Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]5[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=5[N:20]=4)=[CH:14][CH:13]=3)[C:9](=[O:11])[NH:10][C:3]=12.I[CH2:37][CH3:38].[H-].[Na+].O>CN(C=O)C>[CH2:37]([N:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:8]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]4[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=4[N:20]=3)=[CH:16][CH:17]=2)[C:9]1=[O:11])[CH3:38]
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(Oc2nc3ccccc3n2COCC[Si](C)(C)C)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2nccc(C)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.15 g), iodoethane (0.027 mL) and sodium hydride (0.015 g) (60% in oil) in DMF (4.0 mL) was stirred at room temperature for 4 h. To the mixture was added H2O, and the mixture was extracted with AcOEt. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-ethyl-7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (90 mg) as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:19]([O-:21])=[O:20])[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](N)=[CH:27][CH:26]=1.C([O-])(=O)C.[K+]>CO>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:1][C:4]2[C:17]3[C:16](=[O:18])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][C:14]=4[N+:19]([O-:21])=[O:20])[C:9](=[O:22])[C:8]=3[CH:7]=[CH:6][CH:5]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(Nc2cccc3c2C(=O)c2c(cccc2[N+](=O)[O-])C3=O)cc1
Reaction time: 8 h

Procedure:
A mixture of 50 g. of 1,8-dinitro-anthraquinone (82% strength), 150 g of p-anisidine and 21.5 g of anhydrous potassium acetate is heated at 95° - 100° C (duration approx. 5 hours), with vigorous stirring, until no further starting material is present, according to thin layer chromatography. The mixture is diluted with 150 ml of methanol over the course of 30 minutes at 50° - 60° C and is stirred overnight until cold and the reaction product is filtered off, washed with a solution of 30 g of p-anisidine in 30 ml of methanol and finally with 200 ml of methanol and hot water, and dried at 80° C. 51 g of 1-p-anisidino-8-nitro-anthraquinone are obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[N:9]=[CH:8][C:7]2([CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6]1)=[S:4].I[CH3:16]>CO>[CH3:16][S:4][C:3]([N:5]1[N:9]=[CH:8][C:7]2([CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6]1)=[N:2][CH3:1]
Reactant: CNC(=S)N1CC2(C=N1)CCOCC2
Reactant: CI
Solvent: CO
Product: CN=C(SC)N1CC2(C=N1)CCOCC2
Temperature: 50 °C
Yield: 0.2 %

Procedure:
0.50 g (1 mol equiv.) 8-Oxa-2,3-diaza-spiro[4.5]dec-3-ene-2-carbothioic acid methylamide was dissolved in 10 mL methanol; 1.2 mL (10 mol equiv.) iodomethane was added and the reaction mixture was heated at 50° C. for 5 hours. Volatiles were removed under reduced pressure, and the residue was taken up in DCM and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness to yield 0.43 g (99%) N-methyl-8-oxa-2,3-diaza-spiro[4.5]dec-3-ene-2-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 1.53-1.60 (m, 2H), 1.80-1.88 (m, 2H), 2.47 (s, 3H), 3.26 (s, 3H), 3.56-3.64 (m, 2H), 3.68 (s, 2H), 3.83-3.89 (m, 2H), 6.73 (s, 1H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:41][C:42]([CH3:44])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:26][CH2:27][N:28]([CH:42]([CH3:44])[CH3:41])[CH2:29][CH2:30]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)=O
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCNCC4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)CC4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of crude (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(piperazin-1-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (0.144 mmol) in ethanol (2.0 mL) was added acetone (0.21 mL) and acetic acid (12 μL, 0.21 mmol) at 0° C. Reaction mixture was stirred for 15 minutes, then sodium cyanoborohydride (10 mg, 0.158 mmol) was added and reaction mixture was warmed to room temperature over 2 h. Reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate/brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 10% MeOH/CH2Cl2) to give product. LCMS-ESI+: calc'd for C34H42ClN4O3S: 622.2 (M+H+); Found: 621.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:17])[C:5]2[CH:11]=[C:10]([C:12]#[CH:13])[C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:6]=2[N:7]=1.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:17])[C:5]2[CH:11]=[C:10]([C:12]3[NH:20][N:19]=[N:18][CH:13]=3)[C:9](=[O:14])[N:8]([CH2:15][CH3:16])[C:6]=2[N:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C#Cc1cc2c(C)nc(N)nc2n(CC)c1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c(-c2cnn[nH]2)cc2c(C)nc(N)nc21
Temperature: 120 °C
Reaction time: 48 h
Yield: 5.8 %

