Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[CH:25]=3)[C:20]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)=[C:19]2[CH2:47][C:48]([CH3:54])([CH3:53])[C:49]([O:51]C)=[O:50])(=O)=O)C=CC=CC=1.[Na]>O>[CH2:1]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH:25]=2)[C:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[C:19]1[CH2:47][C:48]([CH3:54])([CH3:53])[C:49]([OH:51])=[O:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1S(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: O
Product: CC(C)(Cc1c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1Cc1ccccc1)C(=O)O

Procedure:
The title compound was prepared under the conditions described in Step A and Step B of Example 38, but substituting benzyl chloride for the benzenesulfonyl chloride from Example 38 (Step A). Anal. C, H, N for sodium salt 1/2 H2O Calc. C 71.66; H 5.36; N 4.52 Found. C 71.65; H 5.49; N 4.44.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20]CC)=[O:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.C(O)C.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCc3ccccc3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C(=O)O)cc3c2)cc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 89.6 %

Procedure:
Ethyl 7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (1.9 g) was dissolved in a mixed solvent of tetrahydrofuran (10 mL)-ethanol (10 mL), 1M aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at 50° C. for 45 min. The reaction solution was allowed to cool to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid. The obtained crystals were collected by filtration, and washed successively with water and diethyl ether to give the title compound (1.6 g, yield 89%) as a pale-orange solid. The pale-orange solid was recrystallized from ethanol-hexane to give pale-orange crystals. melting point 232-233° C.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:15]2[CH:16]=[N:17][C:10]3[N:9]([CH3:34])[C:8](=[O:35])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:12](=[O:13])[C:11]=3[C:14]=2[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[CH:24][CH:23]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(F)cc3)c(Oc3ccc(Cl)cc3)cnc21
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(F)cc3)c(Oc3ccc(Cl)cc3)cnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
To a solution of 3-(6-(4-chlorophenoxy)-5-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2-dihydro pyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (50 mg, 0.10 mmol) in THF (3 mL) and water (3 mL) was added LiOH.H2O (10 mg, 0.20 mmol). The reaction was stirred at RT for 15 min then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 6-(4-chlorophenoxy)-5-(4-fluorobenzyl)-3-(3-hydroxypropyl)-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 37% yield) as a white solid. 1H NMR (CDCl3) δ: 8.31 (s, 1H), 7.31-7.27 (m, 2H), 7.22 (dd, J=8.6, 5.5 Hz, 2H), 6.89 (t, J=8.7 Hz, 2H), 6.83-6.77 (m, 2H), 4.72 (s, 2H), 4.24 (t, J=6.1 Hz, 2H), 3.70 (s, 3H), 3.55 (dd, J=11.7, 6.2 Hz, 2H), 3.04 (t, J=6.9 Hz, 1H), 2.01-1.86 (m, 2H). LCMS: MH+ 470 and TR=2.811 min
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[F:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>>[F:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18]([N:6]1[CH:7]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[NH:26][CH:27]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:19]
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: c1ccc2[nH]ccc2c1
Product: O=C(c1ccc(F)cc1F)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
(2,4-Difluoro-phenyl)-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, 2,4-difluorobenzoyl chloride, and indole according to GP 2. Yield, 25%. 1H-NMR (DMSO-d6): δ=6.18 (d, br., J=1.4 Hz, 1H), 6.34 (d, br., J≈5 Hz, 1H), 6.82 (t, J≈7 Hz, 1H), 6.99-7.18 (m, 5H), 7.23-7.28 (m, 1H), 7.32 (s, br., 1H), 7.39-7.59 (m, 4H), 7.85 (s, br., 1H), 7.94 (dd, J=7.9 Hz, J=1.2 Hz, 1H), 8.07 (d, J=7.6 Hz, 1H), 10.71 (s, 1H); (+)-ESI-MS: m/z=437 [M+H]+, 320 [M-indole+H]+.
Reaction SMILES: NC1C(C(N)=[O:9])=C(N2CCC(C3N(C)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1.[NH2:34][C:35]1[C:40]([C:41]#[N:42])=[C:39]([N:43]2[CH2:48][CH2:47][CH:46]([C:49]3[N:50]([CH2:64][CH2:65][N:66]4[CH2:69][CH2:68][