Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2C=CC(O)=CC=2)CCCC1.[Cl:13][C:14]1[CH:38]=[C:37]([CH:39]2C[CH2:43][CH2:42][CH2:41][CH2:40]2)[CH:36]=[CH:35][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][CH2:26][C@:27]([CH3:34])([C:31]([OH:33])=[O:32])[O:28]2)=[CH:23][CH:22]=1>>[Cl:13][C:14]1[CH:38]=[C:37]([CH:39]2[CH2:40][CH2:41][CH2:42][CH2:43]2)[CH:36]=[CH:35][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH2:25][CH2:26][C@:27]([CH3:34])([C:31]([OH:33])=[O:32])[O:28]2)=[CH:23][CH:22]=1
Reactant: C[C@]1(C(=O)O)CCc2ccc(OCCCOc3ccc(C4CCCCC4)cc3Cl)cc2O1
Agent: Oc1ccc(C2CCCC2)cc1
Product: C[C@]1(C(=O)O)CCc2ccc(OCCCOc3ccc(C4CCCC4)cc3Cl)cc2O1

Procedure:
The title compound was prepared following the procedures described in Example 5, Steps B-E employing 4-cyclopentylphenol instead of 4-(2,2,2-trifluoroethoxy)phenol, and (2R)-methyl 2-methyl-7-hydroxychromane-2-carboxylate (Example 23, Step A) instead of ethyl 7-hydroxychromane-2-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([O:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:3]1>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([O:12][CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)COc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
A mixture of tert-butyl 2-[[4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazin-6-yl]oxy]acetate (0.30 g, 0.81 mmol) and trifluoroacetic acid (10 ml) was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure and recrystallized from methanol-diisopropyl ether to give the titled compound (0.17 g, 67%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=O.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>C(O)C>[OH:22][C:11]1[CH:10]=[CH:9][C:8]2[CH:7]3[CH:16]([CH2:15][CH2:14][C:13]=2[CH:12]=1)[CH:17]1[C:4]([CH3:3])([C:20](=[O:21])[C:19](=[CH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[CH2:18]1)[CH2:5][CH2:6]3
Reactant: O=Cc1ccccn1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccccn1)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (1.0 g, 25 mmol) was added to a suspension of estrone (1.35 g, 5.0 mmol) and pyridine-2-carbaldehyde (595 mg, 5.0 mmol) in ethanol (40 mL) at room temperature. The resulting dark orange solution was stirred at room temperature for 4 hours. Then glacial acetic (ca. 10 mL) acid was added with stirring. The colour changed to light yellow and a light yellow solid precipitated. The solid was filtered off and washed with water (50 mL), ethanol (20 mL), diethyl ether (50 mL) and hexane (50 mL) and dried under high vacuum. Yield: 1.638 g (91%) yellow powder.
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:6]=[C:7]([S:11][CH3:12])[CH:8]=[CH:9][CH:10]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:29][N:30]1[CH2:43][CH2:42][C:33]2[NH:34][C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][C:40]=3[C:32]=2[CH2:31]1>CN(C=O)C.[Cu]I>[CH3:29][N:30]1[CH2:43][CH2:42][C:33]2[N:34](/[CH:2]=[C:3](/[C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH3:12])[CH:6]=3)\[CH3:4])[C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][C:40]=3[C:32]=2[CH2:31]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CSc1cccc(C(C)=CBr)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CSc1cccc(/C(C)=C/n2c3c(c4cc(C)ccc42)CN(C)CC3)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
(3-(1-Bromoprop-1-en-2-yl)phenyl)(methyl)sulfane (194 mg, 0.8 mmol) was dissolved in DMF (5 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude product was purified on silica (100-200 mesh) using 0-4% MeOH:DCM as eluent. Yield: 160 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.50 (s, 1H), 7.38 (m, 2H), 7.30 (s, 2H), 7.10 (m, 2H), 6.99 (s, 1H), 4.50 (m, 2H), 3.70 (m, 2H), 3.10 (m, 4H), 2.56 (s, 3H), 2.42 (s, 3H), 1.95 (s, 3H)
Reaction SMILES: [CH2:1]([N:6]1[C:10]([C:11]([NH:13][C:14]2[CH:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[O:20])[N:16]([CH3:32])[CH:15]=2)=[O:12])=[CH:9][C:8]([NH:33][C:34]([C:36]2[N:37]([CH3:44])[CH:38]=[C:39]([N+:41]([O-])=O)[CH:40]=2)=[O:35])=[CH:7]1)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:45]([OH:47])C>[Pd]>[CH:45]([NH:41][C:39]1[CH:40]=[C:36]([C:34]([NH:33][C:8]2[CH:9]=[C:10]([C:11]([NH:13][C:14]3[CH:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[O:20])[N:16]([CH3:32])[CH:15]=3)=[O:12])[N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[CH:7]=2)=[O:35])[N:37]([CH3:44])[CH:38]=1)=[O:47]
Reactant: CCO
Reactant: CC(C)CCn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)Nc1cc(C(=O)NCCCN2CCN(C)CC2)n(C)c1
Agent: [Pd]
Product: CC(C)CCn1cc(NC(=O)c2cc(NC=O)cn2C)cc1C(=O)Nc1cc(C(=O)NCCCN2CCN(C)CC2)n(C)c1
Reaction time: 3 h
Yield: 53 %

