Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH2:13][OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>C(Cl)Cl>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26](=[O:27])[N:8]([CH2:9][CH2:10][C:11]([CH3:15])([CH3:16])[CH2:12][CH2:13][OH:14])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCNCCC(C)(C)CCO
Solvent: ClCCl
Product: CCCCCCCN(CCC(C)(C)CCO)C(=O)Nc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
Part C. A solution of the amine prepared in Part C (4.26 g, 18.6 mmol) in methylene chloride (20 mL) was cooled to 0° C., and a solution of 2,4-difluorophenyl isocyanate (2.20 mL, 18.6 mmol) in methylene chloride (20 mL) was added dropwise with stirring over 1 hour. After slow warming to ambient temperature over 18 hours, the reaction mixture was concentrated under vacuum, and the residual oil was purified by flash chromatography to afford N'-(2,4-difluorophenyl)-N-(3,3-dimethyl-5-hydroxypentyl)-N-heptylurea as a colorless oil (2.31 g, 6.01 mmol, 32%). 1H NMR (CDCl3) δ7.93(br q,1H,J=6.2Hz); 6.89-6.78(m,3H); 3.76(t,2H,J=6.3Hz); 3.38-3.24(m,4H); 2.36(br s,1H); 1.65-1.52(m,6H); 1.36-1.24(m,8H); 0.97(s,6H); 0.89(t,3H,J=6.6Hz).
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:8]=[C:7]2[Sn](CCCC)(CCCC)CCCC.Br[C:34]1[N:39]=[C:38]2[C:40]([C:62]([NH:64][C:65]([CH3:76])([CH3:75])[CH2:66][O:67][Si:68]([C:71]([CH3:74])([CH3:73])[CH3:72])([CH3:70])[CH3:69])=[O:63])=[CH:41][N:42]([C:43]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:37]2=[N:36][CH:35]=1>CN(C=O)C.[Cu]I.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>[Si:68]([O:67][CH2:66][C:65]([NH:64][C:62]([C:40]1[C:38]2=[N:39][C:34]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([O:3][CH:2]([F:1])[F:32])[CH:5]=4)[N:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:17])[CH3:18])[N:8]=3)=[CH:35][N:36]=[C:37]2[N:42]([C:43]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:41]=1)=[O:63])([CH3:75])[CH3:76])([C:71]([CH3:72])([CH3:73])[CH3:74])([CH3:70])[CH3:69]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(CCCN(C)C)c2ccc(OC(F)F)cc12
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN(C)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Temperature: 80 °C
Yield: 46.6 %

Procedure:
To a solution of 3-(5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (120 mg, 0.22 mmol) and 2-bromo-N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (200 mg, 0.26 mmol) in DMF (10 mL) were added CuI (30 mg, 0.16 mmol) and Pd(PPh3)4 (47 mg, 0.041 mmol), Then the reaction mixture was degassed by bubbling nitrogen for 3 minutes and refilled with nitrogen. The mixture was heated to 80° C. for 5 hours under nitrogen. After cooling to room temperature, water (50 mL) was added and product extracted with EtOAc (3×40 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (88 mg, crude) as a yellow oil. LCMS: (M+H)+=858.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:19]=[C:20]1[C:25]2=[CH:26][NH:27][C:28]([CH:29]=O)=[C:24]2[CH2:23][CH2:22][NH:21]1.N1CCCCC1>C(O)C>[N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[C:12]3=[CH:29][C:28]2[NH:27][CH:26]=[C:25]3[C:24]=2[CH2:23][CH2:22][NH:21][C:20]3=[O:19])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2cc(C(=O)N3CCOCC3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(C(=O)N3CCOCC3)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 5-(morpholine-4-carbonyl)-1,3-dihydro-indol-2-one (49.2 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 eq.) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([OH:14])[CH:5]=1.Cl[Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18].O>C1COCC1>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([O:14][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:5]=1
Reactant: Oc1cc(Br)c2ccccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](Oc1cc(Br)c2ccccc2c1)(C(C)C)C(C)C
Temperature: 0 °C
Yield: 95.8 %

