Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:11]2=[CH:12][CH:13]=[CH:14][N:10]2[CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=2[O:6]1)C.C(=O)([O-])[O-].[K+].[K+].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].O>C1C=CC=CC=1>[CH2:35]([O:34][C:32]([N:2]([CH2:4][CH:5]1[C:11]2=[CH:12][CH:13]=[CH:14][N:10]2[CH:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=2[O:6]1)[CH3:1])=[O:33])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: CN(C)CC1Oc2ccccc2C(c2ccccc2)n2cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)N(C)CC1Oc2ccccc2C(c2ccccc2)n2cccc21
Temperature: 65 °C

Procedure:
To a mixture of 11-dimethylaminomethyl-5-phenyl-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (9.92 g) and potassium carbonate (4.28 g) in 150 ml of benzene was added ethyl chloroformate (5.9 ml). This was heated at 65° C. for 6 hours, then added to water and extracted with ethyl ether (4×). The combined organics were washed with water, dried and concentrated to give 10.5 g of an oil which was used without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH:26]=[C:25]([CH2:27][C:28]#[N:29])[N:24]=[CH:23]1>>[C:28]([CH2:27][C:25]1[N:24]=[CH:23][N:22]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH:26]=1)#[N:29]
Reactant: N#CCc1c[nH]cn1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cnc(CC#N)c3)cc2c1=O
Yield: 47 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (1H-imidazol-4-yl)-acetonitrile according to the GPB affording 18.5 mg (47%) of a yellow powder. Rt=2.56 min.
Reaction SMILES: [N+:1]1([O-:10])[O:5][N:4]=[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=12.[N+]([CH2:14][CH3:15])([O-])=O.C(NCC)C>O1CCCC1>[CH3:14][C:15]1[N:4]([OH:5])[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[N+:1]=1[O-:10]
Reactant: CC[N+](=O)[O-]
Reactant: [O-][n+]1onc2ccccc21
Solvent: CCNCC
Solvent: C1CCOC1
Product: Cc1n(O)c2ccccc2[n+]1[O-]
Reaction time: 1 h
Yield: 58.5 %

Procedure:
In the typical procedure, 0.1 mole of benzofurazan 1-oxide and 0.12 mole of nitroethane is dissolved at 100 ml. of tetrahydrofuran. To this mixture there is added at room temperature, 0.12 mole of diethylamine over a period of 0.5 hour. An instantaneous exothermic reaction is observed (40° C.) and within one hour, the product crystallizes from the solution. The solution is allowed to stand overnight at room temperature and filtered to yield 9.6 grams of 2-methyl-1-hydroxy-1-H-benzimidazole 3-oxide (Table I, Example 2). The product can be rectystallized from methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([O:51]CC5C=CC(Cl)=C(Cl)C=5)[CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CCOC(C)=O.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:26][CH:27]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([OH:51])[CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(O)c1)CO3
Reaction time: 4 h
Yield: 88.5 %

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (250 mg) was dissolved in 6 mL of EtOAc:MeOH (1:5) and Pd—C(30 mg, 10% by wt.) was added and stirred under a hydrogen atmosphere (balloon) for 4 hours. Triethylamine (0.3 mL) was added to the reaction mixture and stirred for 5 minutes. The catalyst was filtered and washed with MeOH. The filtrate was evaporated, and the residue was taken up in EtOAc (10 mL) and washed with water and brine, and then dried (Na2SO4), filtered, and evaporated to get (3S,8S)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-3-(3-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino-[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (180 mg). LCMS (m/z): 695.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[C:23]1([CH:29](O)[C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:14])=[O:15])[CH2:10][N:9]1[CH:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:30]([F:32])([F:31])[F:33])=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Reactant: OC(c1ccccc1)C(F)(F)F
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(c1ccccc1)C(F)(F)F

