Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([O:39][C:40]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH3:55])[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:41]=1[NH2:42])[CH3:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[CH:44][C:45]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH3:55])[CH2:49][CH2:48]4)=[CH:46][C:40]=3[O:39][CH2:37][CH3:38])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCCN1CCN(c2ccc(N)c(OCC)c2)CC1
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: CCCN1CCN(c2ccc(Nc3nccc(-c4c(-c5ccc(OCC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
Temperature: 130 °C
Yield: 50.6 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 2-(ethyloxy)-4-(4-propyl-1-piperazinyl)aniline (Example 151, step B) (47 mg, 0.18 mmol), and p-toluenesulfonic acid (90 mg, 0.48 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (67 mg, 0.091 mmol, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.33 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=5.13 Hz, 1H), 8.04 (d, J=2.01 Hz, 1H), 7.72 (dd, J=8.61, 2.01 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.34-7.45 (m, 3H), 7.24 (d, J=8.61 Hz, 1H), 7.18 (t, J=8.06 Hz, 2H), 6.92 (t, J=6.59 Hz, 1H), 6.64 (d, J=2.20 Hz, 1H), 6.53 (d, J=5.13 Hz, 1H), 6.45 (dd, J=8.70, 2.47 Hz, 1H), 4.24 (q, J=6.78 Hz, 2H), 4.04 (q, J=6.96 Hz, 2H), 3.06-3.16 (m, 4H), 2.43-2.52 (m, 4H), 2.25 (t, J=6.96 Hz, 2H), 1.39-1.48 (m, 5H), 1.22 (t, J=6.96 Hz, 3H), 0.85 (t, J=7.33 Hz, 3H). MS (ESI): 733 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]=O.BrN1C(=O)CCC1=O.[SH:31][CH2:32][CH2:33][CH2:34][SH:35].[OH-].[Na+]>ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]1[S:35][CH2:34][CH2:33][CH2:32][S:31]1
Reactant: SCCCS
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C=O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1SCCCS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
To the solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-formyl-1H-pyrazole-3-carbonitrile (0.5 g, 1.4 mmol) in dichloromethane (10 mL) was added N-bromosuccinimide (0.075 g, 0.2 mmol) followed by the addition of 1,3-dimercaptopropane (0.19 g, 1.8 mmol). The resulting solution was stirred at room temperature for eight hours. It was then worked-up by the addition of 2 N sodium hydroxide. The layers were separated and the organic layer was dried (Na2SO4) and concentrated. The resulting solid was further purified via silica gel column eluting with heptane:ethyl acetate (1:1) to afford a white solid (0.2 g, 33%). 19F-NMR: −64.231.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[C:18]3[N:17]=[C:16]([O:19][CH3:20])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[C:6]([Cl:28])[CH:5]=[CH:4][C:3]=1[N:29]([CH3:53])[C:30](=[O:52])[CH2:31][NH:32][C:33]([CH:35]1[CH2:39][CH2:38][N:37]([CH:40]2[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41]2)[CH2:36]1)=[O:34].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>ClCCl>[Cl:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[C:18]3[N:17]=[C:16]([O:19][CH3:20])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[C:6]([Cl:28])[CH:5]=[CH:4][C:3]=1[N:29]([CH3:53])[C:30](=[O:52])[CH2:31][NH:32][C:33]([CH:35]1[CH2:39][CH2:38][N:37]([CH:40]2[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:36]1)=[O:34]
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C4CCN(C5CCN(C(=O)OC(C)(C)C)C5)C4)c3Cl)cccc2n1Cc1ccccn1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C4CCN(C5CCNC5)C4)c3Cl)cccc2n1Cc1ccccn1
Temperature: 0 °C

