Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH:19]=[O:20])[C@H:12]([CH3:18])[CH2:13][C:14]([F:17])([F:16])[F:15])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:21][Mg]Br.CCOC(C)=O.CCCCCC>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH:19]([OH:20])[CH3:21])[C@H:12]([CH3:18])[CH2:13][C:14]([F:15])([F:16])[F:17])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: C[C@H](CC(F)(F)F)[C@@H](C=O)NS(=O)(=O)c1ccc(Cl)s1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)[C@@H](NS(=O)(=O)c1ccc(Cl)s1)[C@H](C)CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-formyl-2-methylbutyl]thiophene-2-sulfonamide (prepared as in Example 16, 1.0 g, 2.86 mmol) in THF (10 mL) was stirred under nitrogen at 0° C. Methyl magnesium bromide (3.0 M in ethyl ether, 1.9 mL, 5.71 mmol.) was added dropwise and the resulting solution was stirred for 1 h at 25° C. After this time period, the reaction was complete by TLC (1:2 EtOAc/hexane). The solution was quenched with saturated aqueous NH4Cl (10 mL) and extracted with ether (40 mL). The organic layer washed with brine (20 mL) and then dried over MgSO4 to obtain a crude oil (0.867 g). The crude product was purified by the Biotage Flash™ 60 chromatography system, eluent: 1:6 EtOAc-hexanes, to afford 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(1-hydroxyethyl)-2-methyl butyl]thiophene-2-sulfonamide as a colorless oil (0.495 g, 49.5%). Mass Spectrum (−ESI): 364 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:16]([CH3:17])[CH2:15][NH:14][C:13](=[O:18])[C@@H:12]1[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([Cl:34])=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.C(OCC)(=O)C>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[C@H:16]([CH3:17])[CH2:15][N:14]([CH2:23][C:24]2[CH:33]=[C:32]3[C:27]([C:28]([Cl:34])=[CH:29][CH:30]=[N:31]3)=[CH:26][CH:25]=2)[C:13](=[O:18])[C@@H:12]1[CH3:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CNC(=O)[C@H](C)N1C(=O)OCc1ccccc1
Reactant: Clc1ccnc2cc(CBr)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc3c(Cl)ccnc3c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 83 %

Procedure:
(2S, 6R)-2,6-Dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (750 mg, 2.86 mmol) is dissolved in 20 mL of THF and 2 mL of DMF. Sodium hydride (60%, 142.6 mg, 6.20 mmol) is added at 0° C., and the reaction is left to stir at room temperature for thirty minutes at which time the 7-bromomethyl-4-chloro-quinoline (952 mg, 3.72 mmol) is added. The reaction is complete after stirring for four hours. Ethyl acetate (200 mL) is added to the mixture, and the reaction is quenched with 3 mL of H2O. The two layers are separated, and ethyl acetate (2×30 mL) is used to extract and dried over magnesium sulfate. The residue after filtration and concentration is chromatographed on silica gel (60% EtOAc/Hexane) to give (2S,6R)-4-(4-chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.04 g, 83%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([O:30][CH:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1.O.C(=O)(O)[O-].[Na+]>[Si:1]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([O:30][CH:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]2)[CH:21]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(F)(F)F)n2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](OCc1cc(OC2CCNCC2)nc(C(F)(F)F)c1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-{[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.19 g, 0.23 mmol, from Step C) in 1,4-dioxane (2.0 mL) was added 4.0 M hydrogen chloride in dioxane (0.50 mL, 2.0 mmol). The reaction mixture was stirred for one hour. Additional 4.0 M hydrogen chloride in dioxane (0.50 mL, 2.0 mmol) was added and stirring was continued for two hours. The mixture was diluted with water, saturated sodium bicarbonate was used to adjust the pH to between 7 and 8, and then the product was extracted with two portions of DCM. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-15% MeOH in DCM afforded product as an oil (62 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 7.69-7.62 (m, 4H), 7.48-7.34 (m, 6H), 7.14-7.11 (m, 1H), 6.91 (s, 1H), 5.17 (tt, J=8.7, 4.0 Hz, 1H), 4.71 (s, 2H), 3.13 (dt, J=12.7, 4.5 Hz, 2H), 2.78 (ddd, J=12.7, 9.7, 3.0 Hz, 2H), 2.07 (dq, J=12.2, 4.1 Hz, 2H), 1.67 (dtd, J=13.0, 9.4, 3.9 Hz, 2H), 1.11 (s, 9H); LCMS (M+H)+: 515.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.CS(O[CH2:24][CH2:25][CH3:26])(=O)=O.[C:27](=[O:30])([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([O:30][C:27]1[CH:18]=[C:6]([CH2:7][CH2:8][CH2:9][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)[CH:5]=[CH:4][CH:3]=1)[CH2:25][CH3:26]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOS(C)(=O)=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1cccc(CCCOc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 234.4 %

