Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33]([OH:35])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:36]([O:43][C:44]1[CH:45]=[C:46]([CH:52]=[C:53]([CH2:55][CH2:56][CH2:57][O:58][CH3:59])[CH:54]=1)[CH2:47][NH:48][CH:49]1[CH2:51][CH2:50]1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].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>C(Cl)Cl.CCOCC>[Si:36]([O:43][C:44]1[CH:45]=[C:46]([CH:52]=[C:53]([CH2:55][CH2:56][CH2:57][O:58][CH3:59])[CH:54]=1)[CH2:47][N:48]([CH:49]1[CH2:51][CH2:50]1)[C:33]([C@@H:10]1[C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:35])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38]
Reactant: COCCCc1cc(CNC2CC2)cc(O[Si](C)(C)C(C)(C)C)c1
Reactant: Cc1cc(Cl)c(OCCOc2ccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(=O)O)cc2)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (3R,4S)-1-(tert-butoxycarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid (piperidine acid 1) (1 eq) and N-[3-{[tert-Butyl(dimethyl)silyl]oxy}-5-(3-methoxypropyl)benzyl]cyclo-propanamine (amine 1) (1.8 eq.) in DCM (0.15 M) was added HATU (1.5 eq.) and Hunig's base (3 eq.). After stirring for 18 hr at rt, the reaction was diluted with ether. The organic extract was washed three times with 1 N aqueous HCl, water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 20% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:4].[CH3:13][N:14](C)C=O>CCOCC>[C:13]([C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:3]=1[NH2:4])#[N:14]
Reactant: Nc1c(Br)cccc1C(F)(F)F
Reactant: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1cccc(C(F)(F)F)c1N

Procedure:
2-Bromo-6-trifluoromethylaniline (12.0 g., 0.05 mol.) and 4.5 g. (0.05 mol.) of cuprous cyanide in 100 ml. of dimethylformamide is refluxed for 12 hours. The reaction mixture is decomposed by addition of aqueous ferrous sulfate solution, ether is added, the layers are separated and the ethereal phase is washed with water, dried (MgSO4) and concentrated to give 2-cyano-6-trifluoromethylaniline.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([Cl:10])=[CH:8][N:7]([CH:11]([F:13])[F:12])[N:6]=1)=[O:4].[OH-].[Li+].O.CO>O1CCCC1>[Cl:10][C:9]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][N:7]([CH:11]([F:12])[F:13])[CH:8]=1
Reactant: COC(=O)c1nn(C(F)F)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nn(C(F)F)cc1Cl
Reaction time: 1 h
Yield: 108.6 %

Procedure:
A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at room temperature with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a 1:1-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was dissolved in water (10 ml) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying of the organic layer over sodium sulphate, and evaporation at reduced pressure yielded a white solid (555 mg) which was triturated with pentane (10 ml). The solid material was filtered, washed with pentane and dried. After drying at reduced pressure the 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid was obtained as a white solid (477 mg, 95% of theory). MS (ISP): m/z=195.0 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:24][CH2:25][CH3:26])=[C:4]([CH:12]=[CH:13][C:14]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#N.[OH-:27].[K+].Cl.C[OH:31].O>>[OH:1][C:2]1[C:3]([CH2:24][CH2:25][CH3:26])=[C:4]([CH:12]=[CH:13][C:14]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:31])=[O:27]
Reactant: CCCc1c(OCCCCC#N)ccc(C(=O)c2ccccc2O)c1O
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCc1c(OCCCCC(=O)O)ccc(C(=O)c2ccccc2O)c1O
Temperature: 25 °C

Procedure:
A solution of 10 g of 5-[3-hydroxy-4-(2 -hydroxybenzoyl)-2-propylphenoxy]pentanenitrile and 12.9 g of potassium hydroxide in approximately 250 ml of 10% methanol/water was heated at reflux for 5 days. The solution was cooled to room temperature, acidified with hydrochloric acid. The crude product which precipitated was recovered by filtration and purified by high pressure liquid chromatography over silica gel eluting with a 30-40% ethyl acetate in hexane gradient containing 0.5% acetic acid. The appropriate fractions were combined, evaporated, and recrystallized from diethyl ether/hexane to provide 8.0 g of the desired title carboxylic acid, m.p. 88.5°-91.5° C.
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:17])([F:16])[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]([CH3:37])[N:35]=[C:34]([C:38]3[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:45])[N:33]=2)=[CH:28][C:27]=1[Cl:46]>O>[Cl:45][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:38]=1[C:34]1[N:33]=[C:32]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:7]([F:16])([F:17])[F:6])=[CH:14][CH:13]=3)=[C:27]([Cl:46])[CH:28]=2)[N:36]([CH3:37])[N:35]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CBr)c(Cl)c1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ccc(OC(F)(F)F)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To 30 ml of N,N-dimethylformamide are added 4-trifluoromethoxy phenol (0.33 g) and potassium carbonate (0.25 g) and 5-(4-bromomethyl-3-chlorophenyl)-3(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (0.70 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 1 hour. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with toluene. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.83 g of desired compound (refractive index: 1.5701).
Reaction SMILES: [Al].[C:2]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9](=[O:16])[C:8](O[Si](CC)(CC)CC)([C:17]([F:20])([F:19])[F:18])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3]>O>[C:12]([C:10]1[CH:11]=[C:6]([C:2]([CH3:3])([CH3:4])[CH3:5])[CH:7]=[C:8]([C:17]([F:19])([F:20])[F:18])[C:9]=1[OH:16])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)C=C(C(C)(C)C)C=C(C(C)(C)C)C1=O
Agent: [Al]
Solvent: O
Product: CC(C)(C)c1cc(C(C)(C)C)c(O)c(C(F)(F)F)c1
Temperature: 70 °C
Yield: 83.2 %

