Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[CH:32]=[C:31]([CH2:33][C:34]([OH:36])=O)[NH:30][N:29]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:37][CH3:38])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43].Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-]>CN(C)C=O.ClCCl>[C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[CH:32]=[C:31]([CH2:33][C:34]([NH:43][C:42]5[CH:44]=[CH:45][CH:46]=[C:40]([F:39])[CH:41]=5)=[O:36])[NH:30][N:29]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:37][CH3:38])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Nc3cc(CC(=O)O)[nH]n3)ncnc2cc1OCCC1CCN(CCOC(C)(C)C)CC1
Reactant: Nc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cc(CC(=O)Nc4cccc(F)c4)[nH]n3)ncnc2cc1OCCC1CCN(CCOC(C)(C)C)CC1
Yield: 65.4 %

Procedure:
{3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid (210 mg, 0.4 mmol) in dimethylformamide (2.1 ml) was reacted with 3-fluoroaniline (58 mg, 0.52 mmol) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107 mg, 0.56 mmol) and 2-hydroxypyridine-1-oxide (53 mg, 0.48 mmol) at 55° C. for 1.5 hours. The reaction mixture was cooled, diluted with dichloromethane (7 ml) and purified by chromatography on silica gel. Elution with dichloromethane:methanol (9:1) and increased polarity to dichloromethane:methanol:ammonia (9:1:0.1) yielded 2-{3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}-N-(3-fluorophenyl)acetamide (162 mg, 65% yield) as a light pink solid:
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl.Cl.C[Si](C)(C)CCOC[N:16]1[C:20]2[N:21]=[CH:22][N:23]=[C:24]([C:25]3[CH:26]=[N:27][N:28]([C:30]4([CH2:34][C:35]#[N:36])[CH2:33][NH:32][CH2:31]4)[CH:29]=3)[C:19]=2[CH:18]=[CH:17]1.Br[C:40]1[CH:54]=[CH:53][C:43]([C:44]([NH:46][C@@H:47]([CH3:52])[C:48]([F:51])([F:50])[F:49])=[O:45])=[CH:42][C:41]=1[F:55]>>[C:35]([CH2:34][C:30]1([N:28]2[CH:29]=[C:25]([C:24]3[C:19]4[CH:18]=[CH:17][NH:16][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:26]=[N:27]2)[CH2:31][N:32]([C:40]2[CH:54]=[CH:53][C:43]([C:44]([NH:46][C@@H:47]([CH3:52])[C:48]([F:51])([F:50])[F:49])=[O:45])=[CH:42][C:41]=2[F:55])[CH2:33]1)#[N:36]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: C[C@H](NC(=O)c1ccc(Br)c(F)c1)C(F)(F)F
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)c(F)c1)C(F)(F)F

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 3, Step 2-3 starting from {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride and 4-bromo-3-fluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (from Step 1, above). LCMS (M+H)+: m/z=513.2. 1H NMR (300 MHz, DMSO-d6): δ 12.64 (s, 1H), 9.08 (s, 1H), 8.83 (s, 1H), 8.61 (d, J=8.5 Hz, 1H), 8.57 (s, 1H), 7.79 (m, 1H), 7.70 (s, 1H), 7.66 (m, 1H), 7.23 (d, J=2.3 Hz, 1H), 6.76 (t, J=8.5 Hz, 1H), 4.80 (m, 1H), 4.68 (d, J=8.0 Hz, 2H), 4.53 (d, J=8.0 Hz, 2H), 3.76 (s, 2H), 1.32 (d, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:11](=O)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[C:7]([OH:10])[C:8]=1[OH:9])#[N:2].[NH2:17][C:18]1C(O)=[CH:22][CH:21]=[C:20]([CH3:25])[CH:19]=1>CN(C)C=O.O>[OH:9][C:8]1[C:7]([OH:10])=[CH:6][C:5]([C:11]2[C:12](=[O:13])[O:14][C:15]3[CH:22]=[CH:21][C:20]([CH3:25])=[CH:19][C:18]=3[N:17]=2)=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: Cc1ccc(O)c(N)c1
Reactant: COC(=O)C(=O)c1cc(O)c(O)c(C#N)c1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2oc(=O)c(-c3cc(O)c(O)c(C#N)c3)nc2c1
Temperature: 25 °C

