Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:18]>[OH-].[Na+].O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:3]=[C:2]([S:1][NH2:18])[S:6][N:5]=2)=[CH:8][CH:9]=1
Reactant: [NH4+]
Reactant: Sc1nc(-c2ccc(Cl)cc2)ns1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: NSc1nc(-c2ccc(Cl)cc2)ns1
Reaction time: 0.17 h

Procedure:
A solution of 11.5 g of 5-mercapto-3-(4-chlorophenyl)-1,2,4-thiadiazole in 200 ml of 5% sodium hydroxide and a solution prepared by diluting 100 ml of 5.25% NaOCl to 200 ml with water were added dropwise simultaneously to 450 ml of ammonium hydroxide solution while maintaining the mixture at 0° with an ice/methanol bath. The resulting mixture was stirred for 10 minutes and the solids were collected, washed with water and dried under high vacuum (with P2O5) to give 7.0 g of solid. Recrystallization of 3 g of this material from 1:1 cyclohexane/benzene (200 ml) gave 1.6 g of crystals, m.p.>150° dec.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.C(OCC)(=O)C.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:10]1[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Cc1csc2c(=O)[nH]cnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1csc2c(Cl)ncnc12
Temperature: 100 °C

Procedure:
A suspension of 7-methyl-3H-thieno[3,2-d]pyrimidin-4-one (2.1 g) in phosphorus oxychloride (10 mL) was heated at 100° C. for 1 hour. The reaction mixture was then cooled and poured into a mixture of ice-water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM) to afford 2.0 g of 4-chloro-7-methyl-thieno[3,2-d]pyrimidine.
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[O:7][C:8]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:9]=2[C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>CO>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][C:9]2[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:22])=[O:2])[O:7][C:8]=2[CH:19]=1
Reactant: CCCCCc1c(/C=C/C(=O)OC)oc2cc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCc1c(/C=C/C(=O)O)oc2cc(OC)ccc12
Yield: 88.8 %

Procedure:
As in Example 112, (E)-3-(6-methoxy-3-pentylbenzofuran-2-yl)-2-propenoic acid methyl ester (4.25 g) in methanol (25 mL) was treated with 2N sodium hydroxide solution (15 mL) at reflux for 1.25 hours. The crude reaction product was crystallized from ethyl acetate to provide 3.6 g of (E)-3-(6-methoxy-3-pentylbenzofuran-2-yl)-2-propenoic acid, mp 146°-147° C. Anal. Calcd for C17H20O4 : C, 70.81; H, 6.99 Found: C, 70.51; H, 6.89
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[C:16](OC1C=CC=CC=1C(Cl)=O)(=[O:18])[CH3:17]>>[CH3:1][C:2]1[C:3]([C:11]2[S:12][C:13]([C:16](=[O:18])[CH3:17])=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Product: CC(=O)c1ccc(-c2noc(C(F)(F)F)c2C)s1
Yield: 58 %

Procedure:
Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and 2-acetoxybenzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (15 then 25%) as eluant to afford product as a tan colored solid (80 mg, 58%). 1H NMR (CDCl3) 2.39 (d, J=1.3, 3H), 3.62 (s, 3H), 7.57 (d, J=4.0, 1H), 7.74 (d, J=4.0, 1H). 19F NMR −63.1. LC/MS 7.82 min, [M+1]+276.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[CH2:22]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[CH2:30]([N:29]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (44 mg), dibenzylamine (32 mg), 1H-1,2,3-benzotriazol-1-ol (31 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (39 mg) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with diethyl ether to give the title compound (53 mg, yield 78%) as pale-brown crystals. melting point 198-199° C.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:16])([CH3:15])[C:8]1[CH:9]=[CH:10][C:11](Cl)=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:63](=[NH:76])([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:63](=[N:76][C:11]1[CH:10]=[CH:9][C:8]([C:7]([CH3:16])([CH3:15])[O:6][SiH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:13][N:12]=1)([C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(Cl)nc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(N=C(c2ccccc2)c2ccccc2)nc1
Temperature: 80 °C

