Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[N:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:4]=1.C([O-])(=O)C.[Na+].[I:28]Cl>C(O)(=O)C.O>[F:22][CH:2]([F:1])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([I:28])=[C:7]2[N:6]=[C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:4]=1
Reactant: ClI
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2cncn12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2c(I)ncn12
Temperature: 25 °C
Reaction time: 17 h
Yield: 112 %

Procedure:
To a stirred solution of 4-difluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (1.56 g, 4.98 mmol) in acetic acid (9 ml) was added at room temperature sodium acetate (0.46 g, 5.63 mmol) and drop wise a solution of iodine monochloride (0.91 g, 5.63 mmol) in acetic acid (4 ml). The reaction mixture was stirred at room temperature for 17 h, diluted slowly with water (150 ml), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 4-difluoromethyl-8-iodo-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (2.45 g, 100%) as a yellow solid. MS (EI) 439.0 [(M)+]; mp 159° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[O:20])=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[F:1][C:2]1[CH:7]=[C:6]([C:19](=[O:20])[CH2:18][C:15]2[CH:16]=[CH:17][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1F
Reactant: CSc1ccc(CC(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)Cc2ccc(SC)cc2)cc1F

Procedure:
1-(3-Fluoro-4-methoxyphenyl)-2-[4-(methylthio)phenyl]-ethan-1-one was prepared by Friedel Crafts acylation of 2-fluoroanisole with 4-(methylthio)phenylacetyl chloride in the presence of aluminum chloride: 1H NMR (CDCl3 /300 MHz) δ 7.80-7.70 (m, 2H), 7.24-7.15 (m, 4H), 6.98 (t, J=8.26 Hz), 4.17 (s, 2H), 3.95 (s, 3H), 2.46 (s, 3H). 19F NMR (CDCl3 /282.2 MHz): -134.804 (m).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][N:19]2[CH2:26][CH2:25][C:22]3([CH2:24][CH2:23]3)[C@H:21]([OH:27])[CH2:20]2)[CH2:10][C@H:9]1[CH3:28])=O)(C)(C)C.[ClH:29]>ClCCl.O1CCOCC1>[ClH:29].[ClH:29].[OH:27][C@@H:21]1[CH2:20][N:19]([CH2:18][CH2:17][CH2:16][N:11]2[C:12](=[O:15])[CH2:13][CH2:14][NH:8][C@H:9]([CH3:28])[CH2:10]2)[CH2:26][CH2:25][C:22]21[CH2:23][CH2:24]2
Reactant: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.500 g (1.26 mmol) of (R)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (example ID) in 8 ml of dichloromethane was treated at 0° C. with 3.16 ml (12.64 mmol, 10 eq.) of 4 M hydrogen chloride solution in dioxane. The solution was stirred overnight and warmed up to room temperature. The solution was evaporated, suspended in toluene and evaporated (3 times) to give 0.610 g (quantitative, purity: 76%) of the title compound as white solid. MS: 296.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.FC(F)(F)C(O)=O>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COC(=O)c1cccc2cc(N)ccc12
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2cc(Nc3ccnc4cc(OC)c(OC)cc34)ccc12
Temperature: 90 °C

Procedure:
To a mixture of methyl-6-amino-1-napthoate (300 mg, 1.5 mmol) and 4-chloro-6,7-dimethoxyquinoline (416 mg, 1.8 mmol) in a 20 mL sealed tube was added isopropyl alcohol (6 mL) and trifluoroacetic acid (287 μL, 3.7 mmol). The reaction vessel was sealed and heated at 90° C. for 1 h before being allowed to cool to ambient temperature. To the resulting thick yellow slurry was added isopropyl alcohol (6 mL). The reaction vessel was sealed and heated at 90° C. for 10 h. The mixture was then cooled to 0° C. and filtered. The resulting solid was washed well with cold CH3OH and dried in vacuo to provide the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 389.3 (M+1). Mass Calc'd for C23H20N2O4: 388.42.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH:11]([C:13](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14])=[O:12]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:13]([CH3:14])[CH:11]=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(C=C(C)C=O)cc1

