Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[N:12]1([C:11]2[C:6]([CH:4]3[CH2:5][N:2]([C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[CH2:3]3)=[N:7][CH:8]=[CH:9][N:10]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: c1cnc(N2CCCCC2)c(C2CNC2)n1
Reactant: Clc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2nc(N3CC(c4nccnc4N4CCCCC4)C3)ccc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 2-azetidin-3-yl-3-piperidin-1-yl-pyrazine hydrochloride (127 mg, 0.5 mmol) and 2-chloro-quinoline (81.5 mg 0.5 mmol) in DMF (5 mL) was added Cs2CO3 (325 mg, 1 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by ISCO silica gel column (10% to 80% EtOAc in petroleum ether) to give 2-[3-(3-piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-quinoline (58 mg, 0.17 mmol yield 17%).
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9]([NH2:11])=[NH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[CH2:8]([C:9]1[N:11]=[C:13]([Cl:12])[S:16][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)Cc1ccccc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Clc1nc(Cc2ccccc2)ns1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 2-phenyl-acetamidine hydrochloride (1.078 g, 6 mmol) in dichloromethane (10 ml) was added perchloromethyl mercaptan (0.61 ml, 5 mmol) via syringe. The mixture was cooled in an ice-methanol bath to −10° C. and a solution of sodium hydroxide (1.2 g, 30 mmol) in water (3 ml) was added dropwise keeping the temperature below −8° C. After complete addition the mixture was stirred 10 min at 0° C. The reaction mixture was diluted with water and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over Na2SO4, filtered and the solvents were evaporated. The residue was purified by chromatography on silica gel using heptane/ethyl acetate as eluent. The title compound was obtained as an orange liquid (0.779 g, 62%). MS ISP (m/e): 211.0 (100) [(M+H)+].
Reaction SMILES: [N+:1]([C:4]([CH3:9])([CH2:7][OH:8])[CH2:5][OH:6])([O-:3])=[O:2].O1CC[CH2:13]OO1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:9][C:4]1([N+:1]([O-:3])=[O:2])[CH2:7][O:8][CH2:13][O:6][CH2:5]1
Reactant: CC(CO)(CO)[N+](=O)[O-]
Reactant: C1COOOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1([N+](=O)[O-])COCOC1

Procedure:
2-Nitro-2-methyl-1,3-propanediol 405.00 grams (3.00 moles), 98% trioxane 92.80 grams (1.00 mole), p-toluenesulfonic acid 3.00 grams (0.016 mole), and benzene 600 ml were placed in a two liter three-necked RB flask. The flask was fitted with a thermometer, a mechanical stirrer and a Dean-Stark trap connected to a condenser. The mixture was stirred and refluxed. The slurry gradually became a homogeneous solution (usually about 30 minutes after heating started) and the benzene-water azeotrope started to distill over. Refluxing was continued until 45 ml of water was collected (i.e., approximately four hours). During this period the solution temperature was between 78° C. and 82° C. After 45 ml of water had been collected, the reaction mixture was cooled and neutralized with 3 ml triethylamine. Benzene was distilled from the clear solution first at atmospheric pressure (approximately 415 ml benzene was recovered at a solution temperature of 82° C.-100° C.) and then at about 125 mm of pressure (approximately 120 ml benzene was recovered at a solution temperature of about 48° C.-110° C.). A clear, pale-yellow, viscous liquid, 450.67 grams, containing a mixture of the reaction products polynitroformal and 5-methyl-5-nitro-1,3-dioxane was obtained as the resulting product.
Reaction SMILES: [C:1]([C:3]1([NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[CH2:6][O:5][CH2:4]1)#[N:2].C([NH:17][C@H](C(O)=O)CS)(=O)C.N>CO>[CH3:11][C:10]([CH3:13])([S:8]([NH:7][C:3]1([C:1](=[NH:17])[NH2:2])[CH2:4][O:5][CH2:6]1)=[O:9])[CH3:12]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: CC(C)(C)S(=O)NC1(C#N)COC1
Agent: N
Solvent: CO
Product: CC(C)(C)S(=O)NC1(C(=N)N)COC1

