Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:10]1=[O:23].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N1CCOCC1)C.[Cl:55][C:56]1[C:61]([C:62]([F:65])([F:64])[F:63])=[CH:60][CH:59]=[CH:58][C:57]=1[CH2:66][NH2:67]>ClCCl>[Cl:55][C:56]1[C:61]([C:62]([F:64])([F:65])[F:63])=[CH:60][CH:59]=[CH:58][C:57]=1[CH2:66][NH:67][C:14]([CH:13]1[CH2:12][N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:10](=[O:23])[N:9]1[CH3:8])=[O:16]
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: CN1C(=O)N(c2ccccn2)CC1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN1C(=O)N(c2ccccn2)CC1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
A mixture of 3-methyl-2-oxo-1-(2-pyridinyl)-4-imidazolidinecarboxylic acid TFA salt (117 mg, 0.35 mmol), 1-hydroxybenzotriazole hydrate (80 mg, 0.525 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (101 mg, 0.525 mmol) and N-ethyl morpholine (0.224 ml, 1.75 mmol) in dichloromethane (8 ml) was stirred at room temperature for 10 minutes. A solution of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (73.4 mg, 0.35 mmol) in dichloromethane (2 ml) was added and the reaction stirred at room temperature for 18 hours. The mixture was partitioned between dichloromethane and saturated sodium hydrogen carbonate solution. The organic phase was separated, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-methyl-2-oxo-1-(2-pyridinyl)-4-imidazolidinecarboxamide (90 mg, 62%). LC/MS [M+H]+=413, retention time=2.55 minutes.
Reaction SMILES: C[O:2][C:3](=[O:34])/[C:4](/[NH:12][C:13](=[O:33])[C:14]1[C:19]([CH3:20])=[CH:18][C:17]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:16][C:15]=1[Cl:32])=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+]>CO.O1CCCC1.O>[Cl:32][C:15]1[CH:16]=[C:17]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])[CH:18]=[C:19]([CH3:20])[C:14]=1[C:13]([NH:12]/[C:4](=[CH:5]\[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)/[C:3]([OH:34])=[O:2])=[O:33]
Reactant: COC(=O)/C(=C/c1ccccc1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCc2cccc(O)c2)cc(Cl)c1C(=O)N/C(=C\c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 42.6 %

Procedure:
A mixture of (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-phenylpropenoic acid methyl ester (Example 212; 23 mg, 0.048 mmol) and lithium hydroxide monohydrate (6 mg, 0.144 mmol) in methanol/tetrahydrofuran/water (2:2:1; 0.25 mL) was stirred at room temperature for 17 h. An second portion of lithium hydroxide monohydrate (2 mg, 0.05 mmol) was added and the solution was stirred for an additional 4 h. The volatiles were removed in vacuo and the residue was taken up in a mixture of chloroform/methanol/water/acetic acid (150:30:10:6) and evaporated to dryness. The residue was re-dissolved in the same solvent mixture (1 mL) and applied to a silica gel column. The column was eluted with in turn with chloroform, chloroform/methanol/water/acetic acid (300:30:10:6) and chloroform/methanol/water/acetic acid (150:30:10:6). The appropriate fractions were combined, evaporated and then lyophilized to give (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-phenylpropenoic acid (9.5 mg, 43% yield) as a colorless powder.
Reaction SMILES: O=[C:2]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]#[N:11])[CH2:5][CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:18].[Na+]>CO>[NH2:18][CH:2]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]#[N:11])[CH2:5][CH2:4][CH2:3]1
Reactant: N#CC1CCCC(=O)CCC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: N#CC1CCCC(N)CCC1

Procedure:
The product of Example 10B (0.259 g, 1.71 mmol), ammonium acetate (1.32 g, 17.14 mmol), and sodium cyanoborohydride (0.43 g, 6.84 mmol) was stirred in methanol (8 mL) for twelve hours. The solvent was evaporated and the residue was partitioned with dichloromethane and water. The organic phase was washed with NaHCO3 solution and brine, dried (Na2SO4), filtered, and evaporated. The crude title compound was used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C[Si](C)(C)C1C=CC([C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[CH:23][CH2:24]3)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:20]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=2[CH:22]=[CH:23][CH2:24]3)=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)c1ccc(-c2cccc3c2C=CC3)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cccc3c2C=CC3)cc1
Yield: 89 %

