Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[C@@H:52]1[O:64][C@H:63]([CH2:65][O:66][C:67](=[O:69])[CH3:68])[C@@H:58]([O:59][C:60](=[O:62])[CH3:61])[C@H:53]1[O:54][C:55](=[O:57])[CH3:56])(=O)C>COCCOC>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:52]2[O:64][C@H:63]([CH2:65][O:66][C:67](=[O:69])[CH3:68])[C@@H:58]([O:59][C:60](=[O:62])[CH3:61])[C@H:53]2[O:54][C:55](=[O:57])[CH3:56])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: COCCOC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN4CCCCC4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 6-[(2,2-diphenylethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9H-purine-2-carboxamide (200 g, 0.426 moles) (Preparation 23) in anhydrous 1,2-dimethoxyethane (800 ml) under an atmosphere of nitrogen was added a solution of trimethylsilyl trifluoromethanesulfonate (200 g, 0.900 moles) in anhydrous 1,2-dimethoxyethane (200 ml) over a period of 15 minutes. During the addition, all the solid dissolved to give a deep red/amber solution and the reaction temperature rose from 20° C. to 31.5° C. The resultant mixture was heated to 55-60° C. and a solution of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (163 g, 0.512 moles) in anhydrous 1,2-dimethoxyethane (400 ml) was added over a period of 40 minutes. The addition apparatus was rinsed through into the reaction mixture with anhydrous 1,2-dimethoxyethane (200 ml). The reaction mixture was heated at 60° C. for 3 hours and was allowed to cool to ambient temperature. This crude reaction solution was held at ambient temperature for 18 hours. The resulting mixture containing the title compound may be used directly without further purification.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[CH2:20]1>CS(C)=O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COc1ccc(CCN2CCC[C@@H](Cl)C2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3COc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
Sixty-percent sodium hydride (0.34 g, 8.6 mmols) was washed with petroleum ether, and then suspended in 30 ml of dimethyl sulfoxide. To the suspension were added 1.38 g (7.0 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. To this reaction solution was added dropwise a solution of 1.8 g (6.3 mmols) of (R)-(−)-3-chloro-1-(3,4-dimethoxyphenethyl)piperidine[[α]D25=−20.3° (c=0.9, ethanol)] in 5 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 12 hours and at 40° C. for 4 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:5. This mixed solvent was distilled off under reduced pressure. Further, the thus-obtained residue was subjected to column chromatography, and extracted with a mixed solvent of chloroform and methanol at a ratio of 200:1. This mixed solvent was then distilled off under reduced pressure to give 0.85 g of (S)-(−)-5,11-dihydro-5-[1-(3,4-dimethoxyphenethyl)-2-pyrrolidinyl-methyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 30%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:11]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc([N+](=O)[O-])cn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc([N+](=O)[O-])cn1

Procedure:
2-Amino-5-nitropyridine was treated with acetic anhydride in dry pyridine in the presence of 4-dimethylaminopyridine at room temperature for 24 hrs under argon. The solvent was removed by rotary evaporation. The residue was dissolved in CH2Cl2, and ether was added to form a solid. The white solid was collected and dried giving 2-acetamido-5-nitropyridine. Hydrogenation of this material using 10% Pd on C in MeOH at room temperature under atmospheric pressure gave 2-acetamido-5-aminopyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:12]=3[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:34][CH:33]=[CH:32][CH2:31]4)=[O:29])=[CH:24][CH:23]=3)[C:10](=[O:35])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([Sn]([N:51]=[N+:52]=[N-:53])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[C:16]([C:19]4[NH:53][N:52]=[N:51][N:20]=4)[CH:17]=[CH:18][C:12]=3[N:11]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:31][CH:32]=[CH:33][CH2:34]4)=[O:29])=[CH:24][CH:23]=3)[C:10](=[O:35])[CH2:9]2)=[O:7])=[CH:36][CH:37]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)CN(C(=O)c1ccc(Cl)cc1)CC(=O)N2Cc1ccc(C(=O)N2CC=CC2)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3cc(-c4nnn[nH]4)ccc32)cc1)N1CC=CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
26 mg (0.051 mmol) of 4-(4-chlorobenzoyl)-7-cyano-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-1,3,4,5-tetrahydrobenzo[e][1,4]-diazepin-2-on was dissolved in 10 ml of toluene. 0.032 ml (0.11 mmol) of tributyltin azide was added to the obtained solution, and they were stirred at 100° C. overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the solvent was evaporated and the obtained crude product was treated in the same manner as in Step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [O:1]=[C:2]1O[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][C:4]2[S:13][C:14]([CH2:16][CH2:17][CH3:18])=[CH:15][C:3]1=2.C([O-])(=O)C.[NH4+:23]>C(O)(=O)C>[O:1]=[C:2]1[NH:23][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][C:4]2[S:13][C:14]([CH2:16][CH2:17][CH3:18])=[CH:15][C:3]1=2
Reactant: CCCc1cc2c(=O)oc(C(=O)OCC)nc2s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCCc1cc2c(=O)[nH]c(C(=O)OCC)nc2s1

