Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O>[Cl:8][C:6]1[CH:7]=[C:2]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C1CCNCC1
Solvent: O
Product: Clc1cc(N2CCCCC2)ncn1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
A mixture of 10.0 g (67.1 mmol) 4,6-dichloropyrimidine and 5.7 g (67.1 mmol) piperidine in 100 ml water is stirred at a bath temperature of 115° C. for 16 h. After cooling to RT, the precipitate is filtered off, washed with water and dried in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[C:4]([NH2:21])[N:3]=1.CO.[OH-].[Na+].Cl[CH2:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1>CN(C)C=O>[CH3:34][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:27][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:7]4[C:2]([NH2:1])=[N:3][C:4]([NH2:21])=[CH:5][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)[CH:33]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: Cc1ccnc(CCl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccnc(COc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
To 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (80 mg, 0.28 mmol) described in Manufacturing Example 18-1-1 were added methanol (4 mL) and 1 N aqueous sodium hydroxide solution (0.29 mL), which was then dissolved by irradiating ultrasonic wave. This solution was concentrated under a reduced pressure. To the resulting residue was added 2-chloromethyl-4-methyl-pyridine (50.9 mg, 0.36 mol.) described in Manufacturing Example 11-1-4 and N,N-dimethylformamide (3 mL), which was stirred for 10 minutes at 60° C. The reaction solution was partitioned into water and ethyl acetate. The organic layer was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2, then ethyl acetate) to obtain the title compound (40 mg, 36.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:31][CH2:32][CH3:33])=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:36][S:37]([CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:39])=[O:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][CH2:40][S:37]([CH3:36])(=[O:38])=[O:39])[CH2:47][CH2:46]3)=[O:21])[C:10]([C:23]3[C:24]([O:31][CH2:32][CH3:33])=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1nc(SC)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1nc(SC)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12) was reacted with 1-(2-methanesulfonylethyl)-piperazine dihydrochloride (example 3) to give cis-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C30H35N6O4S2Cl2 [(M+H)+] 677.1533, observed 677.1532.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH2:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH3:9]>CCOCC>[CH2:6]([NH:10][C:11]([NH:1][CH2:2][CH2:3][CH2:4][NH2:5])=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: NCCCN
Reactant: CCCCN=C=O
Solvent: CCOCC
Product: CCCCNC(=O)NCCCN

Procedure:
30 grams 1,3 diaminopropane in 30 mls ether was slowly (1 hour) reacted with 10 gms butyl isocyanate and refluxed for one-half hour. The precipitate was filtered and washed with ether and dried in vacuum oven, melting point 201°-202°C.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH2:4][CH:5]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[CH2:7][C:6]2=[CH2:13].[H][H]>C(O)(=O)C.C=C>[CH3:1][C:2]1[CH2:3][CH2:4][CH:5]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[CH2:7][CH:6]2[CH3:13]
Reactant: C=C1CC(=O)CCC2=C(C)CCC12
Reactant: [H][H]
Agent: C=C
Solvent: CC(=O)O
Product: CC1=C2CCC(=O)CC(C)C2CC1

Procedure:
528 mg of 1-methyl-4 -methylen-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene were hydrogenated in 20 ml of ethylene acetate with the aid of 200 mg of palladium-on-calcium carbonate (5%). After hydrogen uptake was completed the mixture was filtered off from the catalyst, the filtrate concentrated under reduced pressure and distilled. There was obtained pure 1,4-dimethyl-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene, b.p.0.06 60°; IR(film):νmax = 1700, 1450, 1378, 1250, 1190 cm-1. The compound was a woody, earthy, camphorous odour.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[N].[N+:13]([O-])([OH:15])=[O:14].C(OCC)(=O)C>S(=O)(=O)(O)O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1cccc(F)c1F
Agent: O=S(=O)(O)O
Agent: [N]
Solvent: CCOC(C)=O
Product: CC(=O)c1cc([N+](=O)[O-])cc(F)c1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 28 %