Procedure:
To a mixture of N-(3-cyanooxetan-3-yl)-2-methylpropane-2-sulfinamide (0.1 g, 0.494 mmol) in methanol (2 ml) in a 50 ml sealed tube was added N-acetyl-L-(+)-cysteine (0.081 g, 0.494 mmol), and the reaction mixture stirred for few minutes. A solution of ammonia in methanol (0.5 ml, 3.50 mmol, 7 N) was added, and the reaction mixture stirred at 60° C. for overnight. The reaction mixture was then concentrated under vacuum, and the crude was used for the next step without further purification.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[CH3:13]O>OS(O)(=O)=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1
Reactant: CO
Reactant: O=C(O)c1n[nH]c2ncccc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1n[nH]c2ncccc12
Yield: 90 %

Procedure:
To a solution of 1H-pyrazole[3,4-b]pyridine-3-carboxylic acid (XV) (0.39 g, 2.4 mmol) in dry MeOH (10 mL) was added concentrated H2SO4 (4 drops) and refluxed for 6 h under nitrogen. The solution was cooled and the solvent was evaporated under vacuum. The residue was partitioned between DCM and saturated aqueous NaHCO3 solution. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified on a flash silica gel column (100% DCM→3:97 MeOH:DCM) to produce methyl 1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVI) as a white solid (382 mg, 2.16 mmol, 90% yield). 1H NMR (CDCl3) δ ppm 4.08 (s, 3H), 7.38 (m, 1H), 8.63 (dd, J=8.10 Hz, J=1.51 Hz, 1H), 8.72 (dd, J=4.62 Hz, J=1.41 Hz, 1H); ESIMS found for C8H7N3O2 m/z 178.2 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[C:30](Cl)=[O:31])[CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:29]=3[N:20]=[CH:21][CH:22]=[CH:23]4)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1cccc2cccnc12
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cccc2cccnc12

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and quinoline-8-carbonyl chloride were combined to provide N8-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-8-quinolinecarboxamide as a tan powder, m.p. 91.0-93.0° C. 1H NMR (300 MHz, DMSO-d6) δ10.80 (t, J=5.5 Hz, 1H), 8.79 (dd, J=4.3, 1.8 Hz, 1H), 8.55-8.49 (m, 2H), 8.24 (s, 1H), 8.17 (dd, J=8.1, 1.5 Hz, 1H), 8.06 (d, J=7.2 Hz, 1H), 7.73 (t, J=7.8 Hz, 1H), 7.63-7.59 (m, 2H), 7.40 (dt J=7.1, 1.2 Hz, 1H), 7.14 (dt, J=7.1, 1.2 Hz, 1H), 6.57 (broad s, 2H), 4.68 (t, J=7.0 Hz, 2H), 3.51 (m, 2H), 2.02 (m, 2H), 1.69 (m, 2H); MS (EI) m/e 410.1858 (410.1855 calcd for C24H22N6O).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:24][CH2:25][CH:26]=[CH2:27].O>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]([CH2:6][CH2:5][CH:4]=[CH2:3])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[CH2:24][CH2:25][CH:26]=[CH2:27]
Reactant: COC(=O)Cc1cccc(F)c1
Reactant: C=CCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(CCC=C)(C(=O)OC)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(3-Fluoro-phenyl)-acetic acid methyl ester (4.30 g) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide (25.6 mL, 1M THF solution) was added and the solution was stirred for 30 minutes. 4-Bromo-but-1-ene (2.60 mL) was added and the reaction contents were allowed to warm to room temperature and stir for an hour. The reaction mixture was again cooled to −78° C. Lithium bis(trimethylsilyl)amide (25.6 mL, 1M THF solution) was added and the solution was stirred for 30 minutes. 4-Bromo-1-butene (2.60 mL) was added and the reaction mixture was allowed to warm to room temperature and stir for an hour. The contents were again cooled to −78° C. and further aliquots of Lithium bis(trimethylsilyl)amide (25.6 mL, 1M THF solution) and 4-bromo-1-butene (2.60 mL) were added following the procedure outlined above. After stirring overnight, water (20 mL) was added and the reaction mixture extracted with diethyl ether (2×60 mL). The combined organic extracts were dried with magnesium sulfate and evaporated. The resulting liquid was purified by column chromatography on silica eluting with ethyl acetate/isohexane (1/99) to afford the sub-titled compound (5.0 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11](N)[CH3:12])=[CH:7][CH:6]=1.F[C:17](F)(F)COC1C=CC(C#N)=CC=1>>[F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([NH2:10])[CH3:17])=[CH:7][CH:6]=1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: N#Cc1ccc(OCC(F)(F)F)cc1
Product: CC(N)c1ccc(OCC(F)(F)F)cc1

