Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH:37](=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:37]([NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:4]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCc4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 57.7 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (110 mg, 0.22 mmol) was dissolved (using gentle heating) in dry tetrahydrofuran (15 ml). The stirred solution was then cooled to room temperature and treated with a solution of benzaldehyde (21 mg, 0.20 mmol) in dry tetrahydrofuran (2 ml) followed by addition of sodium triacetoxyborohydride (70 mg, 0.33 mmol). The resultant mixture was stirred at room temperature for 24 hr, diluted with ethyl acetate and then washed sequentially with saturated aqueous sodium hydrogen carbonate and brine. The organic solution was then dried with anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (92:8) to afford the title compound as a solid (67 mg). MS: 581 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](=[O:14])(=[O:13])[NH2:12])[C:7](=[O:15])[CH:6]([CH3:16])[CH2:5]2.[Br:17]Br>C(O)(=O)C>[Br:17][C:6]1([CH3:16])[CH2:5][C:4]2[C:8](=[CH:9][C:10]([S:11](=[O:13])(=[O:14])[NH2:12])=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:15]
Reactant: BrBr
Reactant: CC1Cc2cc(Cl)c(S(N)(=O)=O)cc2C1=O
Solvent: CC(=O)O
Product: CC1(Br)Cc2cc(Cl)c(S(N)(=O)=O)cc2C1=O

Procedure:
According to Example 1 (e), 9.7 g (0.037 mole) of 5-chloro-2-methyl-6-sulfamoyl-1-indanone and 5.97 g (0.037 mole) of bromine in a total of 95 ml of glacial acetic acid yield 2-bromo-5-chloro-2-methyl-6-sulfamoyl-1-indanone, which melts at a temperature of from 136° to 138° C. after reprecipitation from a mixture of ethyl acetate and petroleum ether.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([C:20]=2Cl)=[CH:18][CH:17]=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=3)=[O:10])[CH2:4][CH2:3]1>[Pd].O1CCCC1.ClCCl>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[C:16]([C:22]([F:25])([F:23])[F:24])[CH:15]=3)=[O:10])[CH2:6][CH2:7]1
Reactant: C[C@H]1CC[C@H](NC(=O)c2cnc3cc(C(F)(F)F)ccc3c2Cl)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](NC(=O)c2cnc3cc(C(F)(F)F)ccc3c2)CC1
Reaction time: 0.17 h

Procedure:
The amide (253 mg, 0.68 mmol) in 3:1 tetrahydrofuran-dichloromethane (75 mL) containing 10% Pd on carbon (150 mg) was hydrogenated at 40 p.s.i. H2 for 10 min (ambient temperature). Filtration of the reaction mixture and chromatography through a Biotage silica cartridge (8×4 cm i.d.) using a gradient of hexane to 20% ethyl acetate (in hexane) afforded 40 mg (12%) of 431:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2cnc3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,6-dichloro-9H-purine (16 mmol) is dissolved in DMF (50 mL) and potassium carbonate (50 mmol) is added. α-Bromo-p-tolunitrile (22 mmol) is then added and the mixture is stirred at ambient temperature for 16 hours. After filtration to remove insoluble inorganic salts, the filtrate is poured into water (1500 mL) and extracted with ethyl acetate (2×400 mL), dried over magnesium sulfate and evaporated to yield a residue which is subjected to flash silica gel chromatography using 1:2:10 ethyl acetate/acetone/hexanes. Yield 3.33 g (69%). UV, NMR and MS were consistent with structure assignment.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncn2)c1
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3ccncn3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from 4,5-dichlorophenylenediamine (89 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K43) (164 mg, 0.55 mmol) by refluxing in xylene according to the general procedure M. Obtained as a light yellow solid (63 mg).
Reaction SMILES: C[Si](C)(C)CCO[CH2:6][N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([O:29][CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[C:9]=1Br.[CH2:54]([Sn](CCCC)(CCCC)/C=C\OCC)CCC>O1CCOCC1.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>[C:23]1([C:20]2[N:19]=[CH:18][C:17]([C:16]3[CH:15]=[N:14][N:13]4[C:8]5[NH:7][CH:6]=[CH:54][C:9]=5[C:10]([O:29][CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[N:11][C:12]=34)=[CH:22][CH:21]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: c1ccc(-c2ccc(-c3cnn4c3nc(OC3CCNCC3)c3cc[nH]c34)cn2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A degassed mixture of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)piperidine-1-carboxylate (Int-11c, 0.26 mmol, 216 mg), Pd(PPh3)4 (30 mg, 0.026 mmoL), (Z)-tributyl(2-ethoxyvinyl)stannane (142 mg, 0.39 mmoL) in Dioxane (6 mL) was heated at 100° C. overnight. The reaction mixture was cooled to room temperature, filtered through 9:1 SiO2:KF plug and concentrated in vacuo. The crude (Z)-ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(2-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (Int-11d) was treated with 50% TFA in H2O (6 mL) and stirred overnight. The reaction mixture was concentrated in vacuo. Purification with prep-LC provided 3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yloxy)-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (Int-11e): LCMS tR=2.71 Min (10 min run, UV254nm). Mass calculated for, M+410.1, observed m/z 411.1 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([CH:46]2[CH2:48][CH2:47]2)[C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[CH2:9]1)=O)(C)(C)C.C(OC(N1C[C@@H](CN(C(C)C)C(=O)C2C=CC(OC)=C(OCCCOC)C=2)[C@H](CNC2CC2)C1)=O)(C)(C)C.C(N(CC)CC)C.C(N=C=O)C1C=CC=CC=1>C1COCC1.O>[CH2:39]([NH:38][C:36](=[O:37])[N:35]([CH2:34][C@@H:10]1[CH2:9][NH:8][CH2:12][C@H:11]1[CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)[CH:46]1[CH2:47][CH2:48]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)NCc2ccccc2)C2CC2)C(C)C)ccc1OC
Agent: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1OC
Agent: O=C=NCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CN(C(=O)NCc2ccccc2)C2CC2)C(C)C)ccc1OC

