Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH2:4][CH2:5]N(C)C)C.[CH2:9]([S:16][C:17]#[CH:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>Cl[Cu].CC(C)=O>[CH2:9]([S:16][C:17]#[C:18][C:10]#[C:9][S:16][CH2:17][C:5]1[CH:4]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CSCc1ccccc1
Reactant: CN(C)CCN(C)C
Agent: Cl[Cu]
Solvent: CC(C)=O
Product: C(C#CSCc1ccccc1)#CSCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of trimethylsilylacetylene (10 mL, 71 mmol) in ether (100 mL) under argon at -78° C. was slowly added n-BuLi (2.5 M in hexanes, 28.3 mL, 71 mmol). The solution was warmed to -20° C. and then cooled to -70° C. Sulfur powder (2.3 g, 72 mmol), in a flask connected to the reaction vessel by Gooch tubing, was poured into the reaction mixture. The mixture was warmed to 10° C., becoming a pale yellow solution. Benzyl bromide (8.5 mL, 72 mmol) was added to quench the reaction. The resulting solution was stirred overnight. The solution was quenched by addition of saturated NH4Cl solution (30 mL), and the mixture was extracted with ether (3×50 mL), the combined ether layers washed with brine (1×30 mL) and water (1×30 mL). The organic phase was dried (MgSO4) and concentrated in vacuo affording a yellow oil (16.5 g; 100%): GC EI-MS: 220 (M+). Without further purification a solution of this yellow oil (16.5 g, 72 mmol) in THF (150 mL) was treated with water (10 mL) followed by THF solution (100 mL) of tetra-n-butylammonium fluoride (TBAF; 1.1 eq). The resulting reddish brown solution was stirred for 2.5 h, and then washed with brine (3×50 mL), dried (MgSO4, concentrated in vacuo, and distilled (39°-42° C./0.015 mmHg) affording benzylthioacetylene (2) as a yellow oil (10 g, 96%): 1H NMR (acetone-d6) δ 7.5-7.25 (m, 5 H) 4.05 (s, 2 H) 3.38 (s, 1 H); 13C NMR (acetone-d6 δ 137.89, 129.93, 129.38, 128.56, 85.43, 74.82, 40.07; IR 2041, 3286 cm-1. A mixture of CuCl (0.27 g), TMEDA (0.41 mL) and acetone (40 mL) were placed in a three-necked flask, and with stirring O2 was bubbled through the dark green solution for a few minutes. Compound 2 (8 g, 60 mmol) was added dropwise to the stirred green solution which was maintained at room temperature with a water bath. After 3 h, acetone was removed in vacuo and ice cold HCl solution (0.3 mL conc HCl diluted to 50 mL) was added to the concentrate. The suspension was extracted with ether (1×100, 2×50 mL). The combined ether layers were washed with brine (2×50 mL) and water (1×35 mL), dried (MgSO4), and concentrated in vacuo affording 3 as a yellow solid (7.7 g, 97%).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][C:14]#[N:15].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([C:7]2[N:8]=[N:9][N:10]([CH2:13][C:14]#[N:15])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCl
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCn1nnc(-c2ccccc2)n1

Procedure:
To 146 mg (1 mmol) of 5-phenyltetrazole and 75 mg (1 mmol) of chloroacetonitrile was added three mL of dimethyl formamide. The resulting solution was stirred, then 158 mg (1 mmol) of potassium carbonate was added and the mixture was further stirred at room temperature for 18 hours. Twenty-five mL of water was then added and the mixture was extracted twice with 25 mL of ethyl acetate. Evaporation of the extracts left the crude product, which was purified by silica gel chromatography, leaving an oil that was pure by NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[C@H:12]([CH2:13][OH:14])[CH2:11][CH2:10][S:9]2(=[O:16])=[O:15])[CH:5]=[C:4]([F:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=2)[CH2:22][CH2:21]1)=[O:19].[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH3:40])(=O)=O.O>O1CCCC1>[F:17][C:4]1[CH:5]=[C:6]([N:8]2[C@H:12]([CH2:13][O:14][CH3:40])[CH2:11][CH2:10][S:9]2(=[O:15])=[O:16])[CH:7]=[C:2]([F:1])[C:3]=1[C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=2)[CH2:24][CH2:25]1)=[O:19]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4[C@H](CO)CCS4(=O)=O)cc3F)CC2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H]1CCS(=O)(=O)N1c1cc(F)c(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.8 %

