Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=1[NH:10][C:11]([NH:13]C(=O)C1C=CC=CC=1)=[S:12])#[N:2].[OH-].[Na+]>CCO>[NH2:2][C:1]1[C:3]2[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=2[NH:10][C:11](=[S:12])[N:13]=1
Reactant: Cc1sc(NC(=S)NC(=O)c2ccccc2)c(C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc2[nH]c(=S)nc(N)c2c1C
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A solution of N-(3-cyano-4,5-dimethylthiophen-2-ylcarbamothioyl)benzamide (example 1a) (1.90 g, 6.03 mmol) and NaOH (2 N, 8.3 mL) in EtOH (25 mL) was stirred at 100° C. under nitrogen for half an hour. After cooling to room temperature, the clear reaction solution was filtered and the filtrate was carefully neutralized with 10% AcOH with vigorous stirring at 0° C. The resultant precipitate was collected by filtration, washed with warm water and then 20% EtOH in water to give the final product 4-amino-5,6-dimethylthieno[2,3-d]pyrimidine-2(1H)-thione (1.11 g, 87%) as an off-white solid. M.p.: >260° C. 1H NMR (400 MHz, DMSO-d6) δ2.25 (s, 3H), 2.26 (s, 3H). MS 212 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6](O)[C:7]([CH2:9][CH2:10][CH3:11])=[CH2:8])[CH3:2].S(Br)(Br)=O.[P:21]([O:26]C)([O:24][CH3:25])[O:22][CH3:23]>>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])/[CH:6]=[C:7](\[CH2:9][CH2:10][CH3:11])/[CH2:8][P:21]([O:24][CH3:25])([O:22][CH3:23])=[O:26])[CH3:2]
Reactant: COP(OC)OC
Reactant: C=C(CCC)C(O)C(NC=O)C(=O)OCC
Agent: O=S(Br)Br
Product: CCC/C(=C\C(NC=O)C(=O)OCC)CP(=O)(OC)OC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-pentanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of the 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 15, 2-formylamino- 3-hydroxy-4-propyl-4-pentenoic acid ethyl ester is obtained. Reaction of the 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite in a manner analogous to that described in Example 1 yields E-2-formylamino-4-propyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]2[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:9]=2[NH:8][N:7]=1)=[O:5])C.O.[OH-].[Li+].S([O-])(O)(=O)=O.[K+]>CO.O>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:9]2[NH:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:10]=2[CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)c1n[nH]c2c1CN(C(=O)OC(C)(C)C)CC2
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)O)c2C1
Yield: 96.1 %

Procedure:
A solution of 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester [5.105 g, Reference Example 18(d)] and lithium hydroxide monohydrate (0.870 g) in methanol (30 ml) and water (10 ml) was stirred at 55° C. for 2.5 hours. The mixture was acidified with saturated aqueous potassium hydrogen sulfate solution and extracted three times with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to yield 1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-tert-butyl ester (4.442 g) as a pale yellow solid. MS: 268 (M+H)+. HPLC (METHOD G): RT=2.86 minutes. (b) 4-{[(2,4-dimethoxy-benzyl)-(morpholine-4-carbonyl)-amino]-methyl}-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carboxylic acid
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11](C2C=C(Cl)C=CC=2Cl)[C@H:12]([CH3:18])[CH2:13][CH2:14][N:15]=[N+]=[N-])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:18][C@@H:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:13][CH2:14][NH2:15]
