Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([Cl:37])[CH:28]=2)/[C:24]#[N:25])=[C:19]([F:38])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:36])[F:35])=[C:29]([Cl:37])[CH:28]=2)[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:38])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1ccc(C(F)(F)F)c(Cl)c1)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2ccc(C(F)(F)F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 30.3 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl-phenyl)-acrylonitrile (2.5 g, 6.9 mmol) prepared in Example 71a, AgF (1 g, 8 mmol), and triethylamine (2.4 mL, 17 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 30%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[CH:18]3[CH2:19][CH:16]([CH2:17]3)[C:8]3[N:9]([CH3:15])[C:10]([C:12]([NH2:14])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:20]=1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C@:27]([OH:31])([C:29]#[CH:30])[CH3:28])[N:23]=1>N1CCCCC1.[Cu]I.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>[OH:31][C@:27]([C:24]1[N:23]=[C:22]([CH3:21])[O:26][N:25]=1)([CH3:28])[C:29]#[C:30][C:2]1[CH:3]=[CH:4][C:5]2[CH:18]3[CH2:19][CH:16]([CH2:17]3)[C:8]3[N:9]([CH3:15])[C:10]([C:12]([NH2:14])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:20]=1
Reactant: Cn1c(C(N)=O)nc2c1C1CC(C1)c1ccc(I)cc1-2
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)n(C)c2C2CC3C2)no1
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
To a solution 9-iodo-3-methyl-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide (100 mg, 0.26 mmol) in piperidine (2 mL) was introduced (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (160 mg, 1.05 mmol) and copper(I) iodide (2.5 mg, 0.01 mmol). The solution was de-oxygenated by nitrogen bubbling for five minutes, then tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) added and bubbling continued for a further two minutes. The pressure tube was closed under an atmosphere of nitrogen and the reaction mixture warmed to 40° C. for 2.5 hr. After evaporation of the reaction mixture in vacuo, the residue was suspended in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate (6 mL), water (2×10 mL) and brine (5 mL). The organic extract was dried over sodium sulfate, filtered, and the filtrate adsorbed onto silica gel in vacuo. Purification of the dry-loaded material by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient) was followed by suspension of the product in acetonitrile (0.8 mL). The solid was collected by filtration to furnish the title compound (80 mg, 0.20 mmol, 77%) as a colorless solid: 1H NMR (500 MHz, CDCl3) δ 1.61-1.73 (m, 2H), 2.05 (s, 3H), 2.65 (s, 3H), 2.94 (q, J=8.62 Hz, 2H), 3.47 (td, J=7.25, 3.47 Hz, 1H), 3.57-3.70 (m, 2H), 4.01 (s, 3H), 5.57 (br. s., 1H), 7.02 (d, J=7.88 Hz, 1H), 7.17 (d, J=7.88 Hz, 1H), 7.70 (br. s., 1H), 8.51 (s, 1H); M+H=404.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][CH2:20][O:19][CH2:18]4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[N:29]1([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[C:14]([CH:17]5[CH2:22][CH2:21][CH2:20][O:19][CH2:18]5)[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: C1CNCCN1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(C4CCCOC4)cc23)n1
Product: c1cc(-c2n[nH]c3cnc(C4CCCOC4)cc23)nc(N2CCNCC2)c1
Yield: 20 %

Procedure:
Following the procedure of Example 144, 3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-c]pyridine and piperazine were reacted and consequently deprotected by the procedure of Example 131, to give a racemic mixture purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 30 mg (20%) of 3-(6-(piperazin-1-yl)pyridin-2-yl)-5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-c]pyridine. ESI MS m/z 365.1 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][CH3:12])[C:4](=[O:9])[C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[Na+]>CO.O>[CH2:1]([N:3]([CH2:10][CH2:11][CH3:12])[C:4](=[O:9])[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCCN(CC)C(=O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN(CC)C(=O)C(=O)O
Yield: 38 %

