Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1OC)=O.Cl.COC=O.C([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=O.[OH-].[K+]>CO>[CH2:21]1[CH2:20][CH:19]2[CH:7]3[CH:1]([N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]4[N:18]2[CH2:23][CH2:22]1)[NH:3][CH2:4][CH2:5][CH2:6]3
Reactant: COC1CCCCN1C=O
Reactant: O=CN1CCCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: COC=O
Product: C1CNC2C(C1)C1CCCCN1C1CCCCN21

Procedure:
28.6 g (0.2 mol) of 1-formyl-2-methoxypiperidine and 0.3 mol of methanolic HCl were refluxed for 4 hours. At atmospheric pressure in a boiling range of from 30° to 50° C. a mixture of formic acid methyl ester and methanol, which could be re-used for the preparation of 1-formyl-piperidine, was distilled off. The distillation residue was added dropwise to a solution of 21.7 g of KOH (85% strength, 0.33 mol) in methanol and the whole was refluxed for 4 hours. Working up as described in Example 4 yielded 13.3 g (80.1% of the theory) of isotripiperidein melting at 87°-91° C.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[N:10]=[C:11]([CH2:13][CH3:14])[O:12][C:8]=2[C:7]([C:15]([OH:17])=O)=[CH:6][CH:5]=1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]([F:28])([F:27])[F:26])[C:21]=1[NH2:29]>>[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]([F:28])([F:27])[F:26])[C:21]=1[NH:29][C:15]([C:7]1[C:8]2[O:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=2[C:4]([O:3][CH:2]([F:1])[F:18])=[CH:5][CH:6]=1)=[O:17]
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)O)c2o1
Reactant: Cc1onc(C(F)(F)F)c1N
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(C(F)(F)F)noc3C)c2o1
Yield: 10.2 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid (0.1 g) and 5-methyl-3-trifluoromethylisoxazol-4-ylamine (78 mg). Purification by column chromatography eluting with 20-30% ethyl acetate in hexane afforded the title compound as a white solid (16 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:29])=[C:7]([C:21]([NH:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:22])[C:8]([I:20])=[C:9]([C:18]=1[I:19])[C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])(=[O:3])[CH3:2].B(O)(O)O.[OH-].[K+].[CH2:36](Br)[CH:37]=[CH2:38]>O.CO>[CH2:38]([N:4]([C:5]1[C:18]([I:19])=[C:9]([C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])[C:8]([I:20])=[C:7]([C:6]=1[I:29])[C:21]([NH:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:22])[C:1](=[O:3])[CH3:2])[CH:37]=[CH2:36]
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: C=CCBr
Agent: OB(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCN(C(C)=O)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reaction time: 3 h

Procedure:
To a stirred solution of 5-acetamido-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (7.5 g, 10 mmol) and boric acid (1.24 g, 20 mmol) in water (10 ml) and methanol (7 ml) is added potassium hydroxide (10 M) drop wise until a stable pH 12.5 is established. Allylbromide (860 ul, 10 mmol) is added and potassium hydroxide (10 M) is continuously added to maintain pH 12.5. for 3 h and the mixture is then left stirring over night. The following day the mixture is reduced in vacuo to remove methanol, the resulting aqueous phase is diluted with 50 ml water and treated with acidic and basic ion exchanger. Resins are removed and rinsed and the combined aqueous volume is reduced to dryness in vacuo to yield 5-(N-allylacetamido)-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[Cl:31]C1C=C(C=CC=1)C=O>>[Cl:31][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:3]=1)[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1cccc(Cl)c1
Product: O=C(NCCNCc1cccc(Cl)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]-amide using 3-chlorobenzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 426 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (1H, br. s.) 10.43 (1H, s) 10.26 (1H, s) 7.94-8.11 (1H, m) 7.72-7.80 (1H, m) 7.37-7.52 (1H, m) 7.18-7.33 (1H, m) 7.05-7.14 (1H, m) 6.75-6.85 (1H, m) 6.36-6.44 (1H, m) 3.70 (2H, s) 3.31-3.38 (2H, m) 2.62 (2H, t, J=6.44 Hz)
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(#N)C.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(S(C)(=O)=O)cc1)=C2Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc2c(Br)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reaction time: 1 h

