Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([O:30][CH3:31])[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:31][O:30][C:23]1[CH:22]=[C:21]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]3)[CH2:3][CH2:2]2)[CH:26]=[CH:25][C:24]=1[N+:27]([O-:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(N2CCC(N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 15 h
Yield: 86.9 %

Procedure:
tert-Butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (1.842 g, 6.84 mmol) was added to a stirring mixture of 4-fluoro-2-methoxy-1-nitrobenzene (1.17 g, 6.84 mmol) and K2CO3 (2.83 g, 20.51 mmol) in acetonitrile (15 mL) and the reaction mixture was stirred at 90° C. for 15 h. The reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (hexanes/EtOAc) to give the title product (2.5 g, 87%). m/z 421.
Reaction SMILES: C(O[C:5](=[O:22])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18]C=1)C=C.[N:23]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][CH2:28][C@H:24]1C(O)=O>>[C:34]([O:33][C:31]([N:23]1[CH2:30][CH2:29][CH2:28][CH:24]1[C:5](=[O:22])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][C:15]1[CH:16]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 94 %

Procedure:
Prepared from 40 (1.16 g, 4.0 mmol) and Boc-Pro-OH according to the procedure used to prepare 100 (Scheme XVIII) to afford 1.53 g (94% yield) of the title compound as a white solid. 1H-NMR (500 MHz, CDCl3): δ 1.61 (br, 9H), 1.88 (br, 2H), 2.00-2.50 (m, 3H), 2.80-3.10 (m, H), 3.20-3.60 (m, 2H), 4.05-4.45 (m, 1.5H), 4.58-4.80 (m, 1.5H), 4.83-4.98 (m, H), 5.43-5.53 (m, H), 7.26-7.45 (m, 5H), 7.60-7.80 (d, H); Analytical HPLC: 11.32 min; LC-MS: m/e=405 (M+H+).
Reaction SMILES: [OH2:1].[C:2]([C:24](F)=[O:25])([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([F:23])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])[F:3]>>[C:2]([C:24]([OH:25])=[O:1])([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([F:22])([F:21])[F:23])([F:19])[F:18])([F:15])[F:16])([F:12])[F:13])([F:10])[F:9])([F:6])[F:7])([F:3])[F:4]
Reactant: O
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A 250 ml PFA vessel equipped with a stirrer was used. Water (100 g, 5.6 mol) was temperature conditioned to 60° C. within the vessel, following which C7F15COF (50 g, 0.120 mol; prepared by the method described in JP-A 8-231462) having a purity of 99.9 wt % was added dropwise under stirring in an attempt to form C7F15COOH by a hydrolysis reaction. However, a gel formed, which made stirring impossible.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].[CH3:16][Si](C=[N+]=[N-])(C)C.N#N>CO.C1C=CC=CC=1>[CH3:16][O:4][C:3](=[O:5])[C:2]([CH3:1])([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: N#N
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Yield: 88.2 %

Procedure:
To a solution of 2-methyl-2-(4-nitrophenyl)-propionic acid (1.0014 g, 4.76 mmol) in 10% MeOH/benzene (20 mL) was added dropwise (trimethylsilyl)-diazomethane (2.0 M in hexanes, 3.5 mL, 7.0 mmol). The reaction mixture was stirred at rt until evolution of N2 ceased (<5 min) and then concentrated. The crude residue was purified (FCC) to give the title compound (937.6 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].C[Si]([N:36]=[C:37]=[O:38])(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:27][CH2:28][N:29]([C:37]([NH2:36])=[O:38])[CH2:30][CH2:31]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCN(C(N)=O)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (8.0 mg, 0.0174 mmol), trimethylsilyl isocyanate (4.02 mg, 0.0349 mmol), DIPEA (0.02 mL, 0.09 mmol) and DCM (1 mL) was stirred at rt for 30 min. The solution was concentrated in vacuo, redissolved in MeOH and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=7.1 Hz, 3 H), 1.93-2.05 (m, 2H), 2.07-2.16 (m, 2 H), 2.95-3.06 (m, 2 H), 4.17 (d, J=13.6 Hz, 2 H), 4.41 (tt, J=11.5, 4.2 Hz, 1 H), 5.25-5.34 (m, 1 H), 7.19 (t, J=8.7 Hz, 1 H), 7.36 (d, J=1.5 Hz, 1 H), 7.38-7.52 (m, 2 H), 7.58 (s, 1 H), 7.90 (s, 1 H), 8.32 (d, J=1.8 Hz, 1 H). MS (ES+): m/z 501.02 (100) [MH+]. HPLC: tR=3.15 min (ZQ3, polar—5 min).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28]/[C:29](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[N:30]\[O:31][CH3:32]>C(#N)C.O>[CH3:32][O:31]/[N:30]=[C:29](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(O)cc2)cc1
Reactant: CO/N=C(\CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCc1ccc(-c2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 80 °C
Yield: 60 %

