Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([NH2:14])=[O:13]>C1(C)C=CC=CC=1>[C:1]([O:9][CH2:11][C:12]([NH2:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)CCl
Reactant: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: NC(=O)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.2 %

Procedure:
In the reaction vessel, 4.3 grams (0.09 mole) of a 50% suspension of sodium hydride in mineral oil was washed with two portions of 50 ml each of hexane, then two portions of 50 ml each of toluene. Dry toluene, 75 ml, was added and with stirring a solution of 10.0 grams (0.082 mole) of benzoic acid in 200 ml of dry toluene was added dropwise. The exothermic reaction caused the temperature of the reaction mixture to rise from 27° to 32°. Upon completion of the addition, the reaction mixture was heated under reflux for 1.5 hour. The mixture was cooled to ambient temperature and 8.4 grams (0.09 mole) of 2-chloroacetamide was added in portions. Upon completion of the addition, the reaction mixture was heated under reflux for 18 hours. An additional 150 ml of dry toluene was added and heating under reflux continued an additional 24 hours. The reaction mixture was cooled to ambient temperature and a solid precipitate collected by filtration. The filtrate was extracted with two portions of 200 ml each of water. The milky organic layer was dried twice with sodium sulfate and filtered. the filtrate was evaporated under reduced pressure to a solid residue, which produced bubbling in the presence of aqueous saturated sodium bicarbonate solution, and was concluded to be unreacted benzoic acid. The solid collected by filtration from the original reaction mixture was dissolved in 200 ml of ethyl acetate and washed with two portions of 100 ml each of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to a solid residue. The solid was recrystallized from toluene to give 3.7 grams of (aminocarbonyl)methyl benzoate; mp 118°-120 . The ir and the nmr spectra were consistent with the proposed structure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([OH:12])[CH:9]=[CH:8][N:7]=1.C1C(=O)N([Cl:20])C(=O)C1>CC(O)=O>[Cl:20][C:9]1[C:10]([OH:12])=[N:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7][CH:8]=1
Reactant: Oc1ccnc(-c2cccs2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Oc1nc(-c2cccs2)ncc1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
To the solution of 2-(thiophen-2-yl)pyrimidin-4-ol (100 mg, 0.56 mmol) in HOAc (3 mL) was added NCS (90 mg, 0.67 mmol, 1.2 equiv.) portionwise. The reaction mixture was stirred at 60° C. for 4 h and partitioned between brine and ethylacetate. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to give 5-chloro-2-(thiophen-2-yl)pyrimidin-4-ol (90 mg, 75%). LC-MS (m/z)=213.0 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N+:7]([CH:10]=[CH:11][C:12]1[CH:28]=[CH:27][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)=[CH:14][CH:13]=1)([O-])=O>O1CCCC1>[F:25][C:23]([F:24])([F:26])[C:20]1[CH:21]=[CH:22][C:17]([O:16][C:15]2[CH:27]=[CH:28][C:12]([CH2:11][CH2:10][NH2:7])=[CH:13][CH:14]=2)=[N:18][CH:19]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Entire reaction was performed under argon atmosphere using syringe septa technique. To a stirred suspension of LiAlH4 (3.062 mmol, 2.5 eq) in dry tetrahydrofurane (20 ml) was added 2-[4-(2-nitro-vinyl)-phenoxy]-5-trifluoromethyl-pyridine (1.225 mmol, 1 eq) dissolved in dry tetrahydrofurane (10 ml) dropwise. Reaction mixture was stirred at rt for 2 h. Reaction mixture was quenched with 0.5 ml water. Celite and NaOH (3 ml, 5 N) were added and the mixture was filtered through Celite, rinsing the filter cake well with ether and DCM. Solvents were evaporated till dry. Crude product was purified on Biotage SP1 Snap Si 25; 25 ml/min in the gradient of MeOH in DCM: 0-5% for 3CV then from 5-40% for 30 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-[4-[5-trifluoromethyl-pyridin-2-yloxy)phenyl]-ethylamine s yellow oil (0.443 mmol, yield=36%, purity=91%). [M+H]+=283.30 1H NMR (300 MHz, DMSO-d6) δ/ppm 2.68 (d, 2H), 2.79 (d, J=7.5 Hz, 2H), 7.06-7.13 (m, 2H), 7.19 (d, J=8.7 Hz, 1H), 7.23-7.29 (m, 2H), 8.17-8.20 (m, 1H), 8.20-8.23 (m, 1H), 8.51-8.57 (m, 2H)
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:3]=1[CH3:24].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[N:11]=[C:10]3[N:4]([CH2:5][CH2:6][C:7]4[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=4[CH:9]3[O:12][CH:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[C:3]=2[CH3:24])[CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1c(I)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc(F)c2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 95 °C
Reaction time: 20 h

