Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[C:6]([Si:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:11][CH2:12][C:13]#[CH:14])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:30]([C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:31].[NH4+].[Cl-]>C1COCC1>[Si:10]([O:11][CH2:12][C:13]#[C:14][C:30]([C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:31])([C:6]([CH3:9])([CH3:7])[CH3:8])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C#CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C#CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 56.2 %

Procedure:
In an argon atmosphere, n-BuLi (10.3 mL, 2.64 N hexane solution) was added dropwise to a solution of t-butyldiphenyl(prop-2-yn-1-yloxy)silane (8.576 g) in THF (200 mL) at −78° C. over 10 minutes, and after stirring at room temperature for 50 minutes, the reaction mixture was added dropwise to a solution of (S)-t-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (5.01 g) in THF (200 mL) through a cannula and temperature was raised to room temperature over an hour. The reaction mixture was added to a saturated aqueous solution of NH4Cl (500 mL) and, after extraction with AcOEt, the organic layer was dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by neutral silica gel chromatography (AcOEt/hexane) to give the titled compound (5.36 g, colorless oil.)
Reaction SMILES: [O-2:1].[Mg+2:2].[C:3](=[O:5])=[O:4]>O>[C:3](=[O:1])([OH:5])[O-:4].[Mg+2:2].[C:3](=[O:1])([OH:5])[O-:4]
Reactant: [O-2]
Reactant: O=C=O
Agent: [Mg+2]
Solvent: O
Product: O=C([O-])O

Procedure:
Sodium hydroxide (30%) is added into a magnesium nitrate solution (5.0 mol/L, MgO content: 200 g/L) at a molar ratio of sodium to magnesium of 2. Controlling the reaction for 25 minutes at 20° C., a magnesium hydroxide slurry can be obtained. After filtration, a filter cake of magnesium hydroxide is obtained. Then water is added into the filter cake to prepare slurry at a weight ratio of water to magnesium oxide of 30:1. After that, carbon dioxide (90 vt %) is introduced into the slurry to carry out carbonation at 25° C. Subsequently, a magnesium bicarbonate solution (MgO: 30 g/L, Fe: 0.3 ppm, Al: 0.4 ppm) is obtained after clarification and filtration.
Reaction SMILES: [CH2:1]1[CH2:4][CH:3]([CH2:5][OH:6])[CH2:2]1.[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].Cl>N1C=CC=CC=1>[C:13]1([CH3:14])[CH:15]=[CH:16][C:10]([S:7]([O:6][CH2:5][CH:3]2[CH2:4][CH2:1][CH2:2]2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: OCC1CCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Reaction time: 4.5 h
Yield: 105.8 %

Procedure:
A solution of 24.4 g of Cyclobutane carbinol (prepared in Example 42A) in 570 ml of dry pyridine was stirred under argon at -10° C. and 81.0 g of tosyl chloride added in small portions. The reaction mixture was stirred at -10° C. to -0° C. for 4.5 hr, then poured into 1 liter of chilled 6 N HCl. The layers were separated and the aqueous layer extracted with ether-ethyl acetate. The combined extracts were washed with 10% aqueous sodium bicarbonate (NaHCO3), dried (MgSO4), filtered and evaporated in vacuo to yield 72.0 g of the title compound having the following physical characteristics:
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=1)[CH:12]=2)[C:3]([O:5]C)=O.[NH2:28][C:29]([NH2:31])=[S:30].C([O-])(=O)C.[Na+]>C(O)C>[CH2:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([CH2:7][CH:2]4[S:30][C:29](=[NH:28])[NH:31][C:3]4=[O:5])[CH:9]=[N:10]3)=[CH:15][CH:14]=2)=[N:21][CH:22]=1)[CH3:27]
Reactant: CCc1ccc(COc2ccc3cc(CC(Br)C(=O)OC)cnc3c2)nc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1ccc(COc2ccc3cc(CC4SC(=N)NC4=O)cnc3c2)nc1

