Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH2:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1=[O:19])=[O:7].N1C=CN=C1.[C:31]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:31]([Si:35]([CH3:37])([CH3:36])[O:1][CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH2:5][C:6]([N:8]1[CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][O:10][C:9]1=[O:19])=[O:7])([CH3:34])([CH3:33])[CH3:32]
Reactant: O=C(CCCC(O)c1ccccc1)N1C(=O)OCC1c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
30 g of 3-(5-Hydroxy-5-phenyl-pentanoyl)-4-phenyl-oxazolidin-2-on are solved in 50 ml of DMF. After addition of 14.3 g of imidazol and 19 g of tert.-Butyl-dimethylsilylchlorid in 25 ml of DMF the reaction is stirred at room temperature until all components are dissolved (2-4 h). The reaction solution is evaporated, and after water was added extracted by acetic acid ethylester. After drying of the organic phase by magnesium sulfate and evaporation compound 1 is obtained: C26H35NO4Si (453.6) MS (ESI+) 476 (M+Na+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][S:4][N:3]=1.C([Li])CCC.[I-:15].Cl>C1COCC1>[I:15][C:5]1[S:4][N:3]=[C:2]([CH3:1])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1nscc1C(=O)O
Reactant: [I-]
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nsc(I)c1C(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methylisothiazole-4-carboxylic acid (E-4) (3.9 g, 27.3 mmol) in anhydrous THF (150 mL) at −78° C. under argon, n-butyl lithium solution (27.3 mL, 68.3 mmol) is added dropwise and the resulting mixture is stirred at −78° C. for 1 h. To this mixture, a solution of iodide (13.9 g, 54.6 mmol) in THF (50 mL) is added slowly and the resulting mixture is stirred at RT for 1 h. The mixture is acidified with concentrated HCl to adjust the pH to 3-4, and then extracted with ethyl acetate. The organic layer is washed with aqueous Na2SO3 solution. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product, 5-iodo-3-methylisothiazole-4-carboxylic acid (E-5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:24])([CH2:21][CH:22]=[CH2:23])[CH2:9][CH2:10][NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH3:13])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:21]([C@@:8]1([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:24][C:33](=[O:35])[N:11]([C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH3:13])[CH2:10][CH2:9]1)[CH:22]=[CH2:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCC(O)(CCN[C@@H](C)c1cccc(F)c1)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2cccc(F)c2)C(=O)O1
Yield: 43 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1-((S)-1-(3-fluorophenyl)ethylamino)hex-5-en-3-ol (350 mg, 1.1 mmol) and Et3N (333 mg, 3.3 mmol) in anhydrous CH2Cl2 (6 mL) was added triphosgene (155 mg, 0.52 mmol) in portions at 0° C. under N2. Then the solution was refluxed overnight. After the solvent was removed under reduced pressure, the residue was purified by preparative TLC to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(3-fluorophenyl)ethyl)-1,3-oxazinan-2-one (80 mg, 21%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[N:25]=[C:24]([Cl:26])[C:23]([O:27][CH2:28][C:29](O)=[O:30])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CN1CCOCC1>C1COCC1>[C:16]([C:20]1[N:25]=[C:24]([Cl:26])[C:23]([O:27][CH2:28][C:29]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[O:30])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC(C)(C)c1ccc(OCC(=O)O)c(Cl)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)c(Cl)n1
Yield: 28.2 %

Procedure:
3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (21 mg, 0.08 mmol) was reacted with (6-tert-butyl-2-chloro-pyridin-3-yloxy)-acetic acid (1.0 eq, 20 mg) DMTMM (1.2 eq, 27 mg) and NMM (1.5 eq, 14 μl) in THF to give the title compound (10 mg, 28.2%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1)=[CH2:2].FC(F)(F)C(O)=O.CO[CH2:22][N:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:24][Si](C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:9][C:7]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=[C:3]([CH:1]2[CH2:2][CH2:24][N:23]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:22]2)[N:8]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=Cc1ccc([N+](=O)[O-])c(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 25.2 %

