Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH:13]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:14]([F:17])([F:16])[F:15])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:24]1([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CS(C)=O>[F:15][C:14]([F:17])([F:16])[CH:13]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[O:12][C:11]1[C:2]([NH:33][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: FC(F)(F)C(Oc1nc2ccccc2nc1Cl)c1cccnc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=S(=O)(Nc1nc2ccccc2nc1OC(c1cccnc1)C(F)(F)F)c1ccccc1
Temperature: 150 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
2-Chloro-3-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]-quinoxaline (Compound BJ) (73 mg, 0.21 mmol) was dissolved in dimethyl sulfoxide (2 mL). To this, benzenesulfonamide (33 mg, 0.21 mmol) and potassium carbonate (29 mg, 0.21 mmol) were added at room temperature and the mixture was stirred at 150° C. for 2 hours. The reaction mixture was allowed to cool down to room temperature, a 1% aqueous acetic acid solution (20 mL) was added thereto, and the precipitate was collected by filtration. The obtained solid was subjected to slurry purification using methanol, to give N-{3-[2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy]quinoxalin-2-yl}benzenesulfonamide (Compound 137) (31 mg, 320).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:18][NH:19][CH3:20].[ClH:21].[CH3:22]NC.C([BH3-])#N.[Na+].Cl>CO>[ClH:21].[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:22])[N:19]([CH3:20])[CH3:18]
Reactant: CCCCCC(=O)Cc1cc(OC)ccc1I
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCC(CCc1cc(OC)ccc1I)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 13.0 g (0.036 mole) of 1-(2-iodo-5-methoxyphenyl)heptan-2-one, 46.6 ml (0.18 mole) of a solution of 3.86 M dimethylamine in methanol, 8.24 g (0.101 mole) of dimethylamine hydrochloride, 100 ml of methanol and 1.82 g (0.029 mole) of sodium cyanoborohydride was stirred overnight under an atmosphere of nitrogen. Stirring was continued an additional two hours and the reaction mixture acidified to pH 1 by addition of concentrated hyirochloric acid. The solvent was evaporated in vacuo, the residue partitioned between methylene chloride and water, and the methylene chloride layer separated, washed with Na2S2O5 solution followed by a washing with 3 M sodium hydroxide solution. The organic phase was dried over anhydrous potassium carbonate and evaporated in vacuo to yield a yellow oil. The oil was dissolved in methanol and the solution treated with ethereal hydrogen chloride to pH 5. The solvent was removed in vacuo and the residue dissolved in 45 ml of refluxing ethyl acetate. Some slight turbidity was removed by filtration through filter aid. The filtrate was cooled to room temperature and diluted with 20 ml of diethyl ether. The solution was cooled overnight in a refrigerator and the resulting solid, 3.34 g, removed by filtration. The filtrate was evaporated in vacuo, the residue triturated with ether and seeded to yield a second crop of off-white solid, 1.66 g. One recrystallization from ethyl acetate yielded pure 2-iodo-5-methoxy-N,N-dimethylalphapentylbenzenepropanamine hydrochloride, mp 100°-103° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][CH:4]=1.O.[NH2:14][NH2:15]>C(O)C>[OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:14][NH2:15])=[O:8])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COC(=O)c1ccc(CO)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(CO)cc1

Procedure:
A solution of methyl 4-(hydroxymethyl)benzoate (6.6 g, 40 mmol) and hydrazine hydrate (6 mL) in ethanol (30 mL) was stirred at reflux for 20 hours. The reaction mixture was concentrated to half volume through atmospheric pressure distillation. The solid was collected by filtration and washed with cold ethanol (2×10 mL). The filtrate was further concentrated and a second crop was similarly obtained and combined. The 4-(hydroxymethyl)benzohydrazide was obtained as a white solid (6.1 g, 93%). 400 MHz 1H NMR (DMSO-d6) δ: 9.68 (s, 1H), 7.75 (dd, J=6.4, 1.6 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 5.25 (t, J=6.0 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H), 4.43 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]2[CH2:11][CH2:10][CH2:9]2)[C:6](=[O:12])[NH:5][C:4](=[O:13])[CH:3]=1.Cl.[N:15]([O-])=[O:16].[Na+]>O>[NH2:1][C:2]1[N:7]([CH:8]2[CH2:9][CH2:10][CH2:11]2)[C:6](=[O:12])[NH:5][C:4](=[O:13])[C:3]=1[N:15]=[O:16]
Reactant: Nc1cc(=O)[nH]c(=O)n1C1CCC1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1c(N=O)c(=O)[nH]c(=O)n1C1CCC1
Reaction time: 3 h

