Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH:10]1([C:13]2[CH:17]=[C:16]([NH2:18])[NH:15][N:14]=2)[CH2:12][CH2:11]1.[Na+].[I-].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:18][C:16]2[NH:15][N:14]=[C:13]([CH:10]3[CH2:12][CH2:11]3)[CH:17]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(C3CC3)n[nH]2)nc(Cl)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To the solution of 2,4-dichloro-6-methylpyrimidine (1.63 g) and 3-cyclopropyl-1H-pyrazol-5-amine (1.24 g) in DMF (20 ml) was added NaI (1.49 g) and DIEA (1.72 ml). And the mixture was stirred at 80° C. overnight. The mixture was concentrated to remove DMF. The residue was suspended into EtOAc. The insoluble material was filtered off and washed with EtOAc. The filtrate was concentrated and the residue was pufiried with silica gel column chromatography (eluent: CHCl3/MeOH=98/2˜90/10) to give 2-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-6-methylpyrimidin-4-amine (1054 mg) as a pale pink solid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:8]=1)=[O:5].[CH:26](=O)[CH2:27][CH3:28].C(O)(=O)C>C1COCC1>[F:25][C:20]1[CH:21]=[C:22]([F:24])[CH:23]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:26][CH2:27][CH3:28])[CH2:18][CH2:19]2)[N:8]=1)=[O:5]
Reactant: O=C(Nc1cccc(OC2CCNCC2)n1)c1c(F)cc(F)cc1F
Reactant: CCC=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCN1CCC(Oc2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Yield: 68.7 %

Procedure:
Combine 2,4,6-trifluoro-N-[6-(piperidin-4-yloxy)pyridin-2-yl]-benzamide (example 84, 250 mg, 0.71 mmol), propionaldehyde (124 mg, 2.14 mmol), acetic acid (85 mg, 1.42 mmol), molecular sieve 4 Å (0.4 g) and THF (6 mL), stir for 15 min. Then add NaBH(tri-acetate) portionwise and stir for 3 hr. Quench the reaction with 0.1N NaOH, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 5% 2M NH3-methanol in methylene dichloride provides 192 mg (69%) of the title compound: mass spectrum (ion spray): m/z=394.1 (M+1); 1H NMR (CDCl3, ppm): 8.00 (s, br, 1H), 7.84 (d, br, 1H), 7.64 (t, 1H), 6.78 (m, 2H), 6.52 (d, 1H), 4.94 (m, 1H), 2.75 (m, 2H), 2.32 (m, 4H), 2.04 (m, 2H), 1.85 (m, 2H), 1.55 (m, 2H), 0.92 (t, 3H). Mono-hydrochloride salt: Anal calcd for C20H22F3N3O2.HCl.0.25H2O: C, 55.30; H, 5.45; N, 9.67. Found: C, 55.13; H, 5.36; N, 9.61.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([CH:2]([CH3:12])[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:11])=[O:4])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccccc1C(=O)C(C)Br
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccccc1C(=O)C(C)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 25 g of 2-bromo-2'-methylpropiophenone, 70 ml of dry acetonitrile, 30 g of potassium carbonate and 19 g of 4-benzylpiperidine is stirred for 4 hours at ambient temperature. It is filtered in order to separate off the inorganic residue, and the filtrate is diluted with 200 ml of diethyl ether, which causes precipitation of 4-benzylpiperidine hydrobromide. This is filtered off; the filtrate deposits a second crop of hydrobromide, which is also separated off. The filtrate is then acidified with 300 ml of 3N hydrochloric acid. The intermediate propiophenone hydrochloride is an oil which is insoluble in both phases. The acid aqueous phase is extracted twice with methylene chloride, the extract is washed with water, and aqueous ammonia solution is added. The mixture is stirred and left to separate, the organic phase is dried, filtered and treated with about 100 g of silica in order to retain the traces of 4-benzylpiperidine, the mixture is filtered and the filtrate is evaporated. 10.9 g of an oil are collected.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([P:12](C(OCC)OCC)(=[O:16])[O:13]CC)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1>Cl>[NH2:1][CH2:2][CH2:3][CH:4]([P:12]([OH:16])[OH:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1
Reactant: CCOC(OCC)P(=O)(OCC)C(CCN)c1ccc(Cl)cc1
Agent: Cl
Product: NCCC(c1ccc(Cl)cc1)P(O)O
Temperature: 25 °C

