Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].Cl.Cl.[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C.[NH:45]1[CH2:49][CH2:48][C@@H:47]([OH:50])[CH2:46]1>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:3](=[O:4])[CH2:2][N:45]4[CH2:49][CH2:48][C@@H:47]([OH:50])[CH2:46]4)[CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: O[C@@H]1CCNC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)CN2CC[C@@H](O)C2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chloroacetyl chloride (47 μl) was added to a solution of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline dihydrochloride (250 mg) and diisopropylethylamine (373 μl) in methylene chloride (10 ml) and the mixture was stirred at room temperature for 1 hour. (R)-(+)-3-pyrrolidinol (202 mg) was added, and the solution stirred for 1 hour before being washed with saturated aqueous sodium bicarbonate (10 ml) and purified by flash column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (saturated with ammonia) (100/0 to 95/5) to give a foam. This foam was dissolved in methylene chloride (5 ml) and crystallised by the addition of isohexane (50 ml) to give the title product as a mixture of two diastereoisomers (68 mg); 1H NMR Spectrum: (DMSO d6, 100° C.) 1.52 (m, 2H), 1.87 (m, 3H), 2.09 (m, 1H), 2.38 (m, 1H), 2.61 (m, 1H), 2.77 (m, 1H), 3.18 (m, 1H), 3.36 (d, 1H), 3.53 (m, 2H), 3.68 (m, 1H), 3.89 (m, 1H), 3.94 (s, 3H), 4.15 (m, 1H), 4.23 (m, 1H), 4.53 (m, 1H), 7.27 (m, 2H), 7.41 (m, 1H), 7.59 (m, 1H), 7.89 (s, 1H), 8.38 (s, 1H), 9.24 (br s, 1H); Mass Spectrum: (M+H)+ 530.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl.[CH3:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:28][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][N:22]3[CH3:21])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Reactant: CN1CCCCC1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCCC1COc1ccc2nc(C#N)nc(NCC(C)(C)C)c2c1

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.31 mmol), 1-methyl-2-chloromethyl-piperidine hydrochloride (0.41 mmol) and potassium carbonate (7.2 mmol) are stirred in DMF (3 ml) at 80° C. for 8 hours. The solvent is evaporated, the residue is dissolved in water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=9:1) as mobile phase. The product containing fractions are combined and evaporated. A pale oil with Rf=0.54 (CH2Cl2/MeOH=10:1) is obtained.
Reaction SMILES: OCC(CO)(CO)CO.[C:10]([O:13][CH2:14][C:15]([CH2:26][O:27]C(=O)C)([CH2:21][O:22]C(=O)C)[CH2:16][O:17]C(=O)C)(=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].CCOCC>CC(C)=O>[C:10]([O:13][CH2:14][C:15]([CH2:26][OH:27])([CH2:21][OH:22])[CH2:16][OH:17])(=[O:12])[CH3:11]
Reactant: CC(=O)OCC(COC(C)=O)(COC(C)=O)COC(C)=O
Agent: O=C([O-])[O-]
Agent: OCC(CO)(CO)CO
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(=O)OCC(CO)(CO)CO
Yield: 129.1 %

Procedure:
Pentaerythritol (9.5 grams, 0.07 mol), 7.0 grams (0.02 mol) of pentaerythritol tetraacetate and 500 mg of potassium carbonate were heated for 12 hours at 180° C. A light brown solution resulted which was boiled for 15 minutes in 50 ml of acetone and the resulting precipitate was filtered off. The filtrate was concentrated and passed through a plug of silica gel using acetone as a solvent. The mixture was purified by flash chromatography (1:1, CHCl3 :acetone) to yield a product of Rf =0.1. Addition of 25 ml of ether caused the product to solidify, yielding 4.6 grams of pentaerythritol monoacetate as a white solid.
Reaction SMILES: [O:1]=[O+][O-].[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:15]#[N:16])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=C.C(Cl)Cl>>[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:15]#[N:16])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:1]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc(C2(C#N)CC2)cc1
Solvent: ClCCl
Product: N#CC1(c2ccc(C=O)cc2)CC1
Reaction time: 8 h