Procedure:
3 g (0.0166 mol) of 6-amino-1-cyclobutyl-2,4-(1H,3H)-pyrimidinedione (VIII), was suspended in 25 ml water. To this was added 4 ml of 5N HCl and 1.3 g of NaNO2 (0.019 mol) which was dissolved in water. The reaction mixture was stirred for 3 hours and the red crystals were filtered off and washed with water. Yield 3.1 g (89%) (IX) NMR.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[F:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[NH2:28]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:28][C:27]4[CH:29]=[CH:30][C:31]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)=[C:25]([F:24])[CH:26]=4)=[O:3])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(N4CCOCC4)c(F)c3)(CC1)CC2
Yield: 36.7 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.3 mg) and 3-fluoro-4-morpholinylaniline (62.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(3-fluoro-4-morpholinylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (28.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.C(Cl)Cl>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)CCN(c1ccccc1)C2c1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCN(c1ccccc1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared by analogy to Example 48 except that 1-(4-chloro-phenyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline was used instead of 6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline, and neat CH2Cl2 to 10% MeOH/CH2Cl2 was used as eluent for flash chromatography purification.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[OH:17][CH2:18][C:19]1[CH:32]=[CH:31][C:22]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:21][CH:20]=1.O.[NH2:34][NH2:35]>C(O)C>[Br:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[OH:17][CH2:18][C:19]1[CH:32]=[CH:31][C:22]([C:23](=[N:34][NH2:35])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1
Reactant: O=C(c1ccccc1)c1ccc(CO)cc1
Reactant: NN
Agent: O=C(c1ccccc1)c1ccc(CBr)cc1
Solvent: CCO
Solvent: O
Product: NN=C(c1ccccc1)c1ccc(CO)cc1
Yield: 98 %

Procedure:
4-Bromomethyl benzophenone (2) was prepared as described in Reference Example 1. 4-Bromomethyl benzophenone (2) was converted into 4-Hydroxylmethyl benzophenone (3) as described in Reference Example 2. To solution of 3 (2.5 g, 12 mmol) in ethanol (20 ml) was added hydrazine hydrate (2.9 g 59 mmol). The mixture was heated to reflux for 24 h. then concentrated in vacuo. The residue was portioned between DCM and water and the organic layer collected and concentrated to yield 4 (2.6 g, 98%) a mixture of cis and trans isomers and as a yellow semi solid; δH (CDCl3) 2.84, 3.09 (2×bs, 1H, OH), 4.51, 4.61 (2×s, 2H, CH2OH), 5.32 (bs, 2H, NNH2), 7.13-7.17 (m, 4H, 3-, 3′-, 5-, 5′-H), 7.30-7.43 (m, 5H, 2-, 2′-, 4′-, 6-, 6′-H) ppm; δC (CDCl3) 64.4, 64.6 (2×CH2OH), 126.4, 126.6, 127.7, 128.0, 128.1, 128.6, 128.8, 128.9, 129.3 (Ar—C), 131.8, 132.7 (2×1′-C), 137.5, 138.2 (2×1-C), 141.0, 141.8 (2×4′-C), 149.2 (C═N) ppm; νmax (thin film) 3384, 2870, 1583, 1444, 1412, 1015 cm−1; found (ES) 227.1180, C14H15N2O requires 227.1179.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:1][C:2]1[N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2c(=O)[nH]1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc2ccccc2c(=O)n1CCOc1ccc(C=O)cc1
Yield: 38.9 %

