Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[CH:10]=[C:9]1[C:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[N:21][C:20]=1[O:26][CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(=O)=O>ClCCl.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)[CH:15]=2)[CH:10]=[C:9]1[C:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[N:21][C:20]=1[O:26][CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1nnc(Cl)cc1-c1cc2ccc(C=O)cc2n1C(=O)OC(C)(C)C
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1nnc(Cl)cc1-c1cc2ccc(CN3CCN(C)CC3)cc2n1C(=O)OC(C)(C)C
Yield: 50 %

Procedure:
2.68 g 2-(6-Chloro-3-methoxy-pyridazin-4-yl)-6-formyl-indole-1-carboxylic acid tert-butyl ester is dissolved in 300 mL dichloromethane. 4.73 mL N-methylpiperazine and then 30 mL acetic acid are added. 4.40 g sodium triacetoxyborohydride is added in several portions over 3 hours. Sat. aq. NaHCO3-solution is added and the reaction mixture is stirred until the CO2-evolution stopped. The reaction mixture is diluted with dichloromethane, the aq. phase washed with dichloromethane, the combined org. phases dried (MgSO4) and concentrated in vacuo. HPLC purification affords 2.019 g (50%) 2-(6-chloro-3-methoxy-pyridazin-4-yl)-6-(4-methyl-piperazin-1-ylmethyl)-indole-1-carboxylic acid tert-butyl ester as its trifluoro-acetate salt.
Reaction SMILES: CO/[CH:3]=[C:4]1/[C:5](=[O:20])[NH:6][C:7](=[O:19])[C:8]2[C:13]/1=[CH:12][C:11]([N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)=[CH:10][CH:9]=2.CN(C)C=O.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1>CCOCC>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([NH:33]/[CH:3]=[C:4]2\[C:5](=[O:20])[NH:6][C:7](=[O:19])[C:8]3[C:13]\2=[CH:12][C:11]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18]2)=[CH:10][CH:9]=3)=[N:31][CH:32]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Reactant: Nc1ccc(Br)cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1NC(=O)c2ccc(-n3cccc3)cc2/C1=C/Nc1ccc(Br)cn1
Temperature: 125 °C

Procedure:
A mixture of (E)-4-(methoxymethylene)-6-(1H-pyrrol-1-yl)isoquinoline-1,3(2H,4H)-dione (268 mg, 1.0 mmole), dimethylformamide (8 mL), and 5-bromopyridin-2-amine (173 mg, 1.0 mmole) is heated at 125° C. for four hours. The reaction mixture is cooled, diluted with ether, filtered, washed with fresh ether and dried to give a salmon solid, 176 mg, (43%), mp 317-8° C. dec; MS (ES−): m/z 407.0 (M−H).
Reaction SMILES: CON(C)[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:7][CH:6]=1.[CH2:19]([Mg]Br)[CH3:20]>>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][C:8]1[N:7]=[CH:6][C:5]([C:4](=[O:17])[CH2:19][CH3:20])=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1ccc(OCC(F)(F)F)nc1
Reactant: CC[Mg]Br
Product: CCC(=O)c1ccc(OCC(F)(F)F)nc1
Yield: 87 %

Procedure:
The title compound is prepared in 87% yield (0.53 g, colorless oil) from N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)nicotinamide (0.70 g, 2.65 mmol, Step-2 of Amine-1) and ethyl magnesium bromide instead of methyl magnesium bromide by the similar manner in Step-3 of Amine-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.C([O-])(=O)C.[K+].Br[C:22]1[S:26][C:25]([C:27]#[N:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2[S:26][C:25]([C:27]#[N:28])=[CH:24][CH:23]=2)=[CH:3][C:4]=1[N+:13]([O-:15])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)COc1ccc(Br)cc1[N+](=O)[O-]
Reactant: N#Cc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(-c2ccc(C#N)s2)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 49.3 %

