. ethanol. Subsequently, the reaction mixture was evaporated to dryness, the residue was dissolved in 200 ml. 2N hydrochloric acid, a small amount of undissolved material was filtered off with suction and the hydrochloric acid solution was shaken out several times with chlorofrom. 100 ml. 10N aqueous sodium hydroxide solution were then added to the aqueous acidic solution and the mixture extracted several times with ether. The ethereal extracts were dried over anhydrous sodium sulfate and then evaporated to about 100 ml., the base thereby separating out as a fine crystalline slurry by the use of ice cooling. There were obtained 10.5 g. 1-tert.-butylamino-2-hydroxy-3-(2-amino-3-nitrophenoxy)-propane; m.p. 75° - 77°C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:32])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O.Cl>C(O)C>[C:1]([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH:16]([OH:32])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)COc2ccc(-c3ccc(F)cc3)cc2)cs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(O)COc2ccc(-c3ccc(F)cc3)cc2)cs1
Reaction time: 0.5 h

Procedure:
2-[(4-{[(4′-Fluorobiphenyl-4-yl)oxy]acetyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester 967 mg obtained in Example 2-1 was dissolved in ethanol (10 mL) and, under ice-cooling, sodium borohydride (75 mg) was added and the mixture was stirred for 2 hr 30 min. Water (10 mL) was added, pH was adjusted to about 3 with aqueous hydrochloric acid (1 mol/L), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue purified by column chromatography (Moritex Corporation Purif Pack SI 60 μm size 200 was used. elution solvent: hexane/ethyl acetate=9/1→6/4) to give the title compound as a pale-yellow oily substance (907 mg).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:36]=[CH:35][N:34]([CH2:37][CH2:38][OH:39])[N:33]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8]([NH:31][C:32]2[CH:36]=[CH:35][N:34]([CH2:37][CH2:38][OH:39])[N:33]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccn(CCO)n1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(CCO)n1)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (50 mg, 0.15 mmol, prepared as in Example 1) in methylene chloride (5 mL) and N,N-dimethylformamide (1 drop) cooled to 0° C. was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 88 μL, 0.18 mmol) and stirred at 0° C. for 10 min. After this time, the reaction mixture was warmed to room temperature and then stirred for another 25 min. After this time, the reaction mixture was then concentrated in vacuo and the residue taken up in methylene chloride (2 mL) and added dropwise to a separate reaction flask containing a mixture of 2-(3-amino-pyrazol-1-yl)-ethanol (28 mg, 0.22 mmol) and 2,6-lutidine (32 μL, 0.29 mmol) in methylene chloride (5 mL) cooled to 0° C. The resulting reaction mixture was then allowed to warm to room temperature and stirred for 16 h. After such time, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then extracted with methylene chloride (3×15 mL). The organic layers were then washed with a 1N aqueous hydrochloric acid solution (10 mL), dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate concentrated in vacuo. The crude material was purified via automated flash chromatography (4 g silica gel column, 60-95% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (57 mg, 86%) as a white foam: [α]29D=−28.5°, (c=0.26, methylene chloride); HR-ES(+) m/e calcd for C22H25N4O3F3 [M+H]+ 451.1952, observed 451.1950; 1H NMR (300 MHz, DMSO-d6) δ ppm 10.91 (s, 1H), 8.01 (t, J=8.50 Hz, 2H), 7.69-7.81 (m, 1H), 7.56 (d, J=2.27 Hz, 1H), 6.40 (d, J=2.27 Hz, 1H), 4.97-5.13 (m, 2H), 4.85 (t, J=5.29 Hz, 1H), 4.71 (d, J=18.51 Hz, 1H), 4.02 (t, J=5.67 Hz, 2H), 3.69 (q, J=5.67 Hz, 2H), 0.99-2.12 (m, 11H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.CCCCCCCCCCC.Cl.[CH3:31][O:32][NH:33][CH3:34]>S(Cl)(Cl)=O.C(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([N:33]([CH3:34])[O:32][CH3:31])=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2F)cc1
Reactant: CNOC
Agent: Cl
Solvent: CCCCCCCCCCC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1ccc(OCc2ccccc2F)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
4-(2-fluorobenzyloxy)benzoic acid (P2, 5.5 g, 22.3 mmol) was suspended in thionyl chloride (16.5 mL) and heated to 65° C. and held for 3 hours during which time the reactor was kept under a slow sweep of nitrogen. The mixture was then concentrated to a thick oil under hi vac to remove all traces of residual thionyl chloride. The residue was then diluted in CH2Cl2 (20 mL) and cooled to 0° C. In a separate flask, a solution of diaza(1,3)bicycle[5.4.0]undecane (DBU, 8.0 mL, 8.15 g, 53.52 mmol) and N-methoxy-N-methyl amine hydrochloride (2.61 g, 26.76 mmol) in CH2Cl2 (20 mL) was made and slowly added to the solution at 0° C. After warming to 20-25° C., the mixture was washed with 1 M HCl and then with a saturated NaHCO3 solution. After drying over Na2SO4, the solution was concentrated to a thick residue. The mixture was then purified by flash column chromatography eluting with 0→100% EtOAc/hexanes (gradient). Concentration of the fractions containing the title compound gave an oil that crystallized upon standing (6.0 g, 93% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)(=[O:17])=[O:16])[CH2:9][CH2:10][NH:11][C:12](=[O:14])[O-])=[C:4]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[CH:3]=1.[CH3:37][NH2:38]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][CH2:10][NH:11][C:12]([NH:38][CH3:37])=[O:14])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)(=[O:17])=[O:16])=[C:4]([CH2:28][C:29]2[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=2[F:35])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(CCNC(=O)[O-])c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reactant: CN
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNC(=O)NCCN(c1ccc(Cl)cc1Cc1c(F)cccc1F)S(=O)(=O)c1ccc(OC)c(OC)c1

