Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:19]C1C=CC(NC2C=CC=CC=2)=CC=1.N1C=CC=CC=1C=O>>[F:19][C:7]1[CH:6]=[CH:5][C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)=[CH:3][CH:2]=1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: Fc1ccc(Nc2ccccc2)cc1
Agent: O=Cc1ccccn1
Product: Fc1ccc(-n2nnc(-c3ccccn3)n2)cc1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 4-fluorophenylaniline (33.3 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(4-fluorophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1[CH:16]([S:20](=[O:35])(=[O:34])[NH:21][C:22]1[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=1[CH:31]([CH3:33])[CH3:32])[C:17]([O-])=[O:18])(C)C.C(C1C=C(C(C)C)C=C(C(C)C)C=1O)(C)C.[CH3:52][O:53][C:54]1[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[C:56]([O:62][CH3:63])[C:55]=1[OH:64]>>[CH3:63][O:62][C:56]1[CH:57]=[C:58]([O:60][CH3:61])[CH:59]=[C:54]([O:53][CH3:52])[C:55]=1[O:64][C:17](=[O:18])[CH2:16][S:20](=[O:34])(=[O:35])[NH:21][C:22]1[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=1[CH:31]([CH3:32])[CH3:33]
Reactant: CC(C)c1cc(C(C)C)c(C(C(=O)[O-])S(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)c(C(C)C)c1
Reactant: COc1cc(OC)c(O)c(OC)c1
Agent: CC(C)c1cc(C(C)C)c(O)c(C(C)C)c1
Product: COc1cc(OC)c(OC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)c(OC)c1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,4,6-triisopropylphenol was replaced with 2,4,6-trimethoxyphenol, mp 167°-170° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>ClCCl>[Si:24]([O:6][CH2:5][CH2:4][C@H:3]([NH2:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@@H](CCO)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC[C@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
1.50 g of (S)-3-amino-3-phenylpropan-1-ol hydrochloride were initially charged in 20 ml of dichloromethane and then 2.77 ml of triethylamine and 1.30 g of tert-butyldimethylchlorosilane were added. After stirring at room temperature for 3 hours, the reaction solution was extracted three times with 30 ml of water, dried by means of a phase separator cartridge (Isolute®), concentrated by rotary evaporation and dried under high vacuum. This gave the product (2.06 g) with a molecular weight of 265.5 g/mol (C15H27NOSi); MS (ESI): m/e=266 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:18]=[C:10]3[N:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[CH2:34][NH2:35])[CH2:28][CH2:27]1>O1CCCC1.C(Cl)(=O)OCC>[O:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=2[CH2:34][NH:35][C:15]([C:12]2[CH:13]=[CH:14][N:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:18]=[C:10]3[N:11]=2)=[O:17])[CH2:30][CH2:31]1
Reactant: NCc1ccccc1N1CCOCC1
Reactant: O=C(O)c1ccn2nc(-c3ccccc3)cc2n1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1N1CCOCC1)c1ccn2nc(-c3ccccc3)cc2n1
Temperature: -20 °C
Yield: 68.5 %

Procedure:
To a solution of 2-phenyl- pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid (120 mg), and triethylamine (0.091 ml) in tetrahydrofuran (10 ml), ethyl chlorocarbonate (0.053 ml) was added at −40° C. It was further added with a solution of 2-morpholinobenzylamine (115 mg) in tetrahydrofuran (2 ml), and thereafter heated to −20° C. The reaction solution was distilled under a reduced pressure, and then water was added thereto, extracted with chloroform, and the organic layer was dried with magnesium sulfate. After the reduced-pressure distillation of the solvent, the residue was purified by a silica gel column chromatography, and thereafter recrystallized from acetone-diisopropyl ether to yield N-(2-morpholinophenyl)methyl 2-phenyl-pyrazolo-[1,5-a]-pyrimidine-5-amide (142 mg, 69%). mp: 190-192° C.
