Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:16][O:17][C:18]([C:20]1[CH:29]=[CH:28][C:23]2[O:24][C:25]([CH3:27])=[CH:26][C:22]=2[CH:21]=1)=[O:19]>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:26]1[C:22]2[CH:21]=[C:20]([C:18]([O:17][CH3:16])=[O:19])[CH:29]=[CH:28][C:23]=2[O:24][C:25]=1[CH3:27])=[O:9]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2oc(C)cc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc2oc(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Aluminum chloride (2.52 g, 18.9 mmol) was suspended in methylene chloride (25 ml) and 2,4-dichlorobenzoyl chloride (1.98 g, 9.5 mmol) was added. Then, 5-(methoxycarbonyl)-2-methylbenzo[b]furan (1.5 g, 7.9 mmol) was added and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and then saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give the objective compound (2.9 g, quantitative) as colorless crystals.
Reaction SMILES: [CH3:1][CH:2]([CH:6]([Ge:8]([Cl:11])([Cl:10])[Cl:9])[CH3:7])[C:3](O)=[O:4].S(Cl)([Cl:14])=O>>[CH3:1][CH:2]([CH:6]([Ge:8]([Cl:11])([Cl:10])[Cl:9])[CH3:7])[C:3]([Cl:14])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CC(C(=O)O)C(C)[Ge](Cl)(Cl)Cl
Product: CC(C(=O)Cl)C(C)[Ge](Cl)(Cl)Cl
Yield: 90.4 %

Procedure:
28.0 g (0.1 mol) of 2-methyl-3-(trichlorogermyl)butanoic acid was treated with 100 ml of thionyl chloride. The reaction mixture was distilled under a reduced pressure to obtain 27.0 g of 2-methyl-3-(trichlorogermyl)butanoyl chloride as a pale yellow portion having a boiling point of 99° to 100° C./6 mmHg (yield: 90.4%).
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([C:23]1[CH:24]=[N:25][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:27][CH:28]=1)(O)[CH2:17][CH2:16][CH2:15]2.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:7][C:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH3:10])[CH:13]=2)[C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[N:25][CH:24]=1
Reactant: COc1ccc2c(c1)CCCC2(O)c1ccc(OCCN2CCCC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(Br)=C2c1ccc(OCCN2CCCC2)nc1
Reaction time: 18 h
Yield: 69.3 %

Procedure:
Pyridinium bromide perbromide (3.5 g, 12.2 mmol) was added to a solution of 6-methoxy-1-[6-(2-pyrrolidin-1-ylethoxy)pyridin-3-yl]-1,2,3,4-tetrahydronaphthalen-1-ol (3.3 g, 8.9 mmol) in CH2Cl2 (50 mL). The reaction was stirred for 18 h and aqueous NaHCO3 (satd) was added. The aqueous layer was extracted with CH2Cl2 and the combined organic solution was washed with water and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3 : MeOH, 95:5) provided the desired vinyl bromide (2.65 g, 70%). 1H NMR (250 MHz, CDCl3): δ 8.0 (d, J=2.4 Hz, 1H), 7.41 (dd, J=2.4, 8.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 6.69 (m, 1H), 6.55 (m, 2H), 4.92 (t, J=5.8 Hz, 2H), 3.76 (s, 3H), 2.94 (m, 6H), 2.64 (m, 4 H), 1.82 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12]C)[CH:10]=2)[N:5]=[CH:4][N:3]=1.NC(C(O)=[O:30])CCSC.[OH-].[Na+]>CS(O)(=O)=O>[CH3:22][N:19]1[CH2:20][CH2:21][CH:16]([CH2:15][O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([OH:30])=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[OH:12])[CH2:17][CH2:18]1
Reactant: CSCCC(N)C(=O)O
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(COc2cc3ncnc(O)c3cc2O)CC1
Temperature: 150 °C
Yield: 71 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazoline (see Journal of Medicinal Chemistry, 2002, 45, 1300-12, 9.8 g, 30 mmol), D,L-methionine (7.15 g, 48 mmol) and methanesulphonic acid (50 ml) was heated at 150° C. for 32 hours. The reaction mixture was allowed to cool to room temperature. The pH was adjusted to 8 with aqueous sodium hydroxide then, aqueous sodium hydrogen carbonate and concentrated to half the original volume. The resultant solid was filtered and washed with water and then dried for 16 hours at 60° C. to give 7-[(1-methylpiperidin-4-yl)methoxy]quinazoline-4,6-diol (6.16 g, 71% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13]Cl)[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[CH3:23][NH:24][CH3:25]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13][N:24]([CH3:25])[CH3:23])[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: O=C(CCl)N1CCOc2ccc(Cl)cc2C1c1ccccc1
Reactant: CNC