Procedure:
870 mg (5.0 mmole) of methyl N-ethyl-N-n-propyloxamate was dissolved in 20 ml of methanol. The resulting mixture was stirred under ice-cooling over an ice bath. 594 mg (15 mmole) of sodium hydroxide was dissolved in 10 ml of water and the resulting solution was added dropwise to said mixture. After completion of the dropwise addition, the ice bath was removed and the reaction mixture was stirred for 1 hour at room temperature. After adding 10 ml of 1N aqueous solution of hydrochloric acid, the solvent was distilled off from the reaction solution under reduced pressure. The residue was added with 80 ml of ethanol and the insoluble solids as formed were filtered off. The organic solution after the filtration was concentrated to afford 305 mg (1.9 mmole) of N-ethyl-N-n-propyloxamic acid as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1
Reactant: Cc1ccc(Br)nc1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(NC[C@@H]2[C@H](C)CCCN2C(=O)c2cc(C)ccc2-c2ncccn2)nc1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 416 [M+1]+.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([NH2:14])=[NH:13].[O-]CC.[Na+].C([O:21][C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=O)=O)C>C(O)C>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]1[NH:14][C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[C:22](=[O:21])[N:13]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: N=C(N)CCc1cccc(F)c1F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1nc(CCc2cccc(F)c2F)[nH]c2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of 3-(2,3-difluorophenyl)-propionamidine hydrochloride (Int. A3) (3.90 g, 17.7 mmol) in ethanol (80 ml) was added sodium ethoxide (1.44 g, 21.2 mmol) in portions and resulting slurry stirred at ambient temperature for 1 h. 2-Oxo-cyclopentanecarboxylic acid ethyl ester (3.09 ml, 21.2 mmol) was then added and the mixture refluxed for 2 days. Evaporation of the reaction mixture followed by chromatography (silica, dichloromethane-acetone) gave the title compound (2.76 g, 56%) as a cream solid. 1H-NMR (DMSO) δ 1.94 (2H, m), 2.59 (2H, t), 2.72 (2H, t), 2.82 (2H, t), 3.05 (2H, t), 7.07-7.29 (3H, m), 12.20 (1H, s); MS (APCI+) found (M+1)=277; C15H14F2N2O requires 276.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:20]([CH3:23])=[N:21][S:22][C:10]=2[C:9]=1[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:7])[CH2:2][CH2:3][CH3:4].[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:20]([CH2:23][Br:31])=[N:21][S:22][C:10]=2[C:9]=1[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCOC(=O)c1nc(-c2ccccc2)c2c(C)nsc2c1OC(=O)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOC(=O)c1nc(-c2ccccc2)c2c(CBr)nsc2c1OC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 85.7 %

Procedure:
To a solution of 7-(2,2-dimethyl-propionyloxy)-3-methyl-4-phenyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester (392 mg) in CCl4 (1.8 mL) was added N-bromosuccinimide (172 mg) and benzoyl peroxide (11.1 mg). The reaction mixture was refluxed for 18 h. After cooling to r.t. the mixture was filtered. The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel. Eluting with 0-20% EtOAc/CH2Cl2 gave the title compound (398 mg) as a yellow oil: MS (m/z) 505.1 (M+1), 507.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30].[OH-].[Li+].Cl>C1COCC1.O.O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: COC(=O)CCCCCC1CCc2cc(-c3ccccc3)c(-c3ccccc3)nc2N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1c2nc(-c3ccccc3)c(-c3ccccc3)cc2CCC1CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Enantiomer 2 of methyl 6-(1-methyl-6,7-diphenyl-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexanoate (34 mg, 0.079 mmol) was dissolved in THF/water (2:1) and lithium hydroxide (9.99 mg, 0.238 mmol) was added. The reaction mixture was stirred vigorously at room temperature for 48 h and then diluted with water (20 ml). The pH was adjusted to pH 3-4 by addition of 2M HCl. The aqueous portion was extracted with DCM (3×30 ml) and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a yellow oil;
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:13]1[C:18](=[O:19])[CH2:17][C:16](=O)[NH:15][C:14]1=[O:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([N:13]1[C:18](=[O:19])[CH:17]=[C:16]([Cl:3])[NH:15][C:14]1=[O:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC(=O)N(Cc2ccccc2)C(=O)N1
Solvent: CCO
Product: O=c1cc(Cl)[nH]c(=O)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To 16.8 ml of 50% ethanol, 78.7 ml (844 mmol) of phosphorus oxychloride was added dropwise, with stirring under ice cooling conditions. To this solution, 20.62 g (94.5 mmol) of 3-benzylpyrimidine-2,4,6(1H,3H)-trione was added portionwise. This mixture was stirred at 50° C. for 30 minutes and then at 100° C. for 90 minutes. After cooling, the reaction mixture was poured into ice water and stirred for 1 hour. The resulting precipitate was collected by filtration, washed with water and n-hexane and dried to yield 20.12 g (90.0%, white crystal) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][S:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][S:10](=[O:23])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1ccc(CN2CCSCC2)cc1
Solvent: ClCCl
Product: O=S1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of 4-(4-bromobenzyl)-thiomorpholine (0.20 g, 0.735 mmol) was dissolved in DCM (10 mL) under a nitrogen atmosphere and m-chloroperbenzoic acid (0.13 g, 0.74 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 1 h then purified by flash chromatography (silica, Biotage 50 g column, 0-75% (10% methanol in DCM)) to afford the title compound (0.125 g, 59%). 1H NMR (DMSO-D6, 400 MHz): 7.55-7.49 (m, 2H), 7.31-7.25 (m, 2H), 3.53 (s, 2H), 2.92-2.80 (m, 4H), 2.78-2.65 (m, 2H), 2.64-2.54 (m, 2H). LCMS (Method G): RT=2.66 min, M+H+=289.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][C:8]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([NH:22][O:23]C4CCCCO4)=[O:21])[CH:16]=3)[CH2:11]2)=[O:9])[CH:4]=[CH:5][N:6]=1.[ClH:30]>CO>[ClH:30].[OH:23][NH:22][C:20]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])[CH2:19][CH2:18]2)=[O:21]
Reactant: Cc1nccn1CC(=O)N1CCc2cc(C(=O)NOC3CCCCO3)ccc2C1
Agent: Cl
Solvent: CO
Product: Cc1nccn1CC(=O)N1CCc2cc(C(=O)NO)ccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 18 mg 2-[(2-methyl-1H-imidazol-1-yl)acetyl]-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 1 ml methanol and 1.5 ml 0.1N aqueous HCl is stirred for 3 h at ambient temperature. The reaction mixture is then lyophilized. 18 mg of the title compound are obtained as colorless solid. MH+=329.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:17].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)[N:8]([CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:17]
Reactant: CN1CCNCC1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Solvent: CS(C)=O
Product: CN1CCN(c2cc3c(cc2Cl)c(=O)c(C(=O)O)cn3C)CC1

