Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15]CC)[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH:28]([Mg]Br)([CH3:30])[CH3:29]>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([OH:20])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:28]([CH3:30])[CH3:29])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CC(C)[Mg]Br
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C(O)(c2ccccn2)C(C)C)c2[nH]c(=O)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C. Isopropylmagnesium bromide (2.0 M, 0.14 mL, 0.28 mmol) was added dropwise and the reaction was allowed to stir for 10 mins and then quenched with water. Reaction was extracted three times with EtOAc and combined organic layers were washed once with water and concentrated. Residue was taken up in EtOH (1.5 mL) and 4.0M HCl/dioxane (0.75 mL), heated to 65° C. for two hours, concentrated, then purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Br)[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:7]=1)[O:8][CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:16]
Reactant: Cc1ccc(F)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(F)ccc1C
Reaction time: 0.5 h

Procedure:
To a solution of 5-fluoro-2-methylphenol (1.00 g, 7.93 mmol) and ethylbromoacetate (1.59 g, 9.51 mmol) in DMF (15 mL) was added K2CO3 (1.10 g, 7 93 mmol). After 30 min at RT, DMF was removed by distillation. The crude product was washed with 5% citric acid (30 mL) and water (30 mL), extracted in DCM (3×20 mL), dried over Na2SO4, filtered, concentrated, and dried in vacuo. Desired product obtained as yellow oil (1.30 g, 77%). 1H NMR (CD3OD/400 MHz) δ7.09 (t, 1H, J=8.8 Hz), 6.58 (m, 1H), 6.56 (m, 1H), 4.71 (s, 2H), 4.23 (q, 2H, J=7.2 Hz), 2.18 (s, 3H), 1.27 (t, 3H, J=7.2 Hz). ESHRMS m/z 212.0847 (M+H calculated for C11H13FO3 requires 212.0849).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[CH3:24])=[CH:11][CH:10]=1)=O)C.O.[NH2:33][NH2:34].Cl.CO>C(O)(=O)C>[CH3:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH2:6][CH:5]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:4](=[O:3])[NH:33][N:34]=2)=[CH:10][CH:11]=1
Reactant: NN
Reactant: CCOC(=O)C(CC(=O)c1ccc(OCCCN2CCC[C@H]2C)cc1)c1ccccn1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1CCCN1CCCOc1ccc(C2=NNC(=O)C(c3ccccn3)C2)cc1

Procedure:
In a 50 mL round bottom flask, 4-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4-oxo-2-pyridin-2-yl-butyric acid ethyl ester (950 mg, 1.84 mmol), and hydrazine monohydrate (204 μL, 4.2 mmol), in acetic acid (20 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and NaHCO3 sol., extracted three times, and then dried over MgSO4. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 250 mg (33%). Ethereal HCl was added to a methanol solution to produce crystals. Mp 231-233° C. MS m/z 393 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][O:8][C:9]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:10]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:15][CH:14]=1.CN(C)C.CCOCC>O1CCCC1.O>[C:1]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH:12]=[CH:11][C:10]2[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:9]=2[O:8][CH3:7])=[CH:18][CH:17]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: COc1ccc(OC)c(C=Cc2ccc(OCCCCCCO)cc2)c1
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)C
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C=Cc2cc(OC)ccc2OC)cc1
Temperature: 60 °C
Reaction time: 23 h

Procedure:
Methacryloylchloride 90%, 0.52 ml, 4.8 mmol) was added dropwise To a stirred solution of 6-(2',5'-dimethoxy-4-stilbenoxy)hexanol (14) (1.54 g, 4.32 mmol) and dry trimethylamine (0.76 ml, 5.5 mmol) in dry tetrahydrofuran (25 ml) under argon. The reaction mixture was stirred at 60° C. for 23 h. Ether (200 ml) and water (100 ml) were added. The organic layer was washed with water (3×100 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica (dichloromethane/hexane; 4:1 to 1:0) to yield (15) (1.48 g, 81 %] as an oil; δH (CDCl3) 1.48 (4 H, m, CH2), 1.70 (2 H, m, CH2), 1.80 (2 H, m, CH2), 1.95 (3 H, m, CH3), 3.81 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 3.96 (2 H, J=6.4 Hz, CCH2), 4.16 (2 H, t, J=6.6 Hz, OCH2), 5.55 (1 H, m, HA), 6.10 (1 H, m, HB), 6.76 (1 H, dd, JH4',H3' =8.2 Hz, JH6',H4' =2.9 Hz, H4'), 6.82 (1 H, d, JH4',H3' =8.2 Hz, H3'), 6.87 and 7.46 (4 H, AA'BB', H2, H3, H5, and H6), 7.04 (1 H, d, J=16.5 Hz,. vinytic H), 7.13 (1 H, d, JH4',H6' =2.9 Hz, H6') and 7.32 (1 H, d, J=16.4 Hz, vinylic H); δc (CDCl3) 18.3, 25.69, 25.74, 28.5, 29.1, 53.4, 55.7, 56.2, 64.6, 67.7, 111.3, 112.2, 113.1, 114.5, 120.9, 125.2, 127.5, 127.7, 128.8, 130.4, 136.4, 151.2, 153.7, 158.6 and 167.4.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[C:12]([O:19][CH3:20])[CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:32][CH2:33][CH2:34][CH2:35]Br>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:17]#[N:18])[CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:12]([O:19][CH3:20])[CH:11]=1
Reactant: BrCCCCBr
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-c2nc3ccccc3o2)ccc1C1(C#N)CCCC1
Temperature: 25 °C

Procedure:
[4-(1,3-Benzoxazol-2-yl)-2-methoxyphenyl]acetonitrile (130 mg, 0.49 mmol) in THF (5.0 mL) was cooled to −78° C. under argon atmosphere. Sodium bis(trimethylsilyl)amide (1.8 mL, 1.08 mmol) was added slowly and after fifteen minutes, added 1,4-dibromobutane (0.07 mL, 0.59 mmol) to dark brown reaction mixture. Let mixture warm to rt overnight. After concentrating reaction mixture in vacuo, the resulting pink oil was purified by flash chromatography, using a gradient elution of 1:9 EtOAc:hexanes to 1:4 EtOAc:hexanes. This afforded the desired compound, 1-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]cyclopentanecarbonitrile, as a yellow solid. 1H NMR(CDCl3, 300 MHz) δ 7.86–7.26 (m, 7H), 4.07 (s, 3H), 2.59–1.91 (m, 8H). MS (ESI) 319.1 (M+H)+.
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[S:11]1(=[O:27])=[O:26])(=O)=O.[CH3:28][NH2:29].[ClH:30]>>[ClH:30].[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([CH2:9][C:8]#[C:7][CH2:6][NH:29][CH3:28])[S:11]1(=[O:27])=[O:26]
Reactant: CS(=O)(=O)OCC#CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Reactant: CN
Agent: Cl
Product: CNCC#CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]but-2-yn-1-yl methanesulfonate (0.25 g, 0.60 mmol) was treated with methyl amine to give 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbut-2-yn-1-amine hydrochloride (78 mg) after treatment with HCl.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:40](Cl)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][CH2:9][C@H:10]([NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][O:12][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H](COCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A solution of (2R)-3-(benzyloxy)-2-(tritylamino)propan-1-ol (2.68 g, 6.34 mmol) dissolved in 100 mL of CH2Cl2 was treated with triethylamine (1.00 mL, 7.19 mmol), tert-butyldimethylsilyl chloride (1.08 g, 7.15 mmol) and DMAP (79 mg, 0.65 mmol) and the reaction mixture was stirred under N2 overnight. The reaction mixture was then concentrated and the resulting material was dissolved in 50 mL of CH2Cl2 and washed with H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10% ethyl acetate/hexanes) gave 3.03 g of (2S)-1-(benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-N-tritylpropan-2-amine as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:29])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:11]=2[CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3Cl)cc2c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2cc3cc(C(F)(F)F)ccc3o2)c(Cl)c1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a mixture of 0.38 g of 3-chloro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine and 4 ml of chloroform was added 0.41 g of 70% m-chloroperbenzoic acid under ice-cooling. This mixture was stirred under ice-cooling for 30 minutes and subsequently at room temperature for 2 hours. The reaction mixture was diluted with chloroform, and sequentially washed with a 5% aqueous solution of sodium hydroxide and saturated brine. The organic layer was dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.32 g of 3-chloro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine 1-oxide (hereinafter, referred to as “Present Active Compound 7”).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@H:12]([OH:22])[C:11]1=[O:23])=[O:4].O[Li].O.Cl.[CH2:34]1COCC1.O.CO>>[CH3:28][C:26]([CH3:29])([CH3:27])[C:25]#[C:24][C:7]1[S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]([N:10]2[C@H:15]([CH:16]([CH2:21][CH3:20])[CH2:17][CH2:18][CH2:19][CH3:34])[CH2:14][CH2:13][C@H:12]([OH:22])[C:11]2=[O:23])[CH:8]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](O)CC[C@H]1C1CCCCC1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCCCC(CC)[C@@H]1CC[C@H](O)C(=O)N1c1cc(C#CC(C)(C)C)sc1C(=O)O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a solution of 3-((3S,6S)-6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (1.5 g, 3.59 mmol, 1 equiv.) in THF/H2O/MeOH (5.0 mL/5.0 mL/1.0 mL) was added LiOH.H2O (0.79 g, 17.56 mmol, 5.0 equiv.) at room temperature. The reaction mixture was stirred at 50° C. for 20 minutes. The reaction was then acidified to pH=5 by addition of 3.0 N HCl aq. solution and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated. The residue was purified by prep-HPLC (XBridge Prep C 18 5 um, 30×50 mm) in basic condition (0.1% NH4OH, 10%˜45% CH3CN/H2O, 10 min run, 40 ml/min) to give 850 mg of product (yield 57%). MS: 404 [M+H+]. 1H-NMR (400 MHz, MeOD): δ 6.95 (s, 1H), 4.09 (m, 1H), 3.74 (m, 1H), 2.09 (m, 1H), 1.94-1.67 (m, 8H), 1.38 (m, 1H), 1.33 (s, 9H), 1.17 (m, 5H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].Cl>C1COCC1.O>[S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH3:3])(=[O:16])=[O:15]
Reactant: COCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an oven dried 12 L three-necked roundbottom flask, equipped with a magnetic stir bar and a 1000 mL pressure-equalizing dropping funnel, a solution of NaOH (440.0 g, 11.0 mol) is added to 1800 mL water and the mixture is cooled to approximately 0° C. A solution of triethylene glycol monomethyl ether, Formula A, (656.84 g, 4.0 mol) in THF (1000 mL) is added. The clear solution is stirred vigorously at 0° C. for 15 min and a solution of tosyl chloride (915.12, 4.8 mol) in THF (2.0 L) added dropwise over a 1 h period. The reaction mixture is stirred for an additional 1 h at 0° C., and 10% HCl (5.0 L) is added to quench the reaction (to pH 5-7). The two-phase mixture is transferred to a 4 L separatory funnel, the organic layer removed, and the aqueous layer extracted with t-butylmethyl ether (3×250 mL). The combined organic extracts are washed with brine (2×350 mL), dried (MgSO4), and evaporated under reduced pressure to afford Formula B, 1217.6 g (95%) as a light colored oil. This material is taken to the next step without further purification.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:11]1([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[Si](C#N)(C)(C)C.[N:31]1([C:36](N2C=CN=C2)=[O:37])C=CN=[CH:32]1>[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:21]([C:20]4[CH:23]=[CH:24][C:17]([N:11]5[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]5)=[CH:18][CH:19]=4)[CH2:32][NH:31][C:36]3=[O:37])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=Cc1ccc(N2CCCCC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2[nH]cnc2c1