Procedure:
To a solution of ethyl 3-(4′-hydroxybiphenyl-4-yl)propanoate (0.27 g, 0.001 mmol) in acetonitrile was added potassium carbonate (0.27 g, 0.002 mmol) and (1Z)-2-bromo-N-methoxy-1-phenylethanimine (0.23 g, 0.001 mmol) and refluxed at 80° C. for 3 h. RM was diluted with water and extracted with ethyl acetate, Organic layer was washed with water and brine solution, dried over anhydrous Na2SO4 and concentrated to get crude product which was purified by comb flash to get white gummy solid as product (0.25 g, Yield: 60%): MS (ESI, 120 eV): m/z=418 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 7.59-7.63 (m, 2H), 7.37-7.42 (m, 4H), 7.26-7.28 (m, 3H), 7.15 (d, 2H), 6.88-6.90 (d, 2H), 5.15 (s, 2H), 4.03-4.10 (m, 2H), 3.99 (s, 3H), 2.87-2.93 (t, 2H), 2.54-2.60 (t, 2H), 1.17-1.19 (t, 3H).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([NH2:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:11][C:12]1[C:13]([C:18]([OH:20])=[O:19])=[N:14][CH:15]=[CH:16][N:17]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:1]1([CH3:10])[C:2]([C:7]([NH2:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:21]([NH:11][C:12]1[C:13]([C:18]([OH:20])=[O:19])=[N:14][CH:15]=[CH:16][N:17]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nccnc1C(=O)O
Agent: Cc1ccccc1C(N)=O
Product: CC(=O)Nc1nccnc1C(=O)O
Yield: 76 %

Procedure:
A mixture of 3-aminopyrazine-2carboxylic acid o-toluamide (1.0 g, 4.39 mmol) and acetic anhydride (12 mL) was refluxed 2 hours. The solvent was removed and the residue was triturated with hot ethyl acetate. The ethyl acetate slurry was cooled and the product was collected and rinsed with ether to afford 0.893 g (76%) of 3-acetamidopyrazine-2-carboxylic acid o-toluamide.
Reaction SMILES: C(=O)C1C=CC=CC=1.[CH3:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:41])=[C:32]([N:35]4[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36]4)[CH:33]=3)[C:28](=[O:42])[C:27]([C:43]([OH:45])=[O:44])=[CH:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:41])=[C:32]([N:35]4[CH2:39][CH2:38][CH:37]([N:40]=[CH:9][C:10]5[CH:17]=[CH:16][C:13]([CH3:14])=[CH:12][CH:11]=5)[CH2:36]4)[CH:33]=3)[C:28](=[O:42])[C:27]([C:43]([OH:45])=[O:44])=[CH:26]2)=[CH:21][CH:20]=1
Reactant: NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Reactant: Cc1ccc(C=O)cc1
Solvent: O=Cc1ccccc1
Product: Cc1ccc(C=NC2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3)C2)cc1

