Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2I)=[O:5])[CH3:2]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[C:4]#[C:6][CH2:15][CH3:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCC#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Temperature: -78 °C
Yield: 185.4 %

Procedure:
A mixture of 1.00 g (2.31 mmole) of ethyl-6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate, 134 mg (0.116 mmole) tetrakis(triphenylphosphine)palladium(O), 44 mg (0.231 mmole) copper (I) iodide, 20 mL degassed toluene and 0.965 mL (6.94 mmole) degassed TEA was cooled to −78° C. and treated with an excess of condensed gaseous 1-butyne. The mixture was stirred for thirty minutes at −78° C. and allowed to warm to room temperature and stirred overnight. The reaction mixture was concd and the resulting oil was purified using reverse phase chromatography to afford 0.768 g (93%) of a crystalline solid: 1H NMR (CDCl3/400 MHz) 1.24 (t, 3H, J=7.2 Hz), 1.34 (t, 3H, J=7.2 Hz), 2.45 (q, 2H, J=7.6 Hz), 4.27-4.35 (m, 2H), 5.78 (q, 1H, J=6.8 Hz), 7.10 (d, 1H, J=2.4 Hz), 7.32 (d, 1H, J=2.4 Hz), 7.59 (s, 1H); MS (ES+) 359 (M+1, 100).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:37]=[CH:36][C:14]([O:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:17]=3OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[Cs+].[F:40][C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH2:42]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:40][C:41]1[CH:46]=[C:45]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[C:16]=2[O:15][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:37][CH:36]=2)[CH:44]=[C:43]([F:47])[CH:42]=1
Reactant: OB(O)C1(F)C=CC=C(F)C1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(-c3cc(F)cc(F)c3)ccc2c1
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
Dissolve trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-yl ester (435 mg, 0.80 mmol), cesium fluoride (864 mg, 5.7 mmol) and 1,3-difluoro-benzene boronic acid (383 mg, 2.4 mmol) in dry acetonitrile (5 mL) and stir for 10 minutes. In a separate flask suspend palladium acetate (18 mg, 0.08 mmol), and tricyclohexyl phosphine (33 mg, 0.12 mmol) in dry acetonitrile (15 mL) and sonicate under nitrogen for 10 minutes. Combine contents of both flasks and heat reaction at 60° C. for 15 minutes. Cool reaction and filter through celite and concentrate in vacuo. Purify crude product by silica gel chromatography using a 1-3% gradient of methanol in dichloromethane to yield 400 mg (98%) of the title compound: mass spectrum (ion spray) m/z=504.2 (M+H).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19](Cl)=[O:20].[OH-].[Na+]>ClCCl.O>[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH:13][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:16]([Cl:15])[CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 2 °C