Procedure:
Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (394 mg), propoxyphenyl)propyl methanesulfonate (1099 mg) and potassium carbonate (304 mg) were suspended in DMF (15 ml), and the resulting suspension was stirred at 70° C. for 5 hours. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, is the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain methyl 7-[3-(3-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (765 mg) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[S:15][C:16]([Cl:19])=[CH:17][N:18]=1.[SH:20][C:21]1[N:25]([CH3:26])[CH:24]=[N:23][N:22]=1>>[Cl:19][C:16]1[S:15][C:14]([NH:13][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([S:20][C:21]4[N:25]([CH3:26])[CH:24]=[N:23][N:22]=4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[N:18][CH:17]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Cn1cnnc1S
Reactant: Nc1ncc(Cl)s1
Product: Cn1cnnc1Sc1ccc2ncnc(Nc3ncc(Cl)s3)c2c1

Procedure:
The compound of Example 21 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, 2-amino-5-chlorothiazole and 3-mercapto-4-methyl-1,2,4-triazole.
Reaction SMILES: O1CCCCC1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C@@H:14]([OH:18])[C:15]([OH:17])=O.[C:19]([C:21]1[CH:35]=[CH:34][C:24]([CH2:25][NH:26][C:27](=[O:33])[C@@H:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)=[CH:23][CH:22]=1)#[N:20].ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:27](=[O:33])[C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:15](=[O:17])[C@@H:14]([CH2:13][C:8]2[CH:7]=[CH:12][CH:11]=[CH:10][CH:9]=2)[OH:18])=[CH:34][CH:35]=1)#[N:20]
Reactant: N#Cc1ccc(CNC(=O)[C@@H]2CCCN2)cc1
Reactant: O=C(O)[C@H](O)Cc1ccccc1C1CCCCO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(CNC(=O)[C@@H]2CCCN2C(=O)[C@H](O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.5 g (20.4 mmol) of o-tetrahydropyranyl-3-phenyl-D-lactic acid (WO 93/18060) were dissolved in 30 ml of DMF and, successively, 5.4 g (20.4 mmol), N-(p-cyanobenzyl)prolin-amide, 3.3 g (20.4 nmol) of N-hydroxybenzotriazole, 3.0 g DIPEA and 4.33 g (20.6 mmol) of dicyclohexylcarbodiimide were added. The mixture was left to stir at room temperature for 48 h. The precipitated urea was filtered off with suction and then the solvent was substantially removed under reduced pressure, and the residue was mixed with 50 ml of water and extracted with ethyl acetate. After washing with water, NaHCO3 solution and drying over Na2SO4, the ethyl acetate was distilled off, the remaining oily residue was dissolved in methanol, and the pH was. adjusted to 2 with p-toluenesulfonic acid. This solution was left to stand at room temperature for 6 h. The methanol was then distilled off, and the residue was taken up in ethyl acetate and washed with water, 5% strength citric acid and NaBCO3 solutions. The residue obtained after drying over Na2SO4 and removal of the solvent by distillation was purified by column chromatography (eluent: methylene chloride/acetone/methanol, 45/5/2). 2.5 g of white crystals were obtained, and these melted at 108° C.-110° C. after crystallization from an ether/hexane mixture.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([O:25]C)=O)[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](=[O:25])[NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:17]=[CH:16]4)[C:10]([CH3:27])=[C:9]([F:28])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC(=O)NCc2ccccc2)c1