Procedure:
In the described fashion of Example 1 replacing benzaldehyde with p-methylbenzaldehyde and using the acid (1) (R=cyclopropyl) described in Example 19 one obtains 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-(p-methylbenzylidene)amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid (3) (R=cyclopropyl, Z=p-methylphenyl).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[C@@H:6]([CH3:16])[NH:7][C:8](=[O:15])[C@H:9]([CH2:11][C:12](=[O:14])[OH:13])[NH2:10])[CH2:2][CH3:3].Cl.C[O:20][C:21](=O)[C@H:22]([CH2:38]C1C=CC=CC=1)[NH:23]C(=O)[C@](N)(CC(=O)O)NC(=O)C(C)C>>[CH2:1]([O:4][C:5](=[O:17])[C@@H:6]([CH3:16])[NH:7][C:8](=[O:15])[C@H:9]([CH2:11][C:12](=[O:13])[OH:14])[NH:10][C:21](=[O:20])[C@@H:22]([CH3:38])[NH2:23])[CH2:2][CH3:3]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@](N)(CC(=O)O)NC(=O)C(C)C
Reactant: CCCOC(=O)[C@@H](C)NC(=O)[C@@H](N)CC(=O)O
Agent: Cl
Product: CCCOC(=O)[C@@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N

Procedure:
This compound was prepared from 1.9 g α-L-aspartyl-D-alanine n-propyl ester and 2.2 g N-benzyloxycarbonyl-D-alanine N-hydroxysuccinimide ester in a manner similar to Example 16 (C) and (D). Yield: 1.7 g, m.p.: 223°-225° C.
Reaction SMILES: [CH2:1]=O.[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:19][NH:18][CH:17]([C:20]([NH:22][CH3:23])=[O:21])[CH2:16]3)[CH:14]=2)=[CH:6][C:5]=1[C:24]1[O:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.[Na].N>CO.ClCCl>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([C@H:15]3[CH2:19][N:18]([CH3:1])[C@H:17]([C:20]([NH:22][CH3:23])=[O:21])[CH2:16]3)[CH:14]=2)=[CH:6][C:5]=1[C:24]1[O:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1
Reactant: C=O
Reactant: CNC(=O)C1CC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CN1
Agent: N
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)[C@@H]1C[C@@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CN1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
TFA (5 ml) was added to (2S,4R)-tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-2-(methylcarbamoyl)pyrrolidine-1-carboxylate under argon. The resulting solution was stirred at 25° C. for 1 hour. The solution was evaporated under reduced pressure, adsorbed with ammonia in methanol solution. The crude product was purified by flash chromatography on silica gel eluting with 1 to 6% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford (2S,4R)-4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-N-methyl-pyrrolidine-2-carboxamide (38 mg) as a pale yellow solid. 37% Aqueous formaldehyde (8.42 μl) at 0° C. was added to a stirred solution 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-N-methyl-pyrrolidine-2-carboxamide (38 mg) dissolved in methanol (2 ml) and dichloromethane (2 ml) over a period of 5 minutes under argon. The resulting solution was stirred at 0° C. for 5 minutes. Sodium triacetoxyhydroborate (23.96 mg, 0.11 mmol) was added and the mixture was stirred 5 minutes at 25° C. A solution of ammonia in methanol 7N (1 ml) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 6% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford (2S,4R)-4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-N,1-dimethyl-pyrrolidine-2-carboxamide (30 mg) after overnight stirring in acetonitrile as a solid. NMR Spectrum: (DMSOd6) 2.23-2.32 (m, 1H), 2.35 (s, 3H), 2.47-2.56 (m partially hidden by DMSOd5, 1H), 2.65 (d, 3H), 2.76-2.84 (m, 1H), 3.19-3.27 (m, 1H), 3.47-3.56 (m, 1H), 4.89-4.99 (m, 1H), 7.41-7.50 (m, 2H), 7.67 (bs, 2H), 7.77-7.82 (m, 1H), 7.83-7.87 (m, 1H), 7.90 (q, 1H), 7.97 (s, 1H), 8.37 (s, 1H), 8.44 (d, 1H), 8.53 (d, 1H) Mass spectrum: M+H+ 418
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCc1ccccc1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccccc3)s2)c(C)[nH]c1=O

