Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][C:11]1([CH2:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:15](=[O:16])[N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=2)[C:13](=[O:29])[NH:12]1.CN(C)[CH:40]=[O:41]>>[C:4]([O:41][CH2:40][C:6]#[C:7][CH2:8][N:12]1[C:11]([CH2:10][O:9][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][O:3]2)([CH2:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:15](=[O:16])[N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:18]=2)[C:13]1=[O:29])(=[O:3])[CH3:5]
Reactant: N#Cc1ccc(N2C(=O)NC(COC3CCCCO3)(COC3CCCCO3)C2=O)cc1C(F)(F)F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CC(=O)OCC#CCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(COC1CCCCO1)COC1CCCCO1
Reaction time: 0.5 h

Procedure:
416 mg of 50% sodium hydride and dropwise 4 g of the product obtained in Stage 5 of Example 1 and 15 ml of dimethylformamide are introduced and the resultant mixture is rinsed with 1 ml of dimethylformamide. 10 minutes after the end of the release of hydrogen, 3.2 g of 4-bromo-2-butyne-1-ol acetate prepared as described in J. W. Lown GENE 149, 81 (1994) and 2 ml of dimethylformamide are added, and rinsing is carried out with 0.5 ml of dimethylformamide. After one hour 30 minutes, the reaction medium is poured into 100 ml of water containing 0.5 g of monopotassium phosphate, extraction is carried out 4 times with ether, the organic phase is washed with water and with salt water and dried. Purification is carried out by chromatography on silica eluting with methylene chloride-acetone: 95-5 and 4.47 g of expected product (orange resin) is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.I.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](SC)=[NH:23].ClCCl>C(O)C.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:22]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)=[NH:23])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: CN(C)CCn1ccc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CN(C)CCn1ccc2cc(NC(=N)c3cccs3)ccc21
Reaction time: 3 h
Yield: 21.9 %

Procedure:
A solution of compound 92 (0.104 g, 0.512 mmol) in absolute ethanol (3 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.290 g, 1.02 mmol) at room temperature and the resulting mixture was stirred for 3 hours. The reaction was diluted with saturated aqueous sodium bicarbonate (5 mL) followed by dichloromethane (30 mL) and transferred to a separatory funnel. The aqueous was extracted twice more with dichloromethane (2×30 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 5:95). Product was dried under high vacuum. HPLC revealed a 10% impurity. A second purification by column chromatography using less polar solvent conditions (2M ammonia in methanol:dichloromethane, 0:100-2.5:97.5) afforded pure product 93 (35 mg, 22%) as a yellow oil. 1H NMR (CDCl3) δ 7.43 (d, J=4.5 Hz, 2H), 7.33 (d, J=8.7 Hz, 1H), 7.21 (d, J=1.2 Hz, 1H), 7.13 (d, J=3.0 Hz, 1H), 7.08 (t, J=4.2 Hz, 1H), 6.67 (dd, J=1.8, 8.7 Hz, 1H), 6.43 (d, J=3.0 Hz, 1H), 4.22 (t, J=7.5 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.31 (s, 6H); ES-MS (m/z, %): 313 (M+1); ESI-HRMS calculated for C17H21N4S (MH+): 313.1481, Observed: 313.1467.
Reaction SMILES: [O-]S([O-])=O.[Na+].[Na+].[CH:7]1([C:10]2[NH:11][C:12]([I:16])=[C:13](I)[N:14]=2)[CH2:9][CH2:8]1>O.C(O)C>[CH:7]1([C:10]2[NH:14][CH:13]=[C:12]([I:16])[N:11]=2)[CH2:9][CH2:8]1
Reactant: Ic1nc(C2CC2)[nH]c1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Ic1c[nH]c(C2CC2)n1
Yield: 65.9 %

