Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[CH2:15][O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][O:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)[CH2:10]1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2)cc1
Reaction time: 14 h
Yield: 99.2 %

Procedure:
To a stirred solution of methyl 4-[(2S,4S)-1-tert-butoxycarbonyl-4-methoxy-2-pyrrolidinyl]methoxybenzoate (2.38 g, 3.61 mmol) in CH2Cl2 (46 ml) was added TFA (23 ml) at room temperature. After 14 h stirring, the mixture was concentrated in vacuo. The residue was diluted by the addition of CH2Cl2 and 1 N NaOH, and extracted with CH2Cl2. The combined extracts were washed with brine, dried over Na2SO4, which was concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/MeOH (20/1)], to give methyl 4-[(2S,4S)-4-methoxy-2-pyrrolidinyl]methoxybenzoate (950 mg, 99%) as a yellow oil. 1H-NMR (CDCl3) δ 2.16 (t, J=5.3 Hz, 1H), 2.72 (s, 1H), 2.95 (d, J=6.8 Hz, 1H), 3.11 (d, J=11.0 Hz, 1H), 3.26 (t, J=1.9 Hz, 3H), 3.52 (br, 1H), 3.84 (d, J=1.7 Hz, 3H), 3.92 (s, 1H), 4.00 (d, J=4.1 Hz, 2H), 6.88 (m, 2H), 7.94 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:36]([O:38][CH3:39])=[O:37])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.091 g, 0.24 mmol) and triethylamine (0.05 mL, 0.36 mmol) in CH2Cl2 (1 mL) was added methyl chloroformate (0.03 mL, 0.36 mmol), and the mixture was stirred at room temperature for 20 minutes. Once no starting material was seen by analytical LCMS, the reaction was quenched with H2O and diluted with CH2Cl2 and saturated aqueous NaHCO3. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:16]=[CH:15][C:10]2[N:11]=[C:12]([Br:14])[S:13][C:9]=2[CH:8]=1)(=O)=O.[CH3:17][O:18][C:19]1[C:27]([O:28][CH3:29])=[CH:26][C:22]2[NH:23][CH:24]=[N:25][C:21]=2[CH:20]=1>CN(C=O)C.CCOC(C)=O>[Br:14][C:12]1[S:13][C:9]2[CH:8]=[C:7]([CH2:6][N:23]3[C:22]4[CH:26]=[C:27]([O:28][CH3:29])[C:19]([O:18][CH3:17])=[CH:20][C:21]=4[N:25]=[CH:24]3)[CH:16]=[CH:15][C:10]=2[N:11]=1
Reactant: COc1cc2nc[nH]c2cc1OC
Reactant: CS(=O)(=O)OCc1ccc2nc(Br)sc2c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of (2-bromobenzo[d]thiazol-6-yl)methyl methanesulfonate (460 mg, 1.4 mmol) from Step 3 of this Example in DMF (5 mL) was added 5,6-dimethoxy-1H-benzo[d]imidazole (560 mg, 3.14 mmol) portion wise at rt. The mixture was stirred at rt overnight. The resulting solution was diluted with 40 mL of EtOAc and washed with water, brine. The separated organic layer was dried over MgSO4, and concentrated under reduced pressure The crude product was purified on a silica gel column using a mixture of MeOH—CH2Cl2 (1:20, v/v) as eluent to give 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole as a light yellow solid (427 mg, 75%). LCMS (ESI) m/z 404, 406 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH:8]([CH3:15])[N:7]([CH:16]3[CH2:18][CH2:17]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[O:30][CH3:31].C(O)C>Cl.O>[CH:16]1([N:7]2[CH:8]([CH3:15])[CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:18][CH2:17]1
Reactant: CC1C(=O)N(C)c2cnc(Cl)nc2N(C2CC2)C1C
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CC1)C(C)C(C)C(=O)N2C
Yield: 70.5 %