Reactant: C[C@H](CCN=[N+]=[N-])N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCN)NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)-1-methyl-3-azidopropyl]benzenesulfonamide (0.941 g, 2.16 mmol) in THF (21 mL) was added lithium aluminum hydride (4.33 mL, 1 M in THF) at 0° C. under nitrogen atmosphere. The resulting mixture was allowed to stir at 0° C. for 1 h and subsequently treated by successive dropwise addition of 0.165 mL of water, 0.165 mL of 15% sodium hydroxide solution, and 0.493 mL of water. The mixture was filtered and concentrated under reduced pressure. Silica gel chromatography (3:10 ethyl acetate:hexanes) of the concentrate afforded 0.748 g of 4-chloro-N-2,5-dichlorophenyl)-N-[(R)-1-methyl-3-aminopropyl]benzenesulfonamide as a light brown oil in 85% yield.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=1.[NH:12]1[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[CH3:11][C:4]1[C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=[C:2]([N:12]2[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]2)[CH:3]=1
Reactant: Cc1cc(Cl)nn2cnnc12
Reactant: C1=CCNCC1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(N2CC=CCC2)nn2cnnc12
Temperature: 25 °C

Procedure:
A solution of 84.3 g of 6-chloro-8-methyl-1,2,4-triazolo [4,3-b]pyridazine, 62.4 g of 1,2,5,6-tetrahydropyridine and 101 g of triethylamine in one liter of ethanol was refluxed under nitrogen for 21 hours. The bulk of the solvent was removed at the rotary evaporator. The residual semi-solid was dissolved in 1000 ml of dichloromethane and washed with 500 ml of saturated sodium bicarbonate solution. The aqueous layer was back washed with fresh dichloromethane (2×200 ml) and the combined organic layers were dried over anhydrous sodium sulfate. Evaporation of the solvent gave a light-brown oil which slowly solidified. This was taken up in 230 ml of hot ethyl acetate and cooled. After cooling the mixture slowly to room temperature and then to 5° C., the cream colored needles which formed were collected, washed with ethyl ether/ethyl acetate (2/1) then with ethyl ether and dried to give 8-methyl-6-(1,2,5,6-tetrahydropyridin-1-yl)-1,2,4-triazolo-[4,3-b]pyridazine melting at about 103°-106° C.
Reaction SMILES: [C:1]([N:4]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[C:6]2([CH2:11][CH2:10]S[CH2:8][CH2:7]2)[CH2:5]1)(=[O:3])[CH3:2].O[O:20][S:21]([O-:23])=O.[K+].[NH4+].[Cl-]>CO.O.CC(C)=O>[C:1]([N:4]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[C:6]2([CH2:7][CH2:8][S:21](=[O:23])(=[O:20])[CH2:10][CH2:11]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC2(CCSCC2)c2ccc(Br)cc21
Reactant: O=S([O-])OO
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)N1CC2(CCS(=O)(=O)CC2)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred ice-cooled suspension of crude 1-acetyl-6-bromo-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran] (0.68 g, 2.1 mmol) in MeOH (40 mL), H2O (5 mL) and acetone (10 mL) was added oxone (2.58 g, 4.20 mmol) in H2O (15 mL). The resulting mixture was stirred at rt for 20 h. After this time the mixture was poured into ice and saturated aqueous NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 1-acetyl-6-bromo-1,2,2′,3′,5′,6′-hexahydrospiro-[indole-3,4′-thiopyran]1′,1′-dioxide as a white solid. Mass Spectrum (ESI) m/e=358.0 [(M+1) (79Br)] and 360.0 [(M+1) (81Br)].