Procedure:
L6. (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K1 was reacted with 1-phenyl-2,2,2-trifluoroethanol as described in experiment L5 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(2,2,2-trifluoro-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a white amorphous solid. MS: 486.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]3([NH:31]C(=O)OC(C)(C)C)[CH2:28][O:27]C(C)(C)[O:25][CH2:24]3)[CH2:17][CH2:16]4)[O:10][C:6]=2[CH:5]=[C:4]([Cl:39])[CH:3]=1.CC1(C)OCC(NC(=O)OC(C)(C)C)(CNC2C=CC(CCCCCCCC)=CC=2)CO1>>[NH2:31][C:23]([CH2:22][N:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][C:9]3[O:10][C:6]4[CH:5]=[C:4]([Cl:39])[CH:3]=[C:2]([Cl:1])[C:7]=4[CH:8]=3)=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)([CH2:24][OH:25])[CH2:28][OH:27]
Reactant: CC(C)(C)OC(=O)NC1(CN2CCc3cc(OCc4cc5c(Cl)cc(Cl)cc5o4)ccc32)COC(C)(C)OC1
Agent: CCCCCCCCc1ccc(NCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Product: NC(CO)(CO)CN1CCc2cc(OCc3cc4c(Cl)cc(Cl)cc4o3)ccc21
Yield: 37 %

Procedure:
When the product of Step G was substituted for tert-butyl 2,2-dimethyl-5-((4-octylphenylamino)methyl)-1,3-dioxan-5-ylcarbamate in Example 1, Step B, the identical process afforded the title compound in 37% yield, as a off white solid. 1H-NMR (CD3OD) 2.9 (tr, 2H, J=8.2 Hz); 3.37 (tr, 2H, J=8.2 Hz); 3.43-3.53 (m, 4H); 5.0 (s, 2H); 6.5 (d, 1H, J=8.4 Hz); 6.65-6.7 (m, 1H); 6.76 (s, 2H); 7.19 (d, 1H, J=1.5 Hz); 7.37 (m, 1H).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][C@@H:7]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][CH2:5]1)=[N+]=[N-]>CO.[Pd]>[CH:10]([C@H:7]1[O:6][CH2:5][C@@H:4]([NH2:1])[CH2:9][CH2:8]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [N-]=[N+]=N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Yield: 77 %

Procedure:
Cis-5-azido-2-diphenylmethyl-tetrahydropyran 14 (0.3 g, 1.02 mmol) in methanol (25 ml) was hydrogenated under the catalyst of 10% Pd—C (0.03 g, 10% wt) for 4 hr (Procedure C) to give cis-5-amino-2-diphenylmethyl-tetrahydropyran 15 (0.21 g, 78%) as an oil.
Reaction SMILES: [CH:1]([C:3]1[N:4]([CH2:12][C:13]#[CH:14])[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=O.Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[CH2:12]([N:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:3]1[CH:1]=[N:16][OH:17])[C:13]#[CH:14]
Reactant: C#CCn1ccc(C(=O)OC)c1C=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: C#CCn1ccc(C(=O)OC)c1C=NO
Yield: 106.9 %

Procedure:
2 g of the product of Step A, 725 mg of hydroxylamine hydrochloride and 11 ml of anhydrous pyridine were stirred for 3 hours at ambient temperature and the pyridine was then concentrated under reduced pressure. The residue was taken up in ethyl acetate and the solution was washed with water, dried and concentrated to obtain 2.3 g of methyl 1-(2-propynyl)-2-oximinomethyl-3-pyrrole-carboxylate melting at 88°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([CH2:35][C:36]([OH:38])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:39][Si](C=[N+]=[N-])(C)C.C(OCC)C>CO.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:28][CH2:29]3)(=[O:25])=[O:26])[C:11](=[O:33])[C@:10]([CH2:35][C:36]([O:38][CH3:39])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CO
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid (0.055 g, 0.095 mmol; Example 141) in 1 mL of MeOH and 4 mL of benzene was added a 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether (0.095 mL, 0.189 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h and was then concentrated. The crude material was purified by reverse phase preparatory HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) to provide the title compound as a white powder after lyophilization of the pooled collected fractions.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]([OH:14])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][N:39]1[CH2:44][CH2:45][CH2:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:50][CH:49]=1>CN(C=O)C.C(N(C(C)C)CC)(C)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]([N:57]1[CH2:58][CH2:59][N:54]([C:51]2[CH:50]=[CH:49][C:48]([O:47][CH2:46][CH2:45][CH2:44][N:39]3[CH2:40][CH2:41][CH2:42][CH2:43][CH:38]3[CH3:37])=[CH:53][CH:52]=2)[CH2:55][CH2:56]1)=[O:14]
Reactant: Cn1cc(C(=O)O)c2cc(F)ccc21
Reactant: CC1CCCCN1CCCOc1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCCCN1CCCOc1ccc(N2CCN(C(=O)c3cn(C)c4ccc(F)cc34)CC2)cc1
Reaction time: 18 h
Yield: 45.4 %

