Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:20])[C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]#[N:18])=[CH:12][C:11]=2[Cl:19])[CH:5]=[CH:4][N:3]=1.[CH:21]1([C:24]([NH2:26])=[O:25])[CH2:23][CH2:22]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[Cl:19][C:11]1[CH:12]=[C:13]([C:17]#[N:18])[CH:14]=[C:15]([Cl:16])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:26][C:24]([CH:21]2[CH2:23][CH2:22]2)=[O:25])[CH:7]=1)=[O:20]
Reactant: NC(=O)C1CC1
Reactant: N#Cc1cc(Cl)c(C(=O)Nc2ccnc(Br)c2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1cc(Cl)c(C(=O)Nc2ccnc(NC(=O)C3CC3)c2)c(Cl)c1
Temperature: 140 °C
Yield: 40 %

Procedure:
A mixture of N-(2-bromopyridin-4-yl)-2,6-dichloro-4-cyanobenzamide (74 mg, 0.20 mmol), cyclopropanecarboxamide (34 mg, 0.40 mmol), Pd2(dba)3 (18 mg, 0.020 mmol), Xantphos (23 mg, 0.040 mmol), Cs2CO3 (131 mg, 0.40 mmol), dioxane (1.2 mL) was heated to 140° C. for 1 hour in a microwave reactor under nitrogen atmosphere. The mixture was filtered through Celite and then conentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford the desired product (30 mg, yield: 40%). 1H NMR (500 MHz, DMSO-d6): δ 11.28 (s, 1H), 10.79 (s, 1H), 8.36-8.24 (m, 4H), 7.47 (m, 1H), 2.00 (m, 1H), 0.81-0.79 (m, 4H). LCMS (ESI) m/z: 375 [M+H+].
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[CH2:15][NH2:16].[O-:19][C:20]#[N:21].[K+].C(O)(=O)C>C1COCC1.O.C(OCC)(=O)C>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[CH2:15][NH:16][C:20]([NH2:21])=[O:19]
Reactant: CC(C)(C)CCc1cc(C(F)(F)F)ccc1CN
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)CCc1cc(C(F)(F)F)ccc1CNC(N)=O

Procedure:
A mixture of Example 1B (9.0 g, 35 mmol), potassium cyanate (4.2 g, 52 mmol), and glacial acetic acid (3.1 mL, 52 mmol) in THF (70 mL) and water (7 mL) was stirred at 60° C. for 2 hours, diluted with ethyl acetate, and sequentially washed with saturated aqueous NaHCO3 and brine. The organic layer was concentrated under reduced pressure to provide the title compound. 1H-NMR (DMSO-d6) δ 7.41 (m, 3H), 4.69 (brs, 1H), 4.45 (d, 2H), 4.37 (brs, 2H), 2.64 (ddd, 2H), 1.45 (ddd, 2H), 0.99 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][C:7]2([C:13]1[NH:14][CH2:15][CH2:16][N:17]=1)[CH3:12].C([Li])(C)(C)C.[CH3:23][C:24]([CH3:28])([CH3:27])[CH:25]=[O:26]>C1COCC1.CCCCC>[NH:14]1[CH2:15][CH2:16][N:17]=[C:13]1[C:7]1([CH3:12])[C:8]2[C:3](=[C:2]([CH:25]([OH:26])[C:24]([CH3:28])([CH3:27])[CH3:23])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][O:6]1
Reactant: CC(C)(C)C=O
Reactant: CC1(C2=NCCN2)OCCc2c(Br)cccc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1(C2=NCCN2)OCCc2c(C(O)C(C)(C)C)cccc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(5-bromo-1-methylisochroman-1-yl)-4,5-dihydro-1H-imidazole (Example 2, 0.075 g) in 2 ml of THF was added 0.33 ml of tert-butyl lithium solution in pentane (1.7M) at −78° C. followed by addition of 1.2 ml of 20.8M solution of trimethylacetaldehyde in THF. After stirring at −78° C. for 15 min, the reaction was quenched with ice. The title compound was isolated with separation methods A and G. (Yield 0.003 g).
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:40]=[CH:39][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46]([N:49]=[C:50]=[O:51])=[CH:45][CH:44]=1>O1CCCC1>[O:33]=[C:31]1[NH:30][C:29](=[O:34])[CH:28]([CH2:27][C:26]2[CH:35]=[CH:36][C:23]([O:22][CH2:21][C:19]3[N:18]([CH3:37])[C:17]4[CH:38]=[C:13]([O:12][C:11]5[CH:39]=[CH:40][C:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:50]([NH:49][C:46]6[CH:45]=[CH:44][C:43]([C:42]([F:41])([F:52])[F:53])=[CH:48][CH:47]=6)=[O:51])=[CH:9][CH:10]=5)[CH:14]=[CH:15][C:16]=4[N:20]=3)=[CH:24][CH:25]=2)[S:32]1
Reactant: CCCCCCNc1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: CCCCCCN(C(=O)Nc1ccc(C(F)(F)F)cc1)c1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Reaction time: 48 h

