Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][C:3]=1[CH:9]=O.C(N(CC)CC)C.[SH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>ClCCl>[CH3:8][C:5]1([CH3:7])[CH2:6][C:2]2[S:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9][C:3]=2[CH2:4]1
Reactant: CCOC(=O)CS
Reactant: CC1(C)CC(Cl)=C(C=O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(s1)CC(C)(C)C2

Procedure:
To a solution of 131b (33.0 g, crude) in dichloromethane (400 mL) and triethylamine (60 g, 600 mmol) was added ethyl 2-mercaptoacetate (19.2 g, 160 mmol). See FIG. 15. The reaction mixture was heated at reflux for 6 h. It was then concentrated under reduced pressure. The residue was dissolved in ethanol (400 mL) and triethylamine (60 g, 600 mmol). The mixture was heated at reflux for 12 h. It was concentrated again under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 40:1 petroleum ether/ethyl acetate to 131c as a yellow solid (18.0 g, 32%, over two steps). MS-ESI: [M+H]+ 225.3. 1H NMR (500 MHz, DMSO-d6) δ 7.49 (s, 1H), 4.32 (q, J=7.0 Hz, 2H), 2.72 (s, 2H), 2.56 (s, 2H), 1.35 (t, J=7.0 Hz, 3H), 1.22 (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[C:12]1([CH:18](Br)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:19][CH:18]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(Br)c1ccccc1
Product: CC(c1ccccc1)n1cc(C=O)c2ccccc21

Procedure:
The same procedures used in Example 1 were repeated except for using 870 mg of indole-3-carbaldehyde and α-phenylethyl bromide in place of the benzyl bromide used in Example 1 to give 1.42 g of 1-(α-methylbenzyl)indole-3-carbaldehyde as an orange-colored oily substance. The yield thereof was found to be 95%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([O:18][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:31])=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:31])=[O:14])=[C:11]([O:18][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1C(C)Oc1cc(OCc2ccccc2)ccc1C(=O)O
Solvent: ClCCl
Product: Cc1ccccc1C(C)Oc1cc(OCc2ccccc2)ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 4-benzyloxy-2-(1-o-tolylethoxy)benzoic acid (2.5 g) in dichloromethane (50 mL) is treated with a 2 M solution of oxalyl chloride in dichloromethane (6.5 mL) and stirred at 25° C. for 3.5 hours. The mixture is evaporated to give 4-benzyloxy-2-(1-o-tolylethoxy)benzoyl chloride as a brown liquid (2.73 g).
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[CH2:10][C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:13].C(N(C(C)C)CC)(C)C.[Br:23][CH2:24][CH2:25]Br>CC#N>[Br:23][CH2:24][CH2:25][O:1][N:2]1[C:11](=[O:12])[CH2:10][C:5]2([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][C:3]1=[O:13]
Reactant: O=C1CC2(CCCC2)CC(=O)N1O
Reactant: BrCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CC2(CCCC2)CC(=O)N1OCCBr
Reaction time: 7 h

Procedure:
To a solution of 8-hydroxy-8-azaspiro[4.5]decan-7,9-dione (30 g) in 600 ml of dry CH3CN were added diisopropylethylamine (57 ml) and 1,2-dibromoethane (42.4 ml). The mixture was heated to 70° with stirring. After 7 hours, heating was discontinued and the mixture was stirred at room temperature for 48 hours.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20](=O)[CH2:21]Cl)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]([NH2:27])=[S:26].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:27][C:25]1[S:26][CH:21]=[C:20]([C:14](=[N:13][O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:24]=1
Reactant: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)c1csc(N)n1
Temperature: 40 °C
Yield: 29.2 %