Procedure:
Dichloromethane (150 mL) and then triethylamine (33.0 mL, 234 mmol, 2.0 eq.) were added to glycine methyl ester hydrochloride (14.7 g, 117 mmol, 1.0 eq.). The mixture was stirred and cooled to 2° C. using an ice/water bath. A solution of 3,4-dichlorobenzoyl chloride (24.55 g, 117 mmol, 1.0 eq.) in dichloromethane (75 mL) was added over 7 minutes. The mixture was stirred for 1 hour at 2° C., then left to stir at room temperature overnight (16 hours). Water (225 mL) was added and the mixture was stirred rapidly for 30 minutes at room temperature. The layers were separated. The organic layer was washed with water (225 mL), then evaporated to dryness using a rotary evaporator to give an off-white solid. The isolated solid (26.18 g, 85%) was added to dichloromethane (300 mL, 10 vols.) with 1 M sodium hydroxide solution (300 mL, 10 vols). The lower organic layer was concentrated to dryness in vacuo (25.91 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13](Br)[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cu][C:24]#[N:25]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:24]#[N:25])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C#N)c1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A mixture of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (990.0 mg, 2.54 mmol) and copper(I) cyanide (273.3 mg, 3.05 mmol) in dry N,N-dimethylformamide (2.5 mL) was heated under reflux for 4 h. The reaction was allowed to cool to 25° C., and the crude reaction mixture was directly purified without further chemical work-up. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 100% hexanes then 3/1 hexanes/ethyl acetate) afforded 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (646.5 mg, 76%) as a pale yellow oil: EI-HRMS m/e calcd for C17H21NO4S (M+) 335.1191, found 335.1185.
Reaction SMILES: [C:1]([N:6]1[C:11](=[O:12])[CH:10]2[CH2:13][CH:7]1[CH:8]=[CH:9]2)(=[O:5])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].S(=O)(=O)(O)O.C(OCC)(=O)C>C(O)C>[C:1]([NH:6][CH:7]1[CH2:13][CH:10]([CH2:11][OH:12])[CH:9]=[CH:8]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)N1C(=O)C2C=CC1C2
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCC(=O)NC1C=CC(CO)C1
Temperature: -10 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
73.87 g of (±)-2-butyryl-2-azabicyclo[2.2.1]hept-5-en-3-one were dissolved in ethanol (400 ml) under nitrogen and cooled to -10° C. 15.68 g of sodium borohydride were added in portions over the course of 45 minutes. The reaction was stirred at 0° C. for 3 hours and then the pH was adjusted to 1.5 with conc. sulphuric acid. Ethyl acetate (200 ml) was added to this mixture, and the solids were filtered off. It was then completely evaporated. The residue was taken up in water, washed with methylene chloride, evaporated and dried under high vacuum. 60.55 g of product were obtained. The yield was 80% based on (±)-2-butyryl-2-azabicyclo[2.2.1]hept-5-en-3-one employed.
Reaction SMILES: C1(N[C:8]2[C:21]3[C:20](=[O:22])[C:19]4[C:14](=[CH:15][C:16](S(O)(=O)=O)=[CH:17][CH:18]=4)[C:13](=[O:27])[C:12]=3[CH:11]=[CH:10][C:9]=2S(O)(=O)=O)C=CC=CC=1.NC1C2C(=O)C3C(=CC(S(O)(=O)=O)=CC=3)C(=O)C=2C(Br)=CC=1S(O)(=O)=O.ClC1N=C(Cl)N=C(Cl)C=1Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH:15]1[C:14]2[C:13](=[O:27])[C:12]3[C:21](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:20](=[O:22])[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C1c2cc(S(=O)(=O)O)ccc2C(=O)c2c1ccc(S(=O)(=O)O)c2Nc1ccccc1
Agent: Clc1nc(Cl)c(Cl)c(Cl)n1
Agent: Nc1c(S(=O)(=O)O)cc(Br)c2c1C(=O)c1ccc(S(=O)(=O)O)cc1C2=O
Agent: O=C([O-])[O-]
Solvent: O
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
73.6 g of 1-amino-4-[3',4' -dimethyl-5'-(3"-aminophenyl-1")-disulphimido]-phenylamino-anthraquinone-2,6-disulphonic acid (produced from 1-amino-4-bromoanthraquinone-2,6-disulphonic acid and 3,3'-diamino-5,6-dimethyldibenzene-disulphimide analogously to the data in Example 1) are dissolved in 1300 ml of water and to the solution are added 22.9 g of tetrachloropyrimidine at 80°-85°. The reaction mixture is stirred at 80°-85° the reaction is completed. The pH-value is maintained at 6-7 by the addition of 20% sodium carbonate solution. As soon as the reaction is completed, the dyestuff solution is filtered and the dyestuff then precipitated by the addition of 230 g of solid sodium chloride. The dyestuff is filtered off, subsequently washed with 20% sodium chloride solution and dried in vacuo at 80°. It corresponds to the formula: ##STR35## If, instead of 1-amino-4-[3',4'-dimethyl-5'-(3"-aminophenyl-1")-disulphimido]-phenylamino-anthraquinone-2,6-disulphonic acid, equivalent amounts are used of the aminoanthraquinone dyestuffs, given in Table II, Column II, or of the stated mixtures and, instead of tetrachloropyrimidine, the acylating agents given in Column III, the procedure being otherwise as described in the example and at temperatures given in Column IV then similarly valuable blue reactive anthraquinone dyestuffs are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:15][CH2:14][C:5]2=[C:6]([C:11]([OH:13])=O)[S:7][C:8]([S:9][CH3:10])=[C:4]2[CH2:3]1.[CH3:17][Li]>C(OCC)C>[CH3:16][C:2]1([CH3:1])[CH2:15][CH2:14][C:5]2=[C:6]([C:11](=[O:13])[CH3:17])[S:7][C:8]([S:9][CH3:10])=[C:4]2[CH2:3]1
Reactant: [Li]C
Reactant: CSc1sc(C(=O)O)c2c1CC(C)(C)CC2
Solvent: CCOCC
Product: CSc1sc(C(C)=O)c2c1CC(C)(C)CC2
Reaction time: 2 h

