Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:24]([O-])=O)[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.[N+](C1C(C2C=CC=CC=2)=C(OCCCCC)C=C(C=1)C(O)=O)([O-])=O>>[NH2:24][C:16]1[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:10]=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: CCCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Product: CCCCCOc1cc(C(=O)O)cc(N)c1-c1ccccc1

Procedure:
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenylbenzoic acid with 5-nitro-3-n-pentyloxy-4-phenylbenzoic acid, and following the procedure described, 5-amino-3-n-pentyloxy-4-phenylbenzoic acid is obtained crystallizing with 0.25 mole of water with a melting point of 134°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([NH:17][C@H:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:19][OH:20])=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH2:21]([C@@H:18]1[CH2:19][O:20][C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:28])=[N:17]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C(=O)N[C@@H](CO)Cc1ccccc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1=N[C@H](Cc2ccccc2)CO1
Temperature: 80 °C
Reaction time: 20 h
Yield: 3 %

Procedure:
A sealed tube containing (R)-N1-(2-(5-chloro-1H-indol-3-yl)ethyl)-N2-(1-hydroxy-3-phenylpropan-2-yl)oxalamide (0.104 g, 0.260 mmol) and Burgess reagent [(methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (0.102 g; 0.416 mmol)] in dry THF (6 mL) was stirred at 80° C. for 20 hours. The solution was evaporated and the resulting residue was purified by flash chromatography on silica gel (eluent 7 to 60% ethyl acetate in dichloromethane) to give 0.003 g (3%) of (R)-4-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4,5-dihydrooxazole-2-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Yield: 28 %

Procedure:
8-(4-Amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione was condensed with methanesulfonyl chloride under the conditions previously described to give the stated sulfonamide as an off-white solid (28%); 1H NMR(DMSO-d6, 300 MHz) δH 13.42 (s, 1H), 9.61 (s, 1H), 7.30–6.90 (m, 8H), 5.04 (s, 2H), 3.94 (s, 2H), 3.77 (d, J=6.6 Hz, 2H), 2.87 (s, 3H), 1.25–1.05 (m, 1H), 0.40–0.25 (m, 4H); EI-HRMS m/e calculated for C24H24FN5O4S (M+) 497.1533, found 497.1528.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[C:13]3[C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH2:31])=[CH:26][C:25]=3[CH3:33])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>CO.O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:13]3[C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH2:31])=[CH:26][C:25]=3[CH3:33])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCc1ccn(-c2ccc(-n3ccnc3)cc2)c1-c1ccc(C(N)=O)cc1C
Solvent: CO
Solvent: O
Product: Cc1cc(C(N)=O)ccc1-c1c(CCC(=O)O)ccn1-c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A mixture of ethyl 3-(1-(4-(1H-imidazol-1-yl)phenyl)-2-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-3-yl)propanoate (25 mg, 0.057 mmol) and LiOH monohydrate (42 mg, 1 mmol) in a mixture of methanol (1.5 mL) and water (0.5 mL), and the reaction mixture was stirred at room temperature overnight. Methanol was removed under reduced pressure, and the residue was diluted with water (5 mL), and the aqueous layer was washed with ethyl acetate (5 mL×3). The aqueous layer was adjusted to PH=6-7 with 1N HCl, and the resulting mixture was extracted with a mixture of dichloromethane and isopropanol (3:1, 5 mL×3). The combined organic layer was dried, and evaporated to give 3-(1-(4-(1H-imidazol-1-yl)phenyl)-2-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-3-yl)propanoic acid, (5-4, R1=1H-imidazol-1-yl) (12 mg, yield: 51%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[O:15][CH:16]=[CH:17][C:18]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][CH:16]=[CH:17][C:18]=2[C:19]([O:21][CH3:22])=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccoc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1ccoc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 84.7 %