Procedure:
A mixture of ethyl 2-(2-benzoyloxyethoxyimino)-4-chloro-3-oxobutyrate (syn isomer, 29 g.), thiourea (7.76 g.), sodium acetate (8.37 g.), water (75 ml.) and ethanol was stirred at 40° C. for an hour. The reaction mixture was treated in a conventional manner to give ethyl 2-(2-aminothiazol-4-yl)-2-(2-benzoyloxyethoxyimino)acetate (syn isomer, 9 g.).
Reaction SMILES: Cl[C:2]1[CH:31]=[CH:30][CH:29]=[C:28](Cl)[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[O:33]1C2C=CC=C(C(NC3C(C(O)=O)=NNC=3)=O)C=2[O:36][CH2:35][CH2:34]1>>[N:22]1([CH2:21][C:19]2[CH:18]=[CH:17][C:15]3[NH:16][C:12]([C:8]4[C:7]([NH:6][C:4]([C:3]5[C:28]6[O:36][CH2:35][CH2:34][O:33][C:29]=6[CH:30]=[CH:31][CH:2]=5)=[O:5])=[CH:11][NH:10][N:9]=4)=[N:13][C:14]=3[CH:20]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: O=C(Nc1c[nH]nc1C(=O)O)c1cccc2c1OCCO2
Reactant: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1cccc2c1OCCO2

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), but using 4-[(2,3-dihydro-benzo[1,4]dioxine-5-carbonyl)-amino]-1H-pyrazole-3-carboxylic acid to give 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-amide (39 mg) as a pink solid. (LC/MS: Rt 1.99, [M+H]+ 461.23).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl>O.O1CCOCC1>[CH2:19]([O:18][C:16]([NH:15][CH2:14][C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]([OH:27])=[O:4])=[O:26])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccccc1NC(=O)CNC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1C(=O)O
Reaction time: 8 h

Procedure:
Lithium hydroxide (55 mg, 1.32 mmol) in water (0.8 mL), was added to a solution of the benzoate (1) (300 mg, 0.88 mmol) in dioxane (4 mL). After stirring overnight, the reaction mixture was concentrated at 40° C. to give a viscous oil, which was treated with 10% aqueous hydrochloric acid (3 mL), with the resulting emulsion formed being extracted with ethyl acetate (4×). The organic phases were combined, dried (MgSO4) and concentrated to give the title benzoic acid (2) quantitatively as a white solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:15]([OH:17])=O)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([C:15]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[O:17])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: Nc1nnn[nH]1
Reactant: COc1ccc2nc(C(=O)O)c(OC)nc2c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2nc(C(=O)Nc3nnn[nH]3)c(OC)nc2c1

Procedure:
3,6-Dimethoxy-2-quinoxalinecarboxylic acid (Example 12c) (2 g) and N,N'-carbonyldiimidazole (1.4 g) in tetrahydrofuran (50 ml) were heated under reflux for 15 minutes. 5-Amino-1H-tetrazole (0.8 g) in dimethylformamide (5 ml) was added and the mixture was heated under reflux for a further 30 minutes. The solid that crystallised from the solution on cooling was collected and dried. It had m.p. 250°-251° (d) (59%).
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=O)[NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>O>[S:1]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=[S:19])[NH:4][CH2:3][CH2:2]1
Reactant: O=C1NCCSc2ccsc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: c1ccncc1
Product: S=C1NCCSc2ccsc21