Procedure:
5-(tert-butyl dimethyl silanyloxymethyl)-2-chloro pyridine (5.58 g, 21.6 mmol), BINAP (0.4 g, 0.64 mmol) and benzophenone imine (4.7 g, 25.9 mmol) are dissolved in toluene (50 ml) and the solution is degassed with nitrogen. Sodium t-butoxide (2.91 g, 30.3 mmol) and Pd2(dba)3 (0.2 g, 0.22 mmol) are added and the solution is degassed once more. The mixture is heated at 80° C. for 6 h and then allowed to cool to rt. The mixture is diluted 4-fold with Et2O and then the solution is filtered. Evaporation of solvent in vacuo gave the crude benzhydrylidene-[5-(tert-butyl dimethyl silanyloxymethyl)-pyridin-2-yl]amine. This product is dissolved in MeOH (50 ml) and hydroxylamine (2.85 ml of a 50% aq. Solution, 46.5 mmol) and the solution stirred at rt for 16 h. The mixture is concentrated in vacuo and then the residue is dissolved in Et2O (50 ml) and filtered. The filtrate is ished with brine, dried (MgSO4) and then the solvent is evaporated in vacuo. The crude red oil is purified by SiO2 chromatography (gradient Petrol Ether:EtOAc=8:1 to 100% EtOAc) to give an orange oil which crystallized when triturated with hexane. The solvent is finally removed in vacuo to give 5-(tert-butyl dimethyl silanyloxymethyl)-pyridin-2-ylamine as an orange solid (2.9 g, 56.1%). MS(ESI) m/z 239.2 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][O:24]C(=O)C)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+]>C1COCC1.CO>[OH:24][CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:28])=[O:2])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2COC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To (2′-acetoxymethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.54 mmol) in THF (1 mL) and MeOH (0.8 mL) was added 1N aqueous NaOH (0.6 mL), and the reaction was stirred at room temperature for 1.5 hours. The mixture was partitioned between CH2Cl2 and aqueous HCl, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48]([OH:50])=O.Cl.[NH2:52][CH2:53][C:54]([C:56]1[CH:60]=[CH:59][S:58][CH:57]=1)=[O:55].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:38]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:10]([CH2:11][O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48]([NH:52][CH2:53][C:54](=[O:55])[C:56]1[CH:60]=[CH:59][S:58][CH:57]=1)=[O:50]
Reactant: O=C(O)Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Reactant: NCC(=O)c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)NCC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.3 %

Procedure:
To a mixture of the carboxylic acid 55 (1.04 g, 1.5 mmol), 2-amino-1-(thiophen-3yl)ethanone hydrochloride (533 mg, 3.0 mmol), EDCI (575 mg, 3.0 mmol), and HOBt (507 mg, 3.75 mmol) in DMF (10 mL) was added NMM (0.83 mL, 7.5 mmol). The resulting mixture was stirred at room temperature for 15 h. The reaction mixture was poured into a HCl solution (1.0 M, 50 mL), and extracted with EtOAc. The organic phase was dried over anhydrous MgSO4, filtered and evaporated under vacuum. The residue was further purified by silica column chromatography to provide the titled amide compound (529 mg, 0.65 mmol, 43%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Product: COc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(C)(C)C)cc1

Procedure:
Prepared as described in Example 83 using (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(4-methoxyphenyl)propan-2-amine (90a, 20 mg, 0.05 mmol) and Pivaloyl chloride (19 μl, 0.15 mmol). Yield 13 mg (55%).
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32]>>[C:31]([C:33]1[CH:38]=[C:37]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)[CH:36]=[CH:35][CH:34]=1)#[N:32]
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: N#Cc1cccc(B(O)O)c1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1cccc(C#N)c1
Yield: 63 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 3-cyanophenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as an off-white solid (63% yield); 1H-NMR (d6-DMSO) 1.08 (9H, s), 3.69 (2H, t), 4.12 (2H, t), 6.61 (1H, s), 7.50-7.52 (2H, m), 7.62-7.66 (2H, m); MS ES(+) 231.0 (M+-tBu). IR λmax=2225, 1697 cm−1
Reaction SMILES: C=O.[B-][C:4]#N.[Na+].[NH:7]1[CH2:13][CH2:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2.[OH-].[Na+]>C(#N)C.C(O)(=O)C>[CH3:4][N:7]1[CH2:13][CH2:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2
Reactant: CCOC(=O)C1=Cc2ccccc2NCC1
Reactant: [B-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)C1=Cc2ccccc2N(C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A 37% aqueous formaldehyde solution (1.50 g, 18.4 mmol), sodium cyanotrihydroborate (0.12 g, 18.4 mmol) and acetic acid (0.1 ml) were added to a solution in acetonitrile (8 ml) of the ethyl 2,3-dihydro-1H-benz[b]azepine-4-carboxylate (0.40 g, 1.84 mmol) synthesized in Reference Example 5. After stirring at room temperature for 2 hours, the reaction mixture was poured into a 1N aqueous sodium hydroxide solution and extracted twice with diethyl ether. The extract solution was washed twice with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=4/96) to obtain 0.40 g of ethyl 1-methyl-2,3-dihydro-1H-benz[b]azepine-4-carboxylate.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3].[P:13]([O-:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[CH2:15]([O:14][P:13]([O:17][CH2:18][CH3:19])([C:6]([OH:12])([CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:20])[CH3:16]
Reactant: CCOC(=O)C(=O)CCN(C)C
Reactant: CCOP([O-])OCC
Product: CCOC(=O)C(O)(CCN(C)C)P(=O)(OCC)OCC
Reaction time: 96 h