Procedure:
Under an inert atmosphere of nitrogen 1-(2,3-difluoro-phenyl)-ethanone (5.0 g (32 mmol) was added dropwise to sulphuric acid (95-97%, 20 ml), cooled to 0° C., at such a rate that the temperature was maintained below 5° C. Thereafter, the reaction mixture was cooled to −15° C. and a solution of nitric acid (3.22 ml, 46.4 mmol) in sulphuric acid (95-97%, 4.6 ml) was added dropwise at −15° C. After stirring at −10° C. for 45 minutes, the mixture was poured on ice. Ethyl acetate was added, then the organic layer separated, washed with water, dried over sodium sulphate, and evaporated at reduced pressure. Purification of the crude light yellow oil (5.64 g) by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 yielded the 1-(2,3-difluoro-5-nitro-phenyl)-ethanone (1.83 g, 28% of theory) as a light yellow oil together with a mixture of 1-(2,3-difluoro-5-nitro-phenyl)-ethanone and 1-(2,3-difluoro-6-nitro-phenyl)-ethanone.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.Cl.[NH2:15][OH:16]>CO>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[N:15]/[OH:16])=[CH:6][CH:5]=1
Reactant: NO
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CO
Product: O/N=C/c1ccc(OC(F)(F)F)cc1
Temperature: 65 °C
Yield: 92.6 %

Procedure:
A mixture of 4-(trifluoromethoxy)benzaldehyde (9.5 g, 50 mmol) and hydroxylamine hydrochloride (5.3 g, 75 mmol) in methanol (80 mL) was heated at 65° C. for 2 h. The volatiles were removed under reduced pressure and the residue was dissolved in EtOAc, and washed with H2O, brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The solid thus obtained was then recrystallized from EtOAc and petroleum ether to afford the title compound (9.5 g, 93%) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.52 (d, J=7.2 Hz, 2H), 7.15 (d, J=6.8 Hz, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:15]([OH:17])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]([CH2:22][CH3:23])[CH2:20]O>>[CH3:18][CH:19]([CH2:22][CH3:23])[CH2:20][O:16][C:15](=[O:17])[C@H:11]([CH:12]([CH3:13])[CH3:14])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: CCC(C)CO
Product: CCC(C)COC(=O)[C@@H](NC(=O)Cc1ccccc1)C(C)C

Procedure:
Following General Procedure C and using the N-(phenylacetyl)valine prepared in Step A above and 2-methylbutan-1-ol (Aldrich), the title compound was prepared as a diastereomeric mixture. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: C(O[C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)C.C(NC(C)C)(C)C.C([Li])CCC.[CH2:22]([SnH:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>C1COCC1.C(Cl)Cl>[CH2:31]([Sn:26]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:27][CH2:28][CH2:29][CH3:30])[C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCOC1=CC(=O)CC1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)C1=CC(=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
3-Ethoxy-cyclopent-2-enone (1.0 g, 7.9 mmol) was dissolved in THF (2 ml) and was placed in an addition funnel atop a flask equipped with stirring and a cooling bath. The flask was charged with THF (10 ml) and diisopropylamine (0.88 g, 8.7 mmol) and cooled to 0° C. To the solution was added n-butyllithium (1.9M, 4.6 ml) and the resulting solution stirred for five minutes. While still at 0° C., tributyltinhydride (2.35 ml, 8.7 mmol) was added to give a yellow solution, then after 15 minutes at 0° C., the solution was cooled to -70° C. At -70° C. the 3-ethoxy-cyclopent-2-enone was added dropwise, and after addition was complete, the reaction was stirred at -20° for one hour. The cooling bath was removed and the reaction quenched with NH4Cl solution and diluted with ether. The organic layer was separated, dried (MgSO4), filtered, and evaporated to give an oil. Chromatography on silica gel with CH2Cl2 gave the title compound (1.8 g).
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:54][CH2:55][CH2:56][CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62].CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[C:61]([O:60][C:59]([NH:58][CH2:57][CH2:56][CH2:55][O:54][N:5]1[CH2:4][C:3]2[C:7](=[C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)[CH:9]=[CH:10][CH:2]=2)[C:6]1=[O:34])=[O:65])([CH3:64])([CH3:63])[CH3:62]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCON1Cc2cccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c2C1=O
Yield: 87.6 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (60.0 mg, 0.130 mmol) was dissolved in THF (3.6 mL), and the solution was treated with triphenylphosphine (136 mg, 0.78 mmol), tert-butyl N-(3-hydroxypropyl)carbamate (92 mg, 0.52 mmol) and 40% DEAD-toluene solution (0.236 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-[(3-(tert-butoxycarbonylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (70.5 mg, yield 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH2:28]C)=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:30]#[N:31])[CH:5]=[CH:6][C:7]=1[F:8].[NH:32]1[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]1.[C:38](=[O:41])(O)[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH2:22][CH:23]([N:9]4[CH2:4][CH2:3][CH:38]([OH:41])[CH2:10]4)[CH2:24][N:32]4[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:30]#[N:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O[C@@H]1CCNC1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)CC(CN1CCC(O)C1)N1CCC(O)C1
Reaction time: 4 h

