Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[C:10]2[CH2:18][CH:19]([C:21]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])([CH3:24])[CH2:22][OH:23])[CH2:20][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:36]I>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[C:10]2[CH2:18][CH:19]([C:21]([S:25]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)(=[O:26])=[O:27])([CH3:24])[CH2:22][O:23][CH3:36])[CH2:20][C:9]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)n1c2c(c3cc(Cl)ccc31)CC(C(C)(CO)S(=O)(=O)c1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(C)(C1Cc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 103.2 %

Procedure:
50 mg (0.1 mmol) (RS,SR)-2-(1-benzenesulfonyl-2-hydroxy-1-methyl-ethyl)-7-chloro-2,3-dihydro-1H-cyclopenta[b]indole-4-carboxylic acid tert-butyl ester were dissolved in 5 mL dry THF at 0° C. 5 mg (0.11 mmol, 1.1 eq) NaH (55%) were added and the reaction mixture was stirred for 20 minutes. 10 μL (0.15 mmol, 1.5 eq) methyliodide were then added and the reaction was stirred for 1 hour at 0° C. The reaction was quenched with a saturated NaHCO3 solution. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated to dryness to yield 52 mg (100%) (RS,SR)-2-(1-benzenesulfonyl-2-methoxy-1-methyl-ethyl)-7-chloro-2,3-dihydro-1H-cyclopenta[b]indole-4-carboxylic acid tert-butyl ester as a white powder.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:41])[O:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1>O1CCCC1>[F:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][C:32]([N:13]2[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]3[CH2:12]2)=[O:41])=[CH:35][CH:36]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=C(Cl)Oc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccc(F)cc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (50 mg, 0.17 mmol) in tetrahydrofuran (2 mL) were sequentially added diisopropylethylamine (0.30 mL, 1.7 mmol) and 4-fluorophenyl chlorocarbonate (45 mg, 0.26 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) and crystallized from diisopropyl ether to obtain the title compound (58 mg, yield 79%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH:18]([CH2:23][C:24]([NH2:26])=O)[CH2:19][C:20]([NH2:22])=O)[CH:17]=3)[N:10]3[CH:27]=[CH:28][N:29]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.C(Cl)Cl.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH:18]([CH2:23][C:24]#[N:26])[CH2:19][C:20]#[N:22])[CH:17]=3)[N:10]3[CH:27]=[CH:28][N:29]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC(N)=O)CC(N)=O)c3)n2)cn1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)CC#N)c3)n2)cn1
Reaction time: 1 h
Yield: 97.9 %

Procedure:
3-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)pentanediamide (0.047 g, 0.12 mmol) was partially dissolved in DMF (0.3 mL) and DCM (0.5 mL) and triethylamine (0.08 g, 0.79 mmol) was added. 2,2,2-trichloroacetyl chloride (0.08 g, 0.44 mmol) was added at 0° C., and the reaction was stirred for 1 hour. Additional reagents (40 mg Et3N and 30 mg acid chloride) were added and the reaction was complete. The reaction was concentrated and pumped to dryness. A minimum amount of water was added (1.5 mL) to dissolve the crude product. Excess sodium chloride was added to the aqueous layer and this mixture was extracted with EtOAc (10×10 mL) to recover the desired product. The organic phase was dried using MgSO4 and concentrated to provide 3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)pentanedinitrile (42 mg, 98% yield). MS (apci) m/z=358.1 (M+H). 1H NMR (d6-DMSO) δ 9.12 (s, 1H), 8.59 (s, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 7.78 (s, 1H), 7.76 (s, 1H), 5.30-5.29 (m, 1H), 3.91 (s, 3H), 1.22-1.10 (m, 4H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C(O)(C(F)(F)F)=O.O[CH2:18][N:19]1[CH2:23][CH:22]([CH2:24][CH2:25][CH3:26])[CH2:21][C:20]1=[O:27]>>[CH2:24]([CH:22]1[CH2:23][N:19]([CH2:18][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[C:20](=[O:27])[CH2:21]1)[CH2:25][CH3:26]
Reactant: c1cnc2[nH]ccc2c1
Reactant: CCCC1CC(=O)N(CO)C1
Solvent: O=C(O)C(F)(F)F
Product: CCCC1CC(=O)N(Cc2c[nH]c3ncccc23)C1
Temperature: 70 °C
Yield: 13 %

