Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C@H:7]1[N:14]([S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)(=[O:17])=[O:16])[CH2:13][C:12]2[CH:28]=[CH:29][CH:30]=[CH:31][C:11]=2[CH2:10][O:9][CH2:8]1)(=O)=O.CS(C)=O.C([O-])([O-])=O.[Cs+].[Cs+].[NH:42]1[CH:46]=[CH:45][CH:44]=[N:43]1>CC(=O)OCC>[N:42]1([CH2:6][C@H:7]2[N:14]([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:27]=3[N:26]=[CH:25][CH:24]=[CH:23]4)(=[O:16])=[O:17])[CH2:13][C:12]3[CH:28]=[CH:29][CH:30]=[CH:31][C:11]=3[CH2:10][O:9][CH2:8]2)[CH:46]=[CH:45][CH:44]=[N:43]1
Reactant: c1cn[nH]c1
Reactant: CS(=O)(=O)OC[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cccc2cccnc12)N1Cc2ccccc2COC[C@H]1Cn1cccn1
Temperature: 110 °C
Yield: 32.9 %

Procedure:
Compound 17a (100 mg, 0.21 mmol) was added to DMSO (1 mL) and Cs2CO3 (500 mg, 1.5 mmol). 1H-Pyrazole (70 mg, 1.0 mmol) was added in the mixture and sealed in a microwave tube. The mixture was heated to 110° C. for 30 min under microwave irradiation. The reaction mixture was poured into ice/water (50 mL) and extracted with EA (3×50 mL) and washed with brine (2×50 mL) and dried over anhydrous Na2SO4. The residue was purified by CC eluting with PE:EA=3:1 to give compound 17 as white solid (30 mg, 32% yield). 1H-NMR (400 MHz, CD3OD) δ: 8.73 (d, J=1.6 Hz, 1H), 8.33 (d, J=7.2 Hz, 1H), 8.20 (d, 1H), 7.97 (d, 1H), 7.52-7.50 (m, 2H), 7.40-7.38 (m, 2H), 6.80 (d, 1H), 6.70 (t, 1H), 6.14 (s, 1H), 5.10 (m, 1H), 4.92 (d, J=14.4 Hz, 1H), 4.80 (m, 2H), 4.43 (d, J=14.4 Hz, 1H), 4.35 (q, 1H), 4.22 (q, 1H), 3.76 (d, 1H), 3.66 (d, 1H). MS (ESI+) m/z: 435.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][S:11]([CH3:13])=[O:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH3:6])=[CH:4][CH:3]=1.[CH3:5][C:4]1[CH:3]=[CH:2][CH:9]=[CH:8][C:10]=1[S:11]([C:13]1[CH:2]=[CH:9][CH:8]=[CH:5][C:4]=1[CH3:3])=[O:12]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CS(C)=O
Product: Cc1ccc(Cl)cc1
Product: Cc1ccccc1S(=O)c1ccccc1C

