Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[CH:32]([CH3:36])[CH2:33][C:34]#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:37].[OH-:38].[Na+]>C(O)C>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[CH:32]([CH3:36])[CH2:33][C:34]([OH:38])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: [OH-]
Reactant: CC(CC#N)[C@@H]1O[C@@H](C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Na+]
Solvent: CCO
Product: CC(CC(=O)O)[C@@H]1O[C@@H](C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Yield: 83 %

Procedure:
A mixture of 3-(2,3,4-tri-O-benzyl-α-L-fucopyranosyl)butanenitrile (6 g, 12.36 mmol) in ethanol (100 mL) was treated with water (100 mL) and 5N NaOH (25 mL, 124 mmol) and the resulting mixture heated at reflux for 3 days. Mixture cooled and ethanol removed by evaporation, the remaining aqueous was acidified by the addition of conc. HCl and extracted with EtOAc (3×100 mL); combined EtOAc layers washed with sat. NaCl (100 mL), dried over Na2SO4, filtered and evaporated to give the title compound (5.2 g, 83%) as a light yellow oil. 1H NMR (CDCl3) δ 7.40-7.30 (15H, m), 4.79 (2H, m), 4.71 (1H, d, J=12.0 Hz), 4.65 (2H, m), 4.53 (1H, d, J=11.8 Hz), 4.01 (1H, m), 3.92 (1H, m), 3.83 (1H, m), 3.78 (2H, m), 2.39 (2H, m), 1.75 (2H, m), 1.59 (2H, m), 1.30 (3H, d, J=6.6 Hz).
Reaction SMILES: [CH:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:17][CH:18]([O:21][CH3:22])[O:19][CH3:20].O>C1COCC1>[CH3:20][O:19][CH:18]([O:21][CH3:22])[CH2:17][C:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1CCCC1
Reactant: COC(CBr)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(CC1(C#N)CCCC1)OC
Reaction time: 0.08 h

Procedure:
0.1 mol of cyclopentanecarbonitrile in 50 ml of THF is added in a rapid dropwise manner to a solution, stirred at 78° C. under an argon atmosphere, of 0.1 mol of lithium diisopropylamide (prepared from 0.1 mol of diisopropylamine and 63 ml of 1.6M butyllithium in hexane) in 250 ml of anhydrous THF. The mixture is stirred for 5 minutes at this temperature before adding 0.11 mol of 1-bromo-2,2dimethoxyethane. The mixture is allowed to return to room temperature and is hydrolyzed using 150 ml of water. The medium is allowed to settle, and the aqueous phase is separated and extracted twice with 150 ml of ether. The combined organic phases are washed with 100 ml of aqueous saline solution and 100 ml of water and then dried over magnesium sulfate. The solvents are evaporated off under vacuum and the residual oil is distilled.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([O:30]C)=[O:29])[CH2:23]1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([OH:30])=[O:29])[CH2:23]3)[CH:3]=2)=[N:13][C:14]=1[O:20][CH3:21]
Reactant: COc1ccc(Nc2cc(Cl)nn3ccnc23)nc1OC
Reactant: COC(=O)C1CCCNC1
Product: COc1ccc(Nc2cc(N3CCCC(C(=O)O)C3)nn3ccnc23)nc1OC
Temperature: 160 °C
Yield: 15.4 %

Procedure:
A suspension of 6-chloro-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (200 mg, 0.65 mmol) and methyl piperidine-3-carboxylate (400 mg, 2.8 mmol) was heated at 160° C. for 2 h under N2. After cooling to room temperature, the residue was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=20:1) to give 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxylic acid (40 mg, 15%) as a red solid. LC-MS: 399 [M+1]+, tR=1.261 min.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:15]([N:18]=C=O)(=[O:17])=[O:16].C1(CC#N)C=CC=CC=1>C1(C)C=CC=CC=1>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][S:15](=[O:17])(=[O:16])[NH2:18])=[CH:11][CH:12]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: N#CCc1ccccc1
Product: NS(=O)(=O)Oc1ccc(-c2ccccc2)cc1
Yield: 69 %

