Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([F:13])[F:12])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+]>C(O)C>[F:13][CH:11]([F:12])[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C(F)F)cn1
Reaction time: 5 h

Procedure:
A solution of 5-difluoromethyl-pyridine-2-carboxylic acid methyl ester (700 mg, 3.7 mmol) in ethanol (8.0 ml) was treated with a solution of sodium hydroxide (5M, 1.5 ml) at 0° C. Then the reaction mixture was allowed to attain room temperature and was stirred for 5 hours. For the workup, ethanol was removed at reduced pressure. The resulting solid was dissolved in water (5 ml) and the solution was washed with ethyl acetate (2×5 ml). The aqueous layer acidified with a solution of citric acid (10%, pH˜4), followed by extraction with a 7:3-mixture of dichloromethane and methanol (5×10 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulphate, and evaporated at reduced pressure. The 5-difluoromethyl-pyridine-2-carboxylic acid was obtained as a white solid (400 mg, 62% of theory).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)OCC1.[C:12]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.O>[C:12]([C:14](=[C:5]1[CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH2:10]1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])#[N:13]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)(C)OC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)C(C#N)=C1CCC(=O)CC1

Procedure:
A solution of 1,4-dioxaspiro[4.5]decan-8-one (5 g, 32.0 mmol), tert-butyl 2-cyanoacetate (4.97 g, 35.2 mmol), ammonium acetate (0.2 g) and acetic acid (1.0 mL) in toluene (75 ml) was refluxed using Dean-Stark water separator to isolate water formed for 16 hours. After cooling, the reaction mixture was washed twice with water, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material (4.18 g, 14.96 mmol) was treated with acetic acid (80% in water, 42.8 mL, 599 mmol) at 65° C. overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on Analogix IntelliFlash280 eluting with 5 to 100% ethyl acetate/hexanes to give the title compound. 1H NMR (501 MHz, CDCl3) δ 1.54 (s, 9H), 2.49-2.62 (m, 4H), 3.05-3.16 (m, 2H), 3.37 (t, J=7.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)Cl>[Cl:1][C:2]1[N+:3]([O-:19])=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12
Reactant: Clc1nccc2ccsc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc2ccsc2c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.1 %

Procedure:
To a solution of 7-chlorothieno[2,3-c]pyridine (5.00 g, 29.5 mmol) in DCM (200 mL) was added m-chloroperbenzoic acid (13.2 g, 59.0 mmol). The combined mixture was stirred at RT for 24 h. After that time, it was purified by ISCO chromatography (0 to 6% MeOH:DCM) to afford 3.18 g (58%) of the title compound as a light brown solid. 1H NMR (400 MHz, CDCl3): δ 8.31 (d, J=7.2 Hz, 1 H), 7.69 (d, J=5.2 Hz, 1 H), 7.57 (d, J=6.8 Hz, 1 H), 7.35 (d, J=5.2 Hz, 1 H); MS (ESI): 185.95, 187.96 [M+H]+; HPLC tR=0.88 min (TOF: polar—3 min).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=2[Cl:21])[C:9](=O)[CH3:10])[C:5]([N+:22]([O-])=O)=[CH:4][CH:3]=1.C(O)(=O)C>C(O)C.[Fe]>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=3[Cl:21])[C:9]([CH3:10])=[N:22][C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)N(Cc1ccc(C#N)cc1Cl)c1nc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2ccc(Br)nc2n1Cc1ccc(C#N)cc1Cl
Yield: 9.9 %

Procedure:
To a solution of 6-bromo-2-(N-(2-chloro-4-cyanobenzyl)acetamido)-3-nitropyridine (21.8 g) in ethanol (33 ml)-acetic acid (8.3 ml) was added iron powder (2.29 g) at room temperature, and the mixture was refluxed under heating for 2 hr. The reaction mixture was cooled, the insoluble matter was removed by filtration, and the solvent was evaporated. To the residue was added dichloromethane, and the product was extracted. The solvent was evaporated and the residue was purified by silica gel column chromatography (dichloromethane/methanol=30/1) to give the objective compound (1.90 g) as a pale-yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl.CCN(C(C)C)C(C)C>C(Cl)Cl.C1C=CC2N(O)N=NC=2C=1.CCCCCC.C(Cl)CCl>[C:8]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:22])[NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: Nc1cccnc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCC(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a mixture of 3-aminopyridine (1, 2.82 g, 30 mmole) and 6-tert-Butoxycarbonylamino-hexanoic acid (2, 9.2 g, 40 mmole) in methylene chloride (50 mL) was added HOBt (135 mg, 1 mmole), EDC. HCl (7.6 g, 40 mmole) followed by DIPEA (10.45 mL, 60 mmole). The reaction mixture was stirred at room temperature for 3 h. At this point the TLC showed the disappearance of starting material. The reaction solution was washed with water (3×25 mL), followed by aqueous sodium bicarbonate (25 mL), then brine and finally dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography using 1% methanol in methylene chloride as the eluant to give the pure product as an oily residue. This residue on trituration with hexane gave 3 as a colorless solid (6.3 g, 68%, mp 96-98° C.). 1H NMR (CDCl3) δ 8.68 (br s, 2H), 8.48 (m, 1H), 8.30 (m, 2H), 7.32 (m, 1H), 4.62 (br s, 1H), 3.16 (m, 2H), 2.40 (m, 2H), 2.78 (m, 2H), 1.50 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[CH2:24][C@H:13]23)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)cc1Cl
Yield: 38 %