Procedure:
Ozone was bubbled through a solution of 1-(4-vinylphenyl)cyclopropanecarbonitrile (1.8 g, 0.011 mol) in methylene chloride (40 mL, 0.6 mol) at −78° C. until a blue color appeared and then nitrogen was bubbled through the solution for 10 minutes. Methyl sulfide was added and the mixture was stirred overnight. The mixture was washed with water and brine successively, dried, and concentrated to give the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:11](C(=O)CC1C=CC=CC=1C)[C:12]1[N:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=1)=[O:10].[OH-].[Na+]>O1CCCC1CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]
Reactant: COC(=O)c1ccc(N(C(=O)Cc2ccccc2C)C(=O)Cc2ccccc2C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) mixture of 5.0 g methyl 6-aminopyridine-3-carboxylate, 12.6 ml of N,N-diisopropylethylamine in 40 ml of dichloromethane is added a solution of 12.2 g of 2-methylbenzeneacetyl chloride in 10 ml of dichloromethane. The mixture is stirred under argon at room temperature overnight. The mixture is diluted with 200 ml of dichloromethane and 50 ml of water and the organic layer separated. The organic layer is washed with 50 ml each of 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue (9.0 g) is chromatographed on a silica gel column with hexane-ethyl acetate (3:1) as eluent to give 8.6 g of solid. This solid, mainly methyl 6-[[bis(2-methylbenzeneacetyl)]amino]pyridine-3-carboxylate, is dissolved in 60 ml of tetrahydrofuran-methanol (1:1) and 23 ml of 5N NaOH added to the solution. The mixture is stirred at room temperature overnight and the mixture concentrated under vacuum. Water (25 ml) is added and the mixture is stirred and acidified with cold 1N HCl. The mixture is chilled and the solid filtered and washed with water to give 5.9 g of off-white solid.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C@H:23]1[CH2:26][C@H:25]([C:27]([OH:29])=O)[CH2:24]1)=[O:21].[CH2:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)C[N:31]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH2:30]([NH:31][C:27]([C@H:25]1[CH2:24][C@H:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH2:13]2)=[O:21])[CH2:26]1)=[O:29])[C:38]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(N[C@H]1C[C@H](C(=O)O)C1)N1Cc2ccncc2C1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: NCCCc1ccccc1
Product: O=C(N[C@H]1C[C@H](C(=O)NCc2ccccc2)C1)N1Cc2ccncc2C1

Procedure:
The title compound was prepared as described in Example 1C, substituting benzylamine for 3-phenylpropan-1-amine and trans-3-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)cyclobutanecarboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.26 (t, J=5.9 Hz, 1H), 7.39 (d, J=5.1 Hz, 1H), 7.36-7.28 (m, 2H), 7.27-7.20 (m, 3H), 6.60 (d, J=7.6 Hz, 1H), 4.65-4.59 (m, 4H), 4.45-4.29 (m, 1H), 4.28 (d, J=5.9 Hz, 2H), 2.96-2.84 (m, 1H), 2.41-2.29 (m, 2H), 2.30-2.15 (m, 2H); MS (ESI(+)) m/e 351 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1(CO)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH:35]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:18][CH:17]=1
Reactant: OCC1CCCCCC1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCC4CCCCCC4)cc3)c2cc1OC
Yield: 54 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cycloheptylmethanol (33 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (41 mg, yield 46%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>Cl.N1C=CC=CC=1.ClCCl>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1ccc(-c2ccccn2)c(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Oc1ccc(-c2ccccn2)c(O)c1
Temperature: 160 °C
Yield: 65.7 %

Procedure:
A mixture of 2-(2,4-dimethoxyphenyl)pyridine (14 g) in pyridine hydrochloride (121 g) is heated to 160° C. and the resulting melt is heated at 160° C. for 7 hours. The mixture is then cooled, diluted with dichloromethane, washed with hydrochloric acid (2 M) and water, dried and evaporated. The residual oil is subjected to flash chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (1:1 v/v), to give 2-(2,4-dihydroxyphenyl)pyridine (8.0 g) in the form of a solid, m.p. 170-172° C. [NMR(CDCl3):- 6.3(1H,s),6.4(1H,d),7.3(1H,m), 7.8(1H,d),7.9(1H,t),8.0(1H,d),8.5(1H,d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:13][N:12]=3)=[N:9][N:8](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:5]2=[N:6][CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:13][N:12]=3)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)[C@@H](CC(=O)O)Nc1ccnc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)n1
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](CC(=O)O)Nc1ccnc(-c2n[nH]c3ncc(F)cc23)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of crude (R)-3-((2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoic acid, 138a, (0.11 g, 0.21 mmol) in CH2Cl2 was added triethylsilane (0.15 mL, 0.94 mmol) followed by trifluoroacetic acid (0.15 mL, 1.95 mmol). After stirring the resulting solution at room temperature for 1 hour, the reaction mixture was kept below 5° C. overnight (refrigerator). The mixture was then allowed to warm to room temperature and kept at that temperature for an additional 5 hours. The solution was diluted with toluene and concentrated in vacuo. Trituration with Et2O followed by preparative HPLC purification provided 15 mg of the desired product as the TFA salt. 1H NMR indicated a 3 to 1 mixture of atropisomers: 1H NMR (400 MHz, MeOD, major isomer) δ 8.63-8.45 (m, 2H), 7.96 (d, J=7.3 Hz, 2H), 6.66 (d, J=7.3 Hz, 2H), 4.95 (d, J=10.6 Hz, 2H), 2.84 (dd, J=15.4, 2.4 Hz, 2H), 2.44 (dd, J=15.9, 10.7 Hz, 2H), 0.98 (s, 9H); LCMS Gradient 10-90%, 0.1% trifluoroacetic acid, 5 minutes, C18/ACN, Retention Time=2.12 minutes (M+H) 359.02.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH2:12][CH2:11][C:10]1=[O:31].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(C)cccc1C
Reactant: NC(CO)CO
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1CCC(=O)N2c1c(C)cccc1C
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1c(C)cccc1C

