Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C1C=CC=CC=1.[CH2:16]([SH:20])[CH2:17][CH2:18][SH:19]>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[S:20][CH2:16][CH2:17][CH2:18][S:19]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: SCCCS
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: Oc1ccc(C2SCCCS2)cc1
Temperature: 0 °C

Procedure:
4-Hydroxybenzaldehyde (46 g, 0.377 mol), recrystallized from benzene, and 1,3-propanedithiol (45 ml, 0.449 mol) were added to dry chloroform. The reaction mixture was stirred at 0° C. and HCl gas was bubbled through the solution for 10 minutes. After the exothermic reaction stopped the solution was refluxed for 10 hours. A white precipitate formed. This was filtered off and the chloroform solution was washed with water three times, dried (MgSo4) and evaporated under reduced pressure to yield a light yellow solid. White needles were obtained after recrystallization from chloroform, MP=151°-152° C. The white precipitate was also recrystallized from chloroform to yield white needles that melted at 151°-152° C. IR and NMR confirmed the two compounds to be identical. Total yield after recrystallization: 99%.
Reaction SMILES: [C:1]([CH:4]1[CH:8]2[CH2:9][C:10](=[O:13])[CH:11]=[CH:12][C:7]2([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)OC1=O)(=[O:3])[CH3:2].[Cl-].[NH+]1C=CC=C[CH:25]=1>CO>[CH3:25][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([CH2:4][C:1](=[O:3])[CH3:2])[CH:9]=1
Reactant: c1cc[nH+]cc1
Reactant: CC(=O)C1C(=O)OC2(C#Cc3ccccc3)C=CC(=O)CC12
Agent: [Cl-]
Solvent: CO
Product: COc1ccc(C#Cc2ccccc2)c(CC(C)=O)c1
Yield: 50.4 %

Procedure:
3-Acetyl-3a,7a-dihydro-7a-(phenylethynyl)benzofuran-2,5(3H,4H)dione, (1.75 g 6 mmole), pyridinium chloride (1.5 g, 13 mmole) and MeOH (50 mL) were placed in a 100 mL round bottomed flask and heated at reflux for 2 hr. The solvent was removed under reduced pressure and the residue was partitioned between Et2O and water. The ether phase was washed with 3N hydrochloric acid, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was recrystallized from ethanol (10 mL) to give 0.8 g (50%) of the title compound as a light yellow solid, m.p. 63°-65° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:23][S:24]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25].[C:33]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:33]1([N:30]2[CH2:29][CH2:28][CH:27]([S:24]([CH2:23][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]5[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=5)=[O:12])=[CH:21][CH:22]=4)[O:6][C:2]=3[CH3:1])(=[O:25])=[O:26])[CH2:32][CH2:31]2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C1CCCC1
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A solution of 4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide (300 mg, 0.66 mmol, 1.00 equiv), cyclopentanone (84 mg, 1.00 mmol, 1.51 equiv) and acetic acid (60 mg, 1.00 mmol, 1.51 equiv) in 1,2-dichloroethane (10 mL) was stirred at room temperature for 4 h. Sodium triacetoxyborohydride (420 mg, 1.98 mmol, 3.00 equiv) was added and the resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum and the residue was eluted with water/acetonitrile (95:5-20:80) on a C18 column to give 240 mg (70%) of 4-[4-[(1-cyclopentylpiperidine-4-sulfonyl)methyl]-5-methyl-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide as a colorless solid. LC-MS- (ES, m/z): 523 [M+H]+, 262; 1HNMR (400 MHz, CD3OD, ppm) δ 8.60 (s, 1H), 8.48 (d, 1H), 8.11 (d, 2H), 7.99 (d, 2H), 7.89 (d, 1H), 7.45 (m, 1H), 4.65 (s, 2H), 4.46 (s, 2H), 3.49 (d, 2H), 3.37 (t, 1H), 3.02 (t, 1H), 2.58-2.55 (m, 2H), 2.51 (s, 3H), 2.37 (d, 2H), 2.06-1.96 (m, 4H), 1.83-1.70 (m, 2H), 1.69-1.51 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[F:32][C:20]([F:19])([F:31])[C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[S:3][C:4]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nc(-c2ccccc2)c(-c2ccccc2)s1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Yield: 12 %