Procedure:
Example 132 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 123) and benzylamine to give the title compound (0.008 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:20][OH:21])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH2:18][CH3:19])=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(O)(=O)C>C1C=CC=CC=1>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:21][CH2:20]1)=[CH:9][C:10]([O:17][CH2:18][CH3:19])=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3
Reactant: CCOc1cc2c(cc1OCC)C(C(CO)CO)NCC2
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOc1cc2c(cc1OCC)C1C(CO)COC(c3ccccc3)N1CC2
Yield: 70 %

Procedure:
10 mmoles (2.8 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline and 11 mmoles (1.17 g) of freshly distilled benzaldehyde are refluxed in 50 ml of absolute benzene, in the presence of a catalytic amount of hydrochloric acid or acetic acid for 4 hours. The solvent is distilled off and the residual pale-yellow oil is crystallized by trituration with ether. The aimed compound is obtained in a yield of 70%.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:19]([NH:2][CH:3]([CH:8]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:9]([O:11][CH3:12])=[O:10])[C:4]([O:6][CH3:7])=[O:5])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(N)C(C(=O)OC)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.6 %

Procedure:
To a solution of 5 g (18.5 mmol) of 2-amino-3-phenyl-succinic acid, dimethyl ester hydrochloride in CH2Cl2 (100 mL) was added 7.7 mL (56 mmol) of TEA followed by 6.2 g (22.1 mmol) of trityl chloride. The reaction was stirred at rt for 2 days and then concentrated in vacuo. Et2O was added to the crude residue and the mixture was filtered through a pad of silica gel and concentrated in vacuo to give a colorless oil. The residue was purified by flash column chromatography on silica gel eluted with 3:1 hexanes:Et2O to yield 6 g of 2-(N-tritylamino)-3-phenyl-succinic acid, dimethyl ester as a white solid. The product was a 1.3:1 mixture of diastereomers as judged by 1H-NMR analysis.
Reaction SMILES: [C:1]1([C@@H:7]([C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20](S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(=O)CCC=C1>C1CCCCC1>[C:11]1([C@H:9]2[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:17]3([CH2:22][CH2:21][CH:20]=[CH:27]3)[O:10]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: O[C@@H](c1ccccc1)[C@@H](O)c1ccccc1
Agent: O=C1C=CCC1
Agent: c1cc[nH+]cc1
Solvent: C1CCCCC1
Product: C1=CC2(CC1)O[C@@H](c1ccccc1)[C@H](c1ccccc1)O2
Yield: 676.8 %

Procedure:
A solution of (S,S)-hydrobenzoin (10.0 g, 46.7 mmol), pyridinium p-toluene sulfonate (1.4 g, 5.6 mmol), 2-cyclopentene-1-one (20 mL, 238.7 mmol) and cyclohexane (200 mL) was heated under reflux for 4 h with a Dean-Stark trap to remove water formed during the reaction. The mixture was then cooled in an ice bath for 20 min, and the insolubles were filtered off through filter aid. The resulting solution was washed with a 10% aqueous potassium bicarbonate solution (2×25 mL) and water (2×25 mL), and then dried over anhydrous sodium sulfate. The dried solution was passed through a pad of silica gel 60 (26 g of 230-400 mesh). The pad was further eluted with additional hexanes (475 mL). The resulting solution was concentrated in vacuo to afford 2(S),3(S)-diphenyl-1,4-dioxa-spiro[4.4]non-6-ene (10.55 g, 81%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:13]2[N:25]=[CH:24][N:23]=[C:22]3[C:14]=2[C:15]2[CH2:16][CH2:17][C:18]4[N:28]([CH2:29][CH2:30]O)[N:27]=[CH:26][C:19]=4[C:20]=2[S:21]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:33][CH2:30][CH2:29][N:28]1[C:18]2[CH2:17][CH2:16][C:15]3[C:14]4[C:22]([S:21][C:20]=3[C:19]=2[CH:26]=[N:27]1)=[N:23][CH:24]=[N:25][C:13]=4[O:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccc(CCOc2ncnc3sc4c(c23)CCc2c-4cnn2CCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(CCOc2ncnc3sc4c(c23)CCc2c-4cnn2CCBr)cc1
Yield: 54.1 %