Procedure:
acb) 1.0 g of 3,4-dihydro-thieno[2,3-f][1,4]thiazepin-5(2H)-one was heated under reflux for 5 hours together with 15 ml of pyridine and 1.35 g of phosphorus pentasulfide. After cooling the mixture was poured into 90 ml of water and the crystals were removed by filtration,. After chromatography on silica gel, the product was recrystallized from ethyl acetate. There was obtained 3,4-dihydro-thieno-[2,3-f][1,4]thiazepine-5(2H)-thione as yellow crystals of m.p. 138°-139°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:16](=[N:17][CH:18]=[N:19][C:20]=3[NH2:22])[NH:15][N:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:23]([C@@H:25]1[CH2:29][C@@H:28](O)[CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])#[CH:24].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>C1COCC1>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([C@@H:28]3[CH2:27][N:26]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[C@H:25]([C:23]#[CH:24])[CH2:29]3)[N:14]=[C:13]([C:12]#[C:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[C:21]=12
Reactant: C#C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: COc1cc(C#Cc2n[nH]c3ncnc(N)c23)cc(OC)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#C[C@@H]1C[C@H](n2nc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-((3,5-Dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (14 mg) obtained in Example 1 (Step 1), (2S,4R)-tert-butyl 2-ethynyl-4-hydroxypyrrolidine-1-carboxylate (15 mg) synthesized by the method disclosed in WO2005/007083, and triphenylphosphine (23 mg) were suspended in THF (1.0 ml). DIAD (18 μl) was added to the suspension, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and dissolved in a solution of DMSO. The resulting solution was purified by preparative reversed-phase HPLC purification (water/acetonitrile (0.1% formic acid)) to obtain the title compound as a colorless, amorphous substance (5.0 mg). Physical properties: m/z [M+H]+ 489.2
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(OC(N(C)[C@@H](C)C(N[C@H]1C2(CCOCC2)OC2C=CC=CC=2N(C[C:35]2[C:44]([O:45][CH3:46])=[CH:43][CH:42]=[C:41]3[C:36]=2[CH:37]=[CH:38][C:39]([C:47](O)=[O:48])=[CH:40]3)C1=O)=O)=O)(C)(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:46][O:45][C:44]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[CH:40]=[C:39]([C:47]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:48])[CH:38]=[CH:37]2
Reactant: COc1ccc2cc(C(=O)O)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C2(CCOCC2)Oc2ccccc21
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc2cc(C(=O)NS(C)(=O)=O)ccc2c1
Reaction time: 2 h
Yield: 255.3 %

Procedure:
Methanesulfonamide (10.9 mg, 115 μmol, Eq: 1.25) was added to a mixture of 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-5 (4H)-yl)methyl)-6-methoxy-2-nap hthoic acid (59.4 mg, 91.7 μmol, Eq: 1.00), EDCI (22.0 mg, 115 μmol, Eq: 1.25) and DMAP (14.0 mg, 115 μmol, Eq: 1.25) in DCM (5 mL). After 2 h, the mixture was diluted with DCM, washed with 1 M HCl, brine, dried over Na2SO4 and concentrated to afford 5-((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-5 (4H)-yl)methyl)-6-methoxy-N-(methylsulfonyl)-2-naphthamide (65.4 mg) as a white foam which was used without purification.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11]C(C)(C)C)=O)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23](C(Cl)=O)=[CH:22][CH:21]=1>>[C:20]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([C:9]([N:7]2[CH2:8][C:4](=[N:3][O:2][CH3:1])[CH2:5][C@H:6]2[C:16]([O:18][CH3:19])=[O:17])=[O:11])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 31 %