Procedure:
To a solution of crude 6-ethenyl-2-methyl-3-nitropyridine (440 mg, 2.68 mmol) in dichloromethane (DCM) (5 mL) was added trifluoroacetic acid (0.268 mL, 3.48 mmol). To this stirred solution was added [(methyloxy)methyl](phenylmethyl)[(trimethylsilyl)methyl]amine (2.74 mL, 10.72 mmol) (carefully) and the reaction mixture was stirred under nitrogen for 1.5 hours. The reaction mixture was diluted with DCM and then treated with saturated sodium bicarbonate solution. The organic phase was separated and passed through a hydrophobic frit. The organic solvent was evaporated in vacuo and the residue was dissolved in DCM (5 mL). This was purified by silica (Si) chromatography (0-100% ethyl acetate-cyclohexane with 0-20% methanol gradient). The appropriate fractions were combined and evaporated in vacuo to give the crude product (201 mg) as a brown liquid. Used directly in next step without further purification. LCMS (2 min, formic) Rt 0.71 min, m/z (ES+) 298 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=2)=[C:16]([F:23])[CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: COC(=O)c1cnc(C)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cnc(C)cc1-c1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 43 %

Procedure:
To a solution of methyl 4-chloro-6-methylnicotinate (660 mg, 3.56 mmol) and (4-chloro-2-fluorophenyl)boronic acid (620 mg, 3.56 mmol) in 1,4-dioxane (20 mL) was added cesium carbonate (3.48 g, 10.67 mmol). The reaction mixture was degassed with argon over a period of 5 min. Pd(Ph3P)4 (205 mg, 0.178 mmol) was added to the reaction mixture and heated to 80° C. for 16 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (100 mL). The organic phase was washed with brine (2×50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography to afford methyl 4-(4-chloro-2-fluorophenyl)-6-methylnicotinate (500 mg, 1.53 mmol, 43% yield) as a yellow liquid. LC/MS (ESI) m/e 280.0 [(M+H)+, calcd for C14H12ClFNO2 279.6]; LC/MS retention time (method C): tR=1.87 min.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[OH:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:36]4[CH2:37][CH2:38][CH:33]([CH2:32][CH2:31][OH:30])[CH2:34][CH2:35]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: OCCC1CCNCC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCC(CCO)CC2)nc1

Procedure:
4-(2-Hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate E and 4-(hydroxyethyl)piperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (d, J=2.01 Hz, 1H) 8.43 (t, J=5.65 Hz, 1H) 8.21 (d, J=9.04 Hz, 1H) 7.80-7.88 (m, 2H) 7.54-7.65 (m, 3H) 7.49-7.53 (m, 2H) 7.38 (dd, J=8.66, 1.88 Hz, 1H) 6.84 (d, J=2.00 Hz, 1H) 6.72 (d, J=8.78 Hz, 1H) 4.25-4.33 (m, 5H) 3.38 (q, J=6.10 Hz, 2H) 2.75 (t, J=12.50 Hz, 2H) 1.58-1.67 (m, 3H) 1.28 (q, J=6.53 Hz, 2H) 0.92-1.05 (m, 2H).
Reaction SMILES: CS([C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)[C:14]=3[CH:29]=2)=[N:7][N:6]=1)(=O)=O.[CH3:30][NH2:31].O1CCCC1>CN1CCCC1=O>[CH3:30][NH:31][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[CH:16][N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)[C:14]=3[CH:29]=2)=[N:7][N:6]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3ncn(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Reactant: CN
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CNc1nnc(-c2ccc3ncn(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Yield: 79 %

