Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5]CC)=[O:4].[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[OH-].[Na+]>C1C=CC=CC=1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:8]1([CH2:2][C:3]([OH:5])=[O:4])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=C(O)Cn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
To a solution of ethyl 2-bromoacetate (25 g, 0.15 mole) and indole (11.7 g, 0.1 mole) in 100 ml of benzene is added a solution of sodium hydroxide (25 g, 0.626 mole) in 50 ml of water. To the obtained mixture is added tetra-n-butylammonium bromide (1.6 g, 0.5 mmole). The mixture is stirred at 25° C. for 16 hours. The aqueous phase is acidified to pH 3. The organic phase is separated, dried and evaporated to give the title compound in 92% yield. NMR (DMSO-D6) ppm (δ) 5.05 (s, 2); 6.50 (d, 1), 6.9-7.8 (m, 5).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH2:4][N:5]([CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: Clc1ccc(CNCc2cccnc2)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A 3.2 g. portion of 3-(2,4-dichlorobenzylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and to it was added 2 g. of potassium carbonate and 1.16 ml. of methanesulfonyl chloride. The mixture was stirred at ambient temperature for several days, and was then extracted twice with 15 ml. portions of water, dried, filtered, and evaporated under vacuum to an oil. The residue was dissolved in chloroform and purified over silica gel, eluting first with chloroform and then with 9:1 chloroform:acetone. The product-containing fractions were combined and evaporated under vacuum to obtain 2.9 g. of impure product, which was triturated with petroleum ether to obtain 2.1 g. of the desired product, m.p. 78°-80°.
Reaction SMILES: CS[C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[S:4][CH3:5].[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:8][C:7]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=[C:3]([S:4][CH3:5])[C:6]=1[C:9]#[N:10]
Reactant: NNc1ccccc1
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CCO
Product: CSc1nn(-c2ccccc2)c(N)c1C#N
Yield: 9.1 %

Procedure:
A mixture comprised of 17.0 g (100 mmol) of bis (methylthio)methylenepropanedinitrile, 10.8 g (100mmol) of phenylhydrazine and 80 ml of ethanol was heated under reflux for 2 hours. The solvent was removed through distillation, and 20 ml of ethanol was added to the residue, which was thus crystallized. The resulting crystals were taken out by means of filtration under suction to give 20.9 g (9.1 mmol) of the entitled product as colorless, needle-like crystals having a melting point of from 136° to 137° C. The yield was 91%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:32]([C:31]4[CH:35]=[CH:36][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[O:33])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)cc1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 4-methoxybenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA to yield the title compound.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[C:7](I)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.C([Mg]Cl)(C)C.C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C>C1COCC1>[CH:1]1([N:4]2[CH:8]=[C:7]([B:19]3[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]3)[CH:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Ic1cnn(C2CC2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
In a flask 1-cyclopropyl-4-iodo-1H-pyrazole (405 mg, 1.73 mmol) was dissolved in THF (8.0 mL) and the solution cooled to 0° C. Isopropylmagnesium chloride (2.0 M in THF, 1.04 mL, 2.08 mmol) was added dropwise and the mixture stirred at 0° C. for 45 min, after which 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.53 mL, 2.60 mmol) was added and the mixture allowed to warm to room temperature over 1 h. The mixture was quenched with 50% sat aqueous NH4Cl and extracted with EtOAc. The organic extract was washed with sat. NaCl, dried over MgSO4 and the solution was concentrated. The residue was purified by SiO2 chromatography (20-50% EtOAc/heptane) to afford 405 mg (83%) of 1-cyclopropyl-1H-pyrazole-4-boronic acid pinacol ester as a colorless viscous oil.
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH:20]=[CH:19][C:18]4[C:21]([O:23][C:24](=O)[C:16]5[C:17]=4[C:12]=3[C:13](=[CH:14][CH:15]=5)[C:8]3[C:9]=2[C:4]2[C:5](C(OC(=O)[C:3]=2[CH:2]=1)=O)=[CH:6][CH:7]=3)=[O:22].N1C=CN=C1.[NH2:36][CH:37]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].O.C(C1C=CC(C(C)(C)C)=CC=1N1C(=O)C2C3C4C(=CC=2)C2C5C(C=CC=2)=CC=CC=5C=4C=CC=3C1=O)(C)(C)C>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:38]([CH:37]([N:36]1[C:21](=[O:22])[C:18]2[C:17]3[C:12]4[C:11](=[CH:20][CH:19]=2)[C:10]2[C:9]5[C:4]([CH:3]=[CH:2][CH:1]=2)=[CH:5][CH:6]=[CH:7][C:8]=5[C:13]=4[CH:14]=[CH:15][C:16]=3[C:24]1=[O:23])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCC(N)CCCCCCCC
Reactant: O=C1OC(=O)c2ccc3c4ccc5c6c(ccc(c7ccc1c2c73)c64)C(=O)OC5=O
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc(C(C)(C)C)c(N2C(=O)c3ccc4c5cccc6cccc(c7ccc(c3c47)C2=O)c65)c1
Agent: [Zn+2]
Solvent: O
Product: CCCCCCCCC(CCCCCCCC)N1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54

