Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:18]([C:19]([O:21]C)=[O:20])[C:13]=2[N:12]=[C:11]1[CH3:29].[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:14]2[CH:15]=[C:16]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:13]=2[N:12]=[C:11]1[CH3:29]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(C(=O)O)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylate (65 mg, 0.15 mmol) and LiOH (19 mg, 0.5 mmol) in THF (5 mL) and water (5 mL), was stirred overnight at rt. Then the pH of the reaction mixture was neutralized with 1N aq. HCl. Then the mixture was stirred at rt for 1 h, filtered to give the product (47 mg, 74%, with about 10% monochloride as the impurity) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.53 (s, 3H), 3.12 (t, 4H, J=4.5 Hz), 3.73 (t, 4H, J=4.5 Hz), 5.66 (s, 2H), 6.42 (d, 1H, J=7.8 Hz), 7.26 (t, 1H, J=7.8 Hz), 7.42 (s, 1H,), 7.48 (s, 1H), 7.62 (d, 1H, J=7.8 Hz); LC-MS: m/e=420 [M+1]+
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1.[CH3:31][N:32]([CH2:34][CH2:35][CH2:36]Cl)[CH3:33]>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:36][CH2:35][CH2:34][N:32]([CH3:33])[CH3:31])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1
Reactant: CN(C)CCCCl
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)cc(OC)c1OC
Product: COc1cc(-c2nc3ccc(OCCCN(C)C)cc3n2Cc2ccccc2Br)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 114 with 3-(N,N-dimethylamino)propyl chloride essentially as previously described. mp 141° C., NMR, IR, MS 553, 555.
Reaction SMILES: C([NH:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][C:17]([C:19]([O:21]C)=[O:20])=[CH:18][C:5]1=2)=O.O1CCOCC1.[ClH:29]>O>[ClH:29].[NH2:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:5]1=2
Reactant: COC(=O)c1ccc2c(c1)C(NC=O)c1ccccc1CO2
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: NC1c2ccccc2COc2ccc(C(=O)O)cc21

Procedure:
Heat together 340 mg. of methyl 6,11-dihydro-11-formamidodibenz[b,e]oxepin-2-carboxylate, 10 ml. of dioxane and 10 ml. of concentrated hydrochloric acid at 100° C. for 5 hours. Strip to dryness and dissolve the residue in water and pass through a Bio-Red AG-50W-X8 resin (sulfonic acid type). Collect the acid by elution with 10% ammonium hydroxide solution. Evaporate to dryness, dissolve the residue in tetrahydrofuran and acidify with aqueous hydrochloric acid. Strip to dryness and recrystallize from methanol/ether to obtain the title product (m.p. 245° dec.).
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH2:34][OH:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.I[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1>C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:1][C:2]([CH3:36])([CH2:34][OH:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:38]3[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(O)CO)(c2ccccc2)OC1=O
Reactant: Cn1ccc(I)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(O)CO)(c2ccccc2)OC1=O

Procedure:
A mixture of (S)-6-(2,3-dihydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (105 mg, 211.9 mmol), 4-iodo-1-methylpyridin-2(1H)-one (65 mg, 275.5 mmol), Pd(PPh3)2Cl2 (20 mg) in aq. Cs2CO3 solution (3 mL) was stirred at reflux for 2 h. After the reaction was finished, the mixture was washed with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative HPLC to afford two isomers of (6S)-6-(2,3-dihydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 89.9 %

Procedure:
To 5-fluoro-2-nitrophenyl methyl ether (Example 22, step A) (0.8 g, 4.67 mmol) in 10 mL of dioxane was added, piperazine (1.2 g, 14 mmol). The mixture was heated to 120° C. for 2 h. The mixture was purified by flash chromatography to give the title compound of step A (1 g, 4.2 mmol, 90%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (d, J=9.34 Hz, 1H), 6.55 (d, J=2.56 Hz, 1H), 6.52 (s, 1H), 6.46 (d, J=2.56 Hz, 1H), 3.87 (s, 3H), 3.25-3.33 (m, 4H), 2.73-2.79 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Mg+].[Br-]>C1COCC1.O>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:19])[CH3:23])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg+]
Reactant: CN(C)C1=N[C@@H]2C[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2C[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.9 %

