Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:17]=[C:16](Cl)[N:15]=2)[CH:8]=1)=[O:5].C(N(C(C)C)CC)(C)C.[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40]>C(O)C>[Cl:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:17]=[C:16]([N:45]3[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]3)[N:15]=2)[CH:8]=1)=[O:5]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(C)c1cc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)ccn2)nc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)ccn2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Temperature: 140 °C
Yield: 48.3 %

Procedure:
To a microwave tube with a solution of 2,6-dichloro-N-(2-(2-chloro-6-isopropylpyrimidin-4-ylamino)pyridin-4-yl)benzamide (0.050 g, 0.11 mmol) in ethanol (2 mL) was added diisopropylethylamine (1.5 mL) and 1-(methylsulfonyl)piperazine (0.18 g, 1.1 mmol). The resulting mixture was heated to 140° C. under microwave irradiation for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product (30 mg, 46% yield). 1H NMR ((500 MHz, DMSO-d6): δ 11.05 (s, 1H), 9.77 (s, 1H), 8.77 (s, 1H), 8.16 (d, J=5.5 Hz, 1H), 7.63 (s, 1H), 7.61 (s, 1H), 7.54 (m, 1H), 6.87 (m, 1H), 6.48 (s, 1H), 3.95-3.91 (m, 4H), 3.17-3.14 (m, 4H), 2.85 (s, 3H), 2.67 (m, 1H), 1.17 (d, J=7.0 Hz, 6H). LCMS (ESI) m/z: 564.0 [M+H+].
Reaction SMILES: Cl[C:2]1[N:25]=[CH:24][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[O:23][CH2:22][CH2:21][O:20]4)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH3:26][NH:27][CH3:28]>>[CH3:26][N:27]([C:2]1[N:25]=[CH:24][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]4[O:23][CH2:22][CH2:21][O:20]4)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1)[CH3:28]
Reactant: CNC
Reactant: Clc1cc2c(Nc3ccc(OCC4OCCO4)cc3)ncnc2cn1
Product: CN(C)c1cc2c(Nc3ccc(OCC4OCCO4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure C from 6-chloro-4-[4-(1,3-dioxolan-2-yl)methoxyanilino]pyrido[3,4-d]pyrimidin and dimethylamine (33% aqueous solution); δH (CDCl3) 9.71 (1H,s), 8.87 (1H,s), 8.38 (1H,s), 7.78 (2H,d), 7.35 (1H,s) 7.09 (2H,d), 5.30 (1H,t), 4.00 (6H,m), 3.25 (6H,s); m/z (M+1)+368.
Reaction SMILES: C(OC(OCC)C[N:6]([C:16](=O)[CH3:17])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)C.[ClH:22].[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[OH:33])[CH2:27][CH2:28][NH2:29].C(O)CCC>O>[ClH:22].[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([NH:6][CH2:16][CH:17]2[C:30]3[C:26](=[CH:25][C:24]([OH:23])=[C:32]([OH:33])[CH:31]=3)[CH2:27][CH2:28][NH:29]2)=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CN(C(C)=O)c1ccc([N+](=O)[O-])cc1)OCC
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: O=[N+]([O-])c1ccc(NCC2NCCc3cc(O)c(O)cc32)cc1
Yield: 84.2 %

Procedure:
A mixture of N-acetyl-p-nitroanilinoacetaldehyde diethyl acetal (1 g), 3,4-dihydroxyphenethylamine hydrochloride (1 g), n-butyl alcohol (10 ml) and water (1.5 ml) was refluxed for 7 hours. In the course of the reaction, the above-mentioned acetal (2.5 g) was added to the mixture, twice in 0.5 g portions and five times in 0.3 g portions, one every hour. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was pulverized by adding ether and the powder was collected by filtration, washed with ethyl acetate and water and dried to give 1-(p-nitroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1 g), mp 238° to 239° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[NH2:37])[N:28]=1)=[O:26]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[N:37]=[CH:14][C:13]([OH:20])([C:16]([F:18])([F:19])[F:17])[CH2:12][C:11]([C:5]2[C:6]3[O:10][CH2:9][O:8][C:7]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:21])[CH3:22])[N:28]=1)=[O:26]
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccc(Cl)c2c1OCO2
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3ccc(Cl)c4c3OCO4)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 37, 70 mg (0.21 mmol) of 4-(7-chlorobenzo[1,3]dioxol -4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is reacted with 50 mg (0.25 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester in 0.5 ml of concentrated acetic acid and 20 ml of toluene. After working-up and purification on silica gel with hexane-ethyl acetate (0–100%), 60 mg (55% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[CH:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)[NH:8][CH2:7][CH2:6]2.C1C=CC=CC=1.[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>N1C=CC=CC=1>[CH:34]1([C:40]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)/[C:9]/2=[CH:15]/[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COc1cc2c(cc1OC)C(=Cc1cc(OC)c(OC)c(OC)c1)NCC2
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C/c1cc(OC)c(OC)c(OC)c1)N(C(=O)C1CCCCC1)CC2

