Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[C:24]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[N:23][CH:22]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:10]=[C:9]([C:21]2[N:26]3[CH:27]=[CH:28][N:29]=[C:25]3[C:24]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([N:37]4[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]4)=[CH:35][CH:36]=3)=[N:23][CH:22]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CC1(C)OB(c2ccc(C(N)=O)c(F)c2)OC1(C)C
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccc(C(N)=O)c(F)c4)n4ccnc34)cc2)CC1

Procedure:
In the same way as described for Compound 127, step 4, using 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (82 mg, 0.31 mmol), (5-bromoimidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (60 mg, 0.155 mmol) and Pd(PPh3)4 (45 mg, 0.038 mmol) in dioxane (2.2 mL) and 1.5M Na2CO3 (0.83 mL). The residue is chromatographed on silica gel, eluting with DCM followed by 96:4 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated. The residue is triturated with Et2O to afford the title compound as a solid. HPLC (254 nm): Rt 1.94 min (93.5%); m/z (APCI) 446 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl.O>[CH3:15][O:14][C:13]1[C:12]([O:16][CH3:17])=[CH:11][CH:10]=[C:9]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[C:8]=1[O:7][CH2:6][C:3]1([CH2:2][NH:1][C:35](=[O:37])[CH3:36])[CH2:4][CH2:5]1
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)CC2)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(C)=O)CC2)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-[2-(1-aminomethyl-cyclopropylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 182) (100 mg, 0.272 mmol) in dichloromethane (10 mL), were added triethylamine (0.082 g, 0.811 mmol) and acetyl chloride (42 mg, 0.544 mmol) and the resultant reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-2% methanol in dichloromethane) afforded the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:34])[C@@H:13]([NH:23]C(OCC2C=CC=CC=2)=O)[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:34])[C@@H:13]([NH2:23])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
To a solution of 20.9 g 4-((S)-2-Benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 120 ml ethanol were added 2.0 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite, washed with ethanol and concentrated to give the crude product which was not further purified. Yield: 13.6 g colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([OH:12])=O)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.2 %

Procedure:
A solution of 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid (33.0 mg, 0.13 mmol) in methylene chloride (1.36 mL) was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.07 mL, 0.14 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminothiazole (30.0 mg, 0.29 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.32 mmol) in tetrahydrofuran (0.67 mL). This solution was stirred at 25° C. for 3 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(4-cyano-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (44.1 mg, 100%) as a white solid: mp 64–66° C.; EI-HRMS m/e calcd for C18H19N3OS (M+) 325.1248 found 325.1247.
Reaction SMILES: [CH2:1]([C:4]1([C:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH:20]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].[H][H]>C(O)C.[Pd]>[CH2:1]([C:4]1([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH2:2][CH3:3]
Reactant: C=CCC1(C2=CCN(C)CC2)c2ccccc2CCc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCC1(C2CCN(C)CC2)c2ccccc2CCc2ccccc21
Yield: 7.8 %

Procedure:
Dissolved 4-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methyl-1,2,5,6-tetrahydropyridine (0.33 g, 1.0 mmol) in 50 mL of absolute ethanol, and added 0.15 g of 10% palladium on carbon catalyst. Hydrogenated on a Paar shaker at 60 psi of hydrogen pressure for 24 hours. Filtered catalyst, and evaporated filtrate. Crystallized product from dichloromethane-ether to give 26 mg (8% yield) of 4-[10,11-dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methylpiperidine as a tan solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:43][O:44][C:45]1[CH:46]=[C:47]([NH:55][C:56]2[N:57]=[CH:58][C:59]3[CH2:65][NH:64][CH2:63][CH2:62][C:60]=3[N:61]=2)[CH:48]=[C:49]([O:53][CH3:54])[C:50]=1[O:51][CH3:52]>CN(C=O)C.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:64]1[CH2:63][CH2:62][C:60]2[N:61]=[C:56]([NH:55][C:47]3[CH:46]=[C:45]([O:44][CH3:43])[C:50]([O:51][CH3:52])=[C:49]([O:53][CH3:54])[CH:48]=3)[N:57]=[CH:58][C:59]=2[CH2:65]1)=[O:9]
Reactant: O=C(O)c1ccccn1
Reactant: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)c2ccccn2)C3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-picolinic acid (40.6 mg, 0.33 mmol), N, N-diisopropylethylamine (0.105 mL, 0.60 mmol), and HBTU (125 mg, 0.33 mmol) in DMF (2.0 mL) was stirred at room temperature for 5 minutes, then N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (94.8 mg, 0.30 mmol; see Syntheses of Starting Materials section for prep) added and the reaction continued for 1.5 hours at rt. The reaction mixture was treated with an EtOAc/aqueous Na2CO3(aq) solution work-up to give an orange oil. The oil was chromatographed eluting with 5% MeOH in 1:1 EtOAc/CHCl3 giving an off-white solid (107 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH:24]1(O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>COCCOC>[CH:24]1([O:8][C:6]2[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OC1CCCCC1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Nc1nc(OC2CCCCC2)c([N+](=O)[O-])c(-c2ccco2)n1