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:2]1.[NH2:15][C:16]1[C:17]([C:24]([NH:26][CH2:27][CH2:28][NH2:29])=[O:25])=[N:18][C:19]([Cl:23])=[C:20]([NH2:22])[N:21]=1.C(O)(C)C.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>CO>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[NH2:15][C:16]1[C:17]([C:24]([NH:26][CH2:27][CH2:28][NH:29][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)=[O:25])=[N:18][C:19]([Cl:23])=[C:20]([NH2:22])[N:21]=1
Reactant: NCCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: CO
Product: Nc1nc(N)c(C(=O)NCCNCC(O)COc2cccc3[nH]ccc23)nc1Cl

Procedure:
A mixture of 1,2-epoxy-3-(indol-4-yloxy)propane (0.67 g.), 3,5-diamino-6-chloro-N-(2-aminoethyl)pyrazine-2-carboxamide (1.63 g.) and isopropanol (50 ml.) were refluxed together under nitrogen until thin layer chromatography indicated all of the epoxy compound had reacted (about 3 hours). The solvent was removed by rotary evaporator and the resulting yellow solid was chromatographed on silica gel with a 5:1 mixture of chloroform:methanol to give 1.03 g. of product. This material was dissolved in methanol (110 ml.) with warming and the solution was added to oxalic acid (1 equivalent) in methanol (20 ml.). Upon concentration and cooling of the solution, there was obtained 3,5-diamino-6-chloro-N-2-(2-hydroxy-3-indol-4-yloxy-propylamino)ethyl-pyrazine-2-carboxamide oxalate, m.p. 214°-216° C. with decomposition.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[F:11].[C:12]([O:16][C:17](=[O:33])[CH2:18][N:19]=[C:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:15])([CH3:14])[CH3:13].[I-].[K+].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1.O>[C:12]([O:16][C:17](=[O:33])[CH:18]([N:19]=[C:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[F:11])([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1ccc(F)c(CBr)c1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)c(CC(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cold (10° C.) stirred solution of 2-fluoro-5-methoxybenzyl bromide (35, 50 mg, 0.23 mmol), t-butylglycinate Schiff base 3 (68 mg, 0.23 mmol) and potassium iodide (4.2 mg, 0.05 mmol) in dioxane (2.0 mL) was added dropwise over 30–45 min. benzyltrimethylammonium hydroxide (0.069 mL, 0.23 mmol, 40% aqueous). The reaction mixture was then brought to room temperature and stirred for an additional 3 h. After cooling to 0° C., water (2.0 mL) was added and the mixture was extracted with toluene (6×10 mL). The organic extracts were washed with water (20 mL) and dried over sodium sulfate. Evaporation of the solvent afforded a colorless oil, which was not purified (33%) and the alkylated product 40 was not obtained.
Reaction SMILES: ClC1C=CC(NN=CC)=CC=1N[S:13]([CH3:16])(=[O:15])=[O:14].ClC1C=CC([N+]([O-])=O)=CC=1N.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[NH:38][S:39]([CH3:42])(=[O:41])=[O:40].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[N:38]([S:13]([CH3:16])(=[O:15])=[O:14])[S:39]([CH3:42])(=[O:40])=[O:41]
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC=NNc1ccc(Cl)c(NS(C)(=O)=O)c1
Agent: CS(=O)(=O)Cl
Agent: Nc1cc([N+](=O)[O-])ccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1cc([N+](=O)[O-])ccc1Cl)S(C)(=O)=O
Temperature: 0 °C

Procedure:
To prepare the starting material, acetaldehyde 4-chloro-3-methylsulfonylaminophenylhydrazone, a mixture of 20.0 5 (116 mmoles) of 2-chloro-5-nitroaniline (compound 4, FIG. 1), 24.6 g (243 mmoles) of triethylamine and 100 ml of methylene chloride was cooled in an ice bath, and a solution of 27.8 g (243 mmols) of methylsulfonyl chloride in 20 ml of methylene chloride was added dropwise. When the addition was about half complete the ice bath was removed. After completion of the addition, the mixture was allowed to stand for an hour and then filtered to remove undesired salts. The filtrate was evaporated under reduced pressure to give a yellow solid which was washed with 100 ml of water; the filter cake was then mixed with 100 ml of ethanol and then filtered rapidly, and the resulting off-white solid was dried in vacuo to give 32.7 g of 2-chloro-5-nitro-1-bis(methylsulfonyl)amino-benzene. The latter was then mixed with 50 ml of ethanol; 8 g of NaOH in 20 ml of water was added slowly with stirring, after which the mixture was diluted with 300 ml of water followed by the addition of 45 ml of 6N HCl, yielding a precipitate which was collected by filtration and dried in vacuo to give 24.3 g of 2-chloro-5-nitro-1-methylsulfonylaminobenzene (compound 4, FIG. 1). The latter material was reduced with iron powder to form 17.7 g of 4-chloro-3-methylsulfonylaminoiline.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][N:12]([CH3:16])[CH2:13][C:14]#[CH:15]>CN(C=O)C.C(Cl)Cl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][N:12]([CH3:16])[CH2:13][C:14]#[C:15][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C#CCN(C)C
Reactant: Brc1cnc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a screw top tube, 8.1 mg (0.0425 mmoles) of CuI, 18 mg(0.0256 mmoles) of PdCl2(PPh3)2, and 207 mg (0.8483 mmoles) of 5-Bromo-1H-pyrrolo[2,3-b]pyridine were added. The dry solids were diluted with 1 ml of dry DMF and a stream of N2 was bubbled through the solution for 10 minutes and then 182.6 ul(1.7 mmoles) of Dimethyl-prop-2-ynyl-amine was added and the reaction was stirred in a sealed tube overnight at room temperature. The reaction was diluted with 10 ml of DCM and washed with saturated ammonium chloride solution. The organic layer was separated and dried with MgSO4, filtered, and concentrated to dryness yielding a crude material of 189 mg. MS showed a M+ ion of 200.05 which confirmed the structure above. The crude material was taken to the next step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.B.O1CCCC1.C([Li])CCC.[C:17]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:17]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: c1cocn1
Reactant: O=C1CCCC1
Agent: B
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ncco2)CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
An ambient solution of oxazole (1.00 g, 14.5 mmol) and borane.tetrahydrofuran complex (14.5 mL, 14.5 mmol, 1 M in tetrahydrofuran) was stirred for 30 min. The reaction was cooled to −78° C., and n-butyllithium (9.5 mL, 15.2 mmol, 1.6 M in hexane) was added dropwise. After 30 minutes, cyclopentanone (1.42 mL, 16.0 mmol) was added dropwise. After 30 minutes, the cold (−78° C.) reaction was quenched by the addition of 5% acetic acid in ethanol (70 mL) and warmed to room temperature. The solution was diluted with diethyl ether (10 0 mL) and saturated NaHCO3 (50 mL). Layers were separated, and the organics were washed with brine (1×50 mL), dried over Na2SO4, concentrated, under reduced pressure, and purified by chromatography on SiO2 gel, eluting with 50% ethyl acetate in hexane, to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.59-1.71 (m, 2H), 1.72-1.84 (m, 2H), 1.84-1.96 (m, 2H), 1.98-2.09 (m, 2H), 5.40 (s, 1H), 7.11 (s, 1H), 8.02 (s, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@@H:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[CH2:10][N:9]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(CC)CC)C>ClCCl>[CH3:14][O:13][C@H:11]1[CH2:10][N:9]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:8]([CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12]1
Reactant: CS(=O)(=O)Cl
Reactant: CO[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.175 mL, 2.26 mmol, 1.2 equiv) was added to a solution of (2S,4R)-2-(hydroxymethyl)-4-methoxy-1-pyrrolidinecarboxylate (3-3, 0.500 g, 1.88 mmol, 1 equiv) and triethylamine (0.394 mL, 2.83 mmol, 1.50 equiv) in dichloromethane (30 mL) at 0° C. The resulting mixture was warmed to 23° C. and stirred for 1 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution and dichloromethane (2×40 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexane initially, grading to 100% EtOAc) to provide benzyl (2S,4R)-4-methoxy-2-{[(methylsulfonyloxy]methyl}-1-pyrrolidinecarboxylate (3-4) as a light yellow oil. 1H NMR (300 MHz, CDCl3) major rotamer: δ7.37-7.25 (br m, 5H), 5.17 (d, 1H, J=11.8 Hz), 5.10 (d, 1H, J=11.8 Hz), 4.65 (dd, 1H, J=8.3, 3.8 Hz), 4.24 (br m, 2H), 3.95 (m, 1H), 3.68 (br d, 1H, J=12.0 Hz), 3.45 (dd, 1H, J=12.0, 4.4 Hz), 3.30 (s, 3H), 2.88 (s, 3H), 2.39 (m, 1H), 2.12 (m, 1H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[N:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=1>>[CH3:29][C:27]1[CH:26]=[CH:25][N:24]=[C:23]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)[N:28]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4cccs4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-4-methyl-pyrimidine. MS (ESI) mass calcd. for C22H22N4OS, 390.51; m/z found, 391.2 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[N:51]=[CH:52][C:53]([C:56]2[S:60][C:59]([C:61]#[N:62])=[CH:58][CH:57]=2)=[N:54][CH:55]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[N:54][C:53]([C:56]3[S:60][C:59]([C:61]#[N:62])=[CH:58][CH:57]=3)=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: N#Cc1ccc(-c2cnc(N)cn2)s1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(-c3ccc(C#N)s3)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
A solution of triphenylphosphine (50.0 mg, 0.191 mmol) in methylene chloride (2 mL) cooled to 0° C. was treated with N-bromosuccinimide (35.0 mg, 0.197 mmol). The reaction mixture was stirred at 0° C. for 5 min and then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 51.0 mg, 0.154 mmol). The reaction mixture was allowed to warm to 25° C. over 15 min. The reaction mixture was then treated with 5-(5-amino-pyrazin-2-yl)-thiophene-2-carbonitrile (47.0 mg, 0.232 mmol) followed by pyridine (30.0 uL, 0.371 mmol). The resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then diluted with methylene chloride and washed with a dilute aqueous hydrochloric acid solution. The aqueous layer was extracted with methylene chloride. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH, 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[5-(5-cyano-thiophen-2-yl)-pyrazin-2-yl]-3-cyclopentyl-propionamide (44.4 mg, 55.9%) as a yellow foam: mp 101–107° C. (foam to gel); (ES)+-HRMS m/e calcd for C24H23ClN4O3S2 (M+H)+515.0973, found 515.0974.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[K+].[OH-].[Na+]>O>[Br:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([I:22])[CH:11]=1
Reactant: [I-]
Reactant: COC(=O)c1ccc(Br)cc1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc(Br)cc1I
Reaction time: 0.67 h
Yield: 82.7 %

Procedure:
To methyl 2-amino-4-bromobenzoate (5.75 g) was added ice-cooled 20% sulfuric acid (75 mL), sodium nitrite (2.07 g) was added by small portions under ice-cooling and the mixture was stirred for 40 min. To this reaction mixture was added dropwise a solution obtained by dissolving potassium iodide (8.3 g) in water (25 mL) under ice-cooling, 20% sulfuric acid (30 mL) was added and the mixture was stirred for 2 hr. This reaction mixture was neutralized with 4N aqueous sodium hydroxide solution under ice-cooling, and the mixture was extracted with ethyl acetate, 10% aqueous sodium sulfite solution (45 mL) and sodium chloride. The organic layer was washed once with saturated brine and 10% aqueous sodium sulfite solution, with saturated brine, and dried over sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (7.05 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([OH:33])=O)=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][C@H:35]4[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:33])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:29])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1c(C(=O)O)c2nccc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2nccc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c3) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.CN(C)C(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:4]3[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[CH:7]=[C:2]([Br:1])[N:3]=3)=[CH:29][CH:30]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Br)cn4ccnc34)cc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 6,8-dibromoimidazo[1,2-a]pyrazine (12.5 mmol), 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (12) (13.1 mmol), potassium carbonate (25 mmol), acetonitrile (50 mL) and N,N-dimethylacetamide (20 mL) is heated at 65° C. for 16 hrs. The mixture is cooled to room temperature, treated water (100 mL), and extracted with ethyl acetate (3×80 mL). The extracts are washed with water (3×60 mL) and brine (1×60 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue is chromatographed over silica gel, eluting with ethyl acetate, to give 4-[4-(6-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (13) as a light brown foam.