Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[Li].C(O[C:12](=[O:18])[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])C.O>C(OCC)C>[CH3:17][N:15]([CH2:14][CH2:13][C:12]([C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1)([C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1)[OH:18])[CH3:16]
Reactant: CCOC(=O)CCN(C)C
Reactant: ClC1=CCCCC1
Agent: [Li]
Solvent: CCOCC
Solvent: O
Product: CN(C)CCC(O)(C1=CCCCC1)C1=CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-chloro-1-cyclohexene (5.8 g; 0.049 mol) was added to lithium (1.1 g; 0.049 mol) in diethyl ether (50 ml) in a single portion. After stirring overnight at room temperature, stirring was continued for 7 more hours with reflux. After cooling, ethyl-3-(N,N-dimethylamino)propionate (3.0 g; 0.021 mol) was added and as a result of the exothermic reaction refluxing occurred. After cooling to room temperature and stirring for another 30 minutes 100 ml of water was added. The water layer was separated off and extracted with diethyl ether. The combined ether layer was dried (K2CO3), filtered and evaporated. The yield was 4.5 g (83%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH3:19])[CH:13]=[C:12]2[N:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21]1)C1C=CC=CC=1>[Pd].C(O)C>[CH3:19][C:14]1[CH:13]=[C:12]([N:20]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21]2)[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[N:15]=1
Reactant: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(OCc3ccccc3)ccc2n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(O)ccc2n1

Procedure:
6-Benzyloxy-2-methyl-4-(3-phenylpyrrolidin-1-yl)quinoline (0.3 g; see Example 2 above) and palladium on carbon (10%; 0.2 g) in ethanol (8 mL) was stirred under hydrogen for 3 hours. The mixture was filtered and then concentrated to give the title compound as a yellow oil, which was used without further purification.
Reaction SMILES: C([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:26])[NH:15][C:16]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[C:18]([Br:25])[CH:17]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[N:27]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=2)[N:32]([C:41]([NH2:43])=[O:42])[CH:31]=1)=C=O>O1CCOCC1>[Br:25][C:18]1[CH:19]=[C:20]([CH:21]=[C:16]([NH:15][C:14]([C@@H:13]2[CH2:12][C@@H:11]3[C@@H:9]([CH2:10]3)[N:8]2[C:6](=[O:5])[NH:27][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=3)[N:32]([C:41](=[O:42])[NH2:43])[CH:31]=2)=[O:26])[CH:17]=1)[C:22]([OH:24])=[O:23]
Reactant: COc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cc(Br)cc(C(=O)O)c1
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(NC(=O)N1[C@@H]3C[C@@H]3C[C@H]1C(=O)Nc1cc(Br)cc(C(=O)O)c1)cn2C(N)=O

Procedure:
The title compound (White solid) was prepared according to the general procedure described in Scheme D5 (Steps B and C) using (1R,3S,5R)-3-(3-bromo-5-carboxy-phenylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester) (prepared by using similar protocols as described in Scheme B7, except that the reaction mixture was heated at 65° C. in step A and dioxane was used instead of MeOH in step B) and 3-Isocyanato-5-methoxy-indole-1-carboxylic acid amide (prepared as described in Scheme A1). MS (LC/MS): 556.0 [M+H]+; tR (HPLC conditions c): 4.32 min.
Reaction SMILES: Cl.[C:2]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].C1CCN2C(=NCCC2)CC1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH:36][C:37](=O)[O:38]CC)=[N:28]1>CS(C)=O>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH:36][C:37]([N:7]2[CH2:6][CH2:5][C:4]([C:2]#[N:3])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)=[O:38])=[N:28]1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: CCOC(=O)Nc1n[nH]c2ccccc12
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: N#CC1(c2ccccc2)CCN(C(=O)Nc2n[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
4-Cyano-4-phenylpiperidine hydrochloride (Aldrich Co., 217 mg) was dissolved in dimethyl sulfoxide (3 ml) and DBU (0.16 ml) was added thereto. The mixture was stirred at room temperature for 30 min, and ethyl 1H-indazol-3-ylcarbamate (200 mg) and potassium fluoride-alumina (40 wt %, 200 mg) were added to the mixture. By the following operation as in Example 1, 4-cyano-4-phenyl-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide (253 mg, yield 75%) was obtained.
Reaction SMILES: [OH-].[Na+].[Si:3]([O:10][CH2:11][C:12]1[N:16]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:19])[C:15]([C:27]([O:29]C)=[O:28])=[CH:14][CH:13]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>O1CCOCC1>[C:6]([Si:3]([CH3:5])([CH3:4])[O:10][CH2:11][C:12]1[N:16]([CH2:17][C:18]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[O:19])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][CH:13]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)n1CC(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)O)n1CC(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Aqueous sodium hydroxide solution (1 M, 1.78 mL) was added to a solution of methyl 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (375 mg, 0.89 mmol) in 1,4-dioxane (10 mL) and stirred at 70° C. for 2 h. The resultant brown solution was cooled to room temperature and concentrated in vacuo to −50% of its starting volume. The reaction mixture was acidified to ˜pH 4 by the addition of aqueous HCl (1 M, 1.78 mL) and extracted with EtOAc. The aqueous layer was further extracted with EtOAc (2×10 mL) The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 5-({[tert-butyl (dimethyl)silyl]oxy}methyl)-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid as a brown gum (70% purity, 270 mg, yield ˜95%) The mixture was used without further purification. ESI-MI m/z [M+Na]+ 432.0.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:10]=[C:9]([CH3:21])[N:8]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([CH3:21])[N:8]=[C:7]([C:5]3[S:6][C:2]([N:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:23]4[NH2:22])=[CH:3][CH:4]=3)[CH:12]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Br)s2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(N3C=CC=CC3N)s2)n1

