Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39]2[CH:49]=[CH:48][C:42]([O:43][CH2:44][C:45](O)=[O:46])=[CH:41][CH:40]=2)[S:33]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:43][CH2:44][C:45]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([CH2:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:46])=[CH:48][CH:49]=2)[S:33]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Cc3ccccc3)cc2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Cc3ccccc3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 90.4 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-benzylphenoxy)phenyl]-N-methylcarbamate (0.61 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.51 g), diethyl cyanophosphonate (0.29 g), triethylamine (0.18 g) and anhydrous tetrahydrofuran (10 ml) and the reaction mixture was purified to give the desired product (0.91 g).
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[CH:3]1.[C:12]1(=[O:22])[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>C(Cl)(Cl)Cl>[CH3:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([NH:1][C:12]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:22])[CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1cn(N)c2ccccc12
Solvent: ClC(Cl)Cl
Product: Cc1cn(NC(=O)c2ccccc2C(=O)O)c2ccccc12
Temperature: 25 °C
Yield: 105.6 %

Procedure:
A suspension of 2.0 g of N-amino-3-methylindole, 140 ml of dry chloroform and 2.74 g of phthalic anhydride was stirred at reflux for 4 hours. The suspension was allowed to cool to room temperature, concentrated to approximately 50 ml, filtered and the residue washed with chloroform to provide 4.25 g of a white solid. Recrystallization from ethyl acetate provided 3.18 g (79.0%) of 2-[[(3-methyl(indol-1-yl)amino]carbonyl]benzoic acid, m.p. 191°-193° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1>C(OCC)C>[Cl:13][C:12]1[C:7]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Clc1cccnc1Br
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2ncccc2Cl)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 49 %

Procedure:
To a −60° C. solution of n-butyl lithium (23 mL, 2.5M in hexane, 58.2 mmol) in diethyl ether (40 mL) was added a solution of 2-bromo-3-chloropyridine (Alfa, 8.0 g, 41.6 mmol) in diethyl ether (60 mL) over 15 minutes. The reaction mixture was stirred for 40 minutes followed by a slow addition (about 15 minutes) of a solution of 1,4-dioxaspiro[4.5]decan-8-one (Aldrich, 8.44 g, 54.0 mmol) in diethyl ether (100 mL), and stirred until reaction mixture warmed up to ambient temperature (about 3 hours). The mixture was quenched with saturated NH4Cl, diluted with ethyl acetate and washed with water. The organic layer was separated, concentrated and the residue crystallized from ethyl acetate-hexanes to obtain 5.5 g of the title compound. Two more crystallizations of the mother liquors yielded 1.61 g more material. Total yield 7.13 g (64%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.59 (d, J=12.69 Hz, 2H), 1.80 (d, J=12.69 Hz, 2H), 1.94 (td, J=12.69, 4.36 Hz, 2H), 2.30-2.41 (m, 2H), 3.88 (s, 4H), 5.36 (s, 1H), 7.36 (dd, J=7.93, 4.76 Hz, 1H), 7.88 (dd, J=7.93, 1.59 Hz, 1H), 8.48 (dd, J=4.76, 1.59 Hz, 1H). MS (DCI) m/z 270.10 (M+H)+.
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[C:38]2[NH:43][C:42](=[O:44])[C:41]([CH2:45][CH2:46][C:47]([NH2:49])=[O:48])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]2CC2C=CC(OC)=CC=2OC)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>FC(F)(F)C(O)=O>[C:9]([C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[C:38]2[NH:43][C:42](=[O:44])[C:41]([CH2:45][CH2:46][C:47]([NH2:49])=[O:48])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[NH:22]2)=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(N)=O)c(=O)[nH]2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)(C)c1ccc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(CCC(N)=O)c(=O)[nH]2)cc1
Temperature: 80 °C
Reaction time: 19 h
Yield: 23.2 %

Procedure:
Anisole (0.3 mL) was added to a solution of 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-oxo-1,2-dihydropyridin-3-yl)propanamide (82.6 mg) in trifluoroacetic acid (0.6 mL), and the mixture was stirred at 80° C. for 19 hours. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give the title compound as a colorless oil (14 mg).
Reaction SMILES: [Na].Br[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].C(OCC)C.[Cl-].[Na+].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:3]([CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22])[CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: C=CCCCC(C(=O)OCC)C(=O)OCC
Reaction time: 2 h
Yield: 47.5 %

