Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:11]=2[CH:29]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1>>[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:11]=3[CH:29]=2)=[CH:33][CH:32]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=C1Nc2ccc(OCCCCCl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Product: Cc1ccc(SCCCCOc2ccc3c(c2)C(C2CCCCC2)(C2CCCCC2)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dicyclohexyl-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.
Reaction SMILES: [Cl:1][CH:2]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[Cl:11])[NH2:7].[CH3:17][CH:18]1[CH2:28][CH2:27][C:21]2[C:22]([O:24][C:25](=O)[C:20]=2[CH2:19]1)=[O:23]>>[Cl:11][C:10]1[CH:9]=[CH:8][C:6]([N:7]2[C:25](=[O:24])[C:20]3[CH2:19][CH:18]([CH3:17])[CH2:28][CH2:27][C:21]=3[C:22]2=[O:23])=[CH:5][C:4]=1[CH2:3][CH:2]([Cl:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(Cl)Cc1cc(N)ccc1Cl
Reactant: CC1CCC2=C(C1)C(=O)OC2=O
Product: CCOC(=O)C(Cl)Cc1cc(N2C(=O)C3=C(CC(C)CC3)C2=O)ccc1Cl

Procedure:
2.60 g of 3-(2-chloro-2-ethoxycarbonyleth-1-yl)-4-chloroaniline and 1.65 g of 4-methyl-3,4,5,6-tetrahydrophthalic anhydride were refluxed for 6 hours. After the mixture had been cooled and evaporated down, the residue was taken up in ethyl acetate and the solution was washed three times with water. The organic phase was dried over Na2SO, and then evaporated down. Yield 3.0 g (75%); 1H-NMR (in d6-DMSO/TMS): δ [ppm]=0.96 (d; 3H), 1.05 (t; 3H), 1.64-2.08 (m; 3H), 2.15-2.70 (m; 4H), 3.20-3.55 (m; 2H), 4.14 (q; 2H), 4.78 (dd; 1H), 7.26 (d; 1H), 7.34 (s; 1H), 7.55 (d; 1H).
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[C:3]([C:2]([NH:1][C:25](=[S:26])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=1)([CH3:18])[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12]2)=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2cc([N+](=O)[O-])ccc2n1
Product: CC(C#N)(Cn1cc2cc([N+](=O)[O-])ccc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(5-nitro-2H-indazol-2-yl)propionitrile (62 mg, described in Example 96) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (96 mg, 84%). MS (ES): M/Z [M+H]=450. 1H NMR: (400 MHz, DMSO-d6): 1.72 (s, 3H), 5.22 (q, 2H), 7.81 (d, J=9.5 Hz, 1H), 7.86-7.90 (m, 2H), 7.92-7.97 (m, 2H), 8.00-8.05 (m, 1H), 8.83 (s, 1H), 8.95 (d, J=1.9 Hz, 1H) and 9.07 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C1COCC1.CCOC(C)=O>[CH:14]1([NH:17][C:2]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1cccc([N+](=O)[O-])c1NC1CC1
Temperature: 60 °C

Procedure:
A mixture of 2-bromo-3-nitrobenzoic acid (1.0 g, 4.1 mmol), cyclopropanamine (0.85 mL, 12.2 mmol) in THF (10 mL) under N2 was heated at 60° C. for 1 day. The reaction mixture was diluted with EtOAc, washed with water, brine, and dried over magnesium sulfate. The organic phase was concentrated in vacuo. The residue, as a crude 2-(cyclopropylamino)-3-nitrobenzoic acid: LC-MS (ESI) m/z 223.0 [M+H]+. The crude product was subjected to the next reaction without further purification.
Reaction SMILES: [CH:1]([C:4]1[N:13]([CH3:14])[C:12](=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[N:17])[CH:10]=2)[N:5]=1)(C)[CH3:2].[Br:18]Br.O>C(O)(=O)C>[Br:18][CH:1]([C:4]1[N:13]([CH3:14])[C:12](=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[N:17])[CH:10]=2)[N:5]=1)[CH3:2]
Reactant: BrBr
Reactant: CC(C)c1nc2ccc(C#N)cc2c(=O)n1C
Solvent: O
Solvent: CC(=O)O
Product: CC(Br)c1nc2ccc(C#N)cc2c(=O)n1C
Temperature: 25 °C
Yield: 73.1 %