Procedure:
1.075 g of methyl (3-cyano-4,5-dihydroxyphenyl)-glyoxylate and 0.60 g of 2-amino-p-cresol are stirred at 120° for 70 minutes in 2 ml of dimethylformamide. The mixture is subsequently cooled to room temperature and diluted with 15 ml of water. The precipitate is filtered and dried in a water-jet vacuum at 80° for 6 hours. After recrystallization from acetonitrile there is obtained 2,3-dihydroxy-5-(6-methyl-2-oxo-2H-1,4-benzoxazin-3-yl)-benzonitrile of m.p. 278°-280°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Mg].C([O:14][B:15](OC(C)C)[O:16]C(C)C)(C)C.S(=O)(=O)(O)O>C1COCC1.C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]([B:15]([OH:16])[OH:14])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(B(O)O)c1

Procedure:
3,5-Dimethylbromobenzene (10 g, 54 mmol) and magnesium (2.5 g, 108 mmol) were dissolved in 100 mL of THF and stirred at reflux for five hours. After this time, triisopropylborate (10 g, 54 mmol) as a solution in diethylether (50 mL) was added to the solution, followed by stirring at room temperature overnight. The THF was removed in vacuo to leave a crude oil. This oil was taken up in 100 mL of diethylether and 100 mL of 10% sulfuric acid (aqueous) and stirred for two hours. The organic layer was separated and neutralized with saturated sodium bicarbonate solution, whereafter the solvent was removed in vacuo to yield a white solid. The solid was washed generously with pentane. Yield: 4.0 g (49%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[C:41]=3[Cl:50])[CH2:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO>[ClH:50].[Cl:50][C:41]1[C:42]([C:46]([F:48])([F:47])[F:49])=[CH:43][CH:44]=[CH:45][C:40]=1[CH2:39][N:24]([CH2:25][CH:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:23][CH2:22][CH2:21][O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CC1
Agent: Cl
Solvent: CO
Product: FC(F)(F)c1cccc(CN(CCCOc2cccc(N3CCNCC3)c2)CC(c2ccccc2)c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (475 mg, 0.67 mmol) in a 1:1 mixture of 3M HCl (aq.) and methanol (30 mL total) was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, and the crude material was dissolved in EtOAc. The EtOAc solution was washed with saturated aqueous sodium bicarbonate solution (3×) and brine (1×), dried over sodium sulfate, and filtered. The EtOAc extracts were concentrated and the crude piperazine was treated with 1 M HCl (Et2O) to afford the title compound as a solid, 415 mg (100%). MS(ES) m/e 608.4 (M+).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[Na+]>CN(C)C=O>[CH2:13]([N:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=[N:3]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCI
Reactant: c1ccc2[nH]nnc2c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCCCCn1nc2ccccc2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.9 %