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with benzyl amine as described in Step 5, Example 24 to give the title compound. MS: m/e 389 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:21]=[C:19]1[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:26])[N:20]1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)C1(CCCCBr)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1(CCCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Under argon, 4.2 g (15.15 mmol) of tert-butyl 1-(4-bromobutyl)cyclopropanecarboxylate were initially charged in 50 ml of DMF, 3.34 g (22.72 mmol) of phthalimide and 4.19 g (30.3 mmol) of potassium carbonate were added and the mixture was stirred at 90° C. for 2 h. The reaction mixture was then filtered, and the filtrate was diluted with water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 4.23 g (81.3% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[C:35]([F:36])=[CH:34][C:31]([C:32]#[N:33])=[C:30]([F:37])[CH:29]=1.O1C=NC(C2C=CC(CN([C@@H]3CCCC[C@H]3CO)S(C3C=CC(Cl)=CC=3)(=O)=O)=CC=2)=N1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:27][C:28]2[CH:29]=[C:30]([F:37])[C:31]([C:32]#[N:33])=[CH:34][C:35]=2[F:36])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#Cc1cc(F)c(CBr)cc1F
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: N#Cc1cc(F)c(CN([C@@H]2CCCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1F
Yield: 43.3 %

Procedure:
The title compound was synthesized from 4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (200 mg, 0.66 mmol), cesium carbonate (257 mg, 0.79 mmol), and 4-(bromomethyl)-2,5-difluorobenzonitrile (183 mg, 0.79 mmol) according to the procedure described for N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 11) to give 4-chloro-N-(4-cyano-2,5-difluorobenzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (130 mg, 43%). 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (m, 2H), 7.59 (dd, J=8.81, 5.79 Hz, 1H), 7.51 (m, 2H), 7.28 (dd, J=8.56, 5.04 Hz, 1H), 4.48 (d, J=13.00 Hz, 1H), 4.39 (d, J=14.00 Hz, 1H), 3.64 (td, J=11.58, 3.02 Hz, 1H), 3.55 (ddd, J=11.77, 4.72, 3.40 Hz, 1H), 3.15 (ddd, J=11.58, 9.19, 2.14 Hz, 1H), 2.41 (t, J=6.00 Hz, 1H), 1.68 (d, J=10.58 Hz, 3H), 1.30-1.52 (m, 2H), 0.98-1.19 (m, 4H). Analytical HPLC R.T.=23.37 min. MS [M+H]+=455; [M+Na]+=477.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9](=[O:13])[CH:10]=[N+]=[N-])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:22].O1CCOCC1>CCOCC>[Cl:22][CH2:10][C:9](=[O:13])[C@@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)C=[N+]=[N-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)CCl

Procedure:
To a solution of the crude (S)-tert-butyl 1-cyclohexyl-4-diazo-3-oxobutan-2-ylcarbamate (7 g, ˜65% pure) in anhydrous ether (150 mL) at 0° C. was added dropwise a solution of 3.65 N HCl in dioxane (4.1 mL, 0.015 mmol). The mixture was stirred until tlc showed the starting material had been consumed. Satd aq NaHCO3 was added and the organic layer was separated, washed with satd aq NaHCO3 and brine, and concentrated to afford a solution of crude (S)-tert-butyl 4-chloro-1-cyclohexyl-3-oxobutan-2-ylcarbamate (5.8 g), which was used in the next step without further purification.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[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][CH2:16][CH2:17][CH3:18].[CH2:21](O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)CCCCCCCCCCCCCCC.C(O)(=O)CCCCCCC/C=C\CCCCCCCC>O>[C:1]([O:20][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])(=[O:19])[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][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCCCC
Temperature: 180 °C

