Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.I[CH2:4]I.[CH2:6]=[C:7]1[CH2:16][CH2:15][C:10]2([O:14]CCO2)[CH2:9][CH2:8]1>C(OCC)C.[Cu].[Zn]>[CH2:14]1[C:10]2([CH2:9][CH2:8][C:7](=[O:6])[CH2:16][CH2:15]2)[CH2:4]1
Reactant: C=C1CCC2(CC1)OCCO2
Reactant: ICI
Agent: [Cu]
Agent: II
Agent: [Zn]
Solvent: CCOCC
Product: O=C1CCC2(CC1)CC2
Temperature: 25 °C

Procedure:
A 250 mL round-bottom flask equipped with a reflux condenser was charged with zinc-copper couple (6.5 g, 0.05 mol) and ethyl ether (100 mL). Iodine (0.42 g, 0.00165 mol) was added and stirred until the brown color disappeared. Diiodomethane (26.56 g, 0.09915 mol) was added and heated at reflux for 2 h. 8-Methylene-1,4-dioxaspiro[4.5]decane (10 g, 0.06 mol), dissolved in ethyl ether (50 ml) was added and the mixture was heated at roflux overnight. An additional portion of diiodomethane (26.56 g, 0.09915 mol), zinc-copper couple (6.5 g, 0.05 mol) and iodine (0.42 g, 0.00165 mol) was added and the reaction was continued at reflux for overnight. The reaction mixture was cooled to room temperature, filtered, and the precipitate was rinsed with ethyl ether (100 mL). The combined ether solutions were placed in a 500 mL round-bottom flask and IN hydrochloric acid (200 mL) was added and stirred at room temperature for 1 hour. The layers were separated and the aqueous layer was extracted with ethyl ether (2×200 mL). The combined organic layers were dried and concentrated under educed pressure. The residue was purified by flash chromatography to afford the desired product. (4.6 g 50%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[N:5]=[C:4]([S:23][CH3:24])[N:3]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][O-:28].O1[CH2:35][CH2:34][CH2:33]C1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:6]3[C:7]([C:8]#[N:9])=[C:2]([O:28][CH2:27][C:26]([F:30])([F:29])[F:25])[N:3]=[C:4]([S:23][CH3:24])[N:5]=3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1.[CH2:15]([N:10]([CH:11]([CH3:12])[CH3:26])[CH:34]([CH3:35])[CH3:33])[CH3:14]
Reactant: CSc1nc(Cl)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Reactant: C1CCOC1
Reactant: [O-]CC(F)(F)F
Product: CCN(C(C)C)C(C)C
Product: CSc1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1

Procedure:
In analogy to the procedure described in example 59b, 4-chloro-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methylsulfanyl-pyrimidine-5-carbonitrile (example 57a) was treated with 2,2,2-trifluoroethanolate in tetrahydrofurane at room temperature during 18 hours to yield the 4-phenyl-piperidine in the presence of N-ethyl-diisopropylamine at room temperature during 18 hours to yield 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methylsulfanyl-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile as an amorphous, yellow solid; MS: [M+H]+=427.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([F:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([S:12](Cl)(=[O:14])=[O:13])=[N:3]1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].O>C1COCC1>[C:16]([NH:20][S:12]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[F:11])[N:2]([CH3:1])[N:3]=1)(=[O:14])=[O:13])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cn1nc(S(=O)(=O)Cl)c2c(F)cccc21
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(S(=O)(=O)NC(C)(C)C)c2c(F)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Further, 13.9 g (56 mmol) of 1-methyl-4-fluoro-1H-indazole-3-sulfonylchloride in 50 ml of THF, was added to 12.9 g (177 mmol) of t-butylamine in 100 ml of THF, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was poured into a large excess amount of water, whereupon the crystals were collected by filtration and dried in air to obtain 15.9 g (yield: 99.6%) of 3-(N-t-butylsulfamoyl)-1-methyl-4-fluoro-1H-indazole (compound represented by the formula [I-d]) (slightly purple crystals).