Procedure:
To a solution 2-isopropyl-3-methyl-4-oxo-3,4-dihydro-quinazoline-6-carbonitrile (0.35 g, 1.64 mmol) in glacial acetic acid (10 ml) cooled in an ice bath was added dropwise a solution of bromine (0.52 g, 3.28 mmol) in glacial acetic acid (5 ml). After addition was complete, the reaction was heated to reflux for 18 hours. At which time it was allowed to cool to room temperature. Water was then added to the solution and the mixture was extracted with dichloromethane. The organic layer was then washed with 10% sodium bisulfite solution, and then washed with saturated brine (2×10 ml). The combined organic phase was collected and dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a brown crude product. The resulting residue was purified by silica gel chromatography with 50% dichloromethane in hexane. The product was collected and was dried under reduced pressure to give 2-(1-Bromo-ethyl)-3-methyl-4-oxo-3,4-dihydro-quinazoline-6-carbonitrile (Yield 0.35 g, 73.1%). 1H NMR (400 MHz, CDCl3): δ 2.20 (d, 3H, J=6.54 Hz), 3.78 (s, 3H), 5.17 (q, 1H, J=12.88, 6.54 Hz), 7.81 (d, 1H, J=8.84 Hz), 7.94 (dd, 1H, J=8.34, 2.02 Hz), 8.61 (d, 1H, J=2.02 Hz). MS m/z calc. 291.0, found (ESI); 292.0 (M+1)+. Retention time 2.95 minutes.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:29])[CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:26])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][CH:8]([NH2:27])[C:7]1=[O:28].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])(=O)C.[Na+].[BH3-]C#N.[Na+].Cl>CO.CCOC(C)=O.C(Cl)Cl>[CH3:2][O:3][C:4](=[O:29])[CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:26])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][CH:8]([NH:27][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:7]1=[O:28]
Reactant: COC(=O)CN1C(=O)C(N)CN(C(=O)CCc2ccccc2)c2ccccc21
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CN1C(=O)C(NCc2ccccc2)CN(C(=O)CCc2ccccc2)c2ccccc21
Reaction time: 2.5 h
Yield: 39.6 %

Procedure:
A solution of (3S) 2-oxo-3-amino-5-(3-phenylpropionyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid methyl ester hydrochloride (560 mg, 1.34 mmol), benzaldehyde (146 mg, 1.34 mmol) and sodium acetate (220 mg, 2.68 mmol) in methanol (20 ml) was treated with 4A sieves (2 g) and NaCNBH3 (168 mg, 2.68 mmol). The reaction was stirred for 2.5 h, acidified with 10 aq. HCl to pH 2 and washed with Et2O (2×75 ml). The organic layers were concentrated in vacuo to give an oil. Chromatography (flash, SiO2, 0 to 35% EtOAc/CH2Cl2) gave 250 mg (40%) of 602v as a clear oil.
Reaction SMILES: [CH2:1]1[C:20]2[C:4](=[CH:5][C:6]3[S:12][C:11]4[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:10]=4[CH:9]=[CH:8][C:7]=3[CH:19]=2)[CH2:3][CH2:2]1.[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[CH2:1]1[C:20]2[C:4](=[CH:5][C:6]3[S:12][C:11]4[CH:13]=[C:14]([C:17]5[NH:23][N:22]=[N:21][N:18]=5)[CH:15]=[CH:16][C:10]=4[CH:9]=[CH:8][C:7]=3[CH:19]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc2c(c1)Sc1cc3c(cc1C=C2)CCC3
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C1=Cc2cc3c(cc2Sc2cc(-c4nnn[nH]4)ccc21)CCC3
Yield: 64.1 %