Procedure:
The synthesis was performed by the same procedure as in Metallocene Compound A (1-1) by using 4-methoxyphenylboronic acid in place of 4-trimethylsilylphenylboronic acid in the synthesis of 4-(4-trimethylsilyl-phenyl)-indene to obtain a yellow liquid of 4-(4-methoxy-phenyl)-indene in a yield of 89%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:49]=[CH:48][C:40]([CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[CH:39][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:37]4[CH:38]=[CH:39][C:40]([CH2:41][N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[CH:48][CH:49]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
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: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
To a stirred solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.25 g, 0.56 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (0.20 g, 0.67 mmol) and Pd(PPh3)4 (0.032 g, 0.027 mmol) in 1,4-dioxane (4 mL) and purged with argon for 10 min. 2M Na2CO3 solution (0.22 g, 2.03 mmol) was then added to it before a further argon purge for 10 min. The reaction mixture was stirred at 100° C. for 3 h. After completion of the reaction, water was added and extraction carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give -cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-(morpholinomethyl)phenyl)-1H-indazole-4-carboxamide (68.4% yield). LCMS: 540.25 (M+1)+; HPLC: 99.15% (@ 254 nm) (Rt; 5.583); 1H NMR (DMSO-d6, 400 MHz) δ 11.51 (bs, 1H), 8.62 (t, 1H, J=4.8 Hz), 8.36 (s, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.80 (d, 2H, J=8 Hz), 7.43 (d, 2H, J=8 Hz), 5.88 (s, 1H), 5.34-5.31 (m, 1H), 4.38 (d, 2H, J=4.8 Hz), 3.59-3.58 (m, 4H), 3.52 (s, 2H), 2.38 (m, 4H), 2.21 (s, 3H), 2.11 (s, 3H), 2.04-1.99 (m, 2H), 1.88 (m, 4H), 1.72-1.69 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=[O:9]
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: OCC1CCCN1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CCCC2CO)n1
Yield: 15 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 2-hydroxymethyl-pyrrolidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (15%) as sticky yellow solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][NH:7][C@H:8]1[C:17]2[C:12](=[C:13]([Br:22])[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[NH:11][C@@H:10]([CH:23]2[CH2:25][CH2:24]2)[CH2:9]1.N1C=CC=CC=1.Cl[C:42]([O:44][CH3:45])=[O:43]>ClCCl>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[CH2:6][N:7]([C:42]([O:44][CH3:45])=[O:43])[C@H:8]1[C:17]2[C:12](=[C:13]([Br:22])[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[NH:11][C@@H:10]([CH:23]2[CH2:25][CH2:24]2)[CH2:9]1
Reactant: FC(F)(F)c1cc(CN[C@@H]2C[C@H](C3CC3)Nc3c(Br)cc(C(F)(F)F)cc32)cc(C(F)(F)F)c1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)Nc2c(Br)cc(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
cis-4-[(3,5-bis-trifluoromethyl-benzyl)-amino]-8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Example 100B) (420 mg, 0.75 mmol) and pyridine (148 mg, 1.88 mmol) were dissolved in anhydrous dichloromethane (15 mL) and cooled to 0° C. Methyl chloroformate (142 mg, 1.5 mmol) was added over 1 min. The reaction was stirred at 0° C. for 1 h, then at room temperature for 24 h. The reaction mixture was then diluted with 50 mL of dichloromethane, and washed twice with 1N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title product (400 mg) which was used without further purification. MS m/z 618.8 (M+).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:19]2=[CH:20][CH:21]=[N:22][CH:23]=[C:18]2[C:5]2[C:6]([OH:17])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:25].[N:26]1([CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:25].[CH3:24][C:2]1([CH3:1])[C:19]2=[CH:20][CH:21]=[N:22][CH:23]=[C:18]2[C:5]2[C:6]([O:17][C:35](=[O:36])[CH2:34][CH2:33][CH2:32][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(2-heptyl)-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-8-(2-heptyl)-10-hydroxy-5H[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([C@@H:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:9]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:32](Br)[CH:33]=[CH2:34].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:34]([C@@H:12]1[CH2:13][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:9]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[N:10]([C@@H:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11]1=[O:14])[CH:33]=[CH2:32]
Reactant: C=CCBr
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1.45 g (3.14 mmol) of tert-butyl (2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl)butanoate (Example 1, Step F) and allyl bromide (0.326 mL, 3.76 mmol) in 12.5 mL of THF was added dropwise at −78° C. 3.3 mL of a 1 M solution of lithium bis(trimethylsilyl)-amide in THF (3.3 mmol). After being stirred at −78° C. for 3 h, the reaction was quenched with sat. aqueous NH4Cl solution, extracted with ethyl acetate. The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (50 g SiO2, eluent: 5 to 20% EtOAc/hexanes, gradient elution) provided tert-butyl (2S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate as the faster eluting major isomer.
Reaction SMILES: [Na].[C:2]([O:6][C:7]([NH:9][C@H:10]1[C@@H:13]([CH3:14])[N:12](OC)[C:11]1=[O:17])=[O:8])([CH3:5])([CH3:4])[CH3:3]>N.O1CCCC1>[C:2]([O:6][C:7]([NH:9][C@H:10]1[C@@H:13]([CH3:14])[NH:12][C:11]1=[O:17])=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CON1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]1C
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: C[C@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C
Yield: 94.4 %