Procedure:
A solution of tert-butyl 3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)carbamoyl)-[1,3′-bipyrrolidine]-1′-carboxylate (0.27 g, 0.35 mmol) in dichloromethane (10 ml) was cooled in an ice bath and treated with dropwise addition of trimethylsilyl triflate (0.07 mL, 0.39 mmol) and stirred at 0° C. for ten minutes. The reaction was treated with another dropwise addition of trimethylsilyl triflate (0.06 mL, 0.35 mmol) stirring at 0° C. for one hour. The reaction was quenched with triethyl amine (1 mL), evaporated, treated with aqueous saturated sodium bicarbonate (10 mL) and brine (100 mL) and extracted with dichloromethane (100 mL×3). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to afford N-(2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)-[1,3′-bipyrrolidine]-3-carboxamide (22) as a tan solid, 0.22 g (94%), that was about 90% pure by LC/MS (+ESI) m/z 666 (M++1) with about 10% impurity of MW 786 (M+). 786 (M++1). 1HNMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.93 (m, 1H), 7.59 (m, 1H), 7.45 (m, 1H), 7.32 (m, 1H), 7.19 (m, 1H), 7.04 (m, 1H), 6.95 to 2.00 (many m, 17H). 13CNMR (100 MHz, CDCl3) δ 175.6, 169.5, 169.2, 156.9, 156.1, 149.6, 149.1, 138.4, 137.1, 136.4, 135.8, 135.4, 130.1, 129.8, 122.6, 121.7, 120.8, 107.4, 103.1, 67.1, 62.6, 57.5, 55.0, 54.9, 53.4, 51.4, 50.4, 47.7, 46.1, 44.0, 43.9, 41.9, 30.9, 9.0.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=1)(=[O:26])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:7][CH2:6]2)=O.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[S:24]([NH:23][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][C:14]([NH:13][CH:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:1][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)=[O:37])(=[O:26])=[O:25]
Reactant: O=Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reactant: C1CCNCC1
Product: O=C(CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1)NC1CCCc2cc(CN3CCCCC3)ccc21

Procedure:
The title compound was prepared from N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Step G) by reductive amination with piperidine similar to that described in Example 1, Step H. MS (+ESI m/z): 582 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:10](N1C=CN=C1)([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:11]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Oc1ccc(Cl)c(Cl)c1)n1ccnc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63.7 %

Procedure:
A solution of 5.00 g (30.7 mmol) of 3,4-dichlorophenol in 160 ml of dichloromethane was treated with 6.47 g (39.9 mmol) of 1,1′-carbonyldiimidazol. The reaction was stirred at room temperature over 3.5 h, then partitioned between aq. 0.5 M citric acid and dichloromethane (3×). The organic phase was dried over Na2SO4 evaporated and crystallized from diethyl ether to yield 5.03 g (64%) of the title compound as white crystals. MS: 256.8 (MH+, 2Cl).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=4[F:24])[CH:15]=3)[N:10]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[N:9]=2)[CH:5]=[N:4][CH:3]=1.[CH3:31][N:32]1[C:36](=O)[CH2:35][CH2:34][CH2:33]1>>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:9]=[C:8]2[C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:32]2[CH2:31][CH2:36][CH:35]=[CH:34][CH2:33]2)[N:7]=1
Reactant: CN1CCCC1=O
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1cncc(Cl)n1)nn2C1CCCCO1
Product: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1cncc(N3CC=CCC3)n1)nn2C1CCCCO1
Yield: 83 %