Procedure:
(3R*,4R*)-3-(3-Benzyl-1-cyclopropyl-ureidomethyl)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl Ester To a solution of ((3R*,4R*)-3-cyclopropylaminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (235 mg, 0.440 mmol) in THF (6 mL) is added triethylamine (123 μL, 0.880 mmol) followed by benzylisocyanate (54 μL, 0.440 mmol). The mixture is stirred at RT for 2 h before water is added. Extraction with ethyl acetate, drying of the combined extracts (Na2SO4), filtration and evaporation of the solvent affords the crude product which is purified by flash chromatography on silica gel (eluent gradient: CH2Cl2 100% to CH2Cl2/MeOH 9:1) to give the title compound. MS (LC-MS): 667.1M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 6.26 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=2)[C:33]([O:35][CH3:36])=[O:34])O1.C([O-])([O-])=O.[Na+].[Na+]>O.O1CCOCC1.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>[F:19][C:18]([F:21])([F:20])[C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=3)[C:33]([O:35][CH3:36])=[O:34])[N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cccc(Nc2nc(Cl)nc3scnc23)c1
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
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: C1COCCO1
Product: COC(=O)c1cccc(-c2nc(Nc3cccc(C(F)(F)F)c3)c3ncsc3n2)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a stirred solution of 5-chloro-N-(3-(trifluoromethyl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (330 mg, 1 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (314 mg, 1.2 mmol) and Na2CO3 (498 mg, 4.7 mmol) in 2 mL of water and 20 mL of dioxane was added Pd(PPh3)4 (93 mg, 0.075 mmol) in one portion at room temperature under nitrogen. Then the mixture was stirred at 95° C. for 16 hours under nitrogen. The solvent was evaporated at 40° C. at reduced pressure and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1)) to give methyl 3-(7-(3-(trifluoromethyl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (365 mg, 84.8%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.18 (s, 1H), 8.93 (s, 1H), 8.74 (d, 1H, J=7.8 Hz), 8.61 (s, 1H), 8.21 (brs, 2H), 7.94 (d, 1H, J=7.8 Hz), 7.65-7.60 (m, 2H), 7.48-7.46 (m, 1H), 4.01 (s, 3H). LC-MS: 431 [M+H]+, 429 [M−H]−, tR=1.92 min. HPLC: 95.92% at 214 nm, 97.01% at 254 nm, tR=5.14 min.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][NH:5][C:6](=[O:9])[O:7][CH3:8].[CH2:10](Br)[C:11]#[CH:12].O>O1CCCC1>[CH3:3][O:4][N:5]([CH2:12][C:11]#[CH:10])[C:6](=[O:9])[O:7][CH3:8]
Reactant: C#CCBr
Reactant: CONC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCN(OC)C(=O)OC
Yield: 58.7 %