Procedure:
Na2SO3 (10.42 g, 82.65 mmol) was suspended in 40 ml water and 20 ml ethanol. 2-Cyclopropyl-4,5-diiodo-1H-imidazole (3500 mg, 9.72 mmol) was added and the mixture was stirred at reflux for 16 hours. The reaction mixture was concentrated to 20 ml and then filtered. The solid was dried for 5 hours at 50° C. under reduced pressure (<10 mbar) to get a light brown solid (1.50 g, 66%), MS: m/e=235.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)[CH3:10].ClC1C(Cl)=CC=CC=1C(C1N=CNC=1)=C.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:44])=CC=1>O1CCCC1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][C:13](=[S:44])[NH:14][CH:15]=1)[CH3:10]
Reactant: CC(c1c[nH]cn1)c1cccc(Cl)c1Cl
Reactant: S=C(Cl)Oc1ccccc1
Agent: C=C(c1c[nH]cn1)c1cccc(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1c[nH]c(=S)[nH]1)c1cccc(Cl)c1Cl
Reaction time: 5 h

Procedure:
A 1:1 mixture of 4-[1-(2,3-dichloro-phenyl)-ethyl]-1H-imidazole (Intermediate A4), and 4-[1-(2,3-dichloro-phenyl)-vinyl]-1H-imidazole (Intermediate A3) (0.77 g, 3.2 mmol) in tetrahydrofuran (THF) (10 mL) and water (10 mL) was treated with NaHCO3 (1.64 g, 19.5 mmol) at rt for 10 m. Phenyl chlorothionoformate (1.1 mL, 7.95 mmol) was added and stirring was continued for 5 h. The mixture was diluted with water and extracted with hexane:ethyl acetate (3×). The organic portions were combined, dried over MgSO4, filtered and the solvent was removed under vacuum. The residue was dissolved in MeOH (20 mL) and treated with triethylamine (NEt3) (1 mL) for 18 h at rt. The mixture was concentrated onto silica gel. The material was purified by elution from silica gel with 1 to 2% MeOH: CH2Cl2. The solids were titurated with CHCl3: hexanes and collected on a glass frit to give a white solid 4-[1-(2,3-dichloro-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione (Compound 1) 40 mg.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.ClC([CH:11]([CH2:16][CH3:17])[C:12]([O:14]C)=[O:13])=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl.Cl[CH2:24]CCl>>[CH3:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][C:6]=1[CH2:24][CH2:17][CH2:16][CH2:11][C:12]([OH:14])=[O:13]
Reactant: ClCCCl
Reactant: CCC(C(=O)Cl)C(=O)OC
Reactant: Cc1ccc(C)s1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(CCCCC(=O)O)c(C)s1
Temperature: -10 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
2,5-Dimethylthiophene (8 g, 71.4 mmol) and methyl chloroformylbutyrate (10 g, 65.8 mmol) are dissolved in 40 mL 1,2-dichloroethane. The reaction mixture is then cooled to -10° C. AlCl3 was added in portion in 15 min. The resulting mixture is stirred at 0° C. for another 1 hr., poured into ice and concentrated HCl (3:1), and extracted with dichloromethane. The organic layer is washed with 10% HCl, water and 5% sodium bicarbonate. It is then dried over sodium sulfate and the solvent evaporated under reduced pressure. The resulting yellow oil is redissolved in 60 mL triethyleneglycol with 20 mL 80% hydrazine and 20 g KOH. The reaction mixture is then heated to 140° C. for 10 min. and then to 180° C. to distill off the remaining hydrazine and water. The mixture is maintained at 205° C. overnight. After the reaction is cooled to room temperature, it is diluted with water, acidified with conc. HCl and extrated with ether. The ether layer is washed exaustively with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure yields 5-(2,5-dimethyl-3-thiophenyl)pentanoic acid as a brown oil (12 g, 86%) 1H NMR (CDCl3) 6.45 (s, 1 H), 2.50-2.10 (m, 10 H), 1.83-1.55 (m, 4 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([C:7](=[S:23])[NH2:9])[CH:10]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc([N+](=O)[O-])c(C(N)=O)c1
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(C(N)=S)c1
Temperature: 25 °C
Yield: 159.5 %