Procedure:
A mixture of 8.05 g (0.05 mole) of ethyl 4-(N,N-dimethylamino)-2-oxobutanoate in 31 g (0.225 mole) of diethyl phosphite is stirred at 20°-30° for 3-5 days. The excess diethyl phosphite is removed on a rotary evaporator under high vacuum at a bath temperature of 50°-70° to yield the crude product as a viscous oil. This is purified by chromatography on silica gel using chloroform/methanol as eluant.
Reaction SMILES: [CH3:1][OH:2].Br[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]2[C:6]=1[CH2:7][CH:8]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH:9]1[CH2:18][CH2:17][CH2:16][CH:10]12.Cl>C(OCC)(=O)C>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([CH:8]2[CH2:7][C:6]3[C:11](=[CH:12][C:13]([OH:15])=[CH:14][C:5]=3[CH2:4][O:2][CH3:1])[CH:10]3[CH2:16][CH2:17][CH2:18][CH:9]23)=[CH:24][CH:23]=1
Reactant: Oc1ccc(C2Cc3c(CBr)cc(O)cc3C3CCCC23)cc1
Reactant: CO
Agent: Cl
Solvent: CCOC(C)=O
Product: COCc1cc(O)cc2c1CC(c1ccc(O)cc1)C1CCCC21
Yield: 37 %

Procedure:
Combine Na (0.013 g, 0.53 mmol) and methanol (2 ml) at 0-5° C. and stir until solution forms. Add 6-Bromomethyl-4-(4-hydroxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-8-ol (0.037 g, 0.1 mmol) and stir for 3 hours. Remove solvent in vacuo. Take into ethyl acetate and 1N HCl. Separate organic layer and wash with water. Dry over anhydrous sodium sulfate and remove solvent in vacuo. The residue is chromatographed on silica gel with 25% ethyl acetate/hexanes to yield the titled compound (0.012 g, 37%). 1H NMR (DMSO-d6): 9.16(s, 1H), 9.04 (s, 1H), 7.11 (d, J=7.9 Hz, 2H), 6.71 (d, J=8.8 Hz, 2H), 6.58 (s, 1H), 6.53 (s, 1H), 4.35 (dd, j=16 and 7 Hz, 2H), 3.4 (m, 1H presumed), 3.0 (m, 1H), 2.76 (m, 1H), 2.65 (m, 1H), 2.45(m, 1H) 2.15 (m, 1H), 1.6-1.2 (m, 5H). MS m/z 323 (M−1).
Reaction SMILES: C(S[CH2:4][C:5]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]#[N:18])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=2)([OH:7])[CH3:6])C.C(=O)(O)[O-].[Na+].[OH:28][O:29][S:30]([O-:32])=[O:31].[K+:33].[C:34](OCC)(=O)[CH3:35]>[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O>[OH:28][O:29][S:30]([O-:32])=[O:31].[K+:33].[CH2:34]([S:30]([CH2:6][C:5]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]#[N:18])=[C:12]([C:19]([F:22])([F:20])[F:21])[CH:11]=2)([OH:7])[CH3:4])(=[O:32])=[O:29])[CH3:35]
Reactant: CCOC(C)=O
Reactant: CCSCC(C)(O)c1cc2cc(C#N)c(C(F)(F)F)cc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Product: CCS(=O)(=O)CC(C)(O)c1cc2cc(C#N)c(C(F)(F)F)cc2[nH]1
Reaction time: 8 h

