Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])[C:10]=1[CH3:27].CC(C)([O-])C.[Na+].[CH3:34][C@H:35]1[C@H:39]([CH3:40])OS(=O)(=O)[O:36]1.Cl>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([C@H:39]([CH3:40])[C@@H:35]([OH:36])[CH3:34])[CH:12]=[C:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:15])[C:10]=1[CH3:27]
Reactant: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c[nH]c1-c1ccc(F)cc1Cl
Reactant: C[C@@H]1OS(=O)(=O)O[C@H]1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cn([C@H](C)[C@H](C)O)c1-c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
To a solution of 5-(2-chloro-4-fluorophenyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carboxamide (0.50 g, 1.2 mmol) in anhydrous DMA (8.0 ml) was added sodium tert-butoxide (0.27 g, 2.8 mmol) and stirred at room temperature for 30 min under N2. (4S,5S)-4,5-dimethyl-1,3,2-dioxathiolane 2,2-dioxide (0.28 g, 1.8 mmol) in anhydrous DMA (2.0 ml) was added to the solution and stirred at 70° C. for 2.0 h. The reaction mixture was cooled to room temperature and added 2N HCl (2.0 ml) and concentrated on a rotary evaporator. To this residue was added anhydrous THF (4.0 ml) and 5N HCl (5.0 ml) and stirred at 60° C. for 80 min. The mixture was diluted with ethyl acetate and washed with water, satd NaHCO3 and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica-gel column chromatography (3:7 to 2:8 hexane:ethyl acetate) to give an atropisomeric mixture of the title compound (0.29 g, 50%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:41]=[CH:40][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[S:36](=[O:38])(=[O:37])[NH:35][C:34](=[O:39])[CH2:33]5)=[CH:28][CH:27]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:13]([CH2:12][C:11]2[CH:40]=[CH:41][C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[N:7][CH:6]=3)=[CH:9][CH:10]=2)[N:14]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[S:36](=[O:38])(=[O:37])[NH:35][C:34](=[O:39])[CH2:33]3)=[CH:28][CH:27]=2)[CH:15]=1
Reactant: C1CCNCC1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nc4)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCCCC5)nc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-[4-(6-Chloro-pyridin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (63 mg, 0.1 mmol) was treated as described in general procedure L using piperidine (17 mg, 0.2 mmol) to give 5-(4-{4-(2,4-dichloro-phenyl)-2-[4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: C1(C)C(S([Cl:10])(=O)=O)=CC=CC=1.O[CH2:13][CH2:14][CH:15]1[S:20](=[O:22])(=[O:21])[C:19]2[S:23][C:24]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:25][C:18]=2[NH:17][CH2:16]1.[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32]>N1C=CC=CC=1>[ClH:10].[CH2:30]([NH:34][CH2:13][CH2:14][CH:15]1[S:20](=[O:22])(=[O:21])[C:19]2[S:23][C:24]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:25][C:18]=2[NH:17][CH2:16]1)[CH:31]([CH3:33])[CH3:32]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)C(CCO)CN2
Reactant: CC(C)CN
Solvent: c1ccncc1
Product: CC(C)CNCCC1CNc2cc(S(N)(=O)=O)sc2S1(=O)=O
Product: Cl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Toluenesulfonyl chloride (1.91 g, 10 mmol) was added portionwise over 50 minutes to a cold (-10° C. to -5° C.) solution of 3-(2-hydroxyethyl)-2,3-dihydro-4,4-dioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine (1.56 g, 5 mmol) in pyridine (10 ml). This solution was stirred for about 0.5 hr as the temperature rose to 0° C., then isobutylamine (10 ml) was added. The resulting solution was heated at 100° C. overnight. The reaction mixture was concentrated to dryness, and the residue was treated with chloroform. The resulting white solid, 1.7 g, was dissolved in a minimum amount of water, the pH was adjusted to 7.5 and the solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After removal of the dried solvent, the residue was dissolved in ethanol and treated with excess ethanolic hydrogen chloride. Ether was added to the cloud point and the mixture aged for 18 hours. The resulting solid was collected and dried to yield 1.2 g 3-(2-isobutylaminoethyl)-2,3-dihydro-4,4-dioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine hydrochloride, mp 263°-265° C.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[CH2:6]([C@H:9]1[O:11][C@H:10]1[CH2:12][OH:13])[CH2:7][CH3:8].C(Cl)Cl.[OH2:17]>>[CH2:6]([C@@H:9]1[O:11][C@@H:10]1[C:12]([OH:17])=[O:13])[CH2:7][CH3:8]
