Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][C:9]([C:15]([OH:17])=O)=[CH:8]2)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:51]1[CH:55]=[CH:54][N:53]=[C:52]1[NH:56][C:57]([C:59]1[C:67]2[NH:66][C:65]([NH2:68])=[N:64][C:63]=2[CH:62]=[CH:61][CH:60]=1)=[O:58]>O.CN(C=O)C>[NH:53]1[CH:54]=[CH:55][N:51]=[C:52]1[NH:56][C:57]([C:59]1[C:67]2[N:66]=[C:65]([NH:68][C:15]([C:9]3[N:10]=[CH:11][C:12]4[C:7]([CH:8]=3)=[CH:6][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:14][CH:13]=4)=[O:17])[NH:64][C:63]=2[CH:62]=[CH:61][CH:60]=1)=[O:58]
Reactant: CC(C)Oc1ccc2cnc(C(=O)O)cc2c1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2cnc(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)cc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 9.5 %

Procedure:
0.05 g (0.23 mmol) of 6-isopropoxy-isoquinoline-3-carboxylic acid and 0.19 g (0.50 mmol) of HBTU were combined in a flask charged with DMF (3 mL) and DIEA (1 mL). This reaction mixture was then treated with 0.1 g (0.4 mmol) 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (Intermediate B,) and stirred at 80° C. for 1 h. The reaction mixture was diluted with water, and the resultant solid precipitate was filtered and washed with saturated NaHCO3. The solid was dissolved with MeOH, evaporated onto silica gel and isolated by flash column chromatography (500 mL DCM/20 mL NH3/MeOH) to yield 10 mg (9%) of 6-isopropoxy-isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 456 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10](CN)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:17](CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:17]([CH3:15])[C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccccc1
Reactant: NC[C@H]1CCN(Cc2ccccc2)C1
Solvent: ClCCl
Product: CN(C(=O)c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
0.778 g of (R)-(1-benzylpyrrolidin-3-yl)methylamine is dissolved in 20 ml of dichloromethane. 0.521 ml of triethylamine is added and the solution is cooled to 0° C. in an ice bath. 0.434 ml of benzoyl chloride is added dropwise and the reaction solution is subsequently stirred at 0° C. over 50 minutes. The reaction solution is diluted with 20 ml of dichloromethane and washed with 20 ml of saturated aqueous sodium hydrogencarbonate solution and 20 ml of brine, dried over sodium sulphate and concentrated by evaporation. The residue is purified by means of flash chromatography (SiO2 60F). The title compound is obtained as a colourless oil. Rf=0.75 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=3.08
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@H:21]([CH3:25])[C:22]([OH:24])=O.Cl.[C:27]1([C:33]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:41][CH2:40][C@@H:39]([F:42])[C@@H:38]3[C@H:34]2[CH2:35][NH:36][CH2:37]3)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.C(N(CC)CC)C>[C:43]1([C:33]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:41][CH2:40][C@@H:39]([F:42])[C@@H:38]3[C@H:34]2[CH2:35][N:36]([C:22](=[O:24])[C@H:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[CH3:25])[CH2:37]3)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COc1ccccc1[C@H](C)C(=O)O
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1 h
Yield: 20.8 %

Procedure:
0.32 g of carbonyldiimidazole is added to a solution, cooled to +4° C., of 0.36 g of (S)-2-(2-methoxyphenyl)-propionic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for one hour at +4° C. and then a solution of 0.67 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydro-isoindole hydrochloride in 20 cm3 of dry dichloromethane and 0.28 cm3 of triethylamine, is added. The reaction mixture is stirred at room temperature for 20 hours, diluted with 200 cm3 of dichloromethane and then washed with 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 20 cm), eluting under a nitrogen pressure of 0.4 bar with an ethyl acetate and cyclohexane mixture (60/40 by volume) and collecting fractions of 20 cm3. Fractions 10 to 15 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 0.6 cm3 of isopropyl oxide. The crystals obtained are drained, washed with isopropyl oxide and then dried. 0.19 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoro-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindole is obtained in the form of white crystals; melting point 195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14](O)[CH2:15][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O.C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:24][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: OC(Cn1cncn1)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Clc1ccc(-c2ccc(C(Cl)Cn3cncn3)cc2)cc1
Yield: 92 %