Procedure:
To 0.42 g of phenyl(2-{[4-chloro-2-(2,6-difluorobenzyl)phenyl][(3,4-dimethoxyphenyl)sulfonyl]amino}ethylcarbamate in 1.2 ml of dimethyl sulfoxide is added, at room temperature, 0.053 ml of an aqueous solution of methylamine, and the mixture is left at room temperature for 18 hours. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel to give 0.326 g of the expected product.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1>C1COCC1>[O:28]=[C:4]1[C:3](=[CH:2][NH:29][C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:13])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:15]=3)=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Solvent: C1CCOC1
Product: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CNc1ccc(C(=O)O)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 45, 80 mg, 0.2049 mmol) and THF (2 mL). To the resulting solution was added 4-Amino-benzoic acid (34 mg, 0.248 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The room temperature reaction mixture was concentrated in vacuo. The solid residue was recrystallized from EtOAc (5 mL) and Hexanes (2 mL) yielding the title compound in 81% yield (0.085 g, 0.1668 mmol).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[OH:35]>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:35][C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=2[F:27])=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Oc1cccc(F)c1F
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cccc(F)c1F)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 2,3-difluorophenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.7 Hz), 8.11 (1H, d, J=2.7 Hz), 7.98–7.92 (3H, m), 7.43–7.40 (2H, m), 7.23–7.07 (3H, m), 5.43–5.32 (1H, m), 1.61–1.56 (12H, m); MS (ESI) m/z 489 (M+H)+, 487 (M−H)−.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1>>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Product: O=C(O)CCC(=O)Nc1ccc(Nc2ccccc2)cc1

Procedure:
The experimental protocol used is the same as that described in J. Amer. Chem. Soc. (1951) 73, 4007, starting from N1-phenyl-1,4-benzenediamine and succinic anhydride in order to produce a pale grey-blue powder. Melting point: 175-176° C.
Reaction SMILES: [Cl:1][CH:2]1[CH2:5][CH:4]([CH2:6][OH:7])[CH2:3]1.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+].O>CN(C)C=O>[Cl:1][CH:2]1[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: OCC1CC(Cl)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClC1CC(COCc2ccccc2)C1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A mixture of 3-chlorocyclobutanemethanol (17.3 g, 0.143 mole) and benzylbromide (26.96 g, 0.158 mole) in dry dimethylformamide (123 ml) was stirred at room temperature under an argon atmosphere and a 60% suspension of sodium hydride (6.31 g 0.158 g mole) was added. The reaction was stirred at ambient temperature for 22.5 hours. The reaction mixture was poured into 600 ml of water and the aqueous mixture extracted with ethyl acetate (4×500 ml). The ethyl acetate extracts were combined and dried over anhydrous sodium sulfate and the ethyl acetate evaporated in vacuo yielding the crude product as a yellow oil. The material was purified on a 2-liter Merck silica gel column eluting with 3 liters of hexane, followed by 5% ethyl acetate/hexane. The fractions containing the desired product were combined and the volatiles evaporated in vacuo yielding 28.6 g of the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][CH:6]=[CH:5]2.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+].[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:7][CH:6]=[CH:5]2
Reactant: Oc1ccccc1
Reactant: Clc1nccc2cc(Br)ccc12
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: Brc1ccc2c(Oc3ccccc3)nccc2c1
Temperature: 140 °C
Yield: 98.6 %