Procedure:
The product of Procedure 85 is converted to the desired product by treatment with ethanolic ammonium acetate according to the method of Procedure 5 except that acetic acid is omitted. The product is recrystallized from ethanol, m.p. 169°-170° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][OH:7].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>N1C=CC=CC=1>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:7][CH2:6][CH2:5][CH2:4][CH:3]([C:2]([F:12])([F:13])[F:1])[CH2:8][CH2:9][CH2:10][CH3:11])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC(CCCO)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(CCCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F

Procedure:
0.27 g (1.4 mmol) of 4-trifluoromethyloctanol was dissolved in 5 ml of pyridine and cooled with ice, and 0.27 g (1.4 mmol) of p-toluenesulfonyl chloride was added thereto under stirring, followed by reaction at 15°-20° C. for 3 hours. After the reaction, the mixture was acidified with 2N-hydrochloric acid and extracted with diethyl ether. The resultant ether layer was dired on anhydrous sodium sulfate, followed by distilling-off of the solvent to obtain 4-trifluoromethyloctyl p-toluenesulfonate. Then, 0.4 g (1.1 mmol) of the 4-trifluoromethyloctyl p-toluenesulfonate was dissolved in 1 ml of ethanol and then added to a preliminarily prepared solution of 48 mg (1.1 mmol) of sodium hydroxide and 0.23 g (1.1 mmol) of p-hydroxyphenyl benzyl ether in 1 ml of ethanol. The mixture was heated to 85°-90° C. for 5 hours of reaction and then cooled by standing. The reaction mixture was poured into 20 ml of 2N-hydrochloric acid and extracted with diethyl ether. The resultant ether layer was dried on anhydrous sodium sulfate and purified by silica gel column chromatography (eluent: benzene) to obtain 0.30 g (yield: 69%) of p-benzyloxy(4-trifluoromethyloctyloxy)phenyl.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH2:8])[C:6]#[N:7])[CH3:2].N1C=CC=CC=1.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH:8][C:24]([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25])[C:6]#[N:7])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(N)C#N
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(C#N)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a stirred mixture of 2-amino-2-cyanoacetic acid ethyl ester (19.7 g) and pyridine (12.2 g) in water (123 ml) was added portionwise benzyloxycarbonyl chloride (27.9 g) under ice cooling. The resulting mixture was stirred under ice cooling for 1 hour. Precipitated crystals were collected, washed thoroughly with water, and recrystallized from ethanol to give the title compound (24.2 g, 60.2%) as colorless crystals, mp 111°-112° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[C:25]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:26]=[CH:27][CH:28]=[O:29])=[CH:20][CH:19]=1>O1CCCC1>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[C:25]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:26]=[CH:27][CH:28]([OH:29])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Cn1nnnc1C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a chilled suspension (0° C., ice-water bath) of NaH (0.64 g, 16.0 mmoles) (60% in mineral oil) in 20 mL of dry tetrahydrofuran under argon was added ethyl acetoacetate 2.04 mL (16.0 mmoles) in 4 equal portions. The homogeneous clear solution was stirred at 0° C. for 30 minutes followed by the dropwise addition of 6.4 mL of 2.5 Molar n-BuLi (16.0 mmoles) over a period of 15 minutes. The orange dianion solution was stirred at 0° C. for an additional hour. The ice-water bath was replaced by an acetone-dry ice bath at -78° C. and the dianion was transferred via a cannula into a tetrahydrofuran (20 mL) solution containing 5,5-bis(4-fluorophenyl)-4-(1methyl-1H-tetrazol-5-yl)-2,4-pentadienal (2.82 g, 8.01 mmoles). Analytical TLC showed the major desired product at Rf =0.15 (50% EtOAc in hexanes) and a minor product at Rf =0.2. The crude reaction mixture was diluted with 40 mL of 1N HCl and the aqueous layer was extracted with ethyl acetate (50 mL×2). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. The desired product was purified by flash silica gel column chromatography eluted with 20% EtOAc in hexanes (v/v) to give 2.26 g (58.5%) of the title compound. MS (CI): m/e=483 for (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([Si:20]2(C3C=CC=CC=3)[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:13][C@H:14]2[CH2:15][CH2:16][C@H:17]([Si@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH2:22][CH2:21]3)[CH2:18][CH2:19]2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COCCCCCC1CC[Si](c2ccccc2)([C@H]2CC[C@H](CBr)CC2)CC1
Product: COCCCCC[C@H]1CC[Si@H]([C@H]2CC[C@H](COc3ccc(C(F)(F)F)cc3)CC2)CC1