Procedure:
7.0 g (0.040 mol) of the product from Step A was suspended in toluene (140 mL). Lawesson's reagent (9.4 g, 0.023 mol) was added and the resulting mixture heated at 100° for 3 h (the mixture became homogeneous at 85° C.). After cooling to room temperature, the toluene was removed on the rotary evaporator. The residue was flash chromatographed on silica gel eluting with 20% ethyl acetate/hexane to furnish 7.2 g (95% yield) of the title compound as a yellow semisolid. 1H NMR (400 MHz, CDCl3) δ 7.92-7.94 (d,1H), 7.93 (br s, 1H, overlap with doublet), 7.25-7.32 (m,2H), 7.17 (br s, 1H), 2.45 (s,3H).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.[CH3:15][O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([CH:22]3[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][O:16][CH3:15])[CH2:24][CH2:23]3)=[CH:33][CH:32]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: COCCN1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: N#CCNC(=O)C1(N)CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCN1CCC(c2ccc(C(=O)NC3(C(=O)NCC#N)CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (107 mmol), 4-[1-(2-methoxy-ethyl)-piperidin-4-yl]-benzoic acid hydrochloride (107 mmol), HOBT (107 mmol), WSCD (107 mmol) and triethylamine (107 mmol) are dissolved in DMF (250 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH (with 2N NH3)=9:1 as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether/ethyl acetate and the solid filtered of and dried (vacuum). A pale powder with mp. 160-162° C., Rf=0.42 (CH2Cl2/MeOH (with 3N NH3)=9:1) is obtained.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][Cl:7].C(OCC)(=O)C.O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:24]1([S:36][CH3:37])[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[S:25]1>CN(C)C=O>[Cl:7][CH2:6][CH2:5][CH2:4][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:24]1([S:36][CH3:37])[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[S:25]1
Reactant: COc1ccc(O)c(C2(SC)Sc3ccccc3N(C)C2=O)c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(OCCCCl)c(C2(SC)Sc3ccccc3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
To a stirred suspension of 60% sodium hydride (0.5 g) in dimethylformamide (10 ml), 3,4-dihydro-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-2-methylthio-3-oxo-2H-1,4-benzothiazine (3.5 g, compound No. 8) dissolved in dimethylformamide (5 ml) is added under nitrogen atmosphere and ice-cooling, and the mixture is stirred for 10 minutes at room temperature. 1-Bromo-3-chloropropane (1.9 g) is added to the reaction mixture, and the mixture is stirred for 1 hour at 50°-60° C. The mixture is poured into a mixture of ethyl acetate and water. The organic layer is washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The separated crystals are collected by filtration to give 4.0 g (93.4%) of the titled compound.
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[CH3:25][NH2:26]>CN(C)C=O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([NH:26][CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:10][CH:9]=1
Reactant: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(Br)c1ccccc1
Reactant: CN
Solvent: CN(C)C=O
Product: CNC(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)c1ccccc1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-2-phenyl-acetamide (42 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing 1.0 mL of methylamine (2.0 M in tetrahydrofuran, 2.0 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (29 mg, 0.078, 78%). ESI-MS m/z calc. 371.1, found 372.2 (M+1)+ Retention time 2.33 minutes. 1H NMR (400 MHz, MeOD) δ 2.66 (s, 3H), 4.23 (s, 2H), 5.09 (s, 1H), 7.13-7.56 (m, 10H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[F:22])=[CH:8][C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:6]1)[CH2:2][CH2:3][CH3:4].F[C:29](F)(F)S(OC)(=O)=O.[NH4+].[OH-]>C1(C)C=CC=CC=1.O.CC(C)=O>[CH2:1]([N:5]1[N:6]([CH3:29])[C:7]([C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:15]=[CH:14][C:13]=1[F:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C(C)(C)C)cc1NC(=O)c1cc(C(F)(F)F)ccc1F
Reactant: COS(=O)(=O)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Temperature: 100 °C
Reaction time: 20 h
Yield: 89.2 %