Procedure:
Anhydrous DMF (5.0 mL) was added to a flask charged with 2-amino-8-ethyl-6-ethynyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.204 g, 0.894 mmol), sodium azide (0.070 g, 1.07 mmol), and ammonium chloride (0.057 g, 1.07 mmol). The reaction was capped under nitrogen and heated to 120° C. After 48 h, the reaction was cooled to room temperature and concentrated in vacuo. The residue was purified on reverse phase HPLC (acetonitrile: water 0.1% TFA, 20-60% gradient). The fractions containing product were collected and concentrated to one half volume and poured into saturated NaHCO3 (50 mL). The aqueous phase was washed trice with ethyl acetate (50 mL) and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with methylene chloride and ethyl acetate to afford 2-amino-8-ethyl-4-methyl-6-(1H-1,2,3-triazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (14 mg, 6% yield) as a light yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 8.55 (bs, 1H), 8.41 (bs, 1H), 7.32 (bs, 2H), 4.37 (q, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); MS (EI) for C12H13N7O: 272.0 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:5]([CH3:21])=[N:4]1)[CH3:2].[C:22]([C:30](O)=[O:31])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)CCl>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[C:6]([N:8]([CH2:9][CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)[C:30](=[O:31])[C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]([CH3:21])=[N:4]1)[CH3:2]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: CCn1cc(NCCc2ccc(C(F)(F)F)nc2)c(C)n1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCn1cc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)C(=O)c2ccccc2)c(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of (1-ethyl-3-methyl-1H-pyrazol-4-yl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (100 mg) in CH2Cl2 (5 mL) was added under a nitrogen atmosphere at 0° C. benzoyl formic acid (1.1 eq., commercially available) and EDC (1.1 eq). After stirring for 12 h a rt, the mixture was washed with aqueous Na2CO3 (saturated, 2.5 mL) and water (2.5 mL), the combined aqueous layers were extracted with CH2Cl2 (3×2.5 mL) and the combined organic layers dried over sodium sulfate. Concentration afforded the title compound (161 mg, >100%) as a light yellow oil which was used without further purification for the next step. MS m/e: 431.2 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6]([CH2:9][CH:10]1[CH2:13][N:12]([C:14](OC(C)(C)C)=O)[CH2:11]1)(=[O:8])=[O:7].C(O)(C(F)(F)F)=O.[BH3-]C#N.[Na+].[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34](C=O)=[N:33]1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[S:6]([CH2:9][CH:10]1[CH2:11][N:12]([CH2:14][C:34]2[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[S:32][N:33]=2)[CH2:13]1)(=[O:7])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CC(CS(=O)(=O)c2nccs2)C1
Reactant: O=Cc1nsc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(CC1CN(Cc2nsc3ccccc23)C1)c1nccs1
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
tert-Butyl 3-[(1,3-thiazol-2-ylsulfonyl)methyl]azetidine-1-carboxylate (51 mg, 0.16 mmol) was dissolved in DCM (0.5 mL) and TFA (0.5 mL) was added. The resulting mixture was stirred for 30 min. then concentrated in vacuo. The residual oil was taken up in MeOH (2 mL), then NaCNBH3 (16.2 mg, 0.26 mmol) and 1,2-benzisothiazole-3-carbaldehyde (28.6 mg, 0.18 mmol) [prepared by the method of T. Hasegawa, Y. Akiyama, T. Imai, E. Sato, Y. Yamamoto, J. Tanaka, H. Nagaso, K. Fuji, K. Murase, M. Shiiyama, WO 98/08816] were added. The mixture was stirred overnight then partitioned between 0.5 N NaOH (20 mL) and EtOAc (20 mL). The aqueous phase was washed with EtOAc (20 mL) and the organic layers were combined, washed with saturated brine (20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified using column chromatography, on silica gel, eluting with 50–60% EtOAc in DCM to give the title compound as a colourless oil (19 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 2.96–3.06 (1H, m), 3.12 (2H, m), 3.57 (2H, t, J=7.6 Hz), 3.72 (2H, d, J=7.3 Hz), 4.04 (2H, s), 7.41–7.45 (1H, m), 7.50–7.54 (1H, m), 7.74 (1H, d, J=3.1 Hz), 7.91 (1H, d, J=8.2 Hz), 8.05 (1H, d, J=3.0 Hz), 8.10 (1H, d, J=8.1 Hz). m/z (ES+) 366 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]([C:15]#[N:16])=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:3]=1.B#B.[ClH:21].[OH-].[Na+]>O1CCCC1>[ClH:21].[NH2:16][CH2:15][C:7]1[S:6][C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][C:4]=2[C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#Cc1sc2ccc(Br)cc2c1-c1ccccc1
Agent: B#B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: NCc1sc2ccc(Br)cc2c1-c1ccccc1