Procedure:
A solution of 5-fluoro-1-methyl-1H-indole-3-carboxylic acid (19.3 mg) and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (56 mg) in DMF (1 ml) and diisopropylethylamine (0.035 ml) was stirred for 10 min before 1-{4-[3-(2-methylpiperidin-1-yl)propoxy]phenyl}piperazine (E76b) (21.3 mg) in DMF (0.5 ml) was added. The mixture was stirred for 18 h and then concentrated under reduced pressure. The residue was purified by SPE ion exchange chromatography on an SCX-2 cartridge (1 g). The cartridge was washed with methanol (3 ml) and the product eluted with 2M ammonia in methanol (2.5 ml), to give the title compound (15 mg) LCMS RT=2.42 min, ES+ve m/z 493 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](Cl)[CH:18]=2)[NH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1(=[O:28])[O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22]1>C1C=CC=CC=1>[C:25]([CH2:24][CH2:23][CH2:22][C:21]([N:8]([CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:28])([OH:27])=[O:26]
Reactant: O=C1CCCC(=O)O1
Reactant: Clc1ccc2[nH]cc(CCNCc3ccccc3)c2c1
Solvent: c1ccccc1
Product: O=C(O)CCCC(=O)N(CCc1c[nH]c2ccccc12)Cc1ccccc1
Reaction time: 8 h

Procedure:
113 g (0.396 mol) of 3-(2-benzylaminoethyl)-5-chloroindole are dissolved in 500 ml of benzene. 45.27 g of glutaric anhydride are added in small amounts and the reaction mixture is heated at the reflux temperature for 2 hours and then left to stand overnight. It is evaporated to dryness. This gives the named product.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:29])[NH:7][C:8]2[CH:28]=[CH:27][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])=[CH:27][CH:28]=2)=[O:29])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)NCC3CC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCNCC2)cc1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
tert-Butyl 4-(4-(3-(cyclopropylmethyl)ureido)benzoyl)piperazine-1-carboxylate (46.7 mmol, 18.78 g) was dissolved in dichloromethane (30 mL) and trifluoroacetic acid (233 mmol, 17.33 mL, 26.6 g) added. The reaction was stirred for 1 hour and then concentrated under reduced pressure. The crude material was triturated with ether to give a white powder after high vacuum drying, which was taken up in water and carefully taken to pH 10 with sodium carbonate. The aqueous was extracted with dichloromethane and the combined organic phases were dried, filtered and concentrated under reduced pressure to give the title compound (13.4 g)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C@H:40]([NH2:43])[CH2:41][CH3:42].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C@H:40]([NH:43][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])[CH2:41][CH3:42]
Reactant: CC[C@@H](N)c1ccccn1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with (R)-1-(2-pyridyl)-propylamine hydrochloride (40 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 112 mg of the title compound as a light yellow solid. Optical Rotation: [α]D=−66.8° (c=0.40 mg/ml; CH3OH).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:31]=[CH:30][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:60][O:59]2)=[CH:52][CH:51]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[Cl:28])[CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:60][C@H:58]([OH:59])[CH2:57][O:56][C:53]3[CH:54]=[CH:55][C:50]([OH:49])=[CH:51][CH:52]=3)=[CH:31][CH:30]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccc(Cl)c(Cl)c3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=C(NCc1ccc(Cl)c(Cl)c1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 29.5 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(3,4-dichlorobenzyl)-1-piperidinecarboxamide formate (0.30 g, 0.64 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.233 g, 0.577 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.14 g, 0.17 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28]OS(C)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:28][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Reactant: CS(=O)(=O)OCCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCc1ccccn1
Temperature: 85 °C
Yield: 43.4 %

