Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1[CH2:41][CH2:40][CH2:39][CH2:38]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:38][CH:39]3[CH2:41][CH2:40]3)[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: C1CCNCC1
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.6 %

Procedure:
Into a 10 mL round-bottom flask, was placed 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxopropanenitrile (100 mg, 0.21 mmol, 1.00 equiv), piperidine (18 mg, 0.21 mmol, 1.00 equiv), cyclopropanecarbaldehyde (30 mg, 0.43 mmol, 2.00 equiv), and methanol (5 mL). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 38 mg (33%) of the title compound as a off-white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:35])=[C:11]([C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[CH2:21][N:20](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:19]5)[C:12]=3[O:14]C)[C:7](=[O:36])[C:6]([C:37]([OH:39])=[O:38])=[CH:5]2)[CH2:3][CH2:2]1.C1(O)C=CC=CC=1.C(O)(=O)CC.[OH-].[Na+].C(=O)=O>Br.O.C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:35])=[C:11]([C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[CH2:21][NH:20][CH2:19]5)[C:12]=3[OH:14])[C:7](=[O:36])[C:6]([C:37]([OH:39])=[O:38])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1c(-c2ccc3c(c2)CN(S(=O)(=O)c2ccc(C)cc2)C3)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Br
Agent: O=C=O
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Solvent: CCO
Product: O=C(O)c1cn(C2CC2)c2c(O)c(-c3ccc4c(c3)CNC4)c(F)cc2c1=O
Temperature: 130 °C
Reaction time: 6 h

Procedure:
In 0.5 ml of 47% hydrobromic acid was suspended 50 mg of 1-cyclopropyl-6-fluoro-8-methoxy-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and to the suspension were added 26 mg of phenol and 0.3 ml of propionic acid, after which the resulting mixture was stirred at 130° C. for six hours. The reaction mixture was concentrated under reduced pressure, and to the residue obtained were added 0.3 ml of ethanol, 0.3 ml of 1N aqueous sodium hydroxide solution and 0.3 ml of water to dissolve the residue. Thereafter, a carbon dioxide gas was blown into the solution, and the crystals precipitated were collected by filtration, to obtain 12 mg of pale yellow, crystalline 1-cyclopropyl-6-fluoro-8-hydroxy-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:8][N:9]([C+:11]([N:13]([CH3:15])[CH3:14])Cl)[CH3:10].[CH3:16][N-:17][CH3:18].[Li+]>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:8][N:9]([CH3:10])[C:11](=[N+:17]([CH3:18])[CH3:16])[N:13]([CH3:15])[CH3:14]
Reactant: C[N-]C
Reactant: CN(C)[C+](Cl)N(C)C
Agent: O=C([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: CN(C)C(N(C)C)=[N+](C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
1.85 g (7.44 mmol) of bis(dimethylamino)chlorocarbenium trifluoroacetate and 0.38 g (7.45 mmol) of lithium dimethylamide are dissolved in 15 ml of acetonitrile under a protective-gas atmosphere (argon). The reaction mixture is stirred for 5 hours at room temperature, and LiCl is subsequently filtered off. The salt LiCl is washed with 5 ml of acetonitrile, and the organic phases are combined. The solvent is distilled off, and the residue is dried under reduced pressure at 7 Pa and 50° C., giving 1.81 g of hexamethylguanidinium trifluoroacetate as a viscous oil, corresponding to a yield of 99.2%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][CH:8]([C:10]1[C:19]([C:20](OCC)=[O:21])=[C:18]([OH:25])[C:17]2[C:12](=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH3:9].Cl>>[Cl:7][CH:8]([C:10]1[C:19]([C:20]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:21])=[C:18]([OH:25])[C:17]2[C:12](=[C:13]([C:26]([F:29])([F:27])[F:28])[CH:14]=[CH:15][CH:16]=2)[N:11]=1)[CH3:9]
Reactant: CCOC(=O)c1c(C(C)Cl)nc2c(C(F)(F)F)cccc2c1O
Reactant: Nc1nccs1
Agent: Cl
Product: CC(Cl)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1

Procedure:
Using the procedure of Example 4, 1.5 g of 2-aminothiazole and 1.041 g of the product of Step A were reacted and after the addition of N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with ethyl acetate to obtain 2-(1-chloroethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide which after crystallization from ether melted at ≃190° C. (decomposition).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[CH3:27][N:28](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn]>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([C:27]#[N:28])[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C#N)ccc21
Temperature: 170 °C