Procedure:
7.05 g of sodium were dissolved in a solution of 49 g of diethyl malonate in 175 ml of ethanol. The still warm solution (50° C.) was treated dropwise within 15 minutes with 45.6 g of 5-bromo-1-pentene and the mixture was heated to boiling for 2 hours. After cooling the reaction mixture was poured into 500 ml of diethyl ether and 300 ml of semi-saturated sodium chloride solution. The aqueous phase was separated and back-extracted twice with 200 ml of diethyl ether each time. The organic phases were washed twice with 150 ml of semi-saturated sodium chloride solution each time, dried over sodium sulphate, filtered and concentrated. Chromatographic separation of the resulting, yellow liquid (55.2 g) on silica gel with hexane/ethyl acetate (vol. 95:5) gave 33.2 g of diethyl (4-pentenyl)-malonate as a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:25]([F:28])([F:27])[F:26])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O.[NH2:30][NH2:31].O1CCCC1>O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:14][C:15]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:16]=3[C:17]([NH:30][NH2:31])=[O:19])=[O:18])=[CH:11][C:10]([C:25]([F:26])([F:27])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)NN)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.40 g of 2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 0.09 ml of hydrazine monohydrate and 20 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.26 g of 1-(3-chloro-2-pyridinyl)-N-[2-(hydrazinocarbonyl)-6-methylphenyl]-3-trifluoromethyl-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].[C:8]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].Br[C:22]1[S:23][C:24](Br)=[CH:25][C:26]=1[Br:27]>O.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>[Br:27][C:26]1[CH:25]=[C:24]([C:15]2[CH:16]=[CH:17][C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:13][CH:14]=2)[S:23][C:22]=1[C:15]1[CH:16]=[CH:17][C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:13][CH:14]=1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Brc1cc(Br)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2cc(Br)c(-c3ccc(C(C)(C)C)cc3)s2)cc1
Yield: 88.3 %

Procedure:
Sodium carbonate monohydrate (58.0 g, 468 mmol) was dissolved in water (500 mL) and a solution of 4-(tert-butyl)-phenylboronic acid (40.0 g) and 2,3,5-tribromothiophene (30.0 g, 94 mmol) in THF (500 mL) was added, and deoxygenated by bubbling with argon. Pd(PPh3)4 (5.0 g, 4.30 mmol) was added and the mixture refluxed for 24 h. The mixture was cooled and the aqueous phase separated and extracted with EtOAc. Organic fractions were combined washed with water (500 mL) and dried over MgSO4. The solvent was evaporated and the crude product washed in MeOH, filtered and dried overnight to afford a light yellow, powdery solid (35.46 g, 89%).
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH2:6][CH:5]2[C:11]([O:13]C)=O)[CH:2]=[CH2:3].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(Cl)Cl>[CH2:15]([NH:22][C:11]([CH:5]1[CH2:6][CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: C=CCC12C=CC(CC1C(=O)OC)C2
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C=CCC12C=CC(CC1C(=O)NCc1ccccc1)C2

Procedure:
9.6 g of methyl allylbicyclo[2.2.1]hept-5-ene-2-carboxylate are mixed with 30 ml of benzylamine and 1 g of ammonium chloride, and the mixture is heated for 3 hours under reflux. After cooling, 100 ml of methylene chloride are added, and the reaction mixture is washed with 1N HCl, aqueous soda solution and saturated sodium chloride solution. The organic phase is dried and filtered, and the filtrate is concentrated, affording 3.8 g (73.4% of theory) of a red liquid resin. For the purpose of characterisation, a sample is distilled in a bomb tube. The distillate is a pale yellow oil; η25 =310 mPas.
Reaction SMILES: F[C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[I:8].O.[NH2:13][NH2:14]>C(O)CCC>[F:9][C:6]1[C:7]([I:8])=[C:2]2[NH:14][N:13]=[C:10]([NH2:11])[C:3]2=[N:4][CH:5]=1
Reactant: NN
Reactant: N#Cc1ncc(F)c(I)c1F
Solvent: CCCCO
Solvent: O
Product: Nc1n[nH]c2c(I)c(F)cnc12
Temperature: 105 °C
Yield: 28 %