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]ethanamine, step B, starting from 4-(2,2,2-trifluoroethoxy)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.28-7.34 (m, 2 H) 6.94-7.00 (m, 2 H) 4.70 (q, J=8.78 Hz, 2 H) 3.95 (q, J=6.53 Hz, 1 H) 1.21 (d, J=6.78 Hz, 3 H). MS (ESI) m/z: 220 [M+H]
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:7]=[C:6]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCCC(=O)c1cccc(Br)n1
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: O
Solvent: COCCOC
Product: CCCCC(=O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.8 %

Procedure:
A solution of 1-(6-bromo-2-pyridinyl)-1-pentanone (2.51 g, 10.37 mmol) in DME (13 mL) was treated with 4-(triflouromethyl)benzeneboronic acid (2.36 g, 12.43 mmol), Pd(PPh3)4 (1.19 g, 1.03 mmol) and then a slurry of Na2CO3 (3.29 g, 31.04 mmol) in water (13 mL). The resulting mixture was then heated to reflux over 30 minutes and then stirred at this temperature for 17 hours. The mixture was then allowed to cool to rt and was reduced and the residue partitioned between EtOAc (200 mL) and water (200 mL). The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with saturated aqueous NaHCO3 (250 mL), brine (250 mL), dried (MgSO4), filtered and reduced to give a brown orange solid residue. Purification by Biotage™ chromatography (silica) eluting with cyclohexane:EtOAc (gradient 1:0 to 10:1) afforded the title compound as a white solid (3.02 g).
Reaction SMILES: CO[CH:3](O)[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:17].CC(N([C@H]1CCNC[C@H]1O)C(=O)[O-])(C)C.[C:34]([O:38][C:39](=[O:48])[NH:40][C@H:41]1[CH2:46][CH2:45][NH:44][CH2:43][C@H:42]1[OH:47])([CH3:37])([CH3:36])[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[OH:47][C@H:42]1[C@@H:41]([NH:40][C:39](=[O:48])[O:38][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:46][CH2:45][N:44]([CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[N:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=3)[CH:8]=[CH:7][C:6]2=[O:17])[CH2:43]1
Reactant: COc1cnc2ccc(=O)n(CC(O)OC)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)N(C(=O)[O-])[C@H]1CCNC[C@H]1O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C3)c2c1
Temperature: 25 °C