Procedure:
N-[1-Isopentyl-5-({[1-methyl-5-({[3-(4-methyl-1-piperazinyl)propyl]-amino}carbonyl)-1H-pyrrol-3-yl]amino}carbonyl)-1H-pyrrol-3-yl]-1-methyl-4-nitro-1H-pyrrole-2-carboxamide (120 mg, 0.197 mmol; see step (ii) above) was dissolved in ethanol (20 mL) to which Pd/C-10% (77 mg) was added at 0° C. under N2 with stirring. The reaction mixture was hydrogenated for 3 h at room temperature and atmospheric pressure. The catalyst was removed over Kieselguhr and ethyl formate (20 mL) was added to the ethanolic solution. The reaction mixture was heated under reflux for 48 h. Ethanol and excess ethyl formate were removed under reduced pressure and the crude product was purified by HPLC. The product was obtained as yellow solid with no distinct melting point (75 mg, 53% yield) after freeze-drying.
Reaction SMILES: [C:1]([CH2:11][CH2:12]I)([C:7]([F:10])([F:9])[F:8])([C:3]([F:6])([F:5])[F:4])[F:2].C(O)(=O)C>O.[Zn]>[C:1]([CH2:11][CH3:12])([C:3]([F:4])([F:5])[F:6])([C:7]([F:10])([F:9])[F:8])[F:2]
Reactant: FC(F)(F)C(F)(CCI)C(F)(F)F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CCC(F)(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 56 %

Procedure:
A mixture of perfluoroisopropyl iodide (5.6 g, 0.19 mole), ethylene (5 L, 0.2 mole) and benzoyl peroxide (3.2 g) was heated in a 100 mL steel autoclave at 100° C. for 6 hours with stirring. The reaction product contained perfluoroisopropyl,iodide and (CF3)2CFCH2CH2I in a 1:1 ratio. Distillation of the reaction mixture gave (CF3)2CFCH2CH2I (b.p. 118 to 124° C.) in 33% yield. (CF3)2CFCH2CH2I (10 g) was added dropwise to a mixture of zinc dust (5 g) and acetic acid (30 mL). After the exothermic reaction was completed, the reaction mixture was stirred for 2.5 hours at 60° C., diluted with water and distilled to collect a fraction with a b.p. less than 100° C. The distillate was separated from water, dried over calcium chloride, and redistilled to give (CF3)2CFCH2CH3 (b.p. 39 to 42° C., 56% yield). The 1H and 19F NMR were in accord with the assigned structure.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.COC1C=CC(COC(C2C(C)=C([Br:56])C3C(=CC=CC=3)C=2O)C(OCC)=O)=CC=1>>[Br:56][C:6]1[C:5]2[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=2)[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]=1[CH3:30]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)c(Br)c2ccccc2c1O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1