Procedure:
To a solution of (3aR,5S,6S,7aR)-6-(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-5-carbaldehyde (1.04 g) in anhydrous THF (30 mL) at 0° C. was added a solution of MeMgBr (1.4 M in 1:3 THF/toluene, 5.80 mL, 8.13 mmol) dropwise. The reaction was then stirred at room temperature for 20 h. The mixture was diluted with H2O (50 mL), extracted with EtOAc (2×40 mL). The combined extract was dried over anhydrous Na2SO4. The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 2%-5% 2 M NH3 MeOH solution in DCM to give 1-((3aR,5R,6S,7aR)-6-(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanol (0.840 g, 77%) as a pale yellow foam. MS m/z 337.2 (M+1, 100%); 1H NMR (400 MHz, CDCl3) shown this was a mixture of two diastereomers with a ratio ˜60:40.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:26](Cl)(=[O:28])[CH3:27].O>C(Cl)Cl>[CH:1]([O:4][C:5]([C:7]1([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:26](=[O:28])[CH3:27])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)OC(=O)C1(c2ccc(-c3ccccc3)cc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(C3(C(=O)OC(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.6 %

Procedure:
To 1-(biphenyl-4-yl)cyclopropanecarboxylic acid isopropyl ester (10.2 g, 36 mmol) in CH2Cl2 (100 mL) was added aluminum chloride (10.2 g, 76.5 mmol) followed by acetyl chloride (5.97 g, 76.5 mmol). The solution was stirred at room temperature for 1.5 hours then slowly poured into water. The organic layer was separated and extracted 1 time with sodium potassium tartrate solution (20 g in 250 mL water). The organic layer was dried and evaporated to yield 12.6 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([NH2:14])=[O:13])=[CH:9][CH2:8][CH2:7]2>CO>[F:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=[C:6]2[C:11]=1[C@H:10]([C:12]([NH2:14])=[O:13])[CH2:9][CH2:8][CH2:7]2
Reactant: NC(=O)C1=CCCc2cc(Sc3ccccc3)cc(F)c21
Solvent: CO
Product: NC(=O)[C@@H]1CCCc2cc(Sc3ccccc3)cc(F)c21

Procedure:
A suspension of 8-fluoro-6-phenylsulfanyl-3,4-dihydro-naphthalene-1-carboxylic acid amide (1.46 kg) in methanol (23.2 kg) and [Ru(OAc)2((S)-MeOBIPHEP)] (1.83 g) in methanol (1.5 liters) were combined and subjected to hydrogenation at 40° C. and 150 psig (10.3 bar). Completion of the reaction to form (R)-8-fluoro-6-phenylsulfanyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid amide (not isolated) was monitored by HPLC. The resulting reaction solution was distilled and the solvent exchanged from methanol to THF (7.6 kg). Analysis of an aliquot of the THF solution provided the following data: MP=167.4-168.2° C.; MS (M+1)=302; H1 NMR (300 MHz): δ(DMSO): 1.56-1.84 (2H, m), 1.91 (2H, m), 2.66 (2H, m), 3.67 (1H, t, J=5.65 Hz), 6.80 (1H, dd, J=1.88, 10.17 Hz), 6.88 (1H, bs, NH), 6.92 (1H, m), 7.32-7.44 (6H, m, Phenyl, NH): [α]D=30.5° (MeOH). Chiral Assay (Area Norm): Column: ChiralCel OD-H (250×4.6 mm), mobile phase 85/15 hexane/ethanol(isocratic) Flow rate 0.7 ml/min, 25° C., uv @230 nm.: (R)-isomer 99.32/(S)-isomer 0.68.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:22])[C:15]([O:17]C(C)(C)C)=[O:16])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:22])[C:15]([OH:17])=[O:16])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
2.2 g (purity 82%, 5.0 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 1.5 g (94% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([OH:15])[CH3:14].[ClH:16]>O1CCOCC1>[ClH:16].[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:15][CH2:13][CH3:14])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CCO
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=N)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A stirred mixture of 4-hydroxy-3-nitrobenzonitrile 33 (5.2 g, 32 mmol) in a solution of abs. ethanol (250 ml) and dioxane (40 ml) was cooled in an ice bath as dry HCl gas was bubbled through it for 1 hr. The mixture was stirred overnight at room temperature and the resulting precipitate was collected, washed with ether and dried to give 6.2 g (79%) of the imidate ester HCl 34. 1H NMR (600 MHz, DMSO-d6) δ 11.8 (br s, 1H), 8.64 (s, 1H), 8.21 (d, 1H, J=9 Hz), 7.38 (d, 1H, J=9 Hz), 4.57 (q, 2H, J=7.2 Hz), 1.47 (t, 3H, J=7.2 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:21][C:20]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=2)[C:2]1=[O:1]
Reactant: Cc1ccncc1I
Reactant: N#Cc1ccc2c(c1)C(=O)NCC2
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc(C#N)cc2C1=O
Yield: 38.1 %