Procedure:
To a solution of 5,5-dimethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (508 mg, 1.98 mmol) in diethyl ether (20 mL), a solution of methyllithium (1.1 mL, 1.6 M in diethyl ether) is added at rt. The mixture is stirred at rt for 1 h before another portion of methyllithium (0.25 mL) is added. Stirring is continued for 2 h. The reaction is quenched by the addition of 1 N aq. K2HPO4 solution. The mixture is diluted with diethyl ether, washed with 1 N aq. NaOH, dried over Na2SO4 and evaporated to give 1-(5,5-dimethyl-3-methylsulfanyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (214 mg) as a yellow oil; LC-MS: tR=1.09 min, [M+1]=255.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=1)[CH3:2].[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:7]=1[Br:25])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)c2ccc(OC)cc12
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1c(Br)n(Cc2ccccc2)c2ccc(OC)cc12
Reaction time: 1.5 h
Yield: 42.7 %

Procedure:
A mixture of 5-methoxy-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ester (10.8 g, 32 mmol) and 6.3 g (35 mmol) of N-bromosuccinimide in 250 mL of carbon tetrachloride was stirred for 1.5 hours, washed with Na2S2O3 solution, water, brine, and dried (Na2SO4). After concentrating at reduced pressure, the residue was chromatographed on silica gel and eluted with a gradient, 25% ether/hexane→40% ether/hexane, to give 5.5 g (43% yield) of 2-bromo-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH:17]3[CH2:19][CH2:18]3)[C:3]=12.[CH3:20][S:21]([CH2:24][CH2:25]O)(=[O:23])=[O:22]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:25][CH2:24][S:21]([CH3:20])(=[O:23])=[O:22])[N:15]=[C:16]([CH:17]3[CH2:19][CH2:18]3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(C3CC3)c12
Reactant: CS(=O)(=O)CCO
Product: CS(=O)(=O)CCn1nc(C2CC2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound Ix was synthesized from 4-chloro-3-cyclopropyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(methylsulfonyl)ethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](I)[C:8]([O:12][CH3:13])=[CH:7][CH:6]=1)=[O:4].[CH3:14][O:15][C:16](=[O:19])[CH:17]=[CH2:18].[Cl-].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:14][O:15][C:16](=[O:19])/[CH:17]=[CH:18]/[C:9]1[C:8]([O:12][CH3:13])=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:10]=1
Reactant: COC(=O)c1ccc(OC)c(I)n1
Reactant: C=CC(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1nc(C(=O)OC)ccc1OC
Yield: 58.3 %

Procedure:
Under the conditions of example 1 B, a solution of 22 g of 2-iodo-3-methoxypyridine-6-carboxylic acid methyl ester in 50 ml of dimethylformamide is reacted with 12.6 g of acrylic acid methyl ester in the presence of 5.3 g of bis-triphenylphosphinepalladium(II) chloride, 25.9 g of potassium carbonate and 23.4 g of tetrabutylammonium bromide, worked up, and the crude product is chromatographed on silica gel with hexane/0-30% ethyl acetate. 11 g of 3-(3-methoxy-6-methoxycarbonyl-2-pyridyl)-(2E)-2-propenoic acid methyl ester of melting point 123°-126° C. is obtained.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:14][C@H:13]([S:15][C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH2:35][NH2:36])=[N:8][CH:9]=1)[CH2:2][CH3:3].[F:37][C:38]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:39]=1[CH:40]=O.[BH3-]C#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[F:37][C:38]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:39]=1[CH2:40][NH:36][CH2:35][C@@H:11]1[CH2:12][C@@H:13]([S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][N:10]1[C:7]1[N:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=1
Reactant: CCCc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN)nc1
Reactant: O=Cc1cc(F)ccc1F
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCCc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CNCc2cc(F)ccc2F)nc1
Yield: 92.9 %

