Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:20]([O:37][CH2:38][CH2:39][N:40]([CH2:48][CH2:49]O)[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(C=P(CCCC)(CCCC)CCCC)#N.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:20]([O:37][CH2:38][CH2:39][N:40]([CH2:48][CH2:49][CH:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])([C:33]([CH3:34])([CH3:36])[CH3:35])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N(CCO)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 95.2 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (500 mg, 1.65 mmol) obtained in Example 5 and t-butyl N-[2-(t-butyldiphenylsilyloxy)ethyl]-N-(2-hydroxyethyl)carbamate (950 mg, 2.14 mmol) were dissolved in toluene (20 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (600 mg, 2.49 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 9 hours. After the reaction mixture was allowed to cool down, t-butyl N-[2-(t-butyldiphenylsilyloxy)ethyl]-N-(2-hydroxyethyl)carbamate (500 mg, 1.13 mmol) and cyanomethylenetri-n-butylphosphorane (300 mg, 1.24 mmol) were added thereto. Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=15:1 eluate was concentrated under reduced pressure, whereby the title compound (1.14 g, 1.57 mmol, 95%) was obtained as a pale yellowish browh foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:23].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH2:43]([N:50]1[CH2:55][CH2:54][CH:53]([NH2:56])[CH2:52][CH2:51]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)(Cl)Cl.O>[CH2:43]([N:50]1[CH2:55][CH2:54][CH:53]([NH:56][C:35]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[C:17]([CH3:23])[CH:18]=2)=[O:41])[CH2:52][CH2:51]1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCN(Cc5ccccc5)CC4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (142 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 1-benzyl-4-piperidineamine (91 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (84 mg, yield 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1>C1COCC1.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)C=Cc1cc(Cl)cc(Cl)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCc1cc(Cl)cc(Cl)c1
Reaction time: 3 h
Yield: 97.4 %

Procedure:
To a solution of 10% Pd-C (1.5 g) in THF (200 mL) was added 3-(3,5-dichlorophenyl)-acrylic acid (11.5 g). The reaction was hydrogenated on a Parr shaker at 50 psi for 3 h. The catalyst was removed by filtration through celite and the organic solution was concentrated in vacuo to afford 3-(3,5-dichlorophenyl)-propionic acid (11.3 g). 1H NMR (400 MHz, CDCl3) δ 7.00-7.35 (m, 3H), 2.89 (t, 2H), 2.66 (t, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH2:36](N(CC)CC)[CH3:37]>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH:36]=[CH2:37])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCCO
Product: C=Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Yield: 84.5 %

Procedure:
N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.421 g, 0.781 mmol), potassium vinyl trifluoroborate (0.262 g, 1.953 mmol), PdCl2(dppf)2 (0.057 g, 0.078 mmol), and triethylamine (1.089 ml, 7.81 mmol) in n-propanol (7.81 ml) were heated at 100° C. in a screw-top vial overnight. The reaction mixture was filtered through celite and the celite rinsed with EtOAc. The combined organic portions were washed with water, dried over MgSO4, filtered and concentrated to dryness. The crude mixture was placed on silica gel and chromatography (0 to 80% DCM/EtOAc, gradient) to obtain the title compound (350 mg, 84%). 1H NMR (400 MHz, DMSO-d6) d ppm 10.88 (s, 1H), 8.56 (d, J=5.31 Hz, 1H), 7.67 (ddd, J=14.28, 8.15, 6.13 Hz, 1H), 7.43 (t, J=7.60 Hz, 2H), 7.31 (t, J=7.69 Hz, 1H), 7.22 (t, J=9.25 Hz, 2H), 6.74 (m, 2H), 6.44 (dd, J=17.58, 1.65 Hz, 1H), 5.75 (dd, J=10.62, 2.01 Hz, 1H), 1.43 (m, 9H); MS (ESI): 531 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:8]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)(=[O:20])=[O:19])[CH:7]2[CH2:29][C:30]([OH:32])=O)(=[O:3])[CH3:2].Cl.Cl.[NH:35]1[CH2:39][CH2:38][N:37]=[C:36]1[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][NH2:48])=[CH:42][CH:41]=1>>[ClH:27].[C:1]([C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:8]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)(=[O:19])=[O:20])[CH:7]2[CH2:29][C:30]([NH:48][CH2:47][CH2:46][C:43]1[CH:44]=[CH:45][C:40]([C:36]2[NH:37][CH2:38][CH2:39][N:35]=2)=[CH:41][CH:42]=1)=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)C(CC(=O)O)N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1-2
Reactant: NCCc1ccc(C2=NCCN2)cc1
Agent: Cl
Product: CC(=O)c1ccc2c(c1)C(CC(=O)NCCc1ccc(C3=NCCN3)cc1)N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1-2

