Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]1([CH:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:33]1([CH:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NCCCCCCCC(c1ccccc1)c1ccccc1
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCCCCC(c1ccccc1)c1ccccc1

Procedure:
Batch size: 2.7 g (18.0 mmol) 3-(3-pyridyl)-acrylic acid, 5 ml (57.9 mmol) oxalyl chloride, 3.9 ml (28.0 mmol) TEA and 4.0 g (14,0 mmol) 8,8-diphenyloctylamine.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([CH3:19])[C@H:10](/[CH:11]=[CH:12]/[C:13](=[O:15])[CH3:14])[C@H:9]1[C:16](Cl)=[O:17].[CH2:20]([OH:22])[CH3:21].Cl>C1C=CC=CC=1>[CH3:7][C:8]1([CH3:19])[C@H:10](/[CH:11]=[CH:12]/[C:13](=[O:15])[CH3:14])[C@H:9]1[C:16]([O:22][CH2:20][CH3:21])=[O:17]
Reactant: CCO
Reactant: CC(=O)/C=C/[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H]1[C@@H](/C=C/C(C)=O)C1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2 ml of pyridine, 2.9 g of (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylic acid chloride, 1 ml of ethanol and 25 ml of benzene was stirred at 0° to 5° C. for 20 minutes and at room temperature for 2 hours and was then poured into iced aqueous N/6 hydrochloric acid solution. The mixture was extracted with ether and the organic phase was washed with water, dried and evaporated to dryness at 40° C. under reduced pressure. The 4.19 g of oil residue were chromatographed over silica gel and eluted with a 7-3 cyclohexane-ethyl acetate mixture to obtain 1.43 g of ethyl (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+82°±3° (c=0.5% in benzene).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:15])[CH:3]=1.[CH2:16]([O:18][CH2:19][C@@H:20]([C:22]1[N:27]=[C:26]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH:25]=[CH:24][CH:23]=1)O)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([C:26]2[N:27]=[C:22]([C@H:20]([O:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:15])[CH:3]=3)[CH2:19][O:18][CH2:16][CH3:17])[CH:23]=[CH:24][CH:25]=2)=[CH:29][CH:30]=1)#[N:33]
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: CCOC[C@H](O)c1cccc(-c2ccc(C#N)cc2)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC[C@@H](Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C#N)cc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A stirred mixture of ethyl [(4-hydroxy-2-methylphenyl)oxy]acetate (664 mg, 3.16 mmol), 4-{6-[(1R)-2-(ethyloxy)-1-hydroxyethyl]-2-pyridinyl}benzonitrile (719 mg, 2.68 mmol) and triphenylphosphine (857 mg, 3.27 mmol) in dry DCM (35 mL) was cooled to 0° C. under nitrogen. DIAD (633 μL, 3.21 mmol) was added dropwise over 10 min, and the reaction mixture stirred at 0° C. for a further 2 h. DCM (120 mL) was added to the reaction mixture, washed with aq 1M NaOH (50 mL) and water (100 mL), dried (Na2SO4) and evaporated to give a yellow oil. Purification by Biotage™ chromatography (silica, 90 g cartridge) eluting with cyclohexane:EtOAc (8:1) afforded the title compound as a colourless oil (765 mg).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:22])[O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])[CH2:9]1)C1C=CC=CC=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:22])[O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:18])[F:19])[CH2:9]1
Reactant: C[C@H](OC(=O)N[C@H]1CCN(Cc2ccccc2)C1)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](OC(=O)N[C@H]1CCNC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (2S)-1,1,1-trifluoropropan-2-yl [(3S)-1-benzylpyrrolidin-3-yl]carbamate (1.82 g) in THF (20 ml) and MeOH (20 ml) was added 20% palladium hydroxide on activated carbon (200 mg). The resulting solution was placed under a H2 atmosphere (balloon pressure) and stirred at room temperature for 15 hours. The solution was obtained by filtration through Celite and, washing the filter cake with MeOH, was concentrated in vacuo to give (2S)-1,1,1-trifluoropropan-2-yl(3S)-pyrrolidin-3-ylcarbamate as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:22])=[CH:12][C:13]([CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:16])=[CH:14][C:4]=2[O:3]1.