Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[N:8]([C:9]3[N:14]=[C:13](Cl)[N:12]=[C:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.C(=O)([O-])[O-].[Na+].[Na+].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)=[O:34])[CH:27]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH:1]12[N:8]([C:9]3[CH:10]=[C:11]([CH2:16][N:17]([CH3:19])[CH3:18])[N:12]=[C:13]([C:39]4[CH:38]=[CH:37][C:36]([NH:35][C:33]([NH:32][C:28]5[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=5)=[O:34])=[CH:41][CH:40]=4)[N:14]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2
Reactant: CN(C)Cc1cc(N2C3CCC2COC3)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cccnc3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(C)Cc1cc(N2C3CCC2COC3)nc(-c2ccc(NC(=O)Nc3cccnc3)cc2)n1
Temperature: 120 °C
Yield: 74.6 %

Procedure:
A microwave vial was charged with 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloropyrimidin-4-yl)-N,N-dimethylmethanamine (0.080 g, 0.283 mmol) and sodium carbonate (2M in water, 0.425 mL, 0.849 mmol). DME (1.5 mL) was then added to give a yellow biphasic solution. The solution was sparged with nitrogen for 10 minutes, and tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.017 mmol) and 1-(pyridin-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.106 g, 0.311 mmol) were added. The vial was sealed and heated to 120° C. for 2 hours via microwave. The vessel was then cooled to room temperature and the reaction mixture was filtered through Celite™. The filter cake was washed with ethyl acetate and the filtrate was washed with saturated sodium chloride and concentrated under reduced pressure to provide a brown oil. The crude product was added to a HPLC column and was eluted with 5-90% acetonitrile in water (0.05% TFA buffer) to provide the mono-TFA salt of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(pyridin-3-yl)urea (0.097 g, 75%) as a light yellow solid. HRMS; [M+H]+ Obs'd=460.2454, [M+H]+ Calc'd=460.2455.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.O>CN(C=O)C>[N:22]1([CH2:21][CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCCN2CCCC2)cc1
Temperature: 80 °C
Yield: 70.9 %

Procedure:
To a solution of methyl 4-hydroxybenzoate (4.56 g, 30 mmol) in dry DMF (60 mL) was added cesium carbonate (31.3 g, 96 mmol, 3.2 eq.) and 1-(2-chloroethyl)pyrrolidine hydrochloride (8.1 g, 48 mmol, 1.6 eq.). The reaction was heated at 80° C. for 20 h. The reaction mixture was cooled to ambient temperature then water (240 mL) was added. The mixture was partitioned with ethyl acetate (250 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined extracts were washed with water (240 mL), brine (50 mL), dried (Na2SO4), filtered then concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (90:5:5 hexane:THF:TEA) to give the desired product as an oil (5.3 g, 71%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[C:28]([O:33]C)=[N:29][CH:30]=[CH:31][CH:32]=3)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[C:28](=[O:33])[NH:29][CH:30]=[CH:31][CH:32]=3)[N:17]=2)[CH2:10][CH2:9]1
Reactant: COc1ncccc1CNc1ncc([N+](=O)[O-])c(NC[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](CNc2nc(NCc3ccc[nH]c3=O)ncc2[N+](=O)[O-])CC1
Reaction time: 8 h
Yield: 26.8 %

Procedure:
[trans-4-({2-[(2-Methoxy-pyridin-3-ylmethyl)-amino]-5-nitro-pyrimidin-4-ylamino}-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (100 mg, 0.205 mmol) was dissolved in dioxane (2 mL) and treated with HCl in dioxane (0.85 mL, 4 mmol/mL, 3.40 mmol). After stirring overnight, an oil was seen at the bottom of the solution. The solvent was taken out and the residue dried to give an oily solid. The crude solid was purified with prep TLC (1:9:90 NH3:MeOH:DCM) to give the title product (20.5 mg, 0.055 mmol, 26.8%) as a yellow solid, m/z 374.5 (M+1)+
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([CH3:22])[CH:15]=1>[Pd].C(Cl)Cl.CO.[H][H]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([CH3:22])[CH:15]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2cc3cc([N+](=O)[O-])ccc3n2C)ccc1C#N
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-c2cc3cc(N)ccc3n2C)ccc1C#N

Procedure:
Prepared analogously to Example 1c from 4-(1-methyl-5-nitro-1H-indol-2-yl)-methyl-benzonitrile, palladium on activated charcoal in methylene chloride/methanol and hydrogen.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[S:24][C:23]([C:25]3([O:31][CH3:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[F:12][C:9]([F:10])([F:11])[C:6]1[CH:5]=[CH:4][C:3]([C:2]([C:13]2[CH:14]=[CH:15][C:16]([S:19][C:20]3[S:24][C:23]([C:25]4([O:31][CH3:32])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)=[O:1])=[CH:8][CH:7]=1
Reactant: COC1(c2ccc(Sc3ccc(C(O)c4ccc(C(F)(F)F)cc4)cc3)s2)CCOCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: COC1(c2ccc(Sc3ccc(C(=O)c4ccc(C(F)(F)F)cc4)cc3)s2)CCOCC1
Yield: 75 %