Procedure:
Using analogous reaction conditions as described in Example 1, 1-oxo-1,2,3,4-tetrahydro-isoquinoline-7-carbonitrile (I-32c: 120 mg, 0.6976 mmol) was reacted with 3-iodo-4-methyl-pyridine (152.7 mg, 0.6976 mmol), 1,4-dioxane (5 mL), copper iodide (13.2 mg, 0.06976 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (40 mL, 0.2092 mmol) and potassium phosphate (369.7 mg, 1.744 mmol) to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane) afforded 70 mg of the product (38.14% yield).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH:23]=[O:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CO.[BH4-].[Na+]>O>[CH3:27][Si:2]([CH3:1])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH2:23][OH:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: CCC(CC=O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(CCO)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal (50 mg, 0.0001 mol) in methanol (2 mL, 0.05 mol) was treated with sodium tetrahydroborate (8 mg, 0.0002 mol). The mixture was stirred at room temperature for 1 h, and then water was added and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give the desired product as an oil. LC/MS (M+H)+: m/z=402.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]2=[CH:17][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([Cl:25])[C:23]=3[O:24][CH:14]2[C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:25][C:22]1[C:23]2[O:24][C:14]3[C:13](=[O:26])[N:12]([C@@H:4]([CH2:5][CH:6]4[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]4)[C:3]([OH:27])=[O:2])[CH2:16][C:15]=3[CH2:17][C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC2=Cc3cccc(Cl)c3OC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Yield: 79.8 %

Procedure:
A solution of (S)-2-(5-chloro-3-oxo-3,3a-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid methyl ester (1.5 g, 4.0 mmol) and lithium hydroxide monohydrate (0.22 g, 5.22 mmol) was stirred at 25° C. for 2 hours in tetrahydrofuran-water (3:1) mixture (50 mL). The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was acidified with 2N-hydrochloric acid, and diluted with water. The resulting solution was extracted with ethyl acetate (3×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (1.2 g, 83.3%) as off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C@H:11]([CH3:13])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C@H:11]([CH3:13])[C:10]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)[C@H](C)O
Reactant: Oc1ccc(Cl)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,4-dichlorophenol (compound 3; 3.0 g, 18.4 mmol), ethyl (S)-lactate (compound 8a; 2.39 g, 20.2 mmol, 1.1 eq), and triphenylphosphine (7.23 g, 27.6 mmol, 1.5 eq) in anhydrous THF (50 mL), diisopropylazodicarboxylate (5.46 g, 27.6 mmol, 1.5 eq) was added dropwise. The reaction mixture was stirred 16 hours at room temperature. The solvent was evaporated and the resulting residue was subjected to chromatography on silica gel with 2-5% EtOAc/hexanes. Product-containing fractions were pooled and evaporated to yield a pale yellow oil which was used without further purification: 1H NMR (CDCl3) δ 7.31 (d, 1H), 7.06 (dd, 1H), 6.75 (d, 1H), 4.70 (q, 1H), 4.21 (dq, 2H), 1.62 (d, 3H), 1.20 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[F:20][C:21]([F:30])([F:29])[C:22]1[S:26][C:25]([CH2:27]O)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:25]4[S:26][C:22]([C:21]([F:30])([F:29])[F:20])=[CH:23][CH:24]=4)=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1
Reactant: OCc1ccc(C(F)(F)F)s1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4ccc(C(F)(F)F)s4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (100 mg), [5-(trifluoromethyl)thiophen-2-yl]methanol (143 mg) and triphenylphosphine (308 mg) in tetrahydrofuran (5 ml) was added bis(2-methoxyethyl)azodicarboxylate (275 mg) at 60° C., and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (71 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:24]I.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([O:14][CH3:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
4-(4-Chloro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.641 mmol) was added portionwise as a solid to a suspension of sodium hydride (0.018 g, 0.770 mmol) in dimethylformamide (6 mL) at room temperature. After 30 minutes, methyl iodide (0.109 g, 60 uL, 0.770 mmol) was added and the mixture was stirred overnight. The mixture was poured into an equal volume of water and extracted with ethyl acetate (2×10 mL). The ethyl acetate extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to give a tan oil. The crude oil was purified by silica gel chromatography (hexane to 60:40 hexane/ethyl acetate gradient) to afford 4-(4-Chloro-phenyl)-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester as a clear oil (108 mg, 52%).
Reaction SMILES: O=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([O:15][CH2:16]C)=[O:14])=[CH:11][N:12]=2)[CH:9]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]3[N:8]([C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:12]=3)[CH:9]=2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cnc2ccc(CC=O)cn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cnc2ccc(CCN3CCN(C)CC3)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of crude ethyl 6-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxylate (112) (214 mg, 0.92 mmol) in DCM (5 mL) and 1-methylpiperazine (231 μL, 2.30 mmol) at room temperature was added portion-wise sodium triacetoxyborohydride (586 mg, 2.77 mmol). The reaction was stirred at room temperature overnight. The solvent was concentrated. The crude was taken in 10% sodium bicarbonate and ethyl acetate. The organic was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified by silica chromatography to afford methyl 6-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxylate (113). MS m/z 304.4 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:3][OH:4].Cl.[OH-].[K+].[C:14](=O)(OC(Cl)(Cl)Cl)[O:15]C(Cl)(Cl)Cl>O.C1COCC1>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:2]1[CH2:3][O:4][C:14](=[O:15])[NH:1]1
Reactant: NC(CO)c1ccccn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1NC(c2ccccn2)CO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 30.4 %