Procedure:
3.12 g of 2-amino-4,5-diphenylthiazole and 2.44 g of 4-trifluoromethylbenzenesulfonyl chloride were stirred in pyridine at room temperature for 4.5 hours. Then the reaction mixture was poured into ice-water and the crystals thus precipitated were recovered by filtration and recrystallized from isopropyl ether/ethyl acetate to give 0.55 g of 2-(4-trifluoromethylbenzenesulfonyl)amino-4,5-diphenylthiazole. The melting point of this product was from 248° to 249° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH:21]([CH3:23])[NH:20][CH2:19][CH2:18]2)=[O:12].[Br:24][C:25]1[C:26]([C:32]([O:34][CH3:35])=[O:33])=[N:27][C:28](F)=[CH:29][CH:30]=1.C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH:21]([CH3:23])[N:20]([C:28]1[N:27]=[C:26]([C:32]([O:34][CH3:35])=[O:33])[C:25]([Br:24])=[CH:30][CH:29]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1nc(F)ccc1Br
Reactant: CC1NCCc2cccc(C(=O)Nc3nc4ccccc4s3)c21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2C)ccc1Br
Temperature: 105 °C

Procedure:
A solution of EXAMPLE 163C (1 g), methyl 3-bromo-6-fluoropicolinate (0.715 g) and triethylamine (0.775 mL) in 12 mL DMSO was heated at 70° C. overnight followed by heating at 105° C. for 4 hours. The reaction mixture was diluted with ethyl acetate, washed three times with water and brine, dried over Na2SO4, filtered, and concentrated. The product was purified by flash chromotography (silica gel, 5-25% ethyl acetate/hexanes).
Reaction SMILES: C(O[C:6]1[C:7](=[O:16])[C:8](=[O:15])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])CCC.[CH3:17][C:18]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:19]=1[CH2:20][NH2:21].C(N(CC)CC)C>O1CCCC1>[C:11]([NH:10][C:9]1[C:8](=[O:15])[C:7](=[O:16])[C:6]=1[NH:21][CH2:20][C:19]1[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:18]=1[CH3:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCCOc1c(NC(C)(C)C)c(=O)c1=O
Reactant: Cc1ccc(C)c(CN)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C)c(CNc2c(NC(C)(C)C)c(=O)c2=O)c1
Yield: 48.7 %

Procedure:
Tetrahydrofuran (10 mL), 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (1.13 g, 5.0 mmol, Example 1), 2,5-dimethylbenzylamine (0.858 g, 5.0 mmol), and triethylamine (0.51 g, 5.0 mmol) were stirred together at room temperature for approximately 18 hours. Following removal of solvent, the residue was triturated with water, with diethyl ether, and dried to give 0.698 g of a cream-colored solid. Three recrystallizations of this material from methanol afforded 0.444 g of the title compound as a white solid: mp 246°-247° C. (softens 242° C.). MS (m/z) 287 ([M+H]+). HPLC indicates a major component (>99%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=O.[NH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[C:11]([O:10][C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:17]=[CH:16][CH:15]=1)[CH2:1][NH:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(C)OC(=O)COc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)CNCc1cccc(OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
To a solution of tert-butyl (3-formylphenoxy)acetate (1.50 g) in dichloroethane (20.0 mL) were added tert-butyl glycinate (874 mg) and acetic acid (1.09 mL), and then sodium triacetoxyborohydride (2.69 g) was added thereto under ice-cooling. The reaction suspension was stirred at room temperature for 16 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain tert-butyl N-[3-(2-tert-butoxy-2-oxoethoxy)benzyl]glycinate (1.18 g).
Reaction SMILES: O.Cl.[NH2:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6].C1COCC1.[OH-].[Na+].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:24][C:25]([NH:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)C(C)(C)N
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(C)(C)NC(=O)OCc1ccccc1