Procedure:
The general procedure of Example 39 was repeated using 4-trifluoromethylphenol and 4-(trans-4-bromomethylcyclohexyl)-4-phenyl-1-(5-methoxypentyl)-4-silacyclohexane, thereby obtaining the intended product.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[N:11]=[C:12]([C:14]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[NH:23][C:24]([C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=4)=[O:25])=[O:15])[S:13][C:7]=2[CH2:6]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1.Cl>[ClH:35].[Cl:35][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:24]([NH:23][C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]1[NH:16][C:14]([C:12]1[S:13][C:7]3[CH2:6][N:5]([CH2:4][CH2:3][NH:2][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:10][CH2:9][C:8]=3[N:11]=1)=[O:15])=[O:25])=[CH:34]2
Reactant: NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (110 mg) obtained in Example 40 was dissolved in pyridine (3 ml), methanesulfonyl chloride (30 μl) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and a 85:15 mixed solvent of methylene chloride and methanol, and water were added to conduct liquid separation. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methylene chloride:methanol=100:3) to obtain a pale yellow foamy substance. This product was suspended in 1N hydrochloric acid (0.3 ml), and the suspension was concentrated under reduced pressure to obtain the title compound (63 mg).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[CH:9][C:8]=1[CH:15]([CH3:17])[CH3:16].[CH2:18]([O:20][C:21]1[C:28]([CH3:29])=[C:27]([CH3:30])[C:26]([OH:31])=[C:25]([CH3:32])[C:22]=1[CH2:23][Cl:24])[CH3:19].C(N(CC)CC)C>CN(C)C=O>[ClH:24].[CH2:18]([O:20][C:21]1[C:28]([CH3:29])=[C:27]([CH3:30])[C:26]([OH:31])=[C:25]([CH3:32])[C:22]=1[CH2:23][N:3]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[CH:9][C:8]=1[CH:15]([CH3:17])[CH3:16])[CH3:2])[CH3:19]
Reactant: CCOc1c(C)c(C)c(O)c(C)c1CCl
Reactant: CNCCOc1cc(C)c(O)cc1C(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1c(C)c(C)c(O)c(C)c1CN(C)CCOc1cc(C)c(O)cc1C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
N-Methyl-2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethylamine hydrochloride (10.4 g), 2-ethoxy-5-hydroxy-3,4,6-trimethylbenzyl chloride (9.15 g) and triethylamine (8.10 g) were dissolved in N,N-dimethylformamide (80 ml), and the mixture was stirred at room temperature for 4 hours. After the reaction, the solvent was distilled off and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting liquid (1.0 g) was dissolved in methanol and conc. hydrochloric acid (0.2 ml) was added. The mixture was concentrated to dryness under reduced pressure. Recrystallization from ethanol-diethyl ether gave 910 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:10]=1>>[Cl:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:11]1[CH:10]=[C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Reactant: Cc1noc(N)c1Cl
Product: Cc1noc(NS(=O)(=O)c2cccc(-c3ccccc3)c2)c1Cl
Yield: 63 %

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide was prepared in the same manner as described in Example 12 from 5-amino-4-chloro-3-methylisoxazole and 3-biphenylsulfonyl chloride in 63% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid, m.p. 84-86° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>>[C:21]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)(=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)Nc1c(C(=O)c2cccc(C)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-methylbenzoyl)indole (Example 21) and butyryl chloride. m.p.: 127-130° C. 1H-NMR (CDCl3) δ: 10.03 (1H, br s), 8.35-8.20 (2H, m), 7.62-7.54 (2H, m), 7.48-7.40 (2H, m), 7.28 (1H, d, J=1.8 Hz), 7.08 (1H, dd, J=1.8, 9.2 Hz), 2.55-2.35 (5H, m), 1.90-1.72 (2H, m), 1.04 (3H, t, J=7.3 Hz)
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[CH3:13][O:14][C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C=O)C>[CH3:13][O:14][C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:3][C:4]1=[O:12]
Reactant: O=c1[nH]c2ccccc2s1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)sc2ccccc21

Procedure:
The product is produced as described in example 1 from 3 g. of NaH (80% suspension in mineral oil), 15.1 g. of benzthiazolin-2-one, 200 cc. of DMF, 23.7 g. of 8-bromo-caprylic acid methyl ester and 3 g. NaJ.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][NH:3][C:2]1=[C:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl-].[Na+]>CS(C)=O.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C(=O)OCC)=C1NC=CS1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1nccs1