Reaction SMILES: [Na].[CH3:2][CH:3]1[CH2:11][CH:6]2[O:7][C:8](=[O:10])[CH2:9][CH:5]2[CH2:4]1.[N+](=[CH2:15])([O-])[O-].S(=O)(=O)(O)O.[CH3:21][OH:22]>O.C(O)(=O)C>[C:21]([C@@H:4]1[C@@H:5]2[C@@H:6]([O:7][C:8](=[O:10])[CH2:9]2)[CH2:11][C@H:3]1[CH3:2])(=[O:22])[CH3:15]
Reactant: C=[N+]([O-])[O-]
Reactant: CC1CC2CC(=O)OC2C1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1C

Procedure:
Sodium (1.3 g) was dissolved in methanol (30 mL) and the solution added at 0° to a methanol (40 mL) solution of the crude, optically active (3aR,4S,5R,6aS)-4-nitroethyl)hexahydro-5-methyl-2H-cyclopenta[b]-furan-2-one (10.0 g). This nitronate anion solution was added, 30 minutes later and at -30°, to a cold (-30° ) solution of concentrated sulfuric acid (6 mL) in methanol (40 mL). The resulting mixture was processed as in example III, including hydrolysis with acetic acid (8 mL) in water (30 mL) while stripping, to give 8.47 g (99%) of the crude, optically active (3aR,4S,-5R,6aS)-4-acetylhexahydro-5-methyl-2H-cyclopenta[b]furan-2-one as a yellow oil. This material was used directly in Example XIV.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[C:10]([CH2:27][CH:28]([CH3:30])[CH3:29])=[N+:11]([O-:26])[C:12]([OH:25])=[C:13]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:33])=[N-].B(Br)(Br)Br>ClCCl.CO.C(OCC)C.C(Cl)Cl>[C:1]([O:5][C:6]([O:8][C:9]1[C:10]([CH2:27][CH:28]([CH3:30])[CH3:29])=[N+:11]([O-:26])[C:12]([O:25][CH3:33])=[C:13]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cc1c(OC(=O)OC(C)(C)C)nc(Cc2c[nH]c3ccccc23)c(O)[n+]1[O-]
Reactant: C=[N+]=[N-]
Agent: BrB(Br)Br
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: COc1c(Cc2c[nH]c3ccccc23)nc(OC(=O)OC(C)(C)C)c(CC(C)C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In 0.5 ml of dichloromethane-methanol (3:1) was dissolved 10 mg of 3-tert-butoxycarbonyloxy-6-hydroxy-5-(indol-3-yl)methyl-2-isobutylpyrazine 1-oxide. Thereto were added, under ice cooling, a solution of diazomethane dissolved in diethyl ether and 4-5 drops of a solution of 0.1 M of boron tribromide dissolved in methylene chloride. The container was cook-stoppered and the contents were stirred for 12 hours at room temperature. The contents were then diluted with 5 ml of dichloromethane, and the mixture was washed with an aqueous sodium hydrogen carbonate solution and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by a silica gel thin layer chromatography (dichloromethane:methanol=40:1) to obtain 3.6 mg of the title compound as a pale brown solid substance.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][CH:14]1[CH2:19][CH:18]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]3[N:45]=[CH:46][N:47]=[C:21]23)[CH2:17][CH2:16][O:15]1>C(OCC)(=O)C>[CH3:13][CH:14]1[CH2:19][CH:18]([N:20]2[C:25](=[O:26])[C:24]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[NH:3][C:4](=[O:7])[O:5][N:41]=4)=[CH:32][CH:33]=3)=[C:23]([CH2:42][CH2:43][CH3:44])[N:22]3[N:45]=[CH:46][N:47]=[C:21]23)[CH2:17][CH2:16][O:15]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOC(C)C2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOC(C)C2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.95 g), sodium hydrogen carbonate (1.5 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(2-methyltetrahydro-2H-pyran-4-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.43 g) was added, and the mixture was stirred at 90° C. for 16 hr. 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, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.18 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate 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 as a colorless amorphous solid (0.23 g, 47%).