Procedure:
0.43 g of sodium hydride (60% in oil) was suspended in 10 ml of tetrahydrofuran, and 1.0 g of methyl N-methoxycarbamate and 1.36 g of propargyl bromide were added to the suspension in this order while being cooled with ice. The mixture was heat-refluxed for 4 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated and purified by silica gel column chromatography to obtain 0.8 g of methyl N-methoxy-N-propargylcarbamate.
Reaction SMILES: [CH:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([NH:13][C:14]2[C:18]3[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=2)=[O:28])=[O:12])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:23]([C:20]1[CH:21]=[CH:22][C:17]2[O:16][C:15]([C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=3)=[O:28])=[C:14]([NH:13][C:11]([C@H:8]3[CH2:9][CH2:10][C@H:5]([NH:4][CH:1]([CH3:2])[CH3:3])[CH2:6][CH2:7]3)=[O:12])[C:18]=2[CH:19]=1)([OH:25])=[O:24]
Reactant: COC(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](NC(C)C)CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)O)cc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trans-3-[4-(isopropylamino)cyclohexylcarbonylamino]-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (690 mg) obtained in Example 311 is suspended in tetrahydrofuran/methanol (1:1, 10 ml), and under ice-cooling, thereto is added 4N aqueous sodium hydroxide solution (3 ml). The mixture is warmed to room temperature, and stirred for 18 hours. The reaction solution is concentrated under reduced pressure, and poured into ice-water. The mixture is neutralized with 10% hydrochloric acid, and the precipitates are collected by filtration, washed successively with water, tetrahydrofuran, and diethyl ether, and dried to give the title compound (702 mg).
Reaction SMILES: [C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH:7]([C:17]1[C:18]([CH3:40])=[N:19][O:20][C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3([C:37]([OH:39])=O)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([S:50]([NH2:53])(=[O:52])=[O:51])=[CH:48][CH:49]=1>>[C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH:7]([C:17]1[C:18]([CH3:40])=[N:19][O:20][C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]3([C:37]([NH:53][S:50]([C:47]4[CH:48]=[CH:49][C:44]([CH3:43])=[CH:45][CH:46]=4)(=[O:51])=[O:52])=[O:39])[CH2:36][CH2:35]3)=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Product: Cc1ccc(S(=O)(=O)NC(=O)C2(c3ccc(-c4ccc(-c5onc(C)c5C(CCCc5ccccc5)O[Si](C)(C)C(C)(C)C)cc4)cc3)CC2)cc1

Procedure:
Prepared according to the procedure described in Example 106, Step 4, using 1-(4′-{4-[1-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid and p-toluenesulfonamide.
Reaction SMILES: [CH3:1][C:2]1([C:8]#[N:9])[CH2:6][CH2:5][CH2:4][C:3]1=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:16].[Na+]>CO>[NH2:16][CH:3]1[CH2:4][CH2:5][CH2:6][C:2]1([CH3:1])[C:8]#[N:9]
Reactant: [BH3-]C#N
Reactant: CC1(C#N)CCCC1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1(C#N)CCCC1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 177.7 %

Procedure:
A mixture of 1-methyl-2-oxocyclopentanecarbonitrile (272 mg, 2.209 mmol, from Step 1) and ammonium acetate (917 mg, 11.90 mmol) in methanol (2 mL) was stirred at room temperature for 2 h. Sodium cyanoborohydride (69.4 mg, 1.104 mmol) was added. After 17 h at room temperature, the mixture was concentrated. The residue was dissolved in water and ethyl acetate and stirred vigorously. The ethyl acetate phase was separated, dried (MgSO4), filtered and concentrated to give crude 2-amino-1-methylcyclopentanecarbonitrile (0.2436 g), which was taken to the next reaction without purification.
Reaction SMILES: [CH3:1][CH:2]([C:8]([CH3:13])([CH3:12])[CH:9]=[CH:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:14]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:11][CH:10]=[CH:9][C:8]([CH3:13])([CH3:12])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC=CC(C)(C)C(C)C(=O)OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)C(C)(C)C=CCBr
Yield: 86.6 %

Procedure:
A mixture of 920 mg (5 mmoles) of ethyl 2,3,3-trimethyl-4-hexenoate, 10 ml of carbon tetrachloride, 107 mg (6 mmoles) of N-bromosuccinimide, and 50 mg of benzoyl peroxide was heated under reflux for about two hours. The insoluble succinimide was removed by filtration. The filtrate was washed successively with saturated aqueous sodium bicarbonate solution and water, then dried over magnesium sulfate. The dried solution was distilled to give 1.14 g (86% yield) of ethyl 6-bromo-2,3,3-trimethyl-4-hexenoate, b.p. 80°-81°/0.8 mm.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]([CH3:16])[CH:9]=[C:10]([CH2:11][C:12]([O:14]C)=[O:13])[C:6]=2[C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19].Cl>>[CH3:1][N:2]1[C:7]2[N:8]([CH3:16])[CH:9]=[C:10]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[C:5](=[O:17])[N:4]([CH3:18])[C:3]1=[O:19]
Reactant: COC(=O)Cc1cn(C)c2c1c(=O)n(C)c(=O)n2C
Agent: Cl
Product: Cn1c(=O)c2c(CC(=O)O)cn(C)c2n(C)c1=O