Procedure:
The title compound was prepared from [8-acetyl-5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) according to the method described in Example 1e. MS (EI) 662.3 (MH+).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11]1)=[O:7])(C)(C)C.[CH:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31](C(O)=O)=[C:30]([O:38][CH3:39])[CH:29]=1>>[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:24]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:25])[CH2:11]2)=[O:7])=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN)C1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCNC(=O)C2CCCCC2)C1

Procedure:
2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethylamine (1.00 g) as starting compound was reacted and treated in the same manner as in Example 1 using cyclohexanecarbonyl chloride (0.64 g) and 4-amino-5-chloro-2-methoxybenzoic acid (0.84 g) to give 4-amino-5-chloro-N-(1-(2-cyclohexanecarbonylaminoethyl)pyrrolidin-3-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [ClH:1].C(N(CCC(OCC)=O)C(C1C=CC2N(C)C(CSC3C=CC(C(=N)N)=CC=3)=NC=2C=1)=[O:7])CC.OO.Cl.[CH2:39]([N:42]([CH2:67][CH2:68][C:69]([O:71][CH2:72][CH3:73])=[O:70])[C:43]([C:45]1[CH:66]=[CH:65][C:48]2[N:49]([CH3:64])[C:50]([CH2:52][S:53]([C:55]3[CH:60]=[CH:59][C:58]([C:61](=[NH:63])[NH2:62])=[CH:57][CH:56]=3)=[O:54])=[N:51][C:47]=2[CH:46]=1)=[O:44])[CH2:40][CH3:41].C(OCC)(=O)C.C(O)C>C(O)=O>[ClH:1].[CH2:39]([N:42]([CH2:67][CH2:68][C:69]([O:71][CH2:72][CH3:73])=[O:70])[C:43]([C:45]1[CH:66]=[CH:65][C:48]2[N:49]([CH3:64])[C:50]([CH2:52][S:53]([C:55]3[CH:60]=[CH:59][C:58]([C:61](=[NH:62])[NH2:63])=[CH:57][CH:56]=3)(=[O:7])=[O:54])=[N:51][C:47]=2[CH:46]=1)=[O:44])[CH2:40][CH3:41]
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CS(=O)c1ccc(C(=N)N)cc1)n2C
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CSc1ccc(C(=N)N)cc1)n2C
Agent: Cl
Agent: OO
Solvent: CCO
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CCCN(CCC(=O)OCC)C(=O)c1ccc2c(c1)nc(CS(=O)(=O)c1ccc(C(=N)N)cc1)n2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A solution of 0.40 g (0.70 mMol) of 1-methyl-2-[(4-amidinophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride in 10 ml of formic acid was mixed with 2 ml of 30% hydrogen peroxide solution and the mixture was stirred for 16 hours at room temperature. Then the solvent was distilled off in vacuo, whereupon the desired compound was obtained as a beige solid (contaminated with some 1-methyl-2-[(4-amidinophenyl)sulfinylmethyl]-benzimidazol-5-yl-carboxylic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride). Yield: 95% of theory, C25H31N6O5S (513.62) Rf value: 0.50 (silica gel; ethyl acetate/ethanol/1N hydrochloric acid =50:45:5) EKA mass spectrum: (M+H)+ =514
Reaction SMILES: [C:1]1([C:13]([OH:15])=[O:14])([C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH2:16]1[O:18][CH2:17]1>C(C(C)=O)C(C)C>[OH:8][CH2:7][CH2:2][O:14][C:13]([C:1]1([C:10]([O:12][CH2:17][CH2:16][OH:18])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:1][CH2:10][OH:11])=[O:8])=[O:15]
Reactant: O=C(O)C1CCCCC1(C(=O)O)C(=O)O
Reactant: C1CO1
Solvent: CC(=O)CC(C)C
Product: O=C(OCCO)C1CCCCC1(C(=O)OCCO)C(=O)OCCO