Procedure:
To 643 mg (1.3 mmol) (2S,4R)-C-[1-(5-Propyl-pyrimidin-2-yl)-4-tritylsulfanyl-pyrrolidin-2-yl]-methylamine in 3 ml methanol were added 158 μl (1.43 mmol) 2,5-difluorobenzaldehyde and 5 ml methanol to partially redissolve the compound. This was followed by a solution of 108 mg (0.78 mmol) zinc chloride and 109 mg (1.56 mmol) NaBH3CN in 3 ml methanol. The solution was stirred over night, concentrated and dissolved in ETOAc/sat NaHCO3 solution. The inorganic layer was extracted with EtOAc, the combined organic layers were washed with NaHCO3 and brine, dried over Na2SO4 and evaporated. Purification with column chromatography yielded 750 mg (93%) (2S,4R)-(2,5-Difluoro-benzyl)-[1-(5-propyl-pyrimidin-2-yl)-4-tritylsulfanyl-pyrrolidin-2-ylmethyl]-amine as light yellow gum, MS: 621 (MH+).
Reaction SMILES: [S:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[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].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[I-].[K+]>CN(C=O)C.O.CCOCC>[CH2:21]([O:4][C@@H:3]1[C@@H:5]([O:6][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:7]([O:8][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:9]([CH2:11][O:12][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:10][C@H:2]1[S:1][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](O)[C@@H](O)[C@H]1O
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: c1ccc(COC[C@H]2O[C@@H](Sc3ccccc3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
To the crude 9 (72.1 mmol, 1 eq) dissolved in dry DMF (1500 mL) under argon at 0° C. was added sodium hydride (10.7 g, 446.8 mmol, 6.2 eq). After 15 min, were added dropwise benzyl bromide (54 mL, 454 mmol, 6.3 eq) and a catalytic amount of potassium iodide. The mixture was stirred at room temperature for 3 h, diluted with water (500 mL) and Et2O (600 mL). The aqueous phase was extracted with Et2O (3×300 mL). The organic extracts were combined, dried over MgSO4 and concentrated. Purification by flash chromatography on silica gel (petroleum ether/EtOAc 90:10) afforded 10 as viscous syrup (27.5 g, 60% over 2 steps).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)=[CH:4][C:3]=1[C:29]([CH3:32])([CH3:31])[CH3:30].[OH:33]O>>[OH:1][C:2]1[C:3]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4][C:5]([S:12]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)=[O:33])=[CH:6][C:7]=1[C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: OO
Reactant: CC(C)(C)c1cc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc(C(C)(C)C)c1O

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-hydroxy-3,5di-tert. butyphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: C(OC(OCC)CCCN)C.C([N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])(OCC)=O>CC#N>[C:21]1(=[O:22])[NH:17][C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: CCOC(CCCN)OCC
Solvent: CC#N
Product: O=C1NC(=O)c2ccccc21

Procedure:
To a stirred solution of 4-aminobutyraldehyde diethyl acetal 1a (89.3 mmol) in CH3CN (100 mL) was added N-carbethoxyphthalimide (93.8 mmol). Once the reaction was complete, the acetonitrile was removed under reduced pressure and the aqueous phase extracted with EtOAc (×3). The organic phase were combined, then washed with water (×4), saturated brine (×3), then dried (Na2SO4), filtered, and evaporated under reduced pressure to give the title compound 1b, which crystallized on standing.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([Cl:14])[C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1([CH2:21][CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([C:34](=[O:38])[C:35](Cl)=[O:36])=[CH:26][CH:25]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([Cl:14])[C:8]([O:12][CH3:13])=[C:9]([NH:11][C:35](=[O:36])[C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([O:23][CH2:22][CH2:21][N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:25][CH:26]=2)=[O:38])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(N)cc(C(C)(C)C)cc1Cl
Reactant: O=C(Cl)C(=O)c1ccc(OCCN2CCOCC2)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(Cl)cc(C(C)(C)C)cc1NC(=O)C(=O)c1ccc(OCCN2CCOCC2)c2ccccc12