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1.[CH:29]1([CH2:35][C@@H:36]([CH2:38][OH:39])[NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(N(CC)CC)C>CS(C)=O>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:5]=1.[CH:29]1([CH2:35][C@@H:36]([CH:38]=[O:39])[NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: N[C@H](CO)CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N[C@H](C=O)CC1CCCCC1
Reaction time: 0.58 h

Procedure:
To a mixture of the dipeptide alcohol [18a] (2.0 g, 3.65 mmol), triethylamine (1.30 g, 12.85 mmol, 3.5 eq) and DMSO (6 ml) is added at room temperature SO3 ·pyridine (2.03 g, 12.75 mmol, 3.5 eq) in DMSO (6 ml) and the mixture is stirred for 35 minutes. The reaction mixture is poured on ice, and the resultant aqueous mixture is extracted with ethyl acetate (20 ml×3). The organic layer is subsequently washed with 10% aqueous citric acid, saturated aqueous sodium chloride (×2), 7% aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over MgSO4, and concentrated to dryness in vacuo. The resultant residue is purified with silica gel chromatography (SiO2 :100 g, CH2Cl2 :MeOH=95:5) to obtain Boc-His(Ts)-3-cyclohexylalaninal [14a] (1.67 g, 84%) in amorphous powder.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.P([O-])([O-])([O-])=O.N.CCCCCCC>C(Cl)Cl.O>[CH:35]([C:5]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:2]([CH3:1])=[N:3][N:4]=1)([CH3:36])[CH3:37]
Reactant: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
Maraviroc phosphate (6 gm) was dissolved in methylene chloride (50 ml) and water (40 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with ammonia solution (3 ml) and then the layers were separated. The organic layer was dried with sodium sulfate and treated with carbon. The methylene chloride was distilled off under vacuum at below 45° C. to obtain residual mass. To the residual mass was added n-heptane (40 ml) and stirred for 30 minutes at room temperature. The solid obtained was collected by filtration and dried to obtain 4.6 gm of maraviroc amorphous form (HPLC Purity: 99.96%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:23])=[C:18]([CH:22]=1)[C:19](O)=[O:20].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:23])=[C:18]([CH:22]=1)[C:19]([N:3]([O:4][CH3:5])[CH3:2])=[O:20]
Reactant: CNOC
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Br)ccc1Cl
Reaction time: 0.17 h
Yield: 76.9 %

Procedure:
N-methyl-N-methoxylamine hydrochloride (3.41 g, 35 mmol) was dissolved in 140 mL methylene chloride. Triethylamine (14.6 mL, 105 mmol) was added and the reaction mixture was stirred for 10 minutes. Then the reaction mixture was stirred for 16 hours after 5-bromo-2-chloro-benzoic acid 6a (8.24 g, 35 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (10.69 g, 42 mmol) were added in turn. Thereafter, the reaction mixture was extracted with ethyl acetate (80 mL×3) after 120 mL water were added. The organic extract was washed with saturated sodium chloride solution (60 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound 5-bromo-2-chloro-N-methoxy-N-methyl-benzamide 6b (7.50 g, pale yellow solid), yield: 76.9%. MS m/z (ESI): 280.0 [M+1]; 1H NMR (400 MHz, CDCl3): δ 7.46-7.44 (m, 2H), 7.29-7.26 (m, 1H), 3.49 (s, 3H), 3.37 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[NH:15]1[CH2:19][C@H:18]([OH:20])[C@@H:17]([OH:21])[CH2:16]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:15]3[CH2:19][C@H:18]([OH:20])[C@@H:17]([OH:21])[CH2:16]3)=[O:13])[S:10][C:3]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: O[C@H]1CNC[C@@H]1O
Agent: [Li+]
Product: O=C(c1cc2nccc(Cl)c2s1)N1C[C@H](O)[C@@H](O)C1

Procedure:
The title compound was prepared from lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate and (3S,4S)-pyrrolidine-3,4-diol by a procedure analogous to Example 1B. MS: 299.3/301.3 (MH+); HPLC Rf: 3.091 min.; HPLC purity: 99%.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[C:8]1([CH3:17])[C:9]([N:14]=[C:15]=[S:16])=[CH:10][CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH3:17])[C:15]1=[S:16])[CH3:2]