Procedure:
Following the general methods as outlined in Example 4, starting from 1-tert-butyl 2-methyl(2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate and [1,1′-biphenyl]-4-carbonyl chloride, the title compound was isolated, after flash-chromatography, as a mixture of two isomers as an oil in 31% yield (99% purity by HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:12][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Br)ccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a solution of 5-bromo-2-methyl-benzoic acid (9.9 g, 46 mmol) in DMF (100 mL) was added K2CO3 (7.6 g, 55 mmol) and CH3I (20 g, 140 mmol) slowly. After stirring at room temperature for 4 h, the solvent was removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over Na3SO4. The solvent was removed under vacuum to afford 5-bromo-2-methylbenzoic acid methyl ester (8.6 g, 82%), which was used in next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=2.1, 1H), 7.50 (d, J=2.1, 1H), 7.50 (dd, J=8.1, 2.1, 1H), 7.12 (d, J=8.1, 1H), 3.89 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2C(N)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].IC.[CH3:22][N:23]([CH:25]=O)[CH3:24]>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:25]([N:23]([CH3:22])[CH3:24])=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(N)c2sc(N)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1ccc(N(C)C)c2sc(N)nc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a stirred solution of 2.00 g (1.02 mmol) 4-methoxy-benzothiazole-2,7-diamine in 30 ml DMF at room temperature was added 4.25 g (3.07 mmol) potassium carbonate and the mixture heated to 50° C. A solution of 0.64 ml (1.02 mmol) iodomethane in 10 ml DMF was then added dropwise over 3 h and stirring continued for a further 1 h at 50° C. The mixture was then filtered and the filtrate concentrated in vacuo. Flash chromatography (20/1 dichloromethane/methanol) afforded 600 mg (26%) 4-methoxy-N7,N7-dimethyl-benzothiazole-2,7-diamine as a yellow solid, ES-MS m/e (%): 224 (M+H+, 100); 540 mg (25%) 4-methoxy-N7-methyl-benzothiazole-2,7-diamine as a yellow solid, ES-MS m/e (%): 210 (M+H+, 100) and 340 mg (17%) recovered starting material.
Reaction SMILES: Cl.NN=CC1C=CC([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([CH2:21][CH2:20][CH:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]3)[CH2:13][CH2:12]2)=O)=CC=1.[CH:30]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)=C>C(#N)C>[N:35]1[CH:36]=[CH:37][C:32]([CH2:30][CH2:9][N:11]2[CH2:16][CH2:15][C:14]3([CH2:21][CH2:20][CH:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]3)[CH2:13][CH2:12]2)=[CH:33][CH:34]=1
Reactant: C=Cc1ccncc1
Reactant: CCOC(=O)CC1CCC2(CC1)CCN(C(=O)c1ccc(C=NN)cc1)CC2
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)CC1CCC2(CC1)CCN(CCc1ccncc1)CC2

Procedure:
A solution of 0.48 g (2.0 mmol) of the intermediate from Example 1. Step C and 0.21 g (2.0 mmol) 4-vinylpyridine in 6 ml acetonitrile were heated at 80° C. over night. The solvent was removed under reduced pressure, and the remaining solid title compound was purified by stirring several times with tert.-butylmethylether, filtered with suction, and dried in vacuo.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:7][NH:6][C:5]1=[S:14].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:29])=[C:20]([C:22]2[O:26][N:25]=[C:24]([CH2:27]Cl)[N:23]=2)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CC#N>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:29])=[C:20]([C:22]2[O:26][N:25]=[C:24]([CH2:27][S:14][C:5]3[N:4]([CH2:3][CH2:2][OH:1])[C:8]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[N:7][N:6]=3)[N:23]=2)[CH:21]=1
Reactant: OCCn1c(-c2cccs2)n[nH]c1=S
Reactant: Fc1ccc(Cl)cc1-c1nc(CCl)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: OCCn1c(SCc2noc(-c3cc(Cl)ccc3F)n2)nnc1-c1cccs1
Yield: 62.7 %

Procedure:
4-(2-Hydroxyethyl)-5-(2-thienyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (101 mg), 5-(5-chloro-2-fluorophenyl)-3-(chloromethyl)-1,2,4-oxadiazole (116 mg), and potassium carbonate (86 mg) was stirred in a mixture of DMF (2 ml) and MeCN (15 ml) at r.t. for 3 h before concentration to dryness and washing of the residue with water, and then with EtOAc, to provide 122 mg of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[NH3:20].O>CO>[C:10]1([C:8]2[C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=3[NH:5][C:3](=[O:4])[CH2:2][N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CBr)Nc1ccccc1C(=O)c1ccccc1
Reactant: N
Solvent: O
Solvent: CO
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
A suspension of 2-bromoacetamidobenzophenone (275 g, 0.86 mol) in methanol (1 L) was treated with a solution of saturated ammonia in methanol (3 L), and the resulting solution was stirred at ambient temperature for 6 h, then was heated at reflux for an additional 4 h. After cooling, water (500 mL) was added, and the solution was concentrated by evaporation to about 1 L in volume, yielding crystalline 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one (20) (200.7 g, 98%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C@:16]23[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:17]2[C@@H:18]2[C@@:31]([CH3:34])([CH2:32][CH2:33]3)[C@@:30]3([CH3:35])[C@@H:21]([C@:22]4([CH3:47])[C@@H:27]([CH2:28][CH2:29]3)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]3[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:34][C@:31]12[C@@:30]3([CH3:35])[C@@H:21]([C@:22]4([CH3:47])[C@@H:27]([CH2:28][CH2:29]3)[C:26]([CH3:36])([CH3:37])[C:25]([C:38]3[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19][C@@H:18]1[C@H:17]1[C@H:48]([C:51]([CH3:53])=[CH2:52])[CH2:49][CH2:50][C@:16]1([NH:15][CH2:14][CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[CH2:33][CH2:32]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC3CCCN(C(=O)OC(C)(C)C)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCC3CCCNC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 80.8 %