Procedure:
1.4 g (3.1 mmol) of perylene-3,4,9,10-tetracarboxylic dianhydride, 6.1 g of imidazole, 960 mg (3.7 mmol) of 9-aminoheptadecane (prepared according to DE-A 4,007,618), 150 mg (0.68 mmol) of zinc acetate dihydrate and 3.0 ml (170 mmol) of water are heated in an autoclave (100 ml) at 190° C. for 24 h. Workup is analogous to that used for preparing 2b. Yield 130 mg (7% by extractive recrystallization from methanol, such as described in Chem. Ber. 1985, 118, 4641) orange red crystals showing strong solid fluorescence, m.p. 143°-143.6° C. Rf (CHCl3 /silica gel)=0.94. UV (CHCl3): λmax (ε)=454 nm (sh, 17620), 485 (32530), 508 (29480). Fluorescence (CHCl3, exc. 485 nm): λmax (Irel)=572 (sh, 0.49), 536 (1).
Reaction SMILES: BrCC1C=CC(C2CCCN2C(OC(C)(C)C)=O)=CC=1.ClCC1C=CC(C2C=CC=CN=2)=CC=1.[Cl:35][C:36]1[N:37]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([CH:59]3[CH2:63][CH2:62][CH2:61][N:60]3C(OC(C)(C)C)=O)=[CH:55][CH:54]=2)[CH:38]=[C:39]2[C:44]=1[C:43](=[O:45])[N:42]([CH3:46])[C:41](=[O:47])[N:40]2[CH2:48][CH:49]([CH3:51])[CH3:50].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:35][C:36]1[N:37]([CH2:52][C:53]2[CH:54]=[CH:55][C:56]([CH:59]3[CH2:63][CH2:62][CH2:61][NH:60]3)=[CH:57][CH:58]=2)[CH:38]=[C:39]2[C:44]=1[C:43](=[O:45])[N:42]([CH3:46])[C:41](=[O:47])[N:40]2[CH2:48][CH:49]([CH3:51])[CH3:50]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(C4CCCN4C(=O)OC(C)(C)C)cc3)cc21
Agent: CC(C)(C)OC(=O)N1CCCC1c1ccc(CBr)cc1
Agent: ClCc1ccc(-c2ccccn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(C4CCCN4)cc3)cc21

Procedure:
The synthetic procedure of this compound is analogous to EXAMPLE 6 wherein tert-butyl 2-(4-(bromomethyl)phenyl)pyrrolidine-1-carboxylate is used in step 2 instead of 2-(4-(chloromethyl)phenyl)pyridine. The obtained tert-butyl 2-(4-((5-chloro-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrrolo[3,4-d]pyrimidin-6-yl)methyl)phenyl)pyrrolidine-1-carboxylate is deprotected with TFA in CH2Cl2 at room temperature to give 5-chloro-1-isobutyl-3-methyl-6-(4-(pyrrolidin-2-yl)benzyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione, which is N-methylated with 37% formaldehyde aqueous solution and sodium borohydride in methanol at room temperature to give 5-chloro-1-isobutyl-3-methyl-6-(4-(1-methylpyrrolidin-2-yl)benzyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione in a good overall yield. The obtained intermediate reacts with aniline using the procedure described in step 3 of EXAMPLE 6 to give pure product after HPLC purification. MS (ESI) m/z 486.3 [M+H]+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36](O)=[O:37])[CH2:33][CH2:32]C[CH2:30][CH2:29]1.Cl.[NH2:50][C:51]1[S:52][C:53]([Cl:56])=[CH:54][N:55]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[Cl:56][C:53]1[S:52][C:51]([NH:50][C:36](=[O:37])[CH:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[CH2:34][CH:28]2[CH2:29][CH2:30][CH2:32][CH2:33]2)=[N:55][CH:54]=1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: Nc1ncc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ncc(Cl)s1)C(CC1CCCC1)N1Cc2ccccc2C1=O
Yield: 74.4 %

