Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH:34]C(=O)C1C=CC=CC=1)=[N:21]2>CO>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:29][O:28][C@@H:27]([CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:26][C@H:25]1[CH2:24][S:23][C:22]([NH2:34])=[N:21]2
Reactant: CC(C)C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)C[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: 60 °C

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (3.0 μL, 20 μmol) was added to a solution of N-[(4aR,6S,8aS)-8a-(2,4-difluorophenyl)-6-(2-methylpropyl)-4,4a, 5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C29) (10.5 mg, 23.6 μmol) in methanol (0.4 mL) and the reaction mixture was heated at 60° C. for 18 hours in a sealed vial. Solvent was removed under a stream of nitrogen, and the residue was partitioned between water (3 mL) and ethyl acetate (5 mL). The aqueous layer was extracted with ethyl acetate (5 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification was carried out via reversed phase high-performance liquid chromatography (Column: Waters XBridge C18, 5 μm; Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v); Gradient: 30% to 100% B). Yield: 4.2 mg, 12 μmol, 51%. LCMS m/z 341.1 [M+H+]. 1H NMR (600 MHz, DMSO-d6) δ 7.31-7.36 (m, 1H), 7.15-7.20 (m, 1H), 7.08 (ddd, J=9, 8, 2 Hz, 1H), 3.86 (dd, J=10.5, 1.8 Hz, 1H), 3.54 (d, J=10.5 Hz, 1H), 3.50-3.56 (m, 1H), 2.62-2.73 (m, 3H), 1.71-1.79 (m, 1H), 1.52-1.60 (m, 1H), 1.45-1.50 (m, 1H), 1.40 (ddd, J=14, 8, 6 Hz, 1H), 1.21 (ddd, J=14, 8, 4.5 Hz, 1H), 0.89 (d, J=6.1 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:34]1([C:38]2[O:42][C:41]([NH:43][C:44]3[CH:45]=[CH:46][C:47]([C:50]4[CH:55]=[CH:54][C:53]([C:56]56[CH2:63][CH2:62][C:59]([CH:64]=O)([CH2:60][CH2:61]5)[CH2:58][O:57]6)=[CH:52][CH:51]=4)=[N:48][CH:49]=3)=[N:40][N:39]=2)[CH2:37][CH2:36][CH2:35]1>O1CCCC1>[CH:34]1([C:38]2[O:42][C:41]([NH:43][C:44]3[CH:49]=[N:48][C:47]([C:50]4[CH:55]=[CH:54][C:53]([C:56]56[CH2:63][CH2:62][C:59]([CH:64]=[CH:2][O:3][CH3:4])([CH2:60][CH2:61]5)[CH2:58][O:57]6)=[CH:52][CH:51]=4)=[CH:46][CH:45]=3)=[N:40][N:39]=2)[CH2:35][CH2:36][CH2:37]1
Reactant: COC
Reactant: O=CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cn4)cc3)(CC1)OC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CCC6)o5)cn4)cc3)(CC1)OC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
To a stirred suspension of triphenylphosphine methoxymethane chloride (28.7 mg, 0.084 mmol) in tetahydrofuran (1 ml) was flushed with nitrogen for three times and at 0° C., and was added LiHMDS (0.079 ml, 0.084 mmol). The reddish solution was stirred at 0° C. for 30 minutes, and then at −78° C., a solution of 1-(4-(5-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)amino)pyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octane-4-carbaldehyde (30 mg, 0.070 mmol) in tetrahydrofuran (0.7 ml) was added dropwise. The mixture was allowed to warm to 0° C. for 30 minutes. The reaction was quenched with water (2 ml), and the mixture was partitioned between brine (15 ml) and ethyl acetate (50 ml), aquous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine and dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (heptanes/acetone 1/1) to afford 5-cyclobutyl-N-(6-(4-(4-(2-methoxyvinyl)-2-oxabicyclo[2.2.2]octan-1-yl)phenyl)pyridin-3-yl)-1,3,4-oxadiazol-2-amine (10 mg, 31%) as yellow solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.83-2.51 (m, 14H) 3.56 (s, 3H) 3.63-3.76 (m, 1H) 4.00 (d, J=6.80 Hz, 1H) 4.06 (s, 2H) 5.87 (d, J=6.80 Hz, 1H) 7.49 (d, J=8.72 Hz, 2H) 7.78-7.93 (m, 3H) 8.17 (dd, J=24.00, 8.80 Hz, 1H) 8.71 (d, J=16.80 Hz, 1H). LC/MS, [MS+1] 459.1, RT: 1.44, 1.48; (Condition E).