Procedure:
A strip of aluminum foil weighing 267 mg (9.9 mmol) was amalgmated by immersion in a solution of 2% mercuric chloride in water for 15 seconds, washed with absolute ethanol followed by diethyl ether, cut into small pieces, and added to a solution of 400 mg (0.99 mmol) of 4,6-di-tert-butyl-2-triethylsiloxy-2-trifluoromethyl-3,5-cyclohexadien-1-one in 25 mL of 10% water -90% tetrahydrofuran. The resulting mixture was heated at 70° C. for 1.5 hours, allowed to cool to room temperature, and filtered. The filter cake was washed with 10 mL of tetrahydrofuran. Concentration of the combined filtrates gave a residue which was poured into 25 mL of water. The aqueous mixture was extracted with three 10 mL portions of dichloromethane. Combination, drying and concentration of the organic layers gave a residue which was purified by PTLC (one 2 mm silica gel plate eluted with petroleum ether), affording 226 mg (83% yield) of 2,4-di-tert-butyl-6-trifluoromethylphenol as a colorless liquid: 1H NMR (CDCl3) δ 1.31 (s, 9H), 1.45 (s, 9H), 5.56 (q, H, JHF =4 Hz), 7.39 (d, 1H, J=2 Hz), 7.54 (d, 1H, J=2 Hz); IR (neat) 3624, 2959, 2906, 2868, 481, 1458, 1448, 1363, 1340, 1263, 1251, 1170, 1126, 1097, 887, 694 cm-1; mass spectrum (70 eV) m/z (relative intensity) 274 (20, M+), 259 (100), 239 (68), 98 (20), 57 (22), 41 (34).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C@@H:7]([CH2:10][NH2:11])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[OH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C@@H:7]([CH2:10][NH:11][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[CH:23]=[CH:24][C:25](=[O:29])[O:26][C:27]=4[CH:28]=3)[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: NC[C@H]1COc2cc(O)ccc2O1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCNC[C@H]3COc4cc(O)ccc4O3)cc2o1
Yield: 12.8 %

Procedure:
(S)-2,3-Dihydro-6-hydroxy-1,4-benzodioxin-2-methanamine (2.89 g, 16.0 mmole), 7-(3-chloropropoxy)coumarin (3.46 g, 14.5 mmole), diisopropylethylamine (12.5 ml, 72 mmole) and sodium iodide (2.20 g, 14.7 mmole) were combined in 200 ml of DMF and heated at 80°-100° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum. The residue was column chromatographed on silica gel using first 0.5% methanol/dichloromethane, then 1% methanol/dichloromethane, and finally 3% methanol/dichloromethane as eluant. The product-containing fractions (Rf=0.45 on silica gel with 5% methanol/dichloromethane) were combined and rechromatographed on silica gel using first 75% ethyl acetate/dichloromethane and then 2% methanol/dichloromethane as eluant. The product-containing fractions were concentrated in vacuum and the pure free base (0.98 g) redissolved in methanol and boiled on a hot plate, the methanol gradually being replaced with isopropanol. 4N HCl/isopropanol (7.0 ml) was added and the title compound was collected by filtration and dried in vacuum at 80° C. The procedure yielded 0.71 g of white solid, monohydrochloride, m.p. 236°-239° C.
Reaction SMILES: [O:1]([CH3:13])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4].CO[CH:16](OC)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28](S(O)(=O)=O)=[CH:27][CH:26]=1.[BH4-].[Na+].Cl>C(#N)C>[CH2:16]([O:4][C@H:3]1[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@@H:9]([CH2:11][O:12][CH2:35][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:10][C@@H:2]1[O:1][CH3:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(OC)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1OCc1ccccc1

