Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][Cl:14])[CH:10]([CH2:15][Cl:16])[CH2:9][N:8]=[C:7]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][Cl:14])[CH:10]([CH2:15][Cl:16])[CH2:9][N+:8]([O-:31])=[C:7]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccco2)=NCC1CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: [O-][N+]1=C(c2ccco2)c2cc(Cl)ccc2N(CCCl)C(CCl)C1
Yield: 69.9 %

Procedure:
A solution of 17.8 g of 7-chloro-1-(β-chloroethyl)-2-chloromethyl-5-(2-furyl)-2,3-dihydro-1H-1,4-benzodiazepine in 250 ml of methylene chloride is heated under reflux with 10.4 g of 3-chloroperbenzoic acid for 2 hours. The reaction solution is then rendered alkaline with aqueous dilute sodium hydroxide solution and is worked up in the customary manner, and the reaction product is isolated and then purified by chromatography on aluminium oxide of activity level II, using methylene chloride, and crystallised from methanol. 13 g of 7-chloro-1-(β-chloroethyl)-2-chloromethyl-5-(2-furyl)-2,3-dihydro-1H-1,4-benzodiazepine-4-oxide are obtained. Melting point: 158° to 159° C.
Reaction SMILES: Cl.[C:2]([C:7]1[C:12]([NH:13]N)=[CH:11][CH:10]=[CH:9][CH:8]=1)([O:4][CH2:5][CH3:6])=[O:3].[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O>C(O)(=O)C>[CH2:5]([O:4][C:2]([C:7]1[CH:8]=[CH:9][CH2:10][C:11]2[C:12]=1[N:13]=[C:18]1[CH2:19][CH2:20][CH2:21][C:16]([CH3:23])([CH3:15])[C:17]=21)=[O:3])[CH3:6]
Reactant: CC1(C)CCCCC1=O
Reactant: CCOC(=O)c1ccccc1NN
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)C1=C2N=C3CCCC(C)(C)C3=C2CC=C1
Yield: 58.1 %

Procedure:
Using the procedure of Example 1, the reaction of 29.0 g of 6-carbethoxyphenylhydrazine hydrochloride with 16.9 g of 2,2-dimethylcyclohexanone in 250 ml of 80% aqueous acetic acid afforded 21.1 g (58%) of 1,2,3,4-tetrahydro-1,1-dimethyl-9H-dibenzo [b,d]pyrrole-6-carboxylic acid ethyl ester as an orange solid after chromatographic purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH3:11].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:11]
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)ccc1F