Procedure:
A slurry of 3-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.500 g, 1.171 mmol) and 5-(2,6-difluorophenyl)-3-(6-(5,6-dihydropyridin-1(2H)-yl)pyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.461 g, 0.974 mmol, 83% yield) in 2 mL NMP was sealed and heated to 120° C. The reaction became an orange/brown solution. After 1 h, the reaction was complete. The reaction was partitioned between water and EtOAc. The organic layer was washed with water once, saturated aqueous NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 0-40% EtOAc/hexane. The desired fractions were concentrated to afford 5-(2,6-difluorophenyl)-3-(6-(5,6-dihydropyridin-1(2H)-yl)pyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.461 g, 0.974 mmol, 83% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 474 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:12]1.[C:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:31]=[CH:32][CH:33]=1)#[CH:27]>>[C:37]([O:36][C:35]([NH:34][C:30]1[CH:29]=[C:28]([C:26]#[C:27][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:12]2)[CH:33]=[CH:32][CH:31]=1)=[O:41])([CH3:40])([CH3:39])[CH3:38]
Reactant: C[Si](C)(C)CCOC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2Br)C1
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc([N+](=O)[O-])ccc2N2CCC(NC(=O)OCC[Si](C)(C)C)C2)c1
Yield: 91 %

Procedure:
The desired compound was prepared according to the procedure of Example A11, step C, using 2-(trimethylsilyl)ethyl [1-(2-bromo-4-nitrophenyl)pyrrolidin-3-yl]carbamate and tert-butyl (3-ethynylphenyl)carbamate as the starting materials in 91% yield. LCMS for C29H39N4O6Si (M+H)+: m/z=567.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:6]([CH:33]=1)[CH2:7][N:8]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=1.[OH-].[Na+]>CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:6]([CH:33]=1)[CH2:7][N:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][CH:15]=1)[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(CN(Cc2cc(Br)ccc2OCc2ccccc2)c2ccc(C(=O)OC(C)(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(N(Cc2ccc(C(=O)O)cc2)Cc2cc(Br)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-[N-(5-bromo-2-benzyloxybenzyl)-N-(4-methoxycarbonylbenzyl)amino]benzoate (from example 16) was dissolved in a solution of methanol (10 ml) and tetrahydrofuran (10 ml). To this solution was added aqueous 2N sodium hydroxide (3 ml) and the solution stirred at ambient temperature for 18 hours. The volume of the reaction mixture was reduced by evaporation to half the original volume, water (20 ml) was added and the mixture acidified with acetic acid. The resulting solid was filtered and dried under vacuum at 60° C. to give the title compound (12 g) m.p. 110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CBr
Reactant: COc1ccccc1N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CNc1ccccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a cooled (0° C.) solution of 2-methoxyaniline (13.2 g, 0.108 mol) in CHCl3 (100 mL) was added ethyl bromoacetate (6 mL, 0.05 mol) and the mixture was stirred at room temperature overnight. The resulting solution was washed with 0.5N NaOH and the organic phase was concentrated to a crude product. This was purified by chromatography on silica gel (hexane-EtOAc, 10%) to afford ethyl N-(2-methoxyphenyl)aminoacetate (4.2 g, 40%). This compound was dissolved in MeOH (80 mL), a solution of K2CO3 (4.4 g) in H2O (50 mL) was added and the mixture was refluxed overnight. MeOH was removed and the resulting aqueous solution was extracted with hexane. The aqueous phase was acidified with 5N HCl and extracted with CHCl3 (3×). Evaporation of the solvent afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@@H:10]([O:12][C:13]1[C:14]([NH2:25])=[N:15][CH:16]=[C:17]([C:19]#[C:20][Si](C)(C)C)[CH:18]=1)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@@H:10]([O:12][C:13]1[C:14]([NH2:25])=[N:15][CH:16]=[C:17]([C:19]#[CH:20])[CH:18]=1)[CH3:11]
Reactant: C[C@H](Oc1cc(C#C[Si](C)(C)C)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cnc(N)c(O[C@@H](C)c2c(Cl)ccc(F)c2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
(S)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(2-(trimethylsilyl)ethynyl)-2-aminopyridine (10.6 g, 26.7 mmol) was dissolved in methanol (50 mL), potassium carbonate (7.38 g, 53.4 mmol) was added, and the reaction was stirred overnight at room temperature. TLC test showed that the raw materials were completely reacted. The reaction liquid was concentrated under reduced pressure, extracted with ethyl acetate; the organic layer was washed with water and saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, concentrated; the residue was purified via silica gel column chromatography [petroleum ether:ethyl acetate=3:1 (v:v)] to yield the target product as yellow solid (8.2 g, yield: 94%).
Reaction SMILES: [S:1]1[CH:3]([C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)=[CH2:5])[CH2:2]1>C1C=CC=CC=1>[C:9]1([CH3:12])[CH:8]=[CH:7][C:6]([C:4]2[CH2:3][S:1][CH2:2][CH:5]=2)=[CH:11][CH:10]=1
Reactant: C=C(c1ccc(C)cc1)C1CS1
Solvent: c1ccccc1
Product: Cc1ccc(C2=CCSC2)cc1
Yield: 83.9 %

