Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=4)[CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-n2cnc(-c3c(C)nnn3-c3ccc(F)cc3)c2)nc1
Temperature: 120 °C
Yield: 38.5 %

Procedure:
A mixture of 1-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-4-methyl-1H-[1,2,3]triazole (500 mg, 2.06 mmol), methyl 6-chloronicotinate (353 mg, 2.06 mmol) and potassium carbonate (568 mg, 4.11 mmol) in DMF (10 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into water (150 mL) and the solid that formed was filtered off and dried to afford the title compound (300 mg, 39%) as a light brown solid. MS: m/e=379.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=1.N([O-])=O.[Na+].C(Cl)Cl.[BrH:23]>[Cu]Br>[Br:23][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1
Reactant: Br
Reactant: Nc1ccc(F)c(-c2ncccc2F)c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Br)cc1-c1ncccc1F

Procedure:
4-Fluoro-3-(3-fluoropyridin-2-yl)phenylamine was subjected to reaction with sodium nitrite, in hydrobromic acid in the presence of copper(I) bromide, according to the method of Example 23. 2-(5-Bromo-2-fluorophenyl)-3-fluoropyridine was obtained by chromatography (silica gel, CH2Cl2) as a pink solid: MS (ES+) m/z 270, 272 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=1.[Cl:18][C:19]1[C:25]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:24][C:22]([NH2:23])=[C:21]([CH:32]=[CH2:33])[CH:20]=1.C(O)(C(F)(F)F)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.O.CN1C(=O)CCC1>[NH2:23][C:22]1[C:21]([CH:32]=[CH2:33])=[CH:20][C:19]([Cl:18])=[C:25]([N:26]2[CH2:27][CH2:28][N:29]([C:14]([C:13]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][O:11][C:12]=3[CH3:17])=[O:16])[CH2:30][CH2:31]2)[CH:24]=1
Reactant: C=Cc1cc(Cl)c(N2CCNCC2)cc1N
Reactant: COc1ccccc1-c1noc(C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: C=Cc1cc(Cl)c(N2CCN(C(=O)c3c(-c4ccccc4OC)noc3C)CC2)cc1N
Temperature: 25 °C
Reaction time: 13 h
Yield: 54 %

Procedure:
To the mixture of 3-(2-methoxyphenyl)-5-methylisoxazole-4-carboxylic acid (0.182 g, 0.779 mmol), 4-chloro-5-(piperazin-1-yl)-2-vinylaniline, 2 TFA (0.279 g, 0.599 mmol) and HATU (0.296 g, 0.779 mmol) in a 100-mL round bottom flask was added NMP (5.5 mL) and triethylamine (0.145 g, 1.438 mmol). The resulted solution was stirred at room temperature for 13 hours. Water (50 mL) and DCM (50 mL) were added to the reaction mixture and the two phases were separated in a separatory funnel. The aqueous phase was extracted with DCM (2×40 mL). Solvent was evaporated by rotavap. The product was purified by preparative HPLC (acetonitrile/water−10 nM ammonium acetate) to give 0.146 g (54% yield) of the title compound.
Reaction SMILES: BrC1C=C(Cl)N2C=C(C([O-])=O)N=C2C=1.[Br:15][C:16]1[CH:21]=[C:20](Cl)[N:19]2[CH:23]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:25]=[C:18]2[CH:17]=1.[NH:31]1[CH:35]=[CH:34][CH:33]=[N:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH4+].[Cl-]>CN(C=O)C.O>[Br:15][C:16]1[CH:21]=[C:20]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)[N:19]2[CH:23]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:25]=[C:18]2[CH:17]=1
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)c1cn2c(Cl)cc(Br)cc2n1
Agent: O=C([O-])[O-]
Agent: O=C([O-])c1cn2c(Cl)cc(Br)cc2n1
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(-n3cccn3)cc(Br)cc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 7-bromo-5-chloro-imidazo[1,2-a]pyridine-2-carboxylate (Intermediate 16) (0.867 g, 2.86 mmol) and pyrazole (0.194 g, 2.86 mmol) was dissolved in DMF (15 mL). Cesium carbonate (1.95 g, 2.1 eq.) was added and the mixture stirred at rt. After 16 hours TLC indicated clean but incomplete reaction and stirring was continued over the weekend. Saturated aqueous NH4Cl (50 mL) was added, resulting in effervescence and a gelatinous precipitate which was then broken up, water (30 mL) added and the solid filtered in vacuo. This material was washed with water and sucked dry to give a tan paste. The filtrate was extracted with EtOAc (100 mL), washed with water (30 mL), brine (30 mL), and set aside. The tan paste was dissolved in EtOAc (200 mL), combined with the filtrate, dried over MgSO4, filtered and evaporated to give a brown residue that crystallized upon standing. Trituration with EtOAc (15 mL) and heptane (50 mL) yielded a yellow powder, 0.363 g (38%). MS: 335, 337 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:45])([C:21]3[N:22]=[CH:23][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:25]=3)[CH:18]([CH3:20])[CH3:19])[CH:13]=2)[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:53]1[O:54][CH:55]=[CH:56][CH:57]=1)CCC.[Cl-].[Li+]>CN(C=O)C.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>[O:54]1[CH:55]=[CH:56][CH:57]=[C:53]1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]([C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)([OH:45])[CH:18]([CH3:20])[CH3:19])[CH:11]=[CH:10]2
Reactant: CC(C)C(O)(c1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(O)(c1ccc2cc(-c3ccco3)ccc2c1)c1c[nH]cn1