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCOc2ccc(Cl)cc2C1c1ccccc1
Reaction time: 16 h

Procedure:
A solution of 4.78 g (14.2 millimoles) of the 7-chloro-4-(2-chloroacetyl)-5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine produced in step (a) in 150 ml of CH2Cl2 was saturated with dimethylamine gas at 0°. The flask was stoppered and the solution was stored at -15° for 16 hours.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][CH3:12])[N:9]=[C:8]([C:13]#[N:14])[CH:7]=1.C([O-])(=O)C.[K+].[Br:20]Br>C(O)(=O)C>[Br:20][C:7]1[C:8]([C:13]#[N:14])=[N:9][N:10]([CH2:11][CH3:12])[C:6]=1[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: CCn1nc(C#N)cc1CCCCCl
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCn1nc(C#N)c(Br)c1CCCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(4-Chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile (10.8 g, 51.0 mmol) was treated with potassium acetate (10.0 g, 102 mmol) and bromine (2.9 mL, 56 mmol) in acetic acid (102 mL), and the reaction was stirred overnight at ambient temperature. The acetic acid was removed under reduced pressure, and the residue was partitioned between water and chloroform. The mixture was adjusted to pH 10 with the addition of 2 N aqueous sodium carbonate. The aqueous layer was extracted with chloroform, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting yellow oil was purified by chromatography on a HORIZON HPFC system (eluting with hexanes/ethyl acetate in a gradient from 95:5 to 50:50) to provide 4-bromo-5-(4-chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:17]([C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)[NH2:18]>C(O)(=O)C>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[N:17]=[N:18][C:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]=1[OH:16]
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Reactant: NNc1nc2ccccc2s1
Solvent: CC(=O)O
Product: Oc1c(N=Nc2nc3ccccc3s2)c2ccccc2c2ccccc12
Temperature: 105 °C

Procedure:
A reaction flask was loaded with acetic acid (50 ml) and 9,10-phenanthrenequinone (4.2 g), and the temperature was raised to 105° C. with stirring to dissolve 9,10-phenanthrenequinone. To this mixture, 2-hydrazinobenzothiazole (3.3 g) was added in three hours. After stirring at 100 to 110° C. for one hour, the reaction mixture was filtrated. The filtrated crystals were washed with methanol and dried to give intended crystals (3.9 g).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([C:30](OCC)=[O:31])=[CH:27][C:26]=2[CH:35]=1>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([C:30]([C:19]3[C:14]([F:13])=[N:15][CH:16]=[CH:17][CH:18]=3)=[O:31])=[CH:27][C:26]=2[CH:35]=1
Reactant: CCOC(=O)c1cc2cc(OC)ccc2o1
Reactant: Fc1ccccn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)c3cccnc3F)cc2c1
Reaction time: 0.5 h

Procedure:
At 0° C. a solution of n-BuLi (0.73 ml, 1.17 mmol) is added to diisopropylamine (0.18 ml, 1.3 mmol). The mixture is stirred for 30 minutes at the same temperature before the resulting solution is added dropwise to a solution 2-fluoropyridine (0.1 ml, 1.17 mmol) in THF (3 ml) at −78° C. After stirring for one hour ethyl 5-methoxy-benzofuran-2-carboxylate (0.25 g, 1.17 mmol) in THF (4 ml) is added and stirring is continued for 2 hours at the same temperature. The reaction mixture is allowed to reach room temperature before quenching with saturated aqueous ammonium chloride solution. The product is extracted with ethyl acetate. Chromatography on silicagel gives the title compound, m.p. 130-134° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH2:12][CH:13]1[CH2:15][O:14]1.O>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH:13]1[CH2:15][O:14]1
Reactant: Oc1cccc(Br)c1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc(OCC2CO2)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 113.3 %

Procedure:
To a solution of compound NaH (416.2 mg, 17.34 mmol) in DMF (10 mL) was added 3-bromophenol (1.0 g, 5.78 mmol) at 20° C. After addition the solution was stirred for 5 minutes at this temperature before the addition of 2-(bromomethyl)oxirane (1.2 g, 8.67 mmol). The reaction mixture was stirred for 16 h at 20° C. Once complete the reaction mixture was treated with water (50 mL) and extracted with EA (2×20 mL) and the organic layers combined and washed with NaHCO3, brine (30 mL), dried over Na2SO4 and concentrated to give the compound 2-((3-bromophenoxy)methyl)oxirane (1.5 g, crude) as colorless oil which was used in next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([Cl:19])=[N:11][CH:12]=[C:13]([CH:18]=1)[C:14](OC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:13]([CH2:14][OH:15])[CH:12]=[N:11][C:10]=1[Cl:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1cnc(Cl)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
To a suspension of methyl 5-(benzyloxy)-6-chloronicotinate (3.00 g) in ethanol (40 mL) was added sodium tetrahydroborate (1.02 g), and the mixture was stirred at 60° C. for 3 hr. Water was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.76 g) as a colorless solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20]N1C(=O)CCC1=O.[CH2:28](O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH2:37]>C1COCC1>[Cl:20][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH2:37]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=CCCCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCCCCCCCCl
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To a flame-dried round-bottomed flask was added PPh3 (1.1 equiv, 27.5 mmol, 7.21 g) and THF (65 mL). N-chlorosuccinimide (1.1 equiv, 27.5 mmol, 3.67 g) was dissolved in THF (50 mL) and added dropwise. The mixture was stirred for 5 min, and 9-decen-1-ol (1 equiv, 25 mmol, 3.91 g) was added dropwise in THF (30 mL). After 9 h, the volatile components of the reaction were evaporated and hexanes (100 mL) and H2O (50 mL) were added. The liquid was decanted and the resulting solid was washed with hexanes. The aqueous layer was collected and extracted with hexanes (2×50 mL). The combined organic layers were washed sequentially with bleach (30 mL) and brine (50 mL). The crude product was filtered through a pad of silica (which was washed with ˜400 mL of hexanes) and concentration in vacuo to afford 10-chlorodecene (3.48 g, 20 mmol, 80%), which was deemed pure by NMR and used without further purification. TLC Rf=0.87 (5% EtOAc/Hex); 1HNMR (400 MHz): δ 5.84 (ddt, 1H, J=17.4, 10.3, 6.7 Hz), 5.02 (ddd, 1H, J=17.4, 2.0, 3.6 Hz), 4.93-4.98 (m, 1H), 3.56 (t, 2H, J=6.5 Hz), 2.02-2.12 (m, 2H), 1.74-1.84 (2H), 1.27-1.50 (10H); 13CNMR (100 MHz): δ 139.2, 114.2, 45.2, 33.8, 32.7, 29.3, 29.0, 28.88, 28.85, 26.88.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][N:6]=1.N1C=CC=CC=1.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:22][S:19]([NH:1][C:2]1[S:3][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][N:6]=1)(=[O:21])=[O:20]
Reactant: CCOC(=O)Cc1cnc(N)s1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cc1cnc(NS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of ethyl 2-aminothiazol-5-ylacetate (32 g.) in methylene chloride (160 ml.) was added pyridine (27.2 g.) under ice-cooling, and to the mixture was dropwise added mesyl chloride (29.6 g.) in methylene chloride (29.6 ml.) over 30 minutes at 8° to 10° C. The mixture was further stirred for 8 hours at room temperature. After the reaction, methylene chloride was distilled off from the reaction mixture, and to the residue were added water (300 ml.) and ethyl acetate (300 ml.). The resulting mixture was adjusted to pH 2 with 10% hydrochloric acid under ice-cooling, and the precipitates were collected by filtration and washed with ethyl acetate. The precipitates were recrystallized from ethanol (600 ml.) to give ethyl 2-methanesulfonamidothiazol-5-ylacetate (27.3 g.), mp 153° to 155° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C=O.[CH:12]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])OCC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O.C(OCC)C>[CH2:20]([O:19][CH:12]([O:16][CH2:17][CH3:18])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH3:21]
Reactant: O=CCCCCCCCCCl
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(CCCCCCCCCl)OCC
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