Procedure:
A mixture of 5-[4-[6-(4-n-hexylaminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.39 g), α,α,α-trifluoro-p-tolyl isocyanate (0.15 g) and anhydrous tetrahydrofuran (20 ml) was allowed to stand at room temperature for 2 days. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and then concentrated. The residue was reprecipitated from a mixture of ether and diisopropyl ether to afford the title compound (0.37 g, Rf=0.49: thin layer chromatography on a silica gel plate using ethyl acetate:n-hexane=2:1 as the eluant).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:42]1([N:47]2[C:51]3[N:52]=[C:53]([NH:56][C:57]4[CH:62]=[CH:61][C:60]([N:63]5[C:70](=[O:71])[CH2:69][C@@H:68]6[NH:72][C@@H:65]([CH2:66][CH2:67]6)[CH2:64]5)=[CH:59][N:58]=4)[N:54]=[CH:55][C:50]=3[CH:49]=[C:48]2[C:73]([N:75]([CH3:77])[CH3:76])=[O:74])[CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C=O)C.[Cl-].[Na+].O>[C:1]([NH:4][CH2:5][C:6]([N:72]1[C@@H:68]2[CH2:67][CH2:66][C@H:65]1[CH2:64][N:63]([C:60]1[CH:61]=[CH:62][C:57]([NH:56][C:53]3[N:54]=[CH:55][C:50]4[CH:49]=[C:48]([C:73]([N:75]([CH3:77])[CH3:76])=[O:74])[N:47]([CH:42]5[CH2:46][CH2:45][CH2:44][CH2:43]5)[C:51]=4[N:52]=3)=[N:58][CH:59]=1)[C:70](=[O:71])[CH2:69]2)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(=O)O
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)NCC(=O)N1[C@@H]2CC[C@H]1CN(c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C(=O)C2
Reaction time: 4 h
Yield: 75.1 %

Procedure:
2-Acetamidoacetic acid (12 mg, 0.102 mmol) was combined with diisopropylethylamine (0.018 ml, 0.102 mmol) and HBTU (38.8 mg, 0.102 mmol) in DMF (1 ml) for 15 min. 7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (50 mg, 0.102 mmol) was then added and the reaction allowed to stir for 4 hrs. The reaction was then poured into brine and extracted with ethyl acetate. The combined ethyl acetate extracts were dried with sodium sulfate, filtered, concentrated and the resulting residue purified by silica gel chromatography which gave 2-(5-((1S,6R)-9-(2-acetamidoacetyl)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (45 mg) in 77% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (d, J=8.08 Hz, 2H), 8.82 (s, 1H), 8.14 (d, J=2.53 Hz, 1H), 8.07 (d, J=6.06 Hz, 1H), 7.61 (d, J=9.09 Hz, 2H), 6.63 (s, 2H), 4.76 (m, 2H), 4.53 (br. s., 1H), 4.44 (br. s., 0H), 4.21 (d, J=14.65 Hz, 0H), 3.95 (m, 2H), 3.61 (dd, J=14.91, 5.81 Hz, 1H), 3.04 (m, 6H), 2.78 (m, 1H), 2.40 (m, 3H), 2.00 (m, 6H), 1.89 (s, 3H), 1.66 (m, 3H). MS m/z 588.6 (M+H)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]4[S:21][CH:22]=[CH:23][N:24]=4)=[O:18])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CS(C)=O.O>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][C:17]([C:16]1[C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:28]4[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]4)=[N:7][CH:6]=3)[NH:12][C:11]=2[CH:13]=[CH:14][CH:15]=1)=[O:18]
Reactant: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccc(Cl)nc3)nc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4c(C(=O)Nc5nccs5)cccc4[nH]3)cn2)CC1
Temperature: 140 °C
Reaction time: 0.42 h
Yield: 47.1 %