Procedure:
To a solution of 2-iodo-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 133) (100 mg, 0.23 mmole) in toluene (2 mL) and ethanol (1 mL) in a screw-capped vial are added 3-fluorobenzeneboronic acid (64 mg, 0.46 mmole), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (10 mg) and an 1M aqueous solution of potassium carbonate (0.8 mL). The vial is evacuated and filled with argon. The reaction mixture is stirred at 95° C. for 20 hours. Water is added to the reaction mixture, and the pH is adjusted to 9-10 with 1N aqueous sodium hydroxide. The aqueous phase is extracted three times with ethyl acetate. The pooled organic extracts are dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (95:5:0.1) to (92:8:0.5) to give 2-(3-fluorophenyl)-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 132° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[O:8][N:7]=1)=O)C.[BH4-].[Na+]>C(O)C>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[O:8][N:7]=[C:6]([CH2:4][OH:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(-c2ccco2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(-c2ccco2)on1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
To a solution of 2.00 g of 5-furan-2-yl-isoxazole-3-carboxylic acid ethyl ester in absolute ethanol was slowly added 548 mg of sodiumborohydride at 0° C. After stirring at room temperature for 4 hrs, the reaction was quenched by addition of distilled water. The reaction solution was concentrated under reduced pressure and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to produce 1.41 g of (5-furan-2-yl-isoxazol-3-yl)-methanol. (Yield 88%). This concentrate was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[NH2:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(N)c3)ccn2c1=O
Yield: 39.6 %

Procedure:
Methyl 8-(3-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (195 mg, 0.66 mmol) and (3-aminophenyl)-boronic acid (119 mg, 0.87 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (91 mg, 39%). ESI-MS m/z: 349 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]#[N:8])[C:4]([NH2:6])=[O:5].[CH2:9]([O:16][CH2:17][C@H:18]([O:29][N:30]=[CH:31]N(C)C)[CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[CH2:9]([O:16][CH2:17][CH:18]([O:29][N:30]=[CH:31][NH:2][C@H:3]([C:7]#[N:8])[C:4]([NH2:6])=[O:5])[CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CC(N)C(N)=O
Reactant: CN(C)C=NO[C@H](CCOCc1ccccc1)COCc1ccccc1
Agent: Cl
Solvent: CO
Product: N#C[C@@H](NC=NOC(CCOCc1ccccc1)COCc1ccccc1)C(N)=O
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A solution of 2-amino-2-cyanoacetamide hydrochloride (0.19 g, 1.4 mmol) and (R)-N'-(1,4-dibenzyloxybut-2-oxy)-N,N-dimethylmethanimidamide (0.5 g, 1.4 mmol) in methanol (1.5 ml) was stirred at room temperature for 20 hours. The solvent was removed under reduced pressure and the residue treated with ethyl acetate (20 ml) and brine (0.05 ml). The organic solution was decanted and dried (MgSO4). The solvent was removed under reduced pressure and the residual oil extracted with hexane (3×10 ml). The hexane was decanted and the residual oil was dissolved in warm chloroform (3 ml) and treated with hexane (20 ml). After refrigeration (-18° C.) for 1 hour, the organic solution was decanted and the insoluble oil dried under vacuum to give (R)-2-[N-(1,4-dibenzyloxy-but-2-oxy)iminomethyl]amino-2-cyanoacetamide (0.37 g, 74%); IR: υmax (film) 3340, 3190, 3090, 3060, 3030, 2950, 2920, 2860, 2800, 1700, 1660, 1600, 1495, 1455, 1375, 1310, 1240, 1215, 1145, 1125, 1025, 985, 945, 905, 740, 700 cm-1 ; 1H NMR: δH [(CD3)2SO] 1.87 (2H, m, CH2), 3.54 (4H, m, 2×CH2), 4.05 (0.12H, m, CH), 4.13 (0.88H, m, CH), 4.45 (4H, m, 2×CH2), 5.07 (0.13H, d, J=8 Hz, CH), 5.26 (0.87H, d, J=8 Hz, CH), 6.80 (1H, d, J=10.5 Hz, CH), 6.92 (1H, dd, J=10.5 and 8 Hz, NH), 7.2-7.8 (12H, m, 2×C6H5 plus D2O exchangeable NH2); m/z (NH3CI) M+ 411. Found: C, 61.83; H, 6.50; N, 13.32%. C22H26N4O4. H2O requires: C, 61.67; H, 6.59; N, 13.08%.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:8]=CN=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:4]=1.Cl[C:20]1N=C(C(F)(F)F)C=C[N:21]=1>>[CH3:2][C:3]1[N:4]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[CH:20]=[N:21][CH:8]=1
Reactant: FC(F)(F)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Product: Cc1cncc(N2C[C@@H]3CCNC[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 27, substituting 2-bromo-6-methylpyrazine for 2-chloro-4-(trifluoromethyl)pyrimidine.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CO.[C:6]([N:10]1[CH:18]=[C:17]2[C:12]([C:13](=[O:37])[NH:14][C:15]3([CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:35]=[C:34]5[C:29]([CH:30]=[CH:31][N:32]=[C:33]5Cl)=[CH:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)[CH2:16]2)=[N:11]1)([CH3:9])([CH3:8])[CH3:7]>>[C:6]([N:10]1[CH:18]=[C:17]2[C:12]([C:13](=[O:37])[NH:14][C:15]3([CH2:23][CH2:22][N:21]([C:24]([C:26]4[CH:35]=[C:34]5[C:29]([CH:30]=[CH:31][N:32]=[C:33]5[N:2]([CH3:3])[CH3:1])=[CH:28][CH:27]=4)=[O:25])[CH2:20][CH2:19]3)[CH2:16]2)=[N:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CNC
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCN(C(=O)c3ccc4ccnc(Cl)c4c3)CC1)C2
Solvent: CO
Product: CN(C)c1nccc2ccc(C(=O)N3CCC4(CC3)Cc3cn(C(C)(C)C)nc3C(=O)N4)cc12
Temperature: 60 °C
Reaction time: 65 h
Yield: 61 %