Reaction SMILES: [C:1](=[O:27])([O:3][C@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[O:17][C:16](=[O:18])[CH:15]=[C:14]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]3=2)[NH:7][C@@H:6]([CH3:26])[CH2:5]1)[NH2:2].N1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[C:1](=[O:27])([O:3][C@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[O:17][C:16](=[O:18])[CH:15]=[C:14]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]3=2)[N:7]([C:34](=[O:36])[CH3:35])[C@@H:6]([CH3:26])[CH2:5]1)[NH2:2]
Reactant: CC(=O)Cl
Reactant: C[C@H]1C[C@@H](OC(N)=O)c2c(ccc3oc(=O)cc(Cc4ccccc4)c23)N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc3oc(=O)cc(Cc4ccccc4)c3c2[C@H](OC(N)=O)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[Step 3] 226 mg of the cis-benzyl-8-methyl-3-oxo-7,8,9,10-tetrahydro-3H-pyrano[3,2-f]-quinolin-10-yl carbamate and 0.15 mL of pyridine were dissolved in 10 of dichloromethane followed by adding 66 μL of acetyl chloride while cooling with ice and stirring for 1 hour at room temperature. Following completion of the reaction, the solution was concentrated under reduced pressure and saturated aqueous sodium bicarbonate solution was added to the resulting residue followed by extracting three times with chloroform. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate:hexane=1:1) to obtain 250 mg of cis-benzyl-7-acetyl-8-methyl-3-oxo-7,8,9,10-tetrahydro-3H-pyrano[3,2-f]-quinolin-10-yl carbamate in the form of a yellow solid (99%).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][C:15]1[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=1)[CH:8]=2)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.CCOC(C)=O>C1COCC1>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:5]([CH2:3][OH:2])[NH:6]2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc2ccc(Oc3nc4ccccc4s3)cc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc2ccc(Oc3nc4ccccc4s3)cc2[nH]1
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a cooled (−78° C.) solution of 6-(benzothiazol-2-yloxy)-1H-indole-2-carboxylic acid methyl ester (200 mg, 0.61 mmol) in THF (6 mL) was added LAH (2 M in THF, 0.34 mL, 0.31 g, 0.68 mmol) and the reaction mixture was stirred (−78° C., 1 h). The reaction mixture was treated with H2O (5 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×25 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH (0.2 M NH3):DCM (0-4%) to provide the title compound as a beige solid (97 mg, 53%). MS (ESI): mass calcd. for C16H12N2O2S, 296.1; m/z found, 297.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.63 (s, 1H), 7.72 (d, J=8.1, 1H), 7.64 (dd, J=8.0, 0.7, 1H), 7.57 (d, J=8.5, 1H), 7.41-7.31 (m, 2H), 7.27-7.21 (m, 1H), 7.07 (dd, J=8.5, 2.2, 1H), 6.39 (s, 1H), 4.80 (d, J=5.9, 2H), 1.87 (t, J=5.9, 1H).
Reaction SMILES: C1(S[C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([I:14])[CH:8]=2)CCCC1.ClC1C=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19](OO)=O.[S:26](S([O-])=O)([O-:29])(=O)=[O:27].[Na+].[Na+]>C(Cl)Cl>[CH:19]1([S:26]([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([I:14])[CH:8]=2)(=[O:29])=[O:27])[CH2:18][CH2:23][CH2:24][CH2:25]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: Cc1cc(I)cc(SC2CCCC2)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(I)cc(S(=O)(=O)C2CCCC2)c1
Reaction time: 2 h

Procedure:
A solution of 1-(cyclopentylthio)-3-iodo-5-methylbenzene (440 mg) in DCM (20 ml) at 20° under nitrogen was treated with 3-chloroperoxybenzoic acid (1.046 g, 57-86% pure) and the mixture stirred at 20° for 2 h. 0.5M Aqueous sodium metabisulphite solution was added and the mixture was vigorously stirred at 20° for 18 h. The layers were separated and the organic phase washed with 0.5M aqueous sodium metabisulphite solution. The organic phase was dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified using a SPE bond elut cartridge (2×10 g, silica). Elution with DCM (5 vols) gave the title compound (425 mg). LCMS RT=3.36 min.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(OCC)(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:14]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([I:12])=[C:8]([CH3:13])[N:7]=3)=[O:16])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cnc2nc(C)c(I)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: Cc1nc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2cc1I
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of ethyl 4-hydroxy-6-iodo-7-methyl[1,8]naphthyridine-3-carboxylate Prep 4(0.41 g) and 4-chlorobenzylamine (2.50 mL) is heated at 180° C. for 1 h. The reaction is cooled to room temperature. Ethyl acetate (10 mL) and then hexanes (20 mL) are added and the solid is filtered, washed thoroughly with hexanes, and dried. The crude solid is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1L), 1% MeOH/CH2Cl2 (3L), 1.5% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (2L)) affords the desired product as a white solid (0.30 g, 0.66 mmol, 58%). Physical characteristics are as follows: m.p. 276-277° C.; 1H NMR (300 MHz, DMSO-d6) δ 13.17, 10.10, 8.83, 8.66, 7.40, 7.35, 4.54, 2.77; IR (drift) 3063, 3022, 2957, 2895, 1650, 1596, 1552, 1521, 1493, 1405, 1352, 1323, 1241, 1095, 807 cm−1; MS (ESI) m/z 453.6 (M+H)+, 451.7 (M−H)−; Anal. Calcd for C17H13ClIN3O2: C, 45.01; H, 2.89; N, 9.26; Found: C, 44.92; H, 2.78; N, 9.17.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.N1C=CC=CC=1.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:22]([O:29][C:30]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(NC(=O)OCc3ccccc3)ccc2[nH]1
Reaction time: 1 h

Procedure:
Ethyl 5-aminoindole-2-carboxylate [J. Am. Chem. Soc. 80, 4621 (1958) JCS Perkin I 53 (1977), 0.50 g] is dissolved in 49 ml of methylene chloride and pyridine (0.20 g) is added. The reaction is cooled to 0° and benzylchloroformate (0.36 ml) is added dropwise over 10 min. The reaction is stirred for 1 hr, diluted with chloroform, washed with saturated aqueous sodium bicarbonate, water, saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by flash column chromatography (150 g silica gel) eluting with hexane/ethyl acetate (3/1). The appropriate fractions are pooled and concentrated to give the title compound, NMR (300 MHz, CDCl3) 8.90, 7.79, 7.41-7.33, 7.24, 7.16, 5.22, 4.40 and 1.41 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:13]([C:21]3[CH:26]=[CH:25][C:24](SC)=[CH:23][N:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)=[N:6][CH:7]=1.O1CCC[CH2:30]1.O.O[O:36][S:37]([O-:39])=O.[K+]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([CH:13]([C:21]3[CH:26]=[CH:25][C:24]([S:37]([CH3:30])(=[O:39])=[O:36])=[CH:23][N:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)=[N:6][CH:7]=1
Reactant: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Cl)cn3)[nH]2)nc1
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Cl)cn3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a mixture of 5-chloro-2-(5-{1-[5-(methylsulfanyl)pyridin-2-yl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (117 mg), tetrahydrofuran (2 mL), water (2 mL) and methanol (2 mL) was added Oxone (registered trademark) (207 mg), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (64.6 mg, yield 52%) was obtained as a white amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 446 (MH+).