Procedure:
A mixture containing 2-(6-chloropyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (7; 30 mg, 0.084 mmol) and tert-butyl piperazine-1-carboxylate (170; 156.5 mg, 0.84 mmol) in DMSO (1.2 mL) was stirred at 140° C. in a microwave reactor for 25 min. The reaction mixture was cooled to room temperature and diluted with water. The resulting solids were collected by filtration, washed with water and dried under vacuum to afford tert-butyl 4-(5-(4-(thiazol-2-ylcarbamoyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-yl)piperazine-1-carboxylate 8 as a pale yellow solid (20 mg, 71%). MS (ESI) calcd for C25H27N7O3S: 505.19; found: 506 [M+H].
Reaction SMILES: [NH3:1].CC(O)C.Cl[C:7]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH3:32])[C:27](=[O:33])[CH:26]=[C:25]2[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)([C:16]1[N:20]([CH3:21])[CH:19]=[N:18][CH:17]=1)[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.O>C1COCC1>[NH2:1][C:7]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH3:32])[C:27](=[O:33])[CH:26]=[C:25]2[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)([C:16]1[N:20]([CH3:21])[CH:19]=[N:18][CH:17]=1)[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N
Reactant: Cn1cncc1C(Cl)(c1ccc(C#N)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Cn1cncc1C(N)(c1ccc(C#N)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
NH3/iPrOH (6 ml) was added dropwise at 5° C. to a solution of 4-[chloro[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl](1-methyl-1H-imidazol-5-yl)methyl]-benzonitrile (0.00121 mol), (obtained in stage c), in THF (7 ml). The mixture was stirred at room temperature for 4 hours, poured out into water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: toluene/iPrOH/NH4OH; 90/10/1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.3 g (52%) which were then purified by column chromatography over kromasil (eluent: CH3CN/NH4OAc; 40/60; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.18 g (31%) which were crystallized from CH3CN/diethyl ether. The precipitate was filtered off and dried, yielding 0.13 g (22%) of 4-[amino[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6quinolinyl](1-methyl-1H-imidazol-5-yl)methyl]-benzonitrile, melting point 245° C.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:8](C(OC(C)(C)C)=O)[C@H:9]([C:13]([NH:15][C@H:16]([C:27]([NH:29][C@H:30]([CH2:34][OH:35])[C@@H:31]([CH3:33])[OH:32])=[O:28])[CH2:17][S:18][CH2:19][C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)=[O:14])[C@@H:10]([CH3:12])[OH:11].C1(SC)C=CC=CC=1.C(OCC)C>C(Cl)Cl>[NH2:8][C@H:9]([C:13]([NH:15][C@H:16]([C:27]([NH:29][C@H:30]([CH2:34][OH:35])[C@@H:31]([CH3:33])[OH:32])=[O:28])[CH2:17][S:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=1)=[O:14])[C@@H:10]([CH3:12])[OH:11].[F:4][C:3]([C:1]([OH:7])=[O:2])([F:6])[F:5]
Reactant: Cc1ccc(CSC[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: Cc1ccc(CSC[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
150 ml TFA are added to a solution of 16 g BOC-Thr-Cys(MBzl)-Thr-ol and 17 ml thioanisole in 100 ml methylene chloride pre-cooled to 0° C. The whole is allowed to stand for 20 minutes at room temperature and stirred into ethyl-ether. The precipitated product is filtered off, washed with ethyl-ether and dried to yield the title compound:
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1>C1C=CC=CC=1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:17])=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN1CCCC1=N
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccc(Br)cc1

Procedure:
To 4.9 grams (0.05 mole) of 2 -imino-1 -methylpyrrolidine in anhydrous benzene is added, dropwise with stirring, 9.9 g. (0.05 mole) of p-bromophenylisocyanate, dissolved in anhydrous benzene. Solid material forms as the reaction mixture is stirred at room temperature overnight. This solid, 1 -p-bromophenyl-3 -(1 -methyl-2 -pyrrolidylidene)urea, is collected, (m.p. = 135°-137° C). A second crop (m.p. = 134°-136° C) is also obtained from the mother liquor. The two crops are combined and recrystallized from isopropanol-ether to give pure 1 -p-bromophenyl-3 -(1 -methyl-2 -pyrrolidylidene)urea, m.p. = 136°-138° C.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH2:17].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: Nc1ccc(I)cc1F
Reactant: Cc1c(Cl)c(C(=O)O)nn(C)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)nn(C)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.6 %