Procedure:
A ca. 2:1 mixture of exo- and endo-isomers of bis-[(2,3-O-), (4,6-O-)]benzylidene-α-D-mannopyranoside (Carbohydrates, Ed. Collins, P. M., Chapman and Hall, New York, 1987, p. 350) was prepared by reaction of methyl α-D-mannopyranoside with 2.2 eq of α,α-dimethoxytoluene and catalytic p-toluenesulfonic acid in acetonitrile. This compound was treated with NaBH4 and HCl (Garegg, P. J.; Hultberg, H. Carbohydrate Res. 1981, 93, C10) to provide a mixture of products from which the methyl 2,6-O-benzyl-α-D-mannopyranoside was isolated by flash chromatography. The assignment of this isomer was confirmed by 1H decoupling experiments on the corresponding bis-(3,4-O-diphenylphosphino) derivative (ligand VA). 1H NMR δ7.42-7.24 (m, 10), 4.81 (d, 1, J=1 Hz), 4.75-4.54 (m, 4) 3.78-3.71 (m, 6), 3.36 (s, 3), 2.83 (bs, 1), 2.43 (bs, 1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)CCBr
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2OCCC(C)C)c1
Yield: 88 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 646.5 μl (5.181 mmol) of isopentyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1 and 50/1) to obtain 8.2 mg (0.456 mmol, 88%) of 2-isopentyloxy-2'-hydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl as an oily product.
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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])[O:28][C:29](Cl)(Cl)Cl)Cl.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41]CO)[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][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:28][CH2:29][CH2:41][N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCCN1CCOCC1
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: COc1cc2nccc(Oc3ccc(NC(=O)OCCN4CCOCC4)cc3)c2cc1OC
Yield: 56.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)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, 2-morpholino-1-ethanol (34 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, and the extract was washed with 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 (43 mg, yield 48%).
Reaction SMILES: O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19].FC(F)(F)S(O[Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])(=O)=O>CN1CCCN(C)C1=O>[CH2:23]([O:22][C:16]([O:21][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])=[CH:17][CH:18]([CH3:20])[CH3:19])[CH3:24]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CCOC(=O)CC(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=CC(C)C)O[Si](C(C)C)(C(C)C)C(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (100 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro 2 (1H)-pyrimidinone (140 ml) were mixed at -20° C. and lithium bis (trimethylsilyl) amide (1M in tetrahydrofuran, 100 ml) was added. The mixture was cooled to -70° C., ethyl isovalerate (18.75 ml) added and stirred for 1/2 hour at -70° C. Triisopropylsilyl trifluoromethane sulfonate was added and the mixture left to stir at -75° C. for 1/2 hour before warming to room temperature and stirring for 3 hours. The reaction mixture was quenched with aqueous sodium bicarbonate (8%, 150 ml) and extracted with hexane (1000 ml). The hexane extract was washed with water (4×500 ml), dried (MgSO4), filtered and concentrated in vacuo to afford a crude yellow oil containing the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([NH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)=[O:8]
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: N#Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C(C(=O)Nc2ccc(C#N)cc2)C1(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
Add a solution of 2,2,3,3-tetramethyl-cyclopropane-carbonyl chloride (5 g, 31.1 mmol) in anhydrous DCM to a mixture of 4-aminobenzonitrile (3.34 g, 28.3 mmol) and triethylamine (4.3 mL, 31 mmol) in anhydrous DCM (20 mL) at 0° C. After stirring at 0° C. for 20 min, warm the mixture to room temperature and stir overnight. Partition the reaction mixture between DCM (500 mL) and water (250 mL) and extract the aqueous phase with DCM (250 mL). Wash combined organic extracts with water (3×250 mL), dry over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 over 36 min; 1:0 to 3:1 gradient over 36 min; 3:1 to 1:1 gradient over 71 min; 50 mL/min) to obtain the desired intermediate as a solid (2.31 g, 34%). MS (ES+) m/z: 243.2 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:6]([OH:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].[C:15](=O)([O-:36])[O:16][C:17]1C(C)=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=CN=1.[C:38]1([C:44]2[CH:49]=[CH:48][C:47](C3C=CN(C([O-])=O)C(=O)C=3C)=[CH:46][CH:45]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O.C1COCC1>[OH:9][C@H:6]([CH2:7][CH3:8])[C@H:2]([N:1]([C:47]1[CH:46]=[CH:45][C:44]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:49][CH:48]=1)[C:15]([O:16][CH3:17])=[O:36])[C:3]([OH:5])=[O:4]
Reactant: Cc1c(-c2ccc(-c3ccccc3)cc2)ccn(C(=O)[O-])c1=O
Reactant: CC[C@@H](O)[C@H](N)C(=O)O
Reactant: Cc1c(-c2ccc(-c3ccccc3)cc2)ccnc1OC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](O)[C@@H](C(=O)O)N(C(=O)OC)c1ccc(-c2ccccc2)cc1
Reaction time: 15 h
Yield: 93 %