Procedure:
To a suspension of 5 parts of 3,4-dihydro-6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methylene]isoquinoline in 50 parts of benzene is added 15 parts of pyridine, followed by 3 parts of cyclohexanecarbonyl chloride. The resultant mixture is heated at the boiling point under reflux in a nitrogen atmosphere for 2 hours, then cooled, consecutively washed with water and aqueous 5% sodium becarbonate, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is crystallized from a mixture of ethyl acetate and ether to afford (Z)-2-cyclohexanecarbonyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methylene]isoquinoline melting at 162°-164°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.F[P-](F)(F)(F)(F)F.[N:20]1([O:29][C:30](N(C)C)=[N+](C)C)[C:24]2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CNOC>CN(C)C=O>[CH3:30][O:29][N:20]([CH3:24])[C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.6 %

Procedure:
A mixture of 1H-indole-2-carboxylic acid (from Aldrich, 2.5 g, 16 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.6 g, 20 mmol) and triethylamine (11 mL, 78 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 10 minutes. N,O-Dimethylhydroxylamine hydrochloride (2.0 g, 20 mmol) was added and the resulting suspension was stirred at room temperature for 2 hours. The mixture was quenched with water, extracted with EtOAc. The combined organic layers were dried over Na2SO4, concentrated and purified on silica gel (eluting with 0-50% EtOAc in hexane) to give the desired product (2.7 g, 85%). LCMS calculated for C11H13N2O2(M+H)+: m/z=205.1. Found: 205.1.
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-].[K+].[K+].CC(C)=O.[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[CH2:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCCCCCCOc1ccc(C(=O)OC)cc1
Yield: 86.2 %

Procedure:
Into a flask were introduced methyl 4-hydroxybenzoate (251.0 g, 1.65 mol), potassium carbonate (276.37 g, 1.99 mol) and 1200 g of acetone. This was refluxed for 45 min followed by the drop-wise addition of 1-octylbromide (386.17 g, 1.99 mol) over a 1 hour period. The reaction mixture was refluxed for two days. Filtration of the cooled reaction mixture and evaporation of the filtrate gave an oil. This was taken up in ethyl acetate and extracted with 5% NaOH (2×100 ml) followed by water (2×100 ml). The organic layer was dried (MgSO4), concentrated, and transferred to a pre-weighed 1L three-necked flask. The contents of the flask were subjected to high vacuum distillation to remove the excess 1-octylbromide. The pot residue gave 376 g (86% yield) of methyl 4-octoxybenzoate.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:12][C@H:11]([CH:13]=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:15][C:16]([S:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[Si:1]([O:8][C@@H:9]1[CH2:12][C@H:11](/[CH:13]=[N:21]/[S:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](C=O)C1
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
To a solution of cis-3-(tert-butyldimethylsilanyloxy)-cyclobutanecarbaldehyde (crude from step 3, 900 mg, 4.2 mmol) and 2-methylpropane-2-sulfinamide (509 mg, 4.2 mmol) in dry CH2Cl2 (10 mL) was added anhydrous CuSO4 (1.47 g, 9.24 mmol). The heterogeneous reaction mixture was stirred at room temperature overnight then filtered over Celite, rinsing with CH2Cl2. The filtrate was absorbed onto SiO2 and purified via chromatography with 0% to 20% EtOAc/hexanes to isolate 642 mg (48%) of 2-methyl-propane-2-sulfinic acid 1-[cis-3-(tert-butyldimethylsilanyloxy)-cyclobutyl]-meth-(E)-ylideneamide as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.04 (d, J=5.3 Hz, 1H), 4.25 (quin, J=7.4 Hz, 1H), 2.73-2.88 (m, 1H), 2.46-2.59 (m, 2H), 2.06-2.18 (m, 2H), 1.19 (s, 9H), 0.89 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2.[Na].C(O)CC(C)C.Cl>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6]2
Reactant: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Agent: Cl
Agent: [Na]
Solvent: CC(C)CCO
Solvent: CCOCC
Product: COC(=O)C(C)C1=Cc2ccc(OC)cc2CC1