Procedure:
Combine 1-bromo-2-(4-methanesulfonylphenyl)-3,4-dihydro-6-methoxynaphthalene and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 1.8 equiv.) in 10 volumes acetonitrile and 5 volumes of THF. Under nitrogen atmosphere, heat reaction contents to 73-75° C. Monitor reaction progress by GC analysis until reaction completion. Additional DDQ (0.2-0.3 equiv.) may be required for reaction completion. Cool contents to ambient temperature and add 10 volumes 1 N sodium hydroxide. Stir for approximately 1 hour and filter. Rinse filter cake with 2 volumes water, 3×5 volumes 50% acetonitrile/water and finally 3 volumes methanol. Vacuum dry the filter cake at 65° C. to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH2:23]([N:26]1[CH:30]=[CH:29][C:28]([NH2:31])=[N:27]1)[CH2:24][CH3:25].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:31][C:28]2[CH:29]=[CH:30][N:26]([CH2:23][CH2:24][CH3:25])[N:27]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CCCn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCn1ccc(NC(=O)/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reaction time: 2 h
Yield: 67 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 100 mg, 0.29 mmol), 1-propyl-1H-pyrazol-3-ylamine (40 μL, 0.29 mmol) and N,N-diisopropylethylamine (151 μL, 0.87 mmol) were combined in methylene chloride (1.5 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 33% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(1-propyl-1H-pyrazol-3-yl)-acetamide (88 mg, 67%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C20H25ClN4O4S [M+] 452.13, found 453 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 0.98 (t, J=7.5 Hz, 3H, CH3), 1.64 (m, 4 H, 2×CH2), 1.87 (m, 6 H, 3×CH2), 3.29 (s, 3 H, SO2CH3), 4.01 (st, J=7.0 Hz, 32H, NCH2), 4.88 (m, 1 H, OCH), 6.69 (d, J=2.3 Hz, 1 H, Ar), 7.31 (d, J=2.3 Hz, 1 H, Ar), 7.55 (dd, Jo=8.2, Jm=1.6 Hz, 1 H, Ar), 7.66 (d, Jm=1.6 Hz, 1 H, Ar), 8.18 (d, Jo=8.2 Hz, 1 H, Ar), 9.16 (s, 1 H, NH).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH2:36][CH2:35]1.COCC(O)C>>[CH3:33][N:34]1[CH2:35][CH2:36][N:37]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(NS(C)(=O)=O)c3)n2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(NS(C)(=O)=O)c5)n4n3)cc2)CC1
Yield: 66.7 %