Procedure:
The (−) enantiomer of 2-(2-ethylsulfanyl-1-hydroxy-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-5-carbonitrile, the compound prepared as in Example 86 above (1 equivalent) was dissolved in ethyl acetate (5 mL/mmol). A separate aqueous solution of OXONE® (3 equivalents) and Bu4NHSO4 (0.3 mol %) (10 mL water/g of OXONE®) was prepared and the pH of this solution adjusted to about 7 by the addition of saturated sodium bicarbonate solution. After the pH adjustment, this aqueous solution was added to the ethyl acetate solution and the resulting biphasic mixture vigorously stirred. After 8 hours, an additional 3 equivalents of the pH-adjusted OXONE® solution was added and the mixture stirred overnight. Ethyl acetate (10 mL/mmol of sulfide) was added and the aqueous phase was removed. The organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated to yield a yellow solid. This crude material (yellow solid) was purified using column chromatography (silica gel, ethyl acetate as eluent) to yield the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@H:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@H:35]4[CH2:39][CH2:38][NH:37][C:36]4=[O:40])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: O=C1NCC[C@@H]1NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)N[C@H]3CCNC3=O)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (S)-2-bromo-N-(2-oxopyrrolidin-3-yl)benzene-sulfonamide. MS (ESI): mass calcd. for C20H18FN5O3S, 427.11; m/z found, 428.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.51 (dd, J=2.2, 1.3, 2H), 8.18 (dd, J=7.9, 1.3, 1H), 7.67-7.60 (m, 1H), 7.58-7.51 (m, 1H), 7.45-7.31 (m, 4H), 6.05 (d, J=9.3, 1H), 5.51 (dd, J=9.8, 3.3, 1H), 5.35 (d, J=3.1, 2H), 3.67-3.55 (m, 1H), 3.39-3.19 (m, 2H), 2.65-2.50 (m, 1H), 2.16-1.99 (m, 1H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[N:9]=[C:8]2[NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]2)(=O)C.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:52])[CH2:49][CH2:50][CH3:51].CCOCC>ClCCl>[C:48]([NH:21][C:17]1[CH:16]=[C:15]([C:10]2[N:9]=[C:8]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[N:27]=[CH:26]4)[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([OH:4])[CH:6]=3)[N:11]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:52])[CH2:49][CH2:50][CH3:51]
Reactant: CCCC(=O)Cl
Reactant: CC(=O)Oc1ccc2nc(-c3cccc(N)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2c1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3cc(O)ccc3n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.9 %

Procedure:
To a solution of tert-butyl 5-(6-acetoxy-2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.57 g, 1.12 mmol) and DIEA (0.65 g, 5.03 mmol) in dichloromethane (20 mL) was added butryl chloride (0.180 g, 1.69 mmol). The resulting reaction mixture was stirred at room temperature for 4 h. The volatiles were removed under reduced pressure and the residue was triturated with water causing formation of a precipitate. The solid was collected via filtration and dried under vacuum. The solid was suspended in anhydrous methanol (50 mL) and 28% ammonium hydroxide (0.9 mL) was added. The resulting reaction mixture was stirred at room temperature for 24 h. The volatiles were removed under reduced pressure and the residue upon trituration with ether gave tert-butyl 5-(2-(3-butyramidophenyl)-6-hydroxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.354 g, 0.66 mmol, 59% over two steps). HPLC retention time 6.342 min.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[CH:16][C:15]=1[CH3:22].O>O1CCOCC1>[Br:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([N:21]=[C:5]=[O:11])=[CH:16][C:15]=1[CH3:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)cc(C)c1Br
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(N=C=O)cc(C)c1Br
Temperature: 100 °C
Reaction time: 15 h
Yield: 117.6 %

Procedure:
Triphosgene (2.23 g, 7.52 mmol) was added to a solution of 4-bromo-3,5-dimethyl-phenylamine (4.3 g, 21.49 mmol) in dioxane (71 ml). After stirring at 100° C. for 15 hours, water was added to the reaction solution. After extraction with ethyl acetate, the organic phase was sequentially washed with water and saturated brine and concentrated under reduced pressure to give 2-bromo-5-isocyanato-1,3-dimethylbenzene (2.0 g, 41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[C:6]([C@@H:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[C:25](O)(=[O:27])[CH3:26]>ClCCl>[C:25]([N:9]1[CH2:8][C@H:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:6]2[C:11](=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1)(=[O:27])[CH3:26]
Reactant: CC(=O)O
Reactant: COc1ccc([C@H]2CNCc3c2ccc(OC)c3OC)cc1OC
Solvent: ClCCl
Product: COc1ccc([C@H]2CN(C(C)=O)Cc3c2ccc(OC)c3OC)cc1OC

Procedure:
(i) 2.0 g of (R)-(+)-7,8-dimethoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 10 ml of dichloromethane; after adding 0.86 ml of anhydrous acetic acid thereto at room temperature, the mixture was allowed to react for 30 minutes. The reaction solution was concentrated and subjected twice to azeotropic distillation with toluene. Then dichloromethane was added and the mixture was basified by adding 1N aqueous sodium hydroxide. After separation, the dichloromethane layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was recrystallized from ethylacetate-n-hexane, affording 2.12 g of (R)-(-)-N-acetyl-7,8-dimethoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline. m.p. 128° C.; [α]D20 =-39° (C=1, CHCl3).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[NH:26][C:22]=2[CH:21]=1>C(OCC)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][NH:19][C:20]3[CH:29]=[CH:28][C:23]4[NH:24][C:25](=[O:27])[NH:26][C:22]=4[CH:21]=3)[CH2:6][CH2:7]2)=[CH:13][CH:14]=1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]c(=O)[nH]c2c1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 2-chloro-1-[4-(4-fluoro-benzyl)-piperidine-1-yl]-ethanone and 5-amino-1,3-dihydro-benzimidazol-2-one according to the method described in Example 142b. Melting Point: 249-251° C. (diethylether)