Procedure:
To a suspension of 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (200 mg, 0.99 mmol) and 2-fluoro-4-iodoaniline (478 mg, 1.97 mmol) in THF (6.5 mL) at −78° C. was slowly added a solution of LiHMDS (3.00 mL, 3.00 mmol, 1 M solution in THF). After complete addition, the resulting mixture was slowly warmed to room temperature and stirred for 4 hours. The reaction mixture was quenched with 6 N aqueous HCl (8 mL) at 0° C., warmed to room temperature, and stirred for 1.5 hours. The precipitates were filtered, washed with water and ether, and triturated with ether to afford 158 mg (38%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2.[H-].[Na+].IC.[C:24]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[N:10]([CH3:24])[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2
Reactant: COc1ccncc1-c1cc2cc(C#N)ccc2[nH]1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccncc1-c1cc2cc(C#N)ccc2n1C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile (Example 90, 178 mg, 0.649 mmol) in DMF (4 mL) is added 60% sodium hydride in mineral oil (78 mg, 1.95 mmol) and the suspension is stirred for 30 min. Iodomethane (138 mg, 0.97 mmol) is then added to the reaction mixture which is stirred at ambient temperature for 1 h. Aqueous NaHCO3 (3 mL) is added to quench the reaction and the mixture is filtered and purified by HPLC using an Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to afford 2-(4-methoxy-pyridin-3-yl)-1-methyl-1H-indole-5-carbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.59 (s, 3H), 3.89 (s, 3H), 6.67 (s, 1H), 7.27 (d, J=5.8 Hz, 1H), 7.54 (dd, J=8.6, 1.5 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 8.11 (d, J=1.1 Hz, 1H), 8.42 (s, 1H), 8.60 (d, J=5.8 Hz, 1H). HRMS (ESI) m/z 264.1138 [(M+H)+ calcd for C16H14N3O: 264.1137].
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@H:4](/[CH:5]=[C:6](\[F:12])/[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([C@@H:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>C(Cl)(Cl)Cl>[CH3:16][C:2]1([CH3:1])[C@H:4](/[CH:5]=[C:6](\[F:12])/[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][C@H:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:14]
Reactant: CCOC(=O)/C(F)=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(F)=C/[C@@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, the acid of Step A and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,trans) 2,2-dimethyl-3(Z)-[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+15°±2° (c=0.5% in chloroform).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[Cl:22][C:23]1[N:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>COCCOC>[Cl:22][C:23]1[N:28]=[CH:27][C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:25][CH:24]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2ccc(Cl)nc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 6-chloro-3-pyridinol, using dry DME as reaction solvent: MS (APCI) m/z 424 (M+1).
Reaction SMILES: [C:1]([CH:6]([NH:16][C@H:17]([C:19]([N:21]1[CH:29]2[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:23][C@H:22]1[C:30]([OH:32])=[O:31])=[O:20])[CH3:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)([O:3]CC)=[O:2].[OH-].[Na+]>CO>[C:1]([CH:6]([NH:16][C@H:17]([C:19]([N:21]1[CH:29]2[CH:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:23][C@H:22]1[C:30]([OH:32])=[O:31])=[O:20])[CH3:18])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C(CCc1ccc(Cl)cc1)N[C@@H](C)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(CCc1ccc(Cl)cc1)C(=O)O)C(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
Treat the ester (prepared as described in Example 3) with sodium hydroxide in methanol as described in Example 2 to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](OCC)(=[O:14])[CH2:10][C:11]([CH3:13])=O.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[OH:8][C:7]1[C:2]2=[N:1][C:11]([CH3:13])=[CH:10][C:9](=[O:14])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1O
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)n2cccc(O)c2n1
Temperature: 100 °C
Yield: 60.4 %

Procedure:
To a mixture of 1.1 g of 2-amino-3-hydroxypyridine VIII and 1.1 g of etyl acetoacetate is added 4 ml of polyphosphoric acid and the resultant mixture is stirred under heating at 100° C. for 4 hours. The reaction mixture is poured into ice water, and the resulting solution is adjusted to PH 4 with 2N aqueous sodium hydroxide, then to PH 7 with aqueous sodium carbonate and shaken with CHCl3. The organic layer is washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated to give 0.9 g of the titled compound XV-1.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([S:8]([NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:2]=1.C[Al](C)C.[Si:21]([O:38][C@@H:39]1[CH2:43][CH2:42][O:41][C:40]1=[O:44])([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[Si:21]([O:38][C@H:39]([CH2:43][CH2:42][OH:41])[C:40]([NH:7][C:6]1[CH:1]=[CH:2][C:3]([S:8](=[O:10])(=[O:9])[NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:5]=1)=[O:44])([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: CC(C)(C)[Si](O[C@@H]1CCOC1=O)(c1ccccc1)c1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@H](CCO)C(=O)Nc1ccc(S(=O)(=O)Nc2nccs2)cc1)(c1ccccc1)c1ccccc1
Yield: 94.8 %