12.0 gms of 9-chloro-nonaldehyde was heated at reflux with 20 gms of triethyl orthoformate, 9 gms anhydrous ethanol and one drop of concentrated sulphuric acid for one hour. The reaction was cooled, 10 gms of sodium carbonate was added and the mixture stirred 10 minutes. The mixture was diluted with 100 mls of diethyl ether and extracted twice with 50 mls of saline solution. The organic layer was dried over sodium sulphate, concentrated on rotary evaporator and distilled. The major fraction distilled at 84° at 0.1 torr yielding 13.3 gms of 1,1-diethoxy-9-chloro nonane. N.M.R. (CdCl3): triplet 4.47 ppm (1H), multiplet 3.58 ppm (6H), triplet 1.21 ppm.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH3:11])[C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22]Br>CN(C)C=O>[CH3:11][N:8]1[C:6]2[N:7]=[C:2]3[N:3]([C:4](=[O:12])[C:5]=2[CH:10]=[N:9]1)[CH2:22][CH2:21][CH2:20][S:1]3
Reactant: Cn1ncc2c(=O)[nH]c(S)nc21
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(=O)n3c(nc21)SCCC3
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
In 80 ml of dimethylformamide was dissolved 4.0 g (22.0 mmol) of 4,5-dihydro-6-mercapto-1-methylpyrazolo[3,4-d]pyrimidin-4(1H)-one [Helv. Chim. Acta, 42, 349 (1959)], and 9.1 g (66 mmol) of potassium carbonate and 3.34 ml (32.9 mmol) of 1,3-dibromopropane were added to the solution, followed by stirring at 80° C. for 8 hours. After evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (100:1) to give 1.87 g (38%) of Compound 44. The compound was recrystallized from ethanol for purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]4[N:17]([S:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[CH:18]=[CH:19][C:12]=34)[CH:7]=[C:6]([NH2:30])[C:5]=2[CH:4]=[N:3]1.N1C=CC=CC=1.[CH3:37][C:38]1[S:39][CH:40]=[C:41]([C:43](Cl)=[O:44])[N:42]=1>C(Cl)Cl>[CH3:37][C:38]1[S:39][CH:40]=[C:41]([C:43]([NH:30][C:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]4[N:17]([S:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[CH:18]=[CH:19][C:12]=34)[CH:9]=[C:10]3[C:5]=2[CH:4]=[N:3][N:2]3[CH3:1])=[O:44])[N:42]=1
Reactant: Cc1nc(C(=O)Cl)cs1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(N)c5cnn(C)c5c4)ccnc32)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(NC(=O)c5csc(C)n5)c5cnn(C)c5c4)ccnc32)cc1
Temperature: 25 °C

Procedure:
1-Methyl-6-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-indazol-4-amine (75 mg) and pyridine (0.029 ml) were added to DCM (5 ml) under stirring at RT under nitrogen. 2-Methyl-1,3-thiazole-4-carbonyl chloride (38 mg) was added into the reaction mixture. The reaction mixture was partitioned between water (20 ml) and DCM (20 ml).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[CH:11]=[C:10]1[OH:15]>C(O)(=O)C>[Cl:5][C:6]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:7]=1[CH:8]=[C:9]1[NH:13][C:12](=[O:14])[C:11](=[N:1][OH:3])[C:10]1=[O:15]
Reactant: O=N[O-]
Reactant: O=C1C=C(O)C(=Cc2ccc(Cl)cc2Cl)N1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=Cc2ccc(Cl)cc2Cl)C(=O)C1=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of 1.1 mmol (0.075 g) sodium nitrite was added dropwise to an ice-cooled solution of 2 mmol 5-(2,4-dichlorobenzylidene)-4-hydroxy-1,5-dihydropyrrol-2-one (prepared in accordance with H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, 331, 389-394) and H.-D. Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring. The resulting solution was then stirred at room temperature for 30 minutes and concentrated in vacuo. The residue is purified by recrystallization from ethanol. The yield of 5-(2,4-dichlorobenzylidene)-pyrrolidine-2,3,4-trione 3-oxime was 55%, with a melting point of 180° C.
Reaction SMILES: Cl.[N:2]1(N=C2CCCC(O)=C2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.Cl.[CH3:21][C:22]([OH:24])=O>>[CH:9]1[CH:8]=[CH:7][C:6]2[CH2:5][CH2:4][CH2:3][N:2]3[C:11]=2[C:10]=1[C:3]1[C:22](=[O:24])[CH2:21][CH2:6][CH2:5][C:4]=13
Reactant: CC(=O)O
Reactant: OC1=CC(=NN2CCCc3ccccc32)CCC1
Agent: Cl
Product: O=C1CCCc2c1c1cccc3c1n2CCC3
Temperature: 25 °C
Yield: 33 %

Procedure:
3-(3,4-Dihydro-1(2H)-quinolinylimino)-1-cyclohexen-1-ol hydrochloride (4.78 g, 17 mmol) was mixed with AcOH (37 mL) and conc. HCl (6.1 mL). The reaction mixture was refluxed for 1 h and cooled to RT. The reaction mixture was concentrated in vacuo then the residue was dissolved in CH2Cl2. The organic solution was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel (hex:EtOAc 1:1) to give 5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one (1.25 g, 33%) as a light yellow solid.