Procedure:
5-tert-Butyl-3-chloro-2-methoxy-phenylamine (25) (77 mg, 0.36 mmol) was dissolved in 10 mL DCM. [4-(2-Morpholin-4-yl-ethoxy)-naphthalen-1-yl]-oxo-acetyl chloride (0.54 mmol), prepared as described before, and DIEA (0.37 mL, 1.44 mmol) were added and the reaction was stirred on. The reaction mixture was evaporated and the residue was purified by LC/MS (10-100% AcN). Calculated mass=524. Observed mass=525
Reaction SMILES: C([O:4][C:5]([C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:9][N:8]=1)=O)(C)C.[NH3:18]>CO>[CH2:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([C:5]([NH2:18])=[O:4])=[N:8][CH:9]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: N
Reactant: Cc1cc(C(=O)OC(C)C)ncc1CC(C)C
Solvent: CO
Product: Cc1cc(C(N)=O)ncc1CC(C)C
Temperature: 75 °C
Reaction time: 72 h

Procedure:
A solution of 5-isobutyl-4-methyl-pyridine-2-carboxylic acid isopropyl ester (655 mg, 2.78 mmol, prepared in analogy to the corresponding ethyl ester) in 7 N NH3 in methanol (40 mL) is stirred in a sealed vial at 75° C. for 72 h. The solvent is removed in vacuo and the residue is dissolved again in 7 N NH3 in methanol. The resulting solution is again stirred at 75° C. for 24 h. The solvent is evaporated to give crude 5-isobutyl-4-methyl-pyridine-2-carboxylic amide (535 mg); LC-MS: tR=0.80 min; [M+1]+=193.01. This material is dissolved in DCM (20 mL) and pyridine (1.08 g, 11.13 mmol) is added. The mixture is stirred at rt for 5 min before trifluoroacetic acid anhydride (1.75 g, 1.18 mmol) is added dropwise. The mixture is stirred at rt for 16 h. The mixture is diluted with DCM (100 mL), washed with sat. aq. NaHCO3 solution (3×50 mL) and brine (50 mL). The org. extract is dried over Na2SO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with a gradient of EA in heptane to give 5-isobutyl-4-methyl-pyridine-2-carbonitrile (106 mg) as a pale yellow oil; LC-MS: tR=0.96 min; [M+1]+=175.03.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([CH3:19])([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([CH3:18])([CH3:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(C)(C)Cc1ccc(OC)cc1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CC(C)(C)Cc1ccc(O)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Ethyl 4-(2-bromo-4-methoxyphenyl)-3,3-dimethylbutanoate (4.5 g, 13.7 mmoles) was dissolved in methylene chloride (60 mL) and was cooled to 0° C. and 1M boron tribromide in methylene chloride (27.0 mL) was added. The mixture was stirred at 0° C. for one hour under nitrogen atmosphere. The reaction mixture was quenched with ethanol (60.0 mL) and was warmed to room temperature and was stirred at room temperature for 1 hour. The solvents were removed under reduced pressure and residue was dissolved in ethyl acetate and was washed with a saturated solution of sodium bicarbonate and water, dried (Na2SO4) and concentrated to yield 4.0 g (93%) of desired product. NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:19]([NH:22]CC=C)[CH:20]=[CH2:21].C(=O)([O-])O.[Na+]>>[CH2:19]([NH:22][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:20]=[CH2:21]
Reactant: Cc1csc2c(N3CCC(C)CC3)nc(Cl)nc12
Reactant: C=CCNCC=C
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(N2CCC(C)CC2)c2scc(C)c2n1
Yield: 43.6 %

Procedure:
In a sealed tube were heated 422 mg (1.5 mmol) of 2-chloro-7-methyl-4-(4-methylpiperidino)thieno[3,2-d]pyrimidine and 1.37 g (24.0 mmol) of diallylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/6) to give 198 mg (yield: 43.9%) of the title compound.