Procedure:
To a solution of commercially available 1H-pyrrolo[2,3-b]pyridine x7 (20.31 mmol, 1.2 eq, 3.19 g) dissolved TFA (25 ml) is added 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (16.93 mmol, 1 eq, 2 g). The mixture is heated at 70° C. overnight. The solvent is then evaporated under reduce pressure. CH2Cl2 (600 ml) is then added to the residue, and the resulting organic solution is washed with a saturated aqueous solution of sodium carbonate (200 ml). The organic phase is then dried over MgSO4 and the volatiles are removed under reduced pressure. The product is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 97/3/0.3 (v/v/v)) and recristallized in acetonitrile. 4-propyl-1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)pyrrolidin-2-one 231 is obtained as a white solid.
Reaction SMILES: [I:1][N:2]([C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].N12CCCN=C1CCCCC2.[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(#N)C>[CH2:24]([O:5][C:4](=[O:6])[CH2:3][N:2]([C:7]([O:9][CH2:10][C:11]#[CH:12])=[O:8])[I:1])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: C#CCOC(=O)N(I)CC(=O)O
Reactant: CCCCCCCCBr
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCOC(=O)N(I)CC(=O)OCCCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-Iodopropargyloxycarbonyl glycine (compound 1, 6.50 g., 22.97 mmole) was dissolved in anhydrous acetonitrile (100 ml.), treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (3.5 ml., 23.40 mmole) and stirred at room temperature for 5 minutes. n-Octylbromide (4.00 ml., 23.16 mmole) was added and the reaction mixture was stirred at room temperature for 17 hours, then heated at reflux temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and the resultant residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, 5% aqueous citric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over magnesium chloride, filtered and concentrated under reduced pressure. The resultant residue was purified utilizing column chromatography (silica gel, 200 g.) and eluted with ethyl acetate/hexane (1:10) to afford N-Iodopropargyloxycarbonyl glycine n-octyl ester (Compound 3) as a clear colorless liquid which crystallized on standing. m.p. 43°-46° C. Elemental Analysis: C14H22NO4 l: Calc'd. C: 42.55, H: 5.61, N: 3.54. Found: C: 43.73, H: 5.62, N: 3.54. (Ethyl acetate was present in 0.5 mole %). 1H-NMR (200 MHz, CDCl3) δppm =0.89, m, 3H (--CH3), 1.30, m, 10H (--(CH2)5 --CH3), 1.64, m, 2H (--CH2 --), 4.0,d, J=3.4 Hz., 2H (--N--CH2 --), 4.1-4.2, m, 2H (--CH2 --), 4.86, s, 2H (C--CH2 --O), 5.32, m, 1H (--NH--). IR (neat) 3460, 2920, 2850, 2200, 1740, 1560, 1480, 1400, 1360, 1200, 1060, 980 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[N:25]=[CH:24][NH:23][N:22]=2)=[N:10]1.C1C(=O)N([Br:33])C(=O)C1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:33])[NH:12][C:11]([C:21]2[N:25]=[CH:24][NH:23][N:22]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 45.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (0.82 g, 2 mmol) was reacted with NBS (0.39 g, 2.2 mmol) in chloroform (40 mL) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.44 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]2[CH2:17][O:18][C:19]2[C:24]([F:25])=[CH:23][C:22]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:21][C:20]=2[F:31])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:36]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]2[CH2:17][O:18][C:19]2[C:20]([F:31])=[CH:21][C:22]([CH2:26][CH2:27][C:28]([O:30][CH3:36])=[O:29])=[CH:23][C:24]=2[F:25])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccc(Cl)cc2)c(F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccc(Cl)cc2)c(F)c1
Reaction time: 3 h

Procedure:
To a solution of the product prepared in Example 1 (1.10 g, 2.39 mmol, 1 eq) in methanol (20 mL) at room temperature was added thionyl chloride (0.027 mL, 0.36 mmol, 0.15 eq). After stirring the resulting mixture for 3 hrs, the solution was concentrated. Purification of the mixture by chromatography (40 g) eluting with 2 to 10% ethyl acetate//heptane yielded the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[C:24]([C:26]([NH2:28])=O)[S:25][C:17]3=4)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH:20]=[CH:19][C:18]4[C:23]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[C:24]([C:26]#[N:28])[S:25][C:17]3=4)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: NC(=O)c1sc2c(ccc(=O)n2-c2ccc(OCCN3CCOCC3)cc2)c1-c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1sc2c(ccc(=O)n2-c2ccc(OCCN3CCOCC3)cc2)c1-c1ccccc1
Reaction time: 0.08 h
Yield: 59.1 %