Procedure:
Sodium (1.35 g) is dissolved in about 300 ml of liquid ammonia at -50° C. and 5.87 g of (3S-cis)-3-t-Butoxycarbonylamino-1-methoxy-4-methylazetidinone in 35 ml tetrahydrofuran is added dropwise via syringe. An additional 10 ml of tetrahydrofuran is used for rinsing. Near the end of the addition about 100 mg of additional sodium is added. The mixture is stirred for five more minutes, then quenched by adding 3.35 g of solid ammonium chloride in one portion. Ammonia is blown off with a nitrogen stream and 250 ml of ethyl acetate is added to the residue. After filtration and washing the solid with ethyl acetate, the combined filtrate is stripped of solvent to give 4.82 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[C:14](/[CH:15]=C/C=C/C=C/C=C2\C(C)(C)C3C4C=CC=CC=4C=CC=3N\2CCC(O)=O)=[N+:13]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])[C:12]2[CH:11]=[CH:10][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]1=2.[Br-].CC1(C)C2C3C=CC=CC=3C=CC=2N=C1C.BrCCC(O)=O>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1([CH3:47])[C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH:10]=[CH:11][C:12]=2[N:13]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])[CH:14]1[CH3:15]
Reactant: CC1(C)C(/C=C/C=C/C=C/C=C2/N(CCC(=O)O)c3ccc4ccccc4c3C2(C)C)=[N+](CCC(=O)O)c2ccc3ccccc3c21
Agent: CC1=Nc2ccc3ccccc3c2C1(C)C
Agent: O=C(O)CCBr
Agent: [Br-]
Solvent: Clc1ccccc1Cl
Product: CC1N(CCC(=O)O)c2ccc3ccccc3c2C1(C)C
Temperature: 110 °C

Procedure:
To synthesize cypate, a mixture of 1,1,2-trimethyl-[1H]-benz[e]indole (40.0 g, 19.11 mmol) and 3-bromopropanoic acid (40.0 g, 26.15 mmol) in 1,2-dichlorobenzene (200 mL) was heated at 110° C. for 18 h. After the resulting mixture was cooled to room temperature, the precipitate was collected by filtration, followed by trituration in dichloromethane (DCM) to remove the un-reacted material, and then dried under vacuum to afford 1,1,2-trimethyl[1H]-benz[e]indole-3-propanoic acid. A solution of acetic anhydride (1.20 g, 11.75 mmol) in DCM (5 mL) was added dropwise to a cooled suspension of glutaconaldehyde dianil monohydrochloride (2.84 g, 9.97 mmol) and diisopropylethylamine (DIEA, 2.60 g, 20.11 mmol) in DCM (20 mL). The resulting clear solution was stirred for 1 h and added dropwise to a refluxing solution of 1,1,2-trimethyl[1H]-benz[e]indole-3-propanoic acid (8.2 g, 22.64 mmol) and sodium acetate (3.2 g, 39.01 mmol) in acetonitrile/water (95/5 mL). The mixture was refluxed for 16 h, cooled, filtered, and washed with acetonitrile, 5% HCl solution and ethyl ether. About 6 g (85%) of cypate was obtained. It was further purified by recrystallization from 30% acetonitrile in water. Mass calculated: 625; observed (ESI-MS): 625.34 [M]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:7]2[C:2](=[O:1])[N:3]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:4]3[N:5]([N:26]=[CH:27][N:28]=3)[C:6]=2[CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)OC(C)(C)C)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (9 g), tert-butyl bromoacetate (3.8 mL), potassium carbonate (6 g) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.6 g, 25%).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](OC1C=CC([N+]([O-])=O)=CC=1)=[O:19].[C:36]1([CH2:42][CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([N:47]1[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:49][CH2:48]1)=[O:19]
Reactant: c1ccc(CCN2CCNCC2)cc1
Reactant: CC1=C(C)C(=O)C(C(CCCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)=C(C)C1=O
Solvent: ClCCl
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)N2CCN(CCc3ccccc3)CC2)c2ccccc2)=C(C)C1=O
Reaction time: 18 h
Yield: 92.2 %