Procedure:
(S)-[2,6-difluoro-4-(3-hydroxymethyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (270 mg) described in Example 35 was dissolved in tetrahydrofuran, sodium hydride (48 mg) was added, and the mixture was stirred at room temperature for 30 min. Then, to the reaction mixture was added methyl tosylate (203 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (5 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([P:10](=[O:15])([O:13][CH3:14])[O:11][CH3:12])[P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17]>CN(C=O)C.C1COCC1>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH:3]([P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6])[P:10](=[O:15])([O:11][CH3:12])[O:13][CH3:14])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: COP(=O)(CP(=O)(OC)OC)OC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COP(=O)(OC)C(Cc1ccc([N+](=O)[O-])cc1)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 30 %

Procedure:
Sodium hydride (1.02 g, 25.4 mmol) was added in portions to a stirring solution of tetramethyl methylenebisphosphonate in DMF (40 mL). After 30 min a solution of 4-nitrobenzylbromide (5.00 g, 23.1 mmol) in THF (5 mL) was added and the resulting mixture was stirred at room temperature for 4.5 hr. The reaction was quenched by the addition of saturated aqueous NH4Cl (20 mL). After the addition of water (100 mL) the product was extracted with EtOAc and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated at reduced pressure. The crude product was purified by silica gel chromatography (0% to 10% MeOH in EtOAc) resulting in 12 as a colorless solid (2.55 g, 30%). 1H NMR (400 MHz, CDCl3) δ 2.65 (tt, J=6.5, 23.8, 1H), 3.31 (dt, J=6.5, 16.5, 2H), 3.73 (d, J=7.0, 6H), 3.75 (d, J=7.0, 6H), 7.42 (d, J=8.9, 2H), 8.15 (d, J=8.9, 2H).
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[F:11][C:12]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:4]1[N:3]([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:12]=3[F:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)CN1
Reactant: O=C(O)Cn1nccn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)CN1C(=O)Cn1nccn1
Yield: 63 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4R)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 52, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (77 mg, 63%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.00 (s, 1H), 7.80 (s, 2H), 7.60-7.52 (m, 2H), 7.47-7.36 (m, 1H), 7.29-7.14 (m, 4H), 7.11-6.92 (m, 6H), 5.49 (q, 2H), 4.54-4.46 (m, 1H), 3.92-3.80 (m, 1H), 2.86-2.63 (m, 3H), 2.20-1.88 (m, 2H). MS (EI) for C28H24F3N5O3. found 535.9 (MH+).
Reaction SMILES: O.[CH3:2][O:3][C:4]1[C:18]([CH:19]=O)=[CH:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=1.[C:21]1([C@H:27]2[C@@H:32]([NH2:33])[CH2:31][CH2:30][CH2:29][NH:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4]1[C:18]([CH2:19][NH:33][C@H:32]2[CH2:31][CH2:30][CH2:29][NH:28][C@H:27]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: COc1cc2sc(-c3ccccc3)nc2cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2sc(-c3ccccc3)nc2cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A round bottom flask equipped with a Dean Stark water separator and condenser was charged with 0.96 grams (3.6 mmol) 6-methoxy-2-phenyl-benzothiazol-5-aldehyde and 0.57 grams (3.2 mmol) of (2S, 3S)-2-phenyl-3-amino-piperidine in 90 mL of hours. The reaction mixture was evaporated in vacuo and the residue was redissolved in 90 mL of 1,2-dichlorethane. The solution was treated with 0.89 grams (4.2 mmol) of sodium triacetoxyborohydride and was stirred for 16 hours at room temperature. The reaction mixture was diluted with methylene chloride (600 mL) and washed with 150 mL of bicarbonate solution, 150 mL of water and finally with 150 mL of saturated brine solution. The organic phase was dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel eluting with 97/2/1 methylene chloride, methanol, conc. aqueous ammonium hydroxide solution. Product containing fractions were combined, evaporated and crystallized from hot ether--MeOH to afford 1.1 grams (80%) of the desired product.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[N:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccc(F)nc1
Product: Cc1c2n(c3c(-c4ccc(F)nc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (74 mg, 90%), MS (ISP) m/z=330.5 [(M+H)+], mp 270° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 6-fluoro-pyridin-3-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][CH3:18])[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=S)=[C:25]([CH3:32])[CH:24]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][C:25]=3[CH3:32])[N:17]([CH3:18])[C:12]=2[C:11]=1[C:19]#[N:20])([CH3:9])[C:6](=[O:8])[CH3:7])[CH3:2]
Reactant: Cc1cc(F)ccc1N=C=S
Reactant: CCOC(=O)C(C)(C(C)=O)c1ccc(N)c(NC)c1C#N
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C(C)=O)c1ccc2nc(Nc3ccc(F)cc3C)n(C)c2c1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.5 %