Procedure:
To a solution of 2-amino-2-(pyridin-2-yl)ethanol (3.8 g, 28 mmol) (as the bis HCl salt) in water (50 mL) cooled to 0° C. was added potassium hydroxide (11 g, 19 mmol) followed by THF (50 mL) and the reaction stirred for 20 minutes at 0° C., followed by addition of bis(trichloromethyl) carbonate (8.2 g, 28 mmol) as the solid and stirring at 0° C. for 2 hours. The reaction was next poured into water and extracted with EtOAc and the combined organic layers were washed with 1N NaOH, brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by normal phase chromatography using EtOAc as eluent to yield 4-(pyridin-2-yl)oxazolidin-2-one (1.4 g, 8.5 mmol, 31% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@:26]([OH:41])([C@H:33]([S:35][CH:36]([CH2:39]O)[CH2:37][OH:38])[CH3:34])[CH2:27][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@@:26]([OH:41])([CH2:27][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1)[C@H:33]([S:35][C@@H:36]1[CH2:37][O:38][C@@H:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)=[O:8])=[CH:16][CH:17]=2)[O:2][CH2:39]1)[CH3:34]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=Cc1ccc(C(=O)Nc2ccncc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccncc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(3), a reaction was carried out using 4-formyl-N-(4-pyridyl)benzamide (200 mg, 0.88 mmol), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (318 mg, 0.88 mmol) and p-toluenesulfonic acid monohydrate (469 mg, 2.5 mmol) and the reaction mixture was treated according to a similar procedure to that described in Example 3(3) to give the trans isomer of the title compound (187 mg, yield 37%) as a white solid and the cis isomer (86 mg, yield 17%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [SH2:1].[CH3:2][S:3][C:4]1[S:5][C:6]([C:10]#[N:11])=[C:7]([NH2:9])[N:8]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:2][S:3][C:4]1[S:5][C:6]([C:10](=[S:1])[NH2:11])=[C:7]([NH2:9])[N:8]=1
Reactant: S
Reactant: CSc1nc(N)c(C#N)s1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nc(N)c(C(N)=S)s1
Temperature: 0 °C
Reaction time: 48 h
Yield: 54 %

Procedure:
20 parts of hydrogen sulfide are introduced, over 6 hours, into a mixture of 51.3 parts of 2-methylmercapto-4-amino-5-cyanothiazole, 0.2 part of triethylamine and 150 parts of dimethylformamide. The reaction mixture is left to stand for 48 hours and is then poured into 500 parts of ice water, and the product is filtered off. 33 parts of 2-methylmercapto-4-amino-5-thiocarbamoylthiazole (54% of theory) of melting point 192°-195° C. are obtained.