Reactant: O
Reactant: CCC[C@H]1O[C@H]1CO
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCC[C@@H]1O[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A flask was charged with 34 ml of CCl4, 34 ml of acetonitrle and 2 g of (2S, cis)-3-propyloxiranemethanol. Then 11 g of NaIO4 in 51 ml of water were added, followed by 86 mg of RuCl3 to this biphasic solution. The mixture was stirred vigorously for 3 hrs at RT and 100 ml of methylene chloride was added. The organic phase was separated and water phase was extracted with methylene chloride. The combined black organic phase was dried over MgSO4 and concentrated. The residue was diluted with ether and filtered through celite to give colorless solution. After evaporation of solvent a pure product was obtained (yield 67%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH2:21](Br)[CH:22]=[CH2:23].C1CCN2C(=NCCC2)CC1>ClCCl.CCOC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:18])[C:15]([O:17][CH2:23][CH:22]=[CH2:21])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: C=CCBr
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.150 g, 0.426 mmol) in dichloromethane (5 mL) was treated with allyl bromide (0.155 g, 1.28 mmol) and DBU (0.195 g, 1.28 mmol) and then stirred 2 hours at 20 C. The product mixture was diluted with EtOAc (50 mL), washed with 5% aqueous HCl (20 mL), brine (20 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 0.149 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.34 (s, 1 H), 6.65 (m, 1 H), 6.04 (m, 1 H), 5.47 (d, J=17 Hz, 1 H), 5.30 (d, J=9 Hz, 1 H), 4.59 (s, 2 H), 3.80 (m, 1 H), 3.6−3.3 (m, 3 H), 3.2−2.8 (m, 4 H), 1.31 (m, 3 H). MS calculated for C16H17BrF3NO2+H: 392, observed: 392.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=1)=[CH:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=1.Cl.NO>C(#N)C>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:22][N:6]=[C:7]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:28]=3)[CH:8]=2)=[CH:11][CH:12]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCOc1ccc(C(=O)C=C(N)c2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
Dimethylformamide (44 ml), 1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene (5.5 g) and hydroxylamine hydrochloride (2.0 g) were charged in 300-ml three-necked flask at room temperature and heated, and the reaction was carried out at the inner temperature of 55 to 60° C. for 4 hours. After completion of the reaction, the mixture was cooled down to room temperature, and acetonitrile (110 ml) was added to separate the crystals. The inner temperature was made 0 to 5° C., and the crystals were filtered and washed with acetonitrile (28 ml) and water (110 ml). The crystals were dried overnight in vacuo to give methyl 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate (5.21 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:13][OH:14].[Br:15]Br>S(=O)(=O)(O)O.O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:15][C:6]1[C:5]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:4][C:3]([CH2:13][OH:14])=[C:2]([Cl:1])[CH:7]=1
Reactant: BrBr
Reactant: OCc1cc(OC(F)(F)F)ccc1Cl
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: OCc1cc(OC(F)(F)F)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a solution of (2-chloro-5-trifluoromethoxy-phenyl)-methanol (16.3 g, 71.94 mmol) in sulfuric acid (200 mL) and water (60 mL) was added bromine (12.65 g, 79.13 mmol), followed by silver sulfate (12.34 g, 39.57 mmol). The reaction mixture was stirred at RT for 1 h, poured onto ice, and then extracted with EtOAc (3×100 mL). The organic layers were combined, dried over Na2SO4 and concentrated to afford crude product, which was purified by flash chromatography (0-10% EtOAc in petroleum ether) to give the title intermediate (6.0 g, 27% yield). (m/z): [M−OH]+ calcd for C8H5BrClF3O2 286.91; 288.91. found 289.0.