Procedure:
6-[1-Hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthyl trifluoromethanesulfonate (2.0 g), 2-(tributylstannyl)furan (1.26 mL), tetrakis(triphenylphosphine)palladium (115 mg) and lithium chloride (259 mg) were dissolved in DMF (10 mL) and heated at 80 for 4 h. The reaction mixture was diluted with water, extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated. The residue was purified by column chromatography (eluent; hexane:THF=4:1) and crystallized from ethyl acetate-hexane to give the titled compound (1.48 g) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[NH:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:20]=[O:21])=[CH:16][NH:17]2)=[CH:13][CH:12]=1)=[O:10].[H-].[Na+].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>CN(C)C=O>[Cl:22][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:20]=[O:21])=[CH:16][N:17]2[S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=Cc1c[nH]c2cc(C(=O)Nc3c(Cl)cncc3Cl)ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccc(C(=O)Nc4c(Cl)cncc4Cl)cc32)cc1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 105.7 %

Procedure:
A stirred solution of N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1H-indole-6-carboxamide (0.518 g, Example 18) in dimethylformamide at 0° C. was treated with sodium hydride (0.136 g). The mixture was stirred for 15 minutes, then cooled to −40° C. and then treated with 4-toluenesulphonyl chloride (0.325 g). The reaction mixture was gradually allowed to warm to −20° C. over a period of 90 minutes, then quenched with water (20 ml), then extracted three times with ethyl acetate (25 ml). The combined extracts were dried over sodium sulphate then evaporated to give the title compound (800 mg), which was used without further purification as a white solid, m.p. 245° C. [Elemental analysis:—C, 53.91; H, 3.34; N, 8.30%. Calculated for C22H15Cl2N3O4S:—C, 54.11; H, 3.10; N, 8.60%].
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1>ClCCl>[CH:1]1([C:5]([NH:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)C2CCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
Cyclobutanecarbonylchloride (9 g, 76 mmol) was added to a solution of triethylamine (12.5 ml, 89.7 mmol) and tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (12.87 g, 69 mmol) in dichloromethane (385 ml) at room temperature under nitrogen. After stirring for 18 hours at room temperature, the reaction mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo to yield the title product as a light brown glass, (17.4 g, 94%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:24])[C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([OH:33])=O)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.Cl.[NH2:37][CH2:38][C:39]([NH:41][C@@H:42]([C:46]([O:48]C(C)(C)C)=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[BH4-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:24])[C:16]3[CH:17]=[CH:18][C:19]([S:22][CH3:23])=[CH:20][CH:21]=3)[C@H:9]2[C:25]2[CH:26]=[CH:27][C:28]([O:29][CH2:30][C:31]([NH:37][CH2:38][C:39]([NH:41][C@@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])=[O:33])=[CH:34][CH:35]=2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(C(O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)O)cc2)cc1
Reactant: CC(C)[C@@H](NC(=O)CN)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CSc1ccc(C(O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)N[C@@H](C(=O)O)C(C)C)cc2)cc1
Reaction time: 17 h
Yield: 72.1 %