Procedure:
The title compound was prepared from 2-(5-bromo-thiophen-2-yl)-4-(3,4-dichloro-phenyl)-6-methyl-pyridine (example E.87) (0.25 g, 0.626 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.152 g, 0.689 mmol) according to the general procedure VI. Obtained as a light brown solid (0.055 g, 21%). MS (ISP) 412.1 [(M+H)+], 414.2 [(M+2+H)+] and 416.2 [(M+4+H)+]; mp 180° C.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])=[O:25])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:7].[OH-].[Na+]>C(O)C>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6](=[S:7])[NH:5][C@H:4]([C:3]([OH:34])=[O:2])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]([C:26]2[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=2[Cl:32])=[O:25])=[CH:21][CH:22]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=S)c1c(C)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cl)c1C(=S)N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O
Temperature: 52.5 °C
Reaction time: 3.5 h
Yield: 96.1 %

Procedure:
To a suspension of N-[(2-chloro-6-methylphenyl)thioxomethyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (2.89 mmol, 1.55 g) in ethanol (8 mL) was added aqueous 1.0N sodium hydroxide (5 mL) at room temperature. The mixture was heated to 50-55° C. and the resulting clear solution was stirred for 3-4 h. TLC analysis of the mixture indicated the absence of starting material. The mixture was concentrated to remove ethanol, then was diluted with 15 mL of water and extracted with 25 mL of diethyl ether to remove any neutral impurities. The aqueous layer was acidified with 1N HCl and the precipitated colorless solid was extracted into ethyl acetate (2×30 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to afford 1.45 g (96%) of N-[(2-chloro-6-methylphenyl)thioxomethyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine as an amorphous colorless solid. HRMS: Obs. mass, 521.0241. Calcd. mass, 521.0260 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1>CCOCC>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:42]1[CH:43]=[CH:44][C:45]([C:46]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:47])=[CH:49][CH:50]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Reactant: C1CCNCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(c1ccc(NCCCCCCCCCCCCCCCCBr)cc1)N1CCCCC1
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamine and 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.3 g. of 4-(16-bromohexadecylamino)benzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with 100 ml. portions of water and dried over magnesium sulfate. The solvent is removed in vacuo and the solid is recrystallized in 50 ml. of diethyl ether to yield the product.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH:31]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:32][CH2:33][NH:34]C(OC(C)(C)C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.Cl>ClCCl>[NH2:34][CH2:33][CH2:32][CH:31]([NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][CH:27]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)NCCC(Nc1cccc(-c2nn(COCC[Si](C)(C)C)c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC(Nc1cccc(-c2n[nH]c3nc(NC4CCC(N)CC4)ncc23)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of {4-[3-[6-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyridin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (71 mg, 0.09 mmol) in dichloromethane (2 mL) was added CF3COOH (2.2 mL). This mixture was stirred at room temperature for 4 hours. The solvent was then removed under reduced pressure. A saturated aqueous solution of NaHCO3 was added to the residue, and then extracted with ethyl acetate (3×15 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to give product which was treated with conc. HCl acid to give N-{3-[6-(3-amino-1-phenyl-propylamino)-pyridin-2-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine; hydrochloride as a yellow solid. (Yield 22 mg, 53.3%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>>[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[C:3]=2[F:9])[CH2:13][CH2:12]1
Reactant: Nc1cccc(Cl)c1F
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCC(Nc2cccc(Cl)c2F)CC1
Yield: 32.1 %

