Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([OH:13])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:11](=[O:13])[CH:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:14][CH3:15])=[CH:20][CH:19]=1)#[N:16]
Reactant: COc1ccc(C(OC)C(=O)O)c(F)c1
Reactant: N#Cc1ccc(CN)cc1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1

Procedure:
(RS)-(2-Fluoro-4-methoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Colorless oil. MS 329.2 ([M+H]+)
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([N:10]=[C:11]=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:26]=[C:25]([O:27][C:28]2[C:33]3=[N:34][CH:35]=[C:36]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[N:37]=[C:32]3[N:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:21]=1[NH2:22]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:22][C:21]2[CH:23]=[CH:24][C:25]([O:27][C:28]3[C:33]4[C:32](=[N:37][C:36]([N:38]5[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]5)=[CH:35][N:34]=4)[N:31]=[CH:30][CH:29]=3)=[CH:26][C:20]=2[F:19])=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(c2cnc3c(Oc4ccc(N)c(F)c4)ccnc3n2)CC1
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: CN1CCN(c2cnc3c(Oc4ccc(NC(=O)Nc5cc(C(C)(C)C)nn5-c5ccccc5)c(F)c4)ccnc3n2)CC1

Procedure:
Method F3 was used with 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole and 2-fluoro-4-(3-(4-methylpiperazin-1-yl)pyrido[3,2-b]pyrazin-8-yloxy)aniline to give the title compound as a cream-colored solid. Yield: 44 mg (77%).
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:16])[NH:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[C:4](=[O:16])[NH:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](=[O:10])[CH:9]=1
Reactant: COc1cc(=O)c2cccc(C)c2[nH]c1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc2c(=O)cc(O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 52.4 %

Procedure:
To a stirred suspension of 3-methoxy-9-methyl-1H-1-benzazepine-2,5-dione (39, 200 mg, 921 μmol) in dry CH2Cl2 (2 mL, distilled from CaH2) under N2, there was added a solution of BBr3 in CH2Cl2 (2 mL, 1M, Aldrich) in one portion at rt. The reaction instantaneously became homogeneous and yellow, then a yellow precipitate formed after a few seconds. The reaction was allowed to stir under N2 at rt for 45 min. The reaction was added to saturated NaHCO3 (15 mL) and the resulting beige suspension was allowed to stir for 15 min to give a cloudy, orange solution. The solution was filtered through glass wool to remove any suspended matter. The resulting solution was acidified with concd HCl (pH 2), the solid collected by filtration and washed to neutrality with water (5×2 mL). The damp filter cake was crystallized from 95% EtOH (dissolved in 15 mL, hot filtered, concd to 7 mL) to yield 43 as brown needles (98 mg, 52%, pure by TLC,1H NMR and C,H,N analyses); mp 184°-185.5° C. (EtOH), 1H NMR (DMSO-d6) δ2.46 (s, 3H), 6.28 (s, 1H), 7.19 (t, J=7.5 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 8.03 (d, J=7.8 Hz, 1H), 9.94 (s, 1H), 10.85 (bs, 1H); Anal. Calcd for C11H9NO3 0.5 H2O: C, 62.26; H, 4.75; N, 6.60. Found: C, 62.39; H, 4.53; N, 6.51.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=3)=[CH:10][C:9]=2[CH:8]=[C:7]([O:23][CH3:24])[CH:6]=1)=O.[Li]>C1COCC1>[F:22][C:16]1[CH:15]=[C:14]([C:11]2[O:12][C:13]3[C:5]([CH2:3][OH:2])=[CH:6][C:7]([O:23][CH3:24])=[CH:8][C:9]=3[CH:10]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COC(=O)c1cc(OC)cc2cc(-c3ccc(OC)c(F)c3)oc12
Agent: [Li]
Solvent: C1CCOC1
Product: COc1cc(CO)c2oc(-c3ccc(OC)c(F)c3)cc2c1
Yield: 72.9 %

Procedure:
Fluoro ester 40 (1.00 g, 3.63 mmole), was dissolved in 40 mL THF and stirred under nitrogen. To this solution was added lithium aluminumhydride (1M in THF, 3.81 mL, 3.81 mmole) dropwise over fifteen minutes. After stirring at rt for one half hour, the solvent was removed and the mixture was poured into 2N HCl and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 4:1) to afford 0.800 g (73%) of benzyl alcohol 41 as a tan solid: Mp=128–130° C.; 1H NMR (DMSO-d6) δ 7.78 (dd, 1 H, J=12.5 Hz, 2.0 Hz), 7.69 (dd, 1 H, J=8.7 Hz, 1.1 Hz), 7.29 (t, 2 H, J=8.1 Hz), 7.01 (d, 1 H, J=2.5 Hz), 6.90 (d, 1 H J=2.5 Hz), 5.37 (br s, 1 H), 4.81 (d, 2 H, J=3.1 Hz), 3.90 (s, 3 H), 3.81 (s, 3 H); MS 303 (M+H)+
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1(=[O:21])[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>C1C=CC=CC=1>[C:1]([NH:9][NH:10][C:11](=[O:21])[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: c1ccccc1
Product: O=C(NNC(=O)c1ccccc1C(=O)O)c1ccccc1

Procedure:
At a temperature of about 18°, powdered benzhydrazide (126 g, 1 mole) was suspended in stirred benzene (1.6 l), and 24-mesh phthalic anhydride (148 g, 1 mole) was added portionwise over 15 to 20 minutes. After the addition the reaction mixture was stirred for a further hour. The product, 1-benzoyl-2-(2-carboxybenzoyl) hydrazine (III) (R1 =H) was collected on a filter, pressed free of benzene and air dried, 276 g, 98%, M.P., 205°-208°.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][CH:15]1[CH2:20][NH:19][CH2:18][CH2:17][NH:16]1>>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:19]1[CH2:18][CH2:17][NH:16][CH:15]([CH3:14])[CH2:20]1
Reactant: CC1CNCCN1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Product: Cc1cccc(C)c1NC(=O)CN1CCNC(C)C1

Procedure:
The subtitle compound was prepared from 2-chloro-N-(2,6-dimethylphenyl)acetamide (7 g) and (±)-2-methyl-piperazine (3.55 g) by the method of Example 15 step (ii) as a white solid. Yield 7 g.
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[O:12]1[CH2:26][CH:13]1[CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25]>ClC1C=CC=CC=1Cl>[OH:12][CH:13]([CH2:26][NH:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25]
Reactant: NC1CCCc2ccccc21
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)N1CC(O)CNC1CCCc2ccccc21
Temperature: 150 °C
Reaction time: 4 h
Yield: 45.3 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-1-naphthylamine (99 mg, 0.68 mmol) in o-dichlorobenzene (1 ml) was added N-(2,3-epoxypropyl)phthalimide (137 mg, 0.68 mmol), and the mixture was stirred at 150° C. for 4 h. The reaction mixture was chromatographed on silica gel (eluting with 0.5% methanol/chloroform) to afford N-[2-hydroxy-3-(1,2,3,4-tetrahydro-1-naphthylamino)propyl]phthalimide (108 mg, 47%): MS(ES+) m/e 351 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.78 (m, 2H), 7.66 (m, 2H), 7.36 (m, 1H), 7.10 (m, 2H), 7.02 (m, 1H), 6.77 (br, 1H), 5.09 (m, 1H), 3.98 (m, 1H), 3.86-3.63 (m, 3H), 2.95-2.60 (m, 4H), 1.91-1.66 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21](C(=O)C)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.[ClH:27]>C(O)C>[ClH:27].[Br:1][C:2]1[N:3]=[C:4]([C@H:12]2[CH2:13][CH2:14][C@H:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12
Reactant: CC(=O)N1CCN([C@H]2CC[C@H](c3nc(Br)c4c(C)nccn43)CC2)CC1
Agent: Cl
Solvent: CCO
Product: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCNCC2)CC1

Procedure:
To 1-(4-((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)piperazin-1-yl)ethanone (0.108 mmol, 45.4 mg) in ethanol was added 2 M hydrochloric acid (4.32 mmol, 2.16 ml) and stirred at reflux for four hours. The reaction mixture was cooled, concentrated in vacuo, coevaporated with toluene twice and washed with dichloromethane twice to give 1-bromo-8-methyl-3-((trans)-4-(piperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine hydrochloride (56 mg) product which was used without further purification.
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32](S(C)(=O)=O)=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[OH:1][C:2]1([C:29]2[S:33][C:32]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:9][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[O:14])[CH2:11]2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Reactant: C1CCNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cnc(N4CCCC4)s3)CC2)C1

Procedure:
The title compound was prepared as a white solid from N-({1-[4-hydroxy-4-(2-methanesulfonyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 47a), and pyrrolidine (Aldrich) using the procedure described in Example 50.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][CH:22]=1>>[N:21]1([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[CH:5]=[N:4][CH:3]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1
Reactant: Clc1cncc(Nc2ccc(N3CCOCC3)cc2)n1
Reactant: c1ccc2[nH]cnc2c1
Product: c1ccc2c(c1)ncn2-c1cncc(Nc2ccc(N3CCOCC3)cc2)n1
Yield: 31 %

Procedure:
In a procedure analogous to example 12, reaction of 6-chloro-N-(4-morpholin-4-ylphenyl)pyrazin-2-amine (150 mg, 0.52 mmol) and benzimidazole (67 mg, 0.57 mmol) furnished the product (60 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(C(CC)C([NH:18][CH:19](C([O-])=O)[C:20]([O-:22])=[O:21])=O)C>>[NH2:18][CH:19]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])[C:20]([OH:22])=[O:21]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCl
Reactant: CCC(CC)C(=O)NC(C(=O)[O-])C(=O)[O-]
Product: NC(Cc1ccc(Cl)cc1[N+](=O)[O-])C(=O)O