Procedure:
A solution of {4-[(2R,3R)-1-(4-fluorophenyl)-3-({2-hydroxy-2-[4-(methylthio)phenyl]ethyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetic acid (0.015 g, 0.029 mmol), tert-butyl glycyl-D-valinate hydrochloride (0.009 g, 0.034 mmol) and N-Methylmorpholine (0.013 ml, 0.118 mmol) in DCM (3 ml) was stirred at RT for 10 min, after which TBTU (0.014 g, 0.044 mmol) was added. After 17 h the conversion to the intermediate (m/z: 724.7, M+1) was completed. The solution was diluted with TFA (2 ml) and the mixture was allowed to stir for 2 h. The resulting acid (m/z: 668.6, M+1) was concentrated and the residue was dissolved in MeOH (3 ml). To this solution was added NaBH4 (80 mg, 2.11 mmol) in portions until the reduction of the ketone was completed (LC/MS). The reaction was quenched by the addition of a 0.1M ammonium acetate buffer (3 ml) before most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC, using a gradient of 20-50% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product (0.014 g, 70%) as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:21](=[O:25])[CH:22](Br)[Br:23])=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[C:6]([CH3:26])=[CH:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.P(OCC)(OCC)=O>C1COCC1.CCOC(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:21](=[O:25])[CH2:22][Br:23])=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:11]=2)[C:6]([CH3:26])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1cc(C)c2cc(C(=O)C(Br)Br)c(OCc3ccccc3)cc21
Agent: CCO[PH](=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)n1cc(C)c2cc(C(=O)CBr)c(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
The crude product 1-(1-acetyl-6-benzyloxy-3-methyl-1H-indol-5-yl)-2,2-dibromo-ethanone (0.42 g, 0.88 mmol) was suspended in THF (4 ml), followed by the addition of triethylamine (0.12 ml, 0.89 mmol) and (EtO)2P(O)H (0.137 ml, 0.88 mmol). After stirring overnight at room temperature, the reaction was diluted with EtOAc, washed with H2O, brine and dried over MgSO4. The solvent was removed in vacuo and the crude product purified by column chromatography in hexane/EtOAc (1:1) to give the product (0.039 g, 11%). LC/MS: RT=2.830 min. 400/402 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:5][CH2:6]1)=[O:38]
Reactant: COCC(=O)Cl
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: COCC(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C[Si]([CH:5]=[N+:6]=[N-])(C)C.N12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([C:11]3=[O:18])[CH2:9]1)[CH2:15]2.CO.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(O)(=O)C>[N:6]12[CH2:5][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([C:11](=[O:18])[CH2:9]3)[CH2:17]1)[CH2:15]2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CC2CC3CC1CN(C2)C3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice-cooled solution of trimethylsilyldiazomethane (2 N in hexanes, 9.00 mL, 18.00 mmol; Aldrich) was added a solution of 1-azaadamantan-4-one (2.268 g, 15 mmol; Becker, D. P.; Flynn, D. L. Synthesis 1992, 1080) in tetrahydrofuran (12 mL) dropwise over 20 minutes Anhydrous methanol (6 mL) was added and the mixture was allowed to warm to room temperature. After 18 hours, glacial acetic acid was added dropwise until the mixture was colorless (about 1 mL). The reaction mixture was shaken with saturated sodium carbonate (4 mL), the tetrahydrofuran layer was separated, and the aqueous portion was extracted with dichloromethane (3×12 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to give the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.72 (m, 1H), 1.78 (dddd, J=13.6, 4.0, 2.4, 2.1 Hz, 1H), 1.88 (m, 1H), 1.90 (dddd, J=14.6, 4.0, 2.4, 2.1 Hz, 1H), 2.14 (dddd, J=14.4, 6.5, 4.4, 1.9 Hz, 1H), 2.27 (m, 1H), 2.59 (t, J=5.8 Hz, 1H), 2.63-2.68 (m, 2H), 2.96 (m, 1H), 3.01 (dd, J=4.4, 2.0 Hz, 1H), 3.07 (m, 1H), 3.14 (m, 1H), 3.25 (ddd, J=14.6, 4.9, 1.2 Hz, 1H), 3.43 (dd, J=14.2, 5.1 Hz, 1H); MS (DCI/NH3) m/z 166 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.Br[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][C:8]3[C:7]([CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[N:12][CH:11]=[CH:10][N:9]=3)=[CH:15][CH:16]=2)=[N:23][CH:24]=1
Reactant: Nc1ccc(Oc2nccnc2C2CCOCC2)cc1
Reactant: Cc1ccc(Br)nc1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Product: Cc1ccc(Nc2ccc(Oc3nccnc3C3CCOCC3)cc2)nc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A glass microwave reaction vessel was charged with 4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline (0.251 g, 0.925 mmol), 2-bromo-5-methylpyridine (0.133 g, 0.7708 mmol), BrettPHOS precatalyst (0.012 g, 0.015 mmol), and sodium tert-butoxide (0.185 g, 1.927 mmol). The flask was placed under vacuum then flushed with argon. Dioxane (2.57 mL) was added and the reaction was heated to 90° C. to stir overnight. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide 5-methyl-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 363.1. IC50 (uM) 0.000178.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][C@H:6]([CH3:10])[CH2:5]1.C(N(CC)C(C)C)(C)C.[Cl:20][C:21]1[C:26]([F:27])=[C:25](Cl)[N:24]=[C:23]([CH3:29])[N:22]=1>ClCCl>[Cl:20][C:21]1[C:26]([F:27])=[C:25]([N:7]2[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][C@H:6]2[CH3:10])[N:24]=[C:23]([CH3:29])[N:22]=1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: C[C@@H]1CN(C)CCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Cl)c(F)c(N2CCN(C)C[C@H]2C)n1
Temperature: 35 °C
Reaction time: 72 h
Yield: 118.2 %