Procedure:
2.18 g of 6,7-dichloro-1-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 3.5 cm3 of 1-methylpiperazine and 25 cm3 of dimethylsulphoxide were heated at 110° C. for 3 hours. The solvent was evaporated off in vacuo and the residue was taken up in 100 cm3 of water. The suspension was stirred and mixed with 20 cm3 of N sodium hydroxide solution. The solution obtained, which was slightly turbid, was stirred with animal charcoal and filtered, and then brought to pH 7.5 by the addition of acetic acid. The precipitate was filtered off, washed with water and then recrystallised from methyl cellosolve. 1 g of 6-chloro-1-methyl-7-(4-methylpiperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 286° C., were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][C:3]1=2.[ClH:39]>CO.CCOCC>[ClH:39].[ClH:39].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)cc31)CNCC2
Reaction time: 3 h
Yield: 50 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (95 mg, 0.18 mmol) was dissolved in MeOH (2 mL) and 2 N HCl in Et2O (10 mL) was added. The reaction was allowed to proceed for 3 h. The resulting precipitate was collected by filtration and washed with Et2O to provide the title compound (45 mg, 50%) as a pale yellow solid: mp 318-323° C.; 1H NMR (500 MHz, CD3OD) δ 7.95 (d, J=8.2 Hz, 2H), 7.84 (d, J=8.2 Hz, 2H), 7.81 (d, J=7.1 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.14 (dd, J=8.3, 1.3 Hz, 1H), 6.96 (d, J=1.6 Hz, 1H), 6.87 (dd, J=7.1, 1.7 Hz, 1H), 4.50 (s, 2H), 3.76 (s, 3H), 3.68 (t, J=6.1 Hz, 2H), 3.22 (t, J=6.1 Hz, 2H); ESI MS m/z 424 [M+H]+; HPLC (Method B) 97.6% (AUC), tR=13.9 min.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:19][N:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]1=[O:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:24]2[CH:23]=[CH:22][C:21](=[O:35])[N:20]([CH3:19])[CH:25]=2)=[N:3][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(-c3nc(-c4ccc(=O)n(C)c4)cnc3N)[nH]c2c1
Temperature: 110 °C
Yield: 43.4 %

Procedure:
A mixture of 5-bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (100 mg, 0.3288 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (154.6 mg, 0.6578 mmol), potassium carbonate (136.4 mg, 0.9867 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (26.86 mg, 0.03289 mmol) in DMF (3 mL) were heated to 110° C. for 2 hours. The mixture was diluted with EtOAc, washed with water, and the organic layer concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (47.4 mg, 40% Yield). MS (ES+) 333
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19]OS(C)(=O)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: C1COCCN1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Product: Cc1cc(-c2cc(CN3CCOCC3)c(=O)n(CC(C)C)n2)ccc1F