Procedure:
The title compound was prepared from 4-chloro-2-nitrobenzyl chloride and diethylacetamidomalonate according to the procedures described by Davis, A. L.; et al, in Arch. Biochem, Biophys., 102, 48 (1963).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1cccc(B(O)O)c1
Product: CCCNC(=O)c1nnc2c(-c3cccc(OC)c3)cccc2c1N
Yield: 62.2 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 3-methoxyphenyl boronic acid (147 mg, 0.97 mmol) were reacted to afford the title compound (69 mg, 64.2% yield) as an off-white crystal. 1H NMR (300 MHz, CDCl3) δ 8.58 (br, 1H), 7.87 (dd, J=8.3 Hz, J′=1.4 Hz, 1H), 7.81 (dd, J=7.1 Hz, J′=1.4 Hz, 1H), 7.72 (t, J=8.1 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.15-7.35 (m, overlapped with CHCl3), 6.98 (dd, J=8.1 Hz, J′=1.8 Hz, 1H), 3.86 (s, 3H), 3.46 (q, J=6.7 Hz, 2H), 1.67 (m, J=7.3 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, m/z=337 (M+H) HPLC 1.89 min.
Reaction SMILES: CO[C:3]([C:5]1([CH2:29][CH:30]=O)[CH2:10][CH2:9][CH:8]([O:11][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6]1)=[O:4].[CH3:32][CH:33]1[CH2:37][CH2:36][CH2:35][N:34]1[CH:38]1[CH2:42][CH2:41][C@H:40]([C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:39]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:11][CH:8]1[CH2:7][CH2:6][C:5]2([C:3](=[O:4])[N:49]([C:46]3[CH:47]=[CH:48][C:43]([CH:40]4[CH2:41][CH2:42][CH:38]([N:34]5[CH2:35][CH2:36][CH2:37][CH:33]5[CH3:32])[CH2:39]4)=[CH:44][CH:45]=3)[CH2:30][CH2:29]2)[CH2:10][CH2:9]1
Reactant: CC1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Reactant: COC(=O)C1(CC=O)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1CCCN1C1CCC(c2ccc(N3CCC4(CCC(O)CC4)C3=O)cc2)C1

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 1 by condensing 4-(tert-butyl-diphenyl-silanyloxy)-1-(2-oxo-ethyl)-cyclohexanecarboxylic acid methyl ester (Intermediate 8) with 4-[(S)-3-(2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 15), and subsequently cyclization, followed by de-protection with TBAF in THF at 60° C. for 5 h.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10](/[C:16](/[CH3:29])=[CH:17]\[C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=3)[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+]>CO>[CH3:1][C:2]1([C:8]2[CH:9]=[C:10](/[C:16](/[CH3:29])=[CH:17]\[C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=3)[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)c1ccc(/C=C(/C)c2ccc(OC)c(C3(C)CCCCC3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(C)=C\c2ccc(C(=O)O)cc2)cc1C1(C)CCCCC1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
0.69 g (1.76 mmol) of the ester obtained in Example 31, in 15 ml of methanol, is treated with 1.58 g of sodium hydroxide. The reaction mixture is stirred at 40° C. for 2 h. After the same treatment as in Example 8, 462 mg (72%) of the expected derivative are isolated, which derivative melts at 175°-176° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[CH:16][C:15]([CH3:23])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:21][CH2:20][CH:19]([OH:22])[CH2:18][C:17]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]3[C:14](=[C:15]([CH3:23])[CH:16]=2)[CH2:13][CH2:12][CH2:11]3)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(CC(O)CO)c(OCc2ccccc2)c2c1CCC2
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)Cc2cc(C)c3c(c2OCc2ccccc2)CCC3)cc1
Temperature: 0 °C