Procedure:
In ethanol (20 mL) was dissolved the crude residue (790 mg) of methyl 2-bromo-3-[7-(5-ethyl-2-pyridylmethoxy)-3-quinolyl]propionate. The solution was heated under reflux for 15 hours after addition of thiourea (140 mg, 1.84 mmol.) and sodium acetate (150 mg, 1.84 mmol.). After the completion of reaction was confirmed, ethanol was distilled off. To the residue were added ethyl acetate and aqueous sodium hydrogen carbonate. The organic portion was recovered, washed with water, and dried over sodium sulfate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11](OC)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C[Al]CC(C)C)C.[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.CCOCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C=Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)C[Al]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OCC=Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Treat a solution of the product of Step 1 (15 g, 65 mmol) in dry THF (250 mL), kept cool in a large ambient temperature water bath, with Dibal-H (140 mL, 140 mmol, 2.15 eq) over 30 min. Stir the resulting solution for 30 min at 23° C., pour into Et2O (500 mL), treat with water (5 mL), 15% NaOH (5 mL) and water (15 mL). Stir for 5 min, dilute the mixture with Et2O (200 mL) and treat with 15% NaOH (15 mL). Add MgSO4 to cause a colorless precipitate. Remove the aluminum salts by filtration through a course glass frit. Wash the solids with Et2O (1 L) and concentrate the filtrate in vacuo to give 13.2 g (65 mmol, 99%) of 3-(3,4-dichlorophenyl)-2-propene-1-ol as an off-white solid.
Reaction SMILES: [C:1]1([C:7]2[S:11][N:10]=[C:9]([C:12](OCC)=[O:13])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[BH4-].[Na+].Cl>>[C:1]1([C:7]2[S:11][N:10]=[C:9]([CH2:12][OH:13])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nsc(-c2ccccc2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1nsc(-c2ccccc2)n1
Temperature: 80 °C
Yield: 13.2 %

Procedure:
To a solution of ethyl 5-phenyl-1,2,4-thiadiazole-3-carboxylate (Example 7A, 230 mg, 0.982 mmol) in anhydrous ethanol (3 mL, 51.4 mmol) was added NaBH4 (149 mg, 3.93 mmol) at 0° C. The reaction mixture was heated to 80° C. for 30 min, then HCl 1N (1 mL) was added and ethanol was evaporated. Dichloromethane was added to the reaction followed by brine and this was extracted with dichloromethane (3×). The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified on silica gel column chromatography (100% CH2Cl2 up to 10% EtOAc/CH2Cl2) to provide the title material (25 mgs, 13%). LC (Method B): 1.858 min. LCMS (APCI) calcd for C9H9N2OS [M+H]+ m/z 193.04, found 193.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.89-8.03 (m, 2H), 7.46-7.62 (m, 3H), 4.99 (d, J=5.87 Hz, 2H), 2.81 (t, J=6.06 Hz, 1H)
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:14][S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])[CH:4]=1.N1C[CH2:28][O:27][CH2:26]C1>>[O:27]1[CH2:28][CH2:23][N:2]([C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[N:14][S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:17])[CH:4]=2)[CH2:1][CH2:26]1.[CH3:1][N:2]([CH3:23])[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:14][S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:17])[CH:4]=1
Reactant: C1COCCN1
Agent: CN(C)C1=CC(=NS(=O)(=O)c2cccs2)c2ccccc2C1=O
Product: O=C1C(N2CCOCC2)=CC(=NS(=O)(=O)c2cccs2)c2ccccc21

Procedure:
N-(3-morpholino-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (13c) was prepared according to the procedure for 13b except using 0.2 eq. morpholine, which afforded the title compound 36.3 mg (93.6%) as a wine-red solid, m.p.: 195° C. (dec.).
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:12]1([CH:18]([CH:22]([OH:24])[CH3:23])[CH2:19][CH2:20][OH:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CN=C1.C(OCC)(=O)C>CN(C)C=O.O>[C:12]1([CH:18]([CH2:19][CH2:20][O:21][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[CH:22]([OH:24])[CH3:23])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(O)C(CCO)c1ccccc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)C(CCO[Si](C(C)C)(C(C)C)C(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
1.25 mL of triisopropylsilyl chloride was added dropwise to a solution of 1.0 g of 3-phenylpentane-1,4-diol and 0.45 g of imidazole in 20 mL of N,N-dimethylformamide in a nitrogen atmosphere at a temperature of 5° C. to 10° C., and the obtained mixture was then stirred at room temperature for 19 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/19 to 1/10), so as to obtain 1.2 g of 3-phenyl-5-((tris(propan-2-yl)silyl)oxy)pentan-2-ol in the form of a colorless oily product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][OH:21])[N:19]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])[N:19]=2)([CH3:14])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(CO)cs2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(COS(C)(=O)=O)cs2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-hydroxymethyl-thiazol-2-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.42 g, 1.3 mmol) in methylene chloride (10 mL) was added methanesulfonyl chloride (0.19 g, 1.7 mmol) and triethylamine (0.2 g, 2 mmol) at 0° C. After stirring at 0° C. for 1 hour, the mixture was diluted with EtOAc and washed with H2O and brine. After drying (Na2SO4), the solvent was removed in vacuo, and the residue was purified by silica column chromatography with EtOAc/hexanes to afford the desired product.
Reaction SMILES: O=S(Cl)[Cl:3].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][N:8]=1>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH2:13][Cl:3])[CH:10]=[CH:9][N:8]=1
Reactant: COc1cc(CO)ccn1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(CCl)ccn1
Reaction time: 16 h