Procedure:
A solution of 4-(3-methoxycarbonylfuran-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (0.8 g, 2.1 mmol, 1.0 eq.) and Raney Ni (0.4 g) in MeOH (50 mL) was degassed and purged with hydrogen (3×). The mixture was hydrogenated (1 atm) for 1 hour, then purged with nitrogen, filtered and washed with MeOH (15 mL). The filtrate was concentrated to yield 4-(3-methoxycarbonylfuran-2-yl)piperidine-1-carboxylic acid t-butyl ester (550 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]3=[CH:14][NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Reactant: OB(O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(-c5cccc(F)c5)cc43)cc2)CC1
Temperature: 180 °C
Yield: 28.6 %

Procedure:
To a suspension of 6-bromo-4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione (221 mg, 0.5 mmol) in N,N-dimethylformamide (5 mL) is added 3-fluorobenzeneboronic acid (84 mg, 0.6 mmol), followed by 300 □L of 2M aqueous cesium carbonate and tetrakis triphenylphosphine palladium (30 mg, 0.06 mmol). The reaction mixture is subjected to microwave heating at 180° C. for 300 seconds. The reaction mixture is then diluted with N,N-dimethylformamide and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield 6-(3-Fluoro-phenyl)-4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione (65.2 mg).
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][PH2:9])[C:3]([OH:5])=[O:4].Cl.[CH2:11](O)[CH3:12]>>[CH2:11]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][PH2:9])[CH3:12]
Reactant: CCO
Reactant: NC(/C=C/CP)C(=O)O
Agent: Cl
Product: CCOC(=O)C(N)/C=C/CP

Procedure:
1.0 g of E-2-amino-5-phosphino-3-pentenoic acid is suspended in 20 ml of ethanol and the suspension is saturated with hydrogen chloride gas for 2 hours at 65°. After concentration, the residue is dissolved in 10 ml of ethanol, 10 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphino-3-pentenoic acid ethyl ester, m.p. 172°-173°.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([OH:12])=[CH:8][CH:9]=[C:10]([OH:11])[C:4]2=[CH:3][CH:2]=1.O[CH:14]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH:14]([C:9]2[C:10](=[O:11])[C:4]3[C:5]([C:7](=[O:12])[CH:8]=2)=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:27][CH:26]=1
Reactant: Oc1ccc(O)c2ccccc12
Reactant: COc1ccc(C(O)CCCCC(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(CCCCC(=O)O)C2=CC(=O)c3ccccc3C2=O)cc1
Reaction time: 8 h
Yield: 21.2 %

Procedure:
1,4-Naphthohydroquinone (8 g) was reacted with 6-hydroxy-6-(4-methoxyphenyl)hexanoic acid (11.9 g) in the presence of p-toluenesulfonic acid (3.8 g) in toluene (200 ml) at 80° C. for 15 hours. Then, the reaction mixture was extracted with ethyl acetate and concentrated. The residue was submitted to an overnight reaction with an aqueous solution (120 ml) of iron (III) chloride hexahydrate (31 g) (0.1 ml) in acetic acid (70 ml) at room temperature. This reaction mixture was extracted with ethyl acetate and concentrated and the residue was purified by silica gel column chromatography. Recrystallization from hexane-ethyl acetate gave 4 g of the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][CH2:15][CH:16]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]3)=[C:11]([C:29]([F:32])([F:31])[F:30])[CH:10]=2)O1.[NH2:34][C:35]1[C:36]([C:44]#[N:45])=[N:37][C:38](Cl)=[CH:39][C:40]=1[NH:41][CH3:42].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.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(Cl)Cl.O>[NH2:34][C:35]1[C:40]([NH:41][CH3:42])=[CH:39][C:38]([C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][CH2:15][CH:16]3[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:19]3)=[C:11]([C:29]([F:31])([F:32])[F:30])[CH:10]=2)=[N:37][C:36]=1[C:44]#[N:45]
Reactant: CNc1cc(Cl)nc(C#N)c1N
Reactant: CC(C)(C)OC(=O)N1CC(CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C(F)(F)F)C1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNc1cc(-c2ccc(OCCC3CN(C(=O)OC(C)(C)C)C3)c(C(F)(F)F)c2)nc(C#N)c1N
Temperature: 100 °C