Procedure:
150 g (0.5 mole) of 1-(2-[4"-chloro-4'-biphenylyl]-2-hydroxy-ethyl)-1,2,4-triazole were dissolved in 2 liters of chloroform and heated to the boil, while stirring. 90g (0.75 mole) of thionyl chloride were slowly added dropwise thereto. The reaction mixture was heated for 12 hours under reflux and after cooling, 1.5 liters of toluene were added. The hydrochloride of 1-(2-chloro-2-[4'(4"-chlorophenyl)-phenyl]-ethyl)-1,2,4-triazole, which thereupon precipitated, was filtered off and taken up in 2 liters of water. The free base was obtained by adding sodium bicarbonate, and was taken up in chloroform. After drying over sodium sulfate, the solvent was distilled off and the residue soldified to crystals. 148 g (92% of theory) of 1-(2-chloro-2-[4"-chloro-4'-biphenylyl]ethyl)-1,2,4-triazole of melting point 118° C. were obtained.
Reaction SMILES: C1CCC([N:7]=C=NC2CCCCC2)CC1.[CH3:16][C:17]1([CH3:58])[C:21](=[O:22])[N:20]([C@@H:23]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:24]([NH:26][C@H:27]([CH3:32])[CH2:28][C:29]([OH:31])=O)=[O:25])[C:19](=[O:37])[N:18]1[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH3:55])=[O:47])=[C:41]([O:56][CH3:57])[CH:40]=1.C1C=CC2N(O)N=NC=2C=1.N>CN(C=O)C>[CH3:58][C:17]1([CH3:16])[C:21](=[O:22])[N:20]([C@@H:23]([CH2:33][CH:34]2[CH2:35][CH2:36]2)[C:24]([NH:26][C@H:27]([CH3:32])[CH2:28][C:29]([NH2:7])=[O:31])=[O:25])[C:19](=[O:37])[N:18]1[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH3:55])=[O:47])=[C:41]([O:56][CH3:57])[CH:40]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COc1cc(CN2C(=O)N([C@@H](CC3CC3)C(=O)N[C@H](C)CC(=O)O)C(=O)C2(C)C)ccc1NC(=O)Nc1ccccc1C
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(CN2C(=O)N([C@@H](CC3CC3)C(=O)N[C@H](C)CC(N)=O)C(=O)C2(C)C)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
131 mg (0.636 mmol) of DCC were added to a solution of 330 mg (0.555 mmol) of the compound of Example 1 and 125 mg (0.926 mmol) of HOBT in 4 mL of absolute DMF, the mixture was stirred at room temperature for 1 hour and then 47 μL (0.555 mmol) of a 25% strength aqueous ammonia solution were added. The mixture was allowed to stand overnight at room temperature, a further 16 μL of a 25% strength aqueous ammonia solution were added and the mixture was stirred for 4 hours. After filtration, the filtrate was concentrated in vacuo, the residue was dissolved in ethyl acetate and the ethyl acetate phase was washed twice in each case with an aqueous KHSO4/K2SO4 solution, a saturated NaHCO3 solution and water. After drying the organic phase over sodium sulfate and filtering, the solvent was removed in vacuo and the residue was chromatographed over silica gel using ethyl acetate. After concentrating the product fractions and freeze drying, 272 mg (82%) of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[C:5]([C:15]2[N:16]=[C:17]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]3=[N:19][CH:20]=2)=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(C(C)C)C(C)C>>[CH3:32][S:33]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]2[C:5]([C:15]3[N:16]=[C:17]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:18]4=[N:19][CH:20]=3)=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH2:10]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(NC2CCCNC2)n1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(NC2CCCN(S(C)(=O)=O)C2)n1

