Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH2:14])=[CH:8][CH2:9]2)=[CH:5][C:4]=1[O:15][CH3:16].[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH:14][C:17](=[O:20])[CH2:18][CH3:19])=[CH:8][CH2:9]2)=[CH:5][C:4]=1[O:15][CH3:16]
Reactant: COc1cc2c(cc1F)CC=C2CCN
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)NCCC1=CCc2cc(F)c(OC)cc21

Procedure:
Starting with 2-(6-fluoro-5-methoxy-1H-inden-3-yl)ethylamine hydrochloride and propionyl chloride, the title compound was synthesized in otherwise the same manner as Example 8 (yield 83%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]=[CH:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20](=[O:23])[NH:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:11][CH2:10][C:9]([C:14]3[NH:22][C:21]4[C:20](=[O:23])[NH:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:8][CH2:7]1)[CH2:12][CH2:13]2
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(C=CC(=O)OC)(CC3)CC4)nc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Reaction time: 6 h
Yield: 92.8 %

Procedure:
3-[4-(2,6-Dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylic acid methyl ester (300 mg) was dissolved in 20 mL of THF. 10%Pd on C (25 mg) was added and the resulting reaction mixture was hydrogenated under 50 psi of H2 at rt for 6 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford 280 mg of the desired product.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4][CH:5]=[CH:6][C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.N#N.[NH2:19][C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]([C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:39][CH:38]=1)[C:23](=[O:36])[N:24]2[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1>CN(C=O)C.CC#N.C(Cl)Cl>[NH2:19][C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]([C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:39][CH:38]=1)[C:23](=[O:36])[N:24]2[C:29]1[CH:30]=[C:31]([NH:35][C:7](=[O:8])/[CH:6]=[CH:5]/[CH2:4][N:3]([CH3:10])[CH3:2])[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Reactant: CN(C)CC=CC(=O)O
Agent: Cl
Agent: N#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)C/C=C/C(=O)Nc1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
To a mixture of 4-(dimethylamino)but-2-enoic acid hydrochloride (81 mg, 0.49 mmol) and 1 drop of DMF in 3 mL dry CH3CN was added 0.5 mL oxalyl chloride dropwise under N2. The reaction mixture was stirred at rt for 1 hr, then concentrated to dryness in vacuo. The resulting solid was dissolved in 2 mL dry DCM and was transferred to a stirred solution of 6-amino-9-(3-aminophenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (7) (100 mg, 0.24 mmol) and one drop of TEA in 3 mL dry DCM in an ice-water bath. After stirring for 2 hrs, the reaction was quenched with MeOH. The resulting mixture was concentrated to dry, pre-purified by column chromatography (silica gel, 0 to 5% methanol in DCM), followed by Gilson using 10 to 95% acetonitrile in water (0.1% TFA) to give (E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (8) (61 mg, 48%) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 9.79 (s, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.58-7.32 (m, 6H), 7.25-7.07 (m, 5H), 6.84-6.65 (m, 1H), 6.46 (d, J=15.4 Hz, 1H), 5.88 (s, 2H), 4.02-3.87 (m, 2H), 2.79 (s, 3H), 2.78 (s, 3H). LC-MS (ESI): m/z (M+1) 522.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)=[C:7]([N+:16]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)=[C:7]([CH:6]=1)[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cn[nH]c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2cn[nH]c2)c(N)c1
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A mixture of 4-(4-t-butyl-2-nitrophenyl)pyrazole (0.27 mmol), 10% Pd/C (0.2 eq by weight of nitro compound) and NH4CO2H (2.7 mmol) in ethanol (3 mL) was stirred for 30 min and filtered through a bed of diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue dissolved in water. The solid was filtered, washed with water and dried to give the product (54 mg, 93%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)[CH:4]=[N:3][CH:2]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>CO.CCOC(C)=O.O>[N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:13][CH:14]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=Cc1ccc(-c2cncnc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: OCc1ccc(-c2cncnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Pyrimidin-5-yl-benzaldehyde (1.89 mmol, 350 mg) was dissolved in MeOH. NaBH4 (9.4 mmol, 357 mg) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0° and 9M HCl (0.25 mL) was added dropwise. The reaction mixture was stirred for one half hour. The reaction mixture was then basified with 20% NaOH (pH=10). EtOAc and H2O were added and the layers were separated. The aqueous layer was back extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield a tan solid. Flash chromatography (EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:31][C:32]1[C:40]([F:41])=[N:39][CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=O>O.C(Cl)(Cl)Cl>[Cl:31][C:32]1[C:40]([F:41])=[N:39][CH:38]=[CH:37][C:33]=1[C:34]([N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])=[O:36]
Reactant: CNCCN(C)C
Reactant: O=C(O)c1ccnc(F)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)CCN(C)C(=O)c1ccnc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
N,N,N′-trimethylethane-1,2-diamine (0.92 ml, 6.84 mmol), 1-hydroxybenzotriazole monohydrate (1.05 g, 6.84 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.31 g, 6.84 mmol) were added to a chloroform solution (15 ml) of 3-chloro-2-fluoroisonicotinic acid (1.0 g, 5.70 mmol), and stirred under a nitrogen atmosphere at room temperature for 30 minutes. Saturated saline water was added to the reaction solution, and extracted with chloroform/methanol (9:1). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate=4:1 to 1:1) to obtain 3-chloro-N-[2-(dimethylamino)ethyl]-2-fluoro-N-methylisonicotinamide (1.27 g, yield: 85%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:27](O)=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[F:53][C:54]1[CH:55]=[C:56]([CH:59]=[CH:60][C:61]=1[O:62][C:63]([F:66])([F:65])[F:64])[CH2:57][NH2:58]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@@H:10]([C:27](=[O:28])[NH:58][CH2:57][C:56]2[CH:59]=[CH:60][C:61]([O:62][C:63]([F:64])([F:65])[F:66])=[C:54]([F:53])[CH:55]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCc1ccc(OC(F)(F)F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)[C@@H](C(=O)NCc2ccc(OC(F)(F)F)c(F)c2)C1
Yield: 95.7 %