Procedure:
To a glass scintillation vial was added 2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acid ethyl ester (0.247 g, 0.854 mmol), followed by THF (5 mL) and a magnetic stir bar. To the resulting solution was added 4-fluoro-1-isothiocyanato-2-methyl-benzene (0.191 g, 1.14 mmol) and the solution was stirred at room temperature for 48 h. To the solution was then added mercuric oxide (0.222 g, 1.02 mmol), and stirring was continued at room temperature for 24 h. The brown suspension was then filtered through a ½ inch thick pad of silica, washed with THF, and concentrated to dryness. The resulting deep red solid was further purified by silica gel chromatography, eluting with ethyl acetate:hexane (0% -100%) to provide 2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyric acid ethyl ester (0.204 g, 56%) as a deep red solid. ESMS (m/z): (M+1)+ found, 423.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:15][C:14]=3[O:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:8][CH2:7]1)C.[OH-].[Na+].O1CCCC1>C(O)C>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:31][CH:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][C:4]([OH:38])=[O:3])[CH2:7][N:8]=2)=[CH:19]3)=[CH:22][CH:23]=1)(=[O:28])=[O:29]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A mixture of ethyl(2-{5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (424 mg), 1M aqueous sodium hydroxide solution (2 mL), tetrahydrofuran (10 mL), and ethanol (10 mL) was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was washed with ethyl acetate. The aqueous layer was neutralized with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was solidified with diethyl ether, and the obtained solid was washed with diethyl ether-hexane to give the title compound (270 mg, yield 67%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:30][CH2:31][CH2:32][C@@H:3]12.[Li+].[OH-]>O1CCOCC1>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:30][CH2:31][CH2:32][C@@H:3]12
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 85.8 %

Procedure:
(S)-ethyl 4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate (280 mg, 0.643 mmol) was suspended in 1,4-Dioxane (3.22 mL) and treated with 1N LiOH (3.215 mL, 3.22 mmol). The reaction mixture was stirred at room temperature for 23 h. The reaction mixture was concentrated in vacuo until most of the dioxane was gone and acidified with HCl (4.5 N) until a thick precipitate resulted. It was filtered off, washed with water and dried in vacuum to afford (S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (225 mg, 0.552 mmol, 86% yield) as a brown solid. [M+H] calc'd for C22H25N5O3, 408. found, 408.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=3)[CH:3]=[CH:2]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1ccccc1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Product: COC(=O)c1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using methyl 1H-indole-6-carboxylate and iodobenzene: ESMS m/e: 252.0 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14])(=O)=O.[CH2:15]([O:17][CH2:18][CH2:19][NH2:20])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH2:6][NH:20][CH2:19][CH2:18][O:17][CH2:15][CH3:16]
Reactant: CS(=O)(=O)OCCc1ccccc1Br
Reactant: CCOCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOCCNCCc1ccccc1Br

Procedure:
3.5 g of 2-(2-bromophenyl)ethyl methanesulfonate, 5.59 g of 2-ethoxyethanamine, 8.67 g of potassium carbonate and 70 cm3 of tetrahydrofuran are stirred under the reflux of the solvent under an inert atmosphere for 48 h. The heating is stopped, then the reaction mixture is filtered. The insoluble material is washed twice with ethyl acetate. The filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). The product obtained is purified by flash chromatography over silica (column: 330 g; particle size: 20-40 μm, spherical; eluent: 100% ethyl acetate to 90% ethyl acetate/10% methanol gradient). After concentrating the fractions under reduced pressure, 2.45 g of 2-(2-bromophenyl)-N-(2-ethoxyethyl)ethanamine are obtained in the form of a yellow oil.
Reaction SMILES: [NH:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].CO[CH:16](OC)[CH2:17][C:18](=O)[CH3:19].Cl>C(O)C>[CH3:19][C:18]1[CH:17]=[CH:16][N:1]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)[N:2]=1
Reactant: NNc1nc2ccccc2c(=O)[nH]1
Reactant: COC(CC(C)=O)OC
Agent: Cl
Solvent: CCO
Product: Cc1ccn(-c2nc3ccccc3c(=O)[nH]2)n1