Reactant: Cc1ccccc1N=C=S
Reactant: CCNCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccccc2C)C1=S
Yield: 31 %

Procedure:
The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 7.4 g of 2-tolyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethanol. Title compound (3.6 g) was obtained as a creamy solid, m.p. 105°-108° C. Anal. Calcd. for. C12H14N2O S: C, 61.51; H, 6.02; N, 11.93. Found: C, 61.22; H, 5.96; N, 11.89. Mass spectrum (EI, M.+) m/z 234.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[C:11]([NH:14][C:15]1[C:16](N)=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F)(=[O:13])[CH3:12].[Cl-:26].[NH4+]>C1COCC1.O>[C:11]([NH:14][C:15]1[C:16]([Cl:26])=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:13])[CH3:12]
Reactant: Fc1ccc(S)cc1
Reactant: CC(=O)Nc1c(F)ccc([N+](=O)[O-])c1N
Reactant: [Cl-]
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1c(Sc2ccc(F)cc2)ccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Fluorobenzenethiol (0.128 ml) was added dropwise to a stirred suspension of sodium hydride (0.049 g of a 60% dispersion in mineral oil) in THF (3 ml). The mixture was stirred for 30 minutes then added dropwise to a stirred and cooled (−65° C.) solution of 3-acetamido-2-amino-4-fluoronitrobenzene (0.233 g) in THF (2 ml). The mixture was stirred for 3 hours at −65° C. then allowed to warm to ambient temperature. Saturated aqueous ammonium chloride solution (5 ml), then water (5 ml) were added and the mixture was extracted with ether (2×25 ml). The extracts were combined, washed with water (25 ml) and brine (25 ml), then dried. Volatile material was removed by evaporation and the residue was purified on a silica gel Mega Bond Elut column eluting with 0-40% EtOAc/isohexane to give the title compound. Chromatography on a Biotage cartridge (40 g silica), eluting with 40% EtOAc/isohexane to give the title compound (0.193 g) as a solid. NMR: 2.14 (s, 3H), 6.76 (d, 1H), 7.4 (t, 2H), 7.6 (m, 2H), 7.88 (d, 1H), 10.1 (brs, 1H); m/z: 339.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc2ccncc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCn1c([C@@H]2CCCNC2)nc2ccncc21

Procedure:
(R)-tert-Butyl 3-(3-(3-methoxypropyl)-3H-imidazo[4,5-c]pyridin-2-yl)piperidine-1-carboxylate (36D) (0.279 mmol, 0.105 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were then added and the resultant solution was allowed to stir under nitrogen for 4 hr. The reaction was then concentrated and dried in-vacuo affording (R)-3-(3-Methoxypropyl)-2-(piperidin-3-yl)-3H-imidazo[4,5-c]pyridine (35E) as a clear oil that was used without further purification. ESI-MS: m/z 275.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][CH2:15][C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)(C)(C)C.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[C:40]2[O:41][C:42]([CH3:45])([CH3:44])[O:43][C:39]=2[CH:38]=[C:37]([C:46](Cl)=[O:47])[CH:36]=1.FC(F)(F)C(O)=O>ClCCl>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[C:16]([CH2:15][N:14]([CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:46]([C:37]2[CH:36]=[C:35]([O:34][CH3:33])[C:40]3[O:41][C:42]([CH3:45])([CH3:44])[O:43][C:39]=3[CH:38]=2)=[O:47])[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNCc1cc2ccccc2cn1
Reactant: COc1cc(C(=O)Cl)cc2c1OC(C)(C)O2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N(Cc2cc3ccccc3cn2)C[C@@H]2CCCN2)cc2c1OC(C)(C)O2
Yield: 43.5 %

Procedure:
Experimental conditions analogous to Example 60, from 0.17 g (0.38 mmol) of (S)-2-{[(isoquinolin-3-ylmethyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (double trifluoroacetic acid salt), 6 mL dichloromethane, 159 μL (1.14 mmol) of triethylamine, 0.10 g (0.42 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl chloride and 0.6 mL trifluoroacetic acid. Purification using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 40 min, gave 74 mg of the product as the free base as a colorless solid. LC-MSD, m/z for C26H29N3O4 [M+H]+: 448.6.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[N:4][C:5](F)=[C:6]([Cl:8])[CH:7]=1.CCCCCC.[H-].[Na+].[CH2:19]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29])[CH2:20][CH2:21][CH3:22]>>[CH2:19]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[C:3]([F:10])[N:4]=1)[CH2:20][CH2:21][CH3:22]