Procedure:
A solution of tert-butyl 3-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate (413 mg) in dioxane (3 ml) was added to a flask charged with 3-amino-6-chloro-4-(methylamino)picolinonitrile (160 mg), tris(dibenzylideneacetone)dipalladium (0) (40.1 mg), tricyclohexylphosphine (29.5 mg) and potassium phosphate (372 mg). Water (1.2 ml) was added and the reaction was placed under a nitrogen atmosphere and heated to 100° C. for 2 hours. The mixture was allowed to cool to room temperature then diluted with EtOAc (150 ml) filtered through celite and washed with water (2×100 ml) and brine (50 ml). Organics were dried over sodium sulphate and solvent evaporated under reduced pressure to afford crude product as a brown oil. Purification by flash chromatography (50 g silica column, DCM to 5% MeOH in DCM mobile phase) afforded product still containing minor impurities. DCM was added to the residue causing solid to crash out of solution. The solid was collected by filtration and washed with ether to yield desired product tert-butyl 3-(2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[N:17]1[CH2:22][CH2:21][CH:20]([CH:23]([CH3:34])[CH2:24][N:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[N:27][S:26]2(=[O:33])=[O:32])[CH2:19][CH2:18]1.Cl>C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[N:17]1[CH2:22][CH2:21][CH:20]([CH:23]([CH3:34])[CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[NH:27][S:26]2(=[O:32])=[O:33])[CH2:19][CH2:18]1
Reactant: COc1cc2ncnc(N3CCC(C(C)CN4C=CC(C)=NS4(=O)=O)CC3)c2cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc2ncnc(N3CCC(C(C)CN4CCC(C)NS4(=O)=O)CC3)c2cc1OC
Reaction time: 16 h

Procedure:
Sodium borohydride (0.025 g) was added at room temperature to a stirred solution of 1-(6,7-dimethoxyquinazolin-4-yl)-4-[1-(1,1-dioxo-5-methyl-1,2,6-thiadiazin-2-yl)prop-2-yl]piperidine (0.30 g) (Example 35) in absolute ethanol (5 ml.). After stirring for 16 hours, the mixture was acidified to pH1 with 2M hydrochloric acid and concentrated in vacuo. The residue was treated with aqueous sodium carbonate solution to pH12, extracted with chloroform (3×10 ml.), and the combined extracts were dried (MgSO4) and evaporated to yield an oil which was chromatographed on silica ("Merck 60.9385") eluting with methanol:ethyl acetate, 1:20, to give a solid. Recrystallisation from ethyl acetate-ether afforded 1-(6,7-dimethoxyquinazolin-4-yl)-4-[1-(1,1-dioxo-5-methyltetrahydro-1,2,6-thiadiazin-2-yl)prop-2-yl]piperidine as white microcrystals, m.p. 172°-175°, (0.15 g).
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([Li])[CH2:14][CH2:15][CH3:16]>O1CCCC1>[CH2:16]([C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:8][CH2:9][CH2:10][CH2:11][S:12]1)[CH2:15][C:14]#[CH:13]
Reactant: c1ccc(C2SCCCS2)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCCC1(c2ccccc2)SCCCS1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-phenyl-1,3-dithiane (6.4 g, 32.7 mmol) in tetrahydrofuran (100 mL) at -40° C. under argon atmosphere was added 2.5M n-butyllithium (13.1 mL, 37.7 mmol). After 30 minutes the temperature was adjusted to -20° C. and maintained for 1.5 hour. The temperature of the dark brown solution was lowered to -78° C. and but-4-yne (1.5 g, 14.9 mmol) was added neat. After 1 hour, the temperature was raised to -60° C. for 1.5 hour and the solution was then stored at -20° C. overnight. The reaction mixture was poured onto water, the layers separated, and the aqueous layer was back-extracted with methylene chloride (2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4) and the solvents evaporated at reduced pressure to give the product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:19]3[CH:23]=[CH:22][N:21]=[C:20]3[CH3:24])[O:11][C:12]=2[CH2:13][CH2:14][C:15](OC)=[O:16])=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:19]3[CH:23]=[CH:22][N:21]=[C:20]3[CH3:24])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Agent: COCCO[Al+]OCCOC
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a solution of methyl 4-(4-chlorophenyl)-2-(2-methylimidazol-1-yl)-5-oxazolepropionate (716.6 g) in toluene (7166 ml) was added dropwise sodium bis(2-methoxyethoxy)aluminum hydride (70% toluene solution, 957.6 g) at not higher than 5° C. over 4 h. To the reaction mixture was added dropwise 10% aqueous Rochelle salt solution (7166 ml) at not higher than 10° C. and the precipitated crystals were collected by filtration. The obtained crystals were washed with 10% Rochelle salt and water, and dried under reduced pressure. The residue was suspended in a mixture of ethyl acetate (717 mL) and isopropyl ether (2866 mL) and the suspension was stirred at room temperature for 3 h. The obtained crystals were collected by filtration to give the title compound (509 g, yield: 77.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][CH3:25])=[CH:19][CH:18]=1.C1C(=O)N([Cl:42])C(=O)C1>>[Cl:42][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:24][CH3:25])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC[C@@H](c1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1)N(C)C(=O)OC(C)(C)C
Product: CC[C@@H](c1ccc(-c2c(OC)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1)N(C)C(=O)OC(C)(C)C
Yield: 61 %