Procedure:
Under an argon atmosphere, 1.0 g of 4-bromo-1-isobutoxy-2-nitrobenzene, 1.0 g of bispinacolatodiboron, 1.2g of potassium acetate, and 0.1 g of tetrakis(triphenylphosphine)palladium were heated at 100° C. for 4 days in toluene. Then, 658 mg of 5-bromothiophene-2-carbonitrile, 0.1 g of tetrakis(triphenylphosphine)palladium, 10 ml of 1,4-dioxane, and 12 ml of a 2 M aqueous sodium carbonate solution were added thereto, followed by heating at 100° C. for 4 hours under an argon atmosphere. After the reaction solution was diluted with water and ethyl acetate, the solution was filtrated through celite. The filtrate was extracted with ethyl acetate and the organic layer was washed with brine and then dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10) to obtain 522 mg of 5-(4-isobutoxy-3-nitrophenyl)thiophene-2-carbonitrile. Then, 214 mg of the compound, 0.13 g of triethylamine hydrochloride, and 60 mg of sodium azide were heated at 100° C. for 14 hours in 20 ml of toluene. Additionally, 0.13 g of triethylamine hydrochloride and 60 mg of sodium azide were added thereto, followed by heating at 100° C. for 4 hours. The reaction solution was extracted with water and the aqueous layer was acidified with 1 M hydrochloric acid. The precipitate was collected by filtration, washed with water, dried, and purified by silica gel column chromatography (chloroform:methanol:acetic acid=94.7:5:0.3) to obtain 67 mg of 5-[5-(4-isobutoxy-3-nitrophenyl)-2-thienyl]-1H-tetrazole.
Reaction SMILES: Cl[CH:2]([CH2:27][CH2:28][CH3:29])[C:3]([NH:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=1[C:16](=[O:26])[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[O:19])=O.O1CCC[CH2:31]1>CN(C)C1C=CN=CC=1>[CH2:27]([CH:2]1[C:3]2=[N:5][C:6]3[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=3[C:16]([OH:26])=[C:17]2[C:18](=[N:20][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[O:19]1)[CH2:28][CH2:29][CH3:31]
Reactant: CCCC(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Reactant: C1CCOC1
Agent: CN(C)c1ccncc1
Product: CCCCC1OC(=Nc2nccs2)c2c1nc1c(C(F)(F)F)cccc1c2O

Procedure:
Using the procedure of Step B in Example 6, a mixture of 7 g of the product of Step B, 70 ml of tetrahydrofuran and 2.2 g of 4-dimethylamino-pyridine were reacted to obtain 6.1 g of 3-butyl-1,3-dihydro-1-[(2-thiazolyl)-imino]-5-trifluoromethyl-furo[3,4-b]quinoline-9-ol melting at 228° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][NH2:4].CN(C)C1C=CC=CC=1.[Br:19][CH2:20][C:21](Br)=[O:22]>C(OCC)(=O)C>[Br:19][CH2:20][C:21]([NH:4][CH2:3][C:2]([F:9])([F:1])[C:5]([F:8])([F:7])[F:6])=[O:22]
Reactant: O=C(Br)CBr
Reactant: NCC(F)(F)C(F)(F)F
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(CBr)NCC(F)(F)C(F)(F)F
Temperature: -10 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
2,2,3,3,3-Pentafluoropropylamine (produced by Synquest) (389 g) was dissolved in ethyl acetate (1.56 L), and N,N-dimethylaniline (316 g) was added thereto. After cooling the mixture to −10° C., bromoacetyl bromide (500 g) was added dropwise thereto, and the resulting mixture was stirred at a temperature between 10° C. and 0° C. for 2 hours. The organic layer was sequentially washed with aqueous hydrochloric acid, aqueous sodium bicarbonate and with brine, and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure to obtain 2-bromo-N-(2,2,3,3,3-pentafluoropropyl)acetamide (678 g) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH2:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[C:29](OCC)(=[O:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C1(C)C=CC=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH:28][C:29](=[O:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: CCOC(=O)C(=O)OCC
Reactant: NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
2-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethanamine (112 mg, 0.29 mmol) was dissolved in toluene (2.9 mL) before diethyl oxalate (0.39 mL, 2.88 mmol) was added and stirred at 110° C. for 16 h. The reaction mixture was diluted with 75 mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give ethyl 2-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethylamino)-2-oxoacetate after flash chromatography. MS (ESI) m/z: Calculated: 489.2; Observed: 490.4 (M++H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[CH3:14][N:15]([CH3:28])[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27]CNC[CH2:23]2)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:23][N:22]([CH3:27])[C:19]1[CH:20]=[CH:21][C:16]([N:15]2[CH2:28][CH2:1][N:2]([CH2:4][C:5]3[C:13]4[C:8](=[N:9][CH:10]=[CH:11][CH:12]=4)[NH:7][CH:6]=3)[CH2:3][CH2:14]2)=[CH:17][CH:18]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: CN(C)c1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Yield: 44.8 %