Procedure:
To a solution of the compound of Example 104 (128 mg, 0.27 mmol) in dry DCM (1.5 mL) was added pyridine (44 μL, 0.54 mmol) followed by trifluoroacetic anhydride (46 μL, 0.32 mmol). TLC showed the reaction was complete after 5 minutes and the reaction was then diluted with DCM (20 mL) and washed with 2M NaOH(aq) (20 mL). The DCM layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was co-evaporated with toluene (2×15 mL) to give the title compound as a solid (73 mg). δH (CDCl3) 7.62 (1H, d, J 9.7 Hz), 7.51–7.45 (5H, m), 7.29–7.26 (2H, m), 7.08–7.04 (2H, m), 6.62 (1H, d, J 9.7 Hz), 4.14 (2H, t, J 5.6 Hz), 3.71–3.68 (4H, m), 2.81 (2H, t, J 5.6 Hz), 2.58–2.54 (4H, m). LCMS (ES+) RT 2.47 minutes, 458 (M+H)+.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[C:8]1[C:17]2[CH:16]=[CH:15][S:14][C:13]=2[C:12](=[O:18])[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2.[CH2:23]([O:25][C:26](Cl)=[O:27])[CH3:24]>C1C=CC=CC=1>[C:26]([N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[C:8]1[C:17]2[CH:16]=[CH:15][S:14][C:13]=2[C:12](=[O:18])[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)([O:25][CH2:23][CH3:24])=[O:27]
Reactant: CCOC(=O)Cl
Reactant: CN1CCCCC1=C1c2ccccc2CC(=O)c2sccc21
Solvent: c1ccccc1
Product: CCOC(=O)N1CCCCC1=C1c2ccccc2CC(=O)c2sccc21

Procedure:
Using the procedure of Example IA, react 21.3 g of N-methylpiperidylidene-4H-benzo-[4,5]-cyclohepta-[1,2-b]-thiophene-10(9H)-one in 300 ml of benzene with a solution of 10.9 g of ethylchloroformate in 300 ml benzene to prepare the title compound.
Reaction SMILES: O[C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.C1C=CC(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)=CC=1.N12CCCN=C1CCCCC2.O>C1COCC1>[N:28]([C@H:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc2c(c1)OCC[C@@H]2O
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1ccc2c(c1)OCC[C@H]2N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Azeotropically dried (S)-4-hydroxy-chroman-7-carbonitrile (2.0 g, 11 mmol) was dissolved in dry THF (55 ml). DPPA (3.0 ml, 3.8 g, 14 mmol) was added to the solution at RT and the mixture was stirred for 5 min. The solution was cooled to 0° C. and 1,8-diazabicyclo[5,4,0]undec-7-ene (2.0 mL, 2.1 g, 14 mmol) was added. After stirring for 10 min at 0° C., the reaction was warmed to RT, at which time a white precipitate formed, and was stirred for 14 h. The resulting solution was poured into H2O (100 mL) and extracted with Et2O (300 mL, 3×). The organic phases were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide a residue which was purified by flash column chromatography (silica, 33% hexane in CH2Cl2) to provide the title compound.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.C(N(CC)CC)C.[F:17][CH:18]([F:35])[O:19][C:20]1[CH:21]=[CH:22][C:23]([C:32]([OH:34])=O)=[C:24]2[C:28]=1[O:27][C:26]([CH2:29][O:30][CH3:31])=[CH:25]2.[CH3:36][C:37]1[C:41]([NH2:42])=[C:40]([CH3:43])[O:39][N:38]=1>ClCCl>[CH3:36][C:37]1[C:41]([NH:42][C:32]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH:18]([F:17])[F:35])=[C:28]3[O:27][C:26]([CH2:29][O:30][CH3:31])=[CH:25][C:24]=23)=[O:34])=[C:40]([CH3:43])[O:39][N:38]=1
Reactant: Cc1noc(C)c1N
Reactant: COCc1cc2c(C(=O)O)ccc(OC(F)F)c2o1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1cc2c(C(=O)Nc3c(C)noc3C)ccc(OC(F)F)c2o1
Reaction time: 8 h
Yield: 28.8 %

