Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:35])[CH3:34])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:39]1([CH2:45][C:46]([NH2:48])=[O:47])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:36])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:42]3[CH2:43][CH2:44][N:39]([CH2:45][C:46]([NH2:48])=[O:47])[CH2:40][CH2:41]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH:33]([CH3:34])[CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(C)(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: NC(=O)CN1CCNCC1
Agent: Cl
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(N)=O)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound. HR-MS (ES, m/z) calculated for C34H40N5O4Cl2 [(M+H)+] 652.2452, observed 652.2451.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.[Na].[NH4+].[Cl-]>C(O)C>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:12]=1[CH:13]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:1]2
Reactant: O=Cc1ccccc1Br
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc2c(Br)cccc2[nH]1
Temperature: 7.5 °C
Reaction time: 0.5 h

Procedure:
A solution of 23 mL of ethyl azidoacetate and 7.6 mL of 2-bromobenzaldehyde in 40 mL ethanol was added dropwise to a solution of 4.5 g sodium in 180 mL ethanol, in a bath at −10° C., at a rate such that the reaction temperature does not rise above 8° C. After the addition is complete, the mixture is stirred at 5-10° C. for 30 min. The reaction mixture is then poured into a mixture of 28 g of NH4Cl in 1 L ice, and extracted with 1:4 CH2Cl2hexane. The organic phase is filtered through 150 mL silica gel, which is rinsed with 200 mL of the same solvent. This is evaporated to near dryness, diluted with 300 mL xylene, and stabilised with 60 mg of 2,5-di-t-butylhydroquinone. This mixture is heated with a distillation head until 50 mL of xylene has distilled. The mixture is cooled and evaporated in vacuo to a volume of 80 mL, which is diluted with 80 mL of hexane. A white solid forms upon cooling to 0° C., which is filtered off.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[Br:12][C:13]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1ccc(Br)cc1Br
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(Br)cc1Br

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,4-dibromoaniline to yield 2-[(2,4-dibromophenyl)amino]phenylacetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.C([N:12](CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH2:12])=[O:9])[S:5][CH:6]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(Br)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: NC(=O)c1cc(Br)cs1
Reaction time: 8 h