Procedure:
A solution of the product of Example 44B (2.8 g, 11.5 mmoles), sodium chloride (1.3 g, 22.9 mmoles) and water (0.4 ml, 22.9 mmoles) in dimethyl sulfoxide (48.0 ml) was stirred at about 180° C. for about 30 min. The mixture was cooled, diluted with water (100.0 ml) and was extracted twice with (1:1) ethyl acetate/diethyl ether (80.0 ml each). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2:1) as the mobile phase to provide the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([S:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][C:20]4([O:27][C:26]5[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=5[N:24]5[C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=[C:23]45)[CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:2]1.CC(O)C.C(=O)=O>CO>[O:1]1[CH2:5][CH2:4][C@H:3]([S:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:17]3[CH2:18][CH2:19][C:20]4([C:23]5=[CH:34][CH:33]=[C:32]([C:35]([F:37])([F:36])[F:38])[N:24]5[C:25]5[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=5[O:27]4)[CH2:21][CH2:22]3)=[O:16])=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:2]1
Reactant: O=C(c1ccc(S(=O)(=O)C2CCOC2)cc1)N1CCC2(CC1)Oc1ccccc1-n1c(C(F)(F)F)ccc12
Agent: O=C=O
Solvent: CC(C)O
Solvent: CO
Product: O=C(c1ccc(S(=O)(=O)[C@H]2CCOC2)cc1)N1CCC2(CC1)Oc1ccccc1-n1c(C(F)(F)F)ccc12

Procedure:
(4-(Tetrahydrofuran-3-ylsulfonyl)phenyl)(1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone was subjected to chiral SFC (column: Phenomenex Lux Cellulose-2 (250×10 mm), 5 μm; mobile phase: 40% IPA w/0.2% DEA, 60% CO2; concentration: 30 mg/mL in MeOH; injection volume: 20 μA; pressure: 100 bar; detection wavelength: 254 nm) to give two peaks. For each enantiomer, the solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with aqueous 1M hydrochloric acid (1×1 mL), a saturated aqueous solution of sodium bicarbonate (1×1 mL) and a saturated aqueous solution of sodium chloride (1×1 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield [4-[(3S)-tetrahydrofuran-3-yl]sulfonylphenyl]-[1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone as a yellow solid (peak 1, the stereochemistry was randomly assigned): ESI-MS m/z calc. 546.1. found 547.2 (M+1)+; Retention time: 1.93 minutes (3 min run); NMR (400 MHz, DMSO) δ 7.99 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.37-7.14 (m, 3H), 7.03 (d, J=3.9 Hz, 1H), 6.40 (d, J=4.0 Hz, 1H), 4.53-4.36 (m, 1H), 4.33-4.19 (m, 1H), 4.08-3.94 (m, 1H), 3.91-3.58 (m, 3H), 3.56-3.16 (m, 3H), 2.19-1.82 (m, 6H) and [4[(3R)-tetrahydrofuran-3-yl]sulfonylphenyl]-[1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone as a yellow solid (peak 2, the stereochemistry was randomly assigned): ESI-MS m/z calc. 546.1. found 547.2 (M+1)+; Retention time: 1.93 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.99 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.2 Hz, 1H), 7.36-7.14 (m, 3H), 7.03 (d, J=3.9 Hz, 1H), 6.40 (d, J=4.0 Hz, 1H), 4.54-4.36 (m, 1H), 4.33-4.17 (m, 1H), 4.09-3.95 (m, 1H), 3.90-3.59 (m, 3H), 3.58-3.12 (m, 3H), 2.24-1.77 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:17])[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][CH3:26])[C:22]([C:27]([F:30])([F:29])[F:28])=[CH:21][N:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:8][C:7]1[C:2]([NH:1][C:19]2[N:24]=[C:23]([NH:25][CH3:26])[C:22]([C:27]([F:30])([F:28])[F:29])=[CH:21][N:20]=2)=[CH:3][C:4]([CH3:17])=[C:5]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:6]=1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: Cc1cc(N)c(Cl)cc1C(=O)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNc1nc(Nc2cc(C)c(C(=O)N3CCOCC3)cc2Cl)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 53.3 %

Procedure:
A mixture of (4-amino-5-chloro-2-methylphenyl)(morpholino)methanone (79 mg, 0.31 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (66 mg, 0.31 mmol) and para-toluene sulfonic acid (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 4 h. Saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added and the organic phase was passed through a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by reversed phase HPLC to give (5-chloro-2-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)(morpholino)methanone (71 mg, 53%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=430 at 3.47 min. 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.21 (d, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 5.30 (br s, 1H), 3.79 (br d, 4H), 3.60 (br s, 2H), 3.32 (br s, 2H), 3.11 (d, 3H), 2.32 (s, 3H).