Procedure:
N-[3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide (125.0 mg, 0.0003567 mol), N,N-Diisopropylethylamine (0.205 mL, 0.00118 mol) and 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.136 g, 0.000713 mol) were dissolved in 1-Methoxy-2-propanol (0.410 mL, 0.00419 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 113.55 mg of N-(3-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-methanesulfonamide as a lyophilized powder. (M+H)=478.1. 1H NMR (400 MHz, DMSO, d6) δ 9.78 (m, 1H), 9.32 (s, 1H), 8.98 (s, 1H), 7.90 (m, 2H), 7.67 (m, 2H), 7.53 (m, 1H), 7.27 (d, 1H, J=7.97 Hz), 7.06 (m, 1H), 6.94 (m, 2H), 6.89 (m, 1H), 3.76 (m, 2H), 3.53 (m, 2H), 3.19 (m, 2H), 3.04 (s, 3H), 2.96 (m, 5H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([O:39][C:40]1[CH:46]=[C:45]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH3:55])[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:41]=1[NH2:42])[CH3:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[CH:44][C:45]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH3:55])[CH2:49][CH2:48]4)=[CH:46][C:40]=3[O:39][CH2:37][CH3:38])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCCN1CCN(c2ccc(N)c(OCC)c2)CC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: CCCN1CCN(c2ccc(Nc3nccc(-c4c(-c5ccc(OCC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
Temperature: 130 °C
Yield: 50.6 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 2-(ethyloxy)-4-(4-propyl-1-piperazinyl)aniline (Example 151, step B) (47 mg, 0.18 mmol), and p-toluenesulfonic acid (90 mg, 0.48 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (67 mg, 0.091 mmol, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.33 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=5.13 Hz, 1H), 8.04 (d, J=2.01 Hz, 1H), 7.72 (dd, J=8.61, 2.01 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.34-7.45 (m, 3H), 7.24 (d, J=8.61 Hz, 1H), 7.18 (t, J=8.06 Hz, 2H), 6.92 (t, J=6.59 Hz, 1H), 6.64 (d, J=2.20 Hz, 1H), 6.53 (d, J=5.13 Hz, 1H), 6.45 (dd, J=8.70, 2.47 Hz, 1H), 4.24 (q, J=6.78 Hz, 2H), 4.04 (q, J=6.96 Hz, 2H), 3.06-3.16 (m, 4H), 2.43-2.52 (m, 4H), 2.25 (t, J=6.96 Hz, 2H), 1.39-1.48 (m, 5H), 1.22 (t, J=6.96 Hz, 3H), 0.85 (t, J=7.33 Hz, 3H). MS (ESI): 733 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH2:18])=[S:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:20][C:21](=O)[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C>CO>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:20]=[C:21]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[N:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: NC(=S)Nc1ncccc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)Cc1csc(Nc2ncccc2OCc2ccccc2)n1
Yield: 33.2 %

Procedure:
Following the method of Example 2, Step C, 1-(3-(benzyloxy)pyridin-2-yl)thiourea (2.00 g, 7.71 mmol), methyl 4-chloro-3-oxo-butanoate (1.63 g, 10.8 mmol), and triethylamine (1.83 mL, 13.1 mmol) were reacted in methanol (40 mL) to provide methyl 2-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)acetate (910 mg, 33%) as a yellow oil. 1H NMR (d6-DMSO) δ 10.10 (s, 1H), 7.86 (d, 1H), 7.58 (d, 2H), 7.30-7.42 (m, 4H), 6.90 (d, 1H), 6.80 (s, 1H), 5.25 (s, 2H), 3.62 (s, 3H). Mass spectrum (apci) m/z=356 (100) (M+H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].C(O)C[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CCCCO.CCCCO.CCCCO.CCCCO.[Ti].C(O)C>[Si:5]([CH2:4][CH2:3][CH2:2][SH:1])([O:12][CH2:13][CH2:14][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])([O:6][CH2:7][CH2:8][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[O:9][CH2:10][CH2:11][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: CCO[Si](CCCS)(OCC)OCC
Reactant: CCCCCCCCCCCCCCCCO
Agent: [Ti]
Solvent: CCCCO
Solvent: CCO
Product: CCCCCCCCCCCCCCCCO[Si](CCCS)(OCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCC
Temperature: 105 °C

Procedure:
2002.6 g of 3-mercaptopropyl(triethoxy)silane are mixed with 6108.5 g of hexadecanol as well as with 2 g of tetrabutyl orthotitanate and heated at 95-115° C. for 360 minutes in a 10 liter flask in a distillation apparatus. Ethanol formed in the transesterification is distilled off in vacuo at 15-600 mbar. After cooling, 7022 g of a colourless, solid product are obtained. As can be shown by 1H-NMR and 29Si-NMR, 92% of the EtO—Si groups are replaced by R—O—Si. In the transesterification more than 80 mole % of the ethanol-free compound [(C16H33O)3Si—C3H6—SH is formed, as can be shown for example by 1H-NMR and 29Si-NMR.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4](=[O:12])[C:5]2[N:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[F:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=1[OH:31]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4](=[O:12])[C:5]3[N:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=[C:2]2[O:31][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([F:28])([F:29])[F:30])[C:21]=2[F:20])=[CH:14][CH:15]=1
Reactant: O=c1c2ncccc2nc(Cl)n1-c1ccc(F)cc1
Reactant: Oc1cccc(C(F)(F)F)c1F
Product: O=c1c2ncccc2nc(Oc2cccc(C(F)(F)F)c2F)n1-c1ccc(F)cc1
Temperature: 140 °C