Procedure:
Synthesized according to General procedure 3. The reaction was set up with sulfathiazole (122 g, 477 mmol), CH2Cl2 (1.5 L), trimethylaluminum (2.0 M in hexanes, 239 mL, 477 mmol), and (R)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (125 g, 367 mmol) in CH2Cl2 (250 mL). The reaction was purified via silica gel using 10% MeOH in CH2Cl2 to obtain the desired amide as a white solid (207 g, 348 mmol, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.76 (dd, J=1.8, 7.0 Hz, 1H), 7.74 (s, 1H), 7.59-7.53 (m, 4H), 7.44-7.28 (m, 8H), 7.09 (d, J=4.6 Hz, 1H), 6.46 (d, J=4.6 Hz, 1H), 4.34 (dd, J=4.1, 6.7 Hz, 1H), 3.64-3.59 (m, 1H), 3.54 (dd, J=6.1, 11.4 Hz, 1H), 1.99-1.91 (m, 1H), 1.81-1.70 (m, 1H), 1.10 (s, 9H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=596.5; tR=1.93 min.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([NH:19][C:20]([NH2:22])=[S:21])[S:16][C:17]=3[CH3:18])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([S:32](N)(=[O:34])=[O:33])=[C:27]([CH3:36])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C(C)=CC=CC=1>C(OCC)(=O)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:14]=[C:15]([NH:19][C:20]([NH:22][S:32]([C:28]4[C:29]([CH3:31])=[CH:30][C:25]([O:24][CH3:23])=[CH:26][C:27]=4[CH3:36])(=[O:34])=[O:33])=[S:21])[S:16][C:17]=3[CH3:18])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1sc(NC(N)=S)nc1-c1ccc(C2CCCCC2)cc1
Reactant: COc1cc(C)c(S(N)(=O)=O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)NC(=S)Nc2nc(-c3ccc(C4CCCCC4)cc3)c(C)s2)c(C)c1
Yield: 55.7 %

Procedure:
A mixture of N-[4-(4-cyclohexylphenyl)-5-methyl-2-thiazolyl]thiourea (1.00 g), 4-methoxy-2,6-dimethylphenylsulfonamide (1.30 g), potassium carbonate (500 mg) and xylene (40 ml) was refiuxed with heating for 2 hours. After ethyl acetate (200 ml) was added, the mixture was washed with 2 N-hydrochloric acid and water and dried (magnesium sulfate), after which the solvent was distilled off. The residue was subjected to silica gel chromatography and eluted with methanol-chloroform (5:95, v/v) to yield a crystal of 1-[4-(4-cyclohexylphenyl)-5-methyl-2-thiazolyl]-3-(4-methoxy-2,6-dimethylphenylsulfonyl)-2-thiourea (890 mg, yield 56%). This product was recrystallized from dichloromethane-methanol to yield a colorless prismatic crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[CH2:20]([NH:23][C:24](=[O:31])[CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:21]#[CH:22]>>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:22]#[C:21][CH2:20][NH:23][C:24](=[O:31])[CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1
Reactant: C#CCNC(=O)CN1CCCC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Product: Nc1ccc(Oc2ccnc3cc(C#CCNC(=O)CN4CCCC4)sc23)c(F)c1
Reaction time: 3 h
Yield: 65 %

Procedure:
Prepared from 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 72 mg, 0.186 mmol) and N-(prop-2-ynyl)-2-(pyrrolidin-1-yl)acetamide (34 mg, 0.205 mmol; prepared according to the method described in WO 04/076412A) according to the procedure described for Example 6, Step B, except the reaction was executed at room temperature for 3 hours. The product was purified by preparative TLC (10% MeOH/CH2Cl2). The product was obtained as a waxy solid (69 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=6 Hz, 1H), 7.60 (s, 1H), 7.52 (br s, 1H), 7.03 (t, J=9 Hz, 1H), 6.54 (m, 2H), 6.48 (m, 1H), 4.39 (d, J=6 Hz, 2H), 3.86 (br s, 2H), 3.28 (s, 2H), 2.69 (m, 4H), 1.85 (m, 4H). LRMS (ESI pos) m/e 425 (M+1).