Procedure:
Trifluoromethanesulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl ester(0.12 g), zinc cyanide(70 mg), tris(dibenzylideneacetone) dipalladium 7 mg), 1,1′-bis(diphenylphosphino) ferrocene(8 mg), and zinc powder(2 mg) were added to DMF (1 ml), and the mixture was heated for 20 minutes at 170° C. (microwave reactor). The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=50:50→0:100). The purified product was condensed under reduced pressure to give the title compound(77 mg) as a white solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3(O)[CH2:13][O:12][CH2:11]3)=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(N(S(F)(F)[F:21])CC)C>C(#N)C.[N+](C)([O-])=O>[F:21][C:10]1([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][NH:2][CH2:3]3)[CH2:13][O:12][CH2:11]1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1(c2ccc3c(c2)CNC3)COC1
Solvent: C[N+](=O)[O-]
Solvent: CC#N
Product: FC1(c2ccc3c(c2)CNC3)COC1
Temperature: 0 °C
Yield: 67 %

Procedure:
To 0.58 mmol 3-(2,3-dihydro-1H-isoindol-5-yl)-oxetan-3-ol in 2 ml acetonitrile and 2 ml nitromethane at −60° C. was added 1.15 mmol diethylaminosulfur trifluoride and the mixture was allowed to warm to 0° C. over 30 min. The reaction mixture was re-cooled to −60° C. and quenched by addition of 5 ml saturated aq. sodium carbonate solution. The mixture was warmed to RT and diluted with THF and ethyl acetate, then washed sequentially with water and with brine. The organic phase was separated, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as a brown oil (67% yield). MS (m/e): 194.3 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[CH2:5]([C@@H:7]1[O:9][CH2:8]1)[Cl:6]>C(OCC)C>[CH2:1]([O:4][CH2:8][C@@H:7]([OH:9])[CH2:5][Cl:6])[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: ClC[C@H]1CO1
Solvent: CCOCC
Product: C=CCOC[C@@H](O)CCl
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
A boron trifluoride-diethyl ether complex (0.34 ml) was added to allyl alcohol (11 ml), and the mixture was warmed to 45° C. Then, (R)-epichlorohydrin (5.0 g) was added and the mixture was stirred at the same temperature for 1.5 hours. Diethyl ether was added, followed by washing with water and drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the crude title compound (10 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:40][C:41]([F:61])([F:60])[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:55][C@H:54]3[C@H:56]([NH2:59])[CH2:57][CH2:58][C@H:53]3[CH2:52]2)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1.C(N(C(C)C)C(C)C)C>ClCCl>[F:61][C:41]([F:40])([F:60])[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:55][C@H:54]3[C@H:56]([NH:59][C:13]([C@@H:9]4[CH2:10][CH2:11][CH2:12][N:8]4[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])[CH2:57][CH2:58][C@H:53]3[CH2:52]2)(=[O:49])=[O:50])[CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
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: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxylic acid (53.1 mg, 0.247 mmol), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (94 mg, 0.247 mmol) were combined in dichloromethane (2 mL). After 10 minutes, (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine (75 mg, 0.224 mmol) from Step A of Example 254 was added. After stirring for 10 more minutes, N-ethyl-N-isopropylpropan-2-amine (0.098 mL, 0.561 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 solution, extracted with 2 mL of dichloromethane, washed with 0.1 N HCl, and concentrated in vacuo. The crude material was purified using a 12 g silica gel cartridge with a gradient of 1-5% methanol (2 N ammonia)/dichloromethane over 20 minutes to give the title compound: 1H NMR (501 MHz, pyridine-d5, temperature 90° C.) δ ppm 8.29-8.30 (bs, 1H), 8.13 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.66-7.72 (m, 1H), 7.64 (t, J=7.9 Hz, 1H), 4.29-4.32 (m, 1H), 4.06-4.10 (m, 1H), 3.68-3.71 (m, 1H), 3.46-3.51 (m, 1H), 3.34-3.42 (m, 1H), 3.26 (dd, J=9.9, 7.4 Hz, 1H), 3.06-3.17 (m, 2H), 2.55-2.57 (m, 2H), 2.09 (d, J=3.0 Hz, 1H), 1.88-1.98 (m, 3H), 1.80-1.88 (m, 1H), 1.59-1.68 (m, 1H), 1.55 (dd, J=13.2, 8.7 Hz, 1H), 1.50 (s, 9H), 1.25-1.37 (m, 1H); MS (ESI+) m/z 532 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[CH2:29][C:30]1[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=1>ClCCl>[CH3:20][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][CH2:29][C:30]2[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=2)[C:7]=1[C:8]#[C:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CNc2ncnc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1
Reaction time: 72 h