Procedure:
The yield of p-chlorobenzaldehyde is 58%. Compared with the reaction with DMSO as sulphoxide, the yield is thus higher by a factor of 1.53. The difference between the ionisation potentials is only 0.1 eV in this case.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[CH2:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[N:28][CH:29]=1)[CH3:21].C(OC(C)C)(C)C>>[CH:30]([OH:32])=[O:31].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([CH2:23][O:22][CH2:20][CH3:21])=[CH:29][N:28]=3)[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: CCOCc1ccc(C(=O)O)nc1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Solvent: CC(C)OC(C)C
Product: CCOCc1ccc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)COCC3(F)F)c2)nc1
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A10A) and 5-ethoxymethyl-pyridine-2-carboxylic acid (which might be prepared in analogy to the isopropyl ether described by Robert M. et al., Int. Patent Application Publ. No. WO2005007658) yielded the title compound as a white solid. MS (ISP): m/z=437.2 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]([CH2:7][CH2:8][CH:9]=[CH2:10])CC(O)=O.F[B-](F)(F)F.[CH3:16][O+](C)C.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.Cl.[C:37]([O:40][CH2:41]C)(=[O:39])[CH3:38]>ClCCl>[CH3:41][O:40][C:37](=[O:39])[CH2:38][C@H:2]([O:1][CH3:16])[CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: CCOC(C)=O
Reactant: C=CCC[C@@H](O)CC(=O)O
Reactant: C[O+](C)C
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C=CCC[C@H](CC(=O)OC)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
A stirred solution of (R)-3-hydroxy-hept-6-enoic acid (J. C. S. Chem. Commun. 1983, 599-600, 0.4 g, 2.77 mmol) in anhydrous dichloromethane (20 mL) was treated with trimethyloxonium tetrafluoroborate (1.64 g, 11.08 mmol) and 1,8-bis(dimethylamino)naphthalene (3.56 g, 16.62 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere for 16 hours then treated with 2 M hydrochloric acid (30 mL) and ethyl acetate (50 mL). The mixture was filtered to remove an insoluble solid before separating the two layers. The aqueous layer was extracted with further ethyl acetate (30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to give a yellow gum which was purified by silica gel chromatography using iso-hexanes/ethyl acetate 17:3 to give the title compound (225 mg, 47%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ1.51-1.75 (m, 2H), 2.07-2.25 (m, 2H), 2.38-2.62 (m, 2H), 3.36 (s, 3H), 3.58-3.75 (m, 1H), 3.71 (s, 3H) 4.91-5.10 (m, 2H), 5.73-5.90 (m, 1H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:42]2[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:26](=[O:27])[N:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=2)[C:24]([CH3:38])=[N:23][C:22]=1[CH2:39][CH2:40][CH3:41]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[NH:3][C:4](=[O:7])[O:5][N:49]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:26](=[O:27])[N:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:36])[CH3:37])=[CH:30][CH:29]=2)[C:24]([CH3:38])=[N:23][C:22]=1[CH2:39][CH2:40][CH3:41]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.85 g), sodium hydrogen carbonate (1.2 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C. for 30 min, 3′-fluoro-4′-{[1-(4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.56 g) was added, and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (6 mL), N,N′-carbonyldiimidazole (0.30 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.51 g, 70%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13](CC2C=CC(OC)=CC=2)[C:14]2[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=2)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:37][C:38]1[CH:39]=[CH:40][C:41]([CH3:48])=[C:42]([NH:44][C:45](=[O:47])[CH3:46])[CH:43]=1.OP(O)(O)=O>O.CO>[C:45]([NH:44][C:42]1[CH:43]=[C:38]([NH:37][C:2]2[CH:3]=[C:4]([NH:13][C:14]3[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=3)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH:39]=[CH:40][C:41]=1[CH3:48])(=[O:47])[CH3:46]
Reactant: COc1ccc(CN(c2cccc(C(=O)NCCN(C)C)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Reactant: CC(=O)Nc1cc(N)ccc1C
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: CC(=O)Nc1cc(Nc2cc(Nc3cccc(C(=O)NCCN(C)C)c3)c3ncc(C#N)n3n2)ccc1C

Procedure:
Example 253 was prepared from 253D and N-(5-amino-2-methylphenyl) acetamide following the procedure as described in Example 6. HPLC: Rt=3.110 min. (YMC S5 ODS (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min., hold at 100% 1 min., flow rate 4 mL/min.). MS (ES): m/z=512.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.04 (1 H, br. s.), 9.52-9.58 (2 H, m), 9.21 (1 H, s), 8.94 (1 H, t, J=5.52 Hz), 8.18 (1 H, s), 7.87 (1 H, s), 7.59-7.63 (2 H, m), 7.44-7.54 (2 H, m), 7.06 (1 H, d, J=8.28 Hz), 6.81-6.85 (1 H, m), 3.59 (3 H, q, J=5.69 Hz), 3.24 (2 H, q, J=5.86 Hz), 2.73-2.84 (6 H, m), 2.08 (3 H, s), 1.98 (3 H, s).
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH3:28][C:29]([N:31](C)C)=[O:30]>>[CH2:1]([S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:28][C:29]([NH2:31])=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(=O)N(C)C
Reactant: CCCCCCCCCCCCCCCCCCS
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCCCCCCCCCCCCCCCCSCCCCCCCCCCC(N)=O
Temperature: 100 °C
Reaction time: 5 h