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((1-(tert-butoxycarbonyl)piperidin-3-yl)methylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (0.019 g, 0.026 mmol) in DCM (1 mL) was added TFA (0.25 mL, 3.24 mmol). The mixture was stirred at rt for 1.75 h. Then, the mixture was concentrated under reduced pressure and purified by prep HPLC to give the title compound (14.2 mg, 0.021 mmol, 81% yield) as a white solid. LCMS: m/e 627.6 (M+H)+, 1.50 min (method 2). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (2H, d, J=8.2 Hz), 7.30 (2H, d, J=7.9 Hz), 5.37 (1H, s), 4.85 (1H, d, J=5.5 Hz), 4.75 (1H, s), 2.98-3.83 (6H, m), 2.82-2.91 (1H, m), 2.57-2.72 (1H, m), 0.85-2.33 (44H, m).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[CH2:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=1.B>C1COCC1.C(OCC)C>[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=1
Reactant: CCc1ccc(C(=O)NCc2ccc(F)cc2F)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1ccc(CNCc2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
N-(2,4-Difluorobenzyl)-4-ethylbenzamide (6.20 g, 22.5 mmol) was dissolved in freshly distilled THF (220 mL) and cooled in an ice bath under an argon atmosphere. Borane (28 mL of a 2 M solution of the dimethylsulfide complex in diethyl ether) was added and the ice bath was removed after 15 minutes. The reaction mixture was refluxed overnight and was then allowed to cool to room temperature. The reaction was quenched at 0° C. by careful addition of 10% HCl (11 mL) and the mixture was stirred at room temperature for three hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and aqueous 2 M K2CO3 (200 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×200 mL) and the combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 5.56 g (94%) of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#N)[CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1.[H-].C([Al+]CC(C)C)C(C)C.C[OH:39].Cl>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[N:12]=[CH:13][C:14]([S:17]([C:20]2[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=2)[CH:26]=[O:39])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: CO
Reactant: N#Cc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A suspension of 2-[(E)-2-(2,4-difluorophenyl)vinyl]-5-[(3-cyanophenyl)-sulfonyl]pyridine (Example 33, 200 mg, 0.52 mmol) in dichloromethane (2 mL) and toluene (2 mL) was cooled in an ice-bath while stirring under nitrogen. Diisobutylaluminium hydride (1.5M in toluene, 0.38 mL, 0.57 mmol) was added and the reaction stirred at 0° C. then allowed to warm to room temperature over 3 hours. Methanol was added then 1N aqueous hydrochloric acid and the mixture left to stand overnight. The products were extracted into dichloromethane, dried over MgSO4 and concentrated in vacuo. Dry flash column chromatography using 3% methanol/dichloromethane followed by recrystallisation from methanol gave 3-({6-[(E)-2-(2,4-difluorophenyl)vinyl]pyridin-3-yl}sulfonyl)benzaldehyde (93 mg, 46%). δH (400 MHz, CDCl3): 9.07 (1H, d, J=2.2 Hz), 8.23–8.09 (3H, m), 7.89–7.81 (2H, m), 7.74–7.66 (1H, m), 7.61–7.55 (1H, m), 7.48–7.44 (1H, m), 7.25–7.16 (2H, m), 6.93–6.83 (2H, m); m/z (ES+) 386 [MH+].