Procedure:
To a solution of (3R)-1,3-dimethylpiperazine dihydrochloride (Example 63) (5.88 g, 31.4 mmol) in dichloromethane (126 mL) was added N,N-diisopropylethylamine (18.11 mL, 104 mmol), and 4,6-dichloro-5-fluoro-2-methylpyrimidine (5.69 g, 31.4 mmol). The solution was heated at 35° C. and stirred for 3 days. The solution was cooled to room temperature, diluted with DCM (100 mL), and washed with sat. aq. NaHCO3 (100 mL). The aqueous phase was extracted with a fresh portion of DCM (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude 4-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (9.60 g, >100% yield) as a brown oil that was used without further purification. LCMS: (M+H)+: 258.9.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[C:28]([N:32]([CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)(=[O:31])[CH2:29][CH3:30]>>[C:28]([N:32]([C:33]1[CH:38]=[CH:37][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:35][CH:34]=1)[CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])(=[O:31])[CH2:29][CH3:30]
Reactant: CCC(=O)N(CCN(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: CCC(=O)N(CCN(C)C)c1ccc(N/C(=C2\C(=O)Nc3cc(OC)c(OC)cc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-propionyl-N-(2-dimethylamino-ethyl)-p-phenylenediamine
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][CH2:16][CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH2:15][CH2:16][CH3:17]
Reactant: CCCC1CN(Cc2ccccc2)CCC1O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCC1CNCCC1O