Procedure:
Ethyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (125) was prepared in a similar manner as ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate of Example 67 except using ethyl 2-(4-methoxybenzyloxy)-2-(4-bromo-1-hydroxy-3-methylnaphthalen-2-yl)acetate. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=8.6 Hz, 1H), 7.57-7.42 (m, 4H), 7.36-7.24 (m, 3H), 5.16 (s, 1H), 4.24-4.09 (m, 2H), 2.75 (s, 3H), 1.23 (t, J=7.1 Hz, 3H), 1.00 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][N:3]=1.[C:15]([O-])([O-])=O.[K+].[K+].CI>>[F:1][C:2]1[C:7]([C:8]([O:10][CH3:15])=[O:9])=[C:6]([C:11]([F:12])([F:13])[F:14])[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(C(F)(F)F)ccnc1F
Agent: [K+]
Solvent: CI
Product: COC(=O)c1c(C(F)(F)F)ccnc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a mixture of 2-fluoro-4-(trifluoromethyl)pyridine-3-carboxylic acid (1.06 g) and K2CO3 (0.701 g) in DMF(dry) (10 mL) was added MeI (0.317 ml). The mixture was stirred at room temperature for 3 h. The mixture was directly purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (1.13 g, containing EtOAc and hexane, ca. 75% purity).
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:23]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](O)=[O:4].[CH:34]1([NH2:38])[CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:38][C:3](=[O:4])[CH:2]([OH:1])[CH:6]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[N:22]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23]2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Reactant: NC1CCC1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CCC1)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 2-hydroxy-4-phenyl-3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)butanoic acid with cyclobutylamine; ESI-MS [M+H]+: 496.2
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:22]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1nc(Cl)ccc1Cc1c[nH]c2ncccc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(Cl)ccc1Cc1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a clear solution of 3-(6-chloro-2-methoxypyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (28, 0.516 g, 1.88 mmol) in dimethylformamide (10 mL) was added sodium hydride (60% dispersion, 0.113 g, 2.82 mmol). After stirring at room temperature for 30 minutes, triisopropylsilyl chloride (600 μL, 2.83 mmol) was added. The reaction was stirred at room temperature for 2 hours, then poured into aqueous (1M) sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried (magnesium sulfate), filtered and volatiles were removed by rotary evaporation to give a crude solid. The compound was purified by silica gel column chromatography eluting with 2% ethyl acetate in hexanes. This provided 732 mg of the desired compound as a white, crystalline solid (29, 1.70 mmol, 90%). MS (ESI) [M+H+]+=430.2.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=4)[NH:26][CH:25]=3)[C:13]([C:14]3[N:18]([CH3:19])[CH:17]=[C:16]([C:20](O)=[O:21])[CH:15]=3)=[C:9]2[C:8](=[O:34])[N:7]([CH3:35])[C:6]1=[O:36])[CH:2]([CH3:4])[CH3:3].[CH:37]1([NH2:40])[CH2:39][CH2:38]1.C(P(=O)(OCC)OCC)#N>>[CH:37]1([NH:40][C:20]([C:16]2[CH:15]=[C:14]([C:13]3[N:12]([CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=5)[NH:26][CH:25]=4)[N:11]=[C:10]4[C:9]=3[C:8](=[O:34])[N:7]([CH3:35])[C:6](=[O:36])[N:5]4[CH2:1][CH:2]([CH3:4])[CH3:3])[N:18]([CH3:19])[CH:17]=2)=[O:21])[CH2:39][CH2:38]1
Reactant: NC1CC1
Reactant: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)O)cn3C)c(=O)n(C)c(=O)n4CC(C)C)c2c1
Agent: CCOP(=O)(C#N)OCC
Product: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)NC5CC5)cn3C)c(=O)n(C)c(=O)n4CC(C)C)c2c1

Procedure:
This compound was synthesized by the reaction of 5-{7-isobutyl-5-methyl-2-[(5-methyl-1H-indol-3-yl)methyl]-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and cyclopropylamine using diethyl cyanophosphonate as a coupling reagent Mass: 528.30 (M+H).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([OH:18])=[N:13][C:12]([C:19]([F:22])([F:21])[F:20])=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[F:22][C:19]([F:20])([F:21])[C:12]1[N:13]=[C:14]([OH:18])[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[N:11]=1
Reactant: [H][H]
Reactant: Oc1nc(C(F)(F)F)nc2c1CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Oc1nc(C(F)(F)F)nc2c1CCNC2
Yield: 76.5 %

Procedure:
To 7-benzyl-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (0.47 g, 1.52 mmol) partially dissolved in methanol (20 mL) was added palladium hydroxide on carbon (70 mg, wet, 20% by weight dry basis). The reaction was stirred for 20 hours in a Parr shaker under a pressure of 50 psi hydrogen. The reaction was then filtered through a Celite plug, eluting with methanol (400 mL). The filtrate was concentrated in vacuo to yield 2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol as a light beige solid (255 mg, 77% yield). 1H NMR (400 MHz, MeOD) δ ppm 4.09 (s, 2H), 3.48 (t, J=6.32 Hz, 2H), 2.78 (t, J=6.32 Hz, 2H).
Reaction SMILES: NC1C2SC=C(C3C=C(NC(NC(C)C)=O)C=CC=3)C=2N=C(NC2C=C(OC)C(OC)=C(OC)C=2)N=1.[NH2:37][C:38]1[CH:39]=[C:40]([C:44]2[C:48]3[N:49]=[C:50]([Cl:54])[N:51]=[C:52]([NH2:53])[C:47]=3[S:46][CH:45]=2)[CH:41]=[CH:42][CH:43]=1.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>>[NH2:53][C:52]1[C:47]2[S:46][CH:45]=[C:44]([C:40]3[CH:39]=[C:38]([NH:37][S:56]([CH3:55])(=[O:58])=[O:57])[CH:43]=[CH:42][CH:41]=3)[C:48]=2[N:49]=[C:50]([Cl:54])[N:51]=1
Reactant: Nc1cccc(-c2csc3c(N)nc(Cl)nc23)c1
Reactant: CS(=O)(=O)Cl
Agent: COc1cc(Nc2nc(N)c3scc(-c4cccc(NC(=O)NC(C)C)c4)c3n2)cc(OC)c1OC
Product: CS(=O)(=O)Nc1cccc(-c2csc3c(N)nc(Cl)nc23)c1
Yield: 93.9 %