Procedure:
A solution of p-nitrophenyl 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenyl-heptanoate (0.50 g, 1.05 mmoles) and 4-(2-phenylethyl)piperazine (0.20 g, 1.05 mmoles) in dichloromethane was allowed to stand at room temperature under stirring for 18 hours. After the solvent was evaporated in a reduced pressure, the residue was dissolved in ethylacetate and the solution was washed with aqueous potassium carbonate and water, and dried over magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel column with ethylacetate followed by chloroform-methanol (10:1) as eluant to give 4-[7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoyl]-(2-phenylethyl)piperazine (0.51 g, 92%) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH:9]2[CH2:11][CH2:10]2)=[CH:4][N:3]=1.[C:12]([Zn]C#N)#[N:13]>CN(C=O)C.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.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:6]1[C:5]([CH:9]2[CH2:11][CH2:10]2)=[CH:4][N:3]=[C:2]([C:12]#[N:13])[CH:7]=1
Reactant: N#C[Zn]C#N
Reactant: Clc1cc(Cl)c(C2CC2)cn1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)c(C2CC2)cn1
Temperature: 100 °C
Yield: 73.2 %

Procedure:
To a stirred solution of 2,4-dichloro-5-cyclopropyl-pyridine (example 145a, 2.2 g, 11.76 mmol) in DMF (10 ml) and purged the reaction mixture argon for 10 minutes. To this reaction was added dicyanozinc (926 mg, 7.65 mmol) followed by DPPF (520 mg, 1.02 mmol) and Pd2dba3 (535 mg, 0.58 mmol) at 25° C. and the reaction mixture was again purged with argon for 10 min. The reaction mixture was heated up to 100° C. for 1 hour. The catalyst was filtered off and the solution was diluted with ethyl acetate. The organic phase was poured into a separatory funnel and extracted with brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (1 g, 50%). MS (ESI, m/z): 179.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:15](=[O:27])[NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][N:21]=[CH:22]3)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].CCO>[Pt](=O)=O.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:15](=[O:27])[NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][NH:21][CH2:22]3)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)Nc2cccc3cnccc23)Cc2ccccc2C1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)Nc2cccc3c2CCNC3)Cc2ccccc2C1
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A 100 mL Parr reaction vessel is charged with 2-(Isoquinolin-5-ylcarbamoyl)-indan-2-carboxylic acid ethyl ester (320, 500 mg, 1.39 mmol) and EtOH (10 mL). The reaction vessel is agitated by swirling until dissolution ° C. curred. Acetic acid (10 mL) and platinum (IV) oxide (117 mg, 0.52 mmol) are added. The vessel is fitted on a Parr hydrogenation apparatus, flushed with N2 and then evacuated. The vessel is charged with hydrogen to 50 psi. The apparatus is set to agitate. After 4 h, agitation is ceased. The reaction vessel is evacuated and flushed with nitrogen. This process is repeated. The contents of the reaction vessel are diluted with iPrOH (50 mL) and filtered through a pad of celite. Solvent is removed from the filtrate under reduced pressure. The resulting residue is reconstituted in iPrOH (15 mL) and toluene (15 mL). The solvent is removed under reduced pressure. This process is repeated. Pumping to constant weight yields light beige solid (0.5 g, 99%).