Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH2:20]([O:19][C:15]1[CH:14]=[C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:17][CH:16]=1)[CH3:21]
Reactant: C1CNCCN1
Reactant: CCOc1cccc(-n2c(Cl)c(C=O)c3ccccc32)c1
Product: CCOc1cccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)c1
Yield: 37 %

Procedure:
2-Chloro-1-(3-ethoxyphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(3-ethoxyphenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (37% yield) as a light yellow solid. ESI/MS 350 (M+H); RT=2.69 min; NMR (CDCl3) 10.26 (1H, s); 8.26 (1H, d, J=6 Hz); 7.28 (3H, m); 7.21 (3H, m); 6.95 (1H, d, J=9 Hz); 4.15 (2H, q); 3.29 (4H, m); 2.79 (4H, m); 1.49 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O1CCCC1>>[CH:16]1([CH:14]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[O:12][C:11]=2[CH3:13])[OH:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1oc(-c2ccc(F)cc2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(F)cc2)cc1C(O)C1CCCCC1
Yield: 83 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 5-(4-fluorophenyl)-2-methyl-3-furaldehyde (2.0 g) and 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (15 mL) to give the title compound (2.4 g, 83%) as a white crystal.
Reaction SMILES: [Br:1][CH:2]1[CH2:23][CH2:22][C:5]2=[CH:6][C:7]3[C:8]4[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:4]2[C:3]1=[O:24].[CH3:25][O:26][C:27]([NH:29][C@@H:30]([C@@H:42]([CH3:45])[CH2:43][CH3:44])[C:31]([N:33]1[C@@H:37]([CH3:38])[CH2:36][CH2:35][C@H:34]1[C:39]([OH:41])=[O:40])=[O:32])=[O:28].C([O-])([O-])=O.[K+].[K+]>ClCCl>[CH3:25][O:26][C:27]([NH:29][C@@H:30]([C@@H:42]([CH3:45])[CH2:43][CH3:44])[C:31]([N:33]1[C@@H:37]([CH3:38])[CH2:36][CH2:35][C@H:34]1[C:39]([O:41][CH2:19][C:18]([C:15]1[CH:16]=[CH:17][C:8]2[C:7]3[CH:6]=[C:5]4[CH2:22][CH2:23][CH:2]([Br:1])[C:3](=[O:24])[C:4]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:14]=1)=[O:21])=[O:40])=[O:32])=[O:28]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@@H](C)CC[C@H]1C(=O)O
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a slurry of 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (4.00 g, 8.88 mmol) in dichloromethane (50 mL) was added (2S,5S)-1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)-5-methylpyrrolidine-2-carboxylic acid (2.80 g, 9.32 mmol) and K2CO3 (1.84 g, 13.31 mmol). The resulting slurry was stirred at room temperature for 18 h. The reaction was diluted with dichloromethane and washed with aqueous HCl (0.5 M) and Brine. The aqueous layers were back extracted with dichloromethane (2×), and the combined organic layers were dried over Na2SO4 and concentrated. The crude product was taken directly into the next reaction.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][NH:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[S:25]1[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26]1.Cl>>[Si:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][N:14]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)[C:30]([C:27]2[CH:28]=[CH:29][S:25][CH:26]=2)=[O:31])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccsc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CNc2ccc(C#N)cc2)cc1
Agent: Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CN(C(=O)c2ccsc2)c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 71 %

Procedure:
The procedure of Preparation Example 8 was repeated, except that 203 mg of 4-[N-(4-tert-butyldimethylsilyloxybenzyl)amino]benzonitrile was used in place of 4-[N-(4-benzyloxybenzyl)amino]phenol and 110 mg of 3-thiophenecarbonyl chloride was used in place of methanesulfonyl chloride. The resulting mixture was stirred at room temperature for 19 hours. After the reaction mixture was poured into dilute hydrochloric acid, the product was extracted with ethyl acetate. After the extract was successively washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by TLC (using a 3:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 191 mg of N-(4-tert-butyl-dimethylsilyloxybenzyl)-N-(4-cyanophenyl)-3thiophenecarboxamide.
Reaction SMILES: [O-]CC.[Na+].[Br-].[CH3:6][N:7]([CH3:37])[C:8]1[C:9]([N+:34]([O-:36])=[O:35])=[C:10]([CH:31]=[CH:32][CH:33]=1)[CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:38]1([C:44]2[N:45]=[CH:46][N:47]([CH2:49][CH2:50][CH:51]=O)[CH:48]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[N+:34]([C:9]1[C:10]([CH:11]=[CH:51][CH2:50][CH2:49][N:47]2[CH:48]=[C:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:45]=[CH:46]2)=[CH:31][CH:32]=[CH:33][C:8]=1[N:7]([CH3:6])[CH3:37])([O-:36])=[O:35]
Reactant: O=CCCn1cnc(-c2ccccc2)c1
Reactant: CN(C)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Product: CN(C)c1cccc(C=CCCn2cnc(-c3ccccc3)c2)c1[N+](=O)[O-]
Yield: 142.2 %

Procedure:
An ethanolic solution of 900 mg of sodium ethoxide was dropped into an ethanolic solution containing 6.88 g of 3-dimethylamino-2-nitrobenzyl-triphenylphosphonium bromide and 3.22 g of 3-(4-phenyl-1H-imidazol-1-yl)propionaldehyde. The obtained solution was heated under reflux for 2 hours to conduct a reaction. After the completion of the reaction, the reaction mixture was freed from the solvent by distillation and extracted With 2N NaOH. The aqueous layer was made acidic again with 1N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and distilled to remove the solvent. The obtained oily substance was purified by silica gel chromatography to give 6.80 g of 2-nitro-3-[4-(4-phenyl-1H-imidazol-1-yl)butenyl]-N,N-dimethylaniline. 680 mg of 10% Pd-C was added to a solution of the product in ethyl acetate to conduct catalytic reduction in a hydrogen stream. Thus, 2-dimethylamino-6-[4-(4-phenyl-1H-imidazol-1-yl) butyl]aniline was obtained as an oily substance. This substance was dissolved in chloroform to give a solution. 1.1 g of butyl isocyanate was dropped into the solution. The obtained mixture was heated under reflux for two hours to conduct a reaction. After the completion of the reaction, the reaction mixture was concentrated to precipitate a crystal. This crystal was recrystallized from an ethyl acetate/hexane mixture. Thus, 4.51 g of the title compound was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5](=[O:30])[C@@H:6]2[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17](=[O:29])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10].C(OCC)(=O)C>CC(C)=O>[CH:2]([C:3]1[CH2:4][S:5](=[O:30])[C@@H:6]2[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17](=[O:29])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])=[O:1]
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CO)CS(=O)[C@H]12
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1

Procedure:
To a solution of 0.843 g (1.7 mmole) of 2,2,2-trichloroethyl 3-hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide in 50 ml of acetone at 0° is added over the period of about 2 min. 0.450 ml of 8N CrO3 in H2SO3 and the mixture is stirred at 0° for 5 min., then poured into a mixture of 300 ml ethyl acetate - 300 ml water and the ethyl acetate layer washed with water, dried (MgSO4), and evaporated in vacuo. The residue when chromatographed on silica gel with CHCl3 gives 2,2,2-trichloroethyl 3-formyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C@@H:3]([N:12]1[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH:20]([O:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[C:31]([CH:34]=O)[CH:30]=[CH:29]2)([CH3:22])[CH3:21]>>[F:19][C:2]([F:1])([F:18])[C@@H:3]([N:12]1[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:34]([C:31]3[CH:30]=[CH:29][C:28]4[C:33](=[C:24]([O:23][CH:20]([CH3:22])[CH3:21])[CH:25]=[CH:26][CH:27]=4)[N:32]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: NNc1ccc([C@H](N2CC[C@@H](O)C2)C(F)(F)F)cn1
Reactant: CC(C)Oc1cccc2ccc(C=O)nc12
Product: CC(C)Oc1cccc2ccc(-c3nnc4ccc([C@H](N5CC[C@@H](O)C5)C(F)(F)F)cn34)nc12

Procedure:
Prepared as described in Example 9B, Steps A-F, using (R)-1-((S)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ol in place of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate and using 8-isopropoxyquinoline-2-carbaldehyde in place of 8-methoxyquinoline-2-carbaldehyde in Step F. LCMS APCI (+) m/z 472.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:28](=[O:31])[CH2:29][CH3:30])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CCC(=O)Cl
Product: CCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 14 mg, 38 μmol) and propanoyl chloride (10 mg, 114 μmol). Yield 14 mg (90%).
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[CH:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[N:4]=1.[OH-].[K+].C(O)(=[O:28])C>CS(C)=O.O>[O:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([C:5]3[NH:4][C:3](=[O:28])[N:8]4[CH:9]=[CH:10][N:11]=[C:7]4[CH:6]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: CSc1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]c(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Temperature: 100 °C
Yield: 95.3 %

Procedure:
4-(4-(5-(methylthio)imidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.4000 g, 1.225 mmol) and potassium hydroxide (1.021 mL, 6.127 mmol) were suspended in DMSO (3 mL) and heated at 100° C. for 1.5 hours in a microwave. The reaction mixture was diluted with water (40 mL) and acidified with acetic acid (1.052 mL, 18.38 mmol). The resulting solids were collected by filtration and dried under high vacuum to afford 7-(4-morpholinophenyl)imidazo[1,2-c]pyrimidin-5(6H)-one (0.3460 g, 95.28% yield). MS (apci) m/z=297.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]([O:19][CH3:20])=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:17](=[O:18])[O:19][CH3:20])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: COC(=O)Cl
Product: COC(=O)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
Methyl 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-ylcarbamate was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and methyl chloroformate to give a yellow oil (8% yield). 1H-NMR (CDCl3): δ 8.70 (s, 1H), 7.60 (m, 1H), 7.28-7.16 (m, 2H), 4.98 (m, 1H), 4.90 (m, 1H), 3.74 (s, 3H), 2.66 (m, 2H), 2.21 (m, 1H), 1.90 (m, 2H), 1.81 (m, 1H); MS m/z 324 (M+1).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][OH:37])[CH2:31]1.CS(C)=O>CC(O)C>[OH:37][CH2:36][CH:32]1[CH2:33][CH2:34][CH2:35][N:30]([CH2:3][CH:2]([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:14]=[C:13]([C:15]4[O:19][N:18]=[C:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:16]=4[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=3)=[CH:6][CH:5]=2)[OH:1])[CH2:31]1
Reactant: OCC1CCCNC1
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: OCC1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (30 mg, 0.075 mmol) in 2-propanol (2 mL) was added piperidin-3-yl-methanol (17.31 mg, 0.150 mmol). The reaction mixture was heated to 80° C. DMSO (1 mL) was added to help solubilize. The reaction mixture was stirred overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 MeOH:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 MeOH:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the Example 30 was 16.0 mg, and its purity was 100%. 1H NMR (400 MHz, MeOD) δ ppm 8.18 (2H, d, J=8.28 Hz), 7.49-7.75 (7H, m), 5.05 (1H, d, J=9.03 Hz), 3.36-3.56 (4H, m), 2.83 (2H, br. s.), 2.11-2.53 (2H, m), 1.62-2.02 (4H, m), 1.03-1.20 (1H, m). MS (m+1)=515.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[C:5]1(=O)[CH2:9][CH2:8][CH2:7][CH2:6]1>>[O:1]1[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[NH:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC1
Reactant: NCCO
Product: C1CCC2(C1)NCCO2

Procedure:
2-Hydroxyethylamine and cyclopentanone were reacted according to Method B4b, Step 1 to afford 4-aza-1-oxaspiro[4.4]nonane. The oxazolidine was reduced according to method B4b, Step 2 to afford N-cyclopentyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to afford N-cyclopentyl-N-(2-chloroethyl)amine. The amine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate according to Method C1d to afford 2-(2-methoxy-4-nitrophenylimino)-3-(cyclopentyl)-1,3-thiazolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:14])[C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H][H]>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[OH:14]
Reactant: [H][H]
Reactant: COC1=CC(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(O)c2ccccc2c1O

Procedure:
A solution of 2-methoxy-1,4-naphthoquinone (20.0 g) in tetrahydrofuran (150 mL) was hydrogenated at atmospheric pressure over Pd-C (10%, 0.5 g) until the calculated amount of hydrogen was absorbed, approximately 4 hours. Filtering off the catalyst under an atmosphere of nitrogen gave a solution of the desired product, which was used as such without isolation of the product as the starting material in Examples 1, 2 and 3, infra. Alternatively, the solvent is removed under reduced pressure and the residue recrystallized from diethyl ether/pentane, affording 2-methoxy-1,4-dihydroxynaphthalene.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([S:14][C:15]1[N:19]([CH3:20])[N:18]=[CH:17][C:16]=1[C:21]([NH:23][OH:24])=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:25](Br)[CH:26]=[CH2:27].Cl>O.C1(C)C=CC=CC=1>[CH2:27]([O:24][NH:23][C:21]([C:16]1[CH:17]=[N:18][N:19]([CH3:20])[C:15]=1[S:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:22])[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: Cn1ncc(C(=O)NO)c1SCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCONC(=O)c1cnn(C)c1SCc1ccccc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
In a solution of potassium carbonate (1.3 g, 9.4 mmol) in water (10 ml), a solution of 5-benzylthio-1-methylpyrazole-4-carbohydroxamic acid (2.0 g, 7.6 mmol) and allyl bromide (1.1 g, 9.1 mmol) in toluene (10 ml) were added, and stirred at 50° C. for 4 hours. After cooling to room temperature, the mixture was adjusted to pH 1 by adding 35% hydrochloric acid and extracted with ethyl acetate. The resulting ethyl acetate solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the aimed product (1.9 g). Oily substance. Proton nuclear magnetic resonance chemical shift values δ (ppm) (in CDCl3) 3.42 (s, 3H), 3.95 (s, 2H), 4.49 (d, J=6.3 Hz, 2H), 5.33-5.43 (m, 2H), 6.00-6.16 (m, 1H), 6.93-7.00 (m, 2H), 7.21-7.30 (m, 3H), 8.08 (s, 1H), 9.68 (brs, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19]C)=[O:18])=[CH:10][C:9]([NH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[N:8][CH:7]=2)#[N:2].CO.[OH-].[Li+]>O1CCCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([OH:19])=[O:18])=[CH:10][C:9]([NH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[N:8][CH:7]=2)#[N:2]
Reactant: COC(=O)c1cccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1cccc(C(=O)O)c1

Procedure:
To methyl 3-(3-cyano-6-(2-morpholinoethylamino)-1,7-naphthyridin-4-ylamino)benzoate in tetrahydrofuran (12 mL) was added methyl alcohol (4.5 mL) and lithium hydroxide (1 N, 4.5 mL). After 12 hr the solvents were evaporated and the crude mixture was purified by preparative HPLC to give 3-(3-cyano-6-(2-morpholinoethylamino)-1,7-naphthyridin-4-ylamino)benzoic acid in quantitative yield.
Reaction SMILES: [C:1]([C:3]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[F:15])#[N:2].[OH-:16].[K+]>C(O)(C)(C)C>[CH3:14][C:10]1([CH3:13])[CH:9]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([F:15])=[C:3]([C:1]([NH2:2])=[O:16])[C:12]=2[O:11]1
Reactant: CC1(C)C=Cc2ccc(F)c(C#N)c2O1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1(C)C=Cc2ccc(F)c(C(N)=O)c2O1

Procedure:
Schema 6 illustrates the synthesis of an amino substituted 2,2-dialkyl-2H-1-benzopyran and an amino substituted 2,2-dialkyl-3,4-dihydro-2H-1-benzopyran, for example, 8-amino-5-chloro-7-fluoro-2H-1-benzopyran and 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran by the reaction of an appropriately substituted 2-fluorobenzonitrile with 2-methyl-3-butyn-2-ol under basic conditions in dimethyl sulfoxide, yielding the corresponding 3-(2-cyano-substituted-phenoxy)-3-methyl-1-butyne (XXI). The butyne intermediate is then cyclized at 180° C. in 1,2-dichlorobenzene, giving the appropriate 8-cyano-2,2-dialkyl-7-fluoro-2H-1-benzopyran, for example, 8-cyano-2,2-dimethyl-7-fluoro-2H-1-benzopyran (XXII), which is in turn treated with potassium hydroxide in t-butanol, yielding 2,2-dimethyl-7-fluoro-2H-1-benzopyran-8-ylcarboxamide (XXIII). The so-prepared carboxamide is then reduced with sodium hypochlorite and sodium hydroxide in water and dioxane, affording the corresponding free amine, for example, 8-amino-2,2-dimethyl-7-fluoro-2H-1-benzopyran (XXIV). The intermediate benzopyran is optionally halogenated in the 5-position as described above, yielding the corresponding benzopyran intermediate, for example, 8-amino-5-chloro-2,2-dimethyl-7-fluoro-2H-1-benzopyran (XXV). To obtain an amino substituted 2,2-dialkyl-3,4-dihydro-2H-1-benzopyran, for example, 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran, the benzopyran (XXIV), described above, is first hydrogenated in the presence of 5% palladium on carbon in ethanol. The so-prepared 8-amino-3,4-dihydro-7-fluoro-2H-1-benzopyran (XXVI) is then optionally halogenated in the 5-position, affording the desired 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran (XXVII). Examples 13 and 14 provide detailed descriptions of how these compounds are prepared.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([N+:20]([O-])=O)[CH:11]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].CO.C(=O)(O)[O-].[K+]>[Pd].O>[CH2:1]([S:5]([NH:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH2:20])[CH:11]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)NC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCS(=O)(=O)NC(=O)c1ccc(NC(C)=O)c(N)c1
Yield: 68.5 %

Procedure:
N-(1-butanesulfonyl)-4-acetylamino-3-nitrobenzamide (10.75 g) is dissolved with methanol (200 ml) and water (30 ml), and potassium bicarbonate (7.59 g) is added. The solution is hydrogenated with a 5% palladium/carbon (2.53 g) catalyst under a hydrogen environment for 24 hours at 40° C. The solids are separated through filtration, the residue, which is obtained by concentrating the filtrate, is purified using silica gel column chromatography (eluate: ethyl acetate/methanol=4/1), and 6.72 g of N-1-butylsulfonyl-4-acetylamino-3-aminobenzamide is obtained. 1H-NMR (DMSO-d6, δ): 0.86 (3H, t, J=7.3 Hz), 1.33-1.43 (2H, m), 1.59-1.67 (2H, m), 2.07 (3H, s), 3.37-3.43 (2H, t), 5.12 (2H, br s), 7.13 (1H, dd, J=8.2 and 2.0 Hz), 7.28 (1H, d, J=1.9 Hz), 7.40 (1H, d, J=8.3 Hz), 9.09 (1H, s).
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([C:33](OC)=[O:34])[CH:27]=2>C1(C)C=CC=CC=1>[N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[NH:5][C:33]([C:28]1[CH:27]=[C:26]2[C:31]([CH:32]=[C:24]([C:18]3[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=3[Cl:16])[NH:25]2)=[CH:30][CH:29]=1)=[O:34]
Reactant: COC(=O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: Nc1ccc2ccccc2n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2ccccc2n1)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 100 °C
Reaction time: 0.42 h

Procedure:
To 10 mL of ice-cold toluene was added 844 μL of 2 M trimethylaluminum in toluene then 2-aminoquinoline (233 mg, 1.62 mmol) was added in one portion and the mixture was stirred for 25 min. To this was added a solution of methyl 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylate (470 mg, 1.47 mmol) (from Example 3-5) in toluene (7 mL) dropwise and the resulting solution was heated at 100° C. for 18 h. A second aliquot of trimethylaluminum was added and the mixture heated another 18 h, after which it was cooled to ambient temperature, quenched with 1N HCl, and basified by stirring with 8% NaHCO3. This mixture was filtered, and the filtrate separated. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were dried, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed using a gradient of 20-50% heptane/ethyl acetate to give 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid quinolin-2-ylamide. 1H NMR (DMSO-d6, 400 MHz) δ 11.85 (s, 1H), 11.06 (s, 1H), 8.40 (s, 2H), 8.22 (s, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.81 (dd, J=8.3, 1.5 Hz, 1H), 7.74 (td, J=6.8, 1.5 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.88 (s, 1H), 7.66 (s, 1H), 7.53 (m, 2H), 6.62 (s, 1H). MS (m/z) 432.0 (M+1); retention time=1.57 min (Method 10).