Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C(O)(=O)C.[C-:25]#[N:26].[K+]>C1COCC1.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:17]([C:16]2[CH:19]=[CH:20][C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:14][CH:15]=2)[C:25]#[N:26])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: Nc1ccc(Br)cc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(C#N)Nc2ccc(Br)cc2)cc1
Yield: 77 %

Procedure:
To a solution of 4-bromoaniline (10.0 g, 58.1 mmol) in THF (100 mL) was added 4-tert-butylbenzaldehyde (9.72 mL, 58.1 mmol), acetic acid (13.3 mL, 233 mmol), potassium cyanide (3.79 g, 58.1 mmol) and water (50 mL). The resultant mixture was stirred at room temperature for 16 hours. The resultant solid that formed was collected by vacuum filtration, washed with hexane, and then dried to afford 15.3 g, (77%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (m, 4H), 7.37 (d, J=8.7 Hz, 2H), 6.66 (d, J=8.8 Hz, 2H), 5.34 (d, J=8.1 Hz, 1H), 4.02 (d, J=8.0 Hz, 1H), 1.34 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.C([N:17](C(C)C)CC)(C)C.N[N:24]([CH:32]=[NH:33])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[NH:17]=[C:32]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[NH:33][C:6](=[O:8])[CH2:5][O:4][C:3]1[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1OCC(=O)O
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N(N)C=N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1OCC(=O)NC(=N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 65 h
Yield: 93.7 %

Procedure:
(2,6-Dimethylphenoxy)acetic acid (5.41 g; 30 mmol), diisopropylethylamine (19.39 g; 150 mmol), tert-butyl amino(imino)methylcarbamate (5.73 g; 36 mmol), and 1-hydroxybenzotriazole monohydrate (5.52 g; 36 mmol) were dissolved in N,N-dimethylformamide (120 mL), 2-(1H)-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate (13.66 g; 36 mmol) was added thereto, and the mixture was stirred for 65 hours at room temperature. To the reaction solution, ethyl acetate (400 mL) was added, and the mixture was washed with 10% aqueous citric acid solution, brine, saturated aqueous sodium bicarbonate solution, and then brine. The organic layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure. The resulting crystals were dispersed in diethyl ether, collected by filtration and dried to give 9.03 g of the title compound (yield 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccncc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.27 (3, 9H), 7.41 (m, 3H), 7.50 (dd, 2H, J=4.8 Hz, 1.6 Hz), 7.67-72 (m, 4H), 8.85 (d, 2H, J=6 Hz), 10.19 (s, 1H). MS: m/z 473.9 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([C:23]#[CH:24])([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[N+:20]([O-])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CO.Cl>O.[Fe]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[NH2:20])([C:23]#[CH:24])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C(=O)OCC)CC1
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Product: C#CC1(Oc2ccc(F)cc2N)CCN(C(=O)OCC)CC1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
To a stirred solution of 22.3 g of 1-ethoxycarbonyl-4-ethynyl-4-(4-fluoro-2-nitrophenoxy)piperidine in 535 methanol was added 37 ml of concentrated hydrochloric acid in 150 ml of water. To the stirred mixture was added 78.6 g of iron (reduced, electrolytic) in aliquots. The reaction temperature rose to 45°. The reaction mixture cooled to ambient temperature over 1.5 hr. The mixture was poured into water/ice/sodium carbonate solution, extracted with dichloromethane, washed with water and saturated sodium chloride solution and dried over anhydrous potassium carbonate. Filtration followed by evaporation of solvent provided 20.2 g of an oil. An aliquot of 10.0 g of the oil was dissolved in ether and filtered through 200 g of alumina and the filtrate was evaporated. The residue was dissolved in 10% methanol/dichloromethane, filtered through 200 g of silica gel, and the filtrate was evaporated to provide 8.6 g (84.7%) of product, as an oil.