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, cyclohexanol and DBU in DME. ES-MS m/e (%): 305 (M+H+, 100), 223 ([M+H—C6H10]+, 80).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C@H:17]3[O:21]C(C)(C)[N:19]([C:24](=[O:28])[CH:25]([F:27])[F:26])[C@@H:18]3[CH2:29][F:30])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-]>[CH3:3][N:2]([CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]([OH:21])[C@@H:18]([NH:19][C:24](=[O:28])[CH:25]([F:26])[F:27])[CH2:29][F:30])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1ccc(-c2ccc([C@@H](O)[C@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.4 %

Procedure:
To a solution of 1-{(4S,5R)-5-[4-(6-Dimethylaminomethyl-pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidin-3-yl}-2,2-difluoro-ethanone (0.070 g, 0.166 mmol) in CH2Cl2 (5 mL) is added trifluoroacetic acid (1.0 mL). The resulting reaction mixture is stirred at room temperature for 5 hours. Concentrated to get the crude residue and diluted with aqueous bicarbonate solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash chromatography using 15% methanol in CH2Cl2 as an eluent. Obtained solid is washed with n-pentane and diethyl ether to afford the title compound (0.030 g). 1HNMR (400 MHz, DMSO-d6) δ: 2.44 (s, 6H), 3.90 (bs, 2H), 4.28-4.30 (m, 1H), 4.31-4.33 (m, 0.5H), 4.41-4.45 (m, 0.5H), 4.54-4.55 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.89 (t, J=4.0 Hz, 1H), 5.93 (d, J=4.56 Hz, 1H), 6.20 (t, J=53.76 Hz, 1H), 7.47 (d, J=8.24 Hz, 2H), 7.53 (d, J=8.16 Hz, 1H), 7.72 (d, J=8.24 Hz, 2H), 8.11-8.13 (m, 1H), 8.84-8.87 (m, 2H). LC-MS (m/z): [M+H]=382.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][Si](C(C)C)(C(C)C)C(C)C)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([SH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Sc1ccc2c(ccn2C(=O)OC(C)(C)C)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2cc(S)ccc21
Reaction time: 0.25 h
Yield: 33.6 %

Procedure:
A solution of the product of Example 89B (203.7 mg, 0.502 mmol) in anhydrous tetrahydrofuran (4 mL) at −20° under a nitrogen atmosphere was treated with a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.552 mL, 0.552 mmol) and the reaction stirred at −20° for 15 minutes. The reaction was diluted with ethyl acetate (50 mL) and washed with water (2×25 mL) and brine (25 mL). The organic was dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation under vacuum to provide a yellow oil. Purification by silica gel flash chromatography using 5% ethyl acetate/hexanes as eluent afforded the title compound (42 mg, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC.[Cl-].[Li+].O>CN(C=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>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([CH:13]=[CH2:14])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(Cl)nc1N
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1cnc(C(=O)OC)c(N)n1
Temperature: 85 °C

