Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([C:27]2[CH:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:33]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccnc(N2CCOCC2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccnc(N5CCOCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 86.5 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (57.57 mg, 0.1702 mmol), 2-Morpholin-4-yl-pyridine-4-carbaldehyde (36.0 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to produce 75.1 mg (86%) of the title compound. (300 MHz, DMSO-d6) 13.47 (s, 1H), 8.28 (d, J=5 Hz, 1H), 8.08 (s, 1H), 7.76 (s, 1H), 7.52 s, 1H), 7.36 (d, J=5 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.24 (s, 1H), 6.39 (s, 2H), 5.20 (t, J=17 Hz, 8.5 Hz, 1H), 3.75 (m, 4H), 3.54 (s, 4H), 2.90 (s, 1H), 2.79 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=512 (M+H), HPLC: 1.78 min. (G Method)
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][S:17]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23]3)(=[O:19])=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:30][C:31]1[C:35]([C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[O:37])=[C:34]([CH3:45])[NH:33][C:32]=1[CH:46]=O>N1CCCCC1.C(O)C>[CH3:30][C:31]1[C:35]([C:36]([N:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)=[O:37])=[C:34]([CH3:45])[NH:33][C:32]=1/[CH:46]=[C:23]1\[C:24](=[O:29])[NH:25][C:26]2[C:22]\1=[CH:21][C:20]([S:17]([CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:19])=[O:18])=[CH:28][CH:27]=2
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3OCCN3CCOCC3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4OCCN4CCOCC4)cc32)c(C)c1C(=O)N1CCN(C)CC1
Yield: 50.2 %

Procedure:
5-[2-(2-Morpholin-4-yl-ethoxy)-phenylmethanesulfonyl]-1,3-dihydro-indol-2-one (46 mg, 0.12 mmol) was condensed with 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (30 mg, 0.12 mmol) and piperidine (1 drop) in ethanol (1.5 mL) at rt for 48 hours. The solid was collected by vacuum filtration and purified on a silica gel column to give 39 mg (55%) of the titled compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]=[CH:14][C:15]([OH:17])=[O:16])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)CC(=O)O
Reactant: O=CC1CCC2(CC1)OCCO2
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=CC1CCC2(CC1)OCCO2

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decane-8-carbaldehyde (3.1 g, 18.4 mmol, prepared as in STEP B above), malonic acid (3.8 g, 36.5 mmol), piperidine (0.182 mL, 1.8 mmol) in pyridine (20 mL) was stirred at 70° C. under an argon atmosphere. After 3 h the resulting solution was concentrated. The residue obtained was partitioned between ethyl acetate and water. The layers were separated, and the ethyl acetate layer was washed successively with water and brine. The ethyl acetate layer was dried over sodium sulfate and was filtered, concentrated, and dried in vacuo to yield 3-(1,4-dioxa-spiro[4.5]dec-8-yl)-acrylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2.[OH:35]OS([O-])=O.[K+].O.[OH-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([OH:35])=[O:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH3:15])=[CH:7]2
Reactant: O=S([O-])OO
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C=O)n4)ncnc32)cc1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C(=O)O)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbaldehyde 5 (1.67 g, 3.53 mmol, 1 eq) in DMF (40 mL) at RT, oxone (6.5 g, 10.59 mmol, 3 eq) was slowly added and the resulting mixture was stirred at RT overnight. The reaction was complete based on TLC analysis. The reaction mixture was poured into water (50 mL) and neutralized with concentrated ammonium hydroxide to adjust the pH value to 7-8. The mixture was stirred at RT for 30 min and then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carboxylic acid 10.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:6]([N:19]([CH3:21])[CH3:20])=[N:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[N:9][CH:10]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:56]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[CH:58][C:57]=1[C:66](O)=[O:67]>CN(C=O)C.O>[CH3:21][N:19]([CH3:20])[C:6]1[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:22])=[CH:10][N:9]=[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:66]([C:57]3[CH:58]=[CH:59][C:60]4[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=4)[CH:56]=3)=[O:67])=[CH:14][CH:13]=2)[N:7]=1
Reactant: COC(=O)Cc1cnc(Cc2ccc(N)cc2)nc1N(C)C
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cnc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N(C)C
Reaction time: 3 h

