Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[Br:11][C:12]1[C:13](=O)[CH2:14][CH2:15][CH2:16][C:17]=1[O:18]CC>C1COCC1.C(Br)Br>[Br:11][C:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]=1[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10]
Reactant: COCCCCCl
Reactant: CCOC1=C(Br)C(=O)CCC1
Agent: II
Agent: [Mg]
Solvent: BrCBr
Solvent: C1CCOC1
Product: COCCCCC1=C(Br)C(=O)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To magnesium turnings (9.84 g, 405 mmol) in dry THF (42 mL) as a solvent were added a few crystals of iodine and a few drops of CH2Br2. A solution of 1-chloro-4-methoxybutane (46.8 g, 382 mmol) in dry THF (90 mL) was added dropwise at a rate sufficient to maintain gentle reflux. The reaction mixture was then refluxed for 1 hour and then cooled to room temperature. The resulting Grignard reagent was then added dropwise to a suspension of CeCl3 (94.2 g, 382 mmol) in dry THF (750 mL) at 0° C. After stirring at room temperature for 2 hours, a solution of 2-bromo-3-ethoxy-cyclohex-2-enone (1) (60 g, 274 mmol) in dry THF (300 mL) was added dropwise at 0° C. The reaction mixture was stirred an additional 2 hours at room temperature and then quenched by adding a saturated NH4Cl solution (1000 mL). The mixture was further acidified to approximately pH 1 by the addition. of a 5% HCl solution and stirring was continued for an additional 2 hours. The organic layer was separated, the aqueous layer extracted with Et2O and the combined organic layers were dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue purified over silica (using a isooctane/EtOAc 7:3 mixture as an eluent) to afford 65.5 g (92% yield) of the desired product as a light-yellow oil which was characterized as follows:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=2)[O:2]1.[N+:13]([O-])([OH:15])=[O:14]>>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=2)[O:9]1
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Product: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: -5 °C

Procedure:
0.103 mol (17.2g) of 4,5-methylenedioxy-1-nitrobenzene is added in small portions in the course of 15 minutes to a mixture, cooled to -5° C., consisting of 125 ml of nitric acid (d=1.50) and 125 ml of nitric acid (d=1.40), tne temperature being maintained at between 0° C. and 5° C. 1 hour after the addition is complete, the reaction mixture is poured onto 1 kg of ice; the expected product pre,ipitates. After being dried hot in the presence of phosphorus pentoxide, it melts at 99° C. (literature 98° C. -100° C.). It can optionally be recrystallized from 96° strength ethanol.
Reaction SMILES: [CH:1]([S:4]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=1)=[O:5])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO>[CH:1]([S:4]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(S(=O)C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)S(=O)c1ccc(C(=O)O)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of ethyl 4-isopropylsulfinylbenzoate (245 mg, 1.02 mmol) in EtOH (1 mL) at room temperature was added NaOH (300 μL of 5.0 M, 1.50 mmol) dropwise and the mixture stirred for 30 min. The pH of the mixture was adjusted to 2 with 1N HCl before it was evaporated to dryness. The solids were taken up in water, filtered, washed with water (2×), and desiccated to give 4-isopropylsulfinylbenzoic acid (80%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.30 (s, 1H), 8.11 (d, J=8.2 Hz, 2H), 7.73 (d, J=8.2 Hz, 2H), 3.07-2.97 (m, 1H), 1.22 (d, J=6.9 Hz, 3H), 0.90 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:25])=[C:11]([CH:22]=[CH:23][CH:24]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH2:1]([O:8][C:9]1[C:10]([F:25])=[C:11]([CH:22]=[CH:23][CH:24]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cccc(OCc2ccccc2)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(OCc2ccccc2)c1F
Yield: 93.4 %