Procedure:
A mixture of 24.4 g. of methyl 6-methoxy-2-naphthyl-α-methylacetate, 25 g. of sodium metal, and 500 ml. of anhydrous iso-amyl alcohol are refluxed for 18 hours. The cooled reaction mixture is acidified by the addition of aqueous 1N hydrochloric acid. The product is isolated by diethyl ether extraction to give methyl 6-methoxy-3,4-dihydro-2-naphthyl-α-methylacetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH2:14])[CH3:10]>C1(C)C=CC=CC=1>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][N:14]=[CH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH3:10]
Reactant: O=Cc1ccncc1
Reactant: CCOC(CN)OCC
Solvent: Cc1ccccc1
Product: CCOC(CN=Cc1ccncc1)OCC
Yield: 100 %

Procedure:
300 g pyridine-4-carbaldehyde and 372 g 2,2-diethoxy-ethylamine were refluxed in 2 L toluol over night. The mixture was evaporated to give 621 g of the desired product. The residue was purified by chromatographie on silica to give 100 g desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH2:11][C:12]([O:14]C)=O)[NH2:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:16][N:17]=[C:18]=[O:19]>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:11][C:12](=[O:14])[N:17]([CH3:16])[C:18](=[O:19])[NH:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CN=C=O
Reactant: COC(=O)CN(N)c1cccc(C#N)c1
Solvent: CC#N
Product: CN1C(=O)CN(c2cccc(C#N)c2)NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl [1-(3-cyanophenyl)hydrazino]acetate (700 mg) was dissolved in dry acetonitrile (10 ml) under nitrogen. Methyl isocyanate (0.7 ml) was added to the reaction mixture which was then heated at reflux for 1.5 h. The solvent was removed in vacuo and the oily residue was dissolved in methanol (10 ml) under nitrogen. Sodium methoxide (2.17M solution in methanol; 3.9 ml) was added and the solution was stirred at room temperature for 2 h. The reaction was poured into pH 6.5 phosphate buffer (100 ml) and extracted with ethyl acetate (3×80 ml). The combined, dried organic extracts were concentrated at reduced pressure to give a solid which was triturated with ether (3×20 ml) to give the title compound (640 mg), m.p. 174°-178°. N.m.r. indicated 0.084 mol ethyl acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]1[F:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C@H:13]1[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@H]1CCNC[C@H]1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
(cis)-tert-Butyl 4-(benzyloxycarbonylamino)-3-fluoropiperidine-1-carboxylate (7.5 g, 21.3 mmol) was weighed into a 500 mL 1 neck round bottom and dissolved in 200 mL of DCM, followed by addition of TFA (16.4 mL, 213 mmol) and stirring at ambient temperature for 1 hour, at which time all bubbling had ceased and the reaction appeared complete by TLC. The crude reaction was concentrated in vacuo, followed by aqueous work-up with 2 N NaOH and DCM. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford benzyl (cis)-3-fluoropiperidin-4-ylcarbamate (4.25 g, 16.8 mmol, 79.2% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C@H:7]2[NH:11][C:10](=O)[CH2:9][CH2:8]2)[O:4][N:3]=1.B.[CH2:14]1COCC1>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:8][CH2:9][CH2:10][N:11]2[CH3:14])[O:4][N:3]=1
Reactant: Cc1cc([C@@H]2CCC(=O)N2)on1
Reactant: C1CCOC1
Agent: B
Product: Cc1cc([C@@H]2CCCN2C)on1