Reactant: Fc1nc(F)c(Cl)cc1Cl
Reactant: CCCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CCCCOCCOCCOc1nc(F)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A mixture was prepared by admixing 12.9 grams (0.07 mole) of 3,5-dichloro-2,6-difluoropyridine, 100 milliliters of diethyleneglycol n-butyl ether and 3.3 grams (0.75 mole) of a hexane slurry of sodium hydride. The sodium hydride was a 53 percent oil dispersion and had been washed 3 times with 10 milliliter portions of hexane. Considerable foaming occurred and after foaming ceased, the reaction mixture was stirred for ~10 minutes at room temperature and thereafter diluted with 200 milliliters of water. The mixture was extracted 3 times with 100 milliliter portions of hexane, the extracts combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The oil which remained as a residue was vacuum distilled to yield 14.3 grams of 2-[2-(2-butoxyethoxy)ethoxy]-3,5-dichloro-6-fluoropyridine as a water-white product. The product had a boiling point of 113°-124° C. at 0.3 millimeters of mercury (mm). Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 47.55, 5.37 and 4.36 percent, respectively, as compared with the theoretical contents of 47.87, 5.56 and 4.29 percent, respectively, as calculated for the above named compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.CC1(C)O[C:16](=O)[CH2:15][C:13](=[O:14])[O:12]1>O>[NH:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:15]([C:13]([OH:14])=[O:12])[CH2:16]1
Reactant: Nc1ccccc1C=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: O=C(O)C1=Cc2ccccc2NC1
Temperature: 75 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
2-Aminobenzaldehyde (84.1 mg, 0.69 mmol) and Meldrum's acid (100 mg, 0.69 mmol) were combined in H2O (1 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 86.2 mg of 1,2-dihydro-quinoline-3-carboxylic acid with a yield of 66%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:20][C@H:21]2[CH2:25][CH2:24][CH2:23][O:22]2)[C:11]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C(O)=[O:27].OO.[Mn]([O-])(=O)(=O)=O.[K+].[OH2:37]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:20][C@H:21]2[CH2:25][CH2:24][CH2:23][O:22]2)[C:11]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:9])(=[O:27])=[O:37]
Reactant: O
Reactant: CSc1ccc(C(C[C@H]2CCCO2)C(=O)Nc2cnccn2)cc1Cl
Reactant: O=CO
Agent: O=[Mn](=O)(=O)[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCCO2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
A solution of 2-(3-chloro-4-methylsulfanyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydro-furan-2(R)-yl)-propionamide (0.060 g, 0.16 mmol) in formic acid (0.19 mL, 4.8 mmol) was cooled to 0° C. and then treated with a 30% aqueous hydrogen peroxide solution (0.10 mL, 0.8 mmol). The resulting solution was stirred at 0° C. for 30 min and was then quenched with a 10% aqueous sodium bisulfite solution. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in methanol (1 mL) and was treated dropwise with a solution of potassium permanganate (0.028 g, 0.176 mmol) in water (0.5 mL). The dark brown solution was stirred at 25° C. for 30 min, and was then diluted with methanol (10 mL). The reaction mixture was filtered to remove solids, and the filtrate was concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 1/1 hexanes/ethyl acetate to 1/4 hexanes/ethyl acetate) afforded the 2-(3-chloro-4-methanesulfonyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydro-furan-2(R)-yl)-propionamide (44 mg, 67.1%) as a colorless gum: C18H20ClN3O4S (M+) 409.0863. found 409.0868.