Procedure:
To a solution of benzyl 3-benzyloxy-2-fluorobenzoate (7.13 g, 21 mmol) in methanol (40 ml) was added an aqueous solution of potassium hydroxide (2.38 g, 42 mmol in 40 ml of water) and the mixture heated at reflux for 30 min. The reaction mixture was cooled, washed with diethyl ether (20 ml) and the ethereal layer was discarded. The aqueous layer was acidified to pH 2 with concentrated HCl and extracted with ethyl acetate (3×40 ml). The combined organic extracts were washed with brine (20 ml), dried (MgSO4) and evaporated to afford title compound (4.83 g, 85%) as white solids.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.O1CCOCC1.[CH3:18][C:19]1([CH3:26])[C:23]([CH3:25])([CH3:24])[O:22][BH:21][O:20]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:18][C:19]1([CH3:26])[C:23]([CH3:25])([CH3:24])[O:22][B:21]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=2)[O:20]1
Reactant: CC1(C)OBOC1(C)C
Reactant: CC(C)Oc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 47 %

Procedure:
1-Bromo-4-isopropoxybenzene was combined with dioxane (10.5 mL) and dichloropalladium(dppf) dichloromethane complex (36 mg) under argon. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (0.96 mL) was added followed by triethylamine (1.29 mL). The reaction was heated to 90° C. for 23 hours after which, dichloropalladium(dppf) dichloromethane complex (36 mg), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.96 mL) and triethylamine (1.29 mL) was added. Heating was continued for an additional 19 hours after which, it was cooled to room temperature and diluted with ethyl acetate (25 mL). The mixture was washed with water (2×20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue on silica gel (0% to 50% ethyl acetate/hexane over 40 minutes) gave 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isopropoxybenzene (544 mg). Yield=47%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C(OCC)(=O)C>[CH2:16]([O:15][C:13]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(CCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(CCO)cc1)OCc1ccccc1
Temperature: 25 °C
Yield: 65 %

Procedure:
4-Aminophenethyl alcohol (3.5 g) was dissolved in ethyl acetate (60 ml), to which was added 1N sodium hydroxide (50 ml). To the mixture was added, while stirring at room temperature, carbobenzoxy chloride (4.5 g). The mixture was stirred for 30 minutes. The organic layer was then separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 4-benzyloxycarbonylaminophenethyl alcohol (4.5 g) as a liver brown crystalline product (4.5 g),
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].C(N(CC)CC)C.C(=O)(O)[O-]>C1COCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCBr
Reactant: c1ccc(COc2ccc(CN3CCCNCC3)cc2)cc1
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCN1CCCN(Cc2ccc(OCc3ccccc3)cc2)CC1
Yield: 51.7 %

Procedure:
A solution of hexahydro-1-[[4-(phenylmethoxy)phenyl]methyl]-1H-1,4-diazepine (150 mg, 0.506 mmol) and methyl 3-bromopropanoate (0.22 mL, 2.0 mmol) in THF (6 mL) was treated with triethylamine (0.28 mL, 2 mmol) and the reaction was heated at reflux for 4 hours. The reaction was allowed to cool and treated with an aqueous bicarbonate solution. The combined ethyl acetate extracts were washed with water, dried and concentrated to give 0.1 g of methyl hexahydro-4-[[4-(phenylmethoxy)phenyl]methyl]-1H-1,4-diazepine-1-propanoate; 1H NMR (300 MHz, CDCl3) δ 7.44 (d, 2H), 7.39 (dd, 2H), 7.32 (dd, 1H), 7.24 (d, 2H), 6.93 (d, 2H), 5.05 (s, 2H), 3.67 (s, 3H), 3.56 (s, 2H), 2.85 (t, 2H), 2.48 (t, 2H), 2.77-2.58 (m, 8H), 1.77 (m, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:17]=[C:16]([O:18][CH3:19])[C:12]([C:13]([O-])=[O:14])=[C:11]([CH:20]=[CH2:21])[N:10]=1.[CH:22]([C:25]1[CH:26]=[CH:27][C:28]([CH3:32])=[C:29]([CH:31]=1)[NH2:30])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:17]=[C:16]([O:18][CH3:19])[C:12]2[C:13](=[O:14])[N:30]([C:29]3[CH:31]=[C:25]([CH:22]([CH3:23])[CH3:24])[CH:26]=[CH:27][C:28]=3[CH3:32])[CH2:21][CH2:20][C:11]=2[N:10]=1
Reactant: C=Cc1nc(-c2c(C)cccc2C)cc(OC)c1C(=O)[O-]
Reactant: Cc1ccc(C(C)C)cc1N
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(-c2c(C)cccc2C)nc2c1C(=O)N(c1cc(C(C)C)ccc1C)CC2
Reaction time: 12 h

Procedure:
A solution of 6-(2,6-dimethylphenyl)-4-methoxy-2-vinylnicotinate (1.77 g, 5.95 mmol) and 5-isopropyl-2-methylaniline (4.44 g, 29.8 mmol) in toluene (26.5 mL) and acetic acid (13.2 mL) was heated to 110° C. and stirred at that temperature. After 12 h, the reaction mixture was removed from the heat and concentrated on the rotovap to remove the bulk of the solvent. The residue was partitioned between EtOAc and aqueous 1 N sodium hydroxide solution with added brine. The layers were separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and concentrated. The residue was purified by FCC (0-15% EtOAc/DCM) to provide 2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-methoxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one. The product contained some 5-isopropyl-2-methylaniline and was used in the next step without further purification. MS (ESI+) m/z 415.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[H-].[Na+].[CH2:16]([CH2:26]S([O-])(=O)=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=C.O>CS(C)=O>[CH2:24]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:26]
Reactant: C=CCCCCCCCCCS(=O)(=O)[O-]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
Theobromine (3.45 g, 19.2 mmol) was added to a suspension (30 ml) of sodium hydride (461 mg, 19.2 mmol) in dimethylsulfoxide. After 15 minutes, the 9-decenylmesylate (2.25 g, 11 mmol) was added and the reaction stirred for 18 hours at 25° C., then for 40 minutes at 100° C. The mixture was then poured into water (100 ml) and extracted with three 50 ml aliquots of dichloromethane. The combined organic portions were washed with saturated salt solution (60 ml) and dried over magnesium sulfate. Evaporating the solvent under vacuum left a white solid residue. Recrystallization of the residue in ether produced 3.40 g of 1-(9-decenyl)-3,7-dimethylxanthine (56% yield). 1-(9-Decenyl)-3,7-dimethylxanthine (3.2 g, 10.1 mmol), 4-methylmorpholine-N-oxide (1.41 g, 12 mmol), 3 drops of 2.5% osmium tetroxide solution in t-butanol, acetone (40 ml) and water (10 ml) were stirred for 24 hours. Following addition of 5 ml of a saturated solution of sodium dithionite and a further 15 minutes of stirring, the reaction mixture was extracted with four 50 ml aliquots of 25% ethanol/dichloromethane. The combined organic portions were dried over sodium sulfate. Evaporating the solvents left a white solid residue, which upon recrystallization in ethanol produced 3.3 g of 1-(9,10-dihydroxydecyl)-3,7-dimethylxanthine (93% yield). 1-(9,10-Dihydroxydecyl)-3,7-dimethylxanthine (2.11 g, 6 mmol), prepared above, was stirred with hydrogen bromide (3.58 ml, 4.85 g of a 30% solution in acetic acid, 18 mmol) for 90 minutes. The mixture was then added to a flask containing 40 ml aqueous sodium bicarbonate solution (5 g) and 50 ml dichloromethane. After 10 minutes of vigorous stirring the layers were separated and the aqueous portion washed with two 50 ml aliquots of dichloromethane. The organic portions were combined, dried over sodium sulfate, and evaporating the solvent produced 2.72 g of a yellow oil, inventive compound no. 1583 (100% yield).
Reaction SMILES: C[C:2]1(C)[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:13])[C@H:5]2[N:10]=[N+:11]=[N-:12].CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[N:10]([C@H:5]1[C@H:6]([CH2:7][C:8]([O:9][CH3:2])=[O:17])[NH:3][C:4]1=[O:13])=[N+:11]=[N-:12]
Reactant: CC1(C)OCC[C@@H]2[C@H](N=[N+]=[N-])C(=O)N21
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: COC(=O)C[C@@H]1NC(=O)[C@H]1N=[N+]=[N-]