Procedure:
[7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde methyl hemiacetal (200 mg, 0.7992 mmol) and 1,1-dimethylethyl[(3R,4S)-3-hydroxy-4-piperidinyl]carbamate (for a synthesis see WO2004058144, Example 5(c), cis-(3-hydroxy-piperidin-4-yl)-carbamic acid tert-butyl ester Enantiomer 1) (173 mg, 1 eq.) were stirred in chloroform (10 ml) plus MeOH (0.5 ml) under argon for 2 h. Sodium triacetoxyborohydride (508 mg, 3 eq.) was added in one portion and the mixture was stirred at rt over the weekend, then quenched by addition of saturated aqueous sodium hydrogen cabonate (20 ml) and extracted with 20% v:v MeOH in DCM (3×200 ml). The organic extractes were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica, eluted with 0-20% (2M ammonia in MeOH) in DCM. Appropriate fractions were combined and evaporated under reduced pressure to give 1,1-dimethylethyl ((3R,4S)-3-hydroxy-1-{2-[7-(methyloxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl}-4-piperidinyl)carbamate (263 mg) as an off-white foam.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.[F-].[K+].CC([N:18](C)C)=O>>[NH2:18][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([Cl:1])=[N:3][N:4]=1
Reactant: CC(=O)N(C)C
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: [F-]
Agent: [K+]
Product: Nc1nnc(Cl)c2ccccc12
Temperature: 100 °C

Procedure:
A mixture containing 4 mL of 0.5 M 1,4-dichlorophthalazine in DMA, 2 equivalents of amine and 500 mg of KF is heated in a sealed vial at 100° C. overnight. Purification on silica gel and evaporation provides the desired 1-amino-4-chloro-phthalazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][C:4]([CH3:20])([CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[C:3]([O:2][CH3:1])=[O:21]
Reactant: COC(=O)C(C)(C)CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(C)CN1CCNCC1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A solution of 568 (1.137 g, 3.79 mmol) and TFA (15 ml) in DCM (30 ml) was stirred at rt for 2.5 h. The reaction mixture was concentrated (azeotropes with DCM), diluted with water, stirred for 1 h, and the pH was adjusted to around 9-10 with 1N NaOH. The alkaline solution was extracted with DCM. The extract was dried over anhydrous magnesium sulfate, filtered, concentrated and dried under high vacuum to afford the desired product 569 (667 mg, 3.33 mmol, 88% yield) as a pale-yellow viscous liquid. The crude material was used in the next step without any further purification. MS (z): 201.1 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:19][N:18]4[CH2:27][CH2:28][CH2:29][C:17]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1.[I-].[Na+].[CH3:32][NH:33][CH3:34].O1CCCC1>CN(C)C=O>[CH3:32][N:33]([CH3:34])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:19][N:18]4[CH2:27][CH2:28][CH2:29][C:17]=34)=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: CNC
Reactant: ClCCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1

Procedure:
A solution of 7-(3-chloro-propoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (54 mg, 0.13 mmol), sodium iodide (5 mg, 0.03 mmol), and 2 N dimethylamine in tetrahydrofuran (3 mL, 6 mmol) in N,N-dimethylformamide (5 mL) is heated at 100° C. for 48 h. The mixture is cooled and concentrated in vacuo. The residue is chromatographed on SiO2 (100% ethyl acetate to 10% methanol in ethyl acetate) to yield the title compound, 41 mg (74%), as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.CN.C[CH2:32][N:33](C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[NH:24]1[C:25]2[C:21](=[C:20]([C:18]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[C:11]([NH:10][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([NH:33][CH3:32])[N:7]=4)=[O:9])[CH:19]=3)[CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Agent: CN
Solvent: CO
Solvent: CS(C)=O
Product: CNc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 160 °C

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.90 mmol, prepared as described in Example 18) in DMSO (14 ml). Methylamine (2M in THF, 0.129 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 4 h under microwave irradiation. Further methylamine (2M in THF, 0.129 ml, 0.26 mmol) was added and the mixture was again heated at 160° C. for 1 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method B). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (4.4 mg) as a pale yellow gum.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([Br:26])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19]>C(OCCCC)CCC>[Cl:1][C:2]1[C:11]2[N:10]([C:18]([C:17]3[CH:21]=[C:22]([Br:26])[C:23]([O:24][CH3:25])=[C:15]([Br:14])[CH:16]=3)=[O:19])[CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: Clc1nccc2c1NCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: COc1c(Br)cc(C(=O)N2CCOc3ccnc(Cl)c32)cc1Br
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49.7 %