Procedure:
This compound was prepared according to the procedure used in Example 56. A mixture of 17.0 g (0.1 mole) of 4-phenylphenol, 14.8 g (0.105 mole) of chlorosulfonyl isocyanate and 100 ml of toluene gave 17.2 g (69%) of white crystals, mp 166°-168° C. (benzene-acetonitrile).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8](OC)[C:3]=1[NH:4][CH2:5][CH:6]=[O:7].[CH:14]1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[Cl:26][CH2:27][C:28]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[C:8]([CH3:14])=[CH:9][CH:10]=[CH:11][C:2]=1[CH3:1])=[O:29]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc(C)c1NCC=O
Reactant: c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C)c1N(CC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The dipropyl acetal of 2-(2-methyl-6-methoxyanilino)acetaldehyde (15 grams), benzene (100 ml) and sodium carbonate (6.0 grams) dissolved in water (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture is cooled in an ice bath and chloroacetyl chloride (6.5 grams) is added dropwise with stirring. After addition is completed stirring is continued and the reaction mixture is allowed to warm up to room temperature. After this time the mixture is filtered and the filtrate washed with dilute aqueous hydrochloric acid. The washed filtrate is dried over anhydrous magnesium sulphate and is stripped of solvent under reduced pressure to yield the desired product the dipropyl acetal of 2-[N-(α-chloroacetyl)-2,6-dimethylanilino]acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[CH3:21][O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH:32]C(OC(C)(C)C)=O)=[CH:27][CH:26]=1)=[O:24]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:31]([C:28]2[CH:27]=[CH:26][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:30][CH:29]=2)[N:32]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1ccc(NNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1
Yield: 75.2 %

Procedure:
The title compound was prepared according to the procedure described in step-1 and step-2 of Intermediate-9 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 1.300 g, 4.2 mmol) and tert-butyl 2-[4-(methoxycarbonyl)phenyl]hydrazinecarboxylate (Intermediate-7, 1.150 g, 3.8 mmol) in TFA (5-7 mL) and DCM (40 mL). The reaction mass was quenched with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 1.300 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.84 (s, 3H), 4.44 (d, J=5.7 Hz, 2H), 7.49 (t, 1H), 7.66 (d, J=8.7 Hz, 2H), 8.04-8.13 (m, 4H), 10.07 (m, 1H), 12.69 (s, 1H); MS (m/z): 453.14 (M−H)−.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[CH3:13][C:14]1[N:19]=[C:18]([C:20]2[CH:21]=[C:22]([C:26]3[N:27]=[C:28]([NH2:31])[S:29][CH:30]=3)[CH:23]=[CH:24][CH:25]=2)[CH:17]=[C:16]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[CH:15]=1.C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:6]([NH:5][S:2]([NH:31][C:28]1[S:29][CH:30]=[C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:18]3[CH:17]=[C:16]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)[CH:15]=[C:14]([CH3:13])[N:19]=3)[CH:21]=2)[N:27]=1)(=[O:4])=[O:3])=[O:7])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3csc(N)n3)c2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3csc(NS(=O)(=O)NC(=O)OC(C)(C)C)n3)c2)n1
Yield: 41.8 %

Procedure:
To a stirred and cooled solution of commercially available chlorosulfonyl isocyanate (0.215 mL, 2.47 mmol) in dichloromethane (5 mL) was added tert-butanol (0.232 mL, 2.47 mmol) and the mixture was stirred at 0° C. for 30 min. Then 4-{3-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-phenyl}-thiazol-2-ylamine (example 342) (0.100 g, 0.243 mmol) and triethyl amine (0.42 mL, 2.96 mmol) were added and the mixture was stirred at 23° C. for 0.5 h. Diluted with DCM, washed with sat. NaHCO3-sol. and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with heptane/EtOAc/THF, followed by trituration with diethyl ether/heptane to give the title compound as a white solid (0.060 g, 42%). MS (ISP) 591.3 [(M+H)+]; mp 152° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:14]4[N:15]([N:19]=[C:20]([NH:22][C:23]([CH:25]5[CH2:27][CH2:26]5)=[O:24])[CH:21]=4)[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:2]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([N:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[C:14]4[N:15]([N:19]=[C:20]([NH:22][C:23]([CH:25]5[CH2:26][CH2:27]5)=[O:24])[CH:21]=4)[CH:16]=[CH:17][CH:18]=3)=[CH:11][CH:12]=2)[CH2:2]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1cc2c(-c3ccc(O[C@@H]4CCNC4)cc3)cccn2n1)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC[C@@H](Oc2ccc(-c3cccn4nc(NC(=O)C5CC5)cc34)cc2)C1
Temperature: 0 °C
Yield: 30 %