Procedure:
Sodium hydride (60% in oil, 4.00 g, 100 mmol) was added in small portions within 1 hours to a solution of benzotriazole (14.3 g, 120 mmol) and 1-iodooctane (25 g, 104 mmol) in anhydrous dimethylformamide (100 mL) stirred under argon at room temperature. After the addition, stirring was continued for 3 days. The reaction mixture was poured into ice/water (100 mL), treated with 2 N NaOH (100 mL) and extracted with hexane/ethyl ether (1:1, 3×200 mL). The extract was washed with water (200 mL), dried over anhydrous sodium carbonate, and the solvent was removed under reduced pressure. The residue was chromatographed using silica gel (500 g) and hexane/dichloromethane (1:1) as an eluent. The first fraction gave 2-octyl-2H-benzo[d][1,2,3]triazole (8.16 g, 35% yield) as an oily product. 1H NMR (400 MHz, CDCl3): δ 7.85 (m, 2H, benzotriazole), 7.37 (m, 2H, benzotriazole), 4.71 (t, J=7.3 Hz, 2H, octyl), 2.10 (m, 2H, octyl), 1.32 (m, 4H, octyl), 1.23 (m, 6H, octyl), 0.85 (t, J=7.3 Hz, 3H, octyl).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([S:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([S:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: CSc1ccc(C=O)cc1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CSc1ccc(CO)cc1C#N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A flask is charged with 5-formyl-2-methylsulfanyl-benzonitrile (1.0 g, 5.68 mmol) in MeOH (20 mL) and cooled to 0° C. Sodium borohydride (1.07 g, 28.40 mmol) is added and the mixture is stirred at room temperature for 2 h, followed by removal of solvent in vacuo. The residue is re-dissolved in dichloromethane and washed with water twice. The organic layer is dried over sodium sulfate and concentrated in vacuo to afford 5-hydroxymethyl-2-methylsulfanyl-benzonitrile as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.57 (s, 3H), 4.70 (d, J=5.1 Hz, 2H), 7.33 (d, J=8.3 Hz, 1H), 7.53 (dd, J=8.3, 1.0 Hz, 1H), 7.62 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[NH:12][NH:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:20])[NH:11][NH:12][C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NNC(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Solvent: CO
Product: O=c1[nH][nH]c(-c2ccncc2)c1-c1ccc(Cl)c(Cl)c1

Procedure:
The solution of 4-(3,4-Dichloro-phenyl)-5-pyridin-4-yl-pyrazolidin-3-one 0.30 g, 20 mg Pd/C and 20 mL methanol was stirred at room temperature. Air was bubbled through for 2 hours. Filtered off the Pd/C catalyst, vacuumed down all solvent. The title compound was obtained as white solid 0.29 g. MS (ES+): 306 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][C:22](=O)C(F)(F)F)=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].CI>CS(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][CH3:22])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(NC(=O)C(F)(F)F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNc1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Temperature: 45 °C

Procedure:
4.1 g (11 mmol) of N-{2-[2-(4-cyanophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-trifluoroacetamide are cooled to about 10° C. in 20 mL dimethylsulphoxide and 80% NaH (0.33 g, about 11 mmol) are added in batches with stirring. The mixture is heated to 40-50° C. for 0.5 h and then cooled to 30° C. Methyl iodide (0.75 mL, 11.9 mmol) is then added dropwise. The mixture is stirred for 0.5 h at 40-50° C., diluted with 100 mL ethyl acetate, poured onto water and extracted. The organic phase is again washed with water, dried and evaporated down. The residue is chromatographed over silica gel. The methylated trifluoroacetamide is taken up in MeOH, combined with 10 mL of conc. aqueous ammonia solution and stirred for 4 h at 30-40° C. The methanol is distilled off, the residue is taken up in 75 mL of ethyl acetate, washed with water, dried and evaporated down. The product is crystallised from diethylether. Yield: 2.0 g (63%); melting point: 155-158° C.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:4]=[C:5]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:6][C:7](=[O:11])[C:8]=1[N:9]=O>O>[NH2:2][C:3]1[N:4]=[C:5]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:6][C:7](=[O:11])[C:8]=1[NH2:9]
Reactant: Nc1nc(CCc2ccccc2)[nH]c(=O)c1N=O
Agent: [Na]
Solvent: O
Product: Nc1nc(CCc2ccccc2)[nH]c(=O)c1N
Yield: 20.9 %