Procedure:
A mixture of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.4450 g, 2.54 mmol) and 1-(4-dimethylaminophenyl)piperazine (0.55 g, 2.68 mmol) in toluene (20 ml) was heated at reflux under nitrogen for 7 h. The mixture was allowed to cool and the solid formed was collected. Recrystallisation from methanol gave the title compound (0.382 g, 45%) as colourless needles, m.p. 199°-201° C.; (Found: C, 71.32; H, 7.37; N, 20.71. C20H25N5 requires C, 71.61; H, 7.51; N, 20.88%); δH (DMSO-d6) 2.52 (4H, m, 2×piperazinyl CH2), 2.76 (6H, s, N(CH3)2), 2.95 (4H, m, 2×piperazinyl CH2), 3.67 (2H, s, CH2N), 6.66 (2H, m, ArH), 6.80 (2H, m, ArH), 7.03 (1 H, dd, J 7.8, 4.7 Hz), 7.35 (1H, d, J 2.0 Hz, 2-H), 8.04 (1H, dd, J 7.8, 1.5 Hz, 4-H), 8.19 (1H, dd, J 4.7, 1.5 Hz, 6-H), and 11.41 (1H, br s, NH); m/z (CI+, NH3) 336 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H]2OC(OCC)[O:18][C@@H:14]2[C@@H:13](CO)[CH2:12]1.[CH3:24][O:25][C:26]([O:29][CH3:30])([CH3:28])[CH3:27].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:24]2[O:25][C:26]([CH3:28])([CH3:27])[O:29][C@@H:30]2[C@@H:13]([CH2:14][OH:18])[CH2:12]1
Reactant: CCOC1O[C@@H]2[C@@H](CO)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The above crude ((3aR,4R,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2-ethoxytetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol was taken up in 2,2-dimethoxypropane (214 mL, 1740 mmol) and treated with p-toluenesulfonic acid monohydrate (13.2 g, 69.5 mmol) to afford a brown oil partially suspended in a cloudy solution, which was stirred at rt for 1 h 20 min; HPLC/LC MS indicated complete conversion to the desired product. The reaction was quenched by the careful addition of sodium bicarbonate (8.76 g, 104 mmol) and a minimal amount of water. The volatiles were removed in vacuo and the remaining aqueous layer was diluted with water (100 mL) and extracted with CH2Cl2 (3×400 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford a brown oil. Purification by column chromatography (7×16 cm silica; 0-5% MeOH/CH2Cl2) afforded the title compound (8.30 g, 74% over 3 steps) as a yellow foam: MS (ESI+) for C14H17ClN4O3 m/z 325.1 (M+H)+; MS (ESI−) for C14H17ClN4O3 m/z 369.0 (M+HCO2)−.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@H:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[C:17]1([C@@H:9]2[CH2:8][C@@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1c1ccccc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@H](c3ccccc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 127.3 %

Procedure:
(2S,4S)-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-phenylpiperidine-1-carboxylate (249 mg, 0.82 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 3 mL, 42.82 mmol) and the mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4S)-2-phenylpiperidin-4-yl)isoxazol-3(2H)-one (255 mg, 127%) (the isolated sample contained DMSO). 1H NMR (400 MHz, cdcl3) δ 2.10-2.43 (m, 4H), 3.21 (dt, 1H), 3.26-3.35 (m, 1H), 3.35-3.43 (m, 1H), 4.17 (dd, 1H), 5.73 (s, 1H), 7.34-7.48 (m, 5H). HRMS Calculated for [C14H16N2O2+H]+: 245.1290. Found: 245.1271.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]N=1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:1]1([CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: c1ccncc1
Reactant: Cc1ccccn1
Product: c1ccc(C2CCCNC2)cc1