Procedure:
A mixture of 4-amino-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine (2 g), triethylamine (0.76 g), ethyl 5-chloromethyl-2-furancarboxylate (1.4 g) and dichloromethane (60 ml) was heated to reflux while stirring for 72 hours. The mixture thus obtained was concentrated under reduced pressure. After the resultant residue was washed with water added thereto, an organic phase was dried over anhydrous sodium sulfate and then evaporated. The evaporation residue was purified by column chromatography to obtain a target substance (0.5 g). The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[NH2:23][CH:24]([CH2:29][CH2:30][CH2:31][CH3:32])[C:25]([O:27][CH3:28])=[O:26]>ClCCl>[CH:14](=[N:23][CH:24]([CH2:29][CH2:30][CH2:31][CH3:32])[C:25]([O:27][CH3:28])=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCC(N)C(=O)OC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(N=Cc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Triethylamine (8.67 g) (supplied from Wako Pure chemical Industries), 7.74 g of magnesium sulfate anhydrate and 4.55 g of benzaldehyde were added to a suspension of 7.79 g of methyl 2-aminohexanoate hydrochloride in 70 mL of dichloromethane, and stirred at room temperature overnight. The reaction suspension was filtrated, and the filtrate was concentrated. Then 280 mL of ether was added to the residue. The resulting suspension was filtrated and the filtrate was concentrated. Again 280 mL of ether was added to the residue, and the filtration and the concentration were repeated in the same manner, to yield 10.0 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:22]=[C:21]([Cl:23])[C:20]([C:24]2[CH:25]=[N:26][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:29]=2[C:30]#[N:31])=[CH:19][C:6]=1[C:7]([N:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[CH3:10])=[O:8].[CH3:36][S:37](Cl)(=[O:39])=[O:38].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:23][C:21]1[C:20]([C:24]2[CH:25]=[N:26][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:29]=2[C:30]#[N:31])=[CH:19][C:6]([C:7]([N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH3:10])=[O:8])=[C:5]([O:4][CH2:3][CH2:2][NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-amino-ethoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide (30 mg, 0.06 mmol) in DCM (1 mL), methanesulfonylchloride (7 μL, 0.09 mmol) and DIPEA (16 μL, 0.09 mmol) were added. The mixture was stirred at rt overnight, concentrated, diluted with 1 mL MeOH and purified by prep HPLC yielding 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2-methanesulfonylamino-ethoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide 48-1. MS: 583.0 (M+H)+, tR=7.61 min (method 2).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1[CH2:17][N:16]([CH2:18][C:19](=[O:30])[NH:20][CH:21]2[CH2:25][C:24](=[O:26])[O:23][CH:22]2[O:27]CC)[C:15](=[O:31])[CH:14]([NH:32][C:33]([C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[O:34])[CH2:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>CC#N.O>[C:1]([NH:9][CH2:10][C:11]1[CH2:17][N:16]([CH2:18][C:19](=[O:30])[NH:20][CH:21]2[CH2:25][C:24](=[O:26])[O:23][CH:22]2[OH:27])[C:15](=[O:31])[CH:14]([NH:32][C:33]([C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[O:34])[CH2:13][CH:12]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1OC(=O)CC1NC(=O)CN1CC(CNC(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(CN1CC(CNC(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O)NC1CC(=O)OC1O
Yield: 51 %

Procedure:
A solution of isoquinoline-1-carboxylic acid {6-(benzoylamino-methyl)-1-[(2-ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-2,3,4,7,-tetrahydro-1H-azepin-3-yl}-amide, 32, as prepared in the above example, in CH3CN/H2O is treated with excess trifluoroacetic acid. The solution is stirred several hours then purified by preparative reverse phase HPLC to afford 51 mg (51% yield) of the desired product. 1H NMR (CD3OD) δ 9.15–9.12 (d, J=8.4 Hz, 1H), 8.56–8.54 (d, J=5.7 Hz, 1H), 8.08–8.04 (m, 2H), 7.92–7.76 (m, 4H), 7.57–7.50 (m, 3H), 5.83 (bs, 1H), 5.61–5.56 (d, d, J=12.6, 3.9 Hz, 1H), 4.90–4.85 (d, J=17.4 Hz, 1H), 4.63–4.60 (m, 1H), 4.41–4.01 (m, 3H), 3.65–3.58 (d, d, J=17.4, 2.7 Hz, 1H), 2.91–2.85 (bd, J=18.9 Hz, 1H), 2.75–2.65 (m, 1H), 2.55–2.46 (m, 2H); MS 572 (M+H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[C:8]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:7]=1)C.[NH3:23]>CO>[CH3:21][N:18]1[CH2:19][CH2:20][N:15]([C:8]2[CH:7]=[C:6]([CH2:5][C:4]([NH2:23])=[O:3])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=2)[CH2:16][CH2:17]1
Reactant: N
Reactant: CCOC(=O)Cc1cc(N2CCN(C)CC2)ncc1[N+](=O)[O-]
Solvent: CO
Product: CN1CCN(c2cc(CC(N)=O)c([N+](=O)[O-])cn2)CC1
Temperature: 40 °C