Procedure:
BOP coupling of 3-Cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 277 mg; 1.0 mmol) and 2-amino-5-chlorothiazole hydrochloride (397 mg; 2.30 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 1, Step B) provided after Flash chromatography (Biotage 40M eluent: 20% ethyl acetate/hexanes) 290 mg (74%) of N-(5-Chloro-thiazol-2-yl)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as a light yellow solid: EI-HRMS m/e calcd for C19H21N3O2S (M+) 389.0965, found 389.0966.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:13][C:14]1[N:19]=[C:18]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=1>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[N:19]=4)=[CH:21][CH:22]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1ccc2ccc(N)cc2n1
Reactant: Cc1cccc(-c2ccc(C(=O)O)cc2)n1
Product: Cc1cccc(-c2ccc(C(=O)Nc3ccc4ccc(C)nc4c3)cc2)n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-2-methylquinoline (D66) (33 mg, 0.21 mmol) and 4-(6-methyl-2-pyridyl)benzoic acid (D29) (47 mg, 0.25 mmol) as an off-white solid. MS (ES): MH+ 354, M-H+ 352.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(=O)(=O)=O.N1C=CC=CC=1>CS(C)=O>[CH2:1]([O:8][C:9](=[O:22])[CH:10]([NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(CCO)C(=O)OCc1ccccc1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC(CC=O)C(=O)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
A dimethyl sulfoxide (10 mL) solution of 2-tert-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (13.58 g, 43.9 mmol) and triethyl amine (18.35 mL, 131.7 mmol) was cooled to 0° C. Pyridine sulfur trioxide (21.0 g. 131.7 mmol) in dimethyl sulfoxide (80 mL) was added in a steady stream. The cooling bath was removed and the reaction stirred 1.5 hours. The reaction was poured into 130 mL ice water and extracted with diethyl ether (2×180 mL and 100 mL). The combined organic portion was washed sequentially with saturated sodium bicarbonate, water, brine and dried over magnesium sulfate. The solvent was removed in vacuo and the crude product was chromatographed on silica gel (900 mL) eluting with ethyl acetate/hexanes (1:4), to give the title compound as a clear, colorless oil (9.20 g, 70%). MS (CI) m/z 208.0 (M−99).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:10]2[N:14]=[CH:13][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:11]=2)=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][N:29]=[N:28][CH:27]=1)CCC.[Cl-].[Li+].O1CCOCC1>CO.C(Cl)Cl.[Cu]I.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>[Br:9][C:5]1[C:6]([C:7]#[N:8])=[C:2]([C:26]2[CH:31]=[CH:30][N:29]=[N:28][CH:27]=2)[S:3][C:4]=1[C:10]1[N:14]=[CH:13][N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: N#Cc1c(Br)sc(-c2ncn(C3CCCCO3)n2)c1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1c(-c2ccnnc2)sc(-c2ncn(C3CCCCO3)n2)c1Br
Temperature: 130 °C
Yield: 57.7 %