Procedure:
A solution of 1,2-epithio-3-p-tolyl-3-butene (40 mg, 0.23 mmol) and Cu(hfacac)2 (1.1 mg, 2.3 μmol) in benzene (1 mL) was heated at 80° C. for 2 h in a pressure tube. Concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography (n-pentane) to give 2,5-Dihydro-3-(p-tolyl)thiophene (34 mg, 85%) as a white solid.
Reaction SMILES: [S:1]([NH2:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].O[CH:13]=[C:14]1[C:23](=[S:24])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH3:25])[CH:21]=2)[O:16][CH:15]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[S:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:13]=[C:14]2[C:23](=[S:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH3:25])[CH:21]=3)[O:16][CH:15]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:7][CH:8]=1)(=[O:10])(=[O:2])[NH2:11]
Reactant: Cc1ccc2c(c1)C(=S)C(=CO)C(c1ccccc1)O2
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CCO
Product: Cc1ccc2c(c1)C(=S)C(=CNc1ccc(S(N)(=O)=O)cc1)C(c1ccccc1)O2

Procedure:
To a refluxing solution of 13 g sulfanilamide in 800 ml absolute ethanol is added 21 g 3-hydroxymethylidene-6-methyl-thioflavanone. After sixteen hours the reaction mixture is cooled and the crystals which separated are collected. After recrystallisation in a mixture of acetone and light petroleums, pure 3-(N-4-sulfamoylphenyl)aminomethylidene-6-methyl-thioflavanone is obtained as yellow crystals; m.p. 210°-213° C.
Reaction SMILES: [CH:1]1([S:4]([NH:7][CH2:8][CH:9]2[CH2:13][CH:12]([C:14]([O:16]C(C)(C)C)=[O:15])[CH:11]([CH2:21][CH3:22])[CH2:10]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[CH:1]1([S:4]([NH:7][CH2:8][CH:9]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH:11]([CH2:21][CH3:22])[CH2:10]2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CCC1CC(CNS(=O)(=O)C2CC2)CC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC1CC(CNS(=O)(=O)C2CC2)CC1C(=O)O
Yield: 99.5 %

Procedure:
tert-Butyl 4-(cyclopropanesulfonamidomethyl)-2-ethylcyclopentanecarboxylate (0.080 g, 0.241 mmol, prepared using K from Preparation #21 and cyclopropylsulfonyl chloride) in TFA (4 mL, 51.9 mmol) was stirred at about 25° C. for about 1 h. The organic solvent was removed under reduced pressure to yield crude 4-(cyclopropanesulfonamidomethyl)-2-ethylcyclopentanecarboxylic acid (0.066 g, 100%): LC/MS (Table 1, Method b) Rt=1.81 min; MS m/z: 276 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]=[O:10].[BH4-].[Na+].CCOC(C)=O.CCCCCC>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][OH:10]
Reactant: O=CCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OCCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1F
Temperature: 25 °C
Yield: 100.4 %