Procedure:
A mixture of 0.14 g (0.0005 mole) of (rac)-2-chloro-9-cyclopropyl-5,7,8-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-46), 0.10 g (0.0006 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.145 g of (rac)-4-(9-cyclopropyl-5,7,8-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-46a) as an off-white solid.
Reaction SMILES: [F:1][C:2]1([CH2:9][OH:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1F>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH2:24])(=[O:22])=[O:23])[CH:17]=[CH:18][C:19]=1[O:10][CH2:9][C:2]1([F:1])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: CN1CCC(F)(CO)CC1
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(F)(COc2ccc(S(N)(=O)=O)cc2Cl)CC1
Reaction time: 0.25 h

Procedure:
To a solution of (4-fluoro-1-methylpiperidin-4-yl)methanol (0.265 g) in tetrahydrofuran (2 mL) was added sodium hydride (0.288 g). After 15 minutes, 3-chloro-4-fluorobenzenesulfonamide (0.377 g) was added as a solution in tetrahydrofuran (1 mL). The reaction was stirred for 2 hours, quenched with water (5 mL), adjusted to pH˜7 with 1N aqueous HCl, and extracted with dichloromethane (2×25 mL). The organic layer was washed with brine (25 mL), dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (Reveleris 40 g) eluting with a gradient of 0.1% to 10% methanol containing 2N NH3/dichloromethane over 30 minutes gave the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([OH:13])[C:5]=1[OH:14])([CH3:3])[CH3:2].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[C:16](=[O:17])([O:18][CH2:19][CH3:20])[O:13][C:6]1[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:14][C:16](=[O:17])[O:18][CH2:19][CH3:20]
Reactant: CCOC(=O)Cl
Reactant: CC(C)c1cc(O)c(O)c(C(C)C)c1
Product: CCOC(=O)Oc1cc(C(C)C)cc(C(C)C)c1OC(=O)OCC
Yield: 59.1 %

Procedure:
Prepared from 3,5-diisopropylbenzene-1,2-diol and ethyl chloroformate; purified by flash column chromatography on silica gel to yield a yellow oil (59.1%); 1H NMR (500 MHz, CDCl3, ppm) δ 7.02 (s, 1H), 6.98 (s, 1H), 4.32 (q, 2H, J=7.0 Hz), 4.31 (q, 2H, J=7.0 Hz), 3.11 (heptat, 1H, J=7.3 Hz), 2.89 (heptat, 1H, J=7.0 Hz), 1.38 (t, 3H, J=7.3 Hz), 1.37 (t, 3H, J=7.0 Hz), 1.24 (d, 6H, J=7.0 Hz), 1.22 (d, 6H, J=7.5 Hz).
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]1[N:31]=[N:32][C:33]([Br:37])=[CH:34][C:35]=1[Br:36].C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:23]1([C:2]2[N:31]3[N:32]=[C:33]([Br:37])[CH:34]=[C:35]([Br:36])[C:30]3=[N:29][C:3]=2[C:5]2[CH:6]=[CH:7][C:8]([C:11]3([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:12][CH2:13][CH2:14]3)=[CH:9][CH:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: Nc1nnc(Br)cc1Br
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Br)cc(Br)nn4c3-c3ccccc3)cc2)CCC1
Yield: 28 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1-A (5.80 g, 13.1 mmol), 3-amino-4,6-dibromopyridazine (CAS Registry No. 1206487-35-5, 3.96 g, 15.7 mmol, 1.2 eq), N,N-diisopropylethylamine (2.3 mL, 13.0 mmol, 1.0 eq) and powdered activated 3 Å molecular sieves (10 g) in isopropanol (70 mL) was heated at the reflux temperature for 8 h. On cooling, the mixture was filtered through a pad of Celite. The Celite was washed with DCM, and the combined organics were washed with water, dried with sodium sulfate and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 100 g SNAP cartridge: 100% hexane 2.0 min., gradient to 75% hexane/25% EtOAc 2.5 min., 75% hexane/25% EtOAc 4.5 min., gradient to 50% hexane/50% EtOAc 2 min., 50% hexane/50% EtOAc 4.5 min., gradient to 100% EtOAc 2.5 min., 100% EtOAc 5.7 min.) to give partially purified tert-butyl (1-{4-[3-phenyl-6,8-dibromoimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (2.65 g, ˜82% pure, 28% yield):
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.Cl.[NH2:18][OH:19].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:18][OH:19])[CH:13]=[C:14]([F:16])[CH:15]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1cc(F)cc(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: ON=C(c1ccccc1)c1cc(F)cc(F)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To 3,5-difluorobenzophenone (2.5 g) in ethanol (30 mL) was added hydroxylamine hydrochloride (3 eq) and sodiumcarbonate (3 eq). The reaction mixture was stirred at reflux for 4 hours and then allowed to cool down to room temperature. The precipitate was then isolated by filtration and washed with water to yield the title compound as a white solid (m.p.=91-93° C., Yield=89%), reflux, 4 h
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[O:13][CH3:14].C(O)(=[O:17])C>C(OC(=O)C)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]2[C:6](=[O:12])[O:11][C:7](=[O:17])[NH:8][C:9]=2[CH:10]=1
Reactant: COc1cc2c(cc1Cl)NC(=O)C2=O
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(=O)oc(=O)[nH]c2cc1Cl