Procedure:
A mixture of 10 g of 1b, 31 g of phenol and 4 g of KOH was heated at 140° C. for 2 hours. After cooling to room temperature aqueous 3N NaOH was added and the mixture was extracted with dichloromethane. The dichloromethane extract was washed with aqueous 2N NaOH, washed with water, dried (MgSO4) and concentrated to yield 12.2 g of 1c. 1H-NMR 200 MHz (CDCl3) δ: 7.1-7.6 (6H, m), 7.70 (1H, dd, J=9 Hz and J=2 Hz), 7.95-8.10 (2H, m), 8.31 (1H, d, J=9 Hz).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH:12]([CH:15]([C:28]#[N:29])[N:16]([CH3:27])[C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:28]([CH:15]([CH:12]1[CH2:13][CH2:14][CH:10]([CH2:9][OH:8])[CH2:11]1)[N:16]([CH3:27])[C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)#[N:29]
Reactant: CN(C(=O)OCc1ccccc1)C(C#N)C1CCC(CO[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OCc1ccccc1)C(C#N)C1CCC(CO)C1
Temperature: 23 °C
Reaction time: 5 h
Yield: 37.9 %

Procedure:
To benzyl (3-((tert-butyldimethylsilyloxy)methyl)cyclopentyl)(cyano)methyl(methyl)-carbamate (2.0 g, 4.80 mmol) in dry THF (40 mL) cooled to 0° C. was added tetrabutyl-ammoniumfluoride (1M in THF 17.28 mL). The reaction mixture was stirred at 23° C. for 5 hours. H2O (20 mL) was added to the reaction mixture and the organic material extracted with ethyl acetate (3×30 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The crude material was purified on a Silica gel column (Biotage flash chromatography system), eluted with a gradient of ethyl acetate:hexane (3:7) to ethyl acetate 100% to afford 0.550 g (38% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.39 (5 H, m), 5.13-5.25 (2 H, m), 5.07 (1 H, br s), 3.50-3.60 (2 H, m), 3.01 (3 H, s), 1.30-2.52 (8 H, m). LCMS (+ESI, M+H+) m/z 303.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@@:5]1([CH2:11][N:12]=[C:13]=[O:14])[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6]1.C1(C)C=CC=CC=1.[CH3:23][OH:24]>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@@:5]1([CH2:11][NH:12][C:13]([O:24][CH3:23])=[O:14])[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6]1
Reactant: CO
Reactant: COC(=O)C[C@@]1(CN=C=O)CC[C@@H](C)C1
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@]1(CNC(=O)OC)CC[C@@H](C)C1
Temperature: 25 °C
Yield: 29 %

Procedure:
((1R,3R)-1-Isocyanatomethyl-3-methyl-cyclopentyl)-acetic acid methyl ester (7.82 g, 37 mmol) was refluxed in methanol (30 mL) and toluene (80 mL) for 17 hours and then allowed to cool to room temperature. The solvent was removed under reduced pressure, and the residue was purified by chromatography (silica gel, heptane to heptane:ether 8:2) to give 2.60 g (29%) of [(1R,3R)-1-(methoxycarbonylamino-methyl)-3-methyl-cyclopentyl]-acetic acid methyl ester;
Reaction SMILES: [CH3:1][C:2]([NH:9][S:10]([CH:13]=[CH2:14])(=[O:12])=[O:11])([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[Cl:15][C:16]1[C:21](I)=[CH:20][CH:19]=[CH:18][C:17]=1OC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:2]([NH:9][S:10](/[CH:13]=[CH:14]/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Cl:15])(=[O:12])=[O:11])([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: C=CS(=O)(=O)NC(C)(C)CC(C)(C)C
Reactant: COc1cccc(I)c1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1ccccc1Cl
Temperature: 140 °C
Yield: 31.8 %