Procedure:
A solution of 2,3-dihydro-1H-benzo[b]indeno[5,6-f]thiepin-7-carbonitrile (2.10 g, 7.625 mmole) in dimethylformamide (31.5 ml) stirred under reflux (oil-bath at 170°-180° C.) in an atmosphere of argon was treated with a mixture of sodium azide (743 mg, 11.44 mmole) and ammonium chloride (612 mg, 11.44 mmole). An equal portion of sodium azide and ammonium chloride was added after 1 hour and then at 30 minute intervals seven portions of a mixture of sodium azide (247 mg, 3.81 mmole) and ammonium chloride (204 mg, 391 mmole) were added. After heating for a further 1 hour the reaction mixture was allowed to cool, then it was diluted with water (150 ml) and acidified. An extraction with methylene chloride (250 ml) was performed. The methylene chloride solution was extracted with a mixture of water (100 ml) and 5N sodium hydroxide (10 ml) and after a further wash with water the combined aqueous extract on acidification yields 1.555 g of title compound.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH:11](S(C)=O)SC)=[CH:4][C:3]=2[O:2]1.C[O:18]CCOC>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH:11]=[O:18])=[CH:4][C:3]=2[O:2]1
Reactant: CSC(Cc1ccc2c(c1)OCO2)S(C)=O
Reactant: COCCOC
Product: O=CCc1ccc2c(c1)OCO2
Yield: 45 %

Procedure:
2.08 g of methyl 2-(3,4-methylenedioxyphenyl)-1-methylthioethyl sulfoxide was dissolved in 20 ml. of 1,2-dimethoxyethane, and with the addition of 1.71 g of cupric chloride dihydrate, the solution was refluxed for 15 minutes. The solvent was removed by evaporation at reduced pressure, and 50 ml. of methylene chloride was added. The insoluble water was removed by filtration. The filtrate was concentrated at reduced pressure, and subjected to column chromatography (silica gel, benzene) to give 722 mg of (3,4-methylenedioxyphenyl)acetaldehyde in a yield of 45%.
Reaction SMILES: Cl.Cl.[CH:3]([N:16]1[CH2:21][C@@H:20]2[CH2:22][C@H:17]1[CH2:18][NH:19]2)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS([C:27]1[N:32]=[CH:31][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:28]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[CH:3]([N:16]1[CH2:21][C@@H:20]2[CH2:22][C@H:17]1[CH2:18][N:19]2[C:27]1[N:28]=[CH:29][C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][N:32]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(C(c2ccccc2)N2C[C@@H]3C[C@H]2CN3)cc1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)c1cnc(N2C[C@@H]3C[C@H]2CN3C(c2ccccc2)c2ccccc2)nc1
Reaction time: 2 h
Yield: 64.3 %

Procedure:
Title compound 201 (0.250 g, 0.741 mmol), ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate (0.122 g, 0.529 mmol), potassium carbonate (0.280 g, 2.645 mmol) and DME (5 mL) were combined. The reaction mixture was stirred at 50 oC for 2 hours. The mixture was cooled down and quench with water. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography eluting with 0% to 30% ethyl acetate in hexanes to afford title compound 202 (0.141 g, 64%). LRMS (ESI): (calc) 414.21 (found) 415.0 (MH)+.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].[CH2:7]([O:9][C:10](=[O:14])[CH2:11][C:12]#[N:13])[CH3:8]>C(O)C.C(N(CC)CC)C>[NH2:4]/[C:3](/[C:2]([Cl:6])([Cl:5])[Cl:1])=[C:11](/[C:12]#[N:13])\[C:10]([O:9][CH2:7][CH3:8])=[O:14]
Reactant: CCOC(=O)CC#N
Reactant: N#CC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)/C(C#N)=C(\N)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 87.3 %