Procedure:
1.57 ml (21.6 mmol) of SOCl2 are added dropwise, whilst cooling with ice and under a N2 atmosphere, to a solution of 1.5 g (10.8 mmol) of 2-methoxy-4-(hydroxymethyl)-pyridine [for preparation see J. Org. Chem. 54 (1989), 5580] in 13 ml of chloroform. After 16 h at RT, the mixture is concentrated by evaporation, water and 2N sodium hydroxide solution are added to the residue, and extraction immediately takes place 3 times with chloroform. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation to form 2-methoxy-pyridin-4-yl-methylchloride; 1H NMR (CDCl3) δ8.15 (d, 1H), 6.90 (d, 1H), 6.76 (s, 1H), 4.49 (s, 2H), 3.94 (s, H3C).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[C:5]([NH:8][C:21](=[O:23])[CH3:22])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ncc(Br)nc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a solution of 5-Bromo-3-trimethylsilanylethynyl-pyrazin-2-ylamine (2.30 g, 8 mmol) in anhydrous THF (35 ml) and pyridine (1.62 ml, 20.0 mmol) was added acetyl chloride (682 μl, 9.6 mmol). The mixture was stirred at room temperature overnight, and then stirred at 60° C. for 5 hours. Solvents were removed in vacuum and the resulting brown residue was purified by silica gel chromatogrpahy with a gradient of ethyl acetate/hexane to afford the title compound (474 mg, 1.52 mmol) as light yellow as off white solid. MS: m/z 311.9/313.9 [MH+].
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]=[O:18])=[C:9]([CH3:19])[O:8][N:7]=1)(=O)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1.[Cl-].[NH4+].O.[OH-].[Li+]>CCOC(C)=O.C1COCC1.CO.O.O.C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]2[C:6]([CH2:5][OH:4])=[N:7][O:8][C:9]=2[CH3:19])[OH:18])=[CH:23][CH:22]=1
Reactant: CC(=O)OCc1noc(C)c1-c1ccccc1C=O
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(CO)c1-c1ccccc1C(O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a round bottomed flask was added (4-(2-formylphenyl)-5-methylisoxazol-3-yl)methyl acetate (1.01 g, 3.90 mmol) and THF (20 mL) before the reaction was cooled to −78° C. To this solution was added 1.0 M (4-chlorophenyl)magnesium bromide (4.68 mL, 4.68 mmol) and the reaction stirred at −78° C. for 30 min before addition of ammonium chloride solution. The reaction was warmed to room temperature and diluted with EtOAc. The layers were separated and the aqueous was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was taken up in THF:MeOH:Water (2:2:1, 20 mL) before addition of lithium hydroxide hydrate (0.491 g, 11.70 mmol). The reaction was stirred at room temperature for 1 h before diluting with water and EtOAc. The layers were separated and the aqueous was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude diol was purified via Biotage (EtOAc/hex) to afford (4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanol (1.14 g, 3.44 mmol). LC/MS m/z 330 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:24]#[N:25].[OH:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[CH3:34])[NH2:30].Cl.N1C=CC=CC=1.C(OC(O)C)C>>[ClH:1].[OH:26][C:27]1[CH:28]=[C:29]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:24]#[N:25])[CH:31]=[CH:32][C:33]=1[CH3:34]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCc1ccncc1
Reactant: Cc1ccc(N)cc1O
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2cc1OCCCc1ccncc1
Yield: 65.9 %