Procedure:
In a 50 ml flask equipped with a reflux apparatus, 5-chloro-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (890 mg, 5.22 mmol) was dissolved in butyl ether (20 ml), and 60% sodium hydride in mineral oil (250 mg, 6.26 mmol) was added and stirred at 1250 for 3.5 hours. The mixture was cooled to room temperature and 3,5-dibromo-4-methoxy-benzoyl chloride (2.06 g, 6.26 mmol) was added thereto and then stirred at 1250 for 24 hours. The mixture was cooled to room temperature and filtered and evaporated under reduced pressure. The residue was washed with methanol and dried under reduced pressure to obtain white solid (1.2 g, 50%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:28]=[CH:27][C:26]([F:29])=[CH:25][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1.C(N(CC)CC)C>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:28]=[CH:27][C:26]([F:29])=[CH:25][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)=[CH:19][C:18]=3[F:24])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(NCc1ccc(O)cc1F)c1cc(F)cnc1Oc1ccc2c(c1)OCO2
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(OCc2ccccn2)cc1F)c1cc(F)cnc1Oc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 100 mg (0.25 mmol.) 2-(benzo[1,3]dioxol-5-yloxy)-5-fluoro-N-(2-fluoro-4-hydroxy-benzyl)-nicotinamide [Prepared analogous to preparation 35 by substituting 2-chloro-5-fluoro-nicotinic acid (EP 0634413 A1)], 10 mL DMF and 175 mg (1.25 mmol.) potassium carbonate was added a solution of DMF (5 mL) containing 82 mg (0.5 mmol.) 2-chloromethyl-pyridine hydrochloride (Aldrich) and 1 equivalent of triethyl amine. The resulting mixture was stirred for 3 days at room temperature. Reaction mixture was poured into ice water (200 mL) and the resulting solid was filtered, washed with cold water and dried in vacuo to afford desired product.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.NC(N)=[S:22]>COCCO.O>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2](=[S:22])[NH:3][N:4]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][CH2:16][CH3:17]
Reactant: NC(N)=S
Reactant: CCCOc1ccc(-c2ccc(Cl)nn2)cc1OC
Solvent: O
Solvent: COCCO
Product: CCCOc1ccc(-c2ccc(=S)[nH]n2)cc1OC

Procedure:
T13.9 g of 3-chloro-6-(3-methoxy-4-n-propoxyphenyl)pyridazine are boiled under reflux with 5.5 g of thiourea in 50 ml of ethylene glycol monomethyl ether for 8 hours. After cooling, the mixture is diluted with 250 ml of water and extracted three times with chloroform. The chloroform extracts are dried over sodium sulfate and evaporated. The residue is crystallized from ethanol/ethyl acetate. 4.8 g (34.6% of theory) of the title compound of m.p. 174°-17620 are obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([F:32])=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]4([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=S)[NH:17]4)[CH:15]=3)=[N:7][C:6]=2[CH:31]=1.[NH3:33].C(OO)(C)(C)C>>[F:1][C:2]1[C:3]([F:32])=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]4([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18]([NH2:33])=[N:17]4)[CH:15]=3)=[N:7][C:6]=2[CH:31]=1
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3nc4cc(F)c(F)cc4o3)c(F)cc2F)C1(F)F
Reactant: N
Agent: CC(C)(C)OO
Product: CC1(C)OCC(N)=N[C@](C)(c2cc(-c3nc4cc(F)c(F)cc4o3)c(F)cc2F)C1(F)F
Yield: 24 %

Procedure:
In a manner analogous to that described in Example 2c), the ammonolysis of (R)-5-[5-(5,6-difluoro-benzo oxazol-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (83 mg, 175 μmol) with ammonia (7M in methanol; 1.72 ml) and tert-butylhydroperoxide (70% in water; 183 μl) yielded the title compound (19 mg, 24% yield). MS (ISP): m/z=458.2 [M+H]+.