Procedure:
A solution of dimethylamine in methanol (1.75 mL, 3.50 mmol, 2 M) was added to 2′-tert-butyl-1-(1-chloroisoquinoline-7-carbonyl)-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one (158 mg, 0.350 mmol). The reaction vessel was sealed and the mixture was heated to 60° C. and stirred for 65 hours. The reaction was cooled to room temperature and concentrated. Purification by flash column chromatography (1-15% methanol/dichloromethane) gave the title compound (99 mg, 61%) as a white solid. +APCI (M+H) 461.4; 1H NMR (400 MHz, CDCl3, δ): 8.16-8.20 (m, 1H), 8.12 (d, J=5.9 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.58-7.64 (m, 1H), 7.37 (s, 1H), 7.14 (d, J=5.9 Hz, 1H), 6.00 (br. s., 1H), 3.40-3.71 (m, 4H), 3.10-3.28 (m, 6H), 2.85 (s, 2H), 1.64-1.99 (m, 4H), 1.60 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH:26]([Br:30])[CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(Br)c1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 40.4 %

Procedure:
A mixture of 1.12 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde and 0.49 g of N-bromosuccinimide in 40 mL of CCl4 was irradiated (UV-lamp, pyrex filter) for 0.5 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. Column chromatography (elution: ethyl acetate/benzene) afforded 0.54 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-(1-bromobutyl)-4-chloroimidazole-5-carboxaldehyde. NMR (200 MHz, CDCl3) δ 9.87 (s, 1H); 7.86 (d, 1H); 7.54 (t, 1H); 7.46 (t, 1H); 7.30 (m, 3H); 7.11 (d, 2H); 6.16 (d, 1H); 5.32 (d, 1H); 4.79 (t, 1H); 3.65 (s, 3H); 2.32 (m, 2H); 1.34 (sext., 2H); 0.83 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[F:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.5 %