Procedure:
A solution containing methyl[2-(4-aminobenzyl)-4-(dimethylamino)pyrimidin-5-yl]acetate (0.090 g, 0.30 mmol) and PyBOP (0.187 g, 0.36 mmol) in anhydrous DMF (1 mL) at room temperature was treated with 2-naphthoic acid (0.062 g, 0.36 mmol). The reaction mixture was stirred for 3 hours before diluting with water. The thus quenched reaction mixture was extracted with EtOAc and the combined organic extracts was washed sequentially with 0.5N HCl, saturated NaHCO3, and brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the crude product methyl {4-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][N:16](C(OCC)=O)[CH2:15][CH2:14]3)=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[C:1]1([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)N1CCN(c2ncc(-c3ccccc3)cn2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cnc(N3CCNCC3)nc2)cc1

Procedure:
0.04 mol of ethyl 1-(5-phenyl-2-pyrimidinyl)-4piperazinecarboxylate are boiled under reflux with 0.78 mol of KOH in 400 ml of C2H5OH and 40 ml of H2O under N2 protective gas for 15 hours. The mixture is evaporated to dryness, water is added and the residue is taken up in CH2Cl2. After washing with water, the organic phase is separated off and evaporated to dryness, whereupon the amine is obtained as crystals.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([N:16]([C@H:19]2[CH2:24][CH2:23][C@H:22]([N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:26])[CH2:21][CH2:20]2)[CH2:17][CH3:18])[C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C>[C:30]([O:29][C:27]([N:25]([CH3:26])[C@H:22]1[CH2:21][CH2:20][C@H:19]([N:16]([CH2:17][CH3:18])[C:7]2[C:8]([CH3:15])=[C:9]([CH:14]=[C:5]([C:4]#[C:3][CH2:2][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:6]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:24][CH2:23]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: C1COCCN1
Reactant: CCN(c1cc(C#CCBr)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Solvent: CN(C)C=O
Product: CCN(c1cc(C#CCN2CCOCC2)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of methyl 5-(3-bromoprop-1-yn-1-yl)-3-(((trans)-4-((tert-butoxy carbonyl)-(methyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (1 equiv.) in DMF, morpholine (5 equiv.) was added and reaction was stirred for 12 h at room temperature. On completion, the reaction was quenched with ice water and extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure to afford desired crude title compound that was used in the next step without further purification (98.7% yield)
Reaction SMILES: C(O[C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5])C.CCCN[N:19]([CH2:24][CH3:25])NCCC>>[CH3:4][CH:6]([N:13]([CH2:25][CH2:24][NH:19][C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH:9]([CH3:10])[CH3:8])[CH3:7]
Reactant: CCCNN(CC)NCCC
Reactant: CCOC(=O)C1CCC2CCC(=O)N21
Product: CC(C)N(CCNC(=O)C1CCC2CCC(=O)N21)C(C)C
Temperature: 80 °C

Procedure:
A solution of hexahydro-5-oxo-1H-pyrrolizine-3-carboxylic acid ethyl ester (5.0 g, 0.0254 mol) in N,N-di-(2-methylethyl)aminoethylamine (10 g, 0.0693 mol) is stirred at room temperature 24 hours and heated at 80° C. for 24 hours. The solution is concentrated at reduced pressure and distilled to yield N-[2-[N,N-bis(1-methylethyl)amino]ethyl]-hexahydro-5-oxo-1H-pyrrolizine3-carboxamide, bp 155°-165° C. at 0.025 Torr.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[CH:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][C:18]=1[CH:27]([NH:34][C:9]([CH2:8][NH:7][C:6](=[O:12])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=1)=[O:11])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NC(c1ccccc1)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1cc(C(F)(F)F)ccc1Cl

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(2-chloro-5-trifluoromethyl-phenyl)-C-phenyl-methylamine hydrochloride (CA [13954-13-7]).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]2[S:31][C:32]([C:35]([NH:37][NH2:38])=[O:36])=[CH:33][CH:34]=2)=[O:29])=[CH:20][CH:19]=1.O>CN(C)C=O>[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]2[S:31][C:32]([C:35]([NH:37][N:38]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:36])=[CH:33][CH:34]=2)=[O:29])=[CH:20][CH:19]=1
Reactant: NNC(=O)c1ccc(C(=O)NCCCc2ccncc2)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=O)c1ccc(C(=O)NCCCc2ccncc2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reaction time: 16 h
Yield: 95 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (42 mg, 0.14 mmol) and 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-(pyridin-4-yl)propylamide (40 mg, 0.13 mmol) prepared in Reference Synthetic Example 26 were dissolved in N,N-dimethylformamide (1.0 mL) and left at 70° C. for 16 hours and then at room temperature for 24 hours. Water (0.36 mL) was added with stirring, and the precipitated solid was recovered by filtration to give the desired product, 5-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophen-3-yl]ethylidenehydrazinocarbonyl}thiophene-2-carboxylic acid 3-(pyridin-4-yl)propylamide (yield 95%).
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5]([CH2:22][S:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:6][CH:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])C.[OH-].[K+]>C(O)C>[C:18]([O:17][C:15](=[O:16])[CH:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH:5]([CH2:22][S:23][C:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:4]([OH:43])=[O:3])([CH3:20])([CH3:21])[CH3:19]
Reactant: CCOC(=O)C(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)C(CC(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 46.1 %