Procedure:
Cyclohexanetricarboxylic acid was allowed to react under pressure with ethylene oxide and 0.15% of the catalyst of Example II (based on total wt. of system) in the presence of methyl isobutyl ketone at 150°-160°C for 2 hours. A viscous oil of good purity was obtained after charcoal treatment and evaporation of a methyl isobutyl ketone solution. The infrared spectra and elemental analysis were consistent with the desired product.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9].[C:13]1([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][C:28]=2[O:37]CCO)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[O:23]CCO.CCCCCC>CC#N.C1COCC1>[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9].[C:27]1([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[O:23][CH:1]([OH:6])[CH3:2])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[O:37][CH:7]([OH:11])[CH3:8]
Reactant: OCCOc1ccc2ccccc2c1-c1c(OCCO)ccc2ccccc12
Agent: C=C(C)C(=O)O
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCCCCC
Product: CC(O)Oc1ccc2ccccc2c1-c1c(OC(C)O)ccc2ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 142.6 %

Procedure:
BMPDMS (260 mg), TASHF2 (100 microliters, 0.1 M. in CH3CH) and THF (125 mL) were added to a dry 250 mL 3-necked round-bottomed flask equipped with a magnetic stirrer, a thermocouple, a reflux condenser and a nitrogen bubbler and the mixture was cooled to 0° C. A solution of (±)-2,2'-((1,1'-binaphthalene)-2,2'-diylbis(oxy))-bis(ethanol) dimethacrylate (2.5 g, 4.9 mmole) and TASHF2 (100 μL, 0.1 M. in CH3CN) in THF (125 mL) were added dropwise (0.5 mL/min) to the solution in the 250 mL flask to give a yellow mixture. This mixture was stirred overnight at 0° C. and then condensed. Hexane was added, and the polymer which precipitated was dried to give 1.91 g of a white powdery solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C.[C-:31]#[N:32].[Na+]>CO>[CH:1]([N:14]1[CH2:17][C:16]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:31]#[N:32])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: NCc1ccccc1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#CC1(NCc2ccccc2)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.75 h
Yield: 71.9 %

Procedure:
To a solution of 1-benzhydrylazetidin-3-one (3.3 g, 14 mmol) in methanol (35 ml) was added benzylamine (1.6 ml, 15 mmol) and then acetic acid (0.88 ml, 15 mmol) at room temperature. After stirring for 45 minutes, solid NaCN (0.76 g, 15 mmol) was added in portions over 2 minutes and the mixture was heated to reflux overnight. The reaction, which now contained a precipitate, was cooled and then stirred at room temperature. The solids were collected by vacuum filtration, rinsed with a small volume of cold methanol, and then dried, in vacuo, to give I-1A-3a as a solid (3.56 g, 72%): +APcI MS (M+1) 354.4; 1H NMR (400 MHz, CD3OD) δ 7.40 (d, J=7.5 Hz, 4H), 7.35 (d, J=7.5 Hz, 2H), 7.31–7.20 (m, 7H), 7.16 (t, J=7.3 Hz, 2H), 4.44 (s, 1H), 3.76 (s, 2H), 3.48 (d, J=8.3 Hz, 2H), 3.05 (d, J=8.3 Hz, 2H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([C@H:16]2[CH2:20][C@@H:19]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[O:22])[NH:18][CH2:17]2)[C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[O:10])[CH2:4][CH2:3]1.[C:30]([N:37]1[CH2:41][C@@H:40]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)[C@H:39]([C:49](O)=[O:50])[CH2:38]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[C:30]([N:37]1[CH2:38][C@@H:39]([C:49]([N:18]2[CH2:17][C@@H:16]([N:8]([C@H:5]3[CH2:6][CH2:7][C@@H:2]([CH3:1])[CH2:3][CH2:4]3)[C:9]([C@@H:11]3[CH2:15][CH2:14][CH2:13][O:12]3)=[O:10])[CH2:20][C@H:19]2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])=[O:50])[C@H:40]([C:42]2[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=2)[CH2:41]1)([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31]
Reactant: CN1CCN(C(=O)[C@@H]2C[C@H](N(C(=O)[C@@H]3CCCO3)[C@H]3CC[C@@H](C)CC3)CN2)CC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Product: CN1CCN(C(=O)[C@@H]2C[C@H](N(C(=O)[C@@H]3CCCO3)[C@H]3CC[C@@H](C)CC3)CN2C(=O)[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccc(Cl)cc2)CC1

Procedure:
(2S)-N-(cis-4-methylcyclohexyl)-N-{(3S,5S)-5-[(4-methylpiperazin-1-yl)carbonyl]pyrrolidin-3-yl}tetrahydrofuran-2-carboxamide (0.76 g, 1.87 mmol) obtained in Step E of Example 16 and (3S,4R)-1-BOC-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid obtained in Preparation 14 were reacted according to the same procedure as in the Step F of Example 1 to give the title compound (1.18 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 70 °C
Yield: 50.5 %

Procedure:
A solution of 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 60 (0.5 g, 1.32 mmol)in 30 mL of dimethylformamide was treated with excess ethyl bromoacetate (0.7 mL, 6.60 mmol). After heating at 70° C. for 1 h, triethylamine (0.9 ml, 6.6 mmol) was added dropwise; the reaction mixture was then heated at 70° C. for an additional 30 min, after which it was partitioned between saturated sodium bicarbonate and dichloromethane. The organic extract was concentrated in vacuo, and the residue was applied to a 10 g SCX column which was washed with methanol and eluted with 1 N ammonia in methanol. The yellow fractions were combined and concentrated in vacuo to afford an orange oil, which was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol, then 9:3 dichloromethane-methanol provided 0.31 g (51%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34](Cl)=O>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:11])[C:9]([CH3:10])=[C:34]([C:30]3[O:29][CH:33]=[CH:32][N:31]=3)[N:12]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1
Reactant: O=C(Cl)c1ncco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.6 %

Procedure:
In a 25 mL round-bottomed flask, 1-(4-chloro-2-phenylamino-phenyl)-propan-1-one (522 mg, 2.01 mmol) was combined with THF (4 mL) to give a yellow solution. Sodium bis(trimethylsilyl)amide (1.0 M in THF) (5.02 mL, 5.02 mmol) was added slowly dropwise, resulting in a dark red solution. A mixture of oxazole-2-carbonyl chloride (344 mg, 2.61 mmol) in THF (8 mL) and 8 drops of DMF were added to the reaction mixture. The resulting mixture was stirred at room temperature for 5 hr. The reaction mixture was quenched by the addition of water and the aqueous layer was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered, then concentrated to afford a yellow oil. The crude material was purified by flash chromatography (silica gel, 80 g, 25-65% ethyl acetate in hexanes) to give 7-chloro-3-methyl-2-oxazol-2-yl-1-phenyl-1H-quinolin-4-one (160 mg, 23.6%) as a yellowish solid. MS calcd. for C19H13ClN2O2 [(M+H)+] 337, obsd. 337.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20](B1OC(C)(C)C(C)(C)O1)([CH3:22])=[CH2:21].C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:20]([C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH2:21]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.00 g, 3.05 mmol), isopropenyl boronic acid pinacol ester (513 mg, 3.05 mmol), saturated aqueous sodium carbonate solution (14 ml) and tetrakis(triphenylphosphine)palladium(0) (99.5 mg, 0.0861 mmol) in dimethoxyethane (17 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the desired product (680 mg, 77.0%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:40][CH:37]3[CH2:38][CH2:39][CH:34]([C:31]4[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][CH:32]=4)[CH2:35][CH2:36]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NC1CCC(c2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(c5ccc(Cl)cc5)CC4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.050 g, 0.13 mmol), N,N-dimethylpyridin-4-amine (0.0016 g, 0.013 mmol), and 4-(4-chlorophenyl)cyclohexanamine (0.042 g, 0.20 mmol) in DMF (1 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.031 g, 0.16 mmol), and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield 65 mg of the title compound (86% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.Cl[C:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11].C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1>C(Cl)Cl.CO>[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36]([N:42]3[CH2:47][CH2:46][N:45]([C:10]([NH:1][CH:2]4[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]4)=[O:11])[CH2:44][CH2:43]3)=[CH:37][CH:38]=[N:39]2)=[CH:34][CH:33]=1
Reactant: NC1CCC(O)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1CCC(O)CC1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Yield: 28.2 %

Procedure:
As described for example 78, 4-aminocyclohexanol (84 mg, 0.73 mmol), 4-nitrophenyl chloroformate (146 mg, 0.73 mmol), diisopropyl(ethyl)amine (320 mg, 2.4 mmol), and 7-chloro-4-(piperazin-1-yl)quinoline (150 mg, 0.81 mmol) are reacted affording 80 mg of the product after flash chromatography with CH2Cl2-MeOH. 1H NMR (DSMO-d6) 61.17 (m,-4H), 1.74 (m, 4H), 3.38 (m, 2H), 3.56 (br. s, 4H), 3.82 (br., s, 4H), 7.16 (d, 1H), 7.64 (dd, 1H), 1.97 (d, 1H), 8.2 (d, 1H), 8.62 (d, 1H).