Procedure:
To a solution of Example 81B (50.2 g, 130 mmol) in toluene (500 mL) was added methyl trifluoromethanesulfonate (21.4 mL, 195 mmol). The mixture was warmed to 100° C. and stirred for 20 hours. The mixture was cooled to ambient temperature then diluted with water (200 mL) and acetone (500 mL). This solution was stirred for 30 minutes then concentrated NH4OH (100 mL) was added. The mixture was stirred for 30 minutes then partially concentrated under reduced pressure. The residue was diluted with EtOAc (300 mL) and brine (100 mL), the layers were separated and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 80% hexanes/EtOAc to 100% EtOAc to 10% MeOH in EtOAc) and the fractions collected and concentrated. The material was then dissolved in EtOAc (150 mL) and was washed with 10% NaOH (100 mL). The layers were separated, the aqueous phase was extracted with EtOAc (3×50 mL) and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (46.3 g, 116 mmol, 89% yield) the title compound. MS (ESI+) m/z 400 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:13]([F:14])=[CH:12][C:10]([NH2:11])=[C:9]([F:15])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=1.[Na]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]1([C:7]2[C:13]([F:14])=[CH:12][C:10]([NH:11][C:17]3[CH:22]=[CH:21][C:20]([Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[C:9]([F:15])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Reactant: Nc1cc(F)c(-c2ccccc2)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1ccc(Nc2cc(F)c(-c3ccccc3)cc2F)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 73.6 %

Procedure:
4-phenyl-2,5-difluoroaniline (12 mmol), 4-bromo-trimethylsilylbenzene (10 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.15 mmol), (±)-2,2′-bis(diphenylphosphine)-1,1′-binaphthalene (0.3 mmol) and sodium tert-butoxie (14 mmol) are put in a two-neck round-bottom flask and dissolved in toluene (30 mL). Subsequently, the resulting solution is stirred in a bath under a temperature of about 100° C. for 24 hours. After completion of the reaction, toluene is removed. The reaction mixture is extracted with dichloromethane and water, and then being distilled under reduced pressure. The resulting residence is filtered by silica gel column and distilled under reduced pressure again. Next, by re-crystallizing and filtering with dichloromethane and petroleum ether, 4-phenyl-2,5-difluoro-N-(4-trimethylsilylphenyl)benzenamine (2.6 g) is yielded.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)[CH3:2].[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][NH:22][CH2:23][C:24]3[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[C:28]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:27]=[N:26][C:25]=3[Cl:40])=[CH:20][C:15]=2[O:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCCCCC>CC(O)=O.CCOC(C)=O>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][N:22]([CH2:23][C:24]3[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[C:28]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:27]=[N:26][C:25]=3[Cl:40])[CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: CCCCc1c(-c2ccccc2)nnc(Cl)c1CNCc1ccc2c(c1)OCO2
Reactant: CCOc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCCCc1c(-c2ccccc2)nnc(Cl)c1CN(Cc1cccc(OCC)c1)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-Ethoxybenzaldehyde (0.062 ml, 0.44 mmol) is added to a solution of benzo[1,3]dioxol-5-ylmethyl (5-butyl-3-chloro-6-phenyl-pyridazin-4-ylmethyl)-amine) (0.045 g, 0.1 mmol) in CH2ClCH2Cl (5 mL) and HOAc (0.5 mL). The mixture is stirred at room temperature for 45 minutes, NaBH(OAc)3 (0.140 g, 0.66 mmol) is then added and the mixture is stirred over night. The solvent is removed in vacuo, the residue is partitioned between saturated aqueous NaHCO3 solution (20 mL) and EtOAc (20 mL), the organic layer is washed with water (15 mL), brine (15 mL), and then dried (Na2SO4). Evaporation of the solvent in vacuo provides the product shown above as a yellow oil. Preparative TLC (3:1 Hexane, EtOAc) of the residue provides purified product as a light yellow oil. LC-MS (M+1) 544. 1H NMR (δ, CDCl3) 7.36-7.48 (m, 5H), 7.18 (t, J=7.2 Hz, 1H), 6.70-6.87 (m, 6H), 5.91 (s, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.80 (s, 2H), 3.56 (s, 2H), 3.52 (s, 2H), 2.70 (t, J=7.5 Hz, 2H), 1.41 (t, J=7.2 Hz, 2H), 0.84-1.02 (m, 4H), 0.58 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[CH3:31][C:18]1([N:15]2[CH2:14][CH2:13][C:12](=[O:11])[CH2:17][CH2:16]2)[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(O)CC2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(=O)CC2)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
A solution of oxalyl chloride in dichloromethane (2M, 13.67 mL, 27.33 mmol) was cooled to −78° C. under nitrogen atmosphere and was added to a solution of dimethylsulfoxide (3.87 mL, 54.0 mmol) in dichloromethane (40 mL) at −78° C. under nitrogen atmosphere via cannula. After 10 minutes, a solution of tert-butyl 4-(4-hydroxy-1-piperidyl)-4-methyl-piperidine-1-carboxylate (18.0 mmol) in dichloromethane (20 mL) was added at −78° C. under nitrogen atmosphere to the reaction mixture via cannula. The mixture was stirred at −78° C. for 10 minutes and then triethylamine (10.07 mL, 72.0 mmol) was added dropwise. The reaction was stirred at −78° C. under nitrogen atmosphere for another 20 minutes, then allowed to warm up to 0° C. over 1 hour. The reaction was quenched with water (50 mL) and diluted with dichloromethane (100 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic phases were washed with saturated aqueous ammonium chloride, brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound as yellow oil (5.02 g, 94%), which was used for the subsequent step without further purification. MS (M+1): 297.24.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21]Cl)[C:9]2=[O:23])[CH:7]=1.C(#N)C.[C:30]([OH:34])(=[O:33])[CH2:31][OH:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:34][C:30](=[O:33])[CH2:31][OH:32])[C:9]2=[O:23])[CH:7]=1
Reactant: O=C(O)CO
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CCl)c2cc(C(F)(F)F)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC(=O)CO)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 36 h
Yield: 57.5 %