Procedure:
To a stirred mixture of (2S*,3R*)-2-amino-3-hydroxy-pentanoic acid (0.068 g, 0.51 mmol) and NaHCO3 (0.128 g, 1.53 mmol) in H2O (2.0 mL), at rt, the isomeric mixture containing (4-phenylphenyl)-methyl-2-pyridyl carbonate and (4-phenylphenyl)-methyl-2-oxopyridine-1-carboxylate (0.233 g, 0.77 mmol) [prepared as for example 17, step 1] in THF (2.0 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×10 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×20 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.164 g, 93% over 3 steps), as an off-white solid, which was used in the next step without further purification. MS (ESI) m/z: 361 [M−NH4]+; (ESI) m/z: 342 [M−H]−. 1H NMR (DMSO-d6) δ 0.85 (t, J=7.38 Hz, 3H), 1.42 (p, J=7.31 Hz, 2H), 3.81 (td, J=3.02, 6.87 Hz, 1H), 4.07 (dd, J=3.04, 9.23 Hz, 1H), 4.66 (s, 1H), 5.10 (s, 2H), 6.92 (d, J=9.21 Hz, 1H), 7.28-7.56 (m, 5H), 7.59-7.78 (m, 4H), 12.59 (s, 1H).
Reaction SMILES: ClC1[N:3]=[C:4](N2CCN(CC)CC2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](=[O:23])([O-])[O-].[Cs+].[Cs+].CN(C)C=[O:29]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]1(=[O:23])[NH:3][C:4](=[O:29])[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=[C:10]2[CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: CCN1CCN(c2nc(Cl)cc3ccccc23)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Product: O=C1Cc2ccccc2C(=O)N1

Procedure:
3-Chloro-1-(4-ethylpiperazin-1-yl)isoquinoline (3.5 g) and 4-(1,3,2-dioxaborynan-2-yl)-1-(1,3-dioxolan-2-yl)benzene (5.0 g) were reacted in dimethylformamide (50 ml), in the presence of cesium carbonate (7.3 g) and tetrakistriphenylphosphinepalladium (0.3 g) at 80° C. in a nitrogen stream for 12 hr. The reaction solution was evaporated, and then partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 4.66 g of the title compound as a pale yellow oil. (17-5) 1-(4-Ethylpiperazin-1-yl)-3-(4-formylphenyl)isoquinoline
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:11]=[O:12])[NH:10][C:4]=2[CH:3]=1.CC1C=CC(S([CH2:23][N+:24]#[C-:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[O:12][CH:25]=[N:24][CH:23]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: O=Cc1cc2cnc(Br)cc2[nH]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Brc1cc2[nH]c(-c3cnco3)cc2cn1
Temperature: 65 °C
Yield: 79.3 %

Procedure:
6-Bromo-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (Preparation 138, 604 mg 2.68 mmole), TOSMIC (1047 mg, 5.37 mmole) and potassium carbonate (759 mg, 5.5 mmole) in methanol (30 mL) was stirred and heated at 65° C. for 110 minutes. The methanol was evaporated and the residue partitioned between ethyl acetate (50 mL) and water (20 mL). The layers were separated and the organic solution was washed with water and brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate to afford the title compound (561 mg, 79%). 1H-NMR (d6-acetone, 500 MHz): δ 7.02 (d, J=0.95 Hz, 1H), 7.60 (t, J=0.95 Hz, 1H), 7.62 (s, 1H), 8.30 (s, 1H), 8.67 (d, J=0.95 Hz, 1H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCN1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCN1CCCCC1
Temperature: 25 °C
Yield: 30 %

Procedure:
In a 20 mL scintillation vial equipped with a stirring bar and a septum screw cap, a solution of 3-piperidin-1-yl-propan-1-ol (0.500 g, 3.49 mmol) in DCM (5 mL) was cooled down to 0° C. Then, triethylamine (10 eq.) was added to the vial via a syringe followed by a solution of methanesulfonyl chloride (5 eq.) in DCM (1 mL). The resulting reaction mixture was allowed to slowly warm up to room temperature and stirring was maintained for additional 2 h. The volatiles were removed in vacuo and the resulting crude methanesulfonic acid 3-piperidin-1-yl-propyl ester was used in the next step of the synthesis without further purification (the material was found to contain 30% of the title compound by weight according to 1H NMR).