Procedure:
In a 300 ml flask equipped with a stirrer, a condenser and a calcium chloride dryer tube were charged 13.2 g of octadecanthiol, 14.3 g of 11-bromoundedanamide, 1.7 g of potassium iodide, 20.7 g of potassium carbonate and 100 ml of DMAc, and the mixture was stirred at 100° C. for 5 hours. After cooling the reaction mixture to room temperature, the reaction mixture was poured into ice-water and precipitated crystals were collected by filtration under reduced pressure, and washed with distilled water. The resulting crystals were recrystallized from IPA to obtain 16.4 g of the title compound. Melting point: 108° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][O:18][CH2:19][CH2:20][F:21])=[O:6])[CH:2]=[CH2:3].[C:22]([SH:25])(=[O:24])[CH3:23].[OH-].[Ca+2].[OH-]>CC(C)CC(=O)C>[C:22]([S:25][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][O:18][CH2:19][CH2:20][F:21])[CH2:9]1)(=[O:24])[CH3:23]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COCCF
Reactant: CC(=O)S
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1COCCF

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)-4-methanesulfonyloxypyrrolidine (17.30 g) and thioacetic S-acid (5.88 ml) in 4-methyl-2-pentanone (121 ml) was added calcium hydroxide (3.05 g) below 45° C. Solvent (40 ml) was removed under reduced pressure (50-60 mmHg), at 40°-45° C. The suspension was heated at 80°-85° C. for 5 hours. After cooling, water (30 ml) was added to the suspension. The insoluble material was filtered off and washed with ethyl acetate (50 ml). The filtrate and washing were collected. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (170 g) and eluted with a mixture of hexane and ethyl acetate (1:9-2:8) to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)pyrrolidine (13.80 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-])=O.O.Cl.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CCCC2
Yield: 86687.8 %

Procedure:
7-Nitrotetralone (20.0 g, 0.105 mmol) was dissolved in 400 ml of ethanol, and 40 ml of water, 10 ml of concentrated HCl, and 4.0 g of 10% palladium on carbon were added. The reaction mixture was reacted with hydrogen at 30-40 psi for 16 hours. Following hydrogenation, the reaction mixture was filtered and the solvents were evaporated, yielding white crystals. The crystals were washed with acetone, dissolved in cold 10% NaOH, and extracted with EtOAc (3 x). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated, to give 2-amino-5,6,7,8-tetrahydronaphthalene (13.4 g, 87.1% yield) as a brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.[C:12]([C:16]1[CH:29]=[CH:28][C:19]([CH2:20][N:21]2[CH2:25][CH2:24]OS2(=O)=O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][CH2:25][CH2:24][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=2)=[CH:28][CH:29]=1)([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)c1cc(Br)ccc1Cl
Reactant: CC(C)(C)c1ccc(CN2CCOS2(=O)=O)cc1
Product: CC(C)c1cc(CCNCc2ccc(C(C)(C)C)cc2)ccc1Cl
Yield: 42.2 %

Procedure:
The title compound was synthesized in analogy to example S6-C using 4-bromo-1-chloro-2-isopropylbenzene (120 mg, 0.51 mmol), and 3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine 2,2-dioxide (138 mg, 0.51 mmol). The residue was purified by flash column chromatography to give the desired product (74 mg, 42%) as a light yellow oil. MS (ISP) 344.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][CH:6]=1
Reactant: C1COCCN1
Reactant: O=Cc1cc(Br)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1csc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.3 %