Procedure:
(1-Methanesulfonyl-piperidin-3-yl)-{6-methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from {6-methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-piperidin-3-yl-amine, and methanesulfonyl chloride, using 4 equivalents of DIPEA as base and following the general synthetic procedures described in the above Examples.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([F:16])[C:7]1=2)[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[F:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:17][CH3:19])[CH:14]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(F)c21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)CC1OB(O)c2cc(OC)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of ethyl-2-(4-fluoro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.25 g, 1.0 mmol) in DMF (5 mL) was added potassium carbonate (0.14 g, 1.0 mmol), followed by iodomethane (0.42 g, 3.0 mmol). The reaction mixture was stirred at room temperature overnight and quenched by addition of brine (20 mL). The resulting mixture was extracted with EtOAc (25 mL×2) and the combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/4) on silica gel to give the title compound as a white solid. (253 mg, Yield: 94%). MS (ESI) m/z=269 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=C(OC)[C:10]=1[CH2:11][CH2:12]C)[CH2:6]O.P(Br)(Br)[Br:17].O.C[CH2:22][O:23][CH2:24][CH3:25]>>[CH3:22][O:23][C:24]1[CH:25]=[C:11]([CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[CH:5]([CH3:8])[CH3:6])[CH2:12][Br:17]
Reactant: CCOCC
Reactant: BrP(Br)Br
Reactant: CCCc1c(OC)cc(CO)cc1OC
Solvent: O
Product: COc1cc(CBr)cc(OC)c1C(C)C
Yield: 91.4 %

Procedure:
To 3,5-Dimethoxy-4-1-propylbenzyl alcohol (12.57 g, 59.8 mmol) in dry ether (100 mL) at 0° C. was added PBr3 (3.0 mL, 31.2 mmol) dropwise under nitrogen. The reaction was monitored by TLC. After the reaction was completed (˜4 h), water (180 mL) was added. The organic layer was separated and the aqueous layer was extracted with ether (3×50 mL). The extract was washed with water (20 mL), sat. Na2CO3 (20 mL), water (20 mL) and brine (20 mL), and dried over anhydrous sodium sulfate. Evaporation of the solution yielded pure bromide (14.93 g, 91.4%) as a white solid. 1HNMR (CDCl3, ppm): δ 1.29 (d, J=7.1 Hz, 6H), 3.64 (hept, J=7.1 Hz, 1H), 3.84 (s, 6H), 4.50 (s, 2H), 6.60 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][CH2:17][CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][OH:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].CC(C)([O-:27])C.[K+].F[C:31]1[CH:32]=[C:33]([C:39]#[N:40])[C:34](=[CH:37][CH:38]=1)[C:35]#[N:36].C(OCC)(=O)C>CN(C=O)C>[C:39]([C:33]1[CH:32]=[C:31]([CH:38]=[CH:37][C:34]=1[C:35]#[N:36])[O:22][CH2:21][CH2:20][CH:19]([CH3:23])[CH2:18][C:17]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:27])#[N:40]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ccc(F)cc1C#N
Reactant: CCn1c2ccccc2c2cc(NCCC(C)CCO)ccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CCOc3ccc(C#N)c(C#N)c3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.4 %