Procedure:
Combine 3-chloro-2-fluoroaniline (4.37 g, 30 mmol), 1-methylpiperidin-4-one (3.39 g, 30 mmol), sodium triacetoxyborohydride (5.26 g, 33 mmol), and acetic acid (5.4 g, 90 mmol) and stir at room temperature overnight. Partition the reaction mixture between dichloromethane and saturated aqueous NaCl containing NH4OH, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel columnn (110 g), using a gradient of dichloromethane-2M NH3 in methanol to give 2.34 g of the title compound (32% yield): mass spectrum (ion spray): m/z=243 (M+1); 1H NMR (CDCl3): 6.88 (ddd,1H), 6.63 (ddd, 1H), 6.56 (dd, 1H), 3.85 (br d, 1H), 3.28 (m, 1H), 2.80 (m, 2H), 2.30 (s, 3H), 2.13 (m, 2H), 2.04 (m, 1H), 1.53 (m, 2H). (file: mn4-b6k-284-2)
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([F:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(O)C.[C].[Pd]>[F:12][C:5]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:2][NH:3][C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1c(Cl)[nH]c(-c2ccccc2)c1F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.3 %

Procedure:
To a solution (30 mL) of ethyl 2-chloro-4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (300 mg) in ethanol was added 10% palladium carbon (50% water-containing product, 0.3 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless oil (yield 100 mg, 38%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH2:14][CH2:15][CH:16]2[O:20][CH2:19][CH2:18][O:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:24]([O:23][C:21]([C:11]1([CH2:14][CH2:15][CH:16]2[O:17][CH2:18][CH2:19][O:20]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C1(CCC2OCCO2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(CCC2OCCO2)CCNCC1

Procedure:
To a solution of 4-ethoxycarbonyl-4-[2-(1,3-dioxolan-2-yl)ethyl]piperidine-1-carboxylic acid tert-butyl ester (450 mg) in chloroform (2 ml) was added trifluoroacetic acid (2 ml), and the mixture was stirred for several minutes. After completion of the reaction, the solvent was evaporated and to the obtained residue was added aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give 4-[2-(1,3-dioxolan-2-yl)ethyl]piperidine-4-carboxylic acid ethyl ester. Then, in the same manner as in Example 10, Step 1, the title compound (460 mg) was obtained from sodium hydrogencarbonate (127 mg) and benzyloxycarbonyl chloride (0.22 ml).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:16])[O:14][CH3:15])=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18].C(O)(C(F)(F)F)=O>O>[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:16])[O:14][CH3:15])=[CH:8][C:7]=1[N+:17]([O-:19])=[O:18])=[O:1]
Reactant: COC(=O)Nc1ccc(C2OCCO2)c([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)Nc1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
5C (5.00 g, 18.64 mmol) was added to a solution of TFA (27 mL) and H2O (3 mL) and stirred at rt for 3 h. After 3 h, the reaction mixture was concentrated and the residue was partitioned between H2O and EtOAc. The organic layer was then washed with saturated sodium bicarbonate solution followed by brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated to give a light yellow solid as 5D (3.83 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 10.09 (s, 1H), 8.23 (d, J=1.6 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.86-7.81 (m, 1H), 3.74 (s, 3H) ppm.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH:15]([Br:16])[CH2:14][CH2:13][C:12]3[N:11]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:10]=[CH:9][C:8]2=3)[O:4]1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([CH2:2][CH:3]2[CH2:7][O:6][C:5]3([CH:15]([Br:16])[CH2:14][CH2:13][C:12]4[N:11]([S:17]([C:20]5[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=5)(=[O:18])=[O:19])[CH:10]=[CH:9][C:8]3=4)[O:4]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CBr)O2)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CN3CCCCC3)O2)cc1
Yield: 75 %