Procedure:
Sodium hydride (0.38 g, 15.9 mmol) was added portionwise to a solution of 4-bromo-2-naphthol (3.54 g, 15.9 mmol) in THF (50 mL) with stirring at 0° C. under N2. Ater 0.5 h chlorotriisopropylsilane (3.06 g, 15.9 mmol) was added dropwise at 0. The solution was stirred at room temperature for 2 h, poured into water (200 mL), extracted with DCM (dichloromethane) (4×50 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was chromatographed on silica using hexanes as eluent. The solvent was removed under reduced pressure to give the title compound (5.78 g, 96%) as a colourless oil.
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[O:12][C:13]([C@H:15]1[C@H:20]([NH:21][C:22](=[O:24])[CH3:23])[C@@H:19]([NH:25][C:26]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:18]=[C:17]([C:43]([O:45][CH:46]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[O:16]1)=O.[CH2:59]([NH:62][CH2:63][CH2:64][CH3:65])[CH2:60][CH3:61]>O1CCCC1>[CH:46]([O:45][C:43]([C:17]1[O:16][C@@H:15]([C:13](=[O:12])[N:62]([CH2:63][CH2:64][CH3:65])[CH2:59][CH2:60][CH3:61])[C@H:20]([NH:21][C:22](=[O:24])[CH3:23])[C@@H:19]([NH:25][C:26]([NH:35][C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])=[N:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:18]=1)=[O:44])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CCCNCCC
Reactant: CC(=O)N[C@@H]1[C@@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C=C(C(=O)OC(c2ccccc2)c2ccccc2)O[C@H]1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)[C@H]1NC(C)=O
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a solution of (2R,3R,4S)-3-Acetylamino-4-[2,3-bis(tert-butoxycarbonyl)-guanidino]-3,4-dihydro-2H-pyran-2,6-dicarboxylic acid 6-benzhydryl ester 2-(2,3,4,5,6-pentafluoro-phenyl) ester (0.70 g) in dry tetrahydrofuran (5 ml) was added dipropylamine (0.141 g) and the reaction was stirred at 23° C. for 4 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel (Merck 9385, 50 g) using medium pressure (~4psi) and cyclohexane/ethyl acetate (1:1 v/v) as the eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a pale yellow foam. (0.341 g). 1H NMR (250MHz, D6 -DMSO) 11.46 (1H, s), 8.27 (1H, d, J=6.25 Hz), 8.16 (1H, d, J=7.5Hz), 7.48--7.27 (10H, m), 6.97 (1H, s), 6.14 (1H, d, J=5Hz), 5.18 (1H, m), 4.67 (1H, m), 4.10 (1H, m), 3.61--3.24 (3H, m), 3.14 (1H, m), 1.84 (3H, s), 1.60--1.34 (4H, m), 1.46 (9H, s), 1.40 (9H, s), 0.85 (3H, t, J=7Hz), 0.74 (3H, t, J=7Hz); Mass Analysis; C39H53N5O9. 1.0C6HF5O. Required: C, 58.75; H, 5.92; N, 7.61. Found C, 58.64; H, 5.75; N, 7.61.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[CH2:12]([C:16]1[N:17]([CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33])[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH2:13][CH2:14][CH3:15].[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:36][C:20]1[C:19]2[N:28]=[C:16]([CH2:12][CH2:13][CH2:14][CH3:15])[N:17]([CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33])[C:18]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: [NH4+]
Reactant: CCCCc1nc2cnc3cccnc3c2n1CCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloroperoxybenzoic acid (70% pure, 5.46 g, 22.16 mmol) (mCPBA) was added to a solution of 5-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one (3.44 g, 11.08 mmol, 1 eq) in chloroform (45 mL), and the reaction was stirred for one hour at ambient temperature and then cooled to 5° C. Ammonium hydroxide (10 mL) and p-toluenesulfonyl chloride (2.32 g, 12.19 mmol, 1.1 eq) were sequentially added and the reaction mixture was stirred at 5-10° C. for 1 hour, filtered, and then diluted with dichloromethane (100 mL) and saturated aqueous sodium bicarbonate (75 mL). The aqueous layer was extracted with dichloromethane (2×30 mL) and the combined organic solutions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a brown oil. The material was triturated with acetonitrile to afford 1.65 g of 5-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one. The filtrate from the trituration was purified by BIOTAGE HORIZON High-Performance Flash Chromatography (HPFC) instrument (eluting with chloroform/methanol/ammonium hydroxide (CMA) (80/18/2):chloroform ranging in ratios from 0:100 to 25:75) and subjected to trituration again in acetonitrile to produce an additional 0.240 g of material as an off-white powder, mp 168-169° C. Anal. calcd for C18H23N5O: C, 66.44; H, 7.12; N, 21.52. Found: C, 66.19; H, 7.08; N, 21.22.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].[CH2:25]1[C@@H:29]([C:30]([NH2:32])=[O:31])[NH:28][CH2:27][C@H:26]1[F:33].Cl>>[F:33][C@@H:26]1[CH2:27][N:28]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:24])[N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:29]([C:30]([NH2:32])=[O:31])[CH2:25]1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1
Agent: Cl
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4C[C@@H](F)C[C@H]4C(N)=O)cc2OCC3)n(C(C)C)n1
Yield: 42 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and 4-cis-fluoro-L-prolinamide hydrochloride with added TEA (2.5 eq.), were reacted and the crude product recrystallised from IMS/DCM to give 382 as a white solid (68 mg, 42%). LCMS: RT=2.58 min, [M+H]+441. 1H NMR 400 MHz (DMSO-d6) δ: 9.04 (1 H, s), 7.76 (1 H, s), 7.10 (1 H, s), 6.91 (1 H, s), 5.95 (1 H, s), 5.87-5.80 (1 H, m), 5.42 (1 H, s), 5.29 (1 H, s), 4.49-4.36 (5 H, m), 3.74-3.73 (2 H, m), 2.46-2.45 (1 H, m), 2.20 (3 H, s), 1.40 (6 H, dd, J=6.59, 3.37 Hz)
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:20])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19].CCN(C(C)C)C(C)C.F[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=1>CN1C(=O)CCC1>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[C:10]=1[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=1)=[O:20]
Reactant: Fc1cccc(C(F)(F)F)n1
Reactant: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1Nc1cccc(C(F)(F)F)n1
Reaction time: 0.33 h