Procedure:
The title compound is prepared from 4-amino-3-chloro-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 38% of theory; LC (method 4): tR=1.96 min; Mass spectrum (ESI+): m/z=327/329 (Cl) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>>[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[CH:5]=2)=[O:40])=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(Cl)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 1-(3) and 4-chlorobenzoyl chloride were treated in a manner similar to Example 2-(4) to give 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl 4-chlorophenyl ketone as a colorless powder. APCI-Mass m/Z 620/622 (M+H). 1H-NMR (DMSO-d6) δ 1.69 (s, 3H), 1.97 (s, 3H), 1.98 (s, 3H), 2.04 (s, 3H), 4.11 (br-d, J=4.2 Hz, 2H), 4.30 (m, 1H), 5.28 (t, J=9.8 Hz, 1H), 5.53 (t, J=9.6 Hz, 1H), 5.73 (t, J=9.4 Hz, 1H), 6.34 (d, J=9.2 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.80 (d, J=8.5 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 8.18 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1F)[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=1)[CH:16]=[O:17]
Reactant: Oc1cccc(C(F)(F)F)n1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Temperature: 150 °C
Yield: 44.3 %

Procedure:
To a solution of 6-(trifluoromethyl)pyridin-2-ol (1.205 g, 7.39 mmol) in DMF (7 mL), was added 3,4-difluorobenzaldehyde (0.776 mL, 7.04 mmol) and K2CO3 (1.167 g, 8.44 mmol). The mixture was heated with a microwave condition at 150° C. for 1 h. After cooling, the mixture was diluted with EA, washed with water, brine, and concentrated. The residue was purified via flash chromatography to afford the title compound (890 mg, 44.3% yield) as a white solid. LCMS: rt=2.62 min, [M+H+]=286
Reaction SMILES: [CH3:1][C:2]1([OH:13])[CH2:11][CH2:10][CH2:9][CH:8]2[CH:3]1[CH:4]1[CH2:12][CH:7]2[CH:6]=[CH:5]1.[C:14]([O-])([O-])=[O:15].[Na+].[Na+]>>[CH:14]([O:13][C:2]1([CH3:1])[CH2:11][CH2:10][CH2:9][CH:8]2[CH:3]1[CH:4]1[CH2:12][CH:7]2[CH:6]=[CH:5]1)=[O:15]
Reactant: CC1(O)CCCC2C3C=CC(C3)C21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Product: CC1(OC=O)CCCC2C3C=CC(C3)C21
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
7.4 g (0.042 mole) of 3-methyl-tricyclo[6.2.1.02,7 ]undec-9-en-3-ol--see Example 1--were then added to the above mixture, and the whole mixture was stirred for 3 days at room temperature. The obtained mixture was then decomposed by the addition of 100 ml of a saturated aqueous solution of Na2CO3, extracted with ether (3×50 ml), washed with water (3×50 ml) and dried over Na2SO4. After evaporation 8 g of crude material were obtained which, by distillation at 0.02 Torr, provided the desired compound in a 58% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(=O)CC
Solvent: O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (1.9 g), 2-(4-chlorobenzyl)-3-oxopentanoic acid ethyl ester (0.95 g) and polyphosphoric acid (10 mL) was heated at 120° C. for 5 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium chloride solution and saturated aqueous sodium hydrogen carbonate solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 10:1 by volume) to afford title compound as a brown solid, 0.10 g.
Reaction SMILES: NN.[Cl:3][C:4]1[S:8][C:7]([C:9]([NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[O:10])=[CH:6][C:5]=1[C:33]1[N:37]([CH2:38][CH3:39])[N:36]=[CH:35][C:34]=1[Cl:40]>CO>[NH2:14][CH2:13][C@@H:12]([NH:11][C:9]([C:7]1[S:8][C:4]([Cl:3])=[C:5]([C:33]2[N:37]([CH2:38][CH3:39])[N:36]=[CH:35][C:34]=2[Cl:40])[CH:6]=1)=[O:10])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1
Reactant: CCn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: CO
Product: CCn1ncc(Cl)c1-c1cc(C(=O)N[C@H](CN)Cc2cccc(F)c2)sc1Cl
Reaction time: 1 h
Yield: 82.8 %