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:23][C:2]1([CH3:1])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:22][C:31](=[O:32])[CH2:30][N:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[CH:12][C:13]([CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: CCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Reactant: O=C(O)CN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCC(C)c1cc(OC(=O)CN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CCS1

Procedure:
By reacting 1,2-dihydro-7-(2-heptyl)-9-hydroxy-4-oxo-4H-thieno[2,3-c] [1]benzopyran with methyl magnesium bromide in a procedure similar to that described hereinabove in Example 8, there is obtained 1,2-dihydro-4,4-dimethyl-7-(2-heptyl)-9-hydroxy-4H-thieno[2,3-c] [1]benzopyran. The benzopyran is then reacted with morpholinoacetic acid and dicyclohexylcarbodiimide to yield the desired ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([N:35]=[C:36]=[S:37])=[O:34]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])=[S:37])=[CH:18][CH:17]=1
Reactant: Cc1ccccc1C(=O)N=C=S
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (72 mg, yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14](=[O:36])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:35])[NH:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH:11]=[C:10]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=3)[C:9]=2[OH:44])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:52][C:53]([O:55][CH3:56])=[O:54]>CN(C=O)C>[CH3:56][O:55][C:53](=[O:54])[CH2:52][O:44][C:9]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:13][C:12]([C:14](=[O:36])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:35])[NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)=[CH:11][C:10]=1[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=1
Reactant: COC(=O)CBr
Reactant: O=C(Nc1cccc2ccccc12)OCCCCCCNC(=O)c1cc(-c2cccc(Cl)c2)c(O)c(-c2cccc(Cl)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCOC(=O)Nc2cccc3ccccc23)cc1-c1cccc(Cl)c1
Yield: 64.7 %

Procedure:
To a stirred solution of 3,3″-dichloro-5′-[6-(naphthalen-1-ylcarbamoyloxy)hexylcarbamoyl]-[1,1′;3′1″]-terphenyl-2′-ol (0.320 g, 0.510 mmol) and K2CO3 (0.078 g, 0.561 mmol) in DMF (10 mL) at room temperature was added dropwise methyl bromoacetate (0.097 mL, 1.02 mmol). After 18 h at this temperature, it was concentrated and then diluted with excess EtOAc (250 mL). The organic layer was washed with 1 N HCl (25 mL), sat. aq. NaHCO3 (25 mL), and brine (25 mL) and then dried (MgSO4). After concentration, the residue was purified by flash chromatography (30 to 50% EtOAc/petroleum ether gradient) to afford the product (0.231 g, 65%) as a solid; 1H NMR (DMSO-d6) δ 1.32–1.49 (m, 4H), 1.49–1.73 (m, 4H), 3.23–3.35 (m, 2H), 3.44 (s, 3H), 3.99 (s, 2H), 4.11 (t, J=6.3 Hz, 2H), 7.45–7.63 (m, 10H), 7.69 (s, 2H), 7.73 (d, J=9.4 Hz, 1H), 7.87–7.94 (m, 3H), 8.02–8.12 (m, 1H), 8.61 (t, J=5.5 Hz, 1H), 9.49 (s, 1H); mass spectrum [(+) ESI], m/z 700 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]=[O:12].[CH3:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16].NC1C=CC=CC=1>>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[NH:10][C:11]([NH:16][C:15]1[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=1[CH3:13])=[O:12]
Reactant: Cc1cc(C)c(N=C=O)c(C)c1
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: Nc1ccccc1
Product: Cc1cc(C)c(NC(=O)Nc2c(C)cc(C)cc2C)c(C)c1

Procedure:
2,4,6-Trimethylphenyl isocyanate (Lancaster Co., 20.5 g, 0.127 mol) and 2,4,6-trimethylaniline (17.2 g, 0.127 mol) were reacted in a procedure analogous to that described in Example 1, giving a brown solution. A thick, white flaky precipitate was observed to form about 2 hours after aniline addition. This material was collected by filtration, rinsed with hexanes, and dried in vacuo (crop 1). The CHCl3 reaction filtrate (also containing rinse hexanes) was set aside and was observed to produce additional white precipitate overnight. It was concentrated somewhat using a rotary evaporator and insolubles were similarly collected by filtration, rinsed with hexanes until a pinkish impurity was removed, and dried (crop 2). Three additional crops of material were collected in this fashion. Crop 3 was collected by removal of volatiles from the filtrate of crop 2, crushing the resultant solid, slurrying it in hexanes overnight, and collecting insolubles by filtration and rinsing them with hexanes. Crop 4 was collected by removal of volatiles from the filtrate of crop 3, slurrying with petroleum ether, and collecting insolubles by filtration and rinsing them with petroleum ether. Crop 5 was collected identically by treatment of the filtrate from Crop 4, using smaller slurry and rinse volumes of petroleum ether. The weights of crops 1 to 5 were 11.1 g, 8.32 g, 5.96 g, 2.30 g, and 4.19 g, respectively (total 31.9 g, 84.6%). 1H NMR (solid state CRAMPS, 500 MHz): δ 7.5 (br, aryl), 6.1 and 5.1 (NH), 1.4, 0.9 (sh), and 0.5 (sh) (overlapping, CH3). 13C{1H} NMR (solid state CPMAS, 50 MHz): δ 157.9 and 154.9 (br, C=0, 1 C), 135.0, 129.6, 128.7, and 127.6 (aryl, 12 C), 22.8, 20.0, 19.4, and 17.9 (CH3, 6 C). IR (KBr pellet): 3286 (vs), 3003 (w), 2972 (m), 2918 (s), 2855 (w), 1640 (vs), 1609 (s), 1553 (vs), 1485 (m), 1470 (sh), 1446 (sh), 1377 (w), 1308 (w), 1285 (w), 1252 (sh), 1223 (s), 1065 (w), 1032 (w), 1013 (w), 882 (w), 849 (m), 760 (w), 748 (w), 721 (sh), 696 (m), 580 (w) cm−1. FD-MS m/z (%): 296.7 (MH+, 100). Exact mass calculated for C19H24N2O: 296.19. Melting point (DSC): onset (extrapolated) 236° C., max. 240° C.
Reaction SMILES: [OH:1][C@H:2]1[C@H:9]2[C@H:5]([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@H:3]1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C[N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.N1CCOCC1>C1COCC1>[OH:1][C@H:2]1[C@H:9]2[C@H:5]([O:6][C:7]([CH3:10])([CH3:11])[O:8]2)[O:4][C@H:3]1[C:12]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:14]
Reactant: CN1CCOCC1
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)O)[C@@H](O)[C@@H]2O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC1(C)O[C@@H]2O[C@@H](C(=O)N3CCOCC3)[C@@H](O)[C@@H]2O1
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
Step-IV: To a stirred solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxole-5-carboxylic acid (20 g, 98 mmol) in THF (400 ml) was added TBTU (47.2 g, 147 mmol), N-methylmorpholine (NMM, 16.16 ml, 147 mmol) at room temperature and stirred for 30 min. To it was added morpholine (12.99 ml, 147 mmol) and stirred for 6 h. The solid was filtered off by filtration and it was washed with THF. The filtrate was concentrated and resulting residue was purified by silica gel column chromatography to give 17.8 g of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl)-morpholin-4-yl-methanone as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.33 (s, 3H), 1.49 (s, 3H), 3.42-3.53 (m, 2H), 3.62-3.83 (m, 6H), 4.47 (d, J=2.0 Hz, 1H), 4.57 (d, J=3.6 Hz, 1H), 4.59 (d, J=2.0 Hz, 1H), 6.00 (d, J=3.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1cccc2ccc(Cl)nc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2ccc(Cl)nc12)c1ccccc1
Yield: 88.5 %

Procedure:
In the similar fashion using route 14 general procedure 27, 2-chloroquinolin-8-amine (Intermediate 26) (70 mg, 0.39 mmol), benzenesulfonyl chloride (83 mg, 0.42 mmol) and DMAP (cat.) gave the title compound (110 mg, 88%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:32])=[N:14][C:15]2[N:16]([N:24]=[C:25]([C:27]([O:29]CC)=[O:28])[CH:26]=2)[C:17]=1/[CH:18]=[CH:19]/[CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:32])=[N:14][C:15]2[N:16]([N:24]=[C:25]([C:27]([OH:29])=[O:28])[CH:26]=2)[C:17]=1/[CH:18]=[CH:19]/[CH2:20][CH:21]([CH3:22])[CH3:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(/C=C/CC(C)C)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)O)nn2c1/C=C/CC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
To a solution of (S,E)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-5-methyl-7-(4-methylpent-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (190 mg, 0.426 mmol) in EtOH (4 mL) was added 1N NaOH (0.426 mL, 0.426 mmol) and the resulting mixture was stirred at room temp for 4 h. At this point LCMS indicated completion of reaction. Solvents were then removed under reduced pressure and the mixture was diluted with water (3 mL), acidified with 1N HCl, extracted with ethyl acetate (25 mL), washed with brine (10 mL), dried (Na2SO4), filtered and concentrated to afford (S,E)-6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-5-methyl-7-(4-methylpent-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (145 mg, 0.347 mmol, 81% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.20 (s, 1H), 7.01 (d, J=16.1 Hz, 1H), 6.90 (br. s., 1H), 5.57 (s, 1H), 4.48 (d, J=7.3 Hz, 1H), 4.30-4.22 (m, 2H), 2.72 (br. s., 3H), 2.00-1.85 (m, 1H), 1.32-1.25 (m, 3H), 1.18 (s, 9H), 1.10-0.97 (m, 6H). LCMS (M+H)=418.4.
Reaction SMILES: O=[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Cl.[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23](=[S:26])[NH:24][NH2:25].C(N(CC)CC)C>CCO>[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23]1[S:26][C:2]([CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:25][N:24]=1
Reactant: NNC(=S)c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)NCCC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-oxo-3-phenylpropylcarbamate (0.68 g, 2.73 mmol) and 2,5-difluorobenzothiohydrazide hydrochloride (0.613 g, 2.73 mmol) in EtOH (27 mL) was added triethylamine (0.57 mL, 4.09 mmol). After stirring at room temperature for 8 hours, the mixture was heated to 65° C. for 16 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The solution was washed with water and brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed (30% ethyl acetate in hexanes) to provide the crude product as a brown syrup which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[C:18]1([NH:24][CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:27][CH2:26][CH2:25][NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: NCCNc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccccc2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile and N-phenylethylenediamine in DME. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([C:40](=[O:42])[CH3:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[C:40]([N:34]1[CH2:39][CH2:38][N:37]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:36][CH2:35]1)(=[O:42])[CH3:41]
Reactant: CC(=O)N1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 14 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1 equivalent of 1-(piperazin-1-yl)ethanone as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][C:12]2[C:21]3[C:16](=[C:17]([CH3:24])[C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[N:15]=[C:14]([C:25]3[S:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=3)[CH:13]=2)[CH2:7][C@H:6]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])=[O:4].[Li+].[OH-].Cl>O.C1COCC1>[CH2:37]([O:36][C:34]([C@@H:6]1[CH2:7][C@H:8]([O:11][C:12]2[C:21]3[C:16](=[C:17]([CH3:24])[C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[N:15]=[C:14]([C:25]3[S:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=3)[CH:13]=2)[CH2:9][CH2:10][C@H:5]1[C:3]([OH:4])=[O:2])=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)[C@@H]1CC[C@@H](Oc2cc(-c3nc(C(F)(F)F)cs3)nc3c(C)c(OC)ccc23)C[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(O[C@@H]3CC[C@@H](C(=O)O)[C@H](C(=O)OCc4ccccc4)C3)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Yield: 80 %

Procedure:
A solution of compound 34e (293 mg, 1 eq.) and LiOH (49 mg, 4 eq) in H2O (5 mL) and THF (5 mL) was stirred at room temperature for 4 hrs. The reaction mixture was acidified with 1N HCl to pH 2 and then extracted with DCM. Organics were concentrated under reduced pressure and purified by chromatography on silica gel (DCM/MeOH) to yield compound 34f as beige solid in 80% yield. MS (ESI, EI+): m/z=601 (MH+).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[N:25]=[C:24]2[C:32](OCC)=[O:33])=[CH:19][C:18]=1[F:37])#[N:16].[Cl-].[Ca+2].[Cl-]>CO>[N:2]1([C:32]([C:24]2[N:23]([C:20]3[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[C:18]([F:37])[CH:19]=3)[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[N:25]=2)=[O:33])[CH2:5][CH2:4][CH2:3]1
Reactant: C1CNC1
Reactant: CCOC(=O)c1nc2cccnc2n1-c1ccc(C#N)c(F)c1
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-n2c(C(=O)N3CCC3)nc3cccnc32)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of azetidine hydrochloride (120 mg, 1.3 mmol) and N,N-diisopropylethylamine (168 mg, 1.30 mmol) in methanol (2 mL) was stirred at room temperature for 1 hour. At this point, ethyl 3-(4-cyano-3-fluorophenyl)-3H-imidazo[4,5-b]pyridine-2-carboxylate (C16) (40 mg, 0.13 mmol) and calcium chloride (15 mg, 0.13 mmol) were added, and the reaction mixture was stirred at room temperature for an additional 2 hours. After removal of solvents in vacuo, the residue was purified by reversed phase HPLC (Column: DIKMA Diamonsil C18(2), 5 μm; Mobile phase A: 0.225% formic acid in water; Mobile phase B: 0.225% formic acid in acetonitrile; Gradient: 15% to 45% B) to provide the product as a yellow solid. Yield: 4.0 mg, 12 μmol, 9%. LCMS m/z 322.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.49 (dd, J=4.8, 1.3 Hz, 1H), 8.20 (dd, J=8.2, 1.4 Hz, 1H), 7.77-7.82 (m, 1H), 7.36-7.43 (m, 3H), 4.80-4.89 (m, 2H), 4.18-4.26 (m, 2H), 2.39-2.50 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: OCc1cccc(Br)c1
Reactant: CCOC(=O)CBr
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
Part A: 3-Bromobenzyl alcohol (2.0 g) was dissolved in dimethyl formamide (50 ml) in a dry 100 ml flask under nitrogen. Sodium hydride (0.5 g of a 60% suspension in mineral oil, washed with hexane, 11.8 mmol) was added in portions and the mixture was stirred for one hour at room temperature. Ethyl bromoacetate (1.2 ml, 11.8 mmol) was added drop-wise and the reaction was stirred overnight at room temperature then mixed with water (150 ml) and extracted with methylene chloride (3×20 ml). The extracts were combined, washed with water (50 ml), saturated sodium chloride solution (50 ml) and then dried (MgSO4). The solution was filtered and concentrated and the residue was purified by flash chromatography (SiO2, gradient hexane to ethyl acetate) which gave 2.35 g (80%) of ethyl 3-bromobenzyloxyacetate as an oil.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH:22]([CH3:24])[CH3:23])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH:22]([CH3:24])[CH3:23])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: COc1ccc(-n2cc(C(O)C3CCCCC3)c(C(C)C)n2)cc1
Product: COc1ccc(-n2cc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)c(C(C)C)n2)cc1
Yield: 30.8 %

Procedure:
Using cyclohexyl[1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]methanol (0.70 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.52 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.34 g, 30%) was obtained as a white solid.