Procedure:
A mixture of 0.090 g of 4-chloro-6-methoxy-7-(3-pyridin-4-yl-propoxy)-quinoline-3-carbonitrile, 0.050 g of 3-hydroxy-4-methylaniline, 0.039 g of pyridine hydrochloride and 3 ml of ethoxyethanol was stirred under nitrogen at reflux temperature for 20 minutes. The mixture was cooled and filtered. The product was washed with saturated sodium bicarbonate, water, then dried to give 0.080 g of 4-(3-hydroxy-4-methyl-phenylamino)-6-methoxy-7-(3-pyridin-4-yl-propoxy)-quinoline-3-carbonitrile hydrochloride as a solid, dec >153° C. ; mass spectrum (electrospray, m/e): M+H 440.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[CH:14](OCC)(OCC)OCC>FC(F)(F)C(O)=O>[CH3:14][NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6]
Reactant: CCOC(OCC)OCC
Reactant: C=CCOC(=O)c1cccc(N)c1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)c1cccc(NC)c1
Yield: 17 %

Procedure:
Allyl 3-aminobenzoate (5 g, 28.2 mM) was dissolved in triethyl orthoformate (50 ml) and trifluoroacetic acid (5 drops) was added. The solution was stirred and refluxed up through 3å molecular sieves for 5 hours. Solvent was removed, and the residue dissolved in ethanol (50 ml), followed by the addition of acetic acid (8.08 ml) and sodium cyanoborohydride (6.85 g, 0.108 M) in several portions. The mixture was stirred at ambient temperature for 16 hours, and solvent removed. The residue was dissolved in diethyl ether, washed with water, brine, and dried over MgSO4. Crude product was purified by chromatography on silica, eluting with a gradient from dichloromethane to dichloromethane/ethyl acetate (95:5), to give allyl 3-methylaminobenzoate (0.93 g, 17%). Nmr (CDCl3): δ 2.88 (s, 3H); 4.81 (dt, 2H); 5.23-5.45 (m, 2H); 5.94-6.13 (m, 1H); 6.83 (dd, 1H); 7.25 (dd, 1H); 7.33 (t, 1H); 7.43 (dm, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14](=[O:30])[NH:15][C:16]1[CH:17]=[C:18]([Cl:29])[CH:19]=[C:20]2[C:28]=1[NH:27][C:26]1[CH:25]=[N:24][CH:23]=[CH:22][C:21]2=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[C:38]([O:42][C:43]([N:45]1[CH2:51][CH2:50][CH2:49][C@@H:46]1[CH:47]=O)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C1COCC1.CO.C(Cl)Cl>[C:38]([O:42][C:43]([N:45]1[CH2:51][CH2:50][CH2:49][C@@H:46]1[CH2:47][N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14](=[O:30])[NH:15][C:16]1[CH:17]=[C:18]([Cl:29])[CH:19]=[C:20]2[C:28]=1[NH:27][C:26]1[CH:25]=[N:24][CH:23]=[CH:22][C:21]2=1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CN1CCOC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76.7 %