Procedure:
3-Amino-3-methyl-2-butanone hydrochloride hydrate [J. Org. Chem. 49, 1209 (1984)] (10.6 g., 0.076 mol was dissolved in 700 ml. 1:1 THF:H2O and the pH adjusted to 6.8 with dilute NaOH. Benzylchloroformate (11.93 ml., 0.084 ml.) was added dropwise, maintaining pH 6.8-7.0 by the simultaneous dropwise addition of dilute NaOH. The pH was so maintained until it stabilized. The reaction mixture was extracted 4×100 ml. CHCl3. The organic extracts were combined, filtered and stripped to yield title product as an oil, 9.26.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1.O>CCOCC>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][OH:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCc1cccc(Cl)c1
Yield: 99.7 %

Procedure:
Lithium aluminium hydride (19 g,) was suspended in dry ether (300 ml) and 3-chlorophenylacetic acid (58 g,) in dry ether (600 ml) was added dropwise to the stirred suspension over 1 hr. The mixture was then heated at reflux for 2 hr. when tlc indicated completion of reaction. Excess lithum aluminium hydride was carefully decomposed with water (500 ml). The ether layer was separated off and 2M hydrochloric acid was used to break up the gelatinous aqueous layer which was then extracted with ether (2×400 ml). The combined ether layers were washed with water (300 ml), dried (sodium sulphate) and evaporated in vacuo to give 2-(3-chlorophenyl)ethanol as a pale yellow oil (53.1 g) characterised by its nmr spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]3[O:11][N:10]2[CH3:18])[CH:6]=[CH:7][CH:8]=1.[CH3:19][I:20]>O1CCCC1>[I-:20].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]3[O:11][N+:10]2([CH3:19])[CH3:18])[CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: COc1cccc(C2C3CCCCC3ON2C)c1
Solvent: C1CCOC1
Product: COc1cccc(C2C3CCCCC3O[N+]2(C)C)c1
Product: [I-]

Procedure:
Crude octahydro-3-(m-methoxyphenyl)-2-methyl-1,2-benzisoxazole (15 g.) in tetrahydrofuran (120 ml.) was treated with an excess of methyl iodide (15 ml.). A crystalline solid began to separate almost immediately. After 12 hours the precipitate was filtered and washed with tetrahydrofuran to give the analytically pure product, m.p. 165° with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:25][NH2:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:19]1([C:16]2[CH:17]=[N:18][C:13]([CH3:12])=[CH:14][CH:15]=2)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)=[O:6]
Reactant: Cc1ccc(C2(CN)CCOCC2)cn1
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Product: Cc1ccc(Cl)c(C(=O)NCC2(c3ccc(C)nc3)CCOCC2)c1

Procedure:
From 2-chloro-5-methylbenzoic acid and C-[4-(6-methylpyridin-3-yl)-tetrahydropyran-4-yl]methylamine. LCMS (MH+): m/z=359.0, tR (minutes, Method B)=0.74
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:13]=[CH:12][C:8]2N[CH:10]=[N:11][C:7]=2C=1)[NH2:4].[CH3:14]N1C2C(=CC(C#N)=CC=2)C=C1.[CH3:26][CH2:27]O>>[OH:1][NH:2][C:3]([C:5]1[CH:13]=[C:12]2[C:14](=[CH:26][CH:27]=1)[N:11]([CH3:10])[CH:7]=[CH:8]2)=[NH:4]
Reactant: Cn1ccc2cc(C#N)ccc21
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Reactant: CCO
Product: Cn1ccc2cc(C(=N)NO)ccc21