Procedure:
A suspension of 4-methoxybenzaldehyde (10 g, 0.073 mol) and α-formylethylidenetriphenylphosphorane (25.7 g, 0.081 mol) in dried toluene (200 ml)was heated with stirring at reflux under an atmosphere of nitrogen for 24 h. The cooled reaction mixture was decanted to removed insoluble material and evaporated to give a brown oil. The oil was taken up in diethylether and the resulting suspension purified on flash silica eluting with hexane-diethyl ether (3:2). The resulting oil was a mixture of required product and 4-methoxybenzaldehyde and therefore dissolved in dried toluene (150 ml) and reaction continued as described above with α-formylethylidenetriphenylphosphorane (5.76 g, 0.018 ml) for 7 h. Following the work up and chromatography as above 3-(4-methoxyphenyl)-2-methylpropenaldehyde was obtained as a yellow oil.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](B4OCC(C)(C)CO4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)S(O[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([Br:43])[CH:39]=2)[CH:34]=1)(=O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>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>[C:1]12([C:11]3[CH:12]=[C:13]([C:33]4[CH:34]=[C:35]5[C:40](=[CH:41][CH:42]=4)[CH:39]=[C:38]([Br:43])[CH:37]=[CH:36]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COc1ccc(B2OCC(C)(C)CO2)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=S(=O)(Oc1ccc2cc(Br)ccc2c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc3cc(Br)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 23.5 %

Procedure:
[3-(1-adamantyl)-4-methoxyphenyl]-5,5-dimethyl-1,3,2-dioxaborinane (100 mg, 0.28 mmol), 6-bromo-2-naphthalenyl trifluoromethanesulphonate (67 mg, 0.19 mmol), K3PO4 (160 mg, 0.75 mmol), THF (2 ml) and H2O (0.4 ml) were introduced in a Schlenk tube. The reaction mixture was deoxygenated (3 froze/thaw cycles). Next, Pd(PPh3)4 (11 mg, 0.009 mmol) was added and the mixture was again deoxygenated (2 froze/thaw cycles). After heating at reflux for 17 h, the mixture was diluted in toluene (5 ml) while it was still hot. The solution was filtered through celite and it was washed with hot toluene (2×5 ml). The joined organic phases were washed with hot H2O (2×5 ml). The organic phase was evaporated and a crude (59 mg) was obtained, which was recrystallized with the minimum volume of toluene at reflux (0.55 ml), giving the title compound (20 mg, 24%) as a pale yellow powder. The spectroscopic data coincide with those of the Example 4.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[CH:17]=[C:16]([NH:23][C:24]3[NH:28][N:27]=[C:26]([CH:29]4[CH2:31][CH2:30]4)[CH:25]=3)[N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH:20]1([C:18]2[CH:17]=[C:16]([NH:23][C:24]3[NH:28][N:27]=[C:26]([CH:29]4[CH2:31][CH2:30]4)[CH:25]=3)[N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[N:19]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2nc(Nc3cc(C4CC4)n[nH]3)cc(C3CC3)n2)s1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2nc(Nc3cc(C4CC4)n[nH]3)cc(C3CC3)n2)s1
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
The solution of N-tert-butyl-5-(4-cyclopropyl-6-(3-cyclopropyl-1H-pyrazol-5-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (50 mg, 0.1 mmol) in trifluoroacetic acid (5 mL) was stirred at 60° C. After 0.5 h, the solution was evaporated to give a residue which was recrystallized from ether to afford 5-(4-cyclopropyl-6-(3-cyclopropyl-1H-pyrazol-5-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (VRCompound 298) (21 mg, 52%). LC-MS (m/z)=403.1 [M+H]+; δ (400 MHz, DMSO-d6); 0.71-0.74 (m, 2H), 0.93-1.02 (m, 6H), 1.88-2.00 (m, 2H), 6.19 (bs, 1H), 6.93 (bs, 1H), 7.46 (s, 2H), 8.01 (s, 1H), 8.14 (b, 1H), 9.86 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13](CC4C=CC(OC)=CC=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:8]=23)=[C:4]([F:35])[CH:3]=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH:48]=[CH:47][N:46]=[C:45]([C:49](O)=[O:50])[C:44]2=[O:52])=[CH:39][CH:38]=1>>[F:35][C:4]1[CH:3]=[C:2]([NH:1][C:49]([C:45]2[C:44](=[O:52])[N:43]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)[CH:48]=[CH:47][N:46]=2)=[O:50])[CH:34]=[CH:33][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:8]=12
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1nccn(-c2ccc(F)cc2)c1=O
Product: CN1CCC(Nc2n[nH]c3nccc(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Yield: 53 %