Reaction SMILES: [CH2:1]([CH:3]1[NH:12][C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:15]=[CH:16][CH:17]=[C:4]12)[CH3:2].N1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][C:27]=1[CH3:36]>C(Cl)Cl>[CH2:1]([CH:3]1[N:12]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[C:27]([CH3:36])[CH:28]=2)(=[O:34])=[O:33])[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:15]=[CH:16][CH:17]=[C:4]12)[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C
Reactant: CCC1Nc2cc(F)c(F)cc2-n2cccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1c2cccn2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.6 %

Procedure:
1.35 g (5.0 mmol) of the product from Example 3 was dissolved in 40 ml of methylene chloride and 1 ml of pyridine added. To this solution was added 1.20 g (5.4 mmol) of 4-methoxy-3-methyl benzenesulfonyl chloride. The solution was stirred at room temperature for 6 hours, after which it was concentrated, then diluted with 5 ml of 2N HCl. The residue was extracted 2 times with ethyl acetate, dried (MgSO4) and concentrated. The crude solid so obtained was chromatographed on silica gel, eluting with 20% ethyl acetate:hexane to afford a light yellow solid, which can be recrystallized from ethyl acetate:hexane to yield 1.52 g (72%) of product.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH2:26][N:25]([C:27]([C@@H:29]([NH2:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:24]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:23]=1.C(N(CC)CC)C>C1COCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]1[CH2:26][N:25]([C:27]([C@@H:29]([NH:34][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:24]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:23]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[C@H](N)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1

Procedure:
A solution of 4-nitrophenyl chloroformate (300 mg, 1.49 mmol, 1.2 equiv) in THF (10 mL) was added drop wise to a stirred solution of (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-carbonyl}-2,2-dimethylpropylamine (16-1, 460 mg, 1.24 mmol, 1.0 equiv) and triethylamine (151 mg, 1.49 mmol, 1.2 equiv) in THF (10 mL) at 23° C. After 1 hr the reaction was filtered and the filtrate concentrated to a pale yellow gum which was purified by flash chromatography on silica gel. Elution with dichloromethane to 3% ethyl acetate/dichloromethane provided 2-hydroxyethyl (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylcarbamate (36-1) as a colorless foam. LRMS m/z (M+H) 536.5 found, 535.2 required.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[O:19]1[CH2:24][CH2:23][CH2:22][O:21][CH:20]1[CH2:25][CH2:26][CH:27]([C:29]1[S:33][C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)=[N:31][C:30]=1[CH3:44])O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:27]([C:29]2[S:33][C:32]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:43])[F:42])=[CH:36][CH:35]=3)=[N:31][C:30]=2[CH3:44])[CH2:26][CH2:25][CH:20]2[O:19][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)CCC1OCCCO1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(CCC2OCCCO2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [rac]-3-[1,3]dioxan-2-yl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 3-(4-{3-[1,3]dioxan-2-yl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester as a mixture of two diastereomeric racemates as colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20]N(C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27].C(O)C>ClC(Cl)Cl.C1CCN2C(=NCCC2)CC1>[Cl:25][C:6]1[C:7]([F:24])=[CH:8][C:9]2[C:4]([CH:5]=1)=[N:3][C:2]1[N:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12](=[O:13])[C:11]=1[CH:10]=2
Reactant: CC(C)(C)N
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc3cc(Cl)c(F)cc3cc2c1=O

Procedure:
The 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine is prepared under the conditions of Example 17 but starting from 8.86 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate and 4.03 g of tert.-butylamine in 45 cm3 of trichloromethane and then in 4.53 g of DBU and 45 cm3 of ethanol 5 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1-tert.-butyl-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 239° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[NH:20][C:21]1[C:26]([C:27]#[N:28])=[CH:25][N:24]=[C:23]2[CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=3)[S:31][C:22]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[NH:20][C:21]1[C:26]([C:27]#[N:28])=[CH:25][N:24]=[C:23]2[CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([CH2:38][N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)=[CH:34][CH:33]=3)[S:31][C:22]=12
Reactant: OCCN1CCNCC1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C=O)cc4)sc23)c(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(CN5CCN(CCO)CC5)cc4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 35.2 %

Procedure:
4-(2-Hydroxyethyl)piperazine (104 mg, 0.80 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (227 mg, 0.50 mmol) in 15 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (800 mg, 3.8 mmol) is added. After stirring at 0° C. for 1.5 hours, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction is quenched by the addition of water and then partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 10% methanol in dichloromethane to provide 100 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}phenyl)thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 189-190° C.; 1H NMR (DMSO-d6) δ 2.27-2.44 (m, 10H), 3.41-3.50 (m, 4H), 3.85 (s, 3H), 4.36 (s, 1H), 7.37 (s, 1H), 7.40 (d, J=8 Hz, 2H), 7.67 (d, J=8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.60 (s, 1H), 9.74 (s, 1H); MS 566.3 (M−H)−.