Procedure:
The title compound was prepared following procedure described for Intermediate 1, step 2, but starting from 1-methyl-1H-indole-5-carbonitrile obtained in step 1 (285 mg; 1.82 mmol) in EtOH (3 mL) as an off-white solid (325 mg, 94%). 1H NMR (DMSO-d6) δ 9.37 (s, 1H), 7.84 (s, 1H), 7.52-7.48 (m, 1H), 7.40-7.37 (m, 1H), 7.33-7.32 (m, 1H), 6.43 (d, J=3 Hz, 1H), 5.70 (bs, 2H), 3.78 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH2:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)([C:18]1[CH:26]=[CH:25][C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)(=O)=O.[OH:28][S:29](O)(=O)=[O:30]>C1COCC1.[OH-].[Na+].O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][S:29]([C:20]1[CH:19]=[CH:18][CH:26]=[CH:25][C:21]=1[N+:22]([O-:24])=[O:23])(=[O:30])=[O:28])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)O
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 70 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-amino-propionic acid (14.9 g, 73.2 mmol) was dissolved in a mixture of THF (45 mL) and 3 N aq. NaOH (45 mL). The reaction mixture was cooled to −10° C. and nosyl chloride (17.9 g, 80.5 mmol) was added as a THF solution (75 mL) drop wise over 30 min. The reaction mixture was stirred at −10° C. for 45 min followed by stirring at ambient temperature for 30 min. The reaction mixture was diluted with water (150 mL), acidified with 2% aqueous H2SO4 (to pH ˜2) and diluted with additional water (450 mL). The product was extracted with EtOAc (600 mL total) and washed with water (3×400 mL) and brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered and condensed in vacuo to afford compound A (20.0 g, 70% yield) as a cream solid. LC-MS [M+H-Boc] 290.3 (C14H19N3O8S+H, calc: 390.4). Purity >95% (UV/254 nm). Compound A was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[C:13]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:12]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][OH:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47].O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[C:13]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:12]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][O:37][S:46]([CH3:45])(=[O:48])=[O:47])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO)n(CCNC(=O)OC(C)(C)C)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3COS(C)(=O)=O)n(CCNC(=O)OC(C)(C)C)c2c1

Procedure:
To a solution of methyl 1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-hydroxymethylphenyl)-1H-indole-6-carboxylate (100 mg, 0.19 mmol) in chloroform (2 ml) was added triethylamine (0.04 ml, 0.28 mmol) and methanesulfonyl chloride (0.02 ml, 0.25 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 10 min. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was so successively washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-methanesulfonyloxymethylphenyl)-1H-indole-6-carboxylate as a crude product. The obtained crude product was used for Step 10 without purification.
Reaction SMILES: P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO[C:23](/[N:25]=N/C(OCC)=O)=O.[NH2:32][CH:33]1[C:42]2[C:37](=[CH:38][C:39]([CH2:43]O)=[CH:40][CH:41]=2)[O:36][CH2:35][CH2:34]1.CC(C)(O)C#N>C1COCC1>[NH2:32][CH:33]1[C:42]2[C:37](=[CH:38][C:39]([CH2:43][C:23]#[N:25])=[CH:40][CH:41]=2)[O:36][CH2:35][CH2:34]1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: NC1CCOc2cc(CO)ccc21
Agent: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCc1ccc2c(c1)OCCC2N
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a 125 mL flame dry 3-neck round bottom flask was added P(Ph)3 (4.4 g, 16.74 mmol) and THF (50 mL). After cooling to −20° C., DEAD (3.3 mL, 16.74 mmol) was added dropwise via the addition funnel. After stirring for 20 min at −20° C., (4-aminochroman-7-yl)-methanol (2.0 g, 11.16 mmol) in THF (75 mL) was added dropwise via the addition funnel. It was stirred for another 30 min. acetone cyanohydrin (3.1 mL, 33.48 mmol) was then added dropwise via the addition funnel. The resulting mixture was warmed to RT and stirred for 18 h. Solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (95:5) gave final compound. MS m/z: 189.12 (M+H). Calc'd. for C11H12N2O-188.23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([CH2:29]O)[CH2:13]N1CC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C1)=[N:9][C:8]([O:31]C)=[CH:7][CH:6]=2.C(N(C(C)C)CC)(C)C.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:31])[N:9]3[CH2:13][C:12](=[CH2:29])[C:11]=1[C:10]=23
Reactant: COc1ccc2ncc(Cl)c(C(CO)CN3CC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C3)c2n1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C1Cn2c(=O)ccc3ncc(Cl)c1c32