Agent: [Pd]
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2ccc(N3CCCCC3)cc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.400 g, 3 mmol), 4-(piperidin-1-yl)benzaldehyde (0.570 g, 3 mmol), TMSCN (0.375 mL, 3 mmol), Pd/C (10%, 0.02 g), TEA 1.05 mL, 7.5 mmol), di-(imidazol-1-yl)methanone (0.730 g, 4.5 mmol) as described in method 2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[Li+].[CH3:9]CC[CH2-].[CH:13]1(CBr)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:9]
Reactant: BrCC1CCCCC1
Reactant: Cc1ccccn1
Reactant: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(c1ccccn1)C1CCCCC1
Temperature: -78 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
2-Picoline (5 g, 54 mmol) is dissolved in THF (100 mL) and cooled to −78° C. N-Butyllithium (40 mL of a 1.6M solution in THF, 64.3 mmol) was added to the solution over 10 minutes. The reaction mixture was then warmed to room temperature for 5 minutes and then cooled back down to −78° C. Then cyclohexylmethyl bromide (10 g, 57 mmol) was added, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was then heated at reflux for 6 hours and then cooled to room temperature. The solvent was removed under vacuum and water and ethyl acetate were then added to the residue. The layers were separated and the aqueous was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated to provide a dark oil. The oil was purified by flash chromatography to provide 2-pyridyl-1-cyclohexylethane (9 g, 89%).
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[Br:14]Br.[OH-].[Na+]>C(O)(=O)C.O>[NH2:6][C:7]1[C:12]([Br:14])=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncc(Cl)cc1Br
Temperature: 43 °C
Yield: 70.7 %

Procedure:
An acetic acid (400 mL) suspension of sodium acetate (57.1 g, 0.696 mol) and 2-amino-5-chloropyridine (89.5 g, 0.696 mol) was treated with a solution of bromine (35.9 mL, 0.696 mol) in acetic acid (15 mL) over a period of 1.25 hours with gentle warming to 43° C. The resulting orange slurry was then cooled to 15° C. and filtered to provide a solid which was subsequently dissolved in water, basified (pH 8.5 ) with 1N NaOH, and extracted with ethyl acetate (5×150 mL). The combined organic layers were washed with 10% sodium bisulfite (2×150 mL), dried over magnesium sulfate, and condensed to give 102.1 g (70.7%) of a yellow solid, m.p. 83°-85° C.: IR(CHCl3) 3683, 3504, 3401, 2987, 2482, 2392, 1608, 1571, 1544, 1455, 1389, 1316, 1207, 1127, 1057, 1026, 895, 881, 650, 607, 249, 236cm ; H NMR (300MHz, CDCl3)δ 5.20 (br s, 2H) , 7.70 (d, 1H), J=2.2Hz) , 8.0 (d, 1H, J=2.2 Hz); 13C NMR (CDCl3)δ 104.08, 120.33, 139.62, 145.24, 154.10; exact mass calculated for C5H4N2BrCl=205.9246. High resolution mass spec. 205. 9246.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][O:9][C:10]=1[CH3:11])C.O.[NH2:15][NH2:16]>C(O)CCC>[CH3:12][C:7]1[C:6]([CH2:5][C:4]([NH:15][NH2:16])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: NN
Reactant: CCOC(=O)Cc1c(C)noc1C
Solvent: O
Solvent: CCCCO
Product: Cc1noc(C)c1CC(=O)NN
Yield: 87 %

Procedure:
As described for example 112a, (3,5-dimethyl-isoxazol-4-yl)-acetic acid ethyl ester (Bacon, Edward R.; Daum, Sol J.; Singh, Baldev. 6-Substituted pyrazolo[3,4-d]pyrimidin-4-ones and compositions and methods of use as c-GMP phosphodiesterase inhibitors. PCT Int. Appl. (1996), WO 9628429 A1) in butanol was reacted with hydrazine hydrate (3.2 equivalents) and the resulting mixture was heated under reflux for 24 h. Evaporation of all volatiles and crystallization from n-butanol/toluene afforded the title compound as a white solid (yield: 87%). MS: m/e=170.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[S:11]([CH2:17][C:18]#[N:19])([CH2:14][C:15]#[N:16])(=[O:13])=[O:12]>C(O)C.N1CCCCC1>[C:15]([CH2:14][S:11](/[C:17](=[CH:9]/[C:6]1[S:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:8][CH:7]=1)/[C:18]#[N:19])(=[O:13])=[O:12])#[N:16].[C:15](/[C:14](/[S:11](/[C:17](=[CH:9]/[C:6]1[S:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:8][CH:7]=1)/[C:18]#[N:19])(=[O:13])=[O:12])=[CH:9]\[C:6]1[S:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:8][CH:7]=1)#[N:16]
Reactant: N#CCS(=O)(=O)CC#N
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)/C(C#N)=C/c1ccc([N+](=O)[O-])s1
Product: N#CCS(=O)(=O)/C(C#N)=C/c1ccc([N+](=O)[O-])s1

Procedure:
A mixture of (0.5 g) of 2-nitrothiophen-5-carboxaldehyde and (0.7 g) of sulfonyl diacetonitrile in 6 mL ethanol was refluxed with a few drops of piperidine for 4 hours. Ethanol was removed in a rotavap and the mixture worked up with ethylacetate, diluted acid and brine. A portion of the crude was then purified by HPLC on a C-18 column to provide (0.05 g) of (E)-2-cyanomethylsulfonyl-3-(2-nitrothien-5-yl)acrylonitrile along with (0.03 g) of (E,E)-2-[[1-cyano-2-(2-nitrothien-5-yl)ethenyl]sulfonyl]-3-(2-nitrothien-5-yl)acrylonitrile.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:13][C:12]([C:27]([C:33]([F:36])([F:35])[F:34])([C:29]([F:32])([F:31])[F:30])[OH:28])=[N:11]1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][N:24]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:25][CH2:26]3)=[CH:19][CH:20]=2)[CH2:13][C:12]([C:27]([C:29]([F:30])([F:32])[F:31])([C:33]([F:34])([F:35])[F:36])[OH:28])=[N:11]1
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(N3CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[4-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 405, triethylamine (23.0 uL, 0.17 mmol) and methanesulfonyl chloride (5.0 uL, 0.07 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([Br:21])=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1.[C:22](=S)=[S:23].CI.[CH3:27][S:28]([CH3:30])=O>>[Br:7][C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([Br:21])=[CH:15][CH:16]=3)[C:11](=[C:27]([S:23][CH3:22])[S:28][CH3:30])[C:10]=2[CH:9]=1
Reactant: CS(C)=O
Reactant: S=C=S
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CI
Product: CSC(SC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Reaction time: 0.17 h

Procedure:
Sodium tert-butoxide (31.1 g, 0.32 mol) was added portionwise over 5 min to a solution of 2,7-dibromofluorene (50 g, 0.154 mol) in DMSO (1000 ml) at RT (22° C.) under nitrogen. To the resulting red solution was added carbon disulfide (13 g, 0.17 mol) via a syringe causing an exotherm to 35° C. The reaction was stirred for 10 min until the internal temperature was 30° C. Methyl iodide (46 g, 0.32 mol) was added over 2 min, causing an exotherm to 42° C. The reaction was stirred for 1 h and quenched by the addition of ice water (1000 ml) and conc. ammonia (20 ml). The reaction was stirred for 10 min and then filtered under reduced pressure and washed with further water (500 ml). After drying the crude yield was 64.8 g (98%, purity (HPLC) 97.8%). Recrystallization from ethyl acetate/THF (2:1) afforded 55.2 g (purity (HPLC) 99.2%).): 1H and 13C NMR spectra as expected; M+=428 (t). Anal. Calcd. For C16H12Br2S2: C, 44.9; H, 2.8, N, 0.0. Found C, 44.7; H, 3.1; N, <0.3.