Procedure:
To a solution of (±)-3-[4-(benzyloxy)-7-methyl-2,3-dihydro-1H-inden-5-yl]propane-1,2-diol (9.12 g, 0.029 mol) in anhydrous pyridine (290 mL) cooled to 0° C. was added p-toluenesulfonyl chloride (5.84 g, 0.031 mol) and the reaction mixture was allowed to stir for at 0° C. 12 h. The reaction mixture was quenched by the addition of water (10 mL) and the reaction mixture was allowed to stir at room temperature for 15 min. The reaction mixture was diluted with ethyl acetate (800 mL) and washed with aqueous hydrogen chloride (4×1000 mL, 2.0 N), water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to afford (±)-3-[4-(benzyloxy)-7-methyl-2,3-dihydro-1H-inden-5-yl]-2-hydroxypropyl 4-methylbenzenesulfonate as a crude solid. Treatment of the tosylate with palladium on carbon (10 wt. %, 1.50 g) generally according to the procedure described for Intermediate 11 provided (±)-2-hydroxy-3-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)propyl 4-methylbenzenesulfonate. Treatment of the phenyl with triphenylphoshine (10.17 g, 0.039 mol) and diethylazodicarboxylate (6.75 g, 0.039 mol) generally according to the procedure described for Intermediate 12 gave 9.44 g (91%) of (±)-(5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.62 (silica, ethyl acetate:hexanes 1:4); mp 61-64° C.; Anal. calcd. for C20H22O4S: C, 67.01; H, 6.19. Found: C, 67.02; H, 6.15.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17]O)[N:7]=1)[CH3:2].CS([Cl:24])(=O)=O.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][Cl:24])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nn(CO)c(=O)c2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1nn(CCl)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl-3-hydroxymethyl-4-oxo-3-H-phthalazin-1-ylacetate (1.31 g) and methanesulfonyl chloride (0.69 g) in methylene chloride (10 ml) containing pyridine (0.8 ml) was stirred at room temperature overnight. Upon evaporation of methylene chloride and purification of the residue by chromatography on silica gel, eluting with a mixture of a chloroform and ethyl acetate (9:1), the title product was obtained (yield: 0.51 g; m.p. 99°-100° C.).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[C:23]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:32]2[CH2:33][CH2:34][CH:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][CH2:31]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(c2ccccc2)CC1
Temperature: 65 °C
Yield: 20.6 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 4-phenylpiperidine (0.066 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0067 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.31 g, 0.95 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel (eluting with 0 to 2% methanol in dichloromethane) to give the desired product (25.6 mg, 21%). LCMS calculated for C22H22ClN2O (M+H)+: m/z=365.1; Found: 365.1.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:2].[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32]([NH:34][C@@H:35]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][CH:41]=3)[C:36](O)=[O:37])=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>>[C:47]([O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][C@H:35]([NH:34][C:32](=[O:33])[O:31][CH2:30][CH:28]2[C:29]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:36]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:14][CH2:15][CH3:16])[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:37])=[CH:45][CH:44]=1)([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(CNCc1ccccn1)OCC
Product: CCOC(CN(Cc1ccccn1)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Yield: 90.1 %

Procedure:
According to the procedure described in the synthesis method of Compound III-5, 2,2-diethoxy-N-(pyridin-2-ylmethyl)ethanamine (Compound IX-16) (34.0 g, 150 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (72.3 g, 150 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=3:1) to obtain the title compound (90.0 g, 90%).
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(=O)C([Cl:24])=O>C1(C)C=CC=CC=1>[CH2:1]([Cl:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCCl
Reaction time: 0.25 h

Procedure:
Into a dry 4-neck-round bottomed flask equipped with nitrogen inlet, addition funnel, therometer, mechanical stirrer and heating means, under nitrogen, are cautiously (to avoid foaming), charged 229 g. of oleic acid (99% pure, m.p. 4°; b.p. 286°/100 mmHg), 263 ml of toluene and 109 ml. of oxalyl chloride (b.p. 63°-64°), at a rate so as to keep the (internal) reaction temperature between 25°-30°, over a period of about 15 minutes. After addition is complete the funnel is washed with an additional 25 ml. toluene. The reaction mixture is stirred 25°-30° for about one-half hour, and then at about 50°-55° for 1 hour. The toluene is then distilled off (initially at 35°-40°/63 mm vapor pressure; then at 30°-25°/26 mm for 1.5 hours) to obtain oleyl chloride, which is promptly used for the following Step B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[CH2:14][S:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[O:10])=[C:4]([C:28](=[O:43])[NH:29][C:30]2[CH:34]=[CH:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=3)[N:31]=2)[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[CH2:14][S:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:10])=[C:4]([C:28](=[O:43])[NH:29][C:30]2[CH:34]=[CH:33][N:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=3)[N:31]=2)[CH:3]=1
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)n2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)n2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(4-chloro-2-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-ylcarbamoyl)phenylcarbamoyl)benzylthio)propanoate (150 mg, 0.24 mmol, 1.00 equiv) in dichloromethane (4 mL), and 2,2,2-trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 36.3 mg (27%) of a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.82(s, 1H), 11.48(s, 1H), 8.52(d, J=8.70 Hz, 1H), 8.41(s, 1H), 8.11(s, 1H), 7.92(s, 1H), 7.79(m, 1H), 7.67(m, 1H), 7.57(m, 4H), 7.26(m, 1H), 6.92(d, J=1.8 Hz, 1H), 3.86(s, 2H), 2.60(m, 2H), 2.29(m, 6H). MS (ES, m/z): 563 [M+H]+.