Procedure:
In the same manner as in Example 433 and using 6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1-[3-(trifluoromethoxy)phenyl]-1H-benzimidazole instead of 6-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]-1-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole, using 2M methylamine-tetrahydrofuran solution instead of sodium methoxide, and using 1-methyl-2-pyrrolidone instead of N,N-dimethylformamide, the title compound (yield 79%) was obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:12][C:11]2=[O:23])=[CH:6][CH:5]=1.ClCCl.[I:29]Cl>O>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:15](=[O:16])[C:14]([I:29])=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:12][C:11]2=[O:23])=[CH:8][CH:9]=1
Reactant: O=c1cc(-c2ccccn2)[nH]c(=O)n1-c1ccc(OC(F)(F)F)cc1
Reactant: ClI
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]c(-c2ccccn2)c(I)c(=O)n1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
1.0 g of the obtained 3-(4-trifluoromethoxyphenyl)-6-(2-pyridyl)-2,4(1H,3H)-pyrimidinedione was added to 20 ml of dichloromethane, and 0.7 g of iodine monochloride was added thereto with stirring at room temperature. The resulting solution was further stirred at room temperature for 3 hours, then poured into 100 ml of water and extracted with 100 ml of ethyl acetate. The obtained organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then the solvent was distilled away under reduced pressure to obtain 0.60 g of the objective compound.
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]([OH:17])=[O:16])(OCC)=O)C.[C:18]1([CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1.O>[C:18]1([CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=[CH:14][C:15]([OH:17])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: O=CC=CC=Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=CC=CC=Cc1ccccc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
Butyllithium (12.8 mL of 2.5 N solution) was added to 65 mL of anhydrous tetrahydrofuran (THF) at −65° C. A solution of diethylphosphonoacetic acid (2.92 g) in 25 mL of anhydrous THF was added dropwise to the stirred solution at −65° C. The resulting solution was stirred at −65° C. for an additional 30 minutes and then a solution of 5-phenyl-2,4-pentadienal (2.4 g) in 15 mL of anhydrous THF was added to the reaction at −65° C. The reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight. To the reaction was added 30 mL of water, acidified with 5% hydrochloric acid (14 mL) to a pH of 4.7 and then added an additional 20 mL of water. The aqueous layer was extracted with 10 mL of ether twice and with 10 mL of ethyl acetate once. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was dissolved in 50 mL of hot methanol and then refrigerated overnight. The crystals formed were filtered and dried under vacuum to afford 2.4 g of the desired 7-phenyl-2,4,6-heptatrienoic acid. 1H NMR (DMSO-d6, 300 MHz), δ(ppm) 7.52 (m, 2H), 7.33 (m, 4H), 7.06 (m, 1H), 6.86 (m, 2H), 6.58 (m, 1H), 5.95 (d, 1H).
Reaction SMILES: [F:1][C:2](=[CH2:11])[C:3]([CH3:10])([CH3:9])[C:4]([O:6]CC)=[O:5].[OH-].[K+]>C(O)C.O>[F:1][C:2](=[CH2:11])[C:3]([CH3:10])([CH3:9])[C:4]([OH:6])=[O:5]
Reactant: C=C(F)C(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=C(F)C(C)(C)C(=O)O
Yield: 78.8 %

Procedure:
Hydrolysis of the ester (1 g) with 1 g of potassium hydroxide in ethanol/water overnight furnished 0.65 g of the title acid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@H:10]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1)[CH2:11][CH3:12]>C(Cl)(Cl)Cl>[Br:1][C:19]1[N:20]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C:21]2[C:17]([N:18]=1)=[C:16]([NH2:29])[N:15]=[C:14]([O:13][C@@H:10]([CH3:9])[CH2:11][CH3:12])[N:22]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC[C@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClC(Cl)Cl
Product: CC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
N-Bromosuccinimide (1.182 g, 6.64 mmol) was added portionwise to a solution of 2-{[(1S)-1-methylpropyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.935 g, 6.64 mmol) in chloroform (50 ml) at 0-5° C. The resulting green solution was stirred at 0-5° C. for 1 hour during which time it turned red and the mixture was then allowed to warm to room temperature and stirred overnight. The resulting green solution was washed with water (2×20 ml), separated using a hydrophobic frit and concentrated. The residue was dissolved in dichloromethane and purified by silica gel chromatography (100 g cartridge) using a Flashmaster II apparatus and a 0-100% ethyl acetate-cyclohexane gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow foam (1.79 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][C@H:4]([NH:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:7][CH:6]=1.O1CCCC1.[OH-].[Li+]>CO>[CH3:1][CH:2]([CH3:32])[CH2:3][C@H:4]([NH:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(N[C@@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cn3)cc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C[C@H](Nc1ccc(C(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Temperature: 50 °C

Procedure:
A mixture of (S)-methyl 6-[(3-methyl-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}butyl)amino]nicotinate (53.0 g, 119.5 mmol) was dissolved in methanol (239 ml) and tetrahydrofuran (120 ml) and treated with aqueous lithium hydroxide (120 ml, 239 mmol, 2.0M). An additional aliquot of methanol was added to homogenize the mixture (110 ml, ˜2 ml/g). The reaction was heated to 50° C. for 12 h. The reaction was concentrated in vacuo, and the crude residue was diluted with water (500 ml). The solution was vigorously stirred and slowly acidified with aqueous 1.0M hydrochloric acid (240 ml, to approximately pH 5.0). The precipitated solid was collected by filtration and the remaining solid was dissolved with ethyl acetate and transferred into a separate flask. The crude solid was dried in vacuo and used directly for further transformations.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.F[B-](F)(F)F.[CH3:28][O+](C)C.O>C(Cl)Cl>[CH3:28][O:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19-Hydroxyandrost-4-ene-3,17-dione is dissolved in methylenechloride and trimethyloxonium fluoroborate added thereto. After stirring at room temperature for a period of two hours, water is added to the reaction mixture, the organic layer is separated, dried over magnesium sulfate and the solvent removed under vacuum. The residue is crystallized from an acetone-hexane solution to yield the desired 19-methoxyandrost-4-ene-3,17-dione.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>>[NH:2]=[C:1]([N:37]1[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:30])(=[O:31])[NH2:29])=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Nc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)Nc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 33.8 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylphenyl)benzenesulfonamide following procedure C and using 1 equivalent of 1-methylpiperazine as secondary amine and 1 equivalent of DIEA as base. The product was purified by preparative HPLC.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])(C)C)[CH2:6][CH2:5][C:4](=[O:16])[O:3]1.[CH3:17][CH2:18]OC(C)=O>C(Cl)(Cl)Cl>[CH3:1][C@@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][CH2:11][CH2:14][CH2:17][CH3:18])[CH2:6][CH2:5][C:4](=[O:16])[O:3]1
Reactant: C[C@H]1OC(=O)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)N[C@@H]1CCC(=O)O[C@@H]1C