Procedure:
Chromium trioxide (4.7 g) was added in small portions to a stirred suspension of 6-chloro-5-methoxyisatin (5.9 g) in glacial acetic acid (22 ml) and acetic anhydride (22 ml) at 80°. Some spontaneous ignition of the chromium trioxide was observed where this reagent became exposed to the air in the stirring vortex. The mixture was cooled and diluted with water (100 ml). The solid product was recrystallised from industrial methylated spirit to give the novel compound 7-chloro-6-methoxy-1H-3,1-benzoxazine-2,4-dione containing some unreacted starting material.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8](OCC)=[O:9].[O-]CC.[Na+:16].C(OCC)C>CC(OC)(C)C>[Cl:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][O-:9].[Na+:16]
Reactant: CCOC(=O)CCl
Reactant: CCOC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: CCOC(=O)C(Cl)C[O-]
Reaction time: 16 h

Procedure:
89.31 g (728 mmol) of ethyl chloroacetate and 63.7 g (859.9 mmol) of ethyl formate were dissolved in 500 ml of MTBE. 259.77 g (801 mmol) of an ethanolic solution of sodium ethoxide were added dropwise while stirring. After 16 hours, the supernatant was decanted off from the precipitate formed, the residue was stirred with approx. 500 ml of diethyl ether and filtered with suction, and the solid was washed with a further 500 ml of diethyl ether and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8]O)[CH:7]=1.S(Cl)([Cl:14])=O>ClCCl.CN(C=O)C>[Cl:14][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: COc1ccc(F)cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.0 g (0.12 mol) of (5-fluoro-2-methoxyphenyl)methanol are dissolved in 105 ml of dichloromethane. One drop of DMF is added, and 26.6 ml (0.37 mol) of thionyl chloride are then added slowly. The solution is stirred at RT for 2 hours and evaporated under reduced pressure. The residue is taken up in ethyl acetate, the mixture is cooled and admixed with water and then washed with saturated sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated under reduced pressure.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH2:28][C:27]1[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCN(CCC)CCCCN(Cc1ccc(C#N)cc1)Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
0.570 g (1.98 mmol) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 11.4 ml of ethanol, and 0.540 g (3.97 mmol, 2.0 equivalents) of 4-methoxybenzaldehyde were charged in a 50 ml recovery flask under a nitrogen stream. The mixture was then cooled to 0° C. After the addition of 1.009 g (4.76 mmol, 2.4 equivalents) of sodium triacetoxyborohydride, the mixture was stirred at room temperature for 18 hours. After confirming the disappearance of the raw material by TLC, the reaction solution was added to 50 ml of a saturated sodium bicarbonate aqueous solution, and extracted twice with 50 ml of chloroform. The chloroform layer was washed with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (Chromatorex NH, chloroform:n-hexane=1:1), thereby obtaining 0.559 g of 4-{[(4-dipropylaminobutyl)-(4-methoxybenzyl)amino]-methyl}-benzonitrile (19) as a light yellow oily substance (yield: 69.2%). [HPLC: 99.4% (HPLC measurement conditions B)]
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[C:34](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)(=[O:18])=[O:17])[CH3:34])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 83 %