Procedure:
A 2-liter round-bottom flask was charged with 142 g (0.5 mole) of rubber-maker's technical grade stearic acid, 203 g (0.75 mole) of 1-octadecanol, 11 g of p-toluenesulfonic acid and 200 ml of mixed xylenes. Rubber-maker's technical grade stearic acid typically contains approximately 56 percent by weight stearic acid, 29 percent by weight palmitic acid, 8 percent by weight oleic acid and 7 percent by weight other fatty acids. The flask was fitted with a Dean-Stark trap for water removal, a heating mantel and a thermocouple. The system was flushed with nitrogen and heated to a pot temperature of 180° C. for about 1 hour, wherein 12 ml of water were removed. Volatiles were removed under 29 inches of vacuum at 110° C. to give 342 g of a waxy solid melting at 47-55° C. and giving an infrared spectrum showing loss of hydroxyl absorption bands and formation of ester carbonyl functions.
Reaction SMILES: Cl.ClC1C=CC(NN)=CC=1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[C:15]([F:21])[CH:14]=1.ClC1C=CC(N2[C:37](=[O:38])[C:36]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=3N2)=CC=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:37](=[O:38])[C:36]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=3[NH:20]2)=[C:15]([F:21])[CH:14]=1
Reactant: NNc1ccc(Cl)cc1F
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1)CCCC2
Agent: Cl
Agent: NNc1ccc(Cl)cc1
Product: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCCC2

Procedure:
By substituting 4-chlorophenylhydrazine hydrochloride in the above procedure for 4-chloro-2fluorophenylhydrazine hydrochloride, 2-(4-chlorophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one was prepared, m.p. 183.5°-185° (Lit 186°-187°, Chem. Abs., 67, 11452h).
Reaction SMILES: Br[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[C:14]([NH2:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClC(Cl)C>C(Cl)Cl>[C:15]1([C:14]2[O:21][C:2]3[CH2:3][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6][C:7]=3[N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)c1ccccc1
Reactant: CCOC(=O)C1CCC(=O)C(Br)C1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1CCc2nc(-c3ccccc3)oc2C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
16.0 g (64.23 mmol) ethyl 3-bromo-4-oxo-cyclohexanecarboxylate are combined with 7.8 g (64.39 mmol) benzamide and 50 ml of dichloroethane in a pressure vessel and stirred overnight at 120° C. The reaction mixture is diluted with DCM and washed 2× with 5% potassium carbonate solution as well as 1× with sat. saline solution. The org. phase is dried on magnesium sulphate and the solv. is eliminated completely in vacuo, the residue is purified through silica gel (eluant cyclohexane/EA).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[CH:16]([NH2:19])([CH3:18])[CH3:17]>C1COCC1>[CH:16]([NH:19][S:12]([CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1)(=[O:14])=[O:13])([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(CCS(=O)(=O)Cl)cc1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NS(=O)(=O)CCc1ccc(N)cc1

Procedure:
2-(4-Nitro-phenyl)-ethanesulfonyl chloride (300 mg) was suspended in 5 mL of THF. To the stirring solution was added isopropylamine (600 μL) dropwise at r.t. After 5 hours the solvent was evaporated. The nitro product was purified by flash chromatography (CH2Cl2/CH3OH 10:1 v/v) and was converted to the title compound under normal hydrogenation conditions. The title compound was obtained as a yellow solid (182 mg, 54%). 1H NMR (300 MHz, CD3OD) δ (ppm): 6.96 (d, J=8.3 Hz, 2H), 6.69 (d, J=8.3 Hz, 2H), 3.53 (m, 1H), 3.19 (m, 2H), 2.91 (m, 2H), 1.20 (s, 3H), 1.18 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(=O)(=O)c1ccccc1)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To an ice-cold mixture of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (60 mg, 0.19 mmol, 1.0 eq.) and pyridine (0.3 mL, 3.8 mmol, 20 eq.) in dichloro methane (5 mL) was added benzenesulfonyl chloride (51 mg, 0.29 mmol, 1.5 eq.) under nitrogen. Then the reaction mixture was stirred at room temperature for two hours. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The reaction was quenched with 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layers were concentrated and the residue was purified by silica gel (petroleum ether/ethyl acetate=2:1) to afford 70 mg of methyl 3,3-dimethyl-2-(2-(phenylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; yield: 85%; MS (ESI+APCI) M+1=451.