Reaction SMILES: [C:1]1(=[O:39])[N:5]([CH2:6][C:7](=[O:33])[CH2:8][NH:9][C@@H:10]([C:14]2[O:15][C:16]3[C:21]([C:22](=[O:31])[C:23]=2[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=[C:18]([Cl:32])[CH:17]=3)[CH:11]([CH3:13])[CH3:12])[C:4](=[O:34])[C:3]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]12.CCN(CC)CC.[C:47]1([CH3:56])[C:48]([C:53](Cl)=[O:54])=[CH:49][CH:50]=[CH:51][CH:52]=1>C(Cl)Cl>[C:47]1([CH3:56])[C:48]([C:53]([N:9]([CH2:8][C:7](=[O:33])[CH2:6][N:5]2[C:4](=[O:34])[C:3]3=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]3[C:1]2=[O:39])[C@@H:10]([C:14]2[O:15][C:16]3[C:21]([C:22](=[O:31])[C:23]=2[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:20][CH:19]=[C:18]([Cl:32])[CH:17]=3)[CH:11]([CH3:13])[CH3:12])=[O:54])=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CC(C)[C@@H](NCC(=O)CN1C(=O)c2ccccc2C1=O)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)N(CC(=O)CN1C(=O)c2ccccc2C1=O)[C@@H](c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
To 2-[(R)-1-(3-phthalimido-2-oxo-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-chromen-4-one (0.88 g, 1.5 mMol) in CH2Cl2 (10 mL) was added Et3N (0.23 mL, 1.6 mMol) and toluoyl chloride (0.21 mL, 1.6 mMol). The reaction was stirred at RT for 18 h, concentrated under vacuum, taken up in EtOAc, washed with 1 N HCl, brine, dried (MgSO4) and evaporated to dryness. Purification by flash chromatography on silica gel (5-15% EtOAc/hexane) followed by trituration with pet, ether, filtration and drying under vacuum gave the title compound (0.89 g, 90%) as a white solid: MS (ES) m/e 661.2 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:9]=C[S:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2].S(Cl)([Cl:17])(=O)=O.[CH:19]([Cl:22])(Cl)Cl>>[C:1]([NH:4][C:5]1[C:9]([Cl:17])=[C:19]([Cl:22])[S:7][C:6]=1[C:10]([O:12][CH3:13])=[O:11])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1sccc1NC(C)=O
Reactant: ClC(Cl)Cl
Product: COC(=O)c1sc(Cl)c(Cl)c1NC(C)=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
was obtained by reacting 19.9 g of methyl 3-acetylaminothiophene-2-carboxylate in 100 ml of chloroform with 17.9 ml of sulfuryl chloride (SO2Cl2) in 120 ml of chloroform by stirring at 40° C. for 2 hours and subsequently boiling under reflux conditions for 15 minutes. After the solvent had been distilled off, the residue was crystallized in ethyl acetate.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH:27]2[CH:25]([CH:26]2[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>ClCCl.CO>[C:33]([O:32][C:30](=[O:31])[NH:29][CH:26]1[CH:27]2[CH:25]1[CH2:24][N:23]([CH2:22][CH2:21][N:7]1[C:6]3[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=3[O:4][CH2:3][C:2]1=[O:1])[CH2:28]2)([CH3:36])([CH3:35])[CH3:34]
Reactant: N#Cc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)NC1C2CN(CCOS(C)(=O)=O)CC21
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1C2CN(CCN3C(=O)COc4ccc(C#N)cc43)CC21
Yield: 74 %

Procedure:
3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 60) (231 mg, 1.5 mmol) was deprotonated with sodium hydride and alkylated with 2-{6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}ethyl methanesulfonate (Intermediate 95) (1.55 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) gave 442 mg (94%) product as a yellow gum.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][C:43]1[S:44][C:45]([CH2:48][N:49]2[N:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)=[CH:46][N:47]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:41][CH2:42][C:43]1[S:44][C:45]([CH2:48][N:49]2[N:53]=[C:52]([NH:54][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:51]=[N:50]2)=[CH:46][N:47]=1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: COCc1ncc(Cn2ncc(N)n2)s1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCc1ncc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (30.0 mg, 0.16 mmol) in CH2Cl2 (1.0 mL) was treated at rt with DMAP (4.8 mg, 0.04 mmol), HOBt (26 mg, 0.19 mmol), EDC (76 mg, 0.40 mmol) and DIPEA (0.11 mL, 0.63 mmol) and the resulting mixture was stirred for 30 min at rt. A solution of 2-((2-(methoxymethyl)thiazol-5-yl)methyl)-2H-1,2,3-triazol-4-amine (36 mg, 0.16 mmol) in CH2Cl2 (0.6 mL) was then added and the reaction mixture was stirred overnight at rt. The solvents were removed under reduced pressure. Purification of the residue by HPLC gave the title compound as a beige solid. TLC: rf (4:6 hept-EA)=0.30. LC-MS-conditions 07: tR=0.87 min, [M+H]+=397.39.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C@H:4]([NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=O.CN1CCOCC1.Cl.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:32][CH2:33][CH2:34][NH2:35])=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[CH2:32][CH2:33][CH2:34][NH:35][C:5](=[O:7])[C@@H:4]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:3][CH:2]([CH3:1])[CH3:15])=[CH:27][CH:26]=1