Procedure:
A mixture of 1-benzyl-4-hydroxy-3-n-propylpiperidine (3.3 g, 14.16 mmole) and 20% palladium hydroxide (0.25 g) in methanol (25 ml) was stirred in hydrogen atmosphere (1 atm.) for 24 hr at 30° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 4-hydroxy-3-n-propylpiperidine as oil. Yield 1.8 g (90%), C8H17NO, m/z 144 (M+1), PMR (CDCl3): 0.92 (3H, t, CH3, j=8 Hz), 1.2-1.52 (5H, m, 2×CH2 & H3), 1.72 (1H, m, H5), 1.94 (2H, m, H5, & OH, D2O exchangeable), 2.22 (1H, m, H2), 2.62 (1H, m, H6), 3.12 (1H, m, H2), 3.3 (1H, m, H6), 3.5 (1H, bs, NH, D2O exchangeable), 3.98 (1H, m, H4).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:22])[C@@H:11]([NH:14]C(=O)OC(C)(C)C)[CH2:12][CH3:13].[ClH:23]>O1CCOCC1>[ClH:23].[ClH:23].[NH2:14][C@@H:11]([CH2:12][CH3:13])[CH:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[OH:22]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc2ccccc2o1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](N)C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, tert-butyl (2S)-1-(benzo[d]oxazol-2-yl)-1-hydroxybutan-2-ylcarbamate (800 mg, 2.61 mmol, Eq: 1.00) and HCl 4M in dioxane (17.3 ml) were combined to give a dark brown solution. The reaction was stirred for 2 h at RT. The crude reaction mixture was concentrated in vacuo, and the residual solvent was removed under vacuum. The title compound was obtained as a dark brown gum (910 mg, quant., MS (m/e)=207.1 [M+H+]).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:60][C@H:61]1[CH2:66][CH2:65][C@H:64]([OH:67])[CH2:63][CH2:62]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([NH:60][C@H:61]3[CH2:66][CH2:65][C@H:64]([OH:67])[CH2:63][CH2:62]3)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CC[C@H](O)CC1)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (200 mg, 0.54 mmol; example 5.1) in dry DMF (4 mL) was added dry DIPEA (3.2 mmol) followed by HATU (1.6 mmol) at 0° C. Then the reaction mixture was allowed to warm to rt and stirred for 45 min at that temperature. TLC shows total consumption of acid and formation of a new spot. (trans)-4-Amino-cyclohexanol (0.64 mmol) was added to this reaction mixture at 0° C. Then the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 h. TLC shows total consumption of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid and DMF was removed in vacuo at 60° C. It was then diluted with H2O (5 ml). Aqueous layer was extracted with EtOAc (5×5 mL) and combined organic layers were washed with brine (50 ml), dried over Na2SO4 and concentrated in vacuo. Crude product was subjected to column chromatography [SiO2 (230-400 mesh), EtOAc:Hexane 10:90] to give the title compound (40 mg, 24%) as off-white solid. MS: m/e=470.0 [M+H+].
Reaction SMILES: [CH3:1][C@@H:2]1[C:6]2[NH:7][C:8]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)=[CH:9][C:5]=2[C:4](=[O:19])[NH:3]1.N1C=CC2C(=O)NC3(CC3)[C:21]1=2>>[CH3:17][C:12]1([CH3:18])[C:13]([CH3:16])([CH3:15])[O:14][B:10]([C:8]2[NH:7][C:6]3[C:2]4([CH2:21][CH2:1]4)[NH:3][C:4](=[O:19])[C:5]=3[CH:9]=2)[O:11]1
Reactant: O=C1NC2(CC2)c2[nH]ccc21
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Product: CC1(C)OB(c2cc3c([nH]2)C2(CC2)NC3=O)OC1(C)C

Procedure:
This compound as a brown solid was prepared according to the procedure described for intermediate 705, using 1′H-spiro[cyclopropane-1,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one (704) as the starting material. m/z (ESI, +ve) 275.0 (M+H)+).