Procedure:
A mixture of 2-chloro-3-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-4(3H)-one (55 mg, 0.20 mmol) and 2-fluoro-3-trifluoromethylphenol (50 μl, 0.40 mmol) is heated to 140° C. for 18 hours. After cooling to RT, the crude mixture is purified by column chromatography (gradient from CH2Cl2 to 20% EtOAc/CH2Cl2) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) 8.71 (1H, m), 7.83 (2H, m), 7.70 (4H, m), 7.45 (3H, m). MS (M+1): 420.07; RT=1.13 min.
Reaction SMILES: C([Li])CCC.[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])#[CH:7].[CH:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([CH2:14][CH2:13][CH:12]([OH:21])[C:7]#[C:6][Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CCCc1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Following a modified procedure of Matsuda (Matsuda, F. Et al., Chem. Eur. J. 5, 3252-3259 (1999)); n-butyllithium (1.6 M in hexanes, 8.8 ml, 14.1 mmol, 1.0 eq.) was added dropwise to a solution of ethynyltrimethylsilane (2.0 ml, 14.1 mmol, 1.0 eq.) in THF (6 ml) at −78° C. After addition, the mixture was allowed to warm slowly to 0° C. and stirred for 1 h. The mixture was cooled to −78° C. and a solution of hydrocinnamaldehyde (2.2 ml, 17.0 mmol, 1.2 eq.) in THF (3 ml) was added dropwise. The mixture was then allowed to slowly warm to −10° C. and stirred for 1 h before being quenched by the addition of saturated NH4Cl solution (10 ml) followed by EtOAc (10 ml). The aqueous layer was extracted with EtOAc (3×10 ml), the combined organic phases were washed with brine (15 ml) before being dried (MgSO4), filtered and concentrated to give the crude product. This was purified by column chromatography on silica, eluting with petrol/EtOAc (100:5), giving the title product 81 as a clear, colourless oil (3.1 g, 94%). Analytical data consistent with the literature (Matsuda, F. Et al., Chem. Eur. J. 5, 3252-3259 (1999)).
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:27][CH:28]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)cc2)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CCn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)cc5)cc34)cn2)cc1
Yield: 20.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-phenethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (85 mg, 0.155 mmol) was deprotected in TFA/toluene (2.5/5 ml). This afforded 14 mg (20.2% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.576-8.571 (d, 1H), 8.46-8.45 (d, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.73-7.71 (m, 3H), 7.48-7.46 (d, 2H), 7.25-7.20 (m, 2H), 7.14-7.07 (m, 3H), 7.48-7.43 (t, 2H), 3.56-3.52 (d, 2H), 3.22-3.15 (m, 4H), 3.07-2.98 (dt, 1H), 2.17-2.13 (d, 2H), 2.06-1.91 (m, 2H). MS: m/z=448.4 (M+1), HPLC: 91.78% in method B.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([I:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C1([Mg]Cl)C=CC=CC=1.[CH3:22][C:23]([CH3:27])([CH3:26])[CH:24]=[O:25]>C1COCC1>[I:11][C:5]1[C:4]([O:12][CH3:13])=[CH:3][C:2]([CH:24]([OH:25])[C:23]([CH3:27])([CH3:26])[CH3:22])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: CC(C)(C)C=O
Reactant: COc1cc(I)c([N+](=O)[O-])cc1I
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(O)C(C)(C)C)c([N+](=O)[O-])cc1I
Temperature: 40 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a solution of crude 3,6-diiodo-4-nitroanisole (770 mg, 80% purity, 1.52 mmol) in anhydrous THF (10 mL) at minus 40° C. under a nitrogen atmosphere, phenylmagnesium chloride (2 M in THF, 0.46 mL, 0.92 mmol) was added dropwise at a rate such that the temperature would not exceed minus 35° C. Upon completion of the addition, the mixture was stirred at minus 40° C. for two hours, followed by addition of trimethylacetaldehyde (0.22 mL, 1.97 mmol). The mixture was stirred at minus 30° C. for two hours and then at room temperature for another one hour. The reaction was then quenched with brine (1.0 mL), diluted with CH2Cl2 (100 mL), and the solution was washed with CH3COOH (0.1 N, 50 ml) and brine (50 ml) sequentially. The organic phase was dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield racemic (R/S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (399 mg, 72%). 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H, Ph-H), 7.17 (s, 1H, Ph-H), 5.60 (d, 1H, J=4.0 Hz, PhCH), 3.98 (s, 3H, OCH3), 2.12 (d, 1H, J=4.0 Hz, OH), 0.89 (s, 9H,C(CH3)3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:21]1([CH2:26]Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([CH2:26][N:14]2[C:13](=[O:16])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[N:15]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: BrCC1CCCC1
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CC2CCCC2)c1=O
Yield: 72 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and cyclopentylmethyl bromide {J. Org. Chem., 36, 3103 (1971)} were reacted to yield the title compound as yellow needles (yield: 72.0%).
Reaction SMILES: [C:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>O.CN(C)C=O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][CH2:21][C:4]1([C:1](=[O:3])[CH3:2])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13])[CH3:27]
Reactant: CCOC(=O)CCBr
Reactant: CC(=O)C1Cc2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC1(C(C)=O)Cc2ccccc2C1=O
Temperature: 52.5 °C
Reaction time: 0.33 h