Procedure:
3,5-Difluoro-4-iodopicolinonitrile (1.0 g) was combined with butan-1-ol (10 mL) and hydrazine hydrate (100%, 0.82 mL) was added. The reaction was heated at 105° C. and after 2 hours cooled to room temperature, filtered, the filter rinsed with water, and the filtrate was concentrated to give a residue. The residue was washed with water and filtered to give 6-fluoro-7-iodo-1H-pyrazolo[4,3-b]pyridin-3-amine (27) as a solid (290 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (s, 1H) 5.59 (s, 2H). MS [M+H] found 279.0
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[OH:13][C:14]1[CH:18]=[C:17]([N:19]2[C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:21]1[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[N:19]([C:17]2[S:16][C:15]([C:28]([O:30][CH3:31])=[O:29])=[C:14]([O:13][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=3)[CH:18]=2)[CH:20]=1
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1cccc(C(F)(F)F)c1

Procedure:
In a similar manner as described for example B11, 102.8 mg of 3-(trifluoromethyl)benzyl bromide, 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate, 59.7 mg of potassium carbonate in 3 ml anhydrous DMF yield the title compound.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-nitro thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[CH2:13]([O:15][C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH3:14]>C1(C)C=CC=CC=1>[C:7]1([C:5]2[CH:6]=[C:2]([NH:1][C:19]([NH:18][C:16](=[O:17])[O:15][CH2:13][CH3:14])=[S:20])[NH:3][N:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(=S)Nc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.3 %

Procedure:
To a cold (0° C.) solution of 3-amino-5-phenylpyrazole (10.0 g, 62.8 mmol) in toluene (100 mL) was added ethoxycarbonyl isothiocyanate (8.3 mL, 70 mmol) dropwise via a pressure equalizing funnel. Upon complete addition, the cold bath was removed and the resulting solution was stirred at room temperature for 15hours, at which time a heavy white precipitate had formed. The precipitate was collected by filtration and dried to give ethyl [(3-phenyl-1H-pyrazol-5-yl)amino]carbothioylcarbamate (11 g, 60%) as a white solid. 1H-NMR (DMSO-d6): δ 13.25 (s, 1H), 12.06 (s, 1H), 11.40 (s, 1H), 7.75 (d, 2H), 7.5–7.3 (m, 4H), 4.25 (q, 2H), 1.29 (t, 3H); MS m/z 291 (M+1).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH2:9][CH2:10]2
Reactant: [H][H]
Reactant: O=Cc1ccc2c(c1)CCN2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(c1)CCN2
Reaction time: 8 h
Yield: 80.4 %

Procedure:
Into a 200 mλ atmospheric pressure hydrogenation apparatus equipped with a thermometer and a stirrer, 2.0 g (0.0084 mol) of 1-benzyl-5-formylindoline, 0.4 g of 5% 5 Pd/C and 100 mλ of ethanol were charged, and while introducing hydrogen under atmospheric pressure, a reaction was carried out at from 60 to 70° C. for 8 hours, and when the absorption of hydrogen ceased, the reaction was terminated. After termination of the reaction, the lo palladium catalyst (5% Pd/C) was collected by filtration, and ethanol was distilled off under reduced pressure to obtain a slightly red liquid. The obtained liquid was subjected to vacuum distillation to obtain 0.9 g of 5-methylindoline having a boiling point of 93° C./4 mmHg. The yield was 80.4% (based on the 1-benzyl-5-formylindoline).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[CH3:12].C(N(CC)CC)C.[CH3:20][C:21]1[N:25]([CH2:26][C:27]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]3[S:36][CH:37]=[C:38]([C:40](Cl)=[O:41])[N:39]=3)[CH2:31][CH2:30]2)=[O:28])[N:24]=[C:23]([C:43]([F:46])([F:45])[F:44])[CH:22]=1>ClCCl>[CH3:12][CH:4]1[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]1[N:2]([CH3:1])[C:40]([C:38]1[N:39]=[C:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:27](=[O:28])[CH2:26][N:25]3[C:21]([CH3:20])=[CH:22][C:23]([C:43]([F:44])([F:45])[F:46])=[N:24]3)[CH2:34][CH2:33]2)[S:36][CH:37]=1)=[O:41]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Reactant: CNC1c2ccccc2CC1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)C3c4ccccc4CC3C)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.4 %