Procedure:
N-[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-7-ethoxy-6-quinolinyl)-4-bromo-2-butenamide (150 mg, 0.3 mmol) in 0.7 mL of DMF was reacted with (R)-(+)-3-pyrrolidinol (0.2 mL, 2.4 mmol) at room temperature. After reacting for 4 hours, the reaction solution was added into saturated sodium bicarbonate solution. The resulting precipitate was filtered and washed with water and ether consecutively to give 150 mg of the title compound as a light brown solid, mp 139-143° C.; MS (ES) m/z calcd. 583.2236, found 583.2242 (M+1).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:16][CH:10]([CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:1]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17](=[O:25])[N:2]=2)[N:8]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)Cc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)Cc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 69.8 %

Procedure:
Ethyl 3-(6-cyano-2-pyridyl)-2-methylpropionate (0.79 g, 3.6 mmol) and methyl thiosalicylate (1.2 g, 7.3 mmol) were dissolved in toluene (3 ml), and triethylamine (0.76 ml, 5.4 mmol) was added thereto. The reaction mixture was refluxed for 21 hrs and subjected to a silica gel (70 g) column chromatography. The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected and concentrated to give the titled compound (0.89 g, 70%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=2)[CH2:14][CH2:13]1)=[O:10].[CH3:25][S-:26].[Na+]>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([S:26][CH3:25])[N:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: C[S-]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ccnc(Cl)n3)CC2)c(Cl)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nccc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Temperature: 90 °C
Yield: 96.9 %

Procedure:
3,4-Dichloro-N-[1-(2-chloropyrimidin-4-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 307, 200 mg, 0.515 mmol) and sodium thiomethoxide (108.2 mg, 1.545 mmol) were combined in DMF (12 ml) and heated at 90° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and water. The phases were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic portions were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a peach coloured solid (200 mg, 0.499 mmol, 97% yield) that was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.71 g) and N,N-dimethylformamide (30 mL) was added 60% sodium hydride (0.12 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (1.38 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=[C:5]2[N:4]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:3]1=[O:24].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:33]1([C:30]2[CH:31]=[CH:32][C:27]([CH2:26][N:10]3[C:9]([S:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[C:6]4[C:5]([N:4]([CH2:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:3](=[O:24])[N:2]([CH3:1])[C:7]4=[O:8])=[N:11]3)=[CH:28][CH:29]=2)[CH:37]=[N:36][CH:35]=[N:34]1
Reactant: BrCc1ccc(-n2cncn2)cc1
Reactant: Cn1c(=O)c2c(Sc3ccccc3)[nH]nc2n(CC(C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(Sc3ccccc3)n(Cc3ccc(-n4cncn4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 5-methyl-7-neopentyl-3-(phenylthio)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (40 mg, 0.12 mmol), 1-(4-(bromomethyl)phenyl)-1H-1,2,4-triazole (28 mg, 0.12 mmol) and K2CO3 (16 mg, 0.12 mmol) are suspended in 5 mL of anhydrous DMF. The reaction mixture is stirred at room temperature overnight, and then evaporated to dryness under reduced pressure. The residue is purified by silica gel column chromatography to give pure product as white solids. MS (ESI) m/z 502.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[N:8]=[N:9][N:10]([CH3:12])[N:11]=2)=[CH:4][CH:3]=1.FC1C=CC(CC2N(C)N=NN=2)=CC=1.[Li]CCCC.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[O:41])[CH:35]=1>CCOCC.O1CCCC1>[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]([C:7]2[N:8]=[N:9][N:10]([CH3:12])[N:11]=2)[C:40]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)([C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)[OH:41])=[CH:4][CH:3]=1
Reactant: O=C(c1cccnc1)c1cccnc1
Reactant: Cn1nnc(Cc2ccc(F)cc2)n1
Agent: Cn1nnnc1Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cn1nnc(C(c2ccc(F)cc2)C(O)(c2cccnc2)c2cccnc2)n1
Reaction time: 1 h