Procedure:
A solution of 17.9 g of ethyl 3-amino-1-(4-chlorophenyl)propyl(diethoxymethyl)phosphinate in 200 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 6 hours. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure and co-evaporated twice with 50 ml of water under reduced pressure. The crude product is then dissolved in 50 ml of water, washed twice with 20 ml of diethyl ether and the aqueous layer is then separated and evaporated under reduced pressure. The crude product is then dissolved in 50 ml of ethanol and 5 ml of propylene oxide is added dropwise. The precipitated solid is collected by filtration and dried to give 3-amino-1-(4-chlorophenyl)propylphosphonous acid, m.p. 210°-220° C., 31P=+29.6 ppm (D2O).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:6]([C:8]1[N:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]([C:17]([OH:19])=O)[C:9]=1[CH3:20])=[O:7].Cl.[NH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:6]([C:8]1[N:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]([C:17]([NH:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:19])[C:9]=1[CH3:20])=[O:7]
Reactant: CCOC(=O)CN
Reactant: COc1cc(C(=O)c2c(C)c(C(=O)O)c3ccccn23)ccc1[N+](=O)[O-]
Agent: Cl
Product: CCOC(=O)CNC(=O)c1c(C)c(C(=O)c2ccc([N+](=O)[O-])c(OC)c2)n2ccccc12

Procedure:
This compound is obtained according to the same method as the preceding compound, by coupling 3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-ylcarboxylic acid with ethyl glycinate hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>CCOC(C)=O>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: CCOC(=O)COc1cccc(N)c1
Reactant: O=C(O)c1cccc(-c2ccc(Cl)cc2)n1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(-c3ccc(Cl)cc3)n2)c1

Procedure:
Carboxylic acid (149)(50 mg, 0.21 mmol) was coupled to aniline (64)(42 mg, 0.21 mmol) using Method C. During this reaction, partial hydrolysis occurred. The residue was re-dissolved in EtOAc (2 ml) and the organic layer was washed with 1M HCl (2×1 ml), dried (Na2SO4), filtered and the solvent removed in vacuo to give a mixture of acid and ester, which was used without further purification.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[OH:6])([O-])=O.CC(C)=O.[NH4+].[Cl-]>[Zn].O>[NH2:1][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[OH:6]
Reactant: O=[N+]([O-])CC(O)c1ccc(-c2ccccn2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: NCC(O)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.1 %

Procedure:
To a solution of consisting of 2-nitro-1-(4-pyridin-2-yl-phenyl)-ethanol (275 mg, 1.1 mmol) and acetone (5 mL) were added NH4Cl (900 mg, 16.9 mmol), Zn dust (1.10 g, 16.9 mmol), and water (1 mL). The reaction mixture was stirred for 2 h at rt and then filtered. The filtrate was washed with saturated NaHCO3 and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (45 mg, 19%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH:30]1([CH2:33][NH2:34])[CH2:32][CH2:31]1>>[CH:30]1([CH2:33][NH:34][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:32][CH2:31]1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: NCC1CC1
Product: CS(=O)(=O)c1ccc(NCC2CC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Yield: 40 %

Procedure:
The title compound was prepared according to the procedure described for example 301 from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK) and Cyclopropanemethylamine (40% yield, white foam, MS (m/e): 482.5 (M+H, 100%)
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(O)C>[C:1]1([C:7]2[C:8]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:35](=[O:37])[CH3:36])=[CH:22][CH:21]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 4-3 (0.02 g, 0.06 mMol) and triethylamine (0.02 mL, 0.2 mMol) in absolute ethanol (0.5 mL) was added acetic anhydride (0.02 mL, 0.2 mMol). The reaction was complete after 10 minutes and was purified directly on a C18 reverse phase HPLC to give 18-1 as a solid. LC/MS (M+1) calculated: 394.5; observed: 394.2
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]1([C:7]2[S:8][C:9]3[C:15]([CH2:16][OH:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc2nc(-c3ccccc3)sc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cccc2nc(-c3ccccc3)sc12
Yield: 93.9 %

Procedure:
Ethyl ester of 2-phenylbenzothiazole-7-carboxylic acid (425 mg, 1.50 mmol) was reduced by using lithium aluminium hydride as in Preparation 2-3) to give 2-phenylbenzothiazole-7-methanol (340 mg, 94%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:16][CH2:17][Cl:18].C(N(CC)CC)C>>[Cl:18][CH2:17][CH2:16][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: ClCCBr
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Solvent: CCN(CC)CC
Product: ClCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-piperazine (0.05 mol), 1-bromo-2-chloroethane (0.1 mol) and triethylamine (0.05 mol) was stirred for 30 minutes at 100° C. The mixture was cooled, then partitioned between CH2Cl2 and water. The layers were separated. The organic phase was filtered over dicalite. The organic filtrate was dried, filtered and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 5.2 g (35%) of 4-(2-chloroethyl)-1-(3,4-dichlorophenyl)-piperazine (interm. 9).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[CH:4][C:3]=1[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:43]=[CH:42][C:36]([O:37][CH2:38][C:39](O)=[O:40])=[CH:35][CH:34]=2)[S:27]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][C:39]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=4)=[CH:4][C:3]=3[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:40])=[CH:42][CH:43]=2)[S:27]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(O)c2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(O)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 69.1 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.95 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.89 g), diethyl cyanophosphonate (0.52 g), triethylamine (0.32 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (1.18 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].CC([O-])=O.[K+].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1c(N)cccc1Br
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1c(N)cccc1-c1ccccc1
Temperature: 115 °C
Yield: 65900.6 %

Procedure:
To a solution of 2-amino-6-bromobenzonitrile (5 g, 0.025 mmol) in toluene (70 mL) was added KOAc (5 g, 0.05 mmol), phenylboronic acid (4.27 g, 0.035 mmol) and cat. Pd(TPP)2Cl2. The reaction mixture was heated to 115° C. for 16 h. After this time, the reaction mixture was filtered and the volatiles were evaporated to yield as residue. The residue was purified by column chromatography (1% EtOAc in hexanes) to provide 3-aminobiphenyl-2-carbonitrile (3.2 g, 65% yield) as light yellow solid. LCMS Method Z: retention time 3.65 min; [M+]=195.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[CH:4][NH:5][CH:6]=1.[C:17](N1C=CN=C1)(=[O:19])[CH3:18]>>[C:17]([N:5]1[CH:6]=[C:2]([Cl:1])[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)=[CH:4]1)(=[O:19])[CH3:18]
Reactant: FC(F)(F)c1cccc(-c2c[nH]cc2Cl)c1
Reactant: CC(=O)n1ccnc1
Product: CC(=O)n1cc(Cl)c(-c2cccc(C(F)(F)F)c2)c1
Reaction time: 1.5 h
Yield: 68.3 %

Procedure:
The mixture of 1 g of 4-chloro-3-(3-trifluoromethylphenyl)pyrol and 2 g of N-acetylimidazole was fused for 1.5 hours at 140°-150° C. The resulding reaction mixture was purified by silicagel chloromatography using 10% solution of aceton in n-hexane as solvent to obtain 0.8 g of the desired product (pale reddish brown crystal, m.p. 70°-71.5° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:13]=[C:12]([NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Br)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.C1CCN2C(=NCCC2)CC1>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(NC(=O)CCCBr)cc(C(=O)OC)c1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Yield: 35 %

Procedure:
5-(4-Bromo-butanoylamino)-isophthalic acid dimethyl ester (D61) was treated with DBU as described in D57 to afford D62 as a white solid (35%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)[CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:39][CH2:38]1>CCOC(C)=O>[CH3:36][N:37]1[CH2:38][CH2:39][N:40]([C:43]2[CH:48]=[CH:47][C:46]([NH:49][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][C:13]5[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]6[N:23]([CH2:28][CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=6)=[O:21])=[CH:17][CH:18]=5)[CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:45][CH:44]=2)[CH2:41][CH2:42]1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(Cc2ccc3c(c2)C(=CO)C(=O)N3)cc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(Cc2ccc3c(c2)C(=CNc2ccc(N4CCN(C)CC4)cc2)C(=O)N3)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indol-5-ylmethyl)-phenyl]-amide (prepared below, 70 mg, 0.175 mmol) and THF (1 mL). To the resulting solution was added 4-(4-Methyl-piperazin-1-yl)-phenylamine (66.8 mg, 0.349 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and then diluted with EtOAc (2 mL). The solution was washed with water (2 mL) and the water layer was re-washed with additional EtOAc (2 mL). The combined organic layers were then concentrated in vacuo affording the crude product. The crude product was further purified by silica gel column chromatography with 5% methanol in chloroform as eluant to give the desired product as a solid in 55% yield (55 mg, 0.96 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].IC.[C:12]([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:12])[C:7]=1[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1[nH]c(=O)ccc1Br
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: Cc1c(Br)ccc(=O)n1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-6-methylpyridin-2(1H)-one (164 mg, 0.872 mmol) and iodomethane (0.065 mL, 1.047 mmol) in DMSO (3 mL) was added K2CO3 (145 mg, 1.047 mmol). The mixture was stirred at 60° C. overnight, filtered, and purified via preparative HPLC, eluting with a gradient of 20-70% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4]C1C=CN=C2C=C(C3SC=CN=3)SC=12.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[CH:33]=[C:34]([C:36]3[N:37]([CH3:45])[C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][N:40]=3)[S:35][C:28]=12>>[F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:27]1[CH:32]=[CH:31][N:30]=[C:29]2[CH:33]=[C:34]([C:36]3[N:37]([CH3:45])[C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][N:40]=3)[S:35][C:28]=12
Reactant: COC(=O)c1cnc(-c2cc3nccc(Cl)c3s2)n1C
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Product: COC(=O)c1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1C