Procedure:
Following the procedure of Example 92, 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and morpholine were reacted to yield the title compound as a slightly yellow oil (yield: 97.4%).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([OH:33])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([C@@H:36]1[O:38][CH2:37]1)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C)C=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][C@H:36]5[CH2:37][O:38]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClC[C@H]1CO1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC[C@H]1CO1
Temperature: 80 °C
Yield: 15 %

Procedure:
A stirred mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)urea from Example 95B (160 mg, 0.356 mmol), (R)-(−)-epichlorohydrin (65 mg, 0.702 mmol), cesium carbonate (120 mg, 0.356 mmol) and potassium iodide (40 mg, 0.241 mmol) in dry N,N-dimethylformamide (4 mL) was heated in a sealed vial at 80° C. in a Biotage microwave synthesizer for 90 mins. After cooling to room temperature, the mixture was partitioned between water (50 mL) and a mixture of ethyl acetate (40 mL) and tetrahydrofuran (10 mL). The organic layer was separated, washed with brine (50 mL), dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel chromatography eluting with 100% dichloromethane to 5% methanol in dichloromethane to afford (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(oxiran-2-ylmethoxy)quinazolin-4-yloxy)phenyl)urea as a colorless solid (27 mg, 15%). LC-MS (ESI) m/z 506 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH:14]([CH2:20][CH:21]=[C:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)S(O)(=O)=O>C(Cl)(Cl)Cl.ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:22]3([CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH2:21][CH2:20][CH:14]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:11])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(CC=C1CCOCC1)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCC2(CCOCC2)N1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.5 %

Procedure:
To a solution of ethyl 2-{[(4-nitrophenyl)sulfonyl]amino}-4-(tetrahydro-4H-pyran-4-ylidene)butanoate (164) (1.87 g, 4.7 mmol) in anhydrous chloroform (47 mL) was added trifluoromethanesulfonic acid (0.2 mL, 2.3 mmol) and the reaction stirred at room temperature under nitrogen for 4 h. The reaction was diluted with dichloromethane and washed with saturated NaHCO3 and the organic layer dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 10-70% hexanes/EtOAc to afford the title compound as a white solid (1.47 g, 79% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.19-8.36 (m, 2H) 8.08 (d, J=8.8 Hz, 2H) 4.52 (dd, J=8.5, 2.1 Hz, 1H) 3.99-4.14 (m, 2H) 3.87-3.99 (m, 2H) 3.21-3.49 (m, 2H) 2.58-2.78 (m, 2H) 2.10-2.30 (m, 2H) 1.89-2.06 (m, 2H) 1.77 (dd, J=13.0, 2.1 Hz, 1H) 1.35 (dd, J=12.9, 1.6 Hz, 1H) 1.22 (t, J=7.1 Hz, 3H). LC-MS ESI (M+H)+=399.47.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([CH2:33][CH2:34][OH:35])[CH:32]=1)[CH2:5][N:6]1[CH2:29][CH2:28][C:9]2([O:14][CH2:13][CH2:12][N:11]([C:15]([C:17]3[N:18]=[C:19]([C:22]4[CH:27]=CC=C[CH:23]=4)[S:20][CH:21]=3)=[O:16])[CH2:10]2)[CH2:8][CH2:7]1.N>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([CH2:33][CH2:34][OH:35])[CH:32]=1)[CH2:5][N:6]1[CH2:29][CH2:28][C:9]2([O:14][CH2:13][CH2:12][N:11]([C:15]([C:17]3[N:18]=[C:19]([CH:22]([CH3:27])[CH3:23])[S:20][CH:21]=3)=[O:16])[CH2:10]2)[CH2:8][CH2:7]1
Reactant: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCN(Cc3cc(F)cc(CCO)c3)CC2)C1
Agent: N
Solvent: CO
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(F)cc(CCO)c4)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 2,2,2-trifluoro-1-(9-(3-fluoro-5-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone (example 41, step d) (0.21 g) in methanol (3 mL) was added to ammonia (35% aqueous solution, 15 mL) and the reaction mixture stirred at 20° C. for 1 hour. The mixture was evaporated to dryness under reduced pressure and the residue azeotroped three times with acetonitrile. The residue was dissolved in DMF (7 mL) and treated with 2-isopropylthiazole-4-carboxylic acid (0.098 g) followed by triethylamine (0.290 mL) and then HATU (0.257 g) and the resultant mixture stirred at 20° C. for 1 hour. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.25 g.