Procedure:
To a solution of 20 g (129 mmol) of 2-fluoro-5-nitrotoluene in 400 mL of ethanol was added 2 g of 10% Pd—C. The mixture was shaken under 45 P.S.I. H2 until hydrogen uptake ceased. The catalyst was filtered away and washed with ethanol, then the combined filtrate and washings were concentrated to 15.2 g (94%) of a colorless oil.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:9]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:8]=1.[CH3:30][C:31]([CH3:33])=[O:32].[Cl-].[NH4+]>C1COCC1>[C:26]([C:9]1[CH:8]=[C:7]([C:31]([OH:32])([CH3:33])[CH3:30])[CH:12]=[CH:11][C:10]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2C(C)(C)C)CC1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(C)(C)O)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of n-BuLi (1.6 M in n-hexane, 10.6 mL, 6.62 mmol) in THF (30 mL) was added a solution of tert-butyl 4-(4-bromo-2-tert-butylphenyl)piperazine-1-carboxylate (Example 85, 4.5 g, 11.3 mmol) in THF (15 mL) at −80° C. After stirred for 2 h at that temperature, it was added acetone (4 mL) and allowed to be warmed to room temperature. After 16 h, it was added saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=98:2 to 80:20) to provide tert-butyl 4-[2-tert-butyl-4-(1-hydroxy-1-methylethyl)phenyl]piperazine-1-carboxylate (3.1 g, 73%) as a pale yellow solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.C([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:24](C)[CH:23]=1)C.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[O:16]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][CH:29]3[CH2:30][NH:31][CH2:32][CH2:33][N:28]3[C:25]3[CH:24]=[CH:23][C:22]([C:21]([NH2:20])=[O:35])=[CH:27][CH:26]=3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][CH2:15][CH:8]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(C)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(N2CCNCC2Cc2cnc3c(c2)NC(=O)C2CCCN32)cc1
Temperature: 105 °C
Yield: 62.7 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide hydrochloride (129 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford(S)—N-ethyl-3-methyl-4-(4-(((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (128.5 mg, 0.286 mmol, 62.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-2.03 (m, 3H) 2.09-2.25 (m, 1H) 2.50 (m, 4H) 2.75 (d, J=4.29 Hz, 3H) 2.96-3.14 (m, 4H) 3.35-3.45 (m, 3H) 3.53-3.65 (m, 1H) 3.93-4.05 (m, 1H) 6.98 (d, J=1.77 Hz, 1H) 7.04 (t, J=8.59 Hz, 1H) 7.51-7.67 (m, 3H) 8.27-8.38 (m, 1H) 10.44 (s, 1H). [M+H] calc'd for C25H32N6O2, 449; found, 449.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]12([C:31](=O)[CH:30]3[CH2:33][CH:27]1[CH2:28][CH2:29]3)[CH2:26][CH2:25]2.Cl>O1CCCC1.O>[C:24]12([CH:31]([CH:2]=[O:3])[CH:30]3[CH2:33][CH:27]1[CH2:28][CH2:29]3)[CH2:26][CH2:25]2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1C2CCC(C2)C12CC2
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: O=CC1C2CCC(C2)C12CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 179.4 %

Procedure:
Methoxymethyltriphenylphosphonium chloride (6.41 g) was suspended in tetrahydrofuran (80 mL) and cooled to 0° C. in nitrogen atmosphere. After adding 1.56 M n-butyl lithium-in-hexane solution (36.2 mL) at 0° C., the reaction mixture was stirred for an hour. Into the resulting deep red-colored solution, a spiro[bicyclo[2.2.1]heptane-2,1′-cyclopropane]-3-one (6.41 g) solution in tetrahydrofuran (10 mL) was dropped at 0° C., and thereafter the temperature was raised to room temperature, followed by an overnight's stirring. To the reaction mixture, 5M hydrochloric acid (50 mL) was added at room temperature and stirred for further 3 hours. The reaction mixture was diluted with water and extracted with diethyl ether. The extract washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate=99/1−97/3) to provide 5.04 g of the title compound as a colorless oily substance.
Reaction SMILES: CN(C)[C:3]1[N:8]=[C:7]([NH2:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:5][N:4]=1.S(O)(O)(=O)=O.[N:24]1(C(N)=N)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[C:3]1[N:8]=[C:7]([NH2:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:5][N:4]=1
Reactant: N=C(N)N1CCCCC1
Reactant: CN(C)c1ncc(-c2ccc(Cl)cc2Cl)c(N)n1
Agent: O=S(=O)(O)O
Product: Nc1nc(C2CCCCN2)ncc1-c1ccc(Cl)cc1Cl

Procedure:
This compound was prepared in an analogous manner to the compound of Example 76 from 1-piperidinecarboxamidine sulphate (Bader), mp. 169° C.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:10][C:11](=[O:13])[CH3:12])(=O)[CH3:8].[CH3:14][C@H:15]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:16]/[CH:17]=[CH:18]/C(O)C>>[C:11]([O:10][CH:7](/[CH:18]=[CH:17]/[CH2:16][C@H:15]([CH3:14])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:8])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCC[C@@H](C)C/C=C/C(C)O
Solvent: c1ccncc1
Product: CC(=O)OC(C)/C=C/C[C@H](C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A flame-dried, 250 mL, three-necked flask containing a magnetic stirring bar was charged under argon with 7.9 g (8.1 mL, 0.10 mol) of dry pyridine. After cooling in an ice-bath, 10.2 g (9.4 mL, 0.10 mol) of acetic anhydride and then 10.0 g (0.051 mol) of (2RS,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol were added dropwise, and the reaction was stirred for 2 hours at 0° C. and then overnight at 20° C. The reaction mixture was poured onto 2N HCl/ice and extracted with 2×200 mL of ether. The combined extracts were washed with 2N HCl, sat. NaHCO3 solution, and brine, dried over Na2SO4, filtered and evaporated. Kugelrohr distillation at ca. 105°-130° C./0.1 mmHg afforded 12.05 g (99%) of (2RS,3E,6R)-6,10-dimethyl-3,9- undecadien-2-ol acetate as colorless liquid. Calcd. for C15H26O2 (238.4): C. 75.58; H. 10.99; Found: C, 75.47; H, 11.04%. [α]D25 =-2.16° (2.04% in CHCl3).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[OH:29])[C:24]#[N:25].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(O)(C)C>O1CCCC1>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH:1]([CH3:6])[CH3:2])[C:24]#[N:25]
Reactant: N#Cc1ccc(O)c(Cl)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C#N)cc1Cl
Yield: 95.9 %

Procedure:
Into a round bottom flask containing triphenylphosphine (27.3 g, 104 mmol) and 3-chloro-4-hydroxy-benzonitrile (10 g, 65 mmol) was added anhydrous tetrahydrofuran (600 mL). The mixture was stirred briefly under nitrogen, di-tert-butyl azodicarboxylate (24 g, 104 mmol) was then added. The mixture was stirred for a few minutes, followed by addition of anhydrous isopropanol (6.23 mL, 81.4 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen. The crude product was purified by flash chromatography using 1:4 (v/v) ethyl acetate/heptane as eluent. Fractions were dried to give 3-chloro-4-isopropoxy-benzonitrile (12.2 g, 91%) as a red-orange semi-solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:29][CH2:30][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=[CH:8][C:7]=4[C:5]=3[N:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCOc1cccc2c1Cc1sc(S)nc1-2
Reactant: ICCC(c1ccccc1)c1ccccc1
Product: O=C(O)CCOc1cccc2c1Cc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 49 %

Procedure:
Using ethyl 3-[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]propionate and 3,3-diphenylpropyl iodide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 49%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH:15]=[O:16])[CH2:12][CH2:13]Br)=[CH:6][CH:5]=1.Cl.[NH:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:20].C(=O)(O)[O-].[Na+].O>C(#N)C>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][N:19]([CH3:20])[CH2:13][CH2:12][CH:11]([CH:15]=[O:16])[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:17])=[CH:5][CH:6]=1)[CH3:26]
Reactant: COC(=O)c1ccc(CC(C=O)CCBr)cc1
Reactant: CCOC(=O)CNC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CN(C)CCC(C=O)Cc1ccc(C(=O)OC)cc1

Procedure:
0.500 g (1.67 mmol) of methyl-4-(4-bromo-2-formylbutyl)benzoate from Ex. VIII, 0.257 g (1.67 mmol) of ethyl sarcosinate hydrochloride and 0.309 g (3.68 mmol) of sodium bicarbonate in 10 ml of acetonitrile are heated at reflux for 1 hour. The reaction mixture is cooled, 50 ml of water are added and the mixture is extracted repeatedly with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The crude product is purified by chromatography on silica gel (0.04-0.063 nm) using methylene chloride/methanol 100:3 as mobile phase.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH2:7]1.[CH3:24]O>>[CH3:24][O:22][C:21]([C:19]1[CH:18]=[CH:17][C:16]2[N:12]([C:6]3([Br:5])[CH:7]=[CH:8][CH:9]=[CH:10][CH2:11]3)[CH:13]=[N:14][C:15]=2[CH:20]=1)=[O:23]
Reactant: O=C(O)c1ccc2c(c1)ncn2C1(Br)C=CC=CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(c1)ncn2C1(Br)C=CC=CC1