Procedure:
To a stirred solution of the ester of example 33 (2.1 g, 3.31 mmol) in ethanol (11 mL) was added 17.4 ml of a 10% aqueous solution of potassium hydroxide. The resulting mixture was stirred for 24 hours. After evaporation of the solvent, the obtained residue was taken-up into 50 ml of water and washed with diethyl ether (2×50 mL). The aqueous layer was then acidified to pH 3 with a 10% aqueous solution of hydrochloric acid at 0° C. and immediately extracted with ethyl acetate (5×50 ml). The organic extracts were combined, washed with water, and dried over anhydrous magnesium sulfate. Evaporation under vacuum gave the crude product which was purified by flash chromatography (SiO2, 70% hexane-30% ethyl acetate) to afford 880 mg of the desired compound: 1H NMR (CDCl3, 400 MHz) δ 7.31 (m, 15H), 3.04 (t, 1H), 2.95 (m, 1H), 2.25 (m, 2H), 1.85 (m, 1H), 1.44 (s, 18H); 13C NMR (CDCl3, 400 MHz) 173.9, 168.5, 144.9, 129.7, 128.3, 128.0, 82.0, 51.9, 43.3, 33.7, 30.5, 27.2.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[O:40][CH3:41])=O>>[CH3:41][O:40][C:33]1[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[CH:37][C:32]=1[C:30]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:29]=1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: COc1ccc(OC)c(C(=O)CBr)c1
Product: COc1ccc(OC)c(-c2csc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)c1

Procedure:
100 mg (0.152 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 49 mg (0.182 mmol) of 2-bromo-1-(2,5-dimethoxyphenyl)ethanone were reacted according to the General Method 3. Yield: 20 mg (24% of theory)
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Mg]Br>C1COCC1.C(OCC)C>[C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH:12]([OH:13])[CH3:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Mg]Br
Reactant: O=Cc1sc2ccccc2c1-c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-phenylbenzo[b]thiophene-2-carbaldehyde (430 mg, 1.87 mmol) in THF (10 mL) at −78° C. and under a nitrogen atmosphere was added 3.0M methylmagnesium bromide in diethyl ether (1.24 mL) and stirring continued for 30 min. The reaction mixture was quenched with a saturated solution of NH4Cl (20 mL) and slowly warmed to RT. The mixture was extracted with EtOAc (×2) and the combined organic fractions washed with water, dried (Na2SO4) and concentrated in vacuo affording the title compound as a white solid (472 mg, quantitative). 1H NMR (CDCl3, 400 MHz): δ 7.88-7.84 (1H, m), 7.52-7.28 (8H, m), 5.21 (1H, q, J=6.35 Hz), 2.03 (1H, s), 1.59 (3H, d, J=6.63 Hz)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:12][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: O=C1CCc2c(O)cccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc2c1CCC2=O
Temperature: 50 °C
Reaction time: 72 h
Yield: 98.8 %

Procedure:
4-Hydroxy-1-indanone (5.0 g, 33.7 mmol) was dissolved in acetone (170 mL) and then potassium carbonate (9.0 g, 138.21 mmol) and Mel (9.6 g, 67.5 mmol) were added. The resulting suspension was heated to 50° C. and stirred for 3 days at which time the reaction mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and water. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (5.4 g, 98%) as a yellow solid. GC-MS m/z [M+H]+ 163.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]=[C:12]([C:16]([O:18]C)=[O:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C1=CCCN(C(=O)OC(C)(C)C)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC=C(C(=O)O)C1