Procedure:
To a solution of 4-bromothiophene-2-carboxylic acid (15 g), HOBt ammonium salt (16.5 g) and triethylamine (20.08 mL) in acetonitrile (250 mL) was added EDCI hydrochloride (16.87 g), and the mixture was stirred overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.0 g).
Reaction SMILES: CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:25]([N:27]([CH3:39])[CH:28]=[N:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([OH:37])=[CH:32][C:31]=1[CH3:38])[CH3:26].[CH3:40][O:41][N:42]=[C:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1Cl>CS(C)=O.O>[CH2:25]([N:27]([CH3:39])[CH:28]=[N:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([O:37][CH:44]2[CH2:45][CH2:46][CH2:47][CH2:48][C:43]2=[N:42][O:41][CH3:40])=[CH:32][C:31]=1[CH3:38])[CH3:26]
Reactant: CCN(C)C=Nc1cc(C)c(O)cc1C
Reactant: CON=C1CCCCC1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCN(C)C=Nc1cc(C)c(OC2CCCCC2=NOC)cc1C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
At from 0 to 5° C., 239 mg (2.13 mmol) of potassium tert-butoxide and 26 mg 18-crown-6 (0.10 mmol) were added a little at a time and with stirring to 200 mg (0.97 mmol) of N-ethyl-N′-(4-hydroxy-2,5-dimethylphenyl)-N-methylformamidine (cf. WO 2007/031513) in 3 ml of DMSO, and stirring was continued for about 15 minutes. At from 0 to 5° C., a solution of 313 mg (1.94 mmol) of 2-chlorocyclohexanone O-methyl oxime in 0.5 ml of DMSO was added to this mixture with stirring, and stirring was continued for about 20 hours at from 20 to 25° C. With cooling and a little at a time, 50 ml of water were added, and the mixture was extracted with MTBE. The combined organic phases were dried and then freed from the solvent. Cheomatography on alumina using cyclohexane/MTBE mixtures gave 100 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[Cl:42][C:43]1[CH:55]=[CH:54][C:46](CN2C=CC(N)=N2)=[CH:45][CH:44]=1>C(Cl)Cl>[Cl:42][C:43]1[CH:55]=[CH:54][C:46]([CH2:21][N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17]2)=[CH:45][CH:44]=1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(Cl)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, crude 1-(4-chloro-benzyl)-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford N-[1-(4-chloro-benzyl)-1H-pyrazol-3-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (117 mg, 74%) as a white solid: ESI-LRMS m/e calcd for C25H27C12N3O3S [M+] 519.1, found 520.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.20 (m, 2H, CH2), 1.40-1.93 (m, 8H, 4×CH2), 2.09-2.31 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.51-3.60 (m, 1H, CH), 5.09 (s, 2H, NCH2), 6.69 (d, J=2.3 Hz, 1H, Ar), 7.06 (d, Jo=8.3 Hz, 2H, Ar), 7.26-7.33 (m, 3H, Ar), 7.43 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.57 (d, Jm=1.7 Hz, 1H, Ar), 7.88-8.36 (m, 2H, Ar and NH).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=2)[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28](=[O:31])(=[O:30])[NH2:29])=[O:20])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH:8]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=2)[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([NH:29][C:1](=[O:3])[CH3:2])(=[O:31])=[O:30])=[O:20])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
In a stream of nitrogen and at 0° C., 0.11 ml (1.10 mmol) of acetic anhydride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 400 mg (1.00 mmol) of 3-cyclohexylmethoxy-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 7 and 237 mg (1.90 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 430 mg (yield: 96.9%) of the title compound.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[N:8][CH:9]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][NH:2][CH3:1])[C:26]=2[Cl:27])=[O:21])=[N:8][CH:9]=1
Reactant: CN
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNCc1csc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c1Cl
Temperature: 25 °C
Yield: 37.2 %

Procedure:
To methylamine (2.0 M in tetrahydrofuran, 16 mL, 32 mmol) was added a solution of N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (3.0 g, 6.3 mmol) in DMF (10 mL) and the mixture stirred at ambient temperature. After 4 hours the reaction mixture was poured into water (100 mL), concentrated in vacuo to remove the tetrahydrofuran and extracted with ethyl acetate (2×75 mL). The combined organics were washed with brine (75 mL), dried over MgSO4 and concentrated of all volatiles in vacuo. Purification by flash chromatography on silica gel afforded 1.1 g (38% yield) of N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide as a yellow solid; NMR (DMSO-d6/TFA) 11.4 (s, 1), 11.0 (s, 1), 8.9 (br s, 2), 7.6-8.4 (m, 7), 4.2 (m, 2), 2.6 (m, 3) ppm.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][NH:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)=O.[NH4+].[OH-]>O>[F:1][C:2]([F:14])([F:13])[C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: O=C(NNc1cnccn1)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)c1nnc2cnccn12
Temperature: 150 °C
Yield: 31.6 %

Procedure:
To title compound 477 (3.12 g, 15.14 mmol) was added PPA (15 mL). The mixture was heated to 150° C. for 1 h then poored over water. The aqueous was basified with conc. NH4OH (exotherm) at 0° C. Water was added until everything was dissolved. The mixture was extracted with ethyl acetate (×4). The organics were washed with brine, died over Na2SO4, filtered and concentrated to a brown paste. The residue was purified by flash chromatography (0% to 70% ethyl acetate in hexanes) to afford title compound 478 (0.9 g, 32%) as a brown solid. MS (m/z): 189.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:15]([OH:26])(=O)[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:20](=[O:22])[C:19]3[CH:18]=[CH:17][C:16]([C:15]([NH:1][C:2]4[CH:6]=[C:5]([C:7]5[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=5)[NH:4][N:3]=4)=[O:26])=[CH:24][CH:23]=3)[CH:6]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(-c2cc(N)n[nH]2)cc1
Product: COc1ccc(-c2cc(NC(=O)c3ccc(C(=O)Nc4cc(-c5ccc(OC)cc5)[nH]n4)cc3)n[nH]2)cc1

Procedure:
Compound 473 was prepared from 3-amino-5-(4-methoxyphenyl)pyrazole and terephthalic acid. [M+H]+ calcd for C28H25N6O4: 509.19; found: 508.91.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:14][C:15]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:16]=1[CH:17]=O>>[OH:14][C:15]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(O)c(C=O)c1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: Cc1ccc(O)c(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1

Procedure:
6-[4-(2-Hydroxy-5-methyl-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-hydroxy-5-methylbenzaldehyde (available from Aldrich) (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.23 (s, 3H), 2.58-2.63 (m, 4H), 3.48-3.63 (m, 4H), 3.69 (s, 2H), 5.39 (s, 1H), 6.73-6.78 (m, 2H), 6.98-7.00 (m, 1H), 7.85 (s, 1H), 10.10 (br s, 1H), 12.75 (br s, 1H). Mass spectrum (ES) MH+=301.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:21]=[C:20]([F:30])[CH:19]=2)=[CH:8][CH:7]=1.[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:30][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:21]=1)[C:17]([NH:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:36]2[CH2:37][CH2:38][CH:33]([OH:32])[CH2:34][CH2:35]2)=[CH:7][CH:8]=1)=[O:31]
Reactant: OC1CCNCC1
Reactant: O=C(Nc1ccc(OCCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Product: O=C(Nc1ccc(OCCCN2CCC(O)CC2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from N-[4-(3-chloropropoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and 4-hydroxypiperidine according to conditions described in general procedure L. A yellow powder is produced (0.137 g, 80%). MS: 506 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]([NH2:19])(=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>CC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][C:11](=[S:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC(=S)c1ccccc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(NC(=S)c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 22.7 %

Procedure:
To a solution of 4-fluorobenzoylchloride (1.3 g, 8.5 mmol) in acetone (7.0 ml) was added a solution of thiobenzamide (1.16 g, 8.5 mmol) and pyridine (0.66 g, 8.5 mmol) in acetone (7.0 ml). The mixture was refluxed for 6 h. and cooled to room temperature. The reaction mixture was poured into water/ice and extracted with chloroform. Flash chromatography on silica gel afforded 0.5 g of the title compound as a red solid.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33].O>CO>[OH:33][CH2:32][CH2:31][CH2:30][NH:29][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[N:6][CH:5]=1)=[O:28]
Reactant: NCCCO
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Solvent: CO
Solvent: O
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCCO)cn2)CC1
Reaction time: 2 h
Yield: 78 %

Procedure:
6-[1-[3-(Isopropylamino)-2-pyridyl]piperazine-4-yl-carbonyl]nicotinic acid methyl ester (2.5 g) was dissolved in methanol (40 ml) and with the addition of 3-amino-1-propanol (0.95 g), the mixture was heated to reflux for 12 hours and cooled. The excess of water was added slowly at 25° C. for precipitation, the mixture was stirred for 2 hours and filtered. The filtered solid was recrystallized with isopropanol and ether, filtered and dried to give a desired compound of 2.17 g (yield: 78%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:16]([NH2:18])=[O:17]>ClCCl>[C:16]([C:15]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([NH:12][C:8]([C:7]2[C:6]([Cl:11])=[N:5][CH:4]=[N:3][C:2]=2[Cl:1])=[O:9])[CH:14]=1)(=[O:17])[NH2:18]
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: COc1ccc(C(N)=O)cc1N
Solvent: ClCCl
Product: COc1ccc(C(N)=O)cc1NC(=O)c1c(Cl)ncnc1Cl
Reaction time: 1 h
Yield: 66 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (430 mg, 2.03 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (3 ml) and TEA (283 μl, 2.03 mmol) was added. To this solution, 3-amino-4-methoxybenzamide (338 mg, 2.03 mmol) dissolved in 3 ml dichloromethane was added dropwise and the mixture was stirred for 60 min. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude (366 mg, 93% purity, 66% yield) was used in the next synthetic step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[C:9]2[C:4](=[CH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[CH:7][N:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([SH:30])[CH3:29]>CN(C=O)C.O>[CH2:28]([S:30][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[C:9]2[C:4](=[CH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[CH:7][N:8]=2)[N:3]=1)[CH3:29]
Reactant: CCOC(=O)c1c(Cl)nc2cc(C(F)(F)F)cnc2c1C
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(SCC)nc2cc(C(F)(F)F)cnc2c1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
To a solution of ethyl 2-chloro-4-methyl-7-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate (0.97 g, 3.05 mmol, 1 eq.) in DMF (10 ml) were added K2CO3 (1.26 g, 9.15 mmol, 3 eq.) and ethanethiol (0.66 ml, 9.15 mmol, 3 eq.) at RT. The mixture was stirred at 60° C. for 16 h. Afterwards the mixture was diluted with water (80 ml) and was extracted with EtOAc (3×80 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na2SO4 and evaporated to provide the crude product, which is purified by CC (EtOAc/hexane 1:9) to yield ethyl 2-(ethylthio)-4-methyl-7-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate (0.75 g, 2.18 mmol, 71%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:16])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:23](=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:16]
Reactant: CCCCCCCCCCCCC(=O)N1CCCC[C@H]1C(=O)NCCCCCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)N1CCCC[C@H]1C(=O)NCCCCCCN
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A solution of (S)-(6-{[1-(1-tridecanoyl-piperidin-2-yl)-methanoyl]-amino}-hexyl)-carbamic acid tert-butyl ester (3.9 g, 7.45 mmol) in DCM (40 mL) was treated with TFA (8 mL) at −20° C. for two days until disappearance of the starting material. The reaction mixture was allowed to warm up to rt and was washed with an aqueous saturated solution of K2CO3. Extraction, drying over MgSO4 and evaporation in vacuo gave a yellow oil. Purification via flash chromatography (SiO2, 5×13 cm2 column) using a mixture (90:10:2) of DCM:MeOH(5% aqueous solution of NH3) gave the title compound (1.35 g) as a pale yellow oil. The residue was taken in anhydrous DCM (25 mL) and treated with TFA (246 μL, 365 mg) at —10° C. Evaporation of the solvents gave the title compound (1.67 g, 3.11 mmol) as a yellow oil in a 42% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19](=O)[CH:20]=[CH:21][N:22](C)C)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.O.[NH2:32]N>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:32][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=4)=[CH:6][CH:7]=1
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Br)cc3)c(=O)n(C)c1n2C
Reactant: NN
Solvent: O
Product: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 36 above, with compound 3-(4-bromophenyl)-6-(3-dimethylaminoacryloyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and hydrazine monohydrate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:22])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccnc2cc(OCc3ccccc3)ccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1ccnc2cc(OCc3ccccc3)ccc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a suspension of 7-(benzyloxy)quinolin-4-ol (72 g, 287 mmol) in toluene (134 mL) was added phosphoryl trichloride (44 g, 287 mmol, Tianjin FuChen Chem. Co. Ltd.). The suspension was heated to 120° C. for 1 hour. The reaction mixture was then cooled to 70° C. and diluted with EtOAc (600 mL). The resulted mixture was stirred for 30 minutes while cooling down to 15° C. using an ice bath. The mixture was neutralized with 3 M NaOH aqueous solution to pH 7˜8 while maintaining the temperature of the solution under 20° C. The aqueous layer was separated and extracted with EtOAc (200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a pale yellow solid (70.8 g, 91.6%).