Procedure:
To a solution of N-(9-ethyl-9H-carbazol-3-yl)-5-hydroxy-3-methylpentanamine (0.40 g, 1.23 mmol) in DMF (10.0 mL) was added potassium-t-butoxide (0.304 g, 2.71 mmol) under argon atmosphere. The mixture was stirred at room temperature for 15 min, and 4-fluorophthalonitrile (0.270 g, 1.85 mmol) was added thereto. The reaction solution was stirred at room temperature for 14 hr, and ethyl acetate (100 mL) was added thereto. The organic layer was washed with cold water (2×25 mL) and saturated brine (2×25 mL), and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound (0.285 g, 51%) as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:26]5[CH2:30][CH2:29][CH2:28][C:27]5=[O:31])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: O=C1CCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)nn2)CC1
Yield: 9.1 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (107 mg) described in Preparation Example 233 and pyrrolidin-2-one (26 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (11 mg) was obtained.
Reaction SMILES: S([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C@@H:23]4[CH2:27][CH2:26][C@H:25]([NH:28][C:29]5[N:30]=[CH:31][C:32]([C:35]#[N:36])=[N:33][CH:34]=5)[CH2:24]4)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>O1CCOCC1.O.CCO>[C:20]1([C@@H:23]2[CH2:27][CH2:26][C@H:25]([NH:28][C:29]3[N:30]=[CH:31][C:32]([C:35]#[N:36])=[N:33][CH:34]=3)[CH2:24]2)[N:19]2[C:14]3[CH:13]=[CH:12][NH:11][C:15]=3[N:16]=[CH:17][C:18]2=[N:22][N:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](Nc5cnc(C#N)cn5)C4)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: N#Cc1cnc(N[C@H]2CC[C@@H](c3nnc4cnc5[nH]ccc5n34)C2)cn1
Temperature: 60 °C
Yield: 67.6 %

Procedure:
A mixture of 5-((1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile (0.426 g, 0.853 mmol) and aqueous NaOH (1 N, 1.71 mL, 1.71 mmol) in 1,4-dioxane (4.4 mL) was heated at about 60° C. for about 80 min. The mixture was cooled to ambient temperature and diluted with water (40 mL). A solid precipitated and was collected by vacuum filtration and washed with water to give an off-white solid. The material was dissolved in hot EtOH and allowed to cool to ambient temperature. The precipitate was collected by filtration and dried under vacuum to give an off-white solid that was dried in a vacuum oven at about 70° C. to give an off-white solid (0.199 g). The material was taken up in EtOAc (10 mL) and heated at about 70° C. for about 1.5 h. The solid was collected by vacuum filtration, while rinsing with EtOAc. This material was dried under vacuum to give 54(1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)pyrazine-2-carbonitrile (0.19 g, 64%) as an off-white solid: LC/MS (Table 2, Method a) Rt=1.55 min; MS m/z: 346 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>>[NH2:15][C:7]1[C:6]([C:4]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2ccc(Cl)cc2)c(N)n1

Procedure:
The same procedure as described in Example 353 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 4-chlorophenyl magnesium bromide (Aldrich) to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(4-chloro-phenyl)-methanone. MS (M+H)+, 294.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15](=[O:17])[CH3:16])[CH:5]=[CH:6][C:7]=1[S:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[OH:18]OS([O-])=O.[K+].[OH2:24]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:15](=[O:17])[CH3:16])[CH:5]=[CH:6][C:7]=1[S:8]([CH:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)(=[O:18])=[O:24]
Reactant: CC(=O)c1ccc(SC2CCOCC2)c(Cl)c1
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1ccc(S(=O)(=O)C2CCOCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 67 %

Procedure:
A solution of the product obtained from step 2 (1.38 g, 5.10 mmol) in methanol (25 ml) and tetrahydrofurane (25 ml) was added drop wise to a solution of oxone (5.64 g, 9.17 mmol) in water (25 ml) at 0° C. The suspension was stirred 2 days at RT. Water (25 ml) was added and the reaction mixture was extracted with DCM. The combined organic phases were washed with brine and dried over magnesium sulphate. Evaporation and purification of the crude product by silica gel chromatography using ethyl acetate/n-heptane gave the desired product (1.04 g, 67%).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[C:1]([NH:8][C@@H:9]([C:11]([NH:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:13])[CH3:10])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)CN
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: -70 °C