Procedure:
35.2 g (0.2 mole) of 2-hydrazino-4(3H)-quinazolinone, 500 ml of ethanol and 31.68 g (0.24 mole) of 4,4-dimethoxy-butan-2-one are boiled under reflux for 4.5 hours. The initial suspension has then dissolved. The same volume of 2 N HCl at 50° is added at 50°, whereupon a precipitate soon forms. After warming at 50° for a total of 40 minutes, the 2-(3-methyl-1H-pyrazol-1-yl)-4(3H)-quinazolinone is isolated by filtration with suction. The crude product (35.9 g of melting point 162° to 165° C.) is recrystallized from ethanol and then has a melting point of 165° to 166° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH3:13][N:14](C=O)[CH3:15]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:14]([CH3:15])[CH3:13])=[N:7][N:6]=[CH:5]2
Reactant: CN(C)C=O
Reactant: Clc1nncc2cc(Br)ccc12
Solvent: CCOC(C)=O
Product: CN(C)c1nncc2cc(Br)ccc12

Procedure:
A solution of 6-bromo-1-chloro-phthalazine (2 g) and dimethylamino (8 mL, 2M solution in THF) in DMF (30 mL) was stirred at 85° C. for 3 h. The reaction was then diluted with ethyl acetate (100 mL) and washed with water (2×100 mL), and brine (100 mL). Column chromatography (Hexanes/EtOAc) afforded the desired product (1.0 g) as a brown solid. TLC Rf 0.3 (EA). 1H-NMR (CDCl3) δ: 3.21 (s, 6H), 7.86 (dd, 1H), 7.95 (d, 1H), 7.99 (d, 1H), 8.99 (s, 1H).
Reaction SMILES: [C:1]([Si:5]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17](Cl)=[N:18][CH:19]=[C:14]2[C@H:13]([CH3:21])[N:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:11]1=[O:30])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([Si:5]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17]([NH:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[N:18][CH:19]=[C:14]2[C@H:13]([CH3:21])[N:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:11]1=[O:30])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1
Reactant: COc1ccc(N2C(=O)N([C@H](C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3nc(Cl)ncc3[C@@H]2C)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)N([C@H](C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3nc(Nc4ccccc4)ncc3[C@@H]2C)cc1

Procedure:
A solution of 1-[2-(tert-butyl-diphenyl-silanyloxy)-1-(R)-methyl-ethyl]-7-chloro-3-(4-methoxy-phenyl)-4-(S)-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.28 g; 0.45 mmol) (from Example 15a supra) and aniline (0.10 mL; 1.21 mmol) (Aldrich) in toluene (0.25 mL, dried over molecular sieves) was heated in an oil bath at 110° C. for 2 hours. The reaction was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by flash chromatography (Biotage 40L; 40:60 ethyl acetate-hexanes) to give 1-[2-(tert-butyl-diphenyl-silanyloxy)-1-(R)-methyl-ethyl]-3-(4-methoxy-phenyl)-4-(S)-methyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.23 g; 73.0%). This material showed an e.e. of ˜95%.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[S:13][C:14]1[C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[S:17][CH:18]=1.C1COCC1.O.O>C(OCC)(=O)C>[S:17]1[CH:18]=[C:14]([S:13][C:7]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=2[C:5]([OH:23])=[O:4])[C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]1=2
Reactant: COC(=O)c1cc(C)ccc1Sc1csc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(Sc2csc3ccccc23)c(C(=O)O)c1
Temperature: 25 °C

Procedure:
LiOH (480 mg, 20 mmol) is added to 2-(benzo[b]thiophen-3-ylsulfanyl)-5-methyl-benzoic acid methyl ester (630 mg, 2 mmol) in 16 mL mixture of THF/water (3:1). The reaction mixture is refluxed for 2 hours and cooled to room temperature. Water and ethyl acetate is added and the organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give the title compound, which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2ccccc2)cc1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2ccccc2)c2ccc(OCCN3CCCC3)cc12

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.379 g, 0.619 mmol) and pyrrolidine (1.0 mL, 12 mmol) in THF (80 mL) was stirred at 70° C. in a sealed tube for 3 hours. The reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80° C. in vacuo for 25 minutes gave 1-benzyl-3-(naphthalene-1-sulfonyl)-5-(2-pyrrolidin-1-yl-ethoxy) -1H-indazole as a yellow-orange solid (0.259 g, 82.0% mmol). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 13 hours in vacuo at 81° C. The result was the hydrochloride as a buff foam (0.267 g); Mass Spectrum (+EI, [M+H]+) m/z 512.