Procedure:
To a solution of (R)-{[4-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (example 1-5, prepared by the method analogous to the one described for example 1-1, 48.6 mg, 0.100 mmol) in acetonitrile (3 mL) was added potassium carbonate (27.6 mg, 0.200 mmol) and methyl iodide (9.5 μL, 0.150 mmol). After being heated at 70° C. under an argon atmosphere for 6 hours, the reaction mixture was cooled to room temperature, filtered through a glass funnel and concentrated in vacuo. The residue was purified by column chromatography (gradient elution, 0-5% methanol in dichloro-methane) to afford {(R)-4-[(3,5-bis-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (42.6 mg, 83%) as a white solid. MS cald. (calculated) for C20H21F6N3O4S 513, obsd. (observed) (ESI+) [(M+H)+] 514.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[Na].[C:10]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([NH:17][NH2:18])=O)#[N:11]>CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]1[NH:2][C:15]([C:14]2[CH:19]=[CH:20][CH:21]=[C:12]([C:10]#[N:11])[CH:13]=2)=[N:17][N:18]=1
Reactant: N#Cc1ccccn1
Reactant: N#Cc1cccc(C(=O)NN)c1
Agent: [Na]
Solvent: CO
Product: N#Cc1cccc(-c2nnc(-c3ccccn3)[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
A solution of 2-cyanopyridine (0.18 mL, 1.86 mmol) in methanol (5 mL) was treated with sodium metal (12.8 mg, 0.56 mmol) a stirred at ambient temperature for 1 hour. The reaction mixture was then treated with a solution of 3-cyanobenzhyrazide (0.30 g, 1.86 mmol) in methanol (5 mL) and heated at reflux for 3 hours. The reaction mixture was then concentrated in vacuo. The resulting yellow solid was dissolved in toluene (2 mL) and heated overnight at 175° C. The reaction mixture was concentrated in vacuo. Silica gel chromatography using 2% methanol in dichloromethane afforded 0.12 g (26%) of 2-(2-pyridyl)-5-(3-cyanophenyl)-1,3,4-triazole.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21]C)[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8]C.[CH3:23]C1C(NC2C3C(=CC=CC=3)CCC2)=NC(C)=CN=1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:23]2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cnc(C)c(NC2CCCc3ccccc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: Cc1nc(NC2CCCc3ccccc32)c(C)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.92, 2.08, 2.29, 2.53, 2.86, 4.48, 5.40, 7.21, 7.33; 13C NMR (CDCl3) δ 19.63, 20.32, 23.67, 29.81, 30.00, 49.20, 124.85, 126.66, 127.69, 129.23, 129.63, 137.17, 138.12, 138.25, 148.78, 151.23; MS (ESI+) for C16H18N3Br1 m/z 333.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[S:14])[N:11]([CH3:15])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1.[CH3:23]I>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([S:14][CH3:23])[N:11]([CH3:15])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1
Reactant: CN1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=S
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NN1C
Temperature: 6 °C