Procedure:
The title compound (0.6 g, 39%) was prepared from 2-methyl-4-oxo-3,4-dihydroquinazoline (0.8 g, 5 mmol) and 4-[2-bromoethoxy]benzaldehyde (1.37 g, 6 mmol) in the presence of K2CO3 (1.3 g, 10.0 mmol) as base, by a similar procedure to that described in preparation 1.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][C:5](=O)[CH2:6][CH2:7][CH:8]=O.[Cl-].[NH4+:14]>C(O)C.C(OCC)(=O)C>[F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][C:5]1[NH:14][CH:8]=[CH:7][CH:6]=1
Reactant: O=CCCC(=O)CCC(F)(F)F
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: FC(F)(F)CCc1ccc[nH]1
Yield: 14.5 %

Procedure:
Crude 7,7,7-trifluoro-4-oxo-heptanal (10 g, prepared above) in ethanol (100 ml) was treated with ammonium chloride (400 mmol, 21 g), then heated to reflux for 1 h. The resulting solution was diluted with ethyl acetate (300 ml) and washed with brine (2×50 ml). The organics were concentrated under reduced pressure. Purification of the residue by silica gel chromatography provided 1.3 g (21% overall from 4,4,4-trifluorobutyric acid) of 2-(3,3,3-trifluoro-propyl)-1H-pyrrole. 1H NMR (CDCl3) δ 7.98 (1H, br s), 6.71 (1H, dd, J=4.1, 2.6), 6.15 (1H, dd, J=5.9, 2.8), 5.99-5.94 (1H, m), 2.92-2.85 (2H, m), 2.52-2.35 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCCCC2)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (0.3 g, 1.33 mmol) and cyclohexanone (0.64 g, 6.6 mmol) in methanol (3 mL), acetic acid (0.159 g, 2.6 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.208 g, 3.3 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and was used directly in the next step.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]1([NH:15][OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:17][C:18]1[O:19][CH:20]=[C:21]([CH3:26])[C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[CH:9]1([N:15]([C:23]([C:22]2[C:21]([CH3:26])=[CH:20][O:19][C:18]=2[CH3:17])=[O:24])[OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: ONC1CCCCC1
Reactant: Cc1coc(C)c1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1coc(C)c1C(=O)N(O)C1CCCCC1
Reaction time: 1 h

Procedure:
30 Parts of triethylamine is added to a suspension of 25 parts of N-cyclohexylhydroxylamine hydrochloride in 480 parts of benzene. After the mixture has been stirred for 1 hour, 20 parts of 2,4-dimethylfuran-3-carboxylic chloride is dripped in at room temperature. After the mixture has been stirred for a further 2 hours it is suction filtered, the residue is washed with benzene and the combined benzene phases are washed with water, dried with anhydrous sodium sulfate and evaporated. There is obtained 34 parts of N-cyclohexyl-2,4-dimethylfuran-3-hydroxamic acid in the form of an oil. This oil is dissolved in 370 parts of dichloromethane; at room temperature and while stirring, 18 parts of sodium hydroxide in 70 parts of water, and 28 parts of dimethyl sulfate are added to the solution. After the mixture has been stirred for 1 hour the organic phase is separated, washed with water, dried with sodium sulfate, evaporated and chromatographed using silica gel with a mixture of equal portions of ethyl acetate and cyclohexane. When the eluate is evaporated there is obtained 32 parts of O-methyl-N-cyclohexyl-2,4-dimethylfuran-3-hydroxamic acid having a boiling point at 0.01 mm Hg of 122° to 124° C and the refractive index nD25 : 1.5010. ##SPC13##
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:8]=[N:9][C:10]([NH:13][NH2:14])=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:15](OCC)(=[O:20])[CH2:16][C:17]([CH3:19])=O.[OH-].[NH4+]>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:8]=[N:9][C:10]([N:13]3[C:15]([OH:20])=[CH:16][C:17]([CH3:19])=[N:14]3)=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccc(N2CCOCC2)nn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(O)n(-c2ccc(N3CCOCC3)nn2)n1
Reaction time: 8 h