Procedure:
To a mixture of trichloroacetonitrile (38 mL, 0.38 mol) and cyanoacetic acid ethyl ester (20 mL, 0.2 mol) in ethanol (63 mL) was added triethylamine (1 mL, 7 mmol). The reaction mixture began to turn red and an exotherm occurred after ˜1 minute. The reaction mixture was cooled to 0° C., then stirred for two hours while slowly warming to room temperature. The reaction mixture was concentrated in vacuo to a red oil, which was taken up in DCM, filtered through a plug of silica gel, and concentrated in vacuo to afford 44.95 g (90%) of (Z)-ethyl 3-amino-4,4,4-trichloro-2-cyanobut-2-enoate as a colorless oil that slowly solidified to a white solid. 1H NMR (400 MHz, CDCl3) δ 10.19 (s, 1H), 6.85 (s, 1H), 4.31 (q, J=7.1, 1H), 1.37 (t, J=7.1, 3H).
Reaction SMILES: [ClH:1].Cl.Br[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C@@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20]3[N:29]=[C:28]([N:30]([CH3:32])[CH3:31])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH2:15][CH2:14]2)=[C:6]([O:33][C:34]([F:37])([F:36])[F:35])[CH:5]=1.Cl>CCO.CCOC(C)=O.[Pd]>[ClH:1].[ClH:1].[CH3:32][N:30]([CH3:31])[C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([NH:19][C@H:16]2[CH2:17][CH2:18][C@@H:13]([NH:12][CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][CH:4]=[CH:5][C:6]=3[O:33][C:34]([F:37])([F:36])[F:35])[CH2:14][CH2:15]2)[N:29]=1
Reactant: CN(C)c1nc(N[C@H]2CC[C@@H](NCCc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)c1nc(N[C@H]2CC[C@@H](NCCc3ccccc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of cis-N2-{4-[2-(4-bromo-2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-N4,N4-dimethyl-quinazoline-2,4-diamine dihydrochloride obtained in step B of example 37 (250 mg, 0.4 mmol) in EtOH (5 mL) was added 10% Pd/C (75 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 17 hr, filtered, poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 50% EtOAc in hexane) to give a colorless oil. To a solution of above oil in EtOAc (4 mL) was added 4 M hydrogen chloride in EtOAc (0.25 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated. The residue was suspended with Et2O (15 mL) and stirred at ambient tempareture for 1 hr. The solid was collected by filtration, washed with Et20, and dried under reduced pressure to give cis-N4,N4-dimethyl-N2-{4-[2-(2-trifluoromethoxy-phenyl)-ethylamino]-cyclohexyl}-quinazoline-2,4-diamine dihydrochloride (104 mg, 48%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH:13]=[CH2:14])[N:10]=[C:9]([CH:15]=[CH2:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[N:10]=[C:9]([CH2:15][CH3:16])[CH:8]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1cc(C(=O)OC(C)(C)C)cc(C=C)n1
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C(=O)OC(C)(C)C)cc(CC)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.8 %

Procedure:
To a solution of 2,6-divinyl-isonicotinic acid tert-butyl ester (703 mg, 3.04 mmol) in MeOH (15 mL), Pd/C (50 mg, 10% Pd) is added and the mixture is stirred under 1 atm of H2 at rt for 15 h. The catalyst is filtered off and the filtrate is evaporated. The remaining residue is purified by CC on silica gel eluting with heptane:EA 5:1 to give 2,6-diethyl-isonicotinic acid tert-butyl ester (635 mg) as a colourless oil; LC-MS: tR=1.05 min, [M+1]+=236.13.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[CH:20]=[CH:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.O1CCOCC1>Cl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[N:22]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(C3CCNCC3)n2)n1
Yield: 13 %

Procedure:
A mixture of tert-butyl 4-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]piperidine-1-carboxylate; B; 110 mg; 0.2332 mmol in hydrogen chloride (4 mol/L) in 1,4-dioxane (2.0 ml, 8.0 mmol) and 1,4-dioxane 2.0 mL was stirred at RT 18 h. The reaction was concentrated and submitted for reverse phase HPLC to give 166 (13 mg) in 13% yield. 1H NMR (400 MHz, DMSO) δ 9.80 (s, 1H), 9.46 (s, 1H), 9.34 (s, 1H), 8.71 (s, 1H), 8.63 (s, 1H), 7.99 (t, J=7.9 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.29 (d, J=7.5 Hz, 1H), 3.15 (d, J=12.0 Hz, 2H), 2.94 (tt, J=11.8, 3.5 Hz, 1H), 2.76-2.67 (m, 2H), 2.66 (s, 3H), 2.01 (d, J=12.1 Hz, 2H), 1.85 (qd, J=12.2, 3.8 Hz, 2H). MS (ESI) m/z: 372.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:24][C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][NH2:33])[CH:28]=[CH:29][CH:30]=1.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:33][CH2:32][CH2:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=1)=[O:8]
Reactant: COc1cccc(C(=O)O)c1
Reactant: Cc1cccc(CCN)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NCCc2cccc(C)c2)c1
Reaction time: 1 h