Reactant: CC(C)C[C@H](NC1CCOCC1)C(=O)O
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)C[C@H](NC1CCOCC1)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
A suspension of (S)-4-methyl-2-(tetrahydro-pyran-4-ylamino)-pentanoic acid (430 mg, 2.00 mmol), N-methylmorpholine (0.220 mL, 2.00 mmol), and 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (597 mg, 2.00 mmol) in dry DMF (10 mL) was treated with Triton® B (1.82 mL, 4.00 mmol, 40 weight percent solution in methanol, Aldrich, Milwaukee, Wis.), a clear solution was obtained and cooled to 0° C. in an ice-water bath. Solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.760 g, 2.00 mmol) was then added. After stirring at 0° C. for 30 minutes, was added, the cooling bath was then removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 50 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (50 mL), brine (2×50 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (EtOAc:hexanes:MeOH 50:50:5) to give 300 mg (39%) of the pure titled compound as a clear oil. APCI-MS m/z 459.4 (MH+).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.[F:24][C:25]([F:37])([F:36])[C:26]1[N:31]=[C:30]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[Cl:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:33](=[O:34])[CH2:32][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:24])([F:37])[F:36])[N:31]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)n1
Reactant: Cn1cc(-c2ccc3c(c2Cl)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3c(c2Cl)CCN3C(=O)Cc2cccc(C(F)(F)F)n2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
To a solution of 5-(4-chloro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (300 mg, 0.805 mmol), [6-(trifluoromethyl)-2-pyridinyl]acetic acid (90 wt %) (183 mg, 0.805 mmol), HATU (306 mg, 0.805 mmol), in N,N-Dimethylformamide (DMF) (50 mL) under nitrogen at 0° C. was added DIEA (0.562 mL, 3.22 mmol). The reaction was stirred overnight at room temperature, then poured into water and stirred for one hour. A brown precipitate formed which was collected by filtration and washed with water. The solid was dissolved in ca. 25 mL chloroform, and purified by flash chromatography (0-100% EtOAc in chloroform→0-10% MeOH in EtOAc, 24-g column) to afford 5-(4-chloro-1-{[6-(trifluoromethyl)-2-pyridinyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (161.5 mg) as an off-white solid. LC-MS (ES) m/z=487 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.22-3.30 (m, 2H), 3.74 (s, 3H), 4.22 (s, 2H), 4.37 (t, J=8.34 Hz, 2H), 5.72-6.02 (m, 2H), 7.18-7.25 (m, 2H), 7.71 (d, J=7.83 Hz, 1H), 7.83 (d, J=7.58 Hz, 1H), 8.01 (d, J=8.34 Hz, 1H), 8.10 (t, J=7.96 Hz, 1H), 8.13 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C:12](=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1>CO.CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C:12](=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: O=C1c2[nH]c3cc(Cl)ccc3c(=O)c2C(=O)N1Nc1ccc(Cl)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3ccc(Cl)cc3)nc(O)c12
Temperature: 25 °C
Yield: 23.3 %

Procedure:
A stirred suspension of 6-chloro-2-(4-chloroanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (0.670 g, 1.79 mM) in methanol (60 mL) and methanesulfonic acid (15 mL) was refluxed for 3 hours and cooled to room temperature. The mixture was filtered (the filtrate was saved for use in Example 17), and the collected yellow solids were washed with methanol and ether to give the title compound (0.156 g, 23%) as a yellow powder, mp>400° C.: MS(CI): 374 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]=[C:7]([N:13]1[CH2:17][CH2:16][CH2:15]C1)[CH2:6][CH2:5]2.C(N)(=[O:21])C=C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]2[C:8]3[CH2:15][CH2:16][C:17](=[O:21])[NH:13][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cc1Cl)CCC(N1CCCC1)=C2
Reactant: C=CC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C1CCC2=C(CCc3cc(Cl)c(Cl)cc32)N1

Procedure:
A melt of 10.1 g (0.038 mol) of 1-(6,7-dichloro-3,4-dihydro-2-naphthyl)pyrrolidine. 5.36 g (0.075 mol) of acrylamide and 0.3 g of p-toluenesulfonic acid is stirred under nitrogen at 100° for 2 hours and at 150° for 2 hours. Recrystallization of the melt cake from ethanol yields 8,9-dichloro-1,4,5,6-tetrahydrobenzo[f]quinolin -3(2H)-one with melting point 260-261°.