Procedure:
Cyanuric chloride (19 mg) and triethylamine (0.05 ml) were added to a stirred solution of 7-difluoromethoxy-2-methoxymethylbenzofuran-4-carboxylic acid (85 mg) in dry dichloromethane at room temperature under a dry nitrogen atmosphere. After stirring for 20 minutes 3,5-dimethylisoxazol-4-ylamine (42 mg) was added and the reaction left overnight. The reaction was mixture was preadsorbed onto silica. Purification by column chromatography on silica eluting with 30% ethyl acetate in hexane gave the title compound as a cream solid (33 mg)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[C-:12]#[N:13].[Na+].O>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[C:3]([CH2:2][C:12]#[N:13])[CH:8]=[CH:7][CH:6]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cccc([N+](=O)[O-])c1
Yield: 43.9 %

Procedure:
A solution of 1-(bromomethyl)-3-nitrobenzene (30 g, 0.139 mol) and NaCN (10.21 g, 0.208 mol) in DMF (150 mL) was stirred at 50° C. for 5 hrs. The mixture was poured into water and extracted with ethyl acetate. The combined organic layer were dried, concentrated and purified by silica-gel column chromatography (PE:EA 20:1˜6:1) to give compound 2-(3-nitrophenyl)acetonitrile (9.9 g, yield 44%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH2:18])=[S:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:20][C:21](=O)[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C>CO>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:20]=[C:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[N:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: NC(=S)Nc1ncccc1OCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)Cc1csc(Nc2ncccc2OCc2ccccc2)n1
Yield: 33.2 %

Procedure:
Following the method of Example 2, Step C, 1-(3-(benzyloxy)pyridin-2-yl)thiourea (2.00 g, 7.71 mmol), methyl 4-chloro-3-oxo-butanoate (1.63 g, 10.8 mmol), and triethylamine (1.83 mL, 13.1 mmol) were reacted in methanol (40 mL) to provide methyl 2-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)acetate (910 mg, 33%) as a yellow oil. 1H NMR (d6-DMSO) δ 10.10 (s, 1H), 7.86 (d, 1H), 7.58 (d, 2H), 7.30-7.42 (m, 4H), 6.90 (d, 1H), 6.80 (s, 1H), 5.25 (s, 2H), 3.62 (s, 3H). Mass spectrum (apci) m/z=356 (100) (M+H).
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH:2]=[CH2:3].N#N.Br[C:20]1[CH:39]=[N:38][C:23]2[N:24]([CH2:36][CH3:37])[C:25]3[N:34]=[C:33]([F:35])[CH:32]=[CH:31][C:26]=3[N:27]([CH3:30])[C:28](=[O:29])[C:22]=2[CH:21]=1>CN(C=O)C.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>[CH2:36]([N:24]1[C:23]2[N:38]=[CH:39][C:20]([CH2:3][CH:2]=[CH2:1])=[CH:21][C:22]=2[C:28](=[O:29])[N:27]([CH3:30])[C:26]2[CH:31]=[CH:32][C:33]([F:35])=[N:34][C:25]1=2)[CH3:37]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(F)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: C=CCc1cnc2c(c1)C(=O)N(C)c1ccc(F)nc1N2CC
Temperature: 90 °C
Yield: 76.3 %

Procedure:
Allyltributyltin (32.0 mL, 103.4 mmol) and Pd(Ph3P)4 (5.43 g, 4.70 mmol) were added to a degassed (N2 through solution for 45 min) solution of 8-bromo-5,11-dihydro-11-ethyl-2-fluoro-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (33.0 g, 94.0 mmol) in DMF (470 mL). Additional amounts of Pd(Ph3)4 (1.09 g, 0.94 mmol added after 1, 2,3,4,5 h of reaction) were added to complete the reaction. The mixture was heated to 90° C. for 6 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:EtOAc, 8:2 to 7:3) to give the title compound (22.4 g, 76% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.C([Cl:26])(=O)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[Cl:26])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: OC(c1ccccc1)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClCCl
Product: Fc1ccc(C(Cl)(c2ccccc2)c2ccc(F)cc2)cc1
Reaction time: 12 h

Procedure:
Bis(4-fluorophenyl)phenylmethanol (0.092 mol) was added to a 20% solution of acetyl chloride in dichloromethane (50 mL) at rt. The resulting purple solution was stirred for 12 h after which the solvent was removed by evaporation. Toluene (100 mL) was added to the residue and then evaporated, affording crude bis(4-fluorophenyl)phenylchloromethane which was used without purification in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8]Cl)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C.CO.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:6]=1
Reactant: C1CCNCC1
Reactant: ClCCn1cc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: Brc1cnn(CCN2CCCCC2)c1
Temperature: 60 °C