Procedure:
In 30 ml of acetone is dissolved 330 mg of trans-2,2-dimethyl-7-azido-1-aza-3-oxabicyclo[4.2.0]octan-8-one and under ice-cooling and stirring, 3.3 ml (8N solution) of Jones reagent is added. The mixture is stirred for 2.5 hours, after which 5 ml of isopropyl alcohol is added and the mixture is further stirred for 10 minutes. The insolubles are filtered off with the aid of Celite and the filtrate is concentrated under reduced pressure. The residue is shaken with tetrahydrofuran and a small amount of saturated aqueous sodium chloride. The tetrahydrofuran layer is taken and extracted three times with tetrahydrofuran. The tetrahydrofuran layers are combined, dried over anhydrous sodium sulfate and, after addition of a solution of diazomethane in ether, the mixture is allowed to stand. The solvent is then distilled off and the residue is shaken with water and ethyl acetate. The ethyl acetate layer is taken, washed with aqueous sodium hydrogen carbonate and water in this order and dried over anhydrous sodium sulfate. It is concentrated under reduced pressure and the residue is purified by silica gel column chromatography to give trans-3-azido-4-methoxycarbonylmethyl-2-oxoazetidine.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[C:3]1=[O:13].CN(C=O)C.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][C:4]1[C:3](=[O:13])[N:2]([CH3:1])[C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: O=S(Cl)Cl
Reactant: Cn1c(=O)c(=O)[nH]c2ccccc21
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(Cl)nc2ccccc21

Procedure:
A mixture of 56.1 g. (0.32 m.) of 1,4-dihydro-1-methylquinoxalin-2,3-dione, 10 ml. of DMF, 50 ml. (0.67 m.) of thionyl chloride and 1 l. of toluene was refluxed for 1 hour, cooled, and stripped, finally under high vacuum to a crude dark solid, m.p. 124°-130° C. of sufficient purity to use in the next step.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].[N+:11]([O-])([O-:13])=[O:12].[K+].[OH-].[Na+]>OS(O)(=O)=O>[CH:1]([C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1N
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: CC(C)c1ccc([N+](=O)[O-])cc1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
2-Isopropylaniline (13.5 g, 99.85 mmol) was added portionwise to conc. H2SO4 (100 mL) to generate a yellow homogeneous solution. The solution was then cooled to 0° C. and KNO3 (15.2 g, 150.3 mmol) was added portionwise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured on ice water, then basified with 10% NaOH solution. The aqueous layer was extracted with EtOAc, dried over MgSO4, filtered and concentrated to obtain 2-isopropyl-5-nitroaniline (14.9 g, 83%). 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J=8.4, 2.2 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.27-7.21 (m, 1H), 3.96 (s, 2H), 2.98-2.79 (m, 1H), 1.29 (d, J=6.8 Hz, 6H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:15]2)[C:11]([NH2:23])=[CH:10][C:9]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH3:40])[CH:32]=2)[CH:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([NH:24][C:25]2[N:30]=[C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH3:40])[CH:32]=3)[CH:28]=[CH:27][N:26]=2)=[CH:10][C:11]([NH:23][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([N:14]2[CH2:17][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:15]2)[CH:13]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CC2(CCCN2C)C1
Reaction time: 1 h
Yield: 27.4 %

Procedure:
A solution of acryloyl chloride (24 μL, 0.30 mmol) in CH2Cl2 (1 mL) was added dropwise to 4-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 146, 140 mg, 0.30 mmol) and DIPEA (57 μL, 0.33 mmol) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 1 h and was then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (43 mg, 28%) as a beige solid after trituration with CH3CN; 1H NMR: 1.63-1.76 (2H, m), 2.00-2.10 (2H, m), 2.38 (3H, s), 2.63 (2H, t), 3.64 (2H, d), 3.86 (3H, s), 3.89 (3H, s), 3.93 (2H, d), 5.70 (1H, dd), 6.21 (1H, dd), 6.26 (1H, s), 6.50 (1H, dd), 7.13 (1H, d), 7.16-7.29 (2H, m), 7.51 (1H, d), 7.73 (1H, s), 7.93 (1H, s), 8.26 (1H, d), 8.31-8.39 (2H, m), 9.24 (1H, s); m/z: ES+ MH+ 524.7.
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21]CC)=[O:20])=[CH:11][N:12]3CCC#N)=[CH:7][C:6]=2[Br:25])[CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([OH:21])=[O:20])=[CH:11][NH:12]3)=[CH:7][C:6]=2[Br:25])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(Br)cc2c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2nc(N3CCC3)c(Br)cc2c1=O
Reaction time: 3 h