Procedure:
A solution of 1,1-dimethylethyl ((3R,45)-1-{(2R/S)-2-[3-chloro-6-(methyloxy)-1,5-naphthyridin-4-yl]-3-hydroxypropyl}-3-hydroxy-4-piperidinyl)carbamate (8.75 g, 18.7 mmol) and diisopropylethylamine (4.9 ml) in dichloromethane (90 ml) was treated at 0° C. under argon with para-toluenesulphonic anhydride (6.7 g, 20.6 mmol). After 3 hours at room temperature more para-toluenesulphonic anhydride (0.7 g) was added. After 2.5 days the mixture was washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (2×) and the combined organic extracts dried and evaporated. The residue was chromatographed, eluting with methanol/dichloromethane to give firstly the partially purified title compound (0.84 g, 21%) then 1,1-dimethylethyl {(3R,4S)-1-[(3-chloro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-3-hydroxy-4-piperidinyl}carbamate (3.93 g, 48%). The partially purified title compound (0.84 g) was further purified by chromatography eluting with methanol/dichloromethane affording pure product (0.57 g).
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13]([Cl:25])[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[C:11]2[C:10]([CH3:26])=[CH:9]1)=O)(C)(C)C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CS(O)(=O)=O>O1CCOCC1.CO>[ClH:25].[CH3:26][C:10]1[C:11]2[C:12](=[C:13]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:14]=[CH:15][C:16]=2[C:17]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[O:18])[NH:8][CH:9]=1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Reactant: C1COCCN1
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c[nH]c2c(N3CCOCC3)ncc(C(=O)N3CCOCC3)c12
Product: Cl
Temperature: 180 °C

Procedure:
A mixture of 7-chloro-3-methyl-4-(1-morpholin-4-yl-methanoyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (70 mg), morpholine (64 μl), and methanesulfonic acid (48 μl) in 1,4-dioxane (1 ml) was heated under microwave conditions at 180° C. for 30 minutes. The solid mass obtained was dissolved in methanol, transferred to a round bottom flask and evaporated. The residue was dissolved in dichloromethane (40 ml) and washed with 5% sodium hydrogen carbonate solution (4 ml). The organic layer was dried (MgSO4) and evaporated to give a pale brown foam. The residue was purified by Biotage chromatography over silica gel (50 g), eluting with 2% methanol/dichloromethane followed by 5% methanol/dichloromethane. The residue was dissolved in dichloromethane and treated with a solution of 1M hydrochloric acid in diethyl ether (10 drops). The solution was evaporated and triturated with diethyl ether and the resultant solid was then filtered off, sucked dry then dried at 40° C. under vacuum to afford the title compound (36 mg).
Reaction SMILES: [F:1][C:2]([F:27])([C:5]([F:26])([F:25])[C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH:3]=[CH2:4].[CH:28]1[CH2:32][CH:31]=[CH:30][CH:29]=1.C([O:37]O)(C)(C)C>C1(C)C=CC=CC=1.CCCCCC>[O:37]1[CH:28]2[CH:29]1[CH:30]1[CH2:31][CH:32]2[CH:3]([C:2]([F:27])([F:1])[C:5]([F:25])([F:26])[C:6]([F:23])([F:24])[C:7]([F:21])([F:22])[C:8]([F:19])([F:20])[C:9]([F:17])([F:18])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH2:4]1
Reactant: CC(C)(C)OO
Reactant: C1=CCC=C1
Reactant: C=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1CC2CC1C1OC21
Reaction time: 14 h

Procedure:
128 g (250 mmol) of the Diels-Alder reaction product of 3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluoro-1-decene (perfluorooctylethene) and cyclopentadiene are mixed in 10 ml of dry toluene with 815 mg (2.5 mmol) of molybdenum acetylacetonate, and 104 ml of a 3.6 molar solution of t-butyl hydroperoxide in toluene (375 mmol) is added dropwise at 28° C. within 2 hours. During this period, the temperature rises to 40° C. The solution is then held at 65°C. for 14 hours, and subsequently at 80° C. for another 2 hours. Thereaction mixture is filtered over magnesium silicate, followed by washing with two 20 ml portions of toluene. The low-boiling components are stripped off on a rotary evaporator. The residue obtained is taken up in 50 ml of hexane and left to crystallize for 12 hours at -28° C. Theresulting slurry of solids is filtered off with suction and dried at room temperature in an oil pump vacuum.