Procedure:
Pyridine and 2-methylpyridine
Reaction SMILES: CSC.B.[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15](O)=[O:16])[CH:10]=[C:11]([Cl:13])[CH:12]=1>C1COCC1>[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][OH:16])[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: O=C(O)Cc1cc(Cl)cc(CBr)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCc1cc(Cl)cc(CBr)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of borane dimethyl sulfide complex (2M in THF, 2.8 mL) was added portionwise over 5 minutes to a solution of 2-(3-(bromomethyl)-5-chlorophenyl)acetic acid [Aromatic Intermediate 8, step a] (0.73 g) in dry THF (10 mL) at room temperature. The resulting effervescing solution was stirred for 1 hour, then cooled in ice-water and quenched by the portionwise addition of methanol (3 mL) over 5 minutes. The solution was stirred at room temperature for a further 20 minutes and then concentrated in vacuo. The residue was purified by flash chromatography on silica eluted with 25% ethyl acetate in isohexane to afford the crude subtitled compound as a white solid. Yield 0.46 g.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH:12]=O)=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=1.[CH3:26][NH2:27].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][NH:27][CH3:26])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=1
Reactant: CN
Reactant: CC(C)(C#N)c1ccc(Nc2c(C=O)cnc3ccc(Cl)nc23)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCc1cnc2ccc(Cl)nc2c1Nc1ccc(C(C)(C)C#N)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
2-(4-((6-chloro-3-formyl-1,5-naphthyridin-4-yl)amino)phenyl)-2-methylpropionitrile (2.5 g, 7.1 mmol) was dissolved in ethanol (100 mL), added 3 mL of a solution of methylamine in ethanol (concentration 27%), stirred at room temperature for 10 h. Then, to the system added sodium borohydride (1.5 g, 3.97 mol), continued stirring at room temperature for 18 h, and the reaction was quenched with a saturated aqueous solution of sodium carbonate. Concentrated under reduced pressure to remove ethanol, extracted with 150 mL of dichloromethane, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 2.2 g of a solid.
Reaction SMILES: [CH:1]1([C:11]([O:13]C)=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH3:10])=[O:8].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>>[CH3:10][O:9][C:7]([C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@@H:1]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: COC(=O)C1CCCCC1C(=O)OC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: COC(=O)[C@@H]1CCCC[C@@H]1C(=O)O
Temperature: 40 °C
Reaction time: 43 h
Yield: 85.9 %