Reaction SMILES: [C:1]([CH:4]([C:6]1[N:11]=[C:10]([C:12](=O)[CH2:13]Br)[CH:9]=[CH:8][CH:7]=1)[OH:5])([OH:3])=[O:2].[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[C:22]([NH2:24])=[S:23])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C:22]2[S:23][CH:13]=[C:12]([C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([CH:4]([C:1]([OH:3])=[O:2])[OH:5])[N:11]=3)[N:24]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[CH3:17]
Reactant: O=C(CBr)c1cccc(C(O)C(=O)O)n1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cccc(C(O)C(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 6-(1-carboxy-1-hydroxymethyl)-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide, to obtain 2-(3,4-diethoxyphenyl)-4-[6-(1-carboxy-1-hydroxymethyl)-2-pyridyl]thiazole
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[O:42])[NH:15][C:16]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:19]=[C:18]([O:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[C:34]([NH2:41])[CH:33]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>CO.[Zn]>[C:1]([O:5][C:6](=[O:43])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[O:42])[NH:15][C:16]2[CH:17]=[C:18]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([NH2:41])[CH:33]=3)[CH:19]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc([N+](=O)[O-])c(N)c3)c2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(N)c(N)c3)c2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
{Trans-4-[3-(3-amino-4-nitro-phenoxy)-5-(4-cyano-phenoxy)-phenyl-carbamoyl}-cyclohexyl]-carbamic acid tert-butyl ester (1.0 g, 1.7 mmol), zinc (1.11 g, 17.02 mmol) and ammoniumchloride (0.91 g, 17.02 mmol) were dissolved in 20 ml of methanol and stirred for 2 h at 60° C. After reaction completion contents were filtered through celite and filetrate was concentrated to afford 0.8 g of the required product. 1H NMR (DMSO-d6): δ 1.45 (9H, s), 1.78 (4H, m), 2.45 (4H, m), 3.2 (1H, m), 4.42 (2H, s), 6.45 (2H, m), 6.5 (1H, d), 6.71 (2H, m), 7.15 (2H, d), 7.3 (2H, s), 7.8 (2H, d), 8.28 (1H, d).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[NH:18][C:17]2[CH:19]=[C:20]3[C:25](=[CH:26][C:16]=2[N:15]=1)[CH:24]=[CH:23][CH:22]=[CH:21]3>C(Cl)Cl>[CH3:12][S:13]([C:14]1[NH:15][C:16]2[CH:26]=[C:25]3[C:20](=[CH:19][C:17]=2[N:18]=1)[CH:21]=[CH:22][CH:23]=[CH:24]3)=[O:9]
Reactant: CSc1nc2cc3ccccc3cc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2cc3ccccc3cc2[nH]1
Reaction time: 1.5 h
Yield: 49.8 %

Procedure:
A solution of 4.2 g of m-chloroperbenzoic acid in 100 ml of methylenechloride was added dropwise at 0°-5° to 4.3 g of 2-(methylthio)-1H-naphth[2,3-d]imidazole in 500 ml of methylenechloride. The reaction solution was stirred for 90 minutes at 0°, washed twice with aqueous potassium bicarbonate solution and once with saturated sodium chloride solution, dried over magnesium sulphate, and concentrated by evaporation on a rotary evaporator. Crystallisation from acetonitrile gave 2.3 g of 2-(methylsulphinyl)-1H-naphth[2,3-d]imidazole having a m.p. of 194°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH2:14][NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:32][CH:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>C(Cl)Cl>[CH3:20][CH:19]([S:16]([NH:15][CH2:14][CH:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:35]([CH:33]([CH3:34])[CH3:32])(=[O:37])=[O:36])[CH:3]=2)=[CH:24][CH:23]=1)[CH3:22])(=[O:18])=[O:17])[CH3:21]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(N)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(NS(=O)(=O)C(C)C)c2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 264.3 %

Procedure:
To a solution of {2-[4-(3-aminophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine (125 mg, 0.3587 mmol, prepared in example 3) dissolved in methylene chloride (2.5 mL, anhydrous) was added triethylamine (0.125 mL, 0.8968 mmol) under a nitrogen system. The mixture was cooled to 0° C. and 2-propanesulfonyl chloride (0.06 mL, 0.5381 mmol) was added by syringe. The mixture was allowed to warm to room temperature, and stirred overnight, under a nitrogen system. The reaction was quenched with excess water, and the organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, yielding 431 mg viscous oil. Purification was conducted using a Chromatotron®, on a 4000 μm rotor and eluting with a 1:1 hexane:ethyl acetate solvent system, yielding 400 mg of two inseparable coeluting spots. This mixture was purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate, yielding the title compound (16.7 mg, 1%) as a slow crystallizing foam.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CON(C)[C:19]([C:21]1[C:26]([NH2:27])=[N:25][CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[N:22]=1)=[O:20].Cl>C1COCC1>[NH2:27][C:26]1[C:21]([C:19]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=2)=[O:20])=[N:22][C:23]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)=[CH:24][N:25]=1
Reactant: Br[Mg]c1ccc(CN2CCCCC2)cc1
Reactant: CON(C)C(=O)c1nc(-c2ccc(Cl)c(Cl)c2)cnc1N
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccc(Cl)c(Cl)c2)nc1C(=O)c1ccc(CN2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.25 M [4-(1-piperidinyl-methyl)phenyl]magnesium bromide in THF (5.51 ml, 1.37 mmol) is added dropwise to a solution of 3-amino-6-(3,4-dichloro-phenyl)-pyrazine-2-carboxylic acid methoxy-methyl amide (Intermediate B) (0.09 g, 0.27 mmol) in THF (5 ml) and the resulting solution is stirred for 2 hours. The solution is cooled to 0° C., and 2M HCl (10 ml) is added. The solution is washed with EtOAc (20 ml) and then the pH is adjusted to 11 using 2M NaOH. Extraction with EtOAc (50 ml), drying (MgSO4) and removal of solvent in vacuo affords a yellow oil. Purification by flash chromatography (SiO2, 50-100% EtOAc in iso-hexane) followed by trituration with methanol affords the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-6) δ 9.04 (1H, s), 8.12 (1H, d), 7.97 (2H, bs), 7.93-7.88 (3H, m), 7.71 (1H, d), 7.47 (2H, d), 3.54 (2H, s), 2.36 (4H, bs), 1.52-1.51 (4H, m), 1.43-1.37 (2H, m); MS m/z 441, 443 [M+H]+
Reaction SMILES: C(=O)CCCCCCCCC/C=C\CCCC.CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH:38]([OH:49])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].CCN(CC)CC>>[CH3:48][CH2:47][CH2:46][CH2:45][CH2:44]/[CH:43]=[CH:42]\[CH2:41][CH2:40][CH2:39][C:38](=[O:49])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH3:28]
Reactant: CCCCC/C=C\CCCC(O)CCCCCCCCCC
Agent: CCCC/C=C\CCCCCCCCCC=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCCC/C=C\CCCC(=O)CCCCCCCCCC
Yield: 90.3 %

Procedure:
According to the procedure for compound 6, DMSO (0.080 mL, 1.1 mmol), oxalyl chloride (0.060 mL, 0.67 mmol), alcohol 19 (0.19 g, 0.61 mmol), and Et3N (0.42 mL, 3.1 mmol) were reacted to yield 20 (0.17 g, 91% yield, 88% Z as determined by quantitative 13C-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.39 (1H, m), 5.31 (1H, m), 2.39 (2H, t, J=7.5 Hz), 2.38 (2H, t, J=7.6 Hz), 2.04 (2H, m), 1.99 (2H, m), 1.63 (2H, m), 1.56 (2H, m), 1.20-1.37 (20H, m), 0.88 (6H, m); 13C NMR (CDCl3): δ 211.4, 131.0, 128.7, 42.9, 42.1, 31.9, 31.5, 29.6, 29.5, 29.4 (2C), 29.3 (2C), 23.9, 22.7, 22.6, 14.1 (2C); HRMS (FAB): 309.3148, [C21H40O+H]+ requires 309.3157.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[C:5]([N+:18]([O-])=O)[CH:4]=1>C(OCC)(=O)C.[Pd]>[CH3:21][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([B:9]2[O:10][C:11]([CH3:16])([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13]2)[CH:6]=[C:5]([NH2:18])[CH:4]=1
Reactant: CN(C)c1cc(B2OC(C)(C)C(C)(C)O2)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)c1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Yield: 101.3 %