Procedure:
This compound was prepared in a similar fashion as described in Example 48 step 5 starting from 2-{6[2-(4-nitro-phenyl)-ethoxy]-4,5-dihydro-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluoren-3-yl}-ethanol (4.2 g, 9.6 mmol), carbontetrabromide (6.37 g, 19.20 mmol), and triphenyl phosphine (5.03 g, 19.20 mmol). The desire product was obtained as a light yellow solid (2.6 g) in 54% yield. LCMS RT=3.55 min; [M+H]+=500.1/502.0.
Reaction SMILES: C1([C:7]2[CH:8]=[C:9]([CH:34]=[CH:35][CH:36]=2)[CH:10]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[S:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[CH2:16][CH2:15]2)=O)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1.O.[CH:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[C:9]1([C:10]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:11][C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20](=[S:33])[C:21]3[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=3)[CH2:18][CH2:19]2)=[S:46])[CH:34]=[CH:35][CH:36]=[CH:7][CH:8]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(C(=S)N2CCN(C(=O)C=Cc3cccc(-c4ccccc4)c3)CC2)cc(OC)c1OC
Reactant: c1ccccc1
Solvent: O
Product: COc1cc(C(=S)N2CCN(C(=S)C=C(c3ccccc3)c3ccccc3)CC2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
A solution of 1.000 g of 1-(3-phenylcinnamoyl)-4-[3,4,5-trimethoxy(thiobenzoyl)]piperazine (prepared as described in Example 61) in 10 ml of benzene and 0.805 g of Lawesson's Reagent [consisting mainly of [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] was heated under reflux for 2 hours. At the end of this time, the reaction mixture was cooled to room temperature, poured into water and extracted twice with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure. The residue was purified by column chromatography through 30 g of silica gel eluted with a 3:1 by volume mixture of hexane and ethyl acetate, to give 1.010 g of the title compound as a yellow powder.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][C:51]1[CH:55]=[C:54]([CH:56]2[CH2:60][CH2:59][CH2:58][NH:57]2)[O:53][N:52]=1>>[C:28]([C:32]1[N:33]=[C:34]([N:57]2[CH2:58][CH2:59][CH2:60][CH:56]2[C:54]2[O:53][N:52]=[C:51]([CH3:50])[CH:55]=2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: Cc1cc(C2CCCN2)on1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: Cc1cc(C2CCCN2c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)on1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methyl-5-(pyrrolidin-2-yl)isoxazole. MS (m/e): 452.4
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:11]([CH:13]=[N+]=[N-])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[BrH:23].CCOCC>O1CCCC1.C(OCC)(=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:11]([CH2:13][Br:23])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: Br
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)CBr
Reaction time: 0.08 h