Procedure:
Treat 1.4 g. of 5-bromo-2-cyano-3-phenylbenzo[b]thiophene (0.0045 mole) in 40 ml. of tetrahydrofuran with 10 ml. of 1 molar diborane in tetrahydrofuran. Reflux the solution for 11/2 hours. Slowly add 10 ml. of 5% hydrochloric acid. Heat the mixture for 1/2 hour, cool and add sufficient sodium hydroxide solution to basicity. Extract the solution with ether and wash twice with water. Dry the ether layer (MgSO4), filter and mix with 50 ml. of ether saturated with hydrogen chloride. Dry the precipitate to obtain the title compound; m.p. over 225° (decomp).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][CH2:44][CH:43](O[Si](C(C)C)(C(C)C)C(C)C)[C@H:42]5C)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:77][OH:78]>C1COCC1.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][CH2:44][C@@H:43]([CH2:77][OH:78])[CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CO
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC(O[Si](C(C)C)(C(C)C)C(C)C)[C@H]5C)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@@H](CO)C5)n4c3)c3ccccc32)cc1

Procedure:
A brown solution of Intermediate 77d (135 mg, 0.168 mmol) and TBAF (1M in THF, 0.184 mL, 0.184 mmol) in THF (3 mL) was stirred at RT for 1 h. The solution was concentrated in vacuo, suspended in water (10 mL) and extracted with EtOAc-MeOH (19:1, 2×10 mL). The combined organics were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave a brown solid. FCC, using 5-9% MeOH in DCM, gave a pale brown solid. Further purification by HPLC (XBridge C18 column, 25-75% MeCN in H2O, 0.1% NH4OH) gave the title compound as a white powder after freeze-drying (63.9 mg, 59%). LCMS (Method 5): Rt 4.33 min, m/z 649 [MH+]. NMR (400 MHz, d6-DMSO): 1.27 (9 H, s), 1.29-1.35 (1H, m), 1.71-1.77 (3H, m), 1.82-1.96 (3H, m), 2.01-2.17 (2H, m), 2.36 (3H, s), 3.02-3.07 (2H, m), 3.20 (1H, dd, J 11.9, 3.3), 3.25-3.28 (1H, m), 3.42 (1H, dt, J 10.5, 5.0), 3.52-3.58 (1H, m), 4.69 (1H, t, J 5.1), 4.81 (1H, td, J 8.6, 5.4), 5.48 (1H, t, J 4.3), 6.32 (1H, s), 7.09 (1H, d, J 8.3), 7.12 (1H, dd, J 9.9, 2.1), 7.27-7.39 (8H, m), 7.60 (1H, d, J 9.9), 7.80 (1H, d, J 2.1), 8.04 (1H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[S:31][C:30]([C:32](=[N:34]O)[NH2:33])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[S:31][C:30]([C:32]2[N:34]=[C:23]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[O:16])[CH2:12]3)[O:25][N:33]=2)=[CH:29][CH:28]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1ccc(Cl)s1
Product: CCc1ccc(C2CC(c3nc(-c4ccc(Cl)s4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 39 mg (0.22 mmol, 1.1 eq.) of 5-chloro-N′-hydroxythiophene-2-carboximidamide were reacted according to the General Method 1. Yield: 60 mg (62% of theory)
Reaction SMILES: [CH2:1]([C:8]1(O)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[O:11][CH2:10][CH:9]1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>O>[CH:1](=[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[O:11][CH2:10][CH:9]1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)NC1COc2ccc(OC)cc2C1(O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)NC1COc2ccc(OC)cc2C1=Cc1ccccc1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
6.87 g (12.5 mmol) of ethyl 4-benzyl-4-hydroxy-6-methoxychroman-3-ylcarbamate were added to 80 ml of half concentrated aqueous HCl and stirred at 100° C. for 2.5 h. The mixture was cooled to 0° C. and diluted with water. Sodium hydroxide (50% aqueous solution) was carefully added until pH >10. The aqueous phase was extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried over MgSO4 and the solvent was evaporated to give 5.7 g of crude material. The crude material was purified by flash chromatography to yield 3.1 g (9.1 mmol, 73° X)) of the desired product.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].FC(F)(F)C(O)=O.[OH:13][CH2:14][C@@H:15]1[NH:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][CH:4]([O:13][CH2:14][C@@H:15]1[NH:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16]1)[CH3:5])[CH3:2]