Procedure:
N,N-Dimethyl-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (356 mg, 1.22 mmol) was dissolved in 50 ml of ethyl acetate. This mixture was hydrogenated in an H-Cube® apparatus using 10% palladium on carbon as catalyst at 2-3 bar. The solvent was evaporated to give 324 mg (99% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[CH3:10][O-:11].[Na+]>CO>[CH3:10][O:11][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: OCCCCCCCBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCCCCCCO
Temperature: 90 °C
Reaction time: 7 h

Procedure:
A mixture of 7-bromo-1-heptanol (25 g) and sodiummethoxide, 28% solution in methanol (37 ml) in methanol (250 ml) was stirred for 7 hours at 90° C. After being cooled to room temperature, the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (100:1→25:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 7-methoxy-1-heptanol (18.2 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][S:2](=[O:1])(=[O:30])[CH2:3][CH2:4]2)=[O:9])=[CH:34][CH:33]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(Cl)cc2)CC1
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 4-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless solid (34%).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.Cl.[Pt]=O>[CH:1]1([CH:6]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cncc(C2CCCC2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: C1CCC(C2CCCNC2)C1
Reaction time: 18 h
Yield: 83.5 %

Procedure:
Platinum oxide (0.2 g, 0.82 mmol) was added as a slurry in ethanol to a solution of 3-cyclopentylpyridine (1 g, 6.8 mmol) in ethanol (15 ml) and concentrated hydrochloric acid (1 ml). The mixture was hydrogenated in a Parr apparatus at 50 psi for 18 hours then filtered through Celite. The filtrate was concentrated in vacuo and the residue partitioned between 10% aqueous sodium carbonate solution and ethyl acetate. The organic layer was dried (MgSO4) and concentrated in vacuo to give the title compound (0.87 g, 84%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]([C:11]([OH:13])=[O:12])[NH:2]1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]>[OH-].[Na+].O1CCCC1>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([N:2]3[C@@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: O=C(O)[C@H]1Cc2ccccc2CN1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1Cc2ccccc2CN1S(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
44.2 g (250 mmol) of 1,2,3,4-tetrahydroisoquinoline-3-(R)-carboxylic acid were dissolved in 500 ml of 1N aqueous sodium hydroxide solution and, while stirring, 150 g (300 mmol) of 4′-nitrobiphenyl-4-sulfonyl chloride dissolved in 500 ml of tetrahydrofuran were added. During this, the reaction temperature was kept below 25° C., and the pH of the solution was adjusted to pH 10 by adding 1N NaOH. The reaction mixture was stirred at room temperature for 12 hours (h).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH:7]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1>[CH:7]1([NH:15][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C=C1CC(=O)O1
Reactant: NC1CCCCCCC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CCCCCCC1
Temperature: -5 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
84 g of diketene were added over 30 minutes to a stirred mixture of 127 g of cyclooctylamine and 800 ml of tetrahydrofuran cooled to -5° C. and the mixture was stirred for 4 hours at 20° C. and then evaporated to dryness under reduced pressure to obtain 210 g of N-cyclooctyl-acetylacetamide melting at 44° C. 63 g of the said product and 1 g of p-toluene sulfonic acid were added to a mixture of 150 ml of methanol and 40 g of methyl orthoformate and after stirring the mixture for 16 hours, 1.5 ml of quinoline were added thereto. The mixture was distilled to dryness under reduced pressure