Procedure:
Crude sodium salt of 4-amino-5-nitroso-2-(2-phenylethyl)pyrimid-6-one (3.8 g.) was dissolved in water (5.5 ml.). A trace of insoluble material was filtered off, and sodium dithionite (4.08 g.) was added slowly to the filtrate with stirring. The solid which separated was filtered off, washed with water, and recrystallised from ethanol to give 4,5-diamino-2-(2-phenylethyl)pyrimid-6-one (0.75 g.), m.p. 204°-206° C. (with decomposition).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[CH:21][N:20]=2)[C:15](=[O:32])[N:14]([CH2:33]C)[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[OH:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)=[CH:21][N:20]=2)[C:15](=[O:32])[N:14]([CH3:33])[CH:13]=1
Reactant: CCn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2COC(C)=O)cc(Nc2ccc(C3CCN(C)CC3)cn2)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(c2ccc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)CC1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
A mixture of 232e (180 mg, 0.30 mmol) and lithium hydroxide (130 mg, 3.0 mmol) in THF/i-propanol (6:3, 9 mL) and water (3 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to 232 (55 mg, 35%) as white solid. MS-ESI: [M+H]+ 594.3. 1H NMR (500 MHz, CDCl3) δ 8.72 (d, J=3.0 Hz, 1H), 8.51 (d, J=6.0 Hz, 1H), 8.11 (d, J=3.0 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.44-7.36 (m, 2H), 6.90 (s, 1H), 6.80-6.78 (m, 1H), 5.08-5.04 (m, 1H), 4.64-4.50 (m, 2H), 4.34-4.29 (m, 1H), 4.16-4.10 (m, 2H), 3.91-3.87 (m, 1H), 3.72 (s, 3H), 3.03-3.00 (m, 2H), 2.62-2.56 (m, 4H), 2.46-2.42 (m, 1H), 2.36 (s, 1H) 2.13-2.07 (m, 2H), 1.92-1.82 (m, overlap, 8H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]2[CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]3[O:26][C:9]=2[CH:8]=1.[OH-].[Na+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl.O>[OH:6][C:7]1[CH:12]=[CH:11][C:10]2[CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH:14]3[O:26][C:9]=2[CH:8]=1
Reactant: COc1ccc2c(c1)OC1CN(C(=O)OC(C)(C)C)CCC21
Agent: BrB(Br)Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2c3ccc(O)cc3OC2C1
Reaction time: 1 h
Yield: 230.9 %

Procedure:
Boron tribromide (285 mL, 1 M, 0.285 mol) in DCM was added over 45 min to a solution of tert-butyl 7-methoxy-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (33.3 g, 0.11 mol) in DCM (1.2 L). The reaction mixture was kept at 5-8° C. using a water bath cooling. After 1 h stirring, H2O (250 mL) and NaOH (350 mL, 3 M) were added, followed by di-tert-butyl dicarbonate (59.6 g, 0.27 mol). After 16 h stirring, the layers were separated, the organic layer was washed with 0.3 N HCl and H2O, and concentrated. Crystallization using heptane and drying under house vacuum (h.v.) afforded 74 g of expected product. MS m/z 292 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.O[CH2:31][CH2:32][N:33]([CH3:41])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:35][C:34](=[O:40])[N:33]([CH2:32][CH2:31][N:19]1[C:18](=[O:23])[C:17](=[CH:16][C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]3)[S:21][C:20]1=[O:22])[CH3:41])([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Product: CN(CCN1C(=O)SC(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O)C(=O)OC(C)(C)C