Reactant: C=COCC
Reactant: O=C1CCC[C@H](CO)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(C)OC[C@H]1CCCC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
Ethyl vinyl ether (1.68 mL, 17.5 mmol) and trifluoroacetic acid (0.1 mL) were added sequentially to a solution of (R)-6-hydroxymethylpiperidin-2-one (prepared from D-α-aminoadipic acid according to Huang, et al., Synth. Commun. 1989, 19, 3485–3496, 1.62 g, 12.5 mmol) in CHCl3 (10 mL) at rt. The reaction mixture was stirred at rt for 18 h, then saturated aqueous NaHCO3 (100 mL) was added and the mixture was extracted with CH2Cl2 (3×75 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→4% MeOH/CH2Cl2, gradient) afforded 2.03 g (80%) of (R)-6-(1-ethoxyethoxymethyl)-piperidin-2-one.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][S:19][CH3:20])[C:3]([NH:5][C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>O1CCOCC1>[CH3:1][CH:2]([CH2:18][S:19][CH3:20])[C:3]([NH:5][C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:7]=1[CH3:17])=[S:30]
Reactant: CSCC(C)C(=O)Nc1sc(-c2cccnc2)nc1C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CSCC(C)C(=S)Nc1sc(-c2cccnc2)nc1C
Temperature: 130 °C

Procedure:
To a microwave reaction vessel was added 2-methyl-N-(4-methyl-2-pyridin-3-yl-thiazol-5-yl)-3-methylsulfanyl-propionamide (0.10 g, 0.32 mmol) in dioxane and Lawesson's reagent (0.19 g, 0.48 mmol). The vessel was capped and heated in a Biotage Initiator microwave reactor for 1 min at 130° C., with external IR-sensor temperature monitoring from the side. The reaction was concentrated to dryness and the crude material was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as a yellow semi solid (0.019 g, 18%): 1H NMR (300 MHz, CDCl3) δ 9.9 (m, 1H), 9.2 (d, 1H), 8.65 (d, 1H), 8.4 (m, 1H), 7.4 (m, 1H), 3.15 (m, 1H), 2.9 (m, 2H), 2.5 (s, 3H), 2.2 (s, 3H), 1.5 (d, 3H); ESIMS m/z 324.12 (M+1).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])([OH:10])=[O:9].[C:12]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19](O)[CH2:18][CH2:17]1)(=[O:14])[CH3:13].C(=O)([O-])O.[Na+]>C(#N)C>[C:12]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([O:9][N+:8]([O-:11])=[O:10])[CH2:18][CH2:17]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC(=O)N[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
28.3 ml (0.3 mol) acetic acid anhydride are mixed with 375 ml acetonitrile, cooled in an ice-bath to 0°-5° C. and 12.6 ml (0.3 mol) 100% nitric acid added dropwise. After 30 minutes, 15.7 g (0.1 mol) solid trans-N-acetyl-4-hydroxycyclohexylamine are added thereto with stirring and cooling at 0°-5° C. The reaction mixture is further stirred for 3 h at 0°-5° C. and subsequently allowed to flow carefully into a solution of 150 g (18 mol) sodium hydrogen carbonate in 500 ml ice water. After extraction with ethyl acetate, drying of the organic phase with sodium sulphate and distilling off in a vacuum, there remain 17.8 g of crude product. After recrystallisation from ethyl acetate, there are obtained 10.3 g of the title compound of the m.p. 146°-148° C., i.e. 50% of theory.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.Cl[O-].[Na+]>C(OCC)(=O)C.O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][N:16]1[CH2:17][CH2:18][CH2:19][CH:14]([CH3:13])[CH2:15]1
Reactant: CC1CCCNC1
Reactant: Sc1nc2ccccc2s1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CCCN(Sc2nc3ccccc3s2)C1
Reaction time: 2 h
Yield: 95.5 %