Procedure:
The target compound (360 mg, 93% yield) was prepared in the same manner as the synthesis of the compound of Example 12, using 7-(3-aminophenyl)-2-chlorothieno[3,2-d]pyrimidin-4-amine (300 mg, 1.08 mmol) and methanesulfonyl chloride (94 μL, 1.19 mmol).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[H-].[Na+].Cl[C:18]1[N:19]=[N:20][C:21]([N:24]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[N:25]2)=[CH:22][CH:23]=1>CN(C=O)C>[CH3:30][C:26]1[CH:27]=[C:28]([CH3:29])[N:24]([C:21]2[N:20]=[N:19][C:18]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)[N:25]=1
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)n(-c2ccc(OCc3c(-c4ccccc4)noc3C)nn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.5 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (76 mg, 0.40 mmol) in DMF (0.8 mL) cooled to 0° C. was added sodium hydride (55% dispersion in mineral oil, 19.2 g, 0.44 mmol). The mixture was stirred at room temperature for 1 h. After addition of 3-chloro-6-(3,5-dimethylpyrazol-1-yl)-pyridazine (91.8 mg, 0.44 mmol) the mixture was stirred at room temperature overnight. Then the mixture was evaporated, extracted (ethyl acetate/water) and the organic phase was dried with sodium sulfate and concentrated. Chromatography (SiO2, heptane:ethanol=100:0 to 95:5) afforded the title compound (5.0 mg, 3%) as a white solid. MS: m/e=362.4 [M+H]+.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)([O-])=O>CO.[Pd]>[NH2:1][CH2:4][CH:5]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C[N+](=O)[O-])c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1

Procedure:
Of the compound from Example 12A, 248 mg (1.04 mmol) were introduced in methanol and admixed with 20 mg of palladium (10% on activated carbon). Hydrogenation took place under atmospheric pressure at RT overnight. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. This gave 300 mg (88% of theory) of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH2:14][CH3:15])[CH:11]([OH:16])[C:10]([CH2:18][CH3:19])([CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH2:18]([C:10]1([CH3:17])[CH:11]([OH:16])[CH:12]([CH2:14][CH3:15])[CH2:13][NH:8][CH2:9]1)[CH3:19]
Reactant: [H][H]
Reactant: CCC1CN(Cc2ccccc2)CC(C)(CC)C1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1CNCC(C)(CC)C1O

Procedure:
A mixture of 1-benzyl-3,5-diethyl-4-hydroxy-3-methylpiperidine (1.8 g, 6.89 mmole) and 20% palladium hydroxide (0.2 g) in methanol (20 ml) was stirred in hydrogen atmosphere (4 atm.) for 3 hr at 45° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to give 3,5-diethyl-4-hydroxy-3-methylpiperidine as oil. Yield 1.1 g (94%), C12H2,NO, m/z 172 (M+1).
Reaction SMILES: O[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10]CC)=[O:9].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1cnn(C)c1O
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1ncc(C(=O)O)c1Cl
Reaction time: 65 h