Procedure:
To a mixture of 3-amino-5-chloro-pyrazine-2-carboxylic acid methyl ester (GB 1248146, 161 mg 0.86 mmol), tributyl(vinyl)tin (0.352 ml, 1.204 mmol) and lithium chloride (102 mg, 2.498 mmol) in DMF (4 ml) was added PdCl2(PPh3)2 (30.2 mg, 0.043 mmol) and the mixture was heated to 85° C. for 2.5 h. After cooling to room temperature water was added and the mixture was extracted with EtOAc, the combined organic layers were washed with water and half saturated aq. NaCl, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:9) to provide the title compound as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([OH:14])=O)[C:7]1=[O:15].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:58][CH:59]([C:63]1[S:64][CH:65]=[CH:66][CH:67]=1)[C:60]([OH:62])=[O:61]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:58][CH:59]([C:63]2[S:64][CH:65]=[CH:66][CH:67]=2)[C:60]([OH:62])=[O:61])=[O:14])[C:7]1=[O:15]
Reactant: O=C(O)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: NC(C(=O)O)c1cccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC(C(=O)O)c1cccs1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (0.23 g, 0.00088 mol;) was dissolved in N,N-Dimethylformamide (9 mL, 0.1 mol;) and N,N-Diisopropylethylamine (800 uL, 0.004 mol;), and N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.37 g, 0.00097 mol;) were added. After 5 minutes preactivation Amino-thiophen-2-yl-acetic acid (0.266 g, 0.00169 mol;) was added. Workup consisted of rinsing with 5% citric acid then brine after dissolving the crude in ethyl acetate. The organic layer was then dried with magnesium sulfate and concentrated. The crude material was brought on directly to the next step. ES (+) MS m/e=404.81
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>C(Cl)(Cl)Cl>[CH3:12][C:8]1([CH3:13])[CH2:7][C:5]2[N:6]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:1]=[C:2]3[S:3][C:4]=2[C:10](=[O:11])[CH2:9]1
Reactant: CC1(C)CC(=O)c2sc(N)nc2C1
Reactant: O=C(CBr)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)c2sc3nc(-c4ccccc4)cn3c2C1

Procedure:
A 0.08 m. quantity each of 2-amino-5,5-dimethyl-7-keto-4,5,6,7-tetrahydrobenzothiazole and α-bromoacetophenone are mixed in 150 ml. of chloroform and heated at reflux for 4 hours. The slurry is filtered hot and the insoluble intermediate product is suspended in 600 ml. of water containing 25 g. of sodium acetate. This suspension is heated slowly to boil over 21/2 hours, then allowed to cool. The product is filtered off, washed well with water and dried yielding 12.5 g. of product melting at 175°-178° C. and having the structure: ##STR15##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:15])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH2:11][CH2:12][N:13]=1.C(N(C(C)C)CC)(C)C.[C:25](Cl)(Cl)=[S:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:15]=[C:25]=[S:26])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH2:11][CH2:12][N:13]=1
Reactant: CN1CCN=C1Sc1ccc(N)cc1Cl
Reactant: S=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN=C1Sc1ccc(N=C=S)cc1Cl
Reaction time: 0.33 h
Yield: 97.3 %

Procedure:
To a stirred solution of 3-chloro-4-(1-methyl-4,5-dihydro-1H-imidazol-2-ylsulfanyl)-phenylamine (5.0 g, 21 mmol) and diisopropylethylamine (5.37 g, 41.6 mmol) in dry tetrahydrofuran at 0° C. under N2 inert atmosphere, thiophosgene (2.39 g, 21 mmol) in tetrahydrofuran is added dropwise and stirred for 20 minutes. When the reaction is completed, the reaction mixture is concentrated at room temperature and taken in dichloromethane (100 mL), washed with water (2×50 mL) and dried over anhydrous MgSO4 to get the product as a brown solid (5.8 g, 99%). TLC: pet ether/ethyl acetate (8/2) Rf—0.4. LCMS (method A): mass found (M+H+, 282.0), Rt (min): 3.43, area % 71.5 (max); 1H NMR (400 MHz, DMSO-d6): δ 7.72 (d, J=2.16 Hz, 1H), 7.57 (s, 1H), 7.31 (m, 1H), 7.28 (m, 1H), 6.43 (d, J=8.56 Hz, 1H), 3.61 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COSC1C=CC=CC=1.C1C=C(SSC2N=CC=CC=2)N=CC=1>C(Cl)Cl>[CH3:19][O:17][C:16](=[O:18])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: COSc1ccccc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C