Reaction SMILES: [Cl:1][CH:2]([CH3:15])[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([N:9]1[C:8]2[CH:13]=[CH:14][C:5]([C:3](=[O:4])[CH:2]([Cl:1])[CH3:15])=[CH:6][C:7]=2[O:11][C:10]1=[O:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CC(Cl)C(=O)c1ccc2[nH]c(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(Cl)C(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
120.5 g (401 mmol) 6-(2-chloro-propionyl)-3H-benzoxazol-2-one, 49.4 ml (416 mmol) benzylbromide and 57.5 g (416 mmol) potassium carbonate added to 700 ml acetone are stirred overnight at RT. Then the solv. is completely removed i. V. and the residue is extracted with water and DCM. The org. phase is separated off, dried on magnesium sulphate and the solv. is eliminated by rotary evaporation i.V. The residue obtained is purified through silica gel (eluant: DCM).
Reaction SMILES: C(OP(NC1SC=C(/C(=N/OC)/C(O)=O)N=1)(OCC)=O)C.[CH2:22]([O:24][P:25]([NH:30][C:31]1[S:32][CH:33]=[C:34]([C:36](=[N:69][O:70][CH3:71])[C:37]([NH:39][CH:40]2[C:47](=[O:48])[N:46]3[CH:41]2[S:42][CH2:43][C:44]([CH2:61][S:62][C:63]2[N:67]([CH3:68])[N:66]=[N:65][N:64]=2)=[C:45]3[C:49]([O:51]CC2C=CC(OC)=CC=2)=[O:50])=[O:38])[N:35]=1)([O:27][CH2:28][CH3:29])=[O:26])[CH3:23].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O.C(=O)(O)[O-]>[CH2:28]([O:27][P:25]([NH:30][C:31]1[S:32][CH:33]=[C:34]([C:36](=[N:69][O:70][CH3:71])[C:37]([NH:39][CH:40]2[C:47](=[O:48])[N:46]3[CH:41]2[S:42][CH2:43][C:44]([CH2:61][S:62][C:63]2[N:67]([CH3:68])[N:66]=[N:65][N:64]=2)=[C:45]3[C:49]([OH:51])=[O:50])=[O:38])[N:35]=1)([O:24][CH2:22][CH3:23])=[O:26])[CH3:29]
Reactant: CCOP(=O)(Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc(OC)cc4)=C(CSc4nnnn4C)CSC23)cs1)OCC
Agent: CCOP(=O)(Nc1nc(/C(=N/OC)C(=O)O)cs1)OCC
Agent: O=C([O-])O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Nc1nc(C(=NOC)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CSC23)cs1)OCC

Procedure:
The procedure of example 68 was repeated using 350 mg of [6R-[6-α, 7-β (Z)]]-7-[[[2-[(diethoxyphosphinyl)amino]-4-thiazolyl]-(methoxyimino)acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (4-methoxyphenyl)methyl ester and 0.075 ml anisole in trifluoroacetic acid for 5 minutes. The product was obtained by acidification in aqueous bicarbonate and extraction with methylene chloride in the pH range 3.2 to 3.0 to give 200 mg of the desired product; MS ((+) FAB), 648 (M+H); NMR (300 MHz, d6 -DMSO) δ 1.28 (t, 6, OCH2CH3), 3.71 (pair of doublets, 2, endocyclic-CH2S--), 3.85 (s, 3, NCH3), 3.97 (s, 3, OCH3), 4.07 (m, 4, CH2OP=O), 4.33 (m, 2, exocyclic-CH2S--) 5.01 (d, 1, 6H of 7-ACA), 5.79 (dd, 1, of 7-ACA), 7.19 (d, 1, NH).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:13]([CH2:14]O)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:16][CH3:17])[CH:10]=2)[N:5]=1)[CH3:2].O=S(Cl)[Cl:20]>C(Cl)Cl>[ClH:20].[Cl:20][CH2:14][C:13]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:16][CH3:17])=[CH:8][CH:7]=2.[Cl:20][CH2:14][C:13]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:16][CH3:17])=[CH:8][CH:7]=2
Reactant: O=S(Cl)Cl
Reactant: CCNc1nc2ccc(OC)cc2cc1CO
Solvent: ClCCl
Product: CCNc1nc2ccc(OC)cc2cc1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (2-(ethylamino)-6-methoxyquinolin-3-yl)methanol SLA 28164 (1.150 g, 4.95 mmol) in dry CH2Cl2 (127 mL) a 250 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (7.18 mL, 99.0 mmol). The mixture was stirred for 2 h at RT then concentrated to dryness at 40° C. under vacuum. The residue was taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride SLA 28166 as a yellow solid (1.43 g, 100% yield) that was used immediately in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:6][C:5]=1[OH:21].[CH3:23]OC(C1C(=O)NC(C2C=CC=C(C(F)(F)F)C=2)=CC=1C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5](=[O:21])[N:6]([CH3:23])[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)=[CH:8][C:9]=1[CH3:10])=[O:22]
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1O