Procedure:
Thionyl chloride (10 mL, 0.137 mol) was added dropwise to a stirred suspension of the 1-bromophenyl-1H-benzimidazole-5-carboxylic acid (20 g, 0.063 mol) in MeOH (200 mL) at 0-5° C. The reaction was stirred at reflux for 18 h and then concentrated under reduced pressure. The solid residue was triturated with cold water, basified with aqueous ammonium hydroxide solution and extracted with DCM. The extract was washed with water, aqueous brine solution, dried over MgSO4 and concentrated in vacuo to give the corresponding 1-bromophenyl-1H-benzimidazole-5-carboxylic acid methyl ester: e.g. 1-(4-bromophenyl)-1H-benzimidazole carboxylic acid methyl ester.
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[C:19]([O:1][CH:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC(Cn1ccnc1)c1ccc2ccccc2c1
Solvent: c1ccncc1
Product: O=C(OC(Cn1ccnc1)c1ccc2ccccc2c1)c1ccccc1

Procedure:
A solution of 1.19 g. 1-[2-hydroxy-2-(2-naphthyl)ethyl]imidazole in 20 ml. of pyridine is treated dropwise with stirring with 0.72 ml. of benzoyl chloride and the mixture stirred overnight. The resulting solution is poured into 100 ml. water, extracted with ethyl acetate and the extracts washed, dried (MgSO4) and evaporated in vacuo to remove residual pyridine and afford 1-[2-benzoyloxy-2(2-naphthyl)ethyl]imidazole. The residue is dissolved in ether, treated with ethereal hydrogen chloride and the resulting precipitate recrystallized from acetone/methanol to give 1.3 g. of hydrochloride salt, m.p. 219°-219.5° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].[Cl:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1>[OH:15][C:6]1([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:16])[CH:22]=2)[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[C:13](=[O:14])[N:5]1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: Clc1cccc([Mg]Br)c1
Reactant: CCCCN1C(=O)c2cccnc2C1=O
Solvent: Cc1ccccc1
Product: CCCCN1C(=O)c2cccnc2C1(O)c1cccc(Cl)c1
Temperature: -65 °C

Procedure:
6-(n-Butyl)-pyrrolo[3,4-b]pyridine-5,7-dione (20 g, 98 mmole) was dissolved in toluene (500 mL) and cooled to -65° C. To this mixture was added 3-chlorophenylmagnesium bromide (prepared by heating under reflux 2.5 g magnesium metal, 20 g of 3-chlorobromobenzene and 100 mL of tetrahydrofuran for 1 hour) at such a rate that the temperature of the reaction remain below -40° C. After the addition was complete, the cooling bath was removed and the mixture was allowed to warm to 0° C. The reaction mixture was quenched with aqueous ammonium chloride (25 mL) diluted with ethyl acetate (250 mL) and water (250 mL). After separating the resulting 2 layers, the organic fraction was dried with sodium sulfate (50 g). Filtration, followed by solvent removal gave 7-hydroxy-7-(3-chlorophenyl)-6-(n-butyl)-6,7-dihydropyrrolo[3,4-b]pyridin-5-one as an oil, which was used in the next reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([Sn](C)(C)C)[N:31]=[C:30]([C:38]#[N:39])[N:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(OCC)(=O)C.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>[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:3]=2)[N:31]=[C:30]([C:38]#[N:39])[N:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: C[Sn](C)(C)c1cc(CCCOCc2ccccc2)nc(C#N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc(-c2cc(CCCOCc3ccccc3)nc(C#N)n2)cc(C(F)(F)F)c1