Procedure:
A mixture of 2.51 g. of N-benzyloxycarbonyl-L-valine, 2.62 g. of triphenyl phosphine, 1.40 g. of benzenesulfenic acid methyl ester, 1.10 g. of 2,2'-dipyridyl disulfide and 50 ml. of methylene chloride is stirred at room temperature for 5 hours. The reaction mixture is treated with the same procedure as in Example 1 (1) to give 2.30 g. of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[C:3]=1[NH2:14].CN(C=O)C.[H-].[Na+].[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([Cl:30])=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:28]=[C:27]([NH:14][C:3]2[C:4]([S:8]([CH:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:26]([Cl:30])=[CH:25][N:24]=1
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Fluoro-6-(propane-2-sulfonyl)-phenylamine (3.10 g, 14 mmol) in DMF (10 mL, 0.1 mol) was treated with Sodium hydride, 60% disp. in mineral oil (1.14 g) at 0° C., then 2,4,5-Trichloro-pyrimidine (1.80 mL, 0.0157 mol) was added. The reaction was stirred for 30 minutes at 0° C. and then allowed to warm to rt and stirred at rt for 3 hrs. The reaction mixture was quenched with sat'd NH4Cl Product isolated as an off-white solid: 3.24 g, 62%. MP 192-193, LCMS 365.97 (M+H), HPLC purity 97%, 1H-NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.31 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.53-7.50 (m, 2H), 3.10-3.00 (m, 1H), 1.28 (d, J=5.8 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.Cl.[N:9](OCC)=[O:10]>C(O)C>[CH:1](=[N:9][OH:10])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CCON=O
Reactant: Cc1ccncn1
Agent: Cl
Solvent: CCO
Product: ON=Cc1ccncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
4-Methyl-pyrimidine (0.1 M) was added to 100 ml of ethanol containing 3.5 g (0.1 M) of HCl. While keeping the reaction mixture at 5° there was added over 60 minutes a solution of 9 g (0.12 M) of ethyl nitrite in 60 ml of ethyl alcohol, whereupon the whole was kept under stirring for 1 hour at room temperature. The thus formed 4-formyl-pyrimidine-oxime hydrochloride was separated by filtration, dissolved in water and the aqueous solution neutralized by adding Na2CO3. The title compound was finally obtained by filtration and drying. M.p. 154°-155°. Yield 71%.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[CH:20]=3)[N:15]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[C:43]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:44]=[CH:45][CH:46]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1.C(O)C.O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:41]4[CH:42]=[C:43]([NH:47][S:48]([CH3:51])(=[O:49])=[O:50])[CH:44]=[CH:45][CH:46]=4)[CH:20]=3)[N:15]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 46.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 3-(1-benzyl-1H-pyrazol-4-yl)-5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (220 mg, 0.433 mmol) was coupled with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (intermediate 3) in Sodium carbonate (137.68 mg, 1.29 mmol), PdCl2(dppf) (15.8 mg, 0.02 mmol), toluene/ethanol/water (5/5/2 ml). This on purification by preparative TLC using methanol/chloroform as eluent afforded 120 mg (46.3% yield) of the pure compound.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:17].[CH2:18]([O:20][C:21](=[O:26])[CH:22]=[C:23](Cl)[CH3:24])[CH3:19]>O1CCCC1>[CH2:18]([O:20][C:21](=[O:26])/[CH:22]=[C:23](/[O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[O:8][CH3:7])\[CH3:24])[CH3:19]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: COc1cccc(O)c1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(OC)c1OC
Temperature: 23 °C
Yield: 46.4 %

Procedure:
Potassium t-butoxide (7.54 g, 0.067 mol) was added to a stirred solution of 2,3-dimethoxy-phenol (5.20 g, 0.034 mol) in tetrahydrofuran (30 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 5.00 g, 0.034 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2,3-dimethoxy-phenoxy)-but-2-enoic acid ethyl ester (4.20 g, 47%) as a yellow oil.