Procedure:
A mixture of Step 4 intermediate (130 mg, 0.491 mmol) and concentrated hydrochloric acid (4 mL) was heated at 60° C. for 2 h. The excess of hydrochloric acid was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography using 5% methanol in chloroform to obtain 94 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 3.21 (s, 3H), 3.65-3.72 (m, 8H), 6.29 (s, 1H), 12.62 (br s, 1H); APCI-MS (m/z) 252.38 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=1)#[N:13].Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][C:16]=2[C:27]([F:28])([F:29])[F:30])=[N:22]1)=[O:11])[CH3:8]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2ccc(C#N)cc2C(F)(F)F)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ccc(C#N)cc2C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
Potassium carbonate (0.23 g, 1.7 mmol) and ethyl isocyanate (0.11 g, 1.5 mmol) were added to a solution of 3-(4-cyano-2-trifluoromethylphenyloxy)-5-methylpyrazole (0.40 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a yellowish solid of N-ethyl-3-(4-cyano-2-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.35 g, yield: 69.0%). mp: 103-105° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.23 (t, J=7.3 Hz, 3H), 2.63 (d, J=0.7 Hz, 3H), 3.39 (dq, J=5.9 and 7.2 Hz, 2H), 5.85 (q, J=0.7 Hz, 1H), 6.80-7.00 (m, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.81 (dd, J=1.8 and 8.7 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:23]([O:25][CH3:26])=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.[CH3:27][O-:28].[Na+].CO>[Cu]I.CN(C)C=O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[N:11]1[C:8]2=[N:9][C:10]3[C:6](=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:4]=[CH:3][C:2]=3[O:28][CH3:27])[N:7]2[CH2:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc(Br)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: C[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(OC)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 30.5 %

Procedure:
A mixture of methyl 9-bromo-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (200 mg, 0.439 mmol), sodium methoxide (237 mg, 4.39 mmol), copper(I) iodide (100 mg, 0.525 mmol), methanol (1.8 mL) and N,N-dimethylformamide (2.6 mL) was stirred at 100° C. for 4 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (54.4 mg, 0.134 mmol, 31%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[Br:18][C:19](Br)([Br:23])C([O-])=O.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCCl>[Br:18][C:19]1([Br:23])[C:2]2([CH2:3][C@@H:4]([C:14]([O:16][CH3:17])=[O:15])[N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])[CH2:6]2)[CH2:1]1
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])C(Br)(Br)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)[C@@H]1CC2(CN1C(=O)OC(C)(C)C)CC2(Br)Br
Temperature: 70 °C
Yield: 88.4 %

Procedure:
To a mixture of (S)-1-tert-butyl 2-methyl 4-methylenepyrrolidine-1,2-dicarboxylate (6 g, 24.9 mmol) and tetrabutylammonium bromide (161 mg, 0.02 eq) in anhydrous 1,2-dichloroethane (60 mL, 10 volumes) was added sodium tribromoacetate (17.48 g, 2.2 eq). The mixture was degassed and filled with N2 gas. It was heated at 70° C. for 2.5 hrs before additional sodium tribromoacetate (2.4 g, 0.3 eq) was added. The mixture was heated at 70° C. for 40 min. After the completion of the reaction, it was allowed to cool to room temperature and evaporated. The residue was diluted with 30% hexanes in tert-butyl methyl ether (100 mL) and filtered through a pad of celite. The filtrate was washed with water and brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was passed through a silica gel (5.5 wt. volumes) pad with 0-15% tert-butyl methyl ether in hexanes and concentrated to afford the title compound (9.09 g, 88%) as a yellow oil as a mixture of two regioisomers. 1H NMR (500 MHz, CDCl3): 4.63-4.44 (m, 1H), 3.92-3.86 (m, 1H), 3.79 and 3.74 (2 s, 3H), 3.53-3.42 (m, 1H), 2.83-2.35 (m, 1.5H), 1.91-1.70 (m, 2.5H), 1.48 and 1.43 (2 s, 9H). ESI MS m/z (M+H)+ 413.85.