Procedure:
Using the procedure described in Example 18, 4-[5-(4-(alphahydroxy-4-trifluoromethylbenzyl)phenylthio)thien-2-yl]-4-methoxytetrahydropyran was reacted with pyridinium chlorochromate to give 4-[5-(4-(4-trifluoromethylbenzoyl)phenylthio)thien-2-yl]-4-methoxytetrahydropyran in 75% yield, m.p. 86°-87° C.
Reaction SMILES: [C:1]1([Si:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:29]([CH3:32])([CH3:31])[CH3:30])[O:8][C:9]2[CH:10]=[C:11]([CH:15]([OH:28])[CH2:16][CH2:17][C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CCOCC>C(Cl)Cl>[C:33]1([Si:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:29]([CH3:30])([CH3:31])[CH3:32])[O:8][C:9]2[CH:10]=[C:11]([C:15](=[O:28])[CH2:16][CH2:17][C:18]3[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])[CH:12]=[CH:13][CH:14]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)c1ccccc1CCC(O)c1cccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)c1ccccc1CCC(=O)c1cccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 20 °C

Procedure:
The alcohol of Step 1 (93 g, 0.179 mol), dissolved in CH2Cl2 (300 mL) was added to a mixture of 4A molecular sieve (94 g, milled) and PCC, (pyridinium chlorochromate, 69 g, 0.321 mol) in CH2Cl2 (1 L) at 10° C. The mixture was then allowed to warm to 20° C. for 2 h and ether (1 L) was introduced. The mixture was filtered through silica and was washed with ether (2 L) and EtOAc:hexane 1:1 (1 L). Evaporation of the filtrate and flash chromatography (10% EtOAc:hexane) of the crude mixture on silica gave the title product. Yield: 81 g, 87%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:37][C:38]4[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCc4ccncc4)c(OC)cc23)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine hydrochloride (41 mg), were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C., for 3 hr. Water was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC to give 65 mg (yield 66%) of the title compound.
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]([CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])=[CH:8][CH:7]=1.C(N(CC)CC)C.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH3:2][N:3]([CH:4]([CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]
Reactant: O=C(CBr)c1ccccc1
Reactant: CNC(=O)COc1ccc(CC(C)NC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)COc1ccc(CC(C)N(C)CC(=O)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
N-methyl-2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethanamine hydrochloride (2.73 g) was suspended in tetrahydrofuran (10 ml) containing triethylamine (6 ml) and a solution of α-bromoacetophenone (1.99 g) in tetrahydrofuran (10 ml) was added dropwise. After stirring overnight this solution was treated with saturated sodium carbonate solution, extracted with dichloromethane, the organic phase was dried (magnesium sulphate), filtered and evaporated to give a red oil which was used without further purification.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[CH3:15]>>[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][CH:25]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:18][CH:17]=1)[CH3:15]
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: CCc1ccc(NCc2ccc(N3CCOCC3)cc2)cc1
Product: CCc1ccc(N(Cc2ccc(N3CCOCC3)cc2)C(=O)C2CCCc3ccccc32)cc1
Yield: 68.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.34 g) and (4-ethylphenyl)[(4-morpholinophenyl)methyl]amine (0.59 g) as starting materials, N-(4-ethylphenyl)-N-[(4-morpholinophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.60 g) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5](C(OCC)=O)[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])C.[OH-].[K+].O.Cl>C(O)C>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH:6]([CH:7]([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:5][C:4]([OH:29])=[O:3])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccc(OC)c(OC)c1)C(OCC)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(OCC)C(CC(=O)O)c1ccc(OC)c(OC)c1
Yield: 85.2 %