Procedure:
(2-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}ethyl)methylcarbamic acid tert-butyl ester was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate following General Procedure J.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([OH:18])=O)[CH3:3].[Cl-].[NH4+].C([N:23](CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:1][CH:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([NH2:23])=[O:18])[CH3:3]
Reactant: CC(C)Nc1cc(-c2ccncc2)sc1C(=O)O
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC(C)Nc1cc(-c2ccncc2)sc1C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
A mixture of 3-[(1-methylethyl)amino]-5-(pyridin-4-yl)thiophene-2-carboxylic acid (0.225 g, 0.858 mmol), ammonium chloride (0.459 g, 8.58 mmol) and triethylamine (1.21 mL, 8.58 mmol) in DMF (5 mL) was stirred at room temperature for 15 min. To the resulting mixture was added 1-(3-(dimethylamino)propyl)-3-ethyl carbodiimide hydrochloride (0.493 g, 2.57 mmol), and 1-hydroxybenzotriazole (0.347 g, 2.57 mmol) and the reaction was stirred at room temperature for 65 h. Then, the reaction mixture was diluted with sat. NaHCO3 (120 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×50 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated to give crude 3-[(1-methylethyl)amino]-5-(pyridin-4-yl)thiophene-2-carboxamide (0.225 g) as an orange solid. A mixture of 3-[(1-methylethyl)amino]-5-(pyridin-4-yl)thiophene-2-carboxamide (0.105 g) and 2-methoxypropene (1.53 mL, 16.0 mmol) in acetic acid (1.5 mL) was heated at 35° C. overnight. Then, the reaction mixture was cooled to room temperature and concentrated. The obtained residue was dissolved in methanol (10 mL), and the solution was concentrated with NaHCO3 (1 g) and silica gel (5 mL), and the residue was purified by flash chromatography (Combiflash, silica gel, ethyl acetate to 95:5 ethyl acetate /methanol) to give the title compound (0.063 g, 2 step yield 52%) as an orange solid:
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]([C:14]([F:17])([F:16])[F:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.O[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[CH2:23][CH2:22]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:8]1([C:6]2[CH:7]=[C:3]([CH2:2][O:1][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[CH2:23][CH2:22]4)[S:4][C:5]=2[C:14]([F:17])([F:15])[F:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCc1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: O=C1CCc2cc(O)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2cc(OCc3cc(-c4ccccc4)c(C(F)(F)F)s3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A solution of 0.25 g (0.97 mmol) of 2-hydroxymethyl-4-phenyl-5-trifluoromethyl-thiophene (from Step D), 0.17 g (1.16 mmol) of 5-hydroxy-1-indanone and 0.31 g (0.16 mmol) of triphenylphosphine in 2.5 mL of THF at 0° C. was treated with 0.18 mL (0.16 mmol) of diethylazodicarboxylate. The resulting mixture was warmed to rt, and stirred for 2 h. The reaction was loaded onto silica gel and eluted with 33% ethyl acetate/hexanes to give 0.35 g (0.90 mmol, 78%) of the title compound as a white solid: 1H NMR (500 MHz) δ 7.76 (d, J=8.3 Hz, 1H), 7.42–7.47 (m, 5H), 7.14 (s, 1H), 7.01–7.03 (m, 2H), 5.34 (s, 2H), 3.15 (t, J=5.9 Hz, 2H), 2.72 (t, J=6.0 Hz, 2H); ESI-MS 388.9 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([Cl:17])[N:13]=[CH:12][C:11]=2[C:10]([C:18](O)=[O:19])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28][NH2:29].C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([Cl:17])[N:13]=[CH:12][C:11]=2[C:10]([C:18]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:32]([F:33])=[C:25]([F:24])[CH:26]=2)=[O:19])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: CC(C)c1c(C(=O)O)c2cnc(Cl)cc2n1Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cnc(Cl)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-benzyl-6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid (Compound 15, 138 mg, 0.42 mmol) and 3,4-difluorobenzylamine (0.15 ml, 1.26 mmol) in DMF (4.0 ml) was added EDC (121 mg, 0.63 mmol) and DMAP (77 mg, 0.63 mmol). The mixture was stirred at room temperature for 16 h and was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a light yellow solid.
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([B:11]([OH:13])[OH:12])[C:4]=2[O:3]1.[Li][CH:16](CC)C.C1CCCCC1.CI>C1COCC1>[F:14][C:2]1([F:1])[O:6][C:5]2[C:7]([CH3:16])=[CH:8][CH:9]=[C:10]([B:11]([OH:13])[OH:12])[C:4]=2[O:3]1
Reactant: OB(O)c1cccc2c1OC(F)(F)O2
Reactant: [Li]C(C)CC
Solvent: CI
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)c2c1OC(F)(F)O2
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
(2,2-difluoro-1,3-benzodioxol-4-yl)boronic acid (Intermediate 35, crude material) was dissolved in THF (20 mL) and the resulting solution cooled down to −78° C. sec-BuLi 1.4M solution in cyclohexane (17.4 ml, 24.36 mmol) was added dropwise and the reaction mixture was stirred for 1.5 hours at −78° C. Methyl iodide (4.6 ml, 73 mmol) was then added and the reaction mixture was stirred for 2 hours while the temperature was allowed to reach room temperature. The reaction was quenched by addition of an aqueous 2N solution of HCl and diluted with ethyl acetate. The organic layer was collected and then washed twice with brine, dried over Na2SO4 and evaporated to dryness. Crystallization from n-heptane afforded the title compound (150 ma) as white solid.