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)n(C)c1=O
Temperature: 25 °C
Reaction time: 70 h
Yield: 32.3 %

Procedure:
A solution of 0.62 g (2.0 mmol) of 2-hydroxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid methyl ester/4-methyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid methyl ester in 20 ml of DMF was treated with 0.78 g (2.4 mmol) of cesium carbonate, followed by 0.62 ml=1.41 g (10.0 mmol) of iodomethane. This mixture was stirred for 70 hours at RT, then poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 4:1 to 0:1) to give 0.21 g (33%) of the title compound as light yellow solid; [MS: 326.1 (MH+)] and 0.42 g (65%) of 2-methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid methyl ester as light yellow oil. MS: 326.1 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5]([N:7]2[C:13]([CH3:14])=[CH:12][C:11]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:10]=3[C:9]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[C:22]([CH3:29])[CH:21]=3)=[N:8]2)=[O:6])[CH2:3][CH2:2]1.O.NN>CO.ClCCl.[Ni]>[CH:1]1([NH:4][C:5]([N:7]2[C:13]([CH3:14])=[CH:12][C:11]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:10]=3[C:9]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([CH3:29])[CH:21]=3)=[N:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC1=Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])c(C)c2)=NN1C(=O)NC1CC1
Agent: [Ni]
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC1=Cc2ccc(Cl)cc2C(c2ccc(N)c(C)c2)=NN1C(=O)NC1CC1
Reaction time: 1 h
Yield: 90.1 %

Procedure:
1.38 g (3.35 mmoles) of 8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3H-2,3-benzodiazepine-3-carboxylic acid cyclopropyl amide is dissolved in the mixture of 28 ml of methanol and 14 ml of dichloromethane, and about 1.0 g of wet Raney nickel catalyst and 0.42 ml (8.37 mmoles) of 98% hydrazine hydrate are subsequently added to it under vigorous stirring. The mixture is stirred for further 1 hour, the catalyst is filtered off, washed with dichloromethane, the filtrate is evaporated and the residue is solidified by rubbing with 10 ml of water. The crude product is recrystallized from ethanol. Thus 1.15 g (90%) of the desired compound melting at 233-236° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22][OH:23]>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH:14]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]
Reactant: COc1c(C)c(C)c(OC)c(C(CCCCC#CCCO)c2ccccc2)c1C
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)c(C)c(OC)c(C(CCCCCCCCO)c2ccccc2)c1C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
5% Palladium-carbon (0.2 g) was added to a solution of 1.970 g (5.0 mmole) of 9-(2,5-dimethoxy-3,4,6-trimethylphenyl)-9-phenyl-3-nonyn-1-ol in ethanol (20 ml), and catalytic reduction was conducted at room temperature for 2 hours. The catalyst was filtered out, and the ethanol was distilled off under reduced pressure. The residue was chromatographed on a silica gel column to perform purification (elution with isopropyl ether) to thereby give 1.97 g (99%) of 9-(2,5-dimethoxy-3,4,6-trimethylphenyl)-9-phenylnonanol. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 14.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.O=[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.[C-:22]#[N:23].C([Al+]CC)C.C1(C)C=CC=CC=1>ClCCCl.CCOC(C)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:22]([C:9]1([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)#[N:23]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: OC1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Al+]CC