Procedure:
Following General Procedure H, ((S)-tert-butyl 1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propyl(methyl)carbamate) (200 mg, 0.41 mmol) was reacted with NCS (68 mg, 0.50 mmol) to afford the desired product (130 mg, 61%) as a yellow solid: ESI MS m/z 513 [C27H29ClN2O4S+H]+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][OH:3].[C:5]1([S:11](Cl)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>O>[OH:3][CH2:2][CH2:1][NH:4][S:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:13])=[O:12]
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(NCCO)c1ccccc1
Temperature: 60 °C
Yield: 95.4 %

Procedure:
128.3 g of 2-ethanolamine (2.1 mol) and 150 g of water are introduced into a 1 litre reactor equipped with a thermostatically-controlled jacket, a stirrer and a dropping funnel. 353 g of benzenesulphonyl chloride (2 mol) are introduced into the dropping funnel. The reactor is heated to approximately 60° C. and the benzenesulphonyl chloride is then allowed to run dropwise into the reactor at the rate of approximately 3 ml/min. The exothermicity of the reaction is thus controlled and the temperature changes to reach 70 to 75° C. at the end of addition. The pH is prevented from falling below 9 by gradual addition of a 20% solution of sodium hydroxide in water. After a few hours, the reaction is complete. The reaction mixture is then extracted with a third water-insoluble solvent, such as ethyl acetate. This organic phase is collected. The aqueous phase is extracted and the combined organic phases are distilled under vacuum in order to remove the extraction solvent. 384 g of N-(2-hydroxyethyl)benzenesulphonamide are thus obtained, i.e. a yield of 95.5% with a purity of greater than 99%. This product, which is liquid at room temperature, is characterized by IR spectroscopy and NMR spectro-scopy, as well as by GC and HPLC analysis.
Reaction SMILES: BrC1SC(Cl)=C(Cl)C=1[C:7](=[O:10])[CH2:8][Cl:9].[Br:13][C:14]1[C:18]([Br:19])=[CH:17][S:16][CH:15]=1.ClCC(Cl)=O.CCCCCC.C(OCC)(=O)C>C(#N)C.O>[Cl:9][CH2:8][C:7]([C:15]1[S:16][CH:17]=[C:18]([Br:19])[C:14]=1[Br:13])=[O:10]
Reactant: O=C(CCl)c1c(Br)sc(Cl)c1Cl
Reactant: Brc1cscc1Br
Agent: O=C(Cl)CCl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(CCl)c1scc(Br)c1Br
Yield: 97 %