Procedure:
Ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (10 g, 46 mmol) and 2-chloroiodoanisole (4.8 mL, 39.1 mmol) was dissolved in N,N-dimethylformamide (DMF) (75 mL). Palladium acetate (169 mg, 0.75 mmol) and triphenylphosphine (420 mg, 1.6 mmol) was added to the reaction mixture followed by triethylamine (14.7 mL, 106 mmol). The reaction was flushed with nitrogen and heated at 140° C. for 16 hours. The reaction was cooled to room temperature whereupon 1N HCl (275 mL) was added. The aqueous solution was extracted with ethyl acetate (3×225 mL) and the combined organic solution was dried over MgSO4, filtered and concentrated in vacuo to afford a solid. The solid was dissolved in dichloromethane and purified by dry flash chromatography (SiO2, heptane to 1:1 heptane: ethyl acetate). The fractions were combined to afford (E)-2-(2-chloro-phenyl)-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (4.1 g, 32% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[C:20]([CH3:28])[CH:19]=1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:24]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][C:20]=3[CH3:28])(=[O:25])=[O:26])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: Cc1cc(F)ccc1S(=O)(=O)Cl
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Solvent: c1ccncc1
Product: Cc1cc(F)ccc1S(=O)(=O)Nc1cncc(-c2ccc(C#N)c(Cl)c2)c1
Yield: 48.6 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1 eq) in anhydrous pyridine (500 μl) was added 4-fluoro-2-methyl-benzenesulfonyl chloride (14 μl, 96 μmol, 1.1 eq). The product was purified by precipitation in methanol and lyophilized to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-4-fluoro-2-methyl-benzenesulfonamide (17 mg, >95% purity, yield: 48.7%).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C@@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CSC.[BH3:23].B>C1(C)C=CC=CC=1>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[BH3:23]
Reactant: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Agent: B
Solvent: CSC
Solvent: Cc1ccccc1
Product: OC(c1ccccc1)(c1ccccc1)C1CCCN1
Temperature: 20 °C

Procedure:
A 250-mL three-necked flask fitted with a mechanical stirrer, nitrogen inlet tube, and teflon coated thermocouple probe, was charged with a solution of the free base product of Example 1 Step B (20.7 g, 81.7 mmol) in dry toluene (100 mL). To the stirred solution at 20° C. was added borane-dimethyl sulfide (10M, 10.0 mL, 100 mmol) over 5 minutes via syringe. The borane reacted immediately in an exothermic reaction (raising the internal temperature from 20° C. to 32° C.) forming a thick white precipitate. With continued stirring, the mixture was allowed to cool to room temperature (20° C.) over a 1 hour period. The mixture was filtered, and the product cake washed with dry toluene (25 mL). The product was dried in vacuo (20° C., 0.01 mBar) to constant weight. Yield 15.7 g (72%) of a white crystal line solid. m.p. 130°-132° C. (dec). 1H NMR (CDCl3 ) δ7.7-7.1 (m, 10 H, Ar-H), 5.15 (s, 1 H, --OH), 4.5 (br, 1 H, --NH), 4.2 (m, 1 H, C2-H), 3.25 (m, 2 H, C5-H2), 2.6 (m, 1 H, C4- H), 2.3 (m, 1 H, C4-H), 1.85 (m, 1 H, C3-H), 1.6 (m, 1 H, C3-H), 2.1-0.7 (br, 3 H, BH3). 13C NMR (CDCl3) δ145.8, 144.5 (C1', C1"), 129.1, 128.2 (C3', C5', C3", C5"), 127.4, 127.0 (C4', C4"), 125.2, 125.1 (C2', C6', C2", C6"), 76.5 (Cα), 69.6 (C2), 55.6 (C 5), 20.6 (C4), 19.9 (C3).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.CN(C)C=O.[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[N:32]([CH2:33][CH2:34]OS(C)(=O)=O)[C:31]3[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=3[N:29]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(OCC)(=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[N:32]([CH2:33][CH2:34][N:3]3[C:2]([CH3:1])=[N:6][N:5]=[N:4]3)[C:31]3[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=3[N:29]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: Cc1nnn[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nnnn1CCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 25 °C
Yield: 34.8 %

Procedure:
Treat a stirred solution of 5-methyltetrazole (0.38 g, 4.52 mmol, obtained from TCI US) and dimethylformamide (7 mL) at 0° C. portionwise with sodium hydride (0.19 g, 4.75 mmol, 60% dispersion in oil). Allow to warm to room temperature over one hour and add a solution of 1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)-[1,4]diazepane (0.1.33 g, 3.03 mmol, Preparation 28) and dimethylformamide (7 mL). Heat at 100° C. for 6 hours. Cool, add ethyl acetate (50 mL) and wash with saturated NaHCO3 (3×25 mL) and brine (3×50 mL). Dry (MgSO4) the organic phase, filter and concentrate in vacuo. Purify the residue by chromatography (silica gel, 3.5×50 cm) eluting with ethyl acetate:hexane (1:1) to afford 4-{1-[2-(5-methyl-tetrazol-1-yl}-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.45 g), Rf=0.21 (silica gel, methanol:dichloromethane, 1:1).