Procedure:
Using General Procedure A: A suspension of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-cis-[2,2′;6′,2″]terpyridine (252 mg, 0.94 mmol), methanesulfonic acid 2-pyridin-2-yl-ethyl ester (approx. 4.9 mmol) and K2CO3 (1.30 g, 9.42 mmol) in DMF (5 mL) was heated at 85° C. for 2.5 d. Purification of the crude material by column chromatography on silica gel (CH2Cl2—CH3OH—NH4OH, 96:4:0 then 94:4:2) followed by radial chromatography on silica gel (1 mm plate, CH2Cl2—CH3OH—NH4OH, 25:1:1) provided 152 mg (43%) of COMPOUND 97 as a pale yellow oil. 1H NMR (CDCl3) δ 1.60-1.72 (m, 3H), 1.96-2.23 (m, 5H), 2.51 (s, 6H), 2.61-2.66 (m, 2H), 4.15 (d, 2H, J=12 Hz), 6.33-6.38 (m, 1H), 6.85 (dd, 1H, J=7.2, 5.1 Hz), 7.07 (dd, 2H, J=7.5, 4.8 Hz), 7.27 (dt, 1H, J=7.5, 1.5 Hz), 7.40 (d, 2H, J=7.5 Hz), 8.19 (d, 1H, J=4.8 hz), 8.42-8.47 (m, 2H); 13C NMR (CDCl3) δ 19.18, 25.52, 30.76, 34.77, 49.87, 63.61, 120.80, 122.22, 122.76, 131.72, 136.15, 138.83, 147.10, 149.18, 160.47, 161.42; ES-MS m/z 373 (M+H). Anal. Calcd. for C24H28N4.1.6 H2O: C, 71.83; H, 7.84; N, 13.96. Found: C, 71.84; H, 7.53; N, 13.65.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[N+](C1C=CC([O:33][S:34]([C:37]([F:40])([F:39])[F:38])(=O)=[O:35])=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:35])=[O:33])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
After dissolving 6-methoxy-4-(4-nitrophenoxy)quinolin-7-ol (1.0 g) in dimethylfbrmamide (10 ml), there were added trifluoromethanesulfonic acid4-nitrophenyl ester (640 mg) and potassium carbonate (1.3 g), and the mixture was stirred at room temperature for 5 hours. Water was added, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was used for recrystallization to obtain the title compound (1.0 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:8][C:7]=1[C:18](O)=[O:19]>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:8][C:7]=1[CH2:18][OH:19]
Reactant: COC(=O)CCc1ccc(Cn2cccn2)cc1C(=O)O
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(Cn2cccn2)cc1CO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.6 %

Procedure:
To a solution of 3-(4-(pyrazol-1-ylmethyl)-2-carboxyphenyl)propanoic acid methyl ester (600 mg) in anhydrous THF (8.0 ml) was added dropwise a solution of borane-tetrahydrofuran complex in THF (3.2 ml) at 0° C. and the mixture was stirred at room temperature for 2.5 hours. To the mixture was added a solution of borane-tetrahydrofuran complex in THF (3.5 ml) and the mixture was stirred for 1 hour. To the reaction solution was added ice and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give the title compound (420 mg) having the following physical data.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[O:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1)([O-])=O.CC(O)=O>C1COCC1.[Zn]>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:20][CH3:21])[N:11]=[CH:10][CH:9]=[C:8]2[O:7][C:6]1[CH:5]=[C:4]([NH2:1])[C:24]([NH2:25])=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)c2cc1OC
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(N)c(N)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(3,4-Dinitrophenoxy)-6,7-dimethoxyquinoline (Step a, 0.256 g) was dissolved in THF (40 mL) and HOAc (1 mL) was added followed by zinc dust (1.3 g). Mixture was stirred at RT for 3 h and filtered through a Celite® pad. Solvent was evaporated and residue was washed with NaOH 1 M and extracted with EtOAc. The organic phase was dried, filtered and evaporated to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[C:13](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)[CH:12]=[C:11]([O:23][CH3:24])[N:10]=2)[CH2:5][CH2:4]1.[CH3:25][C:26]1[CH:35]=[C:34]([CH:36]=O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1>>[CH3:24][O:23][C:11]1[N:10]=[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][CH2:36][C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:25])[CH:35]=3)[CH2:4][CH2:5]2)[N:14]=[C:13](/[CH:15]=[C:16]2/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/2)[CH:12]=1
Reactant: Cc1cc(C=O)c2ccccc2n1
Reactant: COc1cc(/C=C2\SC(=O)NC2=O)nc(N2CCC(CN)CC2)n1
Product: COc1cc(/C=C2\SC(=O)NC2=O)nc(N2CCC(CNCc3cc(C)nc4ccccc34)CC2)n1

Procedure:
(Z)-5-((6-methoxy-2-(4-((((2-methylquinolin-4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using (Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Example 153), the general reductive amination procedure and 2-methylquinoline-4-carbaldehyde (45.8 mg, 63 mg theoretical, 72.2%). LC-MS m/z 505 (M+1).