Procedure:
A mixture of 2,4-dibromo-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile (0.248 g, 0.594 mmol), 4-(tributylstannyl)pyridazine (2.30 mg, 0.624 mmol), copper(I) iodide (34.0 mg, 0.178 mmol), lithium chloride (75.6 mg, 1.78 mmol) and tetrakis(triphenylphosphine)palladium(0) (34.3 mg, 0.0297 mmol) in dry 1,4-dioxane (5.0 mL, 64 mmol) was sonicated under a nitrogen atmosphere for 2 min then heated in a capped vial to 130° C. in microwave machine for 20 mins. The suspension was cooled to rt, diluted with 20% MeOH/DCM (˜100 mL), treated with 12 g of silica gel then rotavaped and dried under high vacuum. The coated silica gel was chromatographed on a silica column eluting with MeOH/DCM (0/100 to 5/95) to afford a solid product (0.143 g, yield 57.7%). LCMS: (AA) ES+, 417, 419. 1H NMR (300 MHz, CDCl3) δ: 9.55 (s, 1H), 9.37-9.39 (m, 1H), 8.40 (s, 1H), 7.69-8.00 (m, 1H), 5.55-5.60 (m, 1H), 4.08-4.13 (m, 1H), 3.73-3.81 (m, 1H), 2.18-2.30 (m, 1H), 2.03-2.16 (m, 2H), 1.68-1.82 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2)#[N:2].[OH:23]O.[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2)(=[O:23])[NH2:2]
Reactant: N#Cc1cc2c(c(C(=O)OCc3ccccc3)c1)NCCC2
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cc2c(c(C(=O)OCc3ccccc3)c1)NCCC2
Reaction time: 7 h
Yield: 41.7 %

Procedure:
To the solution of benzyl 6-cyano-1,2,3,4-tetrahydroquinoline-8-carboxylate (2.5 g) in ethanol (20 ml) was added 35% hydrogen peroxide solution (3 ml) and 6N sodium hydroxide solution (0.33 ml). The reaction mixture was stirred at 40°-45° C. for 7 hours. The resulting precipitate was collected by filtration and washed with ethanol to give benzyl 6-carbamoyl-1,2,3,4-tetrahydroquinoline-8-carboxylate (1.10 g, 41.7%).
Reaction SMILES: C([O:4][CH:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[C:11](=[O:23])[CH2:10][S:9]1)(=O)C.C(O[C@@H](CCCCC)CCC1N(CCCCCCC(OC)=O)C(=O)CS1)(=O)C>>[OH:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:11](=[O:23])[CH2:10][S:9]1
Reactant: CCCCCC(CCC1SCC(=O)N1CCCCCCC(=O)OC)OC(C)=O
Agent: CCCCC[C@@H](CCC1SCC(=O)N1CCCCCCC(=O)OC)OC(C)=O
Product: CCCCC[C@H](O)CCC1SCC(=O)N1CCCCCCC(=O)O

Procedure:
This compound is prepared exactly by the same method as described in Example 1, Step B, except that the methyl 7-[2-(3-acetyloxyoctyl)-4-oxo-3-thiazolidinyl]-heptanoate is replaced by methyl 7-[2-(3(S)-acetyloxyoctyl)-4-oxo-3-thiazolidinyl]heptanoate. Purification of the product resulting from this method by column chromatography on silica gel affords the pure title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1.[Br-].[Br-].[Zn+2]>[NH2:20][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][C:6]=1[CH2:7][N:8]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc(C)cn1Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)cn1Cc1cc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 30 h
Yield: 89.7 %

Procedure:
In a reaction vessel under nitrogen charge a solution of ethyl 1-(5-chloro-2-nitrobenzyl)-4-methyl-1H-pyrrole-2-carboxylate (100.0 g, 310 mmoles) in THF (800 mL) and add zinc dibromide (0.22 equiv; 15.4 g, 68.4 mmoles) with stirring at room temperature. Charge a slurry of 5% platinum(S)/charcoal (13.3 g) in THF (25 mL), and place the vessel under hydrogen at 380 kPa. Hydrogenate at room temperature for 30 hr. to 40 hr., monitoring formation of a partially hydrogenated intermediate and filter over diatomite. Rinse the filter aid with THF (300 mL) and concentrate the filtrate, at below 40° C., to arrive at a volume of approximately 200 mL. Add DCM (250 mL), concentrate the solution, at below 40° C., to arrive at a volume of approximately 200 mL, and add additional DCM (600 mL). This process can be repeated as necessary to remove undesired levels of THF from the reaction mixture. Charge water (500 mL), separate the layers, and wash the organic layer with water (300 mL), followed by 25% aqueous solution of sodium chloride (250 mL). Concentrate the solution, 40° C., to arrive at a volume of approximately 200 mL, add heptane (400 mL), and concentrate the solution, at below 40° C., to arrive at a volume of approximately 200 mL. Add heptane (400 mL) and heat the reaction mixture to 40-45° C. with stirring for 2-3 hr. Cool the reaction mixture to 5-10° C. and continue stirring at this temperature for 1-2 hr. Filter the resulting solids and dry in an oven at less than 50° C. under reduced pressure to give ethyl 1-(2-amino-5-chlorobenzyl)-4-methyl-1H-pyrrole-2-carboxylate (81.4 g, 95.8% purity, 85.9% yield) as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH3:13])[N:8]=[C:7]3[C:14]2[N:15]=[C:16]3[C:22]([C:23](O)=[O:24])=[CH:21][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:17]3=[N:18][CH:19]=2)[CH2:3][CH2:2]1.Cl.[CH3:35][O:36][CH2:37][C@@H:38]([NH2:40])[CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:35][O:36][CH2:37][C@@H:38]([NH:40][C:23]([C:22]1[C:16]2[C:17](=[N:18][CH:19]=[C:14]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[CH:5]=4)[N:9]([CH3:13])[N:8]=3)[N:15]=2)[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[CH:21]=1)=[O:24])[CH3:39]
Reactant: COC[C@H](C)N
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2cc(C3CC3)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(C5CC5)cc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(5-cyclopropyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (70 mg, 0.15 mmol), (S)-1-methoxypropan-2-amine hydrochloride (21 mg, 0.16 mmol), and HATU (63 mg, 0.16 mmol). Then added acetonitrile (2 mL) followed by N,N-diisopropylethylamine (0.08 mL, 0.45 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The crude material was purified by flash chromatography over silica gel (gradient: 15% to 100% EtOAc in heptane) to afford 34 mg (42%) of 2-(5-cyclopropyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a white solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[F:5][C:6]([F:15])([F:14])[C:7]1[O:11][C:10]([CH2:12]Cl)=[N:9][N:8]=1.C(O)C>CO>[NH:3]1[CH2:2][CH2:1][NH:4][CH2:12]/[C:10]/1=[N:9]/[NH:8][C:7](=[O:11])[C:6]([F:15])([F:14])[F:5]
Reactant: NCCN
Reactant: FC(F)(F)c1nnc(CCl)o1
Solvent: CO
Solvent: CCO
Product: O=C(N/N=C1/CNCCN1)C(F)(F)F
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 46.8 %

Procedure:
The solution of ethylene diamine (89 g) in methanol (305 mL) is stirred and cooled to −20° C. over about 45 minutes. 5-(trifluoromethyl)-2-(chloromethyl)-1,3,4-oxadiazole (79 g) is added slowly to the solution over 90 minutes at −20° C. The resulting slurry is stirred for about 90 minutes at −20° C. Ethanol (482 mL) is added and the slurry is warmed to −5° C. After stirring for about 2 hours at −5° C., the solid is filtered, washed with ethanol (79 mL) and dried at about 55° C. to afford the title compound. (Yield: 46.8%)
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.Cl.ClC1C=CC(C[C@@H](C2C=CC=CC=2)[C@@H](N)C)=CC=1.[CH3:40][C:41]1([C:51](O)=[O:52])[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[O:43][CH2:42]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@@H:9]([C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)[C@@H:10]([NH:12][C:51]([C:41]2([CH3:40])[CH2:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:43][CH2:42]2)=[O:52])[CH3:11])=[CH:15][CH:16]=1
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC1(C(=O)O)COc2ccccc2C1
Agent: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Product: C[C@H](NC(=O)C1(C)COc2ccccc2C1)[C@@H](Cc1ccc(Cl)cc1)c1ccccc1

Procedure:
The title compounds were prepared as a 1:1 mixture of diastereomers following the procedures described for Examples 5 and 6 substituting 2-amino-3,4-bis(4-chlorophenyl)butane hydrochloride salt (Reference Example 1) with N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-amine hydrochloride (Reference Example 3) and substituting 1,2,3,4-tetrahydro-2-naphthoic acid with 3-methylchromane-3-carboxylic acid (Reference Example 9). LC-MS: m/e 434 (M+H)+ (4.06 min).