Procedure:
In a 500 ml volume flask, there are charged 2-mercaptobenzothiazole (UV absorption spectrum: 329 mμ) (41.28 g), sodium hydroxide (10 g) and water (180 ml), and the resultant mixture is stirred to form a solution. After the addition of 3-methylpiperidine (27.2 g) to the resulting solution, a 15 % by volume aqueous solution of sodium hypochlorite (138.5 ml) is dropwise added thereto in 2 hours, during which the inner temperature is kept below 70° C. The reaction mixture is allowed to stand at the same temperature for 1 hour and then shaken with ethyl acetate (150 ml). The ethyl acetate extract is washed with water and distilled under reduced pressure to give 1-(2-benzothiazolylthio)-3-methyl-piperidine (62.3 g).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[F:27].CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]2[O:15][CH2:14][CH:13]([CH2:12][CH2:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]3)[CH2:16][O:17]2)=[CH:21][C:20]=1[F:27]
Reactant: CCCC[C@H]1CC[C@H](CCC(CO)CO)CC1
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCC[C@H]1CC[C@H](CCC2COC(c3ccc(Br)c(F)c3)OC2)CC1
Yield: 80 %

Procedure:
A solution of 6.1 g (0.025 mol) of 2-[2'-(trans-4"-butylcyclohexyl)ethyl]propane-1,3-diol, 5.1 g (0.025 mol) of 4-bromo-3-fluorobenzaldehyde, and g of TsOH in 125 cm3 of dichloromethane was refluxed for 5 hours over a hot water bath with a Dean-Stark trap. The solution was washed with water and the dichloromethane was distilled off. The residue was recrystallized from a solvent mixture of acetone and methanol to yield 8.4 g (0.02 mol) of 2-(4'-bromo-3'-fluorophenyl)-5-[2'-(trans-4"-butylcyclohexyl)ethyl]-1,3-dioxane.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:14][C:15]([O-:17])=[O:16].[K+]>CN(C=O)C.O>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:17][C:15](=[O:16])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1
Reactant: CC(=O)[O-]
Reactant: COC(=O)C(Br)c1cccc(Br)n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(OC(C)=O)c1cccc(Br)n1
Temperature: 120 °C

Procedure:
Methyl bromo(6-bromopyridin-2-yl)acetate (Example 360, Step 1) (500 mg, 1.62 mmol) and KOAc (635 mg, 6.47 mmol) were taken up in DMF (3.0 mL) and heated to 120° C. for 20 minutes in a microwave. The reaction mixture was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. Silica gel chromatography (0-40% EtOAc/hexanes) afforded the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10].C(N(CC)CC)C>O1CCCC1>[C:12]([NH:14][C:15](=[S:16])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O:11][CH2:9][CH3:10])=[O:13]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)N=C=S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)OCc1ccccc1
Yield: 71.6 %

Procedure:
A mixture of 162 g of benzyl alcohol and 196 g of ethoxycarbonyl isothiocyanate and 1 ml of triethylamine in 1 liter of tetrahydrofuran was refluxed for 24 hours and was concentrated to dryness. The residue was washed with petroleum ether and isopropyl ether to obtain 256 g of benzyl N-carbethoxy-thiocarbamate melting at 96° C.