Procedure:
3.07 g (7.44 mM) of 3-(3,4-dimethoxyphenyl)-4,4-diethoxy-2-ethoxycarbonylbutyric acid ethyl ester and 3.41 g of potassium hydroxide were heated at reflux for 4 hours in 40 ml of ethanol. The solution was poured to water, was acidified with concentrated hydrochloric acid, and was extracted with diethyl ether. The organic extract was dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo to obtain 1.98 g of brown oily 3-(3,4-dimethoxyphenyl)-4,4-diethoxybutyric acid. 1.98 g of the brown oily product thus obtained and 0.90 ml of hydrazine hydrate were added to a mixed solution of 8.3 ml of acetic acid and 6.3 ml of water. The solution was heated at reflux for 5 hours, poured to an aqueous sodium hydrogencarbonate solution, extracted with methylene chloride, and dried. The solvent was evaporated in vacuo to obtain a yellow solid residue. The residue was purified by flash chromatography (SiO2: eluted with a gradient of 60% ethyl acetate/hexane to 70% ethyl acetate/hexane). The solvent was evaporated in vacuo and the resultant product was dried to obtain 0.92 g of a light yellow solid of the above-described compound (yield 53.0%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[CH:22][NH:21][C:20]=1[CH:33]=O>C(O)C.N1CCCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:20]2[NH:21][CH:22]=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(F)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.1 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-fluoro-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (39 mg, 36%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([CH3:34])=[N:12][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:33])OC4C=CC=CC=4)=[CH:18][CH:17]=3)[C:14]=2[CH3:15])[CH:7]=[CH:8][CH:9]=1)=[O:3].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([S:42]([NH:45][C:25]([NH:24][CH2:23][CH2:22][C:19]2[CH:18]=[CH:17][C:16]([N:13]3[C:14]([CH3:15])=[C:10]([C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:2]([NH2:1])=[O:3])[C:11]([CH3:34])=[N:12]3)=[CH:21][CH:20]=2)=[O:33])(=[O:43])=[O:44])=[CH:40][CH:41]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1cccc(C(N)=O)c1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(Cl)cc3)cc2)c(C)c1-c1cccc(C(N)=O)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-(4-{4-[3-(aminocarbonyl)phenyl]-3,5-dimethyl-1H-pyrazol-1-yl}phenyl)ethylcarbamate (step 6 of example 72) and 4-chlorobenzensulfonamide: MS (ESI) m/z 552 [M+H]+, 550 [M−H]−, 1H-NMR (CDCl3) δ 7.92-7.80 (4H, m), 7.58-7.47 (4H, m), 7.29-7.18 (4H, m), 6.33 (1H, br.s), 3.47 (2H, t, J=6.1 Hz), 2.86 (2H, t, J=6.1 Hz), 2.23 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:20][C:21](=O)[CH3:22])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:20][C:21](=[N:25][OH:26])[CH3:22])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12)=NO
Temperature: 60 °C

Procedure:
The product from Example 24 (0.50 g, 0.0015 mol), hydroxylamine hydrochloride (0.21 g, 0.0031 mol) and 4 Å molecular sieves were suspended in pyridine (10 ml) and heated at 60° C. for 14 h. A further amount of hydroxylamine hydrochloride (0.42 g, 0.0062 mol) was added and the reaction mixture heated under reflux for a further 24 h. The reaction mixture was diluted with ethyl acetate (30 ml) and filtered through hiflo. The mixture was washed with 1N hydrochloric acid (100 ml), the acid layer was back extracted with ethyl acetate (2×20 ml) and the combined organic layers were washed consecutively with water (20 ml), saturated sodium hydrogen carbonate solution (20 ml) and brine (20 ml), then dried (MgSO4), filtered, and concentrated in vacuo to give a white solid. This was recrystallised from ethanol/water to give a white crystalline solid; yield=278 mg. Mp=196°-198° C. Found: C, 62.93; H, 4.37; N, 8.10. C18H15ClN2O3 requires C, 63.07; H, 4.41; N, 8.17. δ (360 MHz, DMSO-d6), 1.60 (3H, s, CH3), 4.06 (2H, s, OCH2), 7.28 (1H, dd, J=8.6 and 2.1 Hz, 6-H), 7.32-7.48 (6H, m, aromatics), 7.78 (1H, d, J=8.7 Hz, 5-H), 10.88 (1H, s, NOH), 11.92 (1H, s, br, NH). MS (CI) m/z=343 [MH]+.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C-:11]#[N:12].[K+]>CN(C)C=O>[Br:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Cc1cccc(CBr)c1Br
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(CC#N)c1Br
Temperature: 90 °C
Reaction time: 20 h
Yield: 44.1 %