Procedure:
A solution of potassium hydroxide (44 g, 0.79 mol) in water (450 ml) was added to a solution of methyl 1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate (34.9 g, 145 mmol) in methanol (450 ml). The mixture was refluxed for 3h and evaporated to dryness in vacuo. The residue acidified to pH 2.5 with hydrochloric acid (4M) and extracted with methylene chloride. The organic layer was dried over magnesium sulphate and evaporated to dryness in vacuo to give 1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid. (Yield: 28.4g, 86%)
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH:16][C:17]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([N:29]1[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]1)[CH:23]=2)=[O:18])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH:16][C:17]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH:23]=2)=[O:18]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1NC(=O)c1cnc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(F)cc1NC(=O)c1cnc2cc(N3CCNCC3)ccc2c1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of tert-butyl 4-(3-(2-(tert-butoxycarbonylamino)-5-fluoro-phenyl-carbamoyl)quinolin-7-yl)piperazine-1-carboxylate (100 mg, 0.17 mmol) in DCM (3 mL) was added TFA (1.5 mL). The reaction mixture was stirred at r.t for 1 h and concentrated to give a residue, which was purified by Pre-HPLC to afford compound N-(2-amino-5-fluorophenyl)-7-(piperazin-1-yl)quinoline-3-carboxamide (40 mg, 62%) as a light yellow solid. 1H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 9.34 (s, 1H), 9.05 (s, 3H), 8.10 (s, 1H), 7.68 (s, 1H), 7.43 (s, 1H), 7.24 (s, 1H), 6.96 (s, 2H), 3.71 (s, 4H), 3.31 (s, 4H). LCMS: 1.21 min, m/z=366 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[CH2:32]([O:34][CH2:35][CH2:36][NH2:37])[CH3:33]>CN(C=O)C.O>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:37][CH2:36][CH2:35][O:34][CH2:32][CH3:33])=[O:25])[C:6]1=[O:29]
Reactant: CCOCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
A solution of ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (44 mg, 0.103 mmol) and 2-ethoxyethylamine (15 μL, 0.135 mmol) in DMF (0.9 mL) was heated at 100° C. for 1.5 h. The reaction mixture was diluted with water and the resulting precipitate was collected by filtration. The filter cake was washed water and MeOH and dried under vacuum to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.23 (1H, br m), 8.51 (1H, s), 7.74 (1H, s), 7.31 (2H, dd, J=8.4, 5.7 Hz), 7.12 (2H, t, J˜9 Hz), 5.12 (2H, s), 4.11 (2H, s), 3.51 (4H, s), 3.46 (2H, q, J=7 Hz), 3.12 (3H, s), 2.81 (3H, s), 1.10 (3H, t, J=7 Hz); HRMS calcd for C24H27FN4O5+H+: 471.2044. Found: 471.2050.
Reaction SMILES: Br.[NH:2]([C:4]1[NH:5][CH2:6][CH2:7][N:8]=1)[NH2:3].Br.[OH:10][C@H:11]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@:17]3([OH:34])[CH2:18][CH2:19][C@@H:20]2/[CH:21]=[CH:22]/[CH:23]=O)[CH2:12]1>O.O1CCOCC1>[NH:8]1[CH2:7][CH2:6][N:5]=[C:4]1[NH:2]/[N:3]=[CH:23]/[CH:22]=[CH:21]/[C@H:20]1[CH2:19][CH2:18][C@:17]2([OH:34])[C@H:16]3[C@H:28]([CH2:27][CH2:26][C@:25]12[CH3:33])[C@:29]1([CH3:32])[C@@H:13]([CH2:12][C@@H:11]([OH:10])[CH2:31][CH2:30]1)[CH2:14][CH2:15]3
Reactant: NNC1=NCCN1
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=O)CC[C@]12O
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=N/NC3=NCCN3)CC[C@]12O
Reaction time: 72 h
Yield: 59.9 %

Procedure:
A solution of 1.19 g of 2-hydrazino-2-imidazoline hydrobromide in 20 ml of water and 60 ml of dioxane was made acid to pH 3 with 0.1N HBr. A solution of 2.08 g of (E)-3β,14β-dihydroxy-5β-pregn-20-ene-21-carboxaldehyde (Fullerton D. S. et al., J. Med. Chem., 1976, 19, 1330) in 25 ml of dioxane was added at room temperature. After 3 days, the solution was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 90/10/1 as the eluant; the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with ethyl acetate and ethanol to give 1.54 g of the title compound (I-ac) as a white solid.