Procedure:
To a solution of crude 5(S)-(3-methyl-5-isoxazolyl)-2-pyrrolidinone (5.33 g, 32.1 mmol, the product of step 13b) in THF (50 mL) was added borane-THF (99.5 mL, 1.0M, 99.5 mmol) slowly at room temperature. The reaction mixture was heated at reflux for two hours. After removal of THF under vacuum, a solution of formaldehyde (10.0 mL) and formic acid (5.0 mL) was carefully added, and the reaction mixture was refluxed for one hour. Ethyl acetate (300 mL) was added, followed by the addition of sodium carbonate until basic. The organic layer was decanted, and the residue was washed with ethyl acetate (4×20 mL). The combined organic solvents were dried over sodium carbonate. The solvent was evaporated, and the residue was distilled (bp. ~150° C./~50 mm Hg) to give the title compound (3.12 g, 59%; 24% overall yield). The compound was further purified by HPLC chromatography (CHCl3 /MeOH, 20:1 and 10:1). HPLC (analytical Chiralark OD column) analysis indicated >99% ee. [α]D23° =-13.1° (c 0.9, MeOH). MS (DCl/NH3) m/e: 153 (M+H)+. 1H NMR (CDCl3) δ 1.80-2.00 (m, 3H), 1.99 (br s, 1H, NH), 2.14-2.21 (m, 1H), 2.28 (s, 3H), 2.96-3.16 (m, 2H), 4.32 (dd, 1H), 5.95 (s, 1H).
Reaction SMILES: [OH2:1].[PH2]([O-])=O.C([NH+](CC)CC)C.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]#N)[CH:16]=[CH:15][C:14]=1[N:21]1[C:25]2[C:26]3[S:30][C:29]([NH:31][C:32](=[O:34])[CH3:33])=[N:28][C:27]=3[CH2:35][CH2:36][C:24]=2[C:23]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[N:22]1>[Ni].ClCCl.CO>[Cl:12][C:13]1[CH:18]=[C:17]([CH:19]=[O:1])[CH:16]=[CH:15][C:14]=1[N:21]1[C:25]2[C:26]3[S:30][C:29]([NH:31][C:32](=[O:34])[CH3:33])=[N:28][C:27]=3[CH2:35][CH2:36][C:24]=2[C:23]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[N:22]1
Reactant: O
Reactant: CC(=O)Nc1nc2c(s1)-c1c(c(-c3cccnc3)nn1-c1ccc(C#N)cc1Cl)CC2
Agent: [Ni]
Agent: CC[NH+](CC)CC
Agent: O=[PH2][O-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1nc2c(s1)-c1c(c(-c3cccnc3)nn1-c1ccc(C=O)cc1Cl)CC2
Temperature: 55 °C
Reaction time: 3 h

Procedure:
In a hydrogenation reactor under an argon atmosphere, triethylammonium hypophosphite hydrate (2.2 mL, 12 mmol) is added at 10° C. to a suspension of Raney nickel (8 g, 93 mmol) in 75 mL dichloromethane and 75 mL methanol. After the release of gas has died away N-[1-(2-chloro-4-cyanophenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazolo[4,3-g]benzothiazol-7-yl]-acetamide (PCT/EP05055021) (2.7 g, 5.6 mmol) is added and the mixture is stirred for 3 h at 55° C. The reaction mixture is filtered and the filtrate is evaporated down. The residue is purified on silica gel with dichloromethane/methanol.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[CH2:12].[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Cl.O>CS(C)=O>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[CH2:12]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: C=C(c1cc(F)ccc1O)n1ccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=C(c1cc(F)ccc1OCc1ccc(Cl)cc1Cl)n1ccnc1
Temperature: 55 °C
Reaction time: 0.83 h
Yield: 68 %