Procedure:
A mixture of 2-brom-3-methylbenzylbromide (25 g, 0.095 mol) and potassium cyanide (16 g, 0.25 mol) in dimethylformamide (100 ml) was stirred at 90° C. for 20 h. The solvent was evaporated under reduced pressure and to the residue were added toluene and water. The organic layer was separated washed with water, separated and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride as eluent gave 8.8 g (44%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH:34]1[CH2:36][CH:35]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:13]1[C:14]2[N:25]=[N:24][N:23]([CH:26]3[CH2:30][CH:29]([OH:31])[CH:28]([OH:32])[CH:27]3[OH:33])[C:15]=2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=1.[C:43]1(C)[CH:48]=CC(S(O)(=O)=O)=C[CH:44]=1>CC(C)=O.COC(OC)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH:34]1[CH2:36][CH:35]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:13]1[C:14]2[N:25]=[N:24][N:23]([CH:26]3[CH:27]4[O:33][C:43]([CH3:48])([CH3:44])[O:32][CH:28]4[CH:29]([OH:31])[CH2:30]3)[C:15]=2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(O)C(O)C3O)c2n1
Solvent: CC(C)=O
Solvent: COC(C)(C)OC
Product: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(O)C4OC(C)(C)OC43)c2n1
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of product of example 12, step (f) (4.50 g) in acetone (100 ml), 2,2-dimethoxypropane (12.60 ml) and p-toluenesulphonic acid (2.34 g) were added and the reaction mixture stirred for 1 hour. Purification (SiO2, ethyl acetate:isohexane 2:7 as eluant) afforded the subtitle compound (4.34 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:24]3[CH:25]=[C:26](OS(C(F)(F)F)(=O)=O)[CH:27]=[CH:28][CH:29]=3)[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH3:40][N:41](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH2:38]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:11]=[N:10][C:9]([C:12]2([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:40]#[N:41])[CH:25]=3)[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:16][CH2:17]2)=[N:8][CH:7]=1)=[O:5])[CH3:39]
Reactant: CCCC(C)CN1CCC(c2cccc(OS(=O)(=O)C(F)(F)F)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CCCC(C)CN1CCC(c2cccc(C#N)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Temperature: 80 °C
Yield: 84 %

Procedure:
A stirring solution of Trifluoro-methanesulfonic acid 3-[4-(5-diethylcarbamoyl-pyrimidin-2-yl)-1-(2-methyl-pentyl)-piperidin-4-yl]-phenyl ester (260 mg, 0.46 mmol), zinc cyanide (Zn(CN)2) (81 mg, 0.69 mmol) and tetrakistriphenylphosphine palladium (0) (266 mg, 0.23 mmol) in 8 mL DMF was cooled to −78° C. and de-oxygenated via a freeze-thaw process. The reaction mixture was heated to 80° C. for 1.5 hours, cooled to room temperature and filtered. The resulting solution was partitioned between EtOAc and water, the layers were separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layers were dried and concentrated. The resulting crude material was purified by flash chromatography to afford 173 mg (84%) of the desired nitrile. 1HNMR (400 MHz, CDCl3) δ 8.69 (s, 2H), 7.64-7.59 (comp, 1H), 7.41-7.29 (comp, 3H), 3.51-3.49 (comp, 2H), 3.25-3.23 (comp, 2H), 2.97-2.94 (comp, 2H), 2.66 (br s, 2H), 2.27-2.25 (comp, 2H), 2.05-1.90 (comp, 4H), 1.57-1.55 (comp, 1H), 1.31-1.15 (comp, 9H), 0.99-0.95 (comp, 1H), 0.83-0.81 (comp, 6H); MS (M+1) 448.3.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]#[N:8])[NH:5][CH:6]=1.[OH-].[Na+].[I:11]I>ClCCl>[I:11][C:6]1[NH:5][C:4]([C:7]#[N:8])=[N:3][C:2]=1[CH3:1]
Reactant: II
Reactant: Cc1c[nH]c(C#N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1nc(C#N)[nH]c1I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
Into a 25-mL round bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 4-methyl-1H-imidazole-2-carbonitrile (compound 14.2, 350 mg, 3.27 mmol) and aqueous sodium hydroxide (2 M, 5 mL) and stirred for 15 min at room temperature. This was followed by the drop-wise addition of a solution of iodine (1.25 g, 4.92 mmol) in dichloromethane (5 mL). The resulting mixture was stirred for 24 h at room temperature, then diluted with water/ice (10 mL). The aqueous layer was washed with DCM (10 mL), and then the aqueous layer was acidified to pH 5-6 with acetic acid. The aqueous phase was extracted with EtOAc (5×50 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield 500 mg (66%) of the title compound as a brown solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4](=[O:20])[NH:5][CH2:6][CH2:7][CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]=12.[CH:21]([NH2:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH:21]([NH:24][CH2:2][C:3]1[C:4](=[O:20])[NH:5][CH2:6][CH2:7][CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[C:9]=12)([CH3:23])[CH3:22]
Reactant: CC(C)N
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CCl)=C21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC1CCNC(=O)C(CNC(C)C)=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred suspension of 4 g of 1-chloromethyl-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]azepin-2-one in 80 ml of methylene chloride is added 8 ml of isopropylamine. The mixture is stirred at room temperature overnight, 80 ml of saturated aqueous sodium carbonate are added, the organic layer is separated, washed with water, dried and evaporated. The residue is crystallized from diethyl ether and recrystallized from ethyl acetate, to give the 1-isopropylaminomethyl-3,4,5,5a,6,7-hexahydro-9-methoxy-2H-naphth[1,2-d]azepin-2-one melting at 212°-214°.