Procedure:
At RT, NH2NH2 (0.15 ml, 4.78 mmol) was added to 5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-N-{(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-[(3-fluorophenyl)methyl]ethyl}-2-thiophenecarboxamide (280 mg, 0.49 mmol) in MeOH (5 mL). After 10 h the solvent was removed under vacuum. The resulting residue was dissolved in DCM (15 mL), and washed with H2O (10 mL×3). To the DCM solution was added HCl (12 N, 1.0 mL). After 1 h, the aqueous phase was separated and washed with DCM (10 ml×3). Water was removed under high vacuum to give the title compound (179 mg, 67.5%) as an off-white solid: LC-MS (ES) m/z=441 (M+H)+, 1H NMR (d4-MeOD, 400 MHz) δ ppm 7.72-7.67 (m, 1H), 7.62 (s, 1H), 7.35-7.29 (m, 1H), 7.14-7.17 (m, 2H), 7.00-6.96 (m, 1H), 4.53 (m, 1H), 4.14-3.97 (m, 2H), 3.37-3.15 (m, 2H), 3.07-2.97 (m, 2H), and 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:12])[C:4]=2[N:3]=1.ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:12])[C:4]=2[N+:3]=1[O-:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OC1CCCc2ccc(Cl)nc21
Solvent: ClCCl
Product: [O-][n+]1c(Cl)ccc2c1C(O)CCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
To an ice-cold solution of 2-chloro-5,6,7,8-tetrahydroquinolin-8-ol (300 mg, 1.634 mmol) in dichloromethane (5 mL) was added 3-chloroperbenzoic acid (604 mg, 2.451 mmol) in small portions over a period of 5 min. The reaction mixture was slowly warmed to RT and stirred for 20 h. The reaction was quenched by the addition of water. The aqueous phase was removed and the organic layer was washed with a 10% aqueous sodium thiosulfate solution (2×), with a 2M sodium carbonate solution (2×), and with brine (1×). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness furnishing a beige solid. Amount 320 mg. Yield 98%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(OC=1C1C=CC=CC=1)=[C:44]1[N:54](C)[N:55]=[CH:56]C1=CC=2>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]3[N:55]([CH3:56])[N:54]=[CH:44][C:23]3=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: Cn1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Product: Cn1ncc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 98 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-1-methyl-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound as a gummy solid (70 mg, 98%). LCMS (Method B): RT=4.44 min, [M+H]+=522.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([N+:14]#[C-])([CH3:13])[CH2:12][CH:7]2[CH2:6]1)=[O:4].Cl>C(O)C>[CH3:16][N:2]([CH3:1])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([NH2:14])([CH3:13])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: [C-]#[N+]C1(C)CC2CN(C(=O)N(C)C)CC2C1
Agent: Cl
Solvent: CCO
Product: CN(C)C(=O)N1CC2CC(C)(N)CC2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.7 %

Procedure:
To a solution of 5-isocyano-5-methyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 11b (0.388 g, 1.75 mmol) in 15 mL of ethanol was added 0.38 mL of hydrochloric acid (6 N) upon cooling by an ice-water bath. The reaction mixture was warmed up to room temperature and stirred for 1.5 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was quenched with 20 mL of saturated aqueous sodium carbonate. The mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were evaporated to dryness. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-amino-5-methyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 11c (0.28 g, yield 75.7%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:5]([CH3:14])=[C:6]([CH:8]=[CH:9][C:10]=1[S:11][C:12]#N)[NH2:7].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].CI>C(O)C>[CH3:1][O:2][CH2:3][C:4]1[C:5]([CH3:14])=[C:6]([CH:8]=[CH:9][C:10]=1[S:11][CH3:12])[NH2:7]
Reactant: COCc1c(SC#N)ccc(N)c1C
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Solvent: CI
Product: COCc1c(SC)ccc(N)c1C
Yield: 92.7 %

Procedure:
29.1 g (0.14 mol) of 3-methoxymethyl-2-methyl-4-thiocyanoaniline was dissolved in 200 ml of ethanol and mixed with 100 ml of an aqueous solution containing 33.6 g of sodium sulfide nonahydrate at room temperature. Then, 21.9 g of methyl iodide was dropwise added thereto, and the mixture was reacted at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and water and chloroform were added to the residue. Then, the organic layer was separated and washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 25.6 g of the desired product as an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][C:12](=[S:16])[N:13]([CH3:15])[CH3:14])[CH:5]=1.[C:18]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:18])[CH:7]=[C:6]([O:11][C:12](=[S:16])[N:13]([CH3:14])[CH3:15])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)cc(OC(=S)N(C)C)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)cc(OC(=S)N(C)C)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 52 %