Procedure:
A solution of 3(S)-(6-chloro-9H-β-carbolin-8-ylcarbamoyl)-morpholine-4-carboxylic acid tert-butyl ester (1.00 g, 2.32 mmol) in CH2Cl2 (6 ml) was stirred at RT. Trifluoroacetic acid (6 ml) was added and the solution was stirred at RT for 45 min, then concentrated to a residue. The residue was concentrated once more from CH2Cl2 to yield a yellow-brown solid which was dissolved in THF (13 ml) under argon. Gentle warming was sometimes needed to ensure complete dissolution. A solution of N-(tert-butoxycarbonyl)-D-prolinal (693 mg, 3.48 mmol) in THF (2 ml) was added, followed by sodium triacetoxyborohydride (738 mg, 3.48 mmol). The solution was stirred at RT for 30 min, then quenched via addition of 1N aqueous NaOH (30 ml). The mixture was poured into a separatory funnel containing EtOAc (100 ml), H2O (100 ml), and brine (100 ml). The mixture was shaken and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 ml) and the combined organic layers were washed with brine. The organic layer was dried, filtered and concentrated to yield a light brown solid. Column chromatography (2%-4% MeOH/CH2Cl2) yielded 2(R)-[3(S)-(6-Chloro-9H-β-carbolin-8-ylcarbamoyl)-morpholin-4-ylmethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid (915 mg). 1H-NMR (300 MHz, DMSO-d6): δ 11.30 (s, 1); 9.88 (s, 1); 9.04 (s, 1); 8.39-8.37 (m, 1); 8.20-8.15 (m, 2); 7.95 (s, 1); 3.99-3.82 (m, 3); 3.69-3.63 (m, 2); 3.44-3.32 (m, 1); 3.27-3.11 (m, 3); 2.92-2.80 (m, 1); 2.44-2.32 (m, 1); 1.99-1.67 (m, 5); 1.33 (s, 9). HCOOH standard conditions. DAD Rf=1.39 min. M+H=514. Chiral HPLC.
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:19]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:14][N:15]2[CH3:18])=[CH:11][CH:10]=1)=[O:8].Cl>C(OCC)C.O1CCCC1>[C:7]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:19]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[C:20]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:24])=[O:25])=[O:21])=[CH:14][N:15]2[CH3:18])=[CH:11][CH:10]=1)(=[O:8])[CH3:1]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3)c3ccc4c(c3)OCO4)cn(C)c2c1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3)c3ccc4c(c3)OCO4)cn(C)c2c1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
Methylmagnesium bromide (0.23 ml of a 3M solution in diethyl ether) was added dropwise to a stirred solution of N6-methoxy-N6,1-dimethyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1H-6-indolecarboxamide (from Example 103, 174 mg, 0.32 mmol) in anhydrous tetrahydrofuran (5 ml) at −70° C. under a nitrogen atmosphere. The mixture was stirred at −70° C. for an additional 2 hours before warming to room temperature. Aqueous hydrochloric acid (5 ml of 1M solution) was slowly added to the mixture, and then it was extracted with ethyl acetate (100 ml). The organic phase was separated and washed with brine, dried (magnesium sulphate) and the solvent were removed in vacuo. The residue was flash chromatographed using a gradient elution of a mixture of 90% hexane and 10% ethyl acetate, through to 100% ethyl acetate, to give the title compound (18 mg).
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](=[O:37])[N:12]([CH:28]1[CH2:32][CH2:31][CH:30]([C:33]([O:35]C)=[O:34])[CH2:29]1)[CH2:13][CH2:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.[OH-].[Li+]>CO.O>[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](=[O:37])[N:12]([CH:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]1)[CH2:13][CH2:14][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C1CCC(N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc3ccccc3s2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1CCC(N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc3ccccc3s2)C1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(3-(benzo[d]thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)cyclopentanecarboxylate 35 (308 mg, 600 μmol) in 10:1 MeOH/H2O (5.5 ml) was added lithium hydroxide hydrate (50.3 mg, 1199 μmol). The reaction mixture was stirred for overnight at 55° C. Volatiles were removed by concentration under reduced pressure. The leftover residue was solubilized with 60 mL of a 1:1 mixture of Water and Ethyl Acetate. An additional 2 mL of 2M KOH was added. The organic phase was separated and the aqueous phase was extracted further with ethyl acetate (2×20 mL). The organic extracts were discarded and the aqueous layer was acidified with 10 mL of 10% aqueous HCl and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica using 10->45% EtOAc/Hexanes as eluant to afford 36 as a white solid. LCMS (ES) calcd for C29H29N3O3S 499.2 found 500.2 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1.Br[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[C:25]#[N:26]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:22]3[CH:29]=[C:28]([F:30])[CH:27]=[C:24]([C:25]#[N:26])[CH:23]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1
Reactant: COCCn1ccc(NC(=O)c2nc(C)ccc2N)n1
Reactant: N#Cc1cc(F)cc(Br)c1
Product: COCCn1ccc(NC(=O)c2nc(C)ccc2Nc2cc(F)cc(C#N)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid [1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-amide in accordance with the general method of example, step using 3-Bromo-5-fluorobenzonitrile instead of 3-bromopyridineto yield the final compound as a light yellow solid, MS (ISP): m/e=395.1 (M+H+).