Procedure:
2-Acetyl-1-indanone (15 g, cf. Liebigs Ann. Chem. 347 (1906) 112) was added into a mixture of potassium carbonate (8.5 g) and dry N,N-dimethylformamide (45 ml). The mixture was stirred at 50-55° C. for 20 minutes and ethyl 3-bromopropionate (19 g) was then added and the stirring was continued at 50-55° C. for 6 hours. Water (60 ml) was added to the reaction mixture and the pH of the solution was adjusted to 2-3 with hydrochloric acid. The mixture was stirred at 50-55° C. for one hour. The cooled solution was extracted with toluene, washed with water, dried with sodium sulfate, and the solvent removed under reduced pressure. The yield was 23.5 g.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[CH3:18][S:19][C:20]1[N:25]=[C:24]([C:26]2[S:30][C:29]([S:31](Cl)(=[O:33])=[O:32])=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1.S1C(S(Cl)(=O)=O)=CC2C=CC=CC1=2>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:31]([C:29]2[S:30][C:26]([C:24]3[CH:23]=[CH:22][N:21]=[C:20]([S:19][CH3:18])[N:25]=3)=[CH:27][CH:28]=2)(=[O:32])=[O:33])[C:4]1=[O:17])#[N:13]
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Agent: O=S(=O)(Cl)c1cc2ccccc2s1
Product: CSc1nccc(-c2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)s2)n1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-benzonitrile hydrochloride as described in EXAMPLE 1, Part E using 5-[2-(methylthio)-pyrimidin-4-yl]thiophene-2-sulfonyl chloride in a place of benzo[b]thiophene-2-sulfonyl chloride. The crude product is obtained as a white solid and is of sufficient purity to be used in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1B(O)O.Br[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1C.ClC1C=CC(B(O)O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1
Reactant: Cc1cc(N)ccc1Br
Reactant: OB(O)c1c(Cl)cccc1Cl
Agent: OB(O)c1ccc(Cl)cc1
Product: Nc1ccc(-c2c(Cl)cccc2Cl)cc1
Temperature: 90 °C

Procedure:
The title compound was prepared as described in Example 76, STEP B, but heating at 90° C. for 14 hrs, substituting 4-iodoaniline and 2,6-dichlorophenylboronic acid for 4-bromo-3-methylaniline and 4-chlorophenylboronic acid.