Procedure:
Prepared by a 2-step process from 4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine and 4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid according to the procedure of Example 101, Step B. The crude was rinsed with Et2O to afford 8.8 mg (53%) of the desired product. LRMS (ESI pos) m/e 573.0 (M+1). 1H NMR (400 MHz, CD3OD/CDCl3) δ 8.14 (d, 1H), 8.05 (dd, 1H), 7.86 (m, 2H), 7.57 (m, 2H), 7.51 (d, 1H), 7.34 (m, 3H), 6.12 (d, 1H), 3.71 (m, 1H), 2.92 (m, 2H), 2.35 (s, 3H), 2.29 (m, 2H), 2.22 (m, 2H), 1.65 (m, 2H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −112.1, −129.4.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:31](Cl)(Cl)[C:32](Cl)=[O:33].P(Cl)(Cl)(Cl)=O>[Cu].[Zn].C(OCC)C>[CH2:1]([O:8][CH2:9][C:10]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][C:32](=[O:33])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C(CCCCCCCCCCCCCCCCCC)COCc1ccccc1
Agent: [Cu]
Agent: [Zn]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCC1(COCc2ccccc2)CC(=O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred mixture containing 7.18 g (18 mmol) of the compound prepared in (a) above, 75 ml of anhydrous diethyl ether and 1.4 g of zinc-copper couple was blanketed with nitrogen and treated dropwise at room temperature with a solution containing 3.63 g (20 mmol) of trichloroacetyl chloride and 3.06 g (20 mmol) of phosphorus oxychloride. After stirring the mixture at room temperature for 48 hours, the salts were filtered off and the filtrate concentrated in vacuo. The residue was then chromatographed on silica gel employing a mixture of petroleum ether and methyl-t-butyl ether in a ratio of 9:1 as the eluent to yield a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C1C(=O)N(Br)C(=O)C1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)(Cl)(Cl)Cl.CCO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(I)cc1F
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CN1CCN(Cc2ccc(I)cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a mixture of 2-fluoro-4-iodotoluene (0.94 g, 4.0 mmol) in CCl4 (40 mL) were added BPO (0.02 g, 0.08 mmol) and NBS (0.78 g, 4.4 mmol) under N2. The reaction mixture was refluxed for 5 h, then cooled and concentrated in vacuo. To the residue was added a solution of methylpiperazine (2.00 g, 20 mmol) in EtOH (40 mL) under N2. The mixture was stirred at rt overnight and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as a white solid (0.69 g, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[H-].[Na+].[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23]
Reactant: COc1cccc(CBr)c1OC
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(CC(C#N)(C#N)CCC(F)(F)F)c1OC
Yield: 83.7 %

Procedure:
Using 0.23 g of 2,3-dimethoxybenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.26 g of 2-(2,3-dimethoxybenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (40)).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:23]1[S:24][C:25]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[N:30]2)=[CH:26][CH:27]=1)[NH:6][C:7](=[O:22])[CH:8]([CH2:17][S:18]C(=O)C)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.CO>C(Cl)(Cl)Cl>[N:29]1([CH2:28][C:25]2[S:24][C:23]([CH:5]([C:4]([OH:34])=[O:3])[NH:6][C:7](=[O:22])[CH:8]([CH2:17][SH:18])[CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:27][CH:26]=2)[CH:33]=[CH:32][N:31]=[N:30]1
Reactant: CCOC(=O)C(NC(=O)C(CCc1ccccc1)CSC(C)=O)c1ccc(Cn2ccnn2)s1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NC(C(=O)O)c1ccc(Cn2ccnn2)s1)C(CS)CCc1ccccc1

Procedure:
The title compound was prepared from 2-[5-(1,2,3-triazol-1-ylmethyl)thien-2-yl]-N-[2-(acetylthiomethyl)-4-phenylbutyryl]glycine ethyl ester (Description 57) by the procedure described in Example 24 except that the eluent used was 20% methanol indichloromethane. vmax (CHCl3) 3292, 1731, 1648 and 1602 cm-1. δ (CD3SOCD3) 1.70-1.82 (2H, m), 2.46-2.74 (5H, m), 5.22 (1H, d, J 6.85 Hz), 5.72 (2H, s), 6.85-7.31 (7H, m), 7.68 and 7.72 (1H, two s's), 8.11 and 8.14 (1H, two s's).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]([O:14][CH3:15])=[O:13])[CH2:4]1.Cl[C:17]1[C:18]2[C:25]([CH3:26])=[CH:24][S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)CC)C>C(O)C>[CH3:15][O:14][C:12]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH:3]([NH:2][C:17]1[C:18]3[C:25]([CH3:26])=[CH:24][S:23][C:19]=3[N:20]=[CH:21][N:22]=1)[CH2:4]2)=[O:13]
Reactant: COC(=O)c1cccc2c1CC(N)C2
Reactant: Cc1csc2ncnc(Cl)c12
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2c1CC(Nc1ncnc3scc(C)c13)C2

Procedure:
Using 2-(tert-butoxycarbonylamino)-4-methoxycarbonylindan (45 mg, 0.15 mmol) synthesized in the above Reference Production Example 7, 4N hydrochloric acid-dioxane (0.7 ml) and acetic acid (2.1 ml), a similar procedure to Production Example 213 was carried out to obtain 2-amino-4-methoxycarbonylindan hydrochloride. Then, using the 2-amino-4-methoxycarbonylindan hydrochloride, 4-chloro-5-methylthieno[2,3-d]pyrimidine (28 mg, 0.15 mmol), triethylamine (63 μl, 0.45 mmol), and ethanol (1 ml), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (15 mg, 0.044 mmol) having the following physical properties:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH:14][C:15](=[O:18])[CH2:16][CH3:17])[C:4]=2[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:22]>C1COCC1>[CH3:22][N:14]([CH2:13][C@@H:11]1[CH2:12][C@H:10]1[C:9]1[C:4]2[CH2:3][CH2:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1)[C:15](=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)NC[C@@H]1C[C@H]1c1cccc2c1CCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)N(C)C[C@@H]1C[C@H]1c1cccc2c1CCO2
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
To a solution of (trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl]methyl]propanamide (120 mg, 0.6 mmol) in THF (1.5 mL) was added sodium hydride (30 mg of 60%, 0.75 mmol). The mixture was allowed to stir for 0.5 h and iodomethane (140 mg, 1 mmol) was added. After stirring for 18 h, the solution was concentrated in vacuo. The residue was dissolved in acetonitrile and washed with hexane. The acetonitrile solution was concentrated in vacuo and the residue purified by chromatography on silica eluting with ethyl acetate-hexane (2:8) to give the product as an amber oil (90 mg, 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([S:18]([O-:20])=[O:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Na+].I[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C@@H:29]([OH:31])[CH3:30].N>[Cu]I.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([S:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C@@H:29]([OH:31])[CH3:30])(=[O:20])=[O:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=S([O-])c1cnc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: C[C@H](O)c1ccccc1I
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H](O)c1ccccc1S(=O)(=O)c1cnc2cc(-c3ccc(F)cc3)ccc2c1
Reaction time: 1 h
Yield: 41.3 %

Procedure:
Sodium 7-(4-fluorophenyl)quinoline-3-sulfinate (2.52 g, 8.15 mmol), (1S)-1-(2-iodophenyl)ethanol (2.18 g, 8.79 mmol) and copper(I) iodide (4.69 g, 24.6 mmol) were weighed into a 3-neck round-bottomed flask. A nitrogen atmosphere was established by evacuation and back-filling with nitrogen. Dimethyl sulfoxide (50 mL) was added and the flask placed in an oil bath at 110° C. The reaction mixture was stirred at this temperature for 1 hour. The cooled reaction mixture was poured into concentrated ammonia solution (250 mL) and extracted with ethyl acetate (2×250 ml). The extracts were washed with brine (250 mL), combined, dried (MgSO4) and evaporated to an off-white solid. Recrystallisation from methanol gave the title compound (1.37 g, 41%). 1H NMR (500 MHz, DMSO-d6) δ 9.16 (2H, s), 8.41 (1H, d, J 8.6 Hz), 8.39 (1H, s), 8.19 (1H, dd, J 1.0, 8.0 Hz), 8.15 (1H, dd, J 1.7, 8.5 Hz), 7.99-7.97 (2H, m), 7.84 (1H, dd, J 1.0, 7.8 Hz), 7.78 (1H, t, J 7.1 Hz), 7.62-7.58 (1H, m), 7.39 (2H, t, J 8.8 Hz), 5.52-5.46 (1H, m), 5.29 (1H, d, J 3.9 Hz), 1.20 (3H, d, J 6.2 Hz); m/z (ES+) 408 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[C:27]([F:28])=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][C:20]=1[F:29])[C:13](=[O:30])[CH:12]=[CH:11]2.C(Cl)CCl.C1C=CC2N(O)N=[N:41]C=2C=1.[OH-].[NH4+]>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[C:27]([F:28])=[CH:26][C:22]([C:23]([NH2:41])=[O:25])=[CH:21][C:20]=1[F:29])[C:13](=[O:30])[CH:12]=[CH:11]2
Reactant: O=C(O)c1cc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c(F)c1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: ClCCCl
Product: NC(=O)c1cc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c(F)c1

Procedure:
To a solution of 4-[6-(2,4-difluorophenyl)-2-oxo-2H-quinolizin-1-yl]-3,5-difluorobenzoic acid (Example 38) in NMP was added EDC, HOBT and ammonium hydroxide. After reaction complete, the mixture was concentrated and purified by reverse phase chromatography (10-100% ACN in H2O, Kromisil, C8, 30×100 mm) to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O:9][C:10](=O)[CH2:11][C:12]#[N:13])C>C(OCC)(=O)C>[C:12]([CH2:11][C:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:9])#[N:13]
Reactant: CCOC(=O)CC#N
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: N#CCC(=O)N1CCOCC1
Temperature: 105 °C
Yield: 701.7 %

Procedure:
A 4-neck 500 mL flask was charged with morpholine (77.0 g, 0.088 mol). Ethylcyanoacetate (100.0 g, 0.088 mol) was added. After addition, the reaction mixture was stirred. The mixture progressively turned yellow to clear. The mixture was heated to 100 to 110° C. for 3.0 hours. A solid formed after cooling to room temperature. Ethyl acetate (150 ml) and heptanes (300 ml) were added and the mixture stirred for 30 minutes at room temperature. The solid was filtered to give 95.2 g (71% yield) of 4-cyanoacetylmorpholine. 1H NMR: δ (DMSO-d6) 4.02 (s, 2H); 3.37 (m, 2H); 3.55 (m, 4H); 3.45 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(Cl)(Cl)Cl>[CH2:20]([O:19][C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)nc1)OCc1ccccc1
Yield: 53.3 %

Procedure:
5-Amino-2-chloropyridine(643 mg)in 3 mL of chloroform containing 505 mg of triethylamine was stirred with 853 mg of benzyl chloroformate for 4 hours at 60 degrees C. The mixture was then diluted with 20 mL of chloroform and washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated to give 700 mg of 5-benzyloxycarbonylamino-2-chloropyridine. 5-Benzyloxy carbonylamino-2-chloropyridine (272 mg) and 163 mg of 2,4-dichlorophenol were stirred overnight at room temperature in 1 mL of dimethylformamide containing 138 mg of potassium carbonate. The reaction mixture was evaporated to dryness under high vacuum and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated. Hydrogenolysis in methanol over palladium on carbon gave 5-amino-2-(2,4-dichlorophenoxy) pyridine. The 5-amino-2-(2,4-dichlorophenoxy)pyridine was treated with 4-(trifluoromethylmercapto)phenylisocyanate under conditions similar to those in Example 1 to give N-[2-(2,4-dichlorophenoxy)pyrid-5-yl]-N'-[4-trifluoromethyl mercapto)phenyl]urea.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:29]([OH:31])=[O:30])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:29]([OH:31])=[O:30])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: CC1(C)CCC(CNOCc2ccccc2)(C(=O)O)CC1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC1(C)CCC(CN(C=O)OCc2ccccc2)(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a cold solution of formic acid (12.8 mL, 0.33 mol) in dichloromethane (50 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (4.8 mL, 51 mmol). After 1 h, a solution of 1-(benzyloxyamino-methyl)-4,4-dimethyl-cyclohexanecarboxylic acid from Preparation 30 (5.11 mmol theoretical) in dichloromethane (50 mL) was added. The reaction was stirred at room temperature for 18 h and was concentrated in vacuo. Water (100 mL) was added and the mixture was extracted with dichloromethane (50 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo to yield the title compound (1.55 g, 95%). MH+320.