Procedure:
4-bromo-1-(2-chloroethyl)-1H-pyrazole (see Intermediate 29 for a preparation) (120 mg, 0.573 mmol), potassium carbonate (158 mg, 1.146 mmol) and Piperidine (0.113 mL, 1.146 mmol) was stirred in Acetonitrile (2 mL) and heated to 60° C. for five days. The mixture was fully dissolved in MeOH/water and loaded on to a 10 g SCX cartridge. The SCX cartridge was eluted with MeOH (100 ml), followed by 2M methanolic ammonia (50 ml). The basic fractions were evaporated to dryness to give the desired product (101 mg). LCMS (Method A): Rt=1.04, MH+=260
Reaction SMILES: [S:1]([C:5]1[S:13][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br)#[N:15].C(N(CC)CC)C>C(#N)C.O>[S:1]([C:5]1[S:13][C:8]2[CH2:9][N:10]([CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([C:14]#[N:15])[CH:17]=3)[CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1cc2c(s1)CNCC2
Reactant: N#Cc1cccc(CBr)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: N#Cc1cccc(CN2CCc3cc(S(N)(=O)=O)sc3C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a partial suspension of 2-sulfamoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2.20 g, 10.1 mmol) in acetonitrile (50 ml) containing 3-cyanobenzylbromide (2.36 g, 12 mmol) was added triethylamine (1.70 ml, 12.2 mmol). After stirring at room temperature for three hours, the clear solution was diluted with water and the product was extracted into ethyl acetate/methanol, dried over anhydrous sodium sulfate, filtered and evaporated to give a residue which was triturated with methylene chloride/diethyl ether to give purified product (3.2 g, 96% yield). Recrystallization from hot ethanol gave product (2.4 g), m.p. 137°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20]([OH:22])=O)[C:6]2=[O:17].[C:34](N1C=CN=C1)([N:36]1C=CN=[CH:37]1)=O.CNC.O>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20](=[O:22])[N:36]([CH3:37])[CH3:34])[C:6]2=[O:17]
Reactant: CCOc1cc([C@@H](CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(=O)N(C)C)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a solution of (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid (0.62 g, 1.3 mmol) in tetrahydrofurane (5 ml) was added carbonyldiimidazole (0.3 g, 2 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added THF solution of dimethylamine (2 M, 1.3 ml, 2.6 mmol). The resulted mixture was stirred at room temperature for 4 hrs. Water (20 ml) was added to the reaction mixture. THF was removed in vacuo and to the resulted mixture was added ethyl acetate (30 ml). The mixture was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulted oil was stirred with ether (5 ml) for 2 hrs and filtered to give (1R)-cyclopropanecarboxylic acid {7-chloro-2-[2-dimethylcarbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.5 g, 77%): mp 163-165° C.; 1HNMR (CDCl3): δ 0.86-0.89 (m, 2H, c-CH2), 1.08-1.11 (m, 2H, c-CH2), 1.46 (t, J=7.5 Hz, 3H, OCH2CH3), 1.65-1.68 (m, 1H, c-CH), 2.93 (s, 3H, NCH3), 3.04 (dd, J=5, 16 Hz, 1H, CHH), 3.12 (s, 3H, NCH3), 3.56 (dd, J=5, 16 Hz, 1H, CHH), 3.86 (s, 3H, OCH3), 4.10 (q, J=7.5 Hz, 2H, OCH2CH3), 4.25 (d, J=17 Hz, 1H, NCHH), 4.60 (d, J=17 Hz, 1H, NCHH), 5.58-5.64 (m, 1H, CHN), 6.83-6.97 (m, 3H, Ar), 7.35 (d, J=9 Hz, 1H, Ar), 8.41 (d, J=9 Hz, 1H, Ar), 10.51 (s, 1H, NH); 13C NMR (CDCl3): 8.9, 15.4, 16.8, 36.2, 36.6, 38.0, 48.6, 54.3, 56.6, 65.2, 112.1, 113.1, 119.8, 120.0, 120.1, 122.3, 132.2, 133.2, 137.3, 139.9, 149.2, 149.8, 169.4, 170.1, 173.2; Anal. Calcd. for C26H30ClN3O5: C, 62.46; H, 6.05; N, 8.40. Found: C, 62.43; H, 5.42; N, 8.51.