Procedure:
To a microwave vial were charged N-[(1S,2S)-2-Aminocyclopentyl]-2,6-dimethoxybenzamide hydrochloride (Intermediate 5; 80 mg, 0.266 mmol) in dry NMP (1 ml). To this was then added DIPEA (138 μl, 0.798 mmol) and 2-fluoro-6-(trifluoromethyl)pyridine (CAS number 94239-04-0; 53 mg, 0.319 mmol). The reaction was subjected to microwave irradiation at 200° C. for 30 minutes and then at 250° C. for 20 minutes. The reaction mixture was directly purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:17][OH:18])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][C:5]1=[O:16].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Si:19]([O:18][CH2:17][CH:2]([OH:1])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][C:5]1=[O:16])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc2ncc(=O)n(CC(O)CO)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(=O)n(CC(O)CO[Si](C)(C)C(C)(C)C)c2c1
Reaction time: 12 h

Procedure:
1-(2,3-Dihydroxypropyl)-7-methoxyquinoxalin-2(1H)-one (3.06 g, 12.22 mmol) was dissolved in dichloromethane (75 ml). To the solution, tert-butyldimethylsilyl chloride (2.03 g, 13.44 mmol), triethylamine (2.21 ml, 15.89 mmol) and 4-dimethylamino pyridine (299 mg, 2.44 mmol) were added under cooling on ice, and the reaction mixture was stirred for 12 hours while the temperature was rising to room temperature. The reaction solution was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to yield 5.29 g (quantitative) of the title compound in the form of a dark orange oily product.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1>O.CS(C)=O>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)=[N:13][CH:14]=1
Reactant: Nc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11.2 g (0.2 mole) of potassium hydroxide in 15 ml of water are added dropwise under nitrogen atmosphere to 22 g (0.2 mole) of 4-aminophenol in 100 ml of diemthylsulfoxide. 36 g (0.2 mole) of 2-chloro-5-(trifluoromethyl)pyridine in 30 ml of dimethylsulfoxide are added dropwise at 25° C. The reaction mixture is stirred for 3 hours at room temperature, then poured into ice-water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated by evaporation. The residue is dissolved in ether and the ether solution is extracted with 1 N hydrochloric acid. The acid phase is made alkaline with concentrated NaOH solution and extracted with ether. The ether phase is dried over sodium sulfate and concentrated by evaporation, affording 4-(5-trifluoromethylpyridin-2-yl-oxy)aniline as a brown oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(OCC)(=O)C.CCCCCC>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:21][C:16]2[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]3[O:12][C:11]([CH3:23])=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)[C:14]=3[C:15]=2[CH3:22])=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1oc2c(C)c(C)c(NC(=O)c3ccc(F)cc3)c(C)c2c1-c1ccc(C(C)C)cc1
Yield: 72 %