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (10 g, 53.7 mmol) in dichloromethane (300 mL), add triethyl amine (15.1 mL, 107.4 mmol) and 2-fluorobenzoyl chloride (6.4 mL, 53.7 mmol). Stir the mixture at room temperature overnight. Then add water (200 mL) and separate the organic layer, dry over sodium sulfate, filter and evaporate solvent under reduced pressure to give 17.3 g of 4-(2-fluoro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester. ES+ (m/z) 309[M+H].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[SH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[OH-].[K+]>C(COC)OC>[F:8][C:4]1[N:3]=[C:2]([S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(F)n1
Reactant: Oc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: Oc1ccc(Sc2cccc(F)n2)cc1

Procedure:
A mixture comprising 69 grams (0.6 mole) of 2,6-difluoropyridine, 75.6 grams (0.6 mole) of 4-mercaptophenol and 49.5 grams (0.75 mole) of 85 percent potassium hydroxide was stirred in 300 milliliters of monoglyme for ~ 4 days at room temperature. At the end of this time, the reaction mixture was filtered to remove any solid by-products present. The filtrate was concentrated to remove most of the monoglyme and the residue mixed with 400 milliliters of 5 percent sodium hydroxide. The mixture was washed with methylene chloride and the aqueous solution acidified with concentrated hydrochloric acid. The solid 4-((6-fluoro-2-pyridyl)thio)phenol product precipitated out and was recovered by filtration, washed with water and dried. The product was recovered in a yield of 112 grams (87 percent of theoretical) and melted at 123°-124° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.C([Li])CCC.[C:16](=[O:18])=[O:17].O>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:16]([OH:18])=[O:17])=[CH:3][C:4]=1[CH3:10])#[N:7]
Reactant: Cc1cc(Br)ccc1C#N
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1C#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF (100 ml) at −78° C. under a nitrogen atmosphere was added dropwise a 2.5M solution of n-butyl lithium (4.48 ml, 11.2 mmol). The mixture was stirred at −78° C. for 1 h and then poured onto solid carbon dioxide (5 g) in THF (50 ml). The mixture was allowed to warm to room temperature. Water was added (200 ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 1.2 g (73%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=O)[CH2:17][CH2:16]2)[CH2:10][CH2:11][CH3:12]>C(O)C.O>[CH2:9]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[N:2][OH:3])[CH2:17][CH2:16]2)[CH2:10][CH2:11][CH3:12]
Reactant: NO
Reactant: CCCCc1ccc2c(c1)CCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCc1ccc2c(c1)CCC2=NO

Procedure:
Hydroxylamine hydrochloride (0.89 g, 12.8 mmol) and sodium acetate (12.8 mmol) are added to a solution of 5-n-butylindan-1-one (1.0 g, 5.31 mmol) in ethanol (30 ml) and water (3 ml). The reaction is heated to reflux for 20 minutes, then water is added and the mixture is extracted with CH2Cl2. The combined organic extracts are washed with brine, dried (MgSO4) and evaporated to afford the title compound. NMR δH 0.86 (t J 7.3 3H), 1.28 (sextet J 7.3 2H), 1.52 (quintet J 7.3 2H), 2.55 (t J 8.0 2H), 2.85-3.0 (m 4H), 7.0 (d J 8.3 1H), 7.05 (s 1H), 7.45 (d J 8.3 2H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1.Br[C:14]1[N:22]=[C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:16]2[N:15]=1.CCN(C(C)C)C(C)C>C(O)C>[N:15]1[N:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]2=[N:22][C:14]=1[N:1]1[CH2:6][CH2:5][CH:4]([C@H:7]2[CH2:9][C@H:8]2[CH2:10][CH2:11][OH:12])[CH2:3][CH2:2]1
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: Brc1nc2ncccn2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: OCC[C@@H]1C[C@@H]1C1CCN(c2nc3ncccn3n2)CC1
Temperature: 120 °C