Procedure:
The product of Example 122, and serinol were reacted by the procedure of Example 60 to afford the title compound 8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3): δ 1.91 (s, 6H), 2.14 (s, 3H), 3.45 (br s, 4H), 3.93 (br s, 1H), 6.20 (br s, 1H), 6.31 (d, 1H, J=9.7 Hz), 6.93 (m, 2H), 7.11 (m, 5H). LC MS (m/e)=449.0 (MH+). Rt=1.62 min.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:23]CN(CC)CC.C(OC(=O)C)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:5])[CH3:23])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A solution of 4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in the previous step, 304 mg, 1.00 mmol) in a 1:1 mixture of DCM/TFA (10 mL) was stirred at room temperature for 3 h and concentrated. The residue was dried in vacuo overnight, was taken up in CH2Cl2 (10 mL) and was cooled to 0° C. To this solution, Et3N (280 μL, 2 mmol) was added drop wise, followed by acetic anhydride (102 μL, 1 mmol). The resulting mixture was stirred at 0° C. for 1 h and allowed to warm to room temperature. The reaction mixture was washed with brine, and the organic layer was separated, dried and concentrated. The resulting product was reduced to obtain the title compound (143 mg, 65%) using a procedure similar to Example 4, step (d). 1H-NMR (CDCl3; 400 MHz): δ 6.97 (d, 2H, J=8.4 Hz), 6.64 (d, 2H, J=8.4 Hz), 4.75 (m, 1H), 3.93 (m, 1H), 3.13 (m, 3H), 2.66 (m, 2H), 2.12 (s, 3H), 1.84 (m, 2H), 1.57 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.N1C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[S:26]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:8][C:2]=1[F:1])(=[O:28])=[O:27]
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cc(Cl)ccc3Cl)c(F)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.5 g of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in 17 ml DCM and 0.5 ml pyridine, 1.5 g of 2,5-dichloro-benzenesulfonyl chloride were added, and the reaction mixture was stirred for 16 h at RT. Then the solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/EtOAc. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.2 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C@H:13]1[C@:17]([CH3:22])([CH2:18][C:19]([OH:21])=[O:20])[C@@H:16]([OH:23])[CH2:15][CH2:14]1)[CH2:7][CH2:6]2.[CH3:24]OC(OC)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C@H:13]1[C@:17]([CH3:22])([CH2:18][C:19]([O:21][CH3:24])=[O:20])[C@@H:16]([OH:23])[CH2:15][CH2:14]1)[CH2:7][CH2:6]2
Reactant: COC(C)(C)OC
Reactant: COc1ccc2c(c1)CCC([C@@H]1CC[C@H](O)[C@@]1(C)CC(=O)O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)C[C@]1(C)[C@@H](O)CC[C@H]1C1CCc2cc(OC)ccc2C1