Procedure:
To a solution of 4-bromothiophene-2-carbaldehyde 63 (Avocado, UK) (1.20 g, 6.3 mmol) in THF (50 mL) at rt was added dropwise morpholine (0.96 g, 11 mmol). After the reaction was stirred at rt for 5 minutes, NaBH(OAc)3 (3.18 g, 15 mmol) was added in one portion. The resulting mixture was stirred at rt for 3 h. Ethyl acetate (80 mL) was added and then washed with NaHCO3 (20 mL×2) and brine (20 mL). The organic layer was dried with MgSO4. After the solvent was evaporated, the residue was purified by silica gel column chromatography to give 64 (1.31 g). 1H NMR (400 MHz, CDCl3) 6, 2.50–2.52(m, 4H), 2.67 (s, 2H), 3.72–3.75 (m, 4H), 6.87(s, 1H), 7.15 (d, J=1.4 Hz, 1H). MS (EI) m/z (M+H+) 263.
Reaction SMILES: CI.[Mg].[CH2:4](OCC)C.[ClH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]2[N:16]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:15]3[CH2:27][N:28]([CH2:30][CH2:31][CH2:32][C:33](=[O:41])[C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[CH2:29][C:14]=3[C:13]=2[CH:12]=1>O.O1CCCC1>[ClH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]2[N:16]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:15]3[CH2:27][N:28]([CH2:30][CH2:31][CH2:32][C:33]([C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)([OH:41])[CH3:4])[CH2:29][C:14]=3[C:13]=2[CH:12]=1
Reactant: CCOCC
Reactant: O=C(CCCN1Cc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)C1)c1ccc(F)cc1
Agent: Cl
Agent: [Mg]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(CCCN1Cc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)C1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
A methyl Grignard reagent prepared from 852 mg. (6 m moles) of methyl iodide and 144 mg. (6 m mole) of magnesium in 40 ml. of diethyl ether is divided into equal portions. To one-half is added portionwise 500 mg. (1.1 m moles) of 7-fluoro-4-(p-fluorophenyl)-2-[3-(p-fluorobenzoyl)propyl]-1,2,3,4-tetrahydropyrrolo[3,4-b]indole hydrochloride in 20 ml. of tetrahydrofuran, and the mixture allowed to stir for 1 hour. To the mixture is then added the other half of the Grignard solution, and stirring maintained for 30 min. The mix is poured into ice and water and extracted with ether. The combined ether extracts are dried over magnesium sulfate, concentrated to dryness, and the residue chromatographed on 20 g. of silica gel using 3:1 diethyl ether-ethanol as the eluate, each collecting fractions being 3 ml. Fractions 10-27 are combined and converted to the hydrochloride salt, 180 mg.
Reaction SMILES: C(OC(=O)[N:7]([CH2:26][CH2:27][O:28][CH3:29])[C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)(C)(C)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][C:33]=1[C:41]([F:44])([F:43])[F:42]>>[ClH:31].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([N:12]3[CH:11]=[N:10][C:9]4[C:13]3=[N:14][CH:15]=[N:16][C:8]=4[NH:7][CH2:26][CH2:27][O:28][CH3:29])=[CH:22][CH:21]=2)=[O:40])=[CH:34][C:33]=1[C:41]([F:42])([F:43])[F:44]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COCCN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Product: COCCNc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Product: Cl

Procedure:
The title compound can be synthesized from (2-methoxyethyl)-[9-(4-nitrophenyl)-9H-purin-6-yl]carbamic acid tert-butyl ester and 4-chloro-3-(trifluoromethyl)phenyl isocyanate by the methods of Steps B and C of Example 1 and Example 30.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[H-].[Na+].[CH3:31][O:32][CH2:33][CH2:34]Cl>ClCCl.ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:34][CH2:33][O:32][CH3:31])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: COCCCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (2.03 g, 6.41 mmol) and dimethylformamide (50 mL). Cool in an ice-bath. Add sodium hydride (0.28 g, 60% n in oil, 7.0 mmol). After 20 minutes, add 2-chloroethyl methyl ether (0.7 mL, 7.66 mmol). Heat to 85° C. After 18 hours, cool to ambient temperature and dilute with dichloromethane, and extract with water, a saturated aqueous sodium bicarbonate solution, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol/concentrated ammonium hydroxide 95/5/0.05 to give 1-(t-butoxycarbonyl)-4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:30]([F:33])([F:32])[F:31])=[C:25]([CH:29]=1)[C:26](Cl)=[O:27]>C1COCC1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:30]([F:31])([F:32])[F:33])=[C:25]([CH:29]=1)[C:26](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:27]
Reactant: O=C(Cl)c1cc(Cl)ccc1C(F)(F)F
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cc(Cl)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To the product of Example 126A (0.20 g, 1.1 mmol) in 35 mL THF at 0° C. was added Et3N (0.37 mL, 2.7 mmol) followed by 5-chloro-2-trifluoromethyl-benzoyl chloride (Matrix, 0.26 g, 1.3 mmol) in 5 mL THF dropwise via syringe. This mixture was stirred at ambient temperature for 1 hour then was warmed to reflux and allowed to stir for 8 hours. The mixture was then cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified via flash column chromatography (SiO2, 4:1 hexanes:EtOAc) to provide the title compound (0.23 g, 0.57 mmol, 53% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.26 (s, 3H), 2.28 (s, 3H), 3.30 (s, 3H), 3.71 (t, J=4.9 Hz, 2H), 4.36 (t, J=4.9 Hz, 2H), 7.45 (ddd, J=8.5, 2.0, 0.7 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H); MS (DCI/NH3) m/z 393 (M+H)+; Anal. calculated for C16H16ClF3N2O2S: C, 48.92; H, 4.11; N, 7.13. Found: C, 48.66; H, 3.81; N, 7.01.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:18]=[CH:17][N:16]2[N:19]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:21]([C:22](=O)[C:23]#[CH:24])=[C:15]2[CH:14]=1.C(OCC)(=O)C>C(O)C>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:20]2[C:21]([C:22]3[CH:23]=[CH:24][N:4]=[C:3]([S:2][CH3:1])[N:5]=3)=[C:15]3[CH:14]=[C:13]([Cl:12])[CH:18]=[CH:17][N:16]3[N:19]=2)=[CH:31][CH:30]=1
Reactant: C#CC(=O)c1c(-c2ccc(OC)cc2)nn2ccc(Cl)cc12
Reactant: CSC(=N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(SC)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.4 %