Procedure:
A mixture of 0.98 g (5 mmoles) of 3-morpholino-6-pyridazinyl-hydrazine, 0.65 g (5 mmoles) of ethyl acetoacetate and 15 ml of ethanol is stirred at reflux temperature for 3 hours. After cooling the mixture is stirred with 1 ml of concentrated aqueous ammonium hydroxide solution at room temperature for 4 hours and then left to stand overnight. The separated crystals are filtered, washed with water and recrystallized from ethanol. Yield: 0.5 g (39%); m.p.: 189°-192° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[S:11](=[O:15])(=[O:14])([OH:13])[OH:12]>C1(C)C=CC=CC=1>[S:11]([O-:15])([O-:14])(=[O:13])=[O:12].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][NH+:2]=1.[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][NH+:2]=1
Reactant: c1ccc2cnccc2c1
Reactant: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: O=S(=O)([O-])[O-]
Product: c1ccc2c[nH+]ccc2c1

Procedure:
In 900 g of toluene, 600 g of the same crude isoquinoline as used in the refining process of No. 1 above was dissolved. To the resultant solution, sulfuric acid in amounts equimolar with the isoquinoline was added to react thereon. The crystals consequently formed were separated by filtration to afford crystals of isoquinolinium sulfate. The crystals were washed with 900 g of toluene and then decomposed with an alkali by following the procedure of No. 1. Consequently, there was obtained 450 g of isoquinoline having a total sulfur content of 300 ppm. Then, the aforementioned isoquinoline and 22.5 g of Raney nickel added thereto were treated at 100° C. in an atmosphere of nitrogen for 1 hour. The resultant reaction mixture was subjected to solid-liquid separation and to simple distillation to afford 420 g of refined isoquinoline having a total sulfur contet of less than 1 ppm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1([CH2:11]O)[CH2:10][CH2:9]1.[N+:13]([C:16]1[CH:20]=[CH:19][NH:18][N:17]=1)([O-:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N+:13]([C:16]1[CH:20]=[CH:19][N:18]([CH2:11][C:8]2([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH2:9][CH2:10]2)[N:17]=1)([O-:15])=[O:14]
Reactant: OCC1(OC2CCCCO2)CC1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccn(CC2(OC3CCCCO3)CC2)n1
Temperature: 0 °C
Yield: 21 %

Procedure:
[1-(Tetrahydro-pyran-2-yloxy)-cyclopropyl]-methanol (1.00 g, 5.81 mmol), 3-nitro-1H-pyrazole (prepared in example 3, 656 mg, 5.81 mmol), and triphenylphosphine (1.52 g, 5.81 mmol) were combined and dissolved in anhydrous tetrahydrofuran (30 mL). The reaction was chilled to 0° C. under nitrogen. While stirring, diisopropyl azodicarboxylate (1.72 mL, 8.72 mmol) was added dropwise over a period of 2 min. The ice bath was removed and the reaction continued to stir at 25° C. for 30 min. The reaction was concentrated in vacuo to give a thick golden oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 5% ethyl acetate/hexanes to 35% ethyl acetate/hexanes) afforded 3-nitro-1-[1-(tetrahydro-pyran-2-yloxy)-cyclopropylmethyl]-1H-pyrazole (326 mg, 21%) as a white powder: H1-NMR (400 MHz, CDCl3) δ 0.74-0.82 (1H, m), 0.86-0.94 (1H, m), 0.95-1.02 (1H, m), 1.05-1.03 (1H, m), 1.40-1.70 (5H, m), 1.74-1.84 (1H, m), 3.46-3.54 (1H, m), 3.83-3.90 (1H, m), 3.94 (1H, d, J=14.4 Hz), 4.66-4.72 (1H, m), 4.87-4.94 (1H, m), 6.88 (1H, d, J=2.8 Hz), 7.84 (1H, d, J=2.4 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:37])[C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14](=O)[CH2:15][C:16](=O)/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.Cl.Cl.[NH2:40][NH2:41].CO.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:1][N:2]([CH3:37])[C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[NH:41][N:40]=[C:16](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[CH:15]=2)=[CH:8][CH:7]=1
Reactant: NN
Reactant: CN(C)C(=O)COc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(OCCN3CCOCC3)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)COc1ccc(/C=C/c2cc(/C=C/c3ccc(OCCN4CCOCC4)cc3)n[nH]2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To 2.70 g of N,N-dimethyl-2-[4-[(1E,6E)-7-[4-(2-morpholinoethoxy)phenyl]-3,5-dioxo-hepta-1,6-dienyl]phenoxy]acetamide were added 2.80 g of hydrazine dihydrochloride and 54 mL of methanol, and the mixture was stirred at 40° C. overnight. The reaction mixture was allowed to stand to cool, and poured into 200 mL of a saturated aqueous NaHCO3 solution. To this, 600 mL of AcOEt was added, and the organic layer was separated. The obtained organic layer was washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (CHCl3/methanol system) to give 1.76 g of the title compound (66% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1F
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A stirred solution of 2-fluoroanisole (33.7 mL, 301 mmol) in chloroform (250 mL) was cooled to 0° C. and treated drop-wise with chlorosulfonic acid (50.0 mL, 752 mmol). After stirring at room temperature for 14 hours, the reaction mixture was poured into ice-water (700 mL) and the separated, aqueous phase extracted with chloroform (2×200 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 3-fluoro-4-methoxybenzenesulfonyl chloride as a fine, white solid (58.6 g, 87%), m.p. 80° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([N:11](CC)CC)C.[Si](C#N)(C)(C)C>C(#N)C.C(OCC)C>[Cl:1][C:2]1[C:3]([C:9]#[N:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc(Cl)c1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCOCC
Product: N#Cc1ncccc1Cl
Yield: 97.8 %