Procedure:
To a stirred solution of 3-dimethylthiocarbamyloxy-5-hydroxybenzoic acid methyl ester (2.37 g, impure) in DMF (30 mL) at room temperature was added K2CO3 (3.85 g, 27.9 mmol), followed by iodomethane (1.16 mL, 18.6 mmol). After stirring for 3.5 h at room temperature the reaction mixture was partitioned between ethyl ether (200 mL) and H2O (200 mL). The organic layer was washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 33% EtOAc in hexanes as an eluent to furnish 3-dimethylthiocarbamyloxy-5-methoxybenzoic acid methyl ester (1.30 g, 4.83 mmol).
Reaction SMILES: Br[C:2]1[N:6](C(C)C)[N:5]=[CH:4][C:3]=1[CH2:10][C:11]1([N:24]=[C:25]=O)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C([Li])(C)(C)C>CC1CCCO1>[NH:6]1[C:2]2=[CH:25][NH:24][C:11]3([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[CH2:10][CH:3]2[CH2:4][NH:5]1
Reactant: CC(C)n1ncc(CC2(N=C=O)CCN(C(=O)OC(C)(C)C)CC2)c1Br
Agent: [Li]C(C)(C)C
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC1CNNC1=CN2
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
To a mixture of tert-butyl 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)-4-isocyanatopiperidine-1-carboxylate (1.4 g, 3.3 mmol) in 2-methyl tetrahydrofuran (10 mL) was added t-butyl lithium (1.7 M in hexane, 4.3 mL, 7.2 mmol) at −78° C., under argon. After the addition was complete the mixture was allowed to warm to room temperature and was stirred for 18 hours. The mixture was quenched with water (10 mL) and then diluted with ethyl acetate (20 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product was purified by flash column chromatography to give tert-butyl tetrahydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridine]-1-carboxylate (0.77 g, 67%). +ESI (M+H) 374.1; 1H NMR (300 MHz, CDCl3, δ): 7.34 (s, 1H), 6.35 (s, 1H), 5.45 (m, 1H), 3.57 (m, 2H), 3.42 (m, 2H), 2.79 (s, 2H), 1.70 (m, 4H), 1.45 (m, 15H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]#[N:28])=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:11]=2)=[CH:6][C:7]=1[NH:8][CH3:9].Cl.[N:30]([O-])=O.[Na+]>O1CCOCC1.O>[CH3:22][O:21][CH2:20][CH2:19][O:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[N:4]=[C:3]([C:27]#[N:28])[C:2]3[N:1]=[N:30][N:8]([CH3:9])[C:7]=3[CH:6]=2)=[CH:11][C:12]=1[C:23]([F:26])([F:24])[F:25]
Reactant: CNc1cc(-c2ccc(OCOCCOC)c(C(F)(F)F)c2)nc(C#N)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COCCOCOc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
3-amino-6-(4-((2-methoxyethoxy)methoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)picolinonitrile (100 mg) was suspended in dioxane (1500 μl) and water (1500 μl) and cooled to 0° C. Hydrochloric acid (2M, 189 μl) followed by dropwise addition of sodium nitrite (25 mg) in water (500 μl) and the mixture stirred at room temperature for 2 hours. The suspension was filtered and the solid washed with water to afford pale brown solid 6-(4-((2-methoxyethoxy)methoxy)-3-(trifluoromethyl)-phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (92% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:18][S@@](C(C)(C)C)=O)([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH3:10].Cl.O1CCOCC1.[C:32]([N:40]=[C:41]=S)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH3:10])[CH2:11][C@@H:12]([C:13]([F:14])([F:15])[F:16])[O:17][C:41]([NH:40][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:18]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)[S@@](=O)N[C@@](C)(C[C@H](O)C(F)(F)F)c1cccc(F)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@]1(c2cccc(F)c2Cl)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of (R)-N-((2S,4S)-2-(2-chloro-3-fluorophenyl)-5,5,5-trifluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (1.75 g, 4.49 mmol) in DCM (10 mL) and methanol (5.00 mL) was added hydrogen chloride, 4M in 1,4-dioxane (11.22 mL, 44.9 mmol). After 30 min, the mixture was concentrated, diluted with DCM and saturated NaHCO3. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. This material was dissolved in THF (25 mL) and then treated with benzoyl isothiocyanate (0.695 mL, 5.16 mmol). After 30 min, triethylamine (0.751 mL, 5.39 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.947 g, 4.94 mmol) were added, and the resulted reaction mixture was brought up to 70° C. for 40 min. The reaction mixture was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the crude was purified by silica gel column (40 g, 0-40% EtOAc/hexane in 25 min) to afford N-((4S,6S)-4-(2-chloro-3-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide as an off-white solid (1.73 g, 93% yield). MS m/z=415 [M+H]+. Calculated for C19H15ClF4N2O2: 414.8.