Reaction SMILES: [CH3:1]C(=O)C=C.[CH2:6]1[CH2:10][O:9][CH2:8][CH2:7]1.[CH3:11][C:12]([CH:14]=[C:15](C)[CH3:16])=[CH2:13].ClCCl>[Cl-].[Al+3].[Cl-].[Cl-].O>[CH3:11][C:12]1([CH3:13])[CH:14]=[C:15]([CH3:16])[CH2:10][CH2:6][CH:7]1[C:8](=[O:9])[CH3:1]
Reactant: C=CC(C)=O
Reactant: C=C(C)C=C(C)C
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)C1CCC(C)=CC1(C)C
Temperature: 5 °C
Yield: 971.6 %

Procedure:
In a 500 ml sulfonation flask with cooling funnel, dropping funnel and mechanical stirring under air (*) at 5° C. was added but-3-en-2-one (43 ml; 0.52 mol) then THF (4.2 ml; 52 mmol) followed by a careful portionwise addition of aluminum chloride (3.5 g; 26 mmol). White fumes and increase of temperature to 20° C. were observed. The mixture turned red. The temperature was decreased to 15° C. and 2,4-dimethyl-1,3-pentadiene (68 ml; 0.52 mol) was added dropwise (90 min). Exothermic reaction was observed. The reaction mixture was stirred for 8 hours at 25° C. and for 10 hours at 45° C. As the diene was still detected but-3-en-2-one was added dropwise (22 ml; 0.26 mol) (10 min) and the mixture was stirred for additional 48 hours at 25° C. Dichloromethane (200 ml) was added to the mixture which was stirred for 5 min and filtered over celite. The red solution obtained was poured into cold water (1 l) and extracted with dichloromethane (4×300 ml). Combined organic layers were washed with brine (500 ml) and water (500 ml), dried over sodium sulfate and filtered over silica. The solvent was removed in vacuo to afford 84 g (97% of theory) of 1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethanone as a clear red oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:35]([N:37]([CH2:45][CH3:46])[CH2:38][CH2:39][CH:40]([OH:44])[CH2:41][CH2:42][CH3:43])[CH3:36].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:44][CH:40]([CH2:39][CH2:38][N:37]([CH2:35][CH3:36])[CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])=[CH:18][CH:17]=1
Reactant: CCCC(O)CCN(CC)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(CCN(CC)CC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-(diethylamino)-3-hexanol (45 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (5 mg, yield 5%).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[N+:20]([O-])=O.[H][H]>[OH-].[Na+].[Pd]>[NH2:20][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])[C:7]=1[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:23])[CH3:1])[C:11]([OH:13])=[O:12]
Reactant: CN(C)CCCNc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCCNc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
4-(3-Dimethylaminopropylamino)-3-nitro-5-sulphamyl-benzoic acid (6.92 g) was dissolved in 2N sodium hydroxide (25 ml), and the solution was hydrogenated at room temperature and 1.1 atmospheres hydrogen pressure after the addition of a palladium-on-carbon catalyst (0.35 g catalyst containing 10% Pd.). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the filtrate was adjusted to a pH of 8 by addition of 4N hydrochloric acid. The precipitated 3-amino-4-(3-dimethylaminopropylamino)-5-sulphamyl-benzoic acid was collected by suction and recrystallized from water. After drying in vacuo at 115°C for 2 hours, the melting point was 264°C (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([CH2:33][CH2:34]O)=[CH:31][CH:30]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:28][C:29]1[CH:37]=[CH:36][C:32]([CH2:33][CH2:34][O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[CH:31][CH:30]=1
Reactant: Oc1ccccc1Br
Reactant: OCCc1ccc(F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(CCOc2ccccc2Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
2-Bromophenol (3.46 g) was mixed with tetrahydrofuran (60 ml) and triphenylphosphine (6.3 g) was added along with 4-fluorophenethyl alcohol (4.2 g). The mixture was cooled in an ice bath before dropwise addition of diisopropyl azodicarboxylate (4.85 g). The mixture was allowed to warm to room temperature over 18 h. The mixture was evaporated and diethyl ether (100 ml) was added. Stirring was continued for 3 h, the mixture was filtered and the filtrate was evaporated. The product was purified by column chromatography eluting with ethyl acetate/hexane mixtures to give a yellow oil (4.47 g).