Procedure:
N-(3-Bromo-5-trifluoromethyl-phenyl)-methanesulfonamide (37 mg), 4-(3-benzyloxy-propyl)-6-trimethylstannanyl-pyrimidine-2-carbonitrile (40 mg) and dichlorobis(triphenylphosphine)palladium(II) (7 mg) in DMF (1 mL) were heated in a microwave to 180° C. for five minutes. The mixture was diluted with ethyl acetate (10 mL) and filtered through celite. The filtrate was washed with water (10 mL) and saturated sodium chloride solution (10 mL). Organics were separated, dried over sodium sulphate, filtered and solvent was removed under reduced pressure to yield crude product. Purification by HPLC afforded 4-(3-benzyloxy-propyl)-6-(3-methanesulfonylamino-5-trifluoromethylphenyl)-pyrimidine-2-carbonitrile.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:34])[C:21](=[O:33])[CH2:22][NH:23][C:24](=[O:32])[CH2:25][N:26]4[CH2:31][CH2:30][S:29][CH2:28][CH2:27]4)[C:14]=3[Cl:35])[C:5]2=[N:4][C:3]=1[CH3:36].ClC1C=CC=C(C(OO)=[O:45])C=1>C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:34])[C:21](=[O:33])[CH2:22][NH:23][C:24](=[O:32])[CH2:25][N:26]4[CH2:27][CH2:28][S:29](=[O:45])[CH2:30][CH2:31]4)[C:14]=3[Cl:35])[C:5]2=[N:4][C:3]=1[CH3:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN4CCSCC4)c3Cl)cccn2c1Br
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CN4CCS(=O)CC4)c3Cl)cccn2c1Br
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-[(thiomorpholinoacetyl)glycyl]amino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (200 mg) in methylene chloride (2 ml) was added m-chloroperbenzoic acid (80% purity, 76 mg) under ice-bath cooling, and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was washed with water twice and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=5:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-[[(1-oxothiomorpholino)acetyl]glycyl]amino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (96 mg ) as an amorphous.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43](Cl)=[O:44])=[CH:38][CH:37]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:42][C:43]([NH:21][C:18]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:44])=[CH:40][CH:41]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccccc3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-phenylpyrazin-2-amine (7a) (504 mg, 1.33 mmol) and 4-(dimethylamino)pyridine (16.3 mg, 133 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 18 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=4/1) to give Compound 11a (630 mg, 1.01 mmol, 75.4%) as a yellow foamy solid. Rf=0.33 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.18 (s, 6H), 0.23 (s, 6H), 0.94 (s, 9H), 0.96 (s, 9H), 3.47 (s, 2H), 6.72-6.79 (AA′BB′, 2H), 6.96-7.02 (AA′BB′, 2H), 7.03-7.09 (AA′BB′, 2H), 7.29-7.39 (m, 3H), 7.66-7.74 (m, 2H), 8.05-8.12 (AA′BB′, 2H), 8.98 (s, 1H), 10.54 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.9, 18.0, 25.50 (3C), 25.54 (3C), 41.7, 119.5 (2C), 120.3 (2C), 127.8 (2C), 127.9, 128.0 (2C), 128.2 (2C), 128.5, 128.9, 130.3 (2C), 130.5, 137.6, 142.8, 147.6, 148.0, 153.8, 156.7, 169.3; IR (KBr, cm−1) 523, 694, 781, 804, 839, 914, 1020, 1070, 1086, 1105, 1169, 1263, 1371, 1416, 1510, 1605, 1672, 2857, 2886, 2930, 2955, 3040, 3059, 3233; HRMS (ESI+)/z 648.3043 ([M+Na]+, C36H47N3NaO3Si2+ requires 648.3048).
Reaction SMILES: O[C:2]1[C:6](=[O:7])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:3]=1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl.[NH2:23][OH:24].O>N1C=CC=CC=1>[OH:24][N:23]=[C:2]1[C:6](=[O:7])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH:3]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: NO
Reactant: CC(C)(C)OC(=O)C1=C(O)C(=O)N(Cc2ccccc2)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)C1CN(Cc2ccccc2)C(=O)C1=NO
Reaction time: 96 h
Yield: 83.7 %

Procedure:
To a solution of the title compound of Example I (8.07 g, 27.9 mmol) in 150 ml of pyridine was added hydroxylamine hydrochloride (9.69 g, 139 mmol) and resulting solution was stirred for 4 d. Addition of H2O resulted in the formation of precipitate which was filtered to give the title compound (7.11 g, 84%) as a colorless solid. Calculated for C16H20N2O4 1/2H2O: C, 61.35; H, 6.76; N, 8.94. Found C, 61.35; H, 6.57, N, 9.34.