Procedure:
To a 1:1 mixture of 5-(4-fluorobenzyl)-2-methyl-2H-tetrazole and 5-(4-fluorobenzyl)-1-methyl-1H-tetrazole, (0.209 g, 1.09 mmol) in 10 mL of 1:1 ether:tetrahydrofuran at −78° C. was added dropwise n-BuLi (0.434 mL of 2.5 M in hexane, 1.09 mmol). After stirring for one hour, a solution of dipyridin-3-ylmethanone (200 mg, 1.09 mmol) in 3 mL of tetrahydrofuran was added dropwise. Afterh 30 minutes, the reaction was quenched by transferring it via cannula to a −78° C. solution of 100 mL of ether containing 1 mL of concentrated aqueous HCl solution. After concentrating the mixture in vacuo, the resulting residue was taken up in EtOAc and extracted with 10% aqueous Na2CO3 solution and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by preparative reverse-phase HPLC to provide the titled compound, along with a regioisomer (Example VII-4). 1H NMR (500 MHz, d6-DMSO): δ 8.91 (br s, 1H), 8.66 (br s, 1H), 8.36 (d, J=4.4 Hz, 1H), 8.24 (d, J=4.4 Hz, 1H), 8.07 (br d, J=8.3 Hz, 1H), 7.82 (br d, J=8.0 Hz, 1H), 7.51 (dd, J =8.7 and 5.6 Hz, 2H), 7.29 (dd, J=8.3 and 4.9 Hz, 1H), 7.16 (dd, J=8.0 and 4.6 Hz, 1H), 6.95 (t, J=9.0 Hz, 2H), 6.16 (s, 1H), 6.05 (s, 1H), 4.23 (s, 3H). HRMS [M+H] C20H18FN6O calcd 377.1521 , found 377.1527.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[F:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=[N+]([O-])/C=C/c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (8.00 g, 33.6 mmol) in CH2Cl2 (140 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1-fluoro-4-((E)-2-nitro-vinyl)-benzene (5.12 g, 30.6 mmol) and trifluoroacetic acid (0.23 ml, 3.1 mmol) in CH2Cl2 (200 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:4) afforded 6.60 g (72%) of the title compound as a light yellow oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][OH:12].[C:13]([O:18]CC)(=[O:17])[C:14]([CH3:16])=O.B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:16][C:14]1([C:13]([OH:18])=[O:17])[C:1]2=[C:9]3[C:4]([CH:3]=[C:2]2[CH2:10][CH2:11][O:12]1)=[CH:5][CH:6]=[CH:7][CH2:8]3
Reactant: OCCC1=Cc2ccccc2C1
Reactant: CCOC(=O)C(C)=O
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1(C(=O)O)OCCC2=CC3=CC=CCC3=C21

Procedure:
Indene-2-ethanol (3.5 g) described in Examples 474 and 476, is treated with ethyl pyruvate (4 g) and boron trifluoride-etherate (2 ml) in benzene (50 ml) according to the procedure of Example 2 to yield the title compound, m.p. 171°-173° C., νmaxnujol 1720 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: Brc1ccccc1OC[C@H]1CCCN1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCC[C@@H]1COc1ccccc1Br
Yield: 38.6 %

Procedure:
(2R)-2-[(2-Bromophenoxy)methyl]pyrrolidine (1.84 g), potassium carbonate (1.09 g) and methyl iodide (0.49 ml) were stirred in dimethylformamide (10 ml) for 2 h at room temperature. The mixture was concentrated in vacuo and water added (50 ml). The mixture was extracted with diethyl ether (3×30 ml). The organic portions were combined and washed with water (2×20 ml), brine (2×20 ml) and dried (MgSO4) and concentrated in vacuo yielding the title compound as a pale orange oil (0.75 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[S:5][C:6]=1[C@H:7]([O:10]C(=O)[C@H](OC)C1C=CC=CC=1)[CH2:8][CH3:9].[OH-].[Na+].Cl>O1CCCC1.C(O)C.O>[CH3:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)[S:5][C:6]=1[C@H:7]([OH:10])[CH2:8][CH3:9]
Reactant: CC[C@@H](OC(=O)[C@H](OC)c1ccccc1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
To a solution of 3.74 g of (−)-(R)-methoxy-phenyl-acetic acid (R)-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propyl ester in 19 mL of tetrahydrofuran and 19 mL of ethanol at 0° C. was dropwise added 24.5 mL of a molar solution of sodium hydroxide in 20.4 mL of water. The resulting mixture was stirred at 0° C. for 15 minutes then 24.5 mL of a 5N solution of hydrochloric acid in 20.4 mL of water was added. After removal of the organic solvents under vacuum, the mixture was extracted with ethyl acetate, filtered through a silicone treated paper filter and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane 90/ethyl acetate 10) to give 2.09 g of (+)-(R)-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol.