Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH2:13][CH2:14]Cl)([CH3:4])([CH3:3])[CH3:2].[OH:16][C:17]1([C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH2:13][CH2:14][N:20]1[CH2:21][CH2:22][C:17]([OH:16])([C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:18][CH2:19]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1OCCCCl
Reactant: OC1(c2cnc3ccccc3c2)CCNCC1
Product: CC(C)(C)c1ccccc1OCCCN1CCC(O)(c2cnc3ccccc3c2)CC1
Yield: 39 %

Procedure:
Beginning with 0.298 gm (1.3 mMol) 3-chloropropyl 2-tert-butylphenyl ether and 0.300 gm (1.3 mMol) 4-hydroxy-4-(quinolin-3-yl)piperidine, 0.212 gm (39%) of the title compound were recovered as a white, waxy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:26][O:27][C:28]1[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=[CH:35][C:29]=1[CH:30]=[CH:31][C:32](O)=[O:33]>>[CH3:26][O:27][C:28]1[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=[CH:35][C:29]=1[CH:30]=[CH:31][C:32]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)=[O:33]
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(C(=O)C=Cc4ccc(OC)c(OC)c4OC)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and 2,3,4-trimethoxycinnamic acid (65 mg) were reacted in the same manner as in Example 56 to obtain the title compound as a free base.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2=[C:8]3[C:13](=[C:14]([NH2:16])[N:15]=[C:6]2[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]3)([O-])=O>[Ni].CCO.N.C(Cl)Cl>[CH:9]1[C:8]2[C:13](=[C:14]([NH2:16])[N:15]=[C:6]3[CH:5]=[C:4]([NH2:1])[CH:18]=[CH:17][C:7]3=2)[N:12]=[CH:11][CH:10]=1
Reactant: Nc1nc2cc([N+](=O)[O-])ccc2c2cccnc12
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc2c(c1)nc(N)c1ncccc12
Reaction time: 8 h

Procedure:
A mixture of 8-nitrobenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq) and Raney Nickel (wet, 10% wt) in EtOH/ammonia (2:1) was stirred under H2 balloon overnight. The reaction mixture was diluted with DCM. The insoluble solid was filtered off through celite, and the filtrate was concentrated en vaccuo to obtain a crude residue. The crude material was washed with 10% MeOH/DCM and 70% EtOAc/Hexanes to give benzo[f][1,7]naphthyridine-5,8-diamine as an off white solid: 1H NMR (methanol-d4): δ 8.97 (dd, 1H), 8.90 (dd, 1H), 8.41 (d, 1H), 7.83 (dd, 1H), 7.57 (d, 1H), 7.39 (dd, 1H), 3.96 (s, 2).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:3].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1.N1C=CC=CC=1>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1)=[O:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Nc1ccccc1C1Cc2ccccc2N1
Reactant: CCCCCCCCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)Nc1ccccc1C1Cc2ccccc2N1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Octyl chloroformate (2.00 ml) was added dropwise to a solution of 2.15 g 2-(2-aminophenyl)-2,3-dihydro-1H-indole and 2.00 ml pyridine in 35 ml CH2Cl2 at 0° C. The solution was stirred five hours at 0° C. and then quenched with water. The organic layer was separated, washed with 5% HCl and saturated NaCl solution, dried (MgSO4), and concentrated to yield a solid. Purification by flash chromatography using CH2Cl2 /hexane (1:2) as eluent gave 1.74 g solid, m.p. 99°-102° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][CH:22]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][C:22]=1[C:14]([F:17])([F:16])[F:15]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1
Agent: O=P([O-])([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1C(F)(F)F
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(furan-3-yl)pyrazole (0.5 g) in dimethylformamide (15 m) and water (5 ml) was added sodium dithionite (0.112 g) and disodium hydrogen phosphate (0.067 g). The mixture placed in a 400 ml Parr vessel, which was evacuated, then charged with trifluoromethylbromide gas to 20 psi. The mixture was shaken and heated at 50° C., for 2.5 hours, then left at room temperature for 16 hours. The vessel Mwas then evacuated, then charged with trifluoromethylbromide to 40 psi, then shaken and heated to 50° C. for a further 7 hours, then left at room temperature for 16 hours. Further sodium dithionite (0.120 g) and disodium hydrogen phosphate (0.080 g) was added, the vessel evacuated, then charged with trifluoromethylbromide to 40 psi, then shaken and heated to 50° C. as before for 9 hours, then left at room temperature for 48 hours. Further sodium dithionite (0.240 g) and disodium hydrogen phosphate (0.160 g) were added, the vessel was evacuated, then charged w-ith trifluoromethylbromide to 45 psi, then shaken and heated to 50° C. as before for a further 9 hours. The mixture was filtered and then poured into ether (100 ml) and water (100 ml). The organic layer was separated, washed twice with water (50 ml), dried (Na2SO4), and evaporated. The residue was purified by column chromatography on silica gel (25 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2-trifluoromethylfuran-3-yl)pyrazole as a white solid, m.p. 155-7° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Product: CC(C)(C)c1ccc(-n2c(N3CCCCC3)c(C=O)c3ccccc32)cc1
Yield: 87 %

Procedure:
1-(4-tert-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with piperidine as described in Step 2 of Example 29 to afford 1-(4-tert-butylphenyl)-2-piperidin-1-yl-1H-indole-3-carboxaldehyde (87% yield) as an off-white solid. TLC (silica gel, heptane-30% ethyl acetate); Rf=0.23; ESI/MS 361 (M+H); RT=4.48 min; NMR 10.14 (1H, s); 8.11 (1H, d, J=6 Hz); 7.66 (2H, d); 7.46 (2H, d); 7.16 (2H, m); 6.91 (1H, d, J=9 Hz); 3.27 (4H, m); 1.46 (6H, m); 1.36 (9H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)=[N:5][CH:4]=[N:3]1.CN(C)C=O.[Br:17]N1C(=O)CCC1=O>O>[Br:17][C:9]1[S:8][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][N:5]=2)=[N:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ncnc1-c1nccs1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1-c1ncc(Br)s1
Temperature: 22 °C
Reaction time: 18 h
Yield: 969 %

Procedure:
To a mixture of methyl-5-thiazol-2-yl-1H-[1,2,4]triazole (6.55 g; 39 4 mmol) and dimethylformamide (32 mL), add N-bromosuccinimide (14 g, 78.8 mmol) in three portions over 1 h. Stir the mixture at 22° C. for 18 h and then add to water (300 mL) chilled to 0-5° C. Separate the aqueous layer and extract with methyl-t-butyl ether (2×200 mL). Combine the organic layers and wash with 7% aqueous sodium hydrogen carbonate (100 mL) and then dry over sodium sulfate. Filter and evaporate the solvent to afford the title compound (9.5 g, 93%). ES/MS m/z (79Br/81Br) 245/247 (M+1)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[C:16]#[N:17])(=O)=O.[CH:20](/B(O)O)=[CH:21]/[CH3:22]>>[N+:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7](/[CH:20]=[CH:21]\[CH3:22])[C:8]=1[C:16]#[N:17])([O-:15])=[O:14]
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cccc1[N+](=O)[O-]
Reactant: C/C=C\B(O)O
Product: C/C=C\c1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared as in Example 129c from 2-cyano-3-nitrophenyl trifluoromethanesulfonate Example (129d) and cis-1-propen-1-ylboronic acid. The crude product was purified by chromatography on silica gel eluting with solvent gradient 0% to 100% DCM in hexanes, to give 0.80 g (97%) of (Z)-2-nitro-6-(prop-1-enyl)benzonitrile (97%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.25-8.30 (m, 1H), 7.90-7.98 (m, 2H), 6.25-6.70 (m, 1H), 6.17-6.28 (m, 1H), 1.78-1.82 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NCc2ccc(N(C)C)cc2)cc1
Yield: 29.1 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (10.0 g) and 4-methoxyaniline (8.25 g) as a starting material, (4-dimethylaminophenylmethyl) (4-methoxyphenyl)amine (5 g) was obtained. melting point: 92-94° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C([N:24]([CH:27]([CH3:29])C)[CH2:25]C)(C)C.Cl.N1CCC1>ClCCl.C(O)C>[N:24]1([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:10]=3[F:11])[N:6]=2)[CH2:25][CH2:29][CH2:27]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CCC3)nc2c1C#N
Temperature: 60 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-130) (0.11 g, 0.38 mmol) was dissolved in a mixed solvent of dichloromethane (10 ml) and ethanol (7 ml), then diisopropylethylamine (0.21 ml, 1.23 mol) and azetidine hydrochloride (71.5 mg, 0.76 mmol) were added. After stirring at an external temperature of about 60° C. for 3 hours, the reaction liquid was concentrated under reduced pressure and diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1) to obtain a colorless solid (85 mg, 74%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:17]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[N:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:31](=[O:32])[CH2:30][NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:2][CH2:3]3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: c1ccc2c(c1)CCc1ccccc1N2C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC(N2c3ccccc3CCc3ccccc32)CC1
Reaction time: 1 h

Procedure:
60.0 mg (0.216 mmol) of 5-(4-piperidinyl)-10,11-dihydro-5H-dibenzo-[b,f]azepine, 50.0 mg (0.258 mmol) of N-t-butoxycarbonylglycine, 62.1 mg (0.324 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride and 3 mg (0.03 mmol) of 4-dimethylaminopyridine were dissolved in 1 ml of dichloromethane. 43.7 mg (0.432 mmol) of triethylamine was added to the obtained solution, and they were stirred for 1 hour. The product was purified by the silica gel chromatography (hexane:ethyl acetate=89:11 to 65:35) to obtain the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[N+:8]([O-:10])=[O:9])=[CH:20][CH:19]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(Br)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-bromophenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into EtOAc (100 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-bromophenoxy-1-nitrobenzene. The crude product was used for further transformation .
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[CH:15](Br)([CH3:17])[CH3:16]>>[CH:15]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)([CH3:17])[CH3:16]
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Reactant: CC(C)Br
Product: CC(C)n1c2ccccc2c2sccc(=O)c21

Procedure:
By the same method as described in Example 7, 4.8 g of thiopyrano[3,2-b]indol-4(5H)-one is alkylated with isopropyl bromide to give 2.4 g of product, mp 154°-6° C, after recrystallization from methylene chloride-hexane.
Reaction SMILES: [C:1]([S:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([F:11])[CH:5]=1)#[N:2].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1CCCCC1.C1(C)C=CC=CC=1>[C:1]([S:3][C:4]1[CH:10]=[C:9]2[C:7](=[C:6]([F:11])[CH:5]=1)[N:8]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]2[OH:14])#[N:2]
Reactant: N#CSc1ccc(N)c(F)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2c(F)cc(SC#N)cc2c1O
Temperature: 130 °C
Yield: 25.6 %

Procedure:
A mixture of 48 g of 4-(cyanosulfanyl)-2-fluoroaniline and 57.7 g of diethyl ethoxymethylenemalonate is stirred at 130° C. After 1.5 h the mixture is diluted with 200 mL of a 1:1 mixture of cyclohexane and toluene. The mixture is cooled to 0° C. and the precipitate collected by filtration. It is washed with two 75 mL portions of a 1:1 mixture of cyclohexane and toluene, dried in a stream of air, and then it dissolved in 400 mL of diphenyl ether. The mixture is refluxed for 1 h and then cooled to 25° C. It is diluted with 1 L of 1:1 toluene/cyclohexane and the precipitate collected by filtration. The solid is dried in a stream of air to give 20 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[CH2:21][S:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:8]=[C:7]([Cl:28])[CH:6]=1.CN(C)N.C>CCO>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([Cl:28])[CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[CH2:21][S:22][CH2:23][C:24]([F:26])([F:27])[F:25])[CH:10]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Agent: C
Agent: CN(C)N
Solvent: CCO
Product: COC(=O)Cc1cc(Cl)cc(Oc2ccc(N)cc2CSCC(F)(F)F)c1
Temperature: 65 °C
Reaction time: 30 h

Procedure:
{3-Chloro-5-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester (0.07 g, 0.16 mmol), 1,1-dimethylhydrazine (0.08 mL, 1.09 mmol), ferric chloride (0.003 g, 0.02 mmol), and DARCO (0.016 g) were combined in EtOH and stirred at 65° C. for 30 hours. After work-up with EtOAc and H2O, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[O:6][CH:7]=[C:8](N)[C:9]2[C:10]=1[N:11]=[C:12]1[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]1.[CH2:20]=[O:21]>CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[O:6][CH:7]=[C:8]([O:21][CH3:20])[C:9]2[C:10]=1[N:11]=[C:12]1[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]1
Reactant: COC(=O)Cc1occ(N)c2c3ccccc3nc1-2
Reactant: C=O
Solvent: CO
Product: COC(=O)Cc1occ(OC)c2c3ccccc3nc1-2
Yield: 80 %

Procedure:
When the 4-aminopyrano[3,4-b]indole acetic acid methyl ester 12 was treated with aqueous formaldehyde in methanol, an 80% yield of 4-methoxypyrano[3,4-b]indole acetic acid methyl ester 16 was obtained as an 8.5:1 diastereomeric mixture.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: NC1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc2c(NC3CCCCC3)nc(Cl)nc12
Reaction time: 3 h
Yield: 96.1 %

Procedure:
In 3 ml of DMF was dissolved 300 mg (1.4 mmol) of 2,4-dichloro-7-methylthieno [3,2-d]pyrimidine, and after 204 mg (2.1 mmol) of cyclohexylamine was added to the resulting solution, the mixture was stirred for 3 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered to give 379 mg (yield: 98.2%) of the title compound.
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11].[CH3:13]O>[Pd]>[CH3:13][C:7]12[O:10][CH:1]([CH2:9][CH2:8]1)[CH:2]1[CH:6]2[C:5](=[O:11])[CH2:4][C:3]1=[O:12]
Reactant: CO
Reactant: O=C1CC(=O)C2C3C=CC(O3)C12
Agent: [Pd]
Product: CC12CCC(O1)C1C(=O)CC(=O)C12

Procedure:
The 10-oxa-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione (10.5 g) is dissolved in methanol (700 ml). The methanol solution is passed at a rate of 1.5 ml/min through a Thalis H-cube apparatus (from Thalis nanotec) set-up at 40° C. and 40 bar and fitted with a 10% Pd/C cartridge. The so obtained solution is evaporated to give 1-methyl-10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (9.2 g).
Reaction SMILES: [CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:17][C:18]1[CH:28]=[CH:27][C:21]([CH2:22][NH:23][C:24]([NH2:26])=[O:25])=[CH:20][CH:19]=1>>[CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([NH:26][C:24]([NH:23][CH2:22][C:21]2[CH:27]=[CH:28][C:18]([F:17])=[CH:19][CH:20]=2)=[O:25])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)NCc1ccc(F)cc1
Reactant: O=C(Cl)N(C1CCCCC1)C1CCCCC1
Product: O=C(NCc1ccc(F)cc1)NC(=O)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in General Procedure 1 using dicyclohexyl carbamoyl chloride and 4-fluorobenzyl urea.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:20])[CH:23]=[CH2:24]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: C=CCOC(=O)Cl
Product: C=CCOC(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 32.1 %

Procedure:
Beginning with 10.0 mg (0.0437 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 5.5 mg (0.0458 mMol) allyl chloroformate, 4.4 mg (33%) of the title compound were recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH2:30]([O:32][C:33](=[O:43])[C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1)[CH3:31]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([C:33]([O:32][CH2:30][CH3:31])=[O:43])=[CH:35][CH:36]=3)=[O:42])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CCOC(=O)c1ccc(NC(=O)Nc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 4-Isocyanato-benzoic acid ethyl ester according to the procedure of Example 65. HRMS: calcd for C33H24F3N3O4, 583.1719; found (ESI, [M+H]+), 584.1801.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:13](Cl)(Cl)=[O:14].C(N(CC)CC)C>C(Cl)Cl>[O:14]=[C:13]1[NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH:6]=[CH:7][CH:8]=[N:9][C:10]=3[C:11]=2[O:12]1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc2cccnc2c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc3cccnc3c2o1
Reaction time: 8 h
Yield: 91 %

Procedure:
A suspension of 7-amino-8-hydroxyquinoline (3.2 g, 20.0 mmol) in methylene chloride (50 ml) was treated with 25 ml of 1.6M phosgene gas in methylene chloride. Triethylamine (12 ml) was slowly added and the reaction was stirred overnight. The reaction mixture was partially concentrated and water was added. After treating the resulting mixture with aqueous ammonium hydroxide a precipitate formed which was filtered and dried giving 3.4 g (91% yield) of solid. M.P. >300° C.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2(O)[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:41]=[CH:40][CH:39]=3)(O)[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.I.[PH2](O)=O>C(O)(=O)C>[C:38]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:24]2[C:25]3[C:30]([C:17]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)=[C:18]4[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]4)=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: OC1(c2ccccc2-c2cccc3ccccc23)c2ccccc2C(O)(c2ccccc2-c2cccc3ccccc23)c2ccccc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3-c3cccc4ccccc34)c3ccccc23)c(-c2cccc3ccccc23)c1
Temperature: 100 °C
Reaction time: 7 h
Yield: 96.3 %

Procedure:
9,10-bis(2-(1-Naphthyl)phenyl)-9,10-dihydroxy-9,10-dihydro-anthracene (3.5 g, 5.7 mmole) was suspended in acetic acid (80 ml). To the resultant suspension, a 57% hydroiodic acid (15 ml, 0.11 mole, 20 eq) was added and the obtained mixture was stirred at 100° C. for 7 hours. To the reaction mixture, a 50% aqueous solution of hypophosphorous acid (30 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a white solid (3.2 g, 96%) was obtained.