Procedure:
To a solution of the compound (1.24 g) obtained in Example 1001, Step 1 in N,N-dimethylformamide (12 ml) were added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.65 g), 1-hydroxybenzotriazole hydrate (0.52 g) and the compound (0.59 g) obtained in Step 3. After stirring overnight at room temperature, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=4:96-6:94) to give the title compound (1.70 g).
Reaction SMILES: C([Sn]1(CCCC)[O:14][CH2:13][C:8]2([CH2:12][CH:11]=[CH:10][CH2:9]2)[CH2:7][O:6]1)CCC.[CH2:19]([C:21]1([CH2:28][CH3:29])[CH2:26][O:25][C:24](=S)[O:23][CH2:22]1)[CH3:20]>>[CH2:19]([C:21]1([CH2:28][CH3:29])[CH2:26][O:25][C:24]2([O:6][CH2:7][C:8]3([CH:9]=[CH:10][CH2:11][CH2:12]3)[CH2:13][O:14]2)[O:23][CH2:22]1)[CH3:20]
Reactant: CCC1(CC)COC(=S)OC1
Reactant: CCCC[Sn]1(CCCC)OCC2(CC=CC2)CO1
Product: CCC1(CC)COC2(OCC3(C=CCC3)CO2)OC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
To the above solution of 8,8-dibutyl-7,9-dioxa-8-stannaspiro[4.5]dec-2-ene 4 was added 5,5-diethyl-1,3-dioxane-2-thione 1 (10.1 g, 60.3 mmol) in several small portions at room temperature over a period of 20 min. The resulting mixture was allowed to stir at room temperature for 24 hours. The reaction was monitored by TLC (silica gel, 25% ether/hexanes). The reaction mixture was then concentrated under reduced pressure and the residue taken up with ethyl ether (white suspension formed upon standing). The ether solution was filtered and concentrated under reduced pressure to give light yellowish oil. The crude material was purified by column chromatography (silica gel, 10-15% ethyl ether/hexanes). The desired 11,11-diethyl-7,9,13,14-tetraoxadispiro[4.2.5.2]pentadec-1-ene (DECP 5) was obtained as white solid in 72% yield. Mp (DSC) 95.19° C., 1H-NMR (CD13, 300 MHz) δ 5.60 (s, 2H), 3.80 (s, 4H), 3.69 (s, 4H), 2.27 (s, 4H), 1.45-1.37 (q, 4H, J=7.8 Hz), 0.82-0.77 (t, 6H, J−7.8 Hz); 13C-NMR (CD13, 300 MHz) δ 128.52, 114.39, 71.04, 69.48, 39.76, 34.33, 23.16, 7.12; FT-IR (Kbr pellet) (cm−1) 3053, 2968, 1619, 1457, 1360, 1266, 1212, 1178, 1001, 938; Anal. Calcd for C1H24O4: C, 67.14; H, 901; Found: C, 67.44; H, 9.22.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][CH:7]=1.[Cl-].[CH3:20][O:21][CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:20][O:21][CH:22]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCC=O)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: COC=CCCCc1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
By following the same procedure as described in Reference Example 1, tert-butyl 4-(4-oxobutyl)benzoate (993 mg) was treated with (methoxymethyl)triphenylphosphonium chloride to give the subject compound (918 mg) in the form of a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]3[N:10]=2)=[CH:12][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Reactant: O=Cc1ccccc1
Product: Brc1cnc2[nH]c(-c3ccc(NCc4ccccc4)cc3)nc2c1

Procedure:
The title compound was prepared from 4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)aniline (0.289 g, 1 mmol) and benzaldehyde (0.106 g, 1 mmol).
Reaction SMILES: Cl.[F:2][C:3]1[C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([NH2:36])=[CH:8]2.CCN(CC)CC.[CH2:44]([N:46]=[C:47]=[O:48])[CH3:45]>>[CH2:44]([NH:46][C:47]([NH:36][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:12]([O:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)=[C:21]([O:24][CH3:25])[CH:22]=4)[N:17]=[CH:16][CH:15]=3)[C:3]=2[F:2])[CH:8]=1)=[O:48])[CH3:45]
Reactant: COc1cc2c(Oc3ccc4cc(N)ccc4c3F)ccnc2cc1OCCCN1CCOCC1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc2c(F)c(Oc3ccnc4cc(OCCCN5CCOCC5)c(OC)cc34)ccc2c1

Procedure:
5-Fluoro-6-[6-methoxy-7-(3-morpholin-4-ylpropoxy)(4-quinolyloxy)]-2-naphthylamine (Example 9, Step b, 47.7 mg, 0.1 mmol) was reacted with Et3N (55 mg, 0.5 mmol, Aldrich) and ethylisocyanate (35.5 mg, 0.5 mmol, Aldrich) under the conditions of Example 110 to give the title compound as a white solid. M.p. 193.5-196.4° C. MS (ESI, pos. ion) m/z: 549.6 (M+1), 547.4 (M−1). Calc'd for C30H33FN4O5−548.24.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:19]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[Cl:20])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[F:39][C:37]([F:38])([F:40])[C:34]1[CH:33]=[CH:32][C:31]([C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)([Cl:20])[C:11]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)C1(C(Cl)(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(C(Cl)(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)CCNCC1
Yield: 100 %

Procedure:
A solution of 190 milligrams (0.320 mmole) of ethyl 1-[(tert-butyl)oxycarbonyl]-4-{bis[4-(trifluoromethyl)phenyl]chloromethyl}piperidine-4-carboxylate and 2 mL of trifluoro acetic acid (TFA) in 0.5 mL of methylene chloride was stirred at room temperature for 10 minutes. The reaction mixture was then diluted with toluene and concentrated under reduced pressure, yielding 158 milligrams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(OC([N:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH2:21]2)[CH2:17][CH2:16]1)=O)C1C=CC=CC=1.CCN(CC)CC>C(Cl)Cl>[C:1]([N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]2([CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH2:21]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CNc1ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC2(CCNCC2)c2ccccc21
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
Acetyl chloride (1.4 mL, 19.9 mmol) was added to a solution of 5.35 g (16.6 mmol) of 1'-benzyloxycarbonyl-spiro(indoline-3,4'-piperidine) in 33 mL of CH2Cl2 and 3.2 mL (23.2 mmol) of Et3N keeping the temperature between 0-5° C. by cooling in ice bath. After 10 min the cold bath was removed and reaction was stirred for 30 min at which time a TLC indicated complete reaction. The solution was diluted with CH2Cl2 and washed with water, brine and dried over Na2SO4. The filtrate was concentrated to a thick oil and the oil was dissolved in 40 mL of EtOH. Acetic acid (3 mL) and 0.8 g of 10% Pd/C were added to the solution and the resulting mixture was hydrogenated on a Parr apparatus for 3 h. The catalyst was filtered and washed with EtOAc and the combined filtrate was concentrated. The residue was partitioned between CH2Cl2 and water and 2N NaOH was added to this mixture until the aqueous layer was basic. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4 and the filtrate was concentrated to give 2.93 g (77%) of the title compound sufficiently pure for use in the next reaction.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][N:13]=[C:12]([CH2:23]OS(C)(=O)=O)[N:11]=1)=[O:9].C(Cl)Cl.[CH3:42][NH:43][CH3:44]>O>[F:34][C:33]([F:35])([F:36])[C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:14][N:13]=[C:12]([CH2:23][N:43]([CH3:44])[CH3:42])[N:11]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(COS(C)(=O)=O)ncc1-c1ccccc1Cl
Reactant: CNC
Solvent: ClCCl
Solvent: O
Product: CN(C)Cc1ncc(-c2ccccc2Cl)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of 0.62 g (1.07 mmol) methanesulfonic acid 4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-5-(2-chloro-phenyl)-pyrimidin-2-ylmethyl ester in 10 ml CH2Cl2 1.53 ml (8.52 mmol) of a 5.6 M solution of dimethylamine were added. The reaction mixture was stirred for 16 hrs. at RT and than poured into H2O and extracted three times with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 200:10:1) to give 0.40 g (70%) 5-(2-chloro-phenyl)-2-dimethylaminomethyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless oil, MS (ISP): 531.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[C:5]([N:7]1[CH2:21][CH2:20][C:10]2([NH:14][C:13](=[O:15])[C@H:12]([CH2:16][CH2:17][S:18][CH3:19])[NH:11]2)[CH2:9][CH2:8]1)=[O:6].O.C[Si]([Cl:33])(C)C>CC(CC)=O>[ClH:33].[CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[C:5]([N:7]1[CH2:21][CH2:20][C:10]2([NH:14][C:13](=[O:15])[C@H:12]([CH2:16][CH2:17][S:18][CH3:19])[NH:11]2)[CH2:9][CH2:8]1)=[O:6]
Reactant: C[Si](C)(C)Cl
Agent: COc1ccc(C(=O)N2CCC3(CC2)NC(=O)[C@H](CCSC)N3)c(OC)c1
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Reaction time: 8 h

Procedure:
8-(2,4-Dimethoxybenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one (300 mg, 0.8 mmol) was dissolved in ethyl methyl ketone (2 ml), treated with water (8 μL) and TMSCl (106 μL) and stirred overnight. The solid was filtered off and dried in vacuo. The product 8-(2,4-dimethoxybenzoyl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 320 mg (97%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[CH:22]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([C:18]#[N:19])=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:28]([NH:27][CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:29])[CH:8]=[N:7][CH:6]=3)[N:10]2[CH3:21])=[CH:15][CH:14]=1
Reactant: O=C=NC1CCCC1
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CNC(=O)NC3CCCC3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
2-(5-Aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e) and cyclopentyl isocyanate are processed according to the method described in Example 196 to give 1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-3-cyclopentyl-urea as a solid. 1H NMR (400 MHz, MeOD) δ ppm 1.31-1.54 (m, 2H), 1.56-1.68 (m, 2H), 1.68-1.78 (m, 2H), 1.86-2.13 (m, 2H), 3.83 (s, 3H), 3.94-4.09 (m, 1H), 4.52 (s, 2H), 7.38 (dd, J=8.3, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 8.08 (t, J=2.0 Hz, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 408.1591 [(M+H)+ Calcd for C22H23N5OCl: 408.1591].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([Li])CCC.[C:14](=[O:16])=[O:15].O>O1CCCC1>[F:8][C:4]1[N:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:14]([OH:16])=[O:15]
Reactant: Fc1cccc(F)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)nc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
To 2,6-difluoropyridine (58, 7.10 g, 0.0617 mol) in tetrahydrofuran (150.0 mL) under an atmosphere of nitrogen at −78° C., n-butyllithium (26.0 mL, 2.50 M in hexane) was added slowly. After 30 minutes, dry ice (3.0 g) was added to the reaction. After 1 hour, the reaction was allowed to warm to room temperature, then poured into water and extracted with ethyl acetate. The aqueous layer was acidified with 1 N HCl to pH =4-5 and extracted with ethyl acetate. The organic layer was dried over anyhydrous sodium sulfate, filtered and concentrated to give the crude compound as a light yellow solid (59, 5.6 g, 57.0%).
Reaction SMILES: [H-].[Na+].[CH:3]1([O:7][CH2:8][C@H:9]([OH:20])[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([C:31]3[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=3)[N:29]=[CH:30][C:23]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:3]1([O:7][CH2:8][C@H:9]([O:20][C:22]2[N:27]=[CH:26][N:25]=[C:24]3[N:28]([C:31]4[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=4)[N:29]=[CH:30][C:23]=23)[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1cnc(NC(=O)[C@@H](O)COC2CCC2)cn1
Reactant: Cc1ncccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2cccnc2C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.3 %

Procedure:
Sodium hydride (19.54 mg, 0.49 mmol) was added to (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R1) (102 mg, 0.41 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate V5) (100 mg, 0.41 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2×50 mL). The combined organics were washed with saturated brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 5% MeOH in DCM to afford the product (78 mg, 41.6%). 1H NMR (400 MHz, DMSO) δ 1.23-1.36 (m, 1H), 1.38-1.51 (m, 1H), 1.60-1.75 (m, 2H), 1.96-2.07 (m, 2H), 2.13 (s, 3H), 2.27 (s, 3H), 3.71-3.87 (m, 2H), 3.89-3.98 (m, 1H), 5.71-5.78 (m, 1H), 7.28-7.34 (m, 1H), 7.75 (d, 1H), 8.15 (s, 1H), 8.39 (s, 1H), 8.45-8.51 (m, 2H), 8.93 (s, 1H), 11.01 (s, 1H), m/z (ESI+) (M+H)+=461.48; HPLC tR=1.75 min