Procedure:
The reaction vessel was charged with 11.5 grams (479 moles) of sodium hydride (99%) and 850 ml of dry N,N-dimethylformamide. To this mixture, 132 grams (437 moles) of 7-chloro-1,3-dihydro-3-methyl-5-phenyl-2H-1,3,4-benzotriazepine-2-thione (Example 15) was added with stirring using a screw feed solid addition apparatus while the system was flushed with dry nitrogen. Thirty minutes after addition was complete, the resulting reaction mass was cooled to about 6° C. and 30.0 ml (482 moles) of methyl iodide was added quickly with stirring. The temperature of the reaction mixture rose to about 20° C. The reaction mass was stirred for an additional 30 minutes in an ice bath and for about two hours at ambient temperature. The reaction mixture was poured into about 7 liters of ice water. The yellow precipitate which formed was collected, washed with water, and dissolved in about 1 liter of diethyl ether. The ether solution was washed with water, dried with magnesium sulfate, and concentrated in vacuo on a rotary evaporator. The title compound was left as a viscous yellow-orange oil which solidified on triturating with 100 ml of hexane. The resulting yellow product had a melting point of 100° to 102° C. Elemental analysis was used to confirm the structure.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>C(#N)C>[CH2:29]([N:18]1[CH2:19][CH2:20][CH:15]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:10])[C:2]=2[F:1])[CH2:16][CH2:17]1)[CH:28]=[CH2:27]
Reactant: O=S(=O)(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(c2cccc(S(=O)(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-{2-fluoro-3-[(trifluoromethyl)sulfonyl]phenyl}-piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and allylbromide (0.01 g). MS m/z (rel. intensity, 70 eV) 351 (M+, 47), 350 (61), 324 (bp), 322 (29), 133 (36).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][NH:7][C:8]([C:10]1[N:14]=[C:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])[CH:18]=[CH:19][CH:20]=2)[NH:12][N:11]=1)=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1>CS(C)=O>[CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][NH:7][C:8]([C:10]1[N:14]=[C:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH2:41][C:40]3[CH:43]=[CH:44][C:37]([F:36])=[CH:38][CH:39]=3)[CH:18]=[CH:19][CH:20]=2)[NH:12][N:11]=1)=[O:9]
Reactant: C[Si](C)(C)CCOCNC(=O)c1n[nH]c(-c2cccc(-c3ccccc3O)c2)n1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCNC(=O)c1n[nH]c(-c2cccc(-c3ccccc3OCc3ccc(F)cc3)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 0.05 g (0.122 mmol) of 2-trimethylsilylethoxymethyl-5-[2′-(hydroxy)biphenyl-3-yl]-1,2,4-triazole-3-carboxamide (prepared according to procedures described in Example 53) in 4 mL of DMSO was added 0.16 g (0.488 mmol) of cesium carbonate and the reaction mixture was stirred at rt for 20 min. To the reaction mixture was added 0.025 mL (0.244 mmol) of 4-fluorobenzylbromide and the reaction mixture was heated at 80° C. for 18 hr. The reaction mixture was partitioned between water and EtOAc. The organic fraction was washed with water and brine, dried (MgSO4) and filtered. The filtrate was concentrated and the residue was purified by chromatography (silica, EtOAc: hexanes, 3:10) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].Cl.[Cl:12][CH2:13][C:14](=N)OCC>C(O)C>[Cl:12][CH2:13][C:14]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[N:10]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CCOC(=N)CCl
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc2nc(CCl)[nH]c2c1
Yield: 54.9 %

Procedure:
3.42 g of 3,4-diaminobenzonitrile and 4.06 g of ethyl chloroacetoimidate hydrochloride were dissolved in 100 ml of ethanol, and the solution was refluxed under heating for 3 hours. After cooling and distilling off the solvent, the resulting residue was dissolved in ethyl acetate, washed with water, and then dried. After distilling off the solvent, the crystals thus precipitated were collected by filtration to obtain 2.7 g of 2-chloromethyl-5-benzimidazolecarbonitrile.