Procedure:
(R)—N-(4-(4-(pyrrolidin-3-yloxy)phenyl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (340 mg, 0.94 mmol) and triethylamine (0.16 ml, 1.13 mmol) were suspended in DCM (10 ml) and stirred at 0° C. under N2. Methane sulfonylchloride (77 μL, 0.99 mmol) was added slowly and the resulting solution was allowed to warm to room temperature over 4 h. The reaction mixture was washed with sat. NaHCO3 solution (aq.) and the aqueous phase extracted with DCM. The combined organics were dried (MgSO4), filtered, concentrated in vacuo and purified by preparative HPLC to give (R)—N-(4-(4-((1-(methylsulfonyl)pyrrolidin-3-yl)oxy)phenyl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide. (126 mg, 30% yield).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1.C(N(CC)CC)C.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH2:48][CH:49]([OH:52])[CH:50]=[CH2:51])[CH:42]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:51][CH2:50][C:49](=[O:52])[CH2:48][CH2:47][C:43]1[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: C=CC(O)CCc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CCc1cccnc1)CCc1ccc2ccccc2c1
Temperature: 100 °C
Yield: 47.8 %

Procedure:
Palladium(II) acetate (0.056 g), tri-o-tolylphosphine (0.148 g), 2-bromonaphthalene (0.49 g) and triethylamine (10 ml) were added to a solution of (±)-5-(3-pyridyl)-1-penten-3-ol (0.40 g) in acetonitrile (30 ml) and the mixture heated at 100° C. for 24 hours. The solvents were removed under reduced pressure and water was added to the residue. The mixture was extracted with dichloromethane, the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:ethyl acetate (2:1) to give the sub-title ketone as a brown oil (0.327 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH:27]([CH3:29])[CH3:28].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(F)cc1
Temperature: 100 °C
Yield: 87.2 %

Procedure:
To a mixture of 4-fluoro-N-(4-fluoro-phenyl)-benzenesulfonamide (1.0 g, 3.7 mmol) and K2CO3 (1.03 g, 7.4 mmol) in dimethylformamide (5 mL) was added 1-bromo-2-methylpropane (1.21 mL, 11.2 mmol). The mixture was heated at 100° C. in a microwave reactor for 3 hours. Water was added and then extracted with EtOAc, washed with brine, dried with Na2SO4 then concentrated. The crude product was re-dissolved in cyclohexane then concentrated to give 4-fluoro-N-(4-fluoro-phenyl)-N-isobutyl-benzenesulfonamide (1.05 g, 86%). 1H NMR (300 MHz, CDCl3): δ 7.56-7.57 (m, 2H), 7.12-7.13 (m, 2H), 7.00 (d, 4H), 3.28 (d, 2H), 1.54 (m, 1H), 0.91 (d, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CO.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:19]1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCNC(=O)OCc1ccccc1)NC[C@H]1CCCNC1
Reactant: O=CC1CCCCC1
Agent: [Cl-]
Agent: [Na]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CCNC(=O)OCc1ccccc1)NC[C@H]1CCCN(CC2CCCCC2)C1

Procedure:
To a solution of 600 mg of 3-(benzyloxycarbonyl)amino-N-{((3S)-3-piperidyl)methyl}propanamide in 3 ml of methanol, a solution of 150 mg of sodium cyanoborohydrate and 160 mg of zinc chloride in 8.1 ml of methanol, and 0.30 ml of cyclohexanecarbaldehyde were added at room temperature, followed by an hour's stirring at the same temperature. The reaction liquid was diluted with ethyl acetate and successively washed with saturated aqueous sodium bicarbonate solution and saturated saline, followed by drying over anhydrous sodium sulfate. Upon distilling the solvent off under reduced pressure, 775 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:18])[C:8](=[O:17])[N:9]2[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[N+:19]([O-])=O>CN(C)C=O.[Ni]>[NH2:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[N:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:8](=[O:17])[C:7](=[O:18])[NH:6]2
Reactant: COC(=O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(Cl)cc21
Agent: [Ni]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)c(=O)[nH]c2cc(N)c(Cl)cc21
Yield: 99.4 %

Procedure:
10 g (30.5 mmol) of 7-chloro-1-(methoxycarbonylmethyl)-6-nitro-2,3(1H,4H)-quinoxalinedione were dissolved in 300 ml of dimethylformamide and, after addition of 5 g of Raney nickel, hydrogenated under 1 bar at room temperature. The mixture was then filtered and the filtrate was concentrated under reduced pressure to yield 8.6 g (95%) of the product. Melting point>260° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH2:32]>CN(C=O)C>[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][CH2:26][C:22]2[S:21][CH:25]=[CH:24][N:23]=2)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCCOCCCc1nccs1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCCCc2nccs2)c1C
Temperature: 60 °C
Yield: 60.8 %

Procedure:
Under a nitrogen atmosphere, triethylamine (3.4 mL, 24 mmol) was added dropwise to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (4.50 g, 20.4 mmol) in anhydrous DMF (45 mL). 2-[3-(1,3-Thiazol-2-yl)propoxy]ethylamine (4.55 g, 24.4 mmol) was then added, and the addition funnel was rinsed with additional DMF (15 mL). The reaction was heated at 60° C. for 3.5 hours. The volatiles were then removed under reduced pressure, and the residue was partitioned between water (100 mL) and diethyl ether (250 mL). The organic layer was washed with water (2×50 mL) and brine (3×50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide an orange oil. The crude product (7.41 g) was purified by column chromatography on silica gel (375 g, eluting with 50:50 hexane:ethyl acetate) to provide a solid, which was dried overnight under high vacuum at room temperature to provide 4.6 g of (2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}amine as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].CO>C(OCC)(=O)C>[CH3:18][N:19]([CH3:21])/[CH:20]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:3]
Reactant: COC(=O)c1cc(C(C)=O)ccc1OC
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(C(=O)/C=C/N(C)C)ccc1OC
Temperature: 95 °C
Yield: 90.1 %

Procedure:
Methyl 5-acetyl-2-methoxybenzoate (11.98 g, 48.0 mmol) was added to N,N-dimethylformamide dimethyl acetal (44.6 g, 374.5 mmol) held under a nitrogen atmosphere. The resulting solution was heated at 95° C. for 60 minutes. Methanol (10 ml) was then removed by atmospheric distillation and further N,N-dimethylformamide dimethyl acetal (8.90 g, 74.9 mmol) added. The resulting solution was heated at 95° C. for a further 270 minutes. The reaction was then cooled to 50° C. and ethyl acetate (35 mL) added. Solvent (35 mL) is removed from the reaction by atmospheric distillation and fresh ethyl acetate (35 mL) added. Further solvent (35 mL) is removed from the reaction by atmospheric distillation and fresh ethyl acetate (50 mL) added. The reaction mixture is cooled to RT whereby the desired product crystallises out as a granular, free flowing solid. The solid was isolated by filtration, washed twice with fresh ethyl acetate (2×30 mL) and dried to constant weight to afford 11.39 g of the desired methyl 5-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-methoxybenzoate (8).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH3:18])(=[O:17])=[O:16])[CH:5]=[CH:6][C:7]=1[NH2:8].[C:19]([O-:22])(O)=O.[Na+].[Cl-].[C:25](OCC)(=O)[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH3:18])(=[O:17])=[O:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:19](=[O:22])[CH:25]=[CH2:26]
Reactant: O=C([O-])O
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(N)c(F)c1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Na+]
Product: C=CC(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To 3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylamine (8.510 g) in ethyl acetate (400 ml) was added sat. NaHCO3 (100 ml) and then acryolyl chloride (1.3 equiv.). Stirred at room temperature for 3 hours. Washed EtOAc extract with brine, dried over MgSO4 and evaporated in vacuo. Triturated with ether and then filtered to afford N-(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-acrylamide (9.670 g, 94%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][S:18]([C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>CO.[Pd].C(OCC)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][S:18]([C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CN1CC=C(c2c[nH]c3ccc(NS(=O)(=O)c4cccc5ccccc45)cc23)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: CN1CCC(c2c[nH]c3ccc(NS(=O)(=O)c4cccc5ccccc45)cc23)CC1
Yield: 64.8 %

Procedure:
To a solution of 417 mg (1 mMol) of N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide in 50 ml of methanol are added 100 mg of 5% palladium on carbon. The mixture is hydrogenated at ambient temperature at an initial hydrogen pressure of 3 atmospheres for 20 hours. The reaction mixture is filtered and the filtrate is concentrated at reduced pressure to provide a crude that is suspended in ethyl ether, yielding 272 mg (65%) of N-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide as a solid with m.p.=254-256° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:35])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1OCC)[N:12]=[CH:11][N:10]=[C:9]2[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:22]([Cl:34])[CH:21]=1)=[O:4].[C:36](Cl)(=[O:39])[CH:37]=[CH2:38].[C:41](=O)(O)[O-:42].[Na+]>C1COCC1.O>[Cl:34][C:22]1[CH:21]=[C:20]([NH:19][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:42][CH3:41])=[C:6]([NH:5][C:3]([C@@H:2]([NH:1][C:36](=[O:39])[CH:37]=[CH2:38])[CH3:35])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: CCOc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)[C@H](C)N
Reactant: C=CC(=O)Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)N[C@@H](C)C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OC
Yield: 3 %

Procedure:
300 mg of (2S)-amino-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-ethoxy-quinazolin-6-yl}-propionamide as a starting material was dissolved in 9 ml of THF and 3 ml of water, and reacted with 0.06 ml of acryloylchloride at room temperature for 1 hour after adding 153 mg of sodium bicarbonate. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=15:1) to obtain the title compound (11 mg, 3%).
Reaction SMILES: ClC1C(OCC2(C(F)(F)F)CCCCC2)=C[C:5](F)=[C:6]([CH:14]=1)C(OC(C)(C)C)=O.Cl[C:29]1[C:30]([O:43][CH2:44][CH:45]2[CH2:50][CH2:49][C:48]([CH3:52])([CH3:51])[CH2:47][CH2:46]2)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[CH:14]1([C:29]2[C:30]([O:43][CH2:44][CH:45]3[CH2:50][CH2:49][C:48]([CH3:52])([CH3:51])[CH2:47][CH2:46]3)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=2)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:6][CH2:5]1
Reactant: CC1(C)CCC(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(C)CCC(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CC1

Procedure:
Following the procedure as described in Example 158 step 3, and making variations as required to replace tert-butyl 5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoate with tert-butyl 5-chloro-4-((4,4-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate, the title compound was obtained as a pale yellow oil (2.13 g, 73%): MS (ES+) m/z 399.2 (M+23).
Reaction SMILES: [CH:1]([N:4]([CH2:8][CH2:9][NH2:10])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12].[C:23]1([S:29]([CH:32]2[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:2][CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[CH2:8][CH2:9][NH:10][C:11]([N:34]1[CH2:35][CH2:36][CH2:37][CH:32]([S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH2:33]1)=[O:12])[CH3:3]
Reactant: O=S(=O)(c1ccccc1)C1CCCNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)N(CCN)C(C)C
Product: CC(C)N(CCNC(=O)N1CCCC(S(=O)(=O)c2ccccc2)C1)C(C)C
Yield: 59.8 %

Procedure:
Following the procedure of Example 16, diisopropylaminoethylamine and 1,1'-carbonyldiimidazole and 3-(phenylsulfonyl)piperidine were reacted to give the title compound which was crystallized from diethyl ether-hexane as white solid in 59.8% yield, m.p. 82.5°-84° C.