Procedure:
Into a 100 mL jacketed vessel was placed dimethyl cyclohexane-1,2-dicarboxylate (2, 4 g, 20 mmol) and 39 mL of 0.1M potassium phosphate buffer, pH 8. The mixture was continuously stirred at 40° C. and Novozym™ 435 (320 mg) was added. Stirring was continued at 40° C. for 43 hours and pH was maintained at 8 by addition of 2M NaOH solution. A sample from the reaction was analyzed by GC to confirm that less than 5% of the starting material remained. The reaction mixture was filtered to remove the enzyme and the filtrate was extracted with toluene (20 mL) to remove any residual starting material. The pH of the aqueous phase was readjusted to 3.5 with 2M HCl and it was extracted with 2×50 mL of MTBE. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure to yield 3.2 g (86%) of (1S,2R)-2-(methoxycarbonyl) cyclohexane carboxylic acid (3) as a colorless oil with e.e.=98%. The isolated enzyme is washed with fresh buffer for reuse with a second batch of substrate/buffer.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1/[CH:17]=[CH:18]/[C:19]([N:21]([O:23][CH3:24])[CH3:22])=[O:20].O>CS(C)=O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH:17]1[CH2:4][CH:18]1[C:19]([N:21]([O:23][CH3:24])[CH3:22])=[O:20]
Reactant: C[S+](C)(C)=O
Reactant: CON(C)C(=O)/C=C/c1cc(F)ccc1Br
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CON(C)C(=O)C1CC1c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 122 mg, 3.05 mmol, Aldrich) was added to a suspension of trimethylsulfoxonium iodide (671 mg, 3.05 mmol, Aldrich) in DMSO (6 mL). The mixture was stirred at 25° C. for 30 min, and (E)-3-(2-bromo-5-fluorophenyl)-N-methoxy-N-methylacrylamide was added as a solution in DMSO (3 mL). The mixture was stirred at 25° C. for 12 h, then transferred to a separatory funnel with H2O (40 mL), and the title compound was extracted using 75% ether/hexane (3×40 mL). The organic layer was dried over sodium sulfate and concentrated. Purification by flash column chromatography (33% EtOAc/hexane) afforded the title compound as a colorless oil. MS m/z: 302 and 304 (M+1).
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCCCN(C(=O)C(=O)OCC)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C#CCCCCN(C(=O)C(=O)O)C(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A solution of 0.7 g of 17d in 8 ml of dioxane was mixed with a solution of 0.3 g of KOH in 3 ml of water. The mixture was stirred for 2 h at 50° C. and then diluted with 30 ml of water and acidified to pH3 with 0.5 N HCl. The product was extracted with ethyl acetate. The extract was washed with water, dried and concentrated, to give 0.50 g of 19a as a colorless oil. NMR (CDCl3) δ 1.53 (s and m, 11, tertC4H9 and CH2), 1.78 (m, 2, CH2), 1.97 (t, 1, acetylene), 2.20 (m, 2, CH2), 3.56 (m, 2, CH2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([CH2:16]O)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([CH2:16][N:41]3[C:37](=[O:47])[C:38]4[C:39](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:40]3=[O:42])=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(CO)[C@@H]2C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(CN3C(=O)c4ccccc4C3=O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To alcohol 7 (1.13 g; 4.67 mmol), triphenyl phosphine (1.28 g; 4.88 mmol) and phthalimide (0.73 g; 4.96 mmol) in THF (75 mL) was added DIAD (0.98 mL; 4.94 mmol). The reaction mixture was stirred at room temperature overnight. The volatiles were evaporated and the residue chromatographed with 50% ethyl acetate/hexanes to yield phthalimide 8 as a white foam.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OO)(C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:15]1([C:14]2[O:1][C:2]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:21]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)CC(=O)c1cccnc1
Reactant: NCc1ccccc1
Agent: CC(C)(C)OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccccc2)oc1-c1cccnc1
Temperature: 40 °C
Reaction time: 19 h
Yield: 178.9 %

Procedure:
To a solution of methyl 3-oxo-3-(pyridin-3-yl)propanoate (4 g, 22.3 mmol) in ethyl acetate (200 mL) were added at RT tetrabutylammonium iodide (1.65 g, 4.46 mmol), benzylamine (4.78 g, 4.87 mL, 44.6 mmol) and tert-butyl hydroperoxide (5.5M solution in decane, 16.2 mL, 89.3 mmol). The reaction mixture was stirred at 40° C. for 19 h. Sodium thiosulphate (10% aqueous solution, 200 mL) was added at RT and the reaction mixture was stirred for 10 min (until negative peroxide test). The aqueous phase was separated, the organic phase was washed with water (2×100 mL) and brine (20 mL). The aqueous phases were back-extracted with ethyl acetate (1×100 mL) and the combined organic phase was dried over MgSO4, filtered and evaporated to give 11.18 g of yellow semi-solid. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as yellow solid (1.33 g, 4.75 mmol, 21.3% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:25](=[O:26])[CH2:24][Cl:23])[C@@H:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (R)-3-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (795 mg, 3.68 mmol) in DCM (20 mL) was added triethylamine (1.53 mL, 11.04 mmol). The resulting mixture was cooled to 0° C. before the dropwise addition of chloroacetyl chloride (325 μL, 4.05 mmol). The mixture was warmed to RT and stirred for 5 h. The reaction mixture was partitioned between a saturated aqueous solution of NaHCO3 and DCM. The organic layer was separated and the aqueous layer extracted with DCM. The combined organic fractions were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography to give the title compound as a colourless oil which was a mixture of rotamers (710 mg, 66%).