Procedure:
To a solution of compound 145-B, (22.37 g, 172.7 mmol) in acetonitrile (175 mL) was added triethylamine (48 mL, 346 mmol) and TMS-CN (56 mL, 420 mmol). The solution was heated at reflux for 20 h then evaporated in vacuo. The residue was partitioned between EtOAc (250 mL), 10% aqueous Na2CO3 (50 mL), and filtered over celite. The organic portion of the filtrate was washed with 10% aqueous Na2CO3 (2×50 mL), brine (50 mL), and the organics dried over Na2SO4, filtered, and evaporated in vacuo to afford a dark crystalline residue, which was dissolved in warm diethyl ether (200 mL), filtered, and evaporated in vacuo to afford compound 145-C as a tan-orange powder (23.41 g, 98%). 1H-NMR (DMSO-d6): δ 7.78-7.84 (m, 1H), 8.30 (d, 1H), 8.73 (d, 1H); MS: m/z 139.1 (MH+).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f27) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][CH:16]([OH:24])[CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[F:34][C:35]([F:47])([F:46])[C:36]1[CH:37]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1>CN(C=O)C.C(OCC)(=O)C>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][CH:16]([OH:24])[CH2:17][N:18]2[CH2:23][CH2:22][N:21]([S:42]([C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([C:35]([F:34])([F:46])[F:47])[CH:37]=3)(=[O:44])=[O:43])[CH2:20][CH2:19]2)=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: OC(COc1cccc2[nH]c3ccccc3c12)CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCN(CC(O)COc2cccc3[nH]c4ccccc4c23)CC1
Reaction time: 3 h
Yield: 31.3 %

Procedure:
To a solution of 1-(9H-carbazol-4-yloxy)-3-piperazin-1-ylpropan-2-ol (0.2 g, 0.614 mmol) in DMF (4 mL), was added DIPEA (0.05 mL, 0.301 mmol) followed by the drop-wise addition of 3-trifluoromethylbenzenesulfonyl chloride (0.098 g, 0.61 mmol) at room temperature and the reaction mixture was stirred for 3 hours. Subsequently the reaction mixture was diluted with ethyl acetate (30 mL), washed with water and brine solution. The organic layer was dried on anhydrous Na2SO4, concentrated, and purified by precipitating the compound from dichloromethane by adding hexane, to give the required compound as a pale yellow colored solid (0.102 g, 30% yield). 1H NMR (400 MHz, DMSO): δ 2.30-2.90 (m, 6H), 3.00-3.30 (m, 4H), 4.00-4.30 (m, 4H), 5.00 (s, 1H), 6.61 (d, 1H, J=8 Hz), 7.00-7.20 (m, 2H), 7.25-7.40 (m, 2H), 7.42 (d, 1H, J=8.0 Hz), 7.80-8.00 (m, 2H), 8.06 (d, 1H, J=8 Hz), 8.20-8.30 (m, 2H), 11.26 (d, 1H, J=12 Hz). MS m/z: 534.1 (M+1).