Procedure:
To a 10 mL flask containing (S)-3-(5-chloro-2-methoxy-phenyl)-1-chloromethyl-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-V) (0.200 g, 0.489 mmol) was added 3 mL anhydrous acetonitrile, glycolic acid (0.045 g, 0.588 mmol) and cesium carbonate (0.079 g, 0.245 mmol). The reaction was stirred for 36 hours at room temperature, then the organic layer was diluted with 5 mL diethyl ether and the organic solution was decanted away from the solid cesium chloride. The solvent was evaporated in vacuo and the resulting white foam was purified by flash chromatography (silica gel 4:1 hexanes:acetone) producing the title compound (0.126 g, 58%) as a white powder. 1H NMR (CDCl3 400 MHz): δ=7.79 (s, 1H), 7.38-7.33 (m, 3H), 7.26 (d, 1H, J=7 Hz), 6.75 (d, 1H, J=7 Hz), 5.99 (d, 1H, J=12 Hz), 5.91 (d, 1H, J=12 Hz), 4.26 (s, 2H), 3.49 (s, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)=[N:23][N:22]=1>>[CH3:19][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([C:24]5[O:25][C:21]([CH3:20])=[N:22][N:23]=5)[CH:27]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Reactant: Cc1nnc(-c2cccc(B(O)O)c2)o1
Product: Cc1nnc(-c2cccc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)c2)o1

Procedure:
(1-Methyl-cyclohexyl)-{2-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 3-(5-Methyl-1,3,4-oxadiazol-2-yl)phenylboronic acid following general procedures as described in these Examples. MP 234-236° C., M+H=402.