Procedure:
To a 0° C. solution of (3-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-acetaldehyde (372 mg, 1.31 mmol) in THF/MeOH (10/3 mL) is added portion-wise sodium borohydride (100 mg, 2.62 mmol) and warmed to room temperature. After 1 h TLC (30% EtOAc/hexane) indicates complete consumption of starting material. The reaction mixture is concentrated and the residue is partitioned between EtOAc (100 mL) and 0.2N HCl (20 mL). The aqueous layer is extracted with a second portion of EtOAc (50 mL). The combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound (374 mg, quant.). 1NMR (400 MHz, CDCl3) δ ppm: 7.68 (q, 4H, J=8.2 Hz), 7.38-7.32 (m, 2H), 7.29 (d, 1H, J=11.0 Hz), 3.92 (t, 2H, J=6.6 Hz), 2.97 (t, 2H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([CH2:30][OH:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(OCC)(=O)C>CS(C)=O.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([CH:30]=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)N[C@H](C=O)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 6.7 %

Procedure:
N-(4-Chlorophenylsulfonyl)-L-valyl-L-tryptophanol (1.5 g) was dissolved in dimethyl sulfoxide (20 ml) and dichloromethane (15 ml), and triethylamine (2.0 g) was added. The solution was stirred at room temperature while adding a solution (20 ml) of sulfur trioxide-pyridine complex (2.1 g) in dimethyl sulfoxide, which was followed by stirring for 1 hr. After the completion of the reaction, ethyl acetate was added. The mixture was washed with dilute hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative TLC plate (developing solvent: hexane-ethyl acetate, 1:1, v/v) to give 0.10 g of N-(4-chlorophenylsulfonyl)-L-valyl-L-tryptophanal (Compound 48) as white crystals. [Step 1]
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH:14]=O)=[CH:8]2)[C:2]([CH3:4])=[O:3].C[O:17][C:18](=[O:39])[CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[NH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH:14]=[CH:19][C:18]([OH:39])=[O:17])=[CH:8]2)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc2[nH]c(C=O)cc2c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc2[nH]c(C=CC(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
16 (340 mg, 0.7 mmol) was added to a solution of methyl(triphenylphosphoranylidene)acetate (2|57 mg, 0.77 mmol) in toluene (30 mL) and the reaction mixture was heated to reflux for 3 days. The solvent was removed after cooled to room temperature. Ethyl acetate (10 mL) was added to the residue and the resulted precipitate 17 was filtered. MS (ion spray) (M+H) 259. Without further purification 17 was dissolved in DMF (3 mL) and methanol (5 mL) was added. 3N NaOH solution (2 mL) was added and the reaction mixture was stirred overnight. The solvent was removed and water (10 mL) was added. The solution was neutralized using 20% HCl. The resulting precipitate was filtered and washed with water. 44 mg (26% yield) of yellow solid 18 was obtained. mp: 238°-239° C. 1H NMR (DMSO-d6, ppm): 12.25 (brs, 1 H, COOH), 11.42 (s, 1 H, NH), 9.74 (s, 1 H, NH), 7.88 (s, 1 H, Ar--H), 7.55-7.50 (d, 1 H, J=16.0 Hz, CH=CH), 7.28 (s, 2 H, Ar--H) 6.80 (d, 1 H, J=2.0 Hz, Ar--H), 6.44-6.40 (d, 1 H, J=15.8 Hz, CH=CH), 2.03 (s, 3 H, CH3), Anal. (C13H12N2O3 0.3H2O), C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[C:21]3Cl)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:27]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[C:21]3[NH2:27])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2cccc3c(Cl)nccc23)CC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2cccc3c(N)nccc23)CC1
Temperature: 150 °C
Reaction time: 20 h

Procedure:
A solution of Intermediate 130 (500 mg) in dioxane (2.5 ml) was added with 28% aqueous ammonia solution (2.5 ml) and stirred at 150° C. for 20 hours in a sealed tube. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with dioxane (6 ml), 2 N aqueous sodium hydroxide (2 ml) and di-t-butyl dicarbonate (655 mg) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=30:1) to obtain the title compound (95.0 mg).