Procedure:
The suspension of 2-methyl-2-thiopseudourea (358 mg, 1.29 mmol) and potassium carbonate (178 mg, 1.29 mmol) in ethanol was stirred at room temperature for 10 minutes. 1-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (200 mg, 0.64 mmol) was added. The suspension was stirred at room temperature for 12 hours. Ethyl acetate was added. The ethyl acetate phase was washed with water and brine and dried over magnesium sulfate. Filtration and concentration, followed by chrornatography (3:2 hexanes/ethyl acetate), gave 4-{5-chloro-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl methyl ether (77 mg, 31%) as a white solid. 1H NMR (CDCl3) δ 8.49 (d, 1H), 8.37 (d, 1H), 8.20 (d, 1H), 7.48 (d, 2H), 6.98 (d, 2H), 6.85 (dd, 1H), 6.70 (d, 1H), 3.85 (s, 3H), 2.62 (s, 3H). MS m/z 383 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH2:11])[NH:14][N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: N#CCC(=O)c1cccc(Cl)c1
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2cccc(Cl)c2)n[nH]1
Temperature: 80 °C
Reaction time: 15 h
Yield: 71.2 %

Procedure:
To a stirring solution of 3-(3-chlorophenyl)-3-oxo-propionitrile (2 g, 11.1 mmol) in absolute ethanol (20 mL) was added hydrazine hydrate (3.24 mL, 67 mmol). The reaction mixture was stirred at 80° C. for 15 h, cooled to room temperature, concentrated in vacuo, and absorbed on silica gel. Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 1.53 g (70%) of 5-(3-chloro-phenyl)-2H-pyrazol-3-ylamine as a green solid. 1H NMR (d6-DMSO) δ: 11.6 and 11.9 (2 broad s, 1H, NH+tautomer), 7.69 (s, 1H), 7.60 (d, 1H), 7.38 (t, 1H), 7.29 (d, 1H), 5.77 (broad s, 1H), 4.98 (broad s, 2H, NH2).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].Cl.[C:12]1([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][SH:30])[CH2:23][CH2:22]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[OH2:9].[ClH:10].[ClH:10].[C:1]1([NH:7][C:8](=[SH:30][CH2:29][CH2:28][CH2:27][N:24]2[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:26][CH2:25]2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: SCCCN1CCN(CCCc2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O
Product: OC(Nc1ccccc1)=[SH]CCCN1CCN(CCCc2ccccc2)CC1
Yield: 85 %

Procedure:
The procedure described in Example 2 was followed, using 1.2 g of phenyl isocyanate, 4.0 g of 3-[4-(3-phenylpropyl)piperazin-1-yl]propanethiol dihydrochloride, 2.2 g of triethylamine and 50 ml of methylene chloride, to give 2.1 g (41% of theory) of N-phenyl-S-{3-[4-(3-phenylpropyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride monohydrate as a white crystalline solid, M.p. 240°-243° C.