Procedure:
To a solution of 2,3-dihydro-N,2-dimethyl-1H-inden-1-amine (177 mg, 1.1 mmol) and triethylamine (0.22 mL, 1.6 mmol) in 5 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (421 mg, 1 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with 4 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo to give 215 mg of the title compound, the product of present invention as a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13](Br)[CH:14]=[CH2:15]>CO.[OH-].[K+]>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)[CH:14]=[CH2:13]
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCOc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
32.6 Grams of 3,4-dihydro-6-hydroxy-2(1H)-quinolinone was dissolved in 500 ml of methanol containing 12.6 g of potassium hydroxide. Under stirring this solution, 20 ml of allyl bromide was added thereto at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and further stirred at 60° C. for 4 hours. After the reaction, the reaction mixture was concentrated to a half volume under reduced pressure, then 500 ml of water was added and stirred vigorously, the crystals precipitated were collected by filtration. The crystals were washed with water and small amount of diethyl ether in this order, and dried. Recrystallized from ethanol, 28 g (68.9%) of 6-allyloxy-3,4-dihydro-2(1H)-quinolinone was obtained. Colorless needle-like crystals (recrystallized from ethanol)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: Cc1ccc(N)c(C(N)=O)c1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(C)cc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 8.8 mmol) and 2-amino-5-methylbenzamide (3.30 g, 22.0 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-5-methylbenzamide was isolated as white solid (3.30 g, 82% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (s, 3 H), 2.35 (s, 3 H), 6.64 (d, J=4.03 Hz, 1 H), 7.37 (dd, J=8.60, 1.65 Hz, 1 H), 7.46 (d, J=8.05 Hz, 2 H), 7.64 J=1.65 Hz, 1 H), 7.70 (s, 1 H), 7.71 (d, J=4.03 Hz, 1 H), 7.97 (dt, J=8.69, 1.97 Hz, 2 H), 8.19 (s, 1 H), 8.22 (d, J=8.42 Hz, 1 H), 12.02 (s, 1 H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=NC(C)=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[F:35][C:36]([F:46])([F:45])[C:37]1C=C(C=[CH:43][CH:44]=1)C=O>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:43][CH:44]=[C:37]([C:36]([F:46])([F:45])[F:35])[CH:9]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(Cc2cccc(C(F)(F)F)c2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 3-(trifluoromethyl)benzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.68-7.63 (m, 1H), 7.55-7.51 (m, 3H), 4.84-4.76 (m, 1H), 4.14-4.08 (m, 2H), 3.87-3.84 (m, 1H), 3.71-3.69 (m, 1H), 3.62-3.54 (m, 2H), 3.36 (t, J=8.3 Hz, 1H), 3.01 (m, 1H), 2.86 (m, 1H), 2.63-2.60 (m, 1H), 2.50-2.27 (m, 3H), 1.98-1.83 (m, 3H), 1.21 (d, J=6.6 Hz, 3H). MS: (M+H m/z 462.1).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:6]2)[CH2:3][CH2:2]1.C[O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:29][C:25]4[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=4)[C:22]([OH:31])=[O:21])[CH2:16][CH2:15]3)=[CH:6]2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=C(O)c1cccc(CN2CCC(c3cn(CC4CC4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in Example 157 (part D) starting with 1.5 g (6 mmol) of 1-cyclopropylmethyl-3-piperidin-4-yl-1H-indole, 1.8 g (7.8 mmol) of 3-bromomethyl-benzoic acid methyl ester, 1.2 g (9 mmol) of potassium carbonate and 0.9 g (4.5 mmol) of potassium iodide in 25 mL of iso-butylmethylketone. The crude mixture was purified by flash chromatography over silica gel affording 0.63 g (27% of yield) of the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C@@H:32]2[CH2:34][O:33]2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C@@H:32]([OH:33])[CH2:34][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:28][CH:27]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1

Procedure:
Compound 184 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=155-157° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06 (dd, J=1.2 and 8 Hz, 1H), 7.77 (dd, J=1.2 and 8 Hz, 1H), 7.67 (dt, J=1.2 and 8 Hz, 1H), 7.49 (dt, J=1.2 and 8 Hz, 1H), 7.31 (d, J=9.2 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.10-4.17 (m, 1H), 4.00 (dd, J=1.2 and 4.8 Hz, 2H), 2.99-2.95 (s, 3H), 2.74-2.86 (m, 2H), 2.64-2.7 (m, 2H), 2.51-2.6 (m, 1H), 2.13-2.2 (m, 2H), 1.84-1.98 (m, 2H), 1.3 (s, 9H); LCMS: 508 [M+H]; enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLC Rt=50.98 min.