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][C:17]1[N:18]=[CH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([NH:27][C:28](=[O:33])C(Cl)(Cl)Cl)[CH:23]=[CH:22][CH:21]=2>>[NH2:16][C:17]1[N:18]=[CH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([NH:27][C:28]([NH:13][CH2:12][C:11]1[CH:10]=[CH:9][C:8]([N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=1)=[O:33])[CH:23]=[CH:22][CH:21]=2
Reactant: NCc1ccc(N2CCCCCC2)cc1
Reactant: Nc1cc2c(NC(=O)C(Cl)(Cl)Cl)cccc2cn1
Product: Nc1cc2c(NC(=O)NCc3ccc(N4CCCCCC4)cc3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 1B using 4-(1-azepanyl)benzylamine and the product from Example 150A instead of 2-(3-fluorophenyl)ethylamine and the product from Example 1A. 1H NMR (300 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.19 (s, 1H), 7.88 (d, 1H, J=8.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.09 (m, 3H), 6.76 (t, 1H, J=5.4 Hz), 6.66 (m, 3H), 5.90 (s, 2H), 4.17 (d, 2H, J=5.4 Hz), 3.24 (m, 4H), 1.71 (m, 4H), 1.44 (m, 4H); MS (ESI) 390 (M+H)+; Anal. Calcd for C23H27N5O.0.4H2O: C, 69.64; H, 7.06; N, 17.65. Found: C, 69.53; H, 6.81; N, 17.38.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]4[C@:21]([CH2:23][OH:24])([CH2:22][C:13]=3[CH:12]=[N:11]2)[CH2:20][N:19]([S:25]([C:28]2[CH:29]=[N:30][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH2:18][CH2:17]4)=[CH:6][CH:5]=1.O1CC[CH2:42][CH2:41]1>ICC>[CH2:41]([O:24][CH2:23][C@@:21]12[CH2:20][N:19]([S:25]([C:28]3[CH:29]=[N:30][C:31]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[CH:32][CH:33]=3)(=[O:26])=[O:27])[CH2:18][CH2:17][C:16]1=[CH:15][C:14]1[N:10]([C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)[N:11]=[CH:12][C:13]=1[CH2:22]2)[CH3:42]
Reactant: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A suspension of sodium hydride (1.5 g) in tetrahydrofuran (20 mL) at room temperature was treated sequentially with a solution of [(R)-1-(4-fluorophenyl)-6-[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]-1,4,7,8-tetrahydro-1,2,6-triaza-cyclopent-a[b]naphthalen-4a-yl]methanol (8.0 g) in tetrahydrofuran (60 mL) and iodoethane (3.7 mL), and the resulting mixture was stirred at 50° C. for 1 hour. The mixture was cooled to room temperature and partitioned between ethyl acetate and 1.0 M aqueous hydrochloric acid solution. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with aqueous sodium thiosulfate solution, aqueous potassium carbonate solution, water and brine, and then dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and diethyl ether (1:20 to 1:10 by volume), to afford a cream foam (7.5 g). The cream foam was crystallized from industrial methylated spirits to afford the title compound as a white solid (6.3 g). LCMS (Method A): 552 (M+H)+, Retention time 5.0 minutes. 1H NMR (CDCl3): δ 8.53-8.49 (d, 1H, J=2.4 Hz), 7.79-7.73 (dd, 1H, J=9.2, 2.5 Hz), 7.41-7.33 (m, 3H), 7.15-7.07 (t, 2H, J=8.0 Hz), 6.62-6.55 (d, 1H, J=9.0 Hz), 6.25-6.21 (d, 1H, J=2.3 Hz), 4.15-4.08 (dd, 1H, J=12, 2.3 Hz), 3.89-3.80 (m, 1H), 3.80-3.73 (m, 4H), 3.67-3.59 (m, 4H), 3.52-3.35 (m, 3H), 3.14-3.02 (m, 2H), 2.74-2.61 (m, 1H), 2.41-2.29 (m, 2H), 2.20-2.04 (dd, 2H, J=34, 16 Hz), 1.19-1.11 (t, 3H, J=7.0 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C1CCCCC=1>C(OCC)(=O)C.[Pd]>[F:16][C:10]1([CH2:9][O:8][C:7]2[N:6]=[CH:5][C:4]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:3][CH:2]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: NS(=O)(=O)c1cnc(OCC2(F)CCOCC2)c(Br)c1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(OCC2(F)CCOCC2)nc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide (200 mg) and cyclohexene (0.549 mL) in ethyl acetate (10 mL) was added 10% palladium on carbon (57.6 mg). The suspension was stirred for 60 minutes at 120° C. The reaction mixture was filtered and concentrated. The product was purified by reverse-phase flash chromatography (C18, 15 g, 10%-100% acetonitrile/H2O/trifluoroacetic acid 0.1%).