Procedure:
Following the procedure described above for the synthesis of compound 11 (example 12, step 3, scheme 2) but substituting compound 10 for compound 119, title compound 120 was obtained as a yellow solid (254 mg, 31% yield). MS (m/z) 429.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:20]3[CH:21]=[C:22]([CH:32]=[CH:33][CH:34]=3)[CH2:23][NH:24]C(=O)OC(C)(C)C)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][CH2:23][C:22]1[CH:21]=[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[CH2:13][CH2:12][CH2:11][N:10]3[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:35]=[CH:36][CH:37]=[C:38]([CH3:39])[C:2]=2[CH3:1])[CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CNC(=O)OC(C)(C)C)c4)cccc32)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CN)c4)cccc32)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.1 %

Procedure:
To a solution of tert-butyl 3-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)benzylcarbamate (0.12 g, 0.227 mmol) in DCM (2.5 mL) at 0° C. was added TFA (0.35 mL, 4.54 mmol) dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. After this time, the reaction mixture was quenched with 50% saturated NaHCO3, and the aqueous phase was extracted with DCM. The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford the title compound (0.075 g, 77% yield). LCMS, [M+H]+=429.2.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc2ccccc2c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COC(=O)c1sc2ccccc2c1CBr
Temperature: 25 °C
Yield: 82 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was purged with nitrogen and charged with methyl 3-methylbenzo[b]thiophene-2-carboxylate (2.00 g, 9.70 mmol) and benzene (20 mL). N-bromosuccinimide (1.72 g, 9.70 mmol) and 2,2′-azobisisobutyronitrile (160 mg, 1.00 mmol) were added, and the mixture was refluxed for 2 h. After this time, the mixture was cooled to room temperature and filtered. The filter cake was rinsed with carbon tetrachloride (20 mL) and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 103a in 82% yield (2.27 g) as a white solid: mp 101-102° C.; 1H NMR (500 MHz, CDCl3) d 7.97 (m, 1H), 7.86 (m, 1H), 7.51 (m, 2H), 5.22 (s, 2H), 3.97 (s, 3H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C:15]([NH:17][C:18]2[C:27]([N+:28]([O-])=O)=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO>[NH2:28][C:27]1[C:18]([NH:17][C:15](=[O:16])[C:14]([N:11]2[CH2:10][CH2:9][CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12]2)=[O:31])=[CH:19][C:20]2[O:24][C:23](=[O:25])[NH:22][C:21]=2[CH:26]=1
Reactant: O=C(Nc1cc2oc(=O)[nH]c2cc1[N+](=O)[O-])C(=O)N1CCC(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1cc2[nH]c(=O)oc2cc1NC(=O)C(=O)N1CCC(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A mixture of 3.3 g (7.7 mmol) of 2-(4-benzylpiperidin-1-yl)-N-(5-nitro-2-oxo-2,3-dihydro-benzoxazol-6-yl)-2-oxo-acetamide, 100 ml of methanol and 0.3 g of 10% Pd/C catalyst is hydrogenated for 8 h. The catalyst is filtered off and the filtrate is concentrated. The residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and toluene:acetone=2:1 as eluent to yield 1.06 g (34.5%) of the title compound. Mp.: 296° C. (toluene-acetone).