and the residual oil was dissolved in toluene. The solution was heated at 145° C. for 4 hours while distilling off a methanol-toluene azeotrope. The mixture was distilled to dryness under reduced pressure and the oil residue was chromatographed over silica gel. An 8-2 methylene chloride-acetone mixture was used as the eluant and the product was empasted with isopropyl ether to obtain 45 g of N-cyclooctyl-3-methoxy-crotonamide melting at 116° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:16][C:17]1[N:18]=[C:19]([S:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH:11]3[CH2:12][CH2:13]3)=[O:10])=[CH:6][CH:7]=2)[CH:20]=[N:21][CH:22]=1
Reactant: Clc1cncc(Cl)n1
Reactant: O=C(Nc1ccc(S)cc1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Sc2cncc(Cl)n2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of N-(4-mercaptophenyl)cyclopropane carboxamide (16.1 mmol) in THF (25 mL) at 0° C. was added sodium hydride (16.1 mmol) portionwise. Once the addition was complete the resulting solution was stirred at room temperature for 30 min. After this time, the reaction mixture was cooled to 0° C. and a solution of 2,6-dichloropyrazine (13.4 mmol) was added and the resulting mixture stirred at room temperature for 16 h. Water (30 mL) and ethyl acetate (30 mL) were added and the layers separated. The aqueous layer was extracted further with ethyl acetate (2×30 mL), the combined organic layers dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/Petroleum ether, 0-100% gradient EtOAc) to give the title compound (2.95 g, 72%) as a cream coloured solid; 1H NMR (400 MHz, DMSO-d6) δ 0.91 (2H, m), 1.13 (2H, m), 1.54 (1H, m), 7.53 (1H, br s), 7.57 (2H, m), 7.65 (2H, m), 7.96 (1H, s), 8.22 (1H, s); MS (ES+): m/e=306.14 (100%).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].C(O[C:12]1(O[Si](C)(C)C)[CH2:14][CH2:13]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:12]1([N:6]2[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]2)[CH2:14][CH2:13]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: N#CC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#CC1CCN(C2CC2)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
5.0 g (45.4 mmol) of 4-cyanopiperidine were dissolved in 83 ml of methanol, and 11.9 g (68.1 mmol) of [(1-ethoxy-1-cyclopropyl)oxy]trimethylsilane, 2.9 ml (3.0 g, 49.9 mmol) of acetic acid and 6.0 g (91.0 mmol) of sodium cyanoborohydride were added. The reaction mixture was stirred at 60° C. for 16 h, cooled to RT and then filtered through kieselguhr, the filter cake was washed with methanol and the filtrate was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed twice with 1 N aqueous sodium hydroxide solution and once with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 6.0 g (88% of theory)
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21].O>CCO>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=1[C:20]([F:21])([F:22])[F:23]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
A 5N aqueous solution of NaOH (10.2 mL, 51.0 mmol) was added into a solution of methyl 2′-methyl-2-(trifluoromethyl)biphenyl-4-carboxylate (5.00 g, 17.0 mmol) in EtOH (150 mL). The resulting mixture was stirred at 60° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure to give a brown solid. The residue was taken up with water (300 mL) and washed twice with EtOAc. The aqueous layer was acidified with a concentrated aqueous solution of HCl until pH=2, and then concentrated until precipitation (half of the volume). The precipitate was filtered off affording the title compound as a beige solid (3.33 g, 70%). 1H NMR (DMSO-d6, 300 MHz) δ 13.55 (br s, 1H), 8.31 (s, 1H), 8.25 (d, J=7.9 Hz, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.37-7.12 (m, 4H), 1.99 (s, 3H). HPLC (Method A), Rt 4.6 min (Purity: 98.7%). UPLC/MS, M−(ESI): 279.2.