Procedure:
A suspension of EXAMPLE 82A (0.50 g) in methanol (100 mL) at reflux was treated with 1M LiOH (50 mL), stirred for 3 hours then cooled, treated with 10% citric acid, and filtered to provide the desired product. NMR (300 MHz, DMSO-d6) δ 17.21 (s, 1H), 8.68 (s, 1H), 8.32 (s, 1H), 4.29 (m, 4H), 2.26 (m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[OH:27][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:12]=[CH:13][N:14]=2)=[C:2]([CH:7]=1)[O:27][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1
Reactant: N#Cc1ccc(CO)cc1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3ccc(C#N)cc3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 4-hydroxymethyl-benzonitrile (107 mg; 0.789 mmol), example 90 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:20][C:19]3[C:18]([O:21][CH2:22][CH3:23])=[C:17]4[CH:24]=[CH:25][CH:26]=[CH:27][C:16]4=[C:15]([O:28][CH2:29][CH3:30])[C:14]=3[CH2:13]2)=[CH:8][CH:7]=1)C.[OH-].[Li+]>O1CCCC1.O>[CH2:22]([O:21][C:18]1[C:19]2[CH2:20][N:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:31])=[O:3])=[CH:11][CH:10]=3)[CH2:13][C:14]=2[C:15]([O:28][CH2:29][CH3:30])=[C:16]2[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=12)[CH3:23]
Reactant: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c2c(c(OCC)c3ccccc13)CN(c1ccc(CC(=O)O)cc1)C2
Yield: 42.6 %

Procedure:
A solution of ethyl[4-(4,9-diethoxy-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate (10 mg, 0.024 mmol) in tetrahydrofuran (4 ml) and a solution of lithium hydroxide (6 mg, 0.24 mmol) in water (1 ml) were stirred vigorously for 14 h. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (2×5 ml) and the organic extracts discarded. The aqueous phase was acidified with 2N hydrochloric acid to pH=5 and extracted with ethyl acetate (3×5 ml). The combined organic extracts were dried over magnesium sulphate and the solvent removed in vacuo to give the product as a red solid (4 mg, 43%).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:26]=[CH:25][C:10]([C:11]([O:13][CH2:14][C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3]>CCOC(C)=O.C(Cl)Cl.CO.[Pd]>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:26]=[CH:25][C:10]([C:11]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)NCc1ccc(C(=O)OCC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NCc1ccc(C(=O)OCC(=O)O)cc1
Reaction time: 4 h
Yield: 98.5 %

Procedure:
A mixture of 2-(benzyloxy)-2-oxoethyl 4-(methylsulfonamidomethyl)-benzoate (0.4 g, 1.060 mmol) and 10% w/w Pd/C (0.056 g, 0.053 mmol) in EtOAc and MeOH 1/1 (30 ml) was shaken under H2 atmosphere (25 psi) for 4 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness affording 2-(4-(methyl-sulfonamidomethyl)benzoyloxy)acetic acid (0.3 g, 1.044 mmol, 99% yield). The product was used without purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH:13]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][N:8]=1.CON(C)[C:29](=[O:31])[CH3:30].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.C1COCC1>[Si:19]([O:18][CH:13]([C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:29](=[O:31])[CH3:30])[CH:12]=1)[C:14]([F:17])([F:16])[F:15])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CON(C)C(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC(c1ccnc(Br)c1)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)ccn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To toluene (9 mL) were added dropwise at −78° C. n-butyllithium (2.66 mol/L solution in n-hexane, 1.12 mL, 2.97 mmol) and a solution of 2-bromo-4-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)pyridine (1.00 g, 2.70 mmol) obtained in Step 2 in toluene (3.0 mL), and the mixture was stirred at the same temperature for 30 minutes. THF (3.0 mL) was added to the resulting solution and the mixture was stirred at −78° C. for 30 minutes. N-methoxy-N-methylacetamide (1.38 mL, 13.5 mmol) was added and the mixture was stirred for 2 hours allowing the temperature to rise slowly to room temperature. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 1-(4-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)pyridin-2-yl)ethanone (645 mg, 72% yield).