Solvent: ClCCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(N2CCC(O)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a stirred solution of 4-hydroxypiperidine (2.02 g, 20.0 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (3.99 g, 20.0 mmol) in 1,2-dichloroethane (50 mL) was added titanium isopropoxide (4.6 mL, 22.0 mmol) and the mixture was stirred for 18 h at room temperature. A solution of diethylaluminum cyanide in toluene (1M, 48.0 mL, 48.0 mmol) was added and stirred at room temperature for 24 h. Diluted with EtOAc and the reaction was quenched at 0° C. with saturated NaHCO3 (20 mL). The mixture was stirred a further 2 h, filtered through Celite, and the resulting filtrate was concentrated in vacuo to afford the title compound (5.89 g, 95%) as white solid, which was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][C:3]=1[NH2:4].ClOC(C)(C)C.[CH3:22][S:23][CH2:24][C:25](=O)[CH3:26].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:26][C:25]1[NH:4][C:3]2[C:5]([C:24]=1[S:23][CH3:22])=[C:6]([N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)[C:7]([F:9])=[CH:8][C:2]=2[Br:1]
Reactant: Nc1cc(N2CCOCC2)c(F)cc1Br
Reactant: CSCC(C)=O
Agent: CC(C)(C)OCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1c(C)[nH]c2c(Br)cc(F)c(N3CCOCC3)c12
Yield: 79.2 %

Procedure:
A solution of 145 g of 2-bromo-4-fluoro-5-morpholinoaniline in 1 l of methylene chloride and the solution was cooled to a temperature of not higher than -50° C. on a dry ice-acetone bath. At the same temperature as above 60 g of tert-butyl hypochlorite was added dropwise to the solution during which operation the reaction system changed from heterogeneous mixture to homogeneous solution. Then, 67 g of methylthio-2-propanone was added dropwise to the solution and the mixture was reacted at the same temperature as above for 2 hours followed by adding dropwise 80 ml of triethylamine. After completion of addition, the temperature of the mixture was elevated slowly to room temperature. After room temperature was attained 1 l of water was added to separate the methylene chloride layer which then was dried over sodium sulfate and concentrated under reduced pressure to give 150 g of 2-methyl-3-methylthio-5-fluoro-4-morpholino-7-bromoindole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[F:25])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[ClH:26].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[F:25])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cc(N)cc3ccoc23)[C@H](F)C1
Product: Cl
Product: O=S(=O)(Nc1cc(O[C@@H]2CCNC[C@H]2F)c2occc2c1)c1ccccc1Cl

Procedure:
The title compound was prepared according to the procedure described for Example 84 starting from tert-butyl trans-4-[(5-amino-1-benzofuran-7-yl)oxy]-3-fluoropiperidine-1-carboxylate (Intermediate 53) and 2-chlorobenzenesulfonyl chloride. Yield: 40 mg (22%), HPLC purity=100%, m/z=425 (M+H)+, 1H NMR (270 MHz, methanol-d4) δ ppm 2.09-2.35 (m, 2H) 3.10-3.57 (m, 3H) 3.62-3.79 (m, 1H) 4.73-4.96 (m, 1H) 4.97-5.23 (m, 1H) 6.74 (d, J=2.23 Hz, 1H) 6.85 (d, J=1.98 Hz, 1H) 7.05 (d, J=1.73 Hz, 1H) 7.31-7.40 (m, 1H) 7.45-7.58 (m, 2H) 7.71 (d, J=2.23 Hz, 1H) 7.96 (dd, J=7.79, 1.61 Hz, 1H).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[C:14]3[S:21][CH:20]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=4[F:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:8][CH2:7]1.C([O-])([O-])=O.[K+].[K+].I[CH:40]([CH3:42])[CH3:41]>CNC=O.CC(C)=O>[F:32][C:23]1[CH:24]=[C:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:26]=[CH:27][C:22]=1[C:19]1[C:15]2[N:16]=[CH:17][N:18]=[C:13]([O:12][CH:9]3[CH2:10][CH2:11][N:6]([C:5]4[N:1]=[N:2][N:3]([CH:40]([CH3:42])[CH3:41])[N:4]=4)[CH2:7][CH2:8]3)[C:14]=2[S:21][CH:20]=1
Reactant: CC(C)I
Reactant: CS(=O)(=O)c1ccc(-c2csc3c(OC4CCN(c5nn[nH]n5)CC4)ncnc23)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CNC=O
Solvent: CC(C)=O
Product: CC(C)n1nnc(N2CCC(Oc3ncnc4c(-c5ccc(S(C)(=O)=O)cc5F)csc34)CC2)n1
Temperature: 25 °C

Procedure:
700 mg of 4-(1-(2H-tetrazol-5-yl)piperidin-4-yloxy)-7-(2-fluoro-4-methanesulfonyl-phenyl)thieno[3,2-d]pyrimidine obtained in step 94-1 and 41 mf of K2CO3 were added in a mixture of methylformamide and acetone, and 44 μl of 2-iodopropane was dropwise added with stirring. The resulting mixture was stirred at 50° C. for 12 hr, cooled to room temperature and extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under a reduced pressure to obtain 51 mg of the title compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[CH:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].C(O[C:26]([C:28]1[N:29]([NH:33][CH2:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=1)=[O:27])C=C.[O-]CC.[Na+].C(O)C>ClCCl.CN(C)C=O>[CH3:39][C:36]([CH3:37])([CH3:38])[CH2:35][CH2:34][N:33]1[C:17](=[O:18])[C:16]([C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=3[S:13](=[O:15])(=[O:14])[CH:12]=2)=[C:26]([OH:27])[C:28]2=[CH:32][CH:31]=[CH:30][N:29]12
Reactant: C=CCOC(=O)c1cccn1NCCC(C)(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)CCn1c(=O)c(C2=CS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c(O)c2cccn21
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
N,N-Dicyclohexylcarbodiimide (0.476 mL of a 1.0 M solution in dichloromethane, 0.476 mmol) was added to a solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (Example 8h, 0.190 g, 0.572 mmol) and 1-(3,3-dimethyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 4c, 0.119 g, 0.475 mmol) in a 3:1 mixture of dichloromethane and N,N-dimethylformamide (6 mL) at 25° C. The reaction mixture was stirred at 25° C. for 1 h then was filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ethanol (12 mL) at 25° C. A 21% solution of sodium ethoxide in ethanol (0.23 mL, 0.71 mmol) was added and the reaction mixture was heated at 80° C. for 5 h. After cooling to 25° C., the mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 40-100% ethyl acetate in hexanes) afforded a solid which was triturated with diethyl ether to afford the desired product, N-{3-[1-(3,3-dimethyl-butyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (0.101 g, 0.20 mmol, 42% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 1.07 (9H, s), 1.65-1.72 (2H, m), 3.09 (3H, s), 4.25-4.29 (2H, m), 5.54 (2H, s), 6.43-6.45 (1H, m), 7.01-7.03 (1H, m), 7.08-7.09 (1H, m), 7.30 (1H, d, J=8.5 Hz), 7.39 (1H, bs), 7.61 (1H, dd, J1=2.3 Hz, J2=8.6 Hz), 7.73 (1H, d, J=2.4 Hz). LC-MS (ESI) calcd for C22H26N4O6S2 506.13. found 507.27 [M+H+].
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3].C([Li])CCC.CCCCCC.P(Cl)(OCC)(OCC)=O.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][N:30]=1>O1CCCC1.O>[Br:28][C:29]1[N:30]=[CH:31][C:32](/[CH:35]=[CH:1]/[S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3])=[CH:33][CH:34]=1
Reactant: CCOS(C)(=O)=O
Reactant: O=Cc1ccc(Br)nc1
Agent: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOS(=O)(=O)/C=C/c1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
Ethyl methanesulfonate (1.00 mL, 9.34 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) in an oven dried round bottle under an atmosphere of argon. The solution was cooled to −78° C. and 2.5 M n-butyllithium in hexane (4.09 mL, 10.23 mmol) was added dropwise over 15 min. The mixture was stirred at −78° C. for 15 min and diethyl chlorophosphate (0.78 mL, 5.38 mmol) was added dropwise. The reaction was stirred at −78° C. for 1 h and then the temperature was allowed to reach 0° C. before recooling to −78° C. A solution of 2-bromo-5-formylpyridine (1.0 g, 5.38 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise over 15 min and the resulting mixture was stirred for 15 min and then allowed to reach ambient temperature. Water (3 mL) was added and the solvent was evaporated in vacuo. The residue was partitioned between diethyl ether and water. The aqueous phase was extracted with diethyl ether and the formed precipitate was filtered off and rinsed with diethyl ether. This was pure product which was pooled with the rest of the material after purification. The aqueous phase was extracted once more with diethyl ether and the combined organic phases were dried over magnesium sulfate and concentrated. Purification by column chromatography, using a gradient of 10-60% ethyl acetate in heptane as the eluent, gave 0.77 g pooled with the material from the extractive work up to give 1.42 g (90% yield) of the title compound.