Procedure:
Data for tert-butyl (2R,3R)-2-methyl-6-oxo-tetrahydro-2H-pyran-3-ylcarbamate: m.p.=98.2-99.5° C.; Rf=0.27 (50% EtOAc in hexanes); IR (neat): 3337, 2979, 2935, 1709 (C═O), 1697 (C═O), 1527, 1250, 1171, 1059 cm−1; [α]D25+38.8 (c 1.0, CHCl3); 1H NMR (300 MHz, 293 K, CDCl3) δ 4.74 (br, 1H), 4.52 (ddd, 1H, J=12.9, 6.3, 2.4 Hz), 3.99 (m br, 1H), 2.55 (dd, 2H, J=8.1, 6.9 Hz), 2.24-2.12 (m, 1H), 1.99-1.88 (m, 1H), 1.43 (s, 9H), 1.33 (d, 3H, J=6.6 Hz); 13C NMR (75 MHz, 293K, CDCl3) δ 171.2, 155.5, 79.8, 77.4, 46.6, 28.2, 26.0, 25.5, 16.8; HRMS (EI+) calcd. for C11H19NO4 (M)+ 229.1314. found 229.1306.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:24][S-:25].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:24][S:25][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCOCC3)cc2n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nc(N2CCOCC2)c2sc(CN3CCOCC3)cc2n1
Temperature: 100 °C
Yield: 99.9 %

Procedure:
2-Chloro-4-morpholin-4-yl-6-morpholin-4-ylmethyl-thieno[3,2-d]pyrimidine (0.2 g, 0.56 mmol) in DMF (3 mL) was treated with sodium thiomethoxide (0.12 g, 1.71 mmol) in a sealed tube and the reaction mixture heated at 100° C. with stirring. After 2 h the contents of the tube were diluted with EtOAc, washed with saturated aqueous NaHCO3 (×2) then brine, and the organic phase was isolated, dried (Na2SO4), filtered and concentrated to afford the title compound as a light brown solid (0.205 g, 100%). LCMS (Method D): RT=1.80 min, [M+H]+ 366.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:38]([F:41])([F:40])[F:39])=[C:34]([CH:37]=1)[CH2:35]Br>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:35][C:34]3[CH:37]=[C:30]([F:29])[CH:31]=[CH:32][C:33]=3[C:38]([F:40])([F:39])[F:41])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Fc1ccc(C(F)(F)F)c(CBr)c1
Product: Fc1ccc(C(F)(F)F)c(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and 5-fluoro-2-trifluoromethylbenzyl bromide as in the procedure of Example 43. MS (ESI) m/z 556.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH:11]([CH3:16])[C:12](OC)=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[N:1]1[C:10]2[C:5](=[C:6]([CH:11]([CH3:16])[CH2:12][OH:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(C)c1cccc2ncccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)c1cccc2ncccc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
Methyl 2-(5-quinolyl)propanoate (100 mg, 0.47 mmol) was dissolved in dry THF(10 mL) and cooled to −78° C. on a dry ice/acetone bath. Lithium aluminum hydride (1M in ether, 0.93 mL, 0.93 mmol) was added dropwise. The mixture stirred for 10 minutes while warming to 0° C. The reaction was quenched with KHSO4(1M aq., 1 mL). The mixture was made basic with NaOH(1M aq) and extracted into ethyl acetate. The organics were washed with brine, dried over MgSO4 and then removed under reduced pressure to give 2-(5-quinolyl)-1-propanol (65 mg, 74%). HPLC (10% to 90% acetonitrile in 0.1N aqueous ammonium acetate over 10 min at 2 mL/min using a waters Symmetry C18, 150×4.6 mm column) 2.96 min.