Procedure:
Boc-TyrCHN2 (0.40 g, 1.32 mmoles) was dissolved in 20 mL of tetrahydrofuran, and the resulting solution was cooled to about -10°. Anhydrous HBr: ether (2.3M, 0.58 mL, 1.3 mmoles) was added, and after about 5 minutes, solvent was evaporated, leaving a residue. The residue was dissolved in ethyl acetate, and the resulting solution was washed with water and saturated aqueous sodium chloride. The solution was then dried over anhydrous sodium sulfate and ethyl acetate was evaporated, yielding an oil. The oil was applied to a 2 cm column containing 10 g of silica gel, and the column eluted with chloroform. Eluate solvent was evaporated, and the remaining residue was triturated with hexane to yield crystalline Boc-TyrCH2Br (0.22 g, mp 109.5°-111°).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]2[C:9]([CH2:12][CH:13](N)CO)=[CH:10][NH:11][C:3]=12.[C:17]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:21])[CH2:18][CH2:19][CH3:20].B(F)(F)[F:29].CCOCC>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:17]1([CH2:18][CH2:19][CH3:20])[C:10]2[NH:11][C:3]3[C:4]([C:9]=2[CH2:12][CH2:13][O:21]1)=[C:5]([Br:8])[C:6]([F:29])=[CH:7][C:2]=3[CH3:1])[CH3:27]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: FB(F)F
Reactant: Cc1ccc(Br)c2c(CC(N)CO)c[nH]c12
Solvent: CCOCC
Solvent: ClCCl
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)cc(F)c(Br)c21
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 4-bromo-7-methyl tryptophol (400 mg g, 1.47 mmol) and ethyl butyrylacetate (0.28 mL, 1.76 mmol) in CH2Cl2 (5 mL) was added BF3.OEt2 (0.22 mL, 1.76 mmol) dropwise at room temperature. The solution was stirred for 2 hours and then washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 15% EtOAc in hexanes) to give 496 mg (82%) of title compound as a pale yellow solid. Mp=137-138° C.; 1H NMR (CDCl3): 300 MHz δ 9.73 (bs, 1H), 6.76 (d, J=10.1 Hz, 1H), 4.21 (m, 2H), 4.05 (m, 1H), 3.91 (m, 1H), 3.05-2.89 (m, 4H), 2.53 (s, 3H), 2.07 (m, 1H), 1.92 (m, 1H), 1.38 (m, 1H), 1.30 (t, J=6.98 Hz, 3H), 1.21 (m, 1H), 0.89 (t, J=7.08 Hz, 3H).
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[C:10]([CH2:11]Cl)=[CH:9][CH:8]=[CH:7][N:6]=1>CCO.O>[Cl:4][C:5]1[C:10]([CH2:11][C:1]#[N:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: [C-]#N
Reactant: ClCc1cccnc1Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1cccnc1Cl
Temperature: 25 °C

Procedure:
In a 3 L reactor, set for reflux under positive nitrogen pressure and using a bleach scrubber, was prepared a solution of potassium cyanide (68.32 g, 1.04M) in EtOH (136 mL) and water (255 mL). The mixture was heated to reflux, at which point a solution of 2-chloro-3-(chloromethyl)pyridine (Intermediate 1; 170.0 g, 1.04M) in EtOH (170 mL) was added dropwise over 30 minutes. The whole mixture was maintained at reflux for a further 150 minutes. The mixture was then allowed to cool just below boiling point and the equipment set for distillation. A total of 8.5 volumes of EtOH were removed. On cooling, half a volume of water was added. At a temperature of 40° C., the solution was seeded and crystallised instantaneously. The thick beige slurry was allowed to cool to ambient temperature and then to 0° C. This mixture was filtered, rinsed with cold water (2 vols) and dried at 45° C. in a vacuum oven overnight. The title compound was afforded as a beige solid in excellent yield and purity (126.9 g, 80%). δH (d6-DMSO, 300 MHz) 8.45 (1H, dd), 8.00 (1H, dd), 7.50 (1H, dd), 4.15 (2H, s). LCMS (ES)+ RT 2.15 min, m/e 153.01 & 155.01 (M+1 & M+3, Product).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([I:14])[CH:10]=[C:9]1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([I:14])[CH:10]=[C:9]1[C:15]([NH2:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(I)cc(C(=O)O)n1Cc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(I)cc(C(N)=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of EXAMPLE 129A (450 mg) in tetrahydrofuran (12 mL) at 0° C. was added carbonyldiimidazole (642 mg). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C. and ammonium hydroxide (3 mL) was added. The mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate, washed with brine and concentrated to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([CH:10]([NH2:12])[CH3:11])[CH:3]=1>CO.[C].[Pd]>[ClH:1].[CH3:9][O:8][C:5]1[N:6]=[N:7][CH:2]=[CH:3][C:4]=1[CH:10]([NH2:12])[CH3:11]
Reactant: COc1nnc(Cl)cc1C(C)N
Agent: [Pd]
Solvent: CO
Product: COc1nnccc1C(C)N
Product: Cl

Procedure:
1-(6-Chloro-3-methoxypyridazin-4-yl)ethanamine (67.3 mg, 0.36 mmol) and 10% palladium-carbon (50 wt %, 20 mg) were stirred in methanol (5 mL) under hydrogen atmosphere (1 atm) at room temperature for 16 hours. After filtering through celite, the filtrate was evaporated under reduced pressure. The resulting crude reaction product was used for the next step.