Procedure:
A solution of 2.19 g of (1S,2S,5S)-5-(1,2,3,4-tetrahydro-6-methoxy-2-naphthyl)-2-hydroxy-1-methylcyclo-pentaneacetic acid and 5 ml of 2,2-dimethoxypropane in 40 ml of methanol containing 0.05 g of p-toluenesulfonic acid monohydrate is refluxed for 18 hours. The resultant solution is partitioned between aqueous 5% sodium bicarbonate and ether. The ether phase is separated, dried over magnesium sulfate, and stripped of solvent by vacuum distillation. The residue is crystallized from a mixture of acetone and hexane to give methyl (1S,2S,5S)-5-(1,2,3,4-tetrahydro-6-methoxy-2-naphthyl)-2-hydroxy-1-methylcyclopentaneacetate melting at approximately 86°-87°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([C:10]#[N:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH2:20][OH:21]>C(O)C>[C:1]([O:5][C:6](=[O:12])[NH:7][C@@H:8]([CH3:9])/[C:10](/[NH2:11])=[N:20]/[OH:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)/C(N)=N/O
Temperature: 50 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a mixture of tert-butyl[(1S)-1-cyanoethyl]carbamate (Step 2, 250 mg, 1.5 mmol) in ethanol (3 mL) were added triethylamine (0.41 mL, 2.9 mmol) and hydroxylamine (58 mg, 1.8 mmol). The mixture was stirred at 50° C. overnight. The reaction mixture was concentrated to afford the desired crude product (300 mg) which was directly used in the next step reaction without further purification. 1H-NMR (300 MHz, DMSO-d6): 8.94 (s, 1H), 6.80 (d, J=8.5 Hz, 1H), 5.24 (s, 2H), 4.01 (m, 1H), 1.36 (s, 9H), 1.15 (d, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:20]=[CH:21][C:22]4[C:26]([C:27]([OH:29])=O)=[C:25]([CH3:30])[S:24][C:23]=4[CH:31]=3)[CH:10]=2)=[O:8])[CH2:3]1.[NH2:32][CH2:33][CH:34]1[CH2:36][CH2:35]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:34]1([CH2:33][NH:32][C:27]([C:26]2[C:22]3[CH:21]=[CH:20][C:19]([O:18][C:15]4[CH:14]=[CH:13][N:12]=[C:11]5[CH:10]=[C:9]([C:7]([N:4]6[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]6)=[O:8])[S:17][C:16]=45)=[CH:31][C:23]=3[S:24][C:25]=2[CH3:30])=[O:29])[CH2:36][CH2:35]1
Reactant: Cc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)ccc2c1C(=O)O
Reactant: NCC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)ccc2c1C(=O)NCC1CC1
Yield: 66.1 %

Procedure:
This material was prepared from the reaction of 6-[(2-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 126a (65 mg, 0.14 mmole) with (aminomethyl)cyclopropane (37 μL, 0.43 mmole), diisopropylethylamine (50 μL, 0.29 mmole), and HBTU (81 mg, 0.22 mmole) in a similar manner previously described for example 117 to give a pale yellow solid (47 mg, 46%). 1H NMR (DMSO-d6, 300 MHz) δ8.60 (1H, d, J=5.56 Hz), 8.49 (1H, t, J=5.68 Hz), 8.07, 8.01 (1H, s), 7.97 (1H, d, J=2.27 Hz), 7.84 (1H, d, J=8.59 Hz), 7.34 (1H, dd, J=2.27, 8.84 Hz), 6.78 (1H, d, J=5.31 Hz), 4.38, 4.33 (0.5H, br s), 4.01-3.93 (3H, m), 3.67-3.47 (2H, m), 3.20 (2H, t, J=6.19 Hz), 2.62 (3H, s), 2.07-1.81 (2H, m), 1.08 (1H, m), 0.46 (2H, m), 0.26 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>O1CCCC1>[C:33]([N:15]1[CH2:16][CH2:17][CH:12]([C:6]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:13][CH2:14]1)(=[O:35])[CH3:34]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCNCC1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-4-yl-1,3-dihydro-indol-2-one (35 mg, 0.09 mmol) (from Example 15a supra) in tetrahydrofuran (3 mL) was added triethylamine (14.1 mg, 0.139 mmol), followed by the addition of acetyl chloride (8.7 mg, 0.11 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give rac-3-(1-acetyl-piperidin-4-yl)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a white solid. (Yield 25 mg, 65%). Further purification by precipitation in a cosolvent of dichloromethane and hexanes gave the product as a white solid. (18 mg).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[C:5]([O-])([O-])=O.[K+].[K+].[CH:11]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.[OH-].[K+]>ClCCl.O.CCOCC>[N:20]([CH:11]1[C:19]2[C:14](=[C:15]([CH3:5])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)=[C:1]=[S:2]
Reactant: O=C([O-])[O-]
Reactant: NC1CCc2ccccc21
Reactant: S=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: Cc1cccc2c1CCC2N=C=S
Reaction time: 0.17 h

Procedure:
A mixture of 0.36 ml (4.32 mmol) thiophosgene in 4 ml dichloromethane is cooled to 0° C. after which a cold (0° C.) solution of 0.5 g (3.60 mmol) K2CO3 in 4 ml water is added. The mixture is stirred for 10 min and 0.53 g (3.60 mmol) indan-1-ylamine is then added drop wise with vigorous stirring at 0° C. After an additional 10 min a cold solution of 0.40 g (7.20 mmol) KOH in 4 ml water is added in one portion with cooling. The organic layer and three extracts (Et2O) are combined, dried over MgSO4, filtered and concentrated to give 1-isothiocyanato-4-methyl-indane as an orange brown liquid. The product is used directly without further purification.