Procedure:
To a mixture of 2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethanol (Intermediate 11; 70 mg, 0.4 mmol) and 2-bromo[1,2,4]triazolo[1,5-a]pyrimidine (9 mg, 0.496 mmol) in ethanol (2 mL) was added DIEA (0.22 mL, 1.21 mmol) and the resulting mixture heated via microwave to 120° C. for 1 hr. HPLC of the reaction mixture proved the reaction was complete with the absence of Intermediate 11. The mixture was filtered (glass wool filter paper, Whatman 1821 110), and washed with ethanol. The filtrate was concentrated to dryness under reduced pressure and the resulting residue purified via preparative TLC plates (2×1000 μM silica gel) eluting with 50% ethyl acetate in hexane. The product was removed from the silica gel by extracting with ethyl acetate and the solvent was removed under reduced pressure to afford the title compound as an off-white solid. MS (Multimode) m/z 288 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]1[O:9][CH2:8]1>O>[OH:9][CH2:8][CH2:7][NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4]
Reactant: C1CO1
Reactant: CC(C)(N)CO
Solvent: O
Product: CC(C)(CO)NCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
2-(2-Hydroxy-ethylamino)-2-methyl-propan-1-ol was prepared from 2-amino-2-methyl-propan-1-ol following a modified procedure from Cottle et al. J. Chem. Soc. 1946, 289. To a solution of 2-amino-2-methyl-propan-1-ol (250 mL, 2.61 mol, 1.76 equiv.) in H2O (400 mL) at −5° C. (external temperature, NaCl/ice bath) was added ethylene oxide (65.25 g, 1.48 mol, condensed at −78° C.). The solution was stirred over 16 hours, during which time the temperature warmed to room temperature. The H2O was removed in vacuo and the remaining 2-amino-2-methyl-propan-1-ol was distilled. The crude residue was dissolved in boiling EtOAc and precipitated with the addition of hexanes to provide 2-(2-Hydroxy-ethylamino)-2-methyl-propan-1-ol (145.5 g, 74%) as colorless crystals. LC/MS found 134.03 (M++H, C6H16NO2 requires 134.12).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH:15]=[CH2:16].[Cl-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:3][CH2:2][CH:1]=[CH2:6])[C:8]#[N:9])[CH2:14][CH2:15][CH3:16]
Reactant: N#CCc1ccccc1
Reactant: C=CCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCC(C#N)(CCCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-phenylacetonitrile (1 mL) in DMF (1.0 mL) at 0° C. was added sodium hydride (95% oil dispersion, 547 mg) and the resulting suspension was stirred at 0° C. for 10 min. 4-Bromobut-1-ene (2.2 mL) was added, and the reaction mixture was stirred at room temperature for 2 h. Saturated sodium chloride was added followed by ethyl acetate, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel flash chromatography eluting with 10% ethyl acetate/90% hexanes to give the title compound as an oil (773 mg). 1H NMR (400 MHz, CDCl3) δ 1.8-2.3 (8H, m), 4.95 (4H, m), 5.73 (2H, m), and 7.31 (5H, m).
Reaction SMILES: [CH:1]1([NH2:8])[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[C:9](#[N:12])[CH:10]=[CH2:11]>C(O)C>[C:9]([CH2:10][CH2:11][NH:7][CH:4]1[CH2:5][CH2:6][CH:1]([NH:8][CH2:2][CH2:3][C:4]#[N:7])[CH2:2][CH2:3]1)#[N:12]
Reactant: NC1CCC(N)CC1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCNC1CCC(NCCC#N)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
In a 5-liter reactor, 531.5 g of 1,4-cyclohexanediamine were placed and warmed at 80° C. until total fusion of the product. Then 675 mL of acrylonitrile were added and the mixture was warmed at 80° C. for 1 h, and at 100° C. for 2 h. Then 960 mL of ethanol were added and it was cooled down to room temperature, occurring the precipitation of a solid. After filtering, washing with ethanol and drying, 952.2 g (92.8%) of the title compound were obtained as a brown solid. Elemental analysis (%): theory, C 65.49, H 9.09, N 25.45; found, C 65.80, H 9.20, N 26.16.
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([NH:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:14])=[C:7]([O:28][CH3:29])[CH:6]=1)(=O)C.[OH-].[K+]>C(O)C>[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([NH:12][C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:19][CH2:20]2)=[O:14])=[C:7]([O:28][CH3:29])[CH:6]=1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1NC(=O)N1CCN(Cc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(N)c(Cl)cc1NC(=O)N1CCN(Cc2ccccc2)CC1

Procedure:
A solution of N-(4-acetylamino-5-chloro-2-methoxyphenyl)-4-benzylpiperazine-1-carboxamide (e9) (1.4 g) in ethanol (20 ml) was refluxed for 1 hour with an aqueous (4 ml) solution of potassium hydroxide (0.6 g). The solvent was removed by evaporation and the residue extracted with ethyl acetate. Chromatography of the solution (on alumina with 5% water, in chloroform) followed by evaporation of the solvent yielded N-(4-amino-5-chloro-2-methoxyphenyl)-4-benzylpiperazine-1- carboxamide (e10).