Procedure:
[2-(4-Methyl-piperazin-1-yl)-5-nitro-pyridin-4-yl]-acetic acid ethyl ester (250 mg, 0.81 mmol) is dissolved in methanol (2.5 ml). An aqueous solution of ammonia (25%, 2.5 ml) is added, and the mixture is warmed to 40° C. for 18 h. TLC analysis indicated complete conversion of the starting material. Solvents are removed, and the residue is purified by FCC (CH2Cl2/MeOH, gradient from 97:3 to 90:10) to afford the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 2.21 (s, 3H), 2.38 (m, 4H), 3.72 (m, 4H), 3.80 (s, 2H), 6.84 (s, 1H), 6.93 (s, broad, 1H), 7.46 (s, broad, 1H), 8.85 (s, 1H). ES+−MS: 280.3 [M+H]+, ES−−MS: 278.3 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: NC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(NC3CCCC3)nc(Cl)nc21
Temperature: 70 °C
Yield: 94 %

Procedure:
2,4-Dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), cyclopentanamine (1 equiv), sodium tert-butoxide (7.5 equiv), and 1,4-dioxane (0.28 M) were combined in a sealable vessel with a stir bar. The resulting mixture was put under nitrogen atmosphere, sealed, stirred vigorously, and heated at 70° C. After cooling to room temperature, the reaction mixture was loaded directly onto a silica gel column and purified using flash chromatography (Biotage) (0-20% ethyl acetate in hexane) to give the title compound (94% yield) as a yellow solid. MS (ESI) m/z 493.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[N:12]=[C:11](S(C)(=O)=O)[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[N:12]=[C:11]([N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: C1CCNC1
Product: Fc1ccc(COc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c(N3CCCC3)n2)cc1F

Procedure:
2-(3,4-Difluorobenzyloxy)-4-(methylsulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-pyrimidine (Reference Example 7) (30 mg, 0.05 mmol) was reacted with pyrrolidine (37.7 mg, 0.53 mmol) by the same general procedure described in Example 103 to afford the title compound after flash column chromatography on silica gel (eluted with 90/10 hexanes/ethyl acetate): HPLC/MS: m/e=546 (M++1); Rt=3.70 min. 1H-NMR 400 MHz (CDCl3): δ 1.75-1.80 (br, 4H), 3.10-3.20 (br, 4H), 5.32-5.42 (m, 2H), 6.95 (d, J=9 Hz, 1H), 7.05-7.21 (m, 8H), 7.35-7.40 (m, 1H).
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:17])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:20][CH:21]=1
Reactant: Nc1ccc2c(c1)CCC(NCC(F)F)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)F)CC3)ncc1Cl
Yield: 50 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide to yield 2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide (51.78 mg, 50% yield) as a white powder. 1H-NMR (CDCl3) δ 11.05 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 7.47 (m, 2H), 7.34 (s, 1H), 7.25 (s, 1H), 7.04 (m, 2H), 6.89 (s, 1H), 6.15 (br s, 1H), 5.84 (s, 1H), 3.03 (m, 6H), 2.80 (m, 3H), 2.67 (m, 3H), 2.04 (m, 2H), 1.31 (m, 2H). LC/MS (ESI+)=501 (M+H). MP=182-183° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:14]1([S:20]([N:7]2[C:8]3[C:4](=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: FC(F)(F)c1cccc2[nH]ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c(C(F)(F)F)cccc21
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 4-(trifluoromethyl)-1H-indole (0.535 g, 2.89 mmol; step A above), tetrabutylammonium bromide (0.097 g, 0.30 mmol) and benzenesulfonyl chloride (0.44 mL, 3.5 mmol) in PhMe (5 mL) at rt was added 50 wt % NaOH (3 mL) and H2O (2 mL). The mixture was stirred 30 min, partitioned between Et2O/H2O and the layers were separated. The organic layer was washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.771 g of the title compound as a thick, pale yellow oil: 1H NMR (300 MHz, methanol-d4) δ 8.25 (d, J=8.3 Hz, 1H), 8.00-7.94 (m, 2H), 7.88 (d, J=3.8 Hz, 1H), 7.65-7.58 (m, 1H), 7.57-7.41 (m, 4H), 6.87 (br. s, 1H).