Procedure:
18.9 Grams of Boc-D-alanine are dissolved in 100 ml of methylene chloride, and 22.0 ml of N-methylmorpholine is added. The solution is cooled to -70° C. and 13.0 ml of isobutylchloroformate is added. The reaction mixture is warmed to -15° C. and again cooled to -70° C. and 12.6 g of methyl glycinate hydrochloride is added. The reaction mixture is stirred for sixteen hours at room temperature then extracted three times with a 1.0 M solution of potassium bisulfate, saturated potassium bicarbonate solution, and a saturated sodium chloride solution. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The product is purified by chromatography on silica gel using methanol-chloroform eluant. Removal of the solvent provides methyl Boc-D-alanylglycinate.
Reaction SMILES: [CH2:1]([C:9]1[C:17]2[S:18][CH:19]=[CH:20][C:16]=2[C:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:11]2[S:12][CH:13]=[CH:14][C:10]=12)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.[CH3:34][Sn:35](Cl)([CH3:37])[CH3:36].O>O1CCCC1>[CH2:1]([C:9]1[C:17]2[S:18][C:19]([Sn:35]([CH3:37])([CH3:36])[CH3:34])=[CH:20][C:16]=2[C:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:11]2[S:12][C:13]([Sn:35]([CH3:37])([CH3:36])[CH3:34])=[CH:14][C:10]=12)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCc1c2ccsc2c(CCCCCCCC)c2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCc1c2cc([Sn](C)(C)C)sc2c(CCCCCCCC)c2cc([Sn](C)(C)C)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 4,8-dioctylbenzo[1,2-b:4,5-b′]dithiophene (782 mg, 1.89 mmol) in dry tetrahydrofuran (36 mL) was added n-butyllithium (2.5 M in hexane, 1.66 mL, 4.15 mmol) at −78° C. After 1 hour, trimethyltin chloride (877 mg, 4.40 mmol) was added in one portion. The mixture was stirred at room temperature for 2 hours, poured into water and extracted with ether three times. The organic layer was washed with brine and dried over anhydrous MgSO4. Upon evaporating the solvent, a pale yellow oil was obtained (1.03 g, yield 74%). Upon standing for one week, yellow crystals emerged and were collected (413 mg, yield 29%). 1H NMR (CDCl3, 500 MHz) δ=7.51 (s, 2H), 3.22 (t, J=8.0 Hz, 4H), 1.76-1.89 (m, 4H), 1.45-1.54 (m, 4H), 1.22-1.45 (bs, 16H), 0.90 (t, J=7.0 Hz, 6H), 0.47 (s, 18H).
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].[F:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=3[F:19])[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: Cc1ccc(B(O)O)c(F)c1
Product: CCCNC(=O)c1nnc2c(-c3ccc(C)cc3F)cccc2c1N
Yield: 85.9 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-fluoro-4-methyl-phenylboronic acid (154 mg, 1.000 mmol) were reacted to afford the title compound (141 mg, 86% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (br, 1H), 7.91 (m, 1H), 7.81-7.69 (m, 2H), 7.28 (m, 1H), 7.24-7.16 (m, 1H), 7.13-7.04 (m, 1H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 2.39 (s, 3H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H). MS APCI, m/z=339 (M+H). HPLC 1.86 min.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:18][C:17]2=[O:33])[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH:34](Cl)(Cl)[Cl:35].C(OCC)(=O)C>C1COCC1>[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:26]=[CH:27][C:28](/[CH:31]=[CH:34]/[Cl:35])=[CH:29][CH:30]=3)(=[O:24])=[O:23])[CH2:18][C:17]2=[O:33])[CH2:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(C=O)cc3)CC2=O)CC1
Reactant: ClC(Cl)Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(/C=C/Cl)cc3)CC2=O)CC1

Procedure:
To a suspension of chromiun (II) chloride (737 mg) in THF (10 ml) was added a solution of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-[4-formylbenzenesulfonyl]-2-piperazinone (466 mg) and chloroform (0.160 ml) in THF (7 ml), and the mixture was refluxed for 1 hour. To the reaction solution was added ethyl acetate, and the mixture was washed with water and saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give colorless crystals of the title compound (235 m g).