Procedure:
A solution of 3-methoxybenzoic acid (5.2 g, 0.034 mol) and carbonyldiimidazole (5.5 g, 0.034 mol) in THF (200 ml) was stirred in a flask protected from moisture. To this solution was added 4.6 g (0.034 mol) of 2-(3-methylphenyl)ethylamine in a small volume of THF. Stirring was continued for 1 h and then the reaction mixture was poured into 500 ml of water and extracted twice with 100 ml portions of methylene chloride. The methylene chloride solution was washed with 5% HCl, 10% Na2CO3, and water. Evaporation of this solution afforded the amide G1 (8.7 g, 94%) as a viscous oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[C:48]=[S:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:47]([C:48]([N:43]1[CH2:44][CH2:45][CH:40]([C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:39])[CH2:41][CH2:42]1)=[S:49])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: S=C=Nc1ccccc1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCN(C(=S)Nc2ccccc2)CC1
Yield: 28 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and isothiocyanatobenzene as starting materials in 28% yield. LCMS for C31H30ClN7OS (M+H)+: m/z=584.2.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)=[CH:21][CH:20]=2)([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)(O)=[O:2].CN(C)C=O.S(Cl)([Cl:42])=O>>[Cl:42][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)=[CH:21][CH:20]=2)([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)=[O:2]
Reactant: O=C(O)c1ccc(C(c2ccc(Oc3cccc([N+](=O)[O-])c3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C(c2ccc(Oc3cccc([N+](=O)[O-])c3)cc2)(C(F)(F)F)C(F)(F)F)cc1

Procedure:
146 g (0.3 mol) of 2-(4-carboxyphenyl)-2-[4-(3-nitrophenoxy)phenyl]hexafluoropropane were suspended in 714 g of thionyl chloride, 1 cm3 of dimethylformamide was added, and the mixture was refluxed till evolution of gas was no longer observed. The thionyl chloride was removed by distillation, and the residue was recrystallized from acetonitrile.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([OH:26])=[O:25])=[C:13]2[CH3:27])=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.[C:29]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([O:26][CH3:29])=[O:25])=[C:13]2[CH3:27])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(S(N)(=O)=O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)CC1=C(C)C(=Cc2ccc(S(N)(=O)=O)cc2)c2ccc(OC)cc21
Yield: 202.4 %

Procedure:
A solution of the E acid 3a (950 mg) and toluenesulfonic acid monohydrate (200 mg) in methanol (60 ml) was refluxed for 1-2 hours. The solution was filtered and the filtrate was concentrated to 30 ml. After cooling at 0° to 5° for 1 hour, the crystals were collected and dried. The crude ester was recrystallized from acetonitrile to give the pure E methyl 1-(4-aminosulfonylphenyl)methylene-5-methoxy-2-methyl-1H-3-indenylacetate 5a (850 mg, 86%): m.p. 169.5°-171.0° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[C:27]([CH:35]=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)#[N:2].[O-:37]Cl=O.[Na+].CC(O)(C)C.O>CCO>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[C:27]([C:35]([OH:37])=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:23][CH2:24]2)[CH2:15][CH2:14]1)#[N:2]
Reactant: [O-][Cl+][O-]
Reactant: Cn1cc([C@H]2CC[C@H](N3CCN(c4cc(C=O)cc5cccnc45)CC3)CC2)c2cc(C#N)ccc21
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(C)(C)O
Product: Cn1cc([C@H]2CC[C@H](N3CCN(c4cc(C(=O)O)cc5cccnc45)CC3)CC2)c2cc(C#N)ccc21

Procedure:
The trans was obtained by the process described for Example 73 by combining 0.30 g (0.60 mmol) 8-[4-[(Trans)-4-(5-cyano-1-methyl-1H-indole-3-yl)cyclohexyl]-1-piperazinyl]-6-quinolinecarbaldehyde, 0.48 g (5.5 mmol) NaClO2, 0.48 g (4.1mmol) NaH2PO4, 24 mL t-BuOH, 3 mL CH3CHC(CH3)2, and 6 ml water. The product fractions were pooled, striped, and treated with 54 mg (0.60 mmol) of (CO2H)2 in absolute EtOH to give 97mg (0.16 mmol, a 10% yield) mp: 275° C. MS (ES) m/z: 494 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccc(Cl)cc2C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1

Procedure:
In analogy to example 162, step 2, 3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)-1-(6-methoxypyridin-3-yl)propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colorless solid, MS (ESI+)=432,019 [M+H]+.