Procedure:
A mixture of 10 g of ethyl 5-hydroxy-1-methyl-4-pyrazole carboxylate and 50 ml of phosphorus oxychloride was stirred at 90° to 100° C. for 65 hours. Excessive phosphorus oxychloride was evaporated under reduced pressure, and the residue was poured into ice-water. The precipitated crystals were filtered and dried to obtain 4.5 g of 5-chloro-1-methyl-4-pyrazole carboxylic acid. The filtrate was neutralized with aqueous ammonia (28%) and extracted with ether. After drying of the extract, evaporation of the solvent gave 4.0 g of ethyl 5-chloro-1-methyl-4-pyrazole carboxylate. To 5-chloro-1-methyl-4-pyrazole carboxylic acid were added 30 ml of thionyl chloride and 0.2 ml of dimethylformamide, and the mixture was refluxed for 5 hours. Then, excessive thionyl chloride was evaporated and the residue was added to dry ethanol. After stirring at room temperature for 3 hours, the solvent was evaporated and ether was added to the residue. After washing with water, drying and evaporation of the solvent, there was obtained 4.5 g of ethyl 5-chloro-1-methyl-4-pyrazole carboxylate as an oil. Total of the title compound: 8.5 g.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=O)[CH2:13]Br)[N:7]=1)(=[O:3])[CH3:2].[NH2:16][C:17](=[N:19][C:20]([NH2:22])=[S:21])[NH2:18]>C(O)C>[C:1]([NH:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[N:22]=[C:20]([N:19]=[C:17]([NH2:18])[NH2:16])[S:21][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cccc(C(=O)CBr)n1
Reactant: NC(=S)N=C(N)N
Solvent: CCO
Product: CC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Reaction time: 2 h
Yield: 49.8 %

Procedure:
A mixture of 2-(acetylaminomethyl)-6-bromoacetylpyridine (50.0 g) and diaminomethylenethiourea (15.3 g) in ethanol (400 ml) was stirred at 40° to 50° C. for 2 hours. The solvent was removed by concentration in vacuo. To the residue was added a mixture of water, ethyl acetate and tetrahydrofuran, and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (85:15, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was triturated with a mixture of ethyl acetate and diisopropyl ether to give 4-(6-acetylaminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (18.73 g).
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[NH2:37][CH2:38][C:39]1[O:40][CH:41]=[CH:42][CH:43]=1>>[O:40]1[CH:41]=[CH:42][CH:43]=[C:39]1[CH2:38][NH:37][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=1)=[O:10]
Reactant: NCc1ccco1
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)NCc4ccco4)cc32)cc1

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and 2-aminomethylfuran according to Procedure K: mp>250° C.; 1H NMR (DMSO-d6): δ 4.51 (d, J=5.5 Hz, 2H), 6.31 (d, J=3 Hz, 1H), 6.44 (d, J=3 Hz), 7.02 ( d, J=8.3, 1H), 7.30 (s, 2H), 7.66 (m, 3H), 7.88 (m, 3H), 8.18 (s, 1H), 9.02 (br t, J=5.5 Hz, 1H), 11.4 (s, 1H), 12.8 (s, 1H); APCI-MS m/z 438 (M−H)−; Anal. Calcd for C20H17N5O5S.½H2O: C, 53.57; H, 4.05; N, 15.62; S, 7.15. Found: C, 53.91; H, 4.01; N, 15.13; S, 6.78.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[CH2:18][CH2:19][C:20](NC1SC=CN=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:49][O:50][C:51](=[O:59])[C:52]1[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][CH:53]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:49][O:50][C:51](=[O:59])[C:52]1[CH:57]=[CH:56][C:55]([NH:58][C:20](=[O:21])[CH2:19][CH2:18][CH:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16](=[O:17])[N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:54][CH:53]=1
Reactant: O=C(CCC1c2ccccc2C(=O)N1Cc1ccccc1)Nc1nccs1
Reactant: COC(=O)c1ccc(N)nc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)CCC2c3ccccc3C(=O)N2Cc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product from Example 1, Part E (200 mg, 0.68 mmol) was dissolved in 5 mL DMF. HOBt (312 mg, 2.04 mmol) and EDCI (340 mg, 2.04 mmol) were added and the mixture was stirred at room temperature for 0.5 h. 6-Aminonicotinic acid methyl ester (156 mg, 1.02 mmol) was added and the mixture was stirred for 16 h. The mixture was poured into 100 mL sat'd NaHCO3 and extracted with EtOAc. The combined organic phase was washed with water and brine, then dried (Na2SO4), filtered and evaporated. The product was purified by silica gel chromatography (10 mg, 3%). 1H NMR (300 MHz, acetone-d6) δ 9.64 (br s, 1H), 8.78 (s, 1H), 8.26 (s, 2H), 7.78 (d, J=7 Hz, 1H), 7.62 (m, 2H), 7.51 (m, 1H), 7.34 (m, 5H), 5.25 (d, J=15 Hz, 1H), 4.64 (m, 1H), 4.39 (d, J=15 Hz, 1H), 3.89 (s, 3H), 2.51 (m, 2H), 2.21 (m, 1H), 2.01 (m, 1H). MS: m/z (MH+) 430.