Procedure:
Heating of 4'-bromomethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane with piperidine at 80° C. for 3 hours affords 4'-piperidinomethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane in 75% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-])=O>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=1[NH2:13]
Reactant: COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of 4-methoxy-3-nitrobenzotrifluoride and 10% of 10% Pd/C in methanol was stirred under H2 atmosphere overnight at room temperature. The reaction mixture was filtered through celite, concentrated and dried under vacuum to provide product as an off white solid in 99% yield. ES/MS m/z 192.1 (MH+).
Reaction SMILES: F[C:2]1[C:7]2[C:8](=[O:17])[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[C:15](=[O:16])[C:6]=2[C:5](F)=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[NH2:21][CH2:20][CH2:19][NH:22][C:2]1[C:7]2[C:8](=[O:17])[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[C:15](=[O:16])[C:6]=2[C:5]([NH:21][CH2:20][CH2:19][NH2:22])=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: O=C1c2ccncc2C(=O)c2c(F)ccc(F)c21
Product: NCCNc1ccc(NCCN)c2c1C(=O)c1ccncc1C2=O

Procedure:
The reported synthetic procedures use, as a key intermediate, 6,9-difluorobenzo[g]isoquinoline-5,10-dione.- This compound is reacted with ethylene-diamine which produces the desired 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:52](Cl)(=[O:54])=[O:53])[CH:47]=[CH:48][C:49]=1[O:50][CH3:51]>C(#N)C>[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:52]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:53])=[O:54])[CH:47]=[CH:48][C:49]=1[O:50][CH3:51]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1OC
Yield: 46.1 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0315 g, 0.0682 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0570 mL, 0.409 mmol) and 3,4-dimethoxybenzenesulfonyl chloride (0.0480 g, 0.205 mmol) to obtain 4-(3,4-dimethoxybenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0208 g, yield 46%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21]CC)=[O:20])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:4].[OH-].[Na+].O>C1COCC1>[F:24][C:2]([F:1])([F:25])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: CCOC(=O)c1cccc(-c2cccc(NS(=O)(=O)C(F)(F)F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cccc(NS(=O)(=O)C(F)(F)F)c2)c1
Temperature: 50 °C
Reaction time: 20 h
Yield: 65.2 %

Procedure:
3′-Trifluoromethylsulfonamido-[1,1′-biphenyl]-3-carboxylic acid, ethyl ester (150 mg, 0.40 mmol, 1 eq.) and 1.000 N NaOH (0.80 mL, 0.80 mmol, 2 eq.) were dissolved in THF (5 mL) at room temperature and stirred for 20 hours. Little reaction. Added 100 mg of NaOH and heated at 50° C. for 20 hours. Worked up by adding water then rinsing 2 times with diethyl ether. The aqueous layer's pH was adjusted to 3 with 1N HCl. The acidic aqueous layer was extracted 3 times with ethyl acetate. The ethyl acetate layers were combined, dried over sodium sulfate and stripped to give 3′-trifluoromethylsulfonamido-[1,1′-biphenyl]-3-carboxylic acid (90 mg) of an amber solid. Yield=65%. Mass Spec (ESI) detects (M+H)+=344.0.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH3:19][C:18]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=1)=[O:20]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 99.5 %

Procedure:
4-Trifluoromethylaniline (3.00 g, 18.6 mmol) was dissolved in pyridine (1.62 g, 20.5 mmol), the solution was added with acetic anhydride (2.38 g, 23.3 mmol) with stirring on an ice bath, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and then azeotroped with toluene, and the resulting residue was suspended in hexane, and taken by filtration. The residue was washed with hexane, and then dried under reduced pressure to obtain 4-trifluoromethylacetanilide (3.76 g, 99%) as colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:11][C:10]3([CH2:14][NH:13][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[O:15]1[CH2:18][C:17](=O)[CH2:16]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(O)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][C:10]3([CH2:14][N:13]([CH:17]4[CH2:18][O:15][CH2:16]4)[CH2:12]3)[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(N2CC3(CNC3)C2)cc1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Ic1ccc(N2CC3(C2)CN(C2COC2)C3)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
2-(4-Iodophenyl)-2,6-diazaspiro[3.3]heptane (1.01 g, 3.4 mmol), and 3-oxetanone (0.29 g, 4.0 mmol) was dissolved in DCE (15 mL) and heated to 50° C. for 10 min. Acetic acid (5 drops) and NaBH(OAc)3 (1.07 g, 5.1 mmol) was added and the reaction was stirred for 16 h at 50° C. The mixture was concentrated under reduced pressure and suspended in NaHCO3 (50 mL) and extracted with EtOAc (2×40 mL) and washed with brine. The EtOAc layer was dried (MgSO4), and concentrated to dryness to give the title compound as a white solid (1.15 g, 96%). MS ESI 357.0 [M+H]+, calcd for [C14H17IN2O+H]+357.0.