Procedure:
85% Potassium hydroxide powder (36.0 g, 0.545 mole) was suspended in dimethyl sulfoxide (500 g) and stirred at 55° C. for 50 minutes. After cooling to 25° C., 1-[1-(2-hydroxy-5-fluorophenyl)vinyl]-1H-imidazole (90.0 g, 0.441 mole) was added and the mixture was stirred at room temperature for 1 hour. Then, 2,4-dichlorobenzyl chloride (94.5 g, 0.483 mole) was added dropwise over 1 hour and the mixture was stirred for 2 hours. Water (680 ml) was added dropwise over 25 minutes to the reaction mixture with stirring and then stirring was continued for additional 1 hour. The precipitated crystals were filtered off and washed with water (135 ml×5) and n-hexane (135 ml×3). The resulting crude crystals were recrystallized from n-hexane/ethyl acetate to obtain the title compound (109 g, 68.1%), m.p. 118°-120° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[OH:19])([O-])=[O:2].C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.N(C1C=CC=CC=1)=NC1C=CC=CC=1>O.CO>[OH:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[N:11]1[N+:1]([O-:2])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:10]1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: O=C1c2ccccc2-c2ccccc21
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: c1ccc(N=Nc2ccccc2)cc1
Solvent: CO
Solvent: O
Product: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1

Procedure:
A mixture of methanol 60 ml, water 30 ml, 97% sodium hydroxide 12.4 g and 2-nitro-2'-hydroxy-5'-methylazobenzene 12.9 g was heated and stirred at 45°~50° C. 9-fluorenone 1.0 g and then glucose 5.5 g were added to the resultant mixture over 30 minutes while stirring. The mixture was further stirred at 75° C. (boiling point) for 7 hours. As this result, the azobenzene disappeared to produce 2-(2'-hydroxy-5'-methylphenyl)benzotriazole-N-oxide.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[CH:6]=[N:5][CH:4]=1.[CH3:18]I>C1COCC1.CCOC(C)=O>[CH3:18][N:9]([C:7]1[CH:8]=[N:3][CH:4]=[N:5][CH:6]=1)[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]
Reactant: N#Cc1cccc(Nc2cncnc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cncnc1)c1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
NaH (148 mg, 6.17 mmol, 1.10 eq) was added to a flame-dried round-bottom flask and anhydrous THF (14 mL) was added. The slurry was cooled to 0° C. and compound 15 (1.098 g, 5.596 mmol, 1.000 eq) was added as a solution in THF (14 mL). After stirring at 0° C. for 30 minutes methyl iodide (384 μL, 6.17 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 735 mg (62%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.57 (s, 2H), 7.58-7.56 (m, 1H), 7.51-7.44 (m, 2H), 7.44-7.38 (m, 1H), 3.35 (s, 3H); [M+1]+: 211.2.
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1.Br[CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:35]1([CH2:34][CH2:33][CH2:32][C:2]#[C:3][CH2:4][CH2:5][C:6]2[N:7]=[CH:8][NH:9][CH:10]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCCCc1ccccc1
Reactant: BrC(Br)=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: C(#CCCc1c[nH]cn1)CCCc1ccccc1

Procedure:
4-(7-Phenylhept-3-ynyl)imidazole was prepared in the same manner as described in example 36 except that 4-(4,4-dibromobut-3-enyl)-1-(triphenylmethyl)imidazole and 1-bromo-3-phenylpropane were used.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[CH:10]=[C:11]([NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:28])=[CH:23][CH2:22][CH2:21][C:20]=3[N:19]=2)[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.C[Si](C)(C)[O-:31].[K+]>O1CCOCC1>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[CH:10]=[C:11]([NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:28])=[CH:23][CH2:22][CH2:21][C:20]=3[N:19]=2)[C:12]([C:15]([NH2:16])=[O:31])=[N:13][CH:14]=1
Reactant: C[Si](C)(C)[O-]
Reactant: CC1=CCCc2nc(Nc3cc(N[C@@H]4CCCC[C@@H]4N)cnc3C#N)ccc21
Agent: [K+]
Solvent: C1COCCO1
Product: CC1=CCCc2nc(Nc3cc(N[C@@H]4CCCC[C@@H]4N)cnc3C(N)=O)ccc21
Temperature: 100 °C

Procedure:
A suspension of 5-((1R,2S)-2-aminocyclohexylamino)-3-(5-methyl-7,8-dihydroquinolin-2-ylamino)picolinonitrile (19 mg, 0.051 mmol) and potassium trimethylsilanolate (98 mg, 0.76 mmol) in 1,4-dioxane (1 mL) was heated to 100° C. in an oil bath for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with DMSO, filtered, and purified by reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to yield 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-[(5-methyl-7,8-dihydroquinolin-2-yl)amino]pyridine-2-carboxamide. MS ESI calc'd. for C22H29N6O [M+H]+ 393. found 393.