Procedure:
By using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 72%. Melting point: 242-245° C. (Ethyl acetate-hexane).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[CH3:30].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:33])[CH:27]=[CH:28][C:29]=1[CH3:30]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(N=C=O)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1Cl
Temperature: 40 °C
Yield: 86.6 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol), 3-chloro-4-methylphenyl isocyanate (0.26 g, 1.6 mmol), and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at the same temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed, eluting with 95:5 methylene chloride-methanol, to provide 0.63 g of the product in 90% yield: mp 238-240° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.22 (s, 3H), 2.49-2.65 (m, 2H), 2.84-2.97 (m, 1H), 4.70 (d, J=6.0 Hz, 2H), 5.17 (dd, J=12.5 Hz, d=5.3 Hz, 1H), 6.81 (t, J=6.0 Hz, 1H), 7.10 (dd, J=8.3 Hz, J=2.0 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.75-7.85 (m, 3H), 8.90 (s, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 18.7, 22.0, 30.9, 38.7, 48.9, 116.4, 117.6, 121.9, 127.2, 127.5, 131.0, 131.6, 133.0, 133.7, 134.7, 139.5, 140.1, 155.1, 167.0, 167.6, 169.8, 172.8; Anal. calcd. for C22H19ClN4O5.0.25H2O: C, 57.52; H, 4.27; N, 12.19. Found: C, 57.80; H, 4.33; N, 11.83.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].[N:34]#[C:35]Br>C(Cl)Cl>[C:35]([N:17]1[CH2:16][CH2:15][CH:14]([C@H:12]2[CH2:13][C@H:11]2[CH2:10][CH2:9][O:8][C:7]2[N:6]=[CH:5][C:4]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:3][C:2]=2[CH3:1])[CH2:19][CH2:18]1)#[N:34]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)cnc1OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(CC(=O)OC(C)(C)C)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of tert-butyl (5-methyl-6-{2-[(1S,2R)-2-piperidin-4-ylcyclopropyl]ethoxy}pyridin-3-yl)acetate (770 mg, 2.1 mmol) in 15 mL of DCM was added K2CO3 (3 eq., 852 mg, in 5 mL of water) at room temperature followed by addition of cyanogen bromide (1.2 eq., 0.85 mL of 3M soln in DCM) at room temperature. The mixture was then stirred for 30 min at room temperature and then diluted with 20 mL DCM. The solution was washed with sat'd NaHCO3 aq. soln, separated, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. The residue was purified by ISCO column (40 g silica gel) using ethyl acetate in hexane (0-60%, 700 ml) to give the title compound. LCMS (ESI) m/z 400 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-])=O.[K+].[C:10]([C:13]1[CH:20]=[CH:19][C:16](C=O)=[CH:15][CH:14]=1)([OH:12])=[O:11].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[CH3:8][O:7][C:1]([CH:2]=[CH:3][C:16]1[CH:19]=[CH:20][C:13]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)=[O:6]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COC(=O)C=Cc1ccc(C(=O)O)cc1
Temperature: 0 °C

Procedure:
18.74 g (0.12 mol) of potassium monomethyl malonate were suspended in 18 ml of pyridine. 15.01 g (0.1 mol) of 4-carboxybenzaldehyde and 0.85 g (0.01 mol) of piperidine were added at room temperature with stirring and the mixture was boiled under reflux until the evolution of carbon dioxide had ceased (about 2 h). A further 60 ml of pyridine were added and the mixture was stirred under reflux for a further 1 h. The reaction mixture was treated with stirring with 500 ml of ice and 110 ml of concentrated hydrochloric acid. After the addition was complete, the mixture was stirred for a further 20 min, and the product was filtered off with suction, washed with water and recrystallized from isopropanol. Yield: 12.85 g (62%).
Reaction SMILES: N([O-])=O.[Na+].[N+]([O-])(O)=O.N[N:10]1[C:14]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)=[N:13][N:12]=[C:11]1[SH:20].C([O-])([O-])=O.[Na+].[Na+]>O>[SH:20][C:11]1[N:10]=[C:14]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[NH:13][N:12]=1
Reactant: Nn1c(S)nnc1-n1cccn1
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: Sc1n[nH]c(-n2cccn2)n1
Reaction time: 0.33 h
Yield: 50.1 %

Procedure:
Sodium nitrite (0.4 g) was added to 25 ml of conc HNO3 and 75 ml H2O (after R. A. Henry and W. G. Finnegan, J. Am. Chem. Soc., 76, 290 (1954) and C. A. Amsworth and R. G. Jones J. Am. Chem. Soc., 75, 4915 (1953). Solid 4-amino-3-mercapto-5-(1-pyrazolyl)-1,2,4-triazole (5 g) was added in small batches with stirriing while keeping the temperature below 40° C. After addition, the solution was stirred for 20 minutes and made basic by the addition of 15% aq. Na2CO3. The yellow solution was filtered and acidified with glacial acetic acid (25 ml). The tan precipitate was collected and boiled with ethanol to give 2.3 g of tan powder m.p. 245°-247°.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:13]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[S:3][C:4]3[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: Oc1ccc2nc(Br)sc2c1
Reactant: CC(C)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2nc3ccc(O)cc3s2)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
2-Bromo-6-hydroxybenzothiazole (345 mg, 1.5 mmol), 1-isopropyl-piperazine hydrochloride (271 mg, 1.65 mmol) and dry potassium carbonate (828 mg, 6.00 mmol), were dissolved in 6 mL, of dry N,N-dimethylformamide. The resulted pale brown solution was stirred at 100° C. for 18 h in a closed vial. The reaction mixture was evaporated, suspended in 20 mL of water and extracted with dichloromethane (3×15 mL). The combined organic layers were washed with saturated sodium bicarbonate and brine, then dried over MgSO4. After evaporation the residue was purified by column chromatography (Kieselgel 60) using chloroform-methanol 49:1 as the eluent. The title compound (76 mg, 0.27 mmol, 18%) was obtained as a white solid.