Procedure:
General procedure described for compounds 1 and 2 starting from 3,4-dibromothiophene and chloroacetyl chloride. The product was isolated by column chromatography column (hexane:ethyl acetate 8:1). Yield 97%, m.p.: 86-8° C., 1H-NMR (CDCl3): δ7.7 (s, 1H, Ar), 4.8 (s, 2H, CH2); 13C-NMR (CDCl3): δ185.4 (CO), 140.0 (C—CO), 133.7 (CH), 120.8 (C—Br), 119.6 (C—Br), 50.1 (CH2); M/z (EI): 322, 320, 318, 316 (M+, 3, 11, 15, 7%), 271, 269, 267 (M-CH2Cl, 56, 100, 56%); HPLC: Delta Pak Column C18, 5 μm, 300 A, (150×3.9 mm), Purity 94%, r.t.=6.06 min, acetonitrile/H2O (0.05% H3PO4+0.04% Et3N) 50/50.
Reaction SMILES: ClCCl.C(N(CC)CC)C.Cl.[NH2:12][OH:13].[C:14]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15]>CCCCCC.C(OCC)(=O)C>[Si:18]([O:13][NH2:12])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)[Si](ON)(c1ccccc1)c1ccccc1
Reaction time: 0.75 h
Yield: 69.1 %

Procedure:
Under nitrogen, a 50 L extractor was charged with dichloromethane (20 L), triethylamine (7.1 L, 50.9 mol), and hydroxylamine hydrochloride (1769 g, 25.5 mol). The mixture was stirred for 45 minutes then tert-butylchlorodiphenylsilane (7 kg, 25.5 mol) was added in seven 1 kg portions over 40 minutes. Additional dichloromethane (10 L) was added, filling the vessel to capacity. The joints were stoppered and the mixture stirred at 20° C. for 5 days. The resulting thick white suspension was filtered to remove the precipitate (mostly triethylamine hydrochloride). The filtrate was concentrated to a thick paste by rotary evaporation on two separate evaporators. Ethyl acetate (4 L) was added to each portion and evaporation continued until 2 L of solvent were condensed. The suspension from each half was combined in the 50-L reactor, ethyl acetate (28 L) was added, and the mixture was stirred for 15 minutes. The mixture was filtered (removing the remaining triethylamine hydrochloride) and the solvent evaporated (again using two rotary evaporators). When most of the solvent was removed, hexane (4 L) was added to each portion and evaporation continued until 2 L of solvent were condensed. The two halves were combined in the 50-L reactor, hexane (20 L) was added, and the mixture was stirred for 15 minutes. The resulting white solid was collected by filtration, washed with hexanes, and dried in a vacuum oven at 40° C., giving 4780 g (69% yield) of O-(tert-butyldiphenylsilyl)-hydroxylamine.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([N:15]1[CH2:22][C:21]([F:24])([F:23])[CH2:20][C@@:16]1([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:39][CH2:40][CH:41]([OH:48])[CH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][CH3:45].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl>[F:23][C:21]1([F:24])[CH2:22][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[C:16]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=3)=[CH:28][CH:27]=2)([C:17]([NH:39][CH2:40][CH:41]([OH:48])[CH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][CH3:45])=[O:19])[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@@]1(Cc1ccc(-c2ccc(F)cn2)cc1)C(=O)O
Reactant: CCC(C)(C)CC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(C)(C)CC(O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CC(F)(F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-methylmorpholine (0.2 mL, 1.8 mmol) was added to a solution of 1-(tert-butoxycarbonyl)-4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]proline (175 mg, 0.40 mmol), 1-amino-4,4-dimethylhexan-2-ol (58 mg, 0.40 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (92 mg, 0.48 mmol), and hydroxybenzotriazole (65 mg, 0.48 mmol) in dichloromethane (40 mL). After stirring at ambient temperature overnight, the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated in vacuo to afford tert-butyl 4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]-2-{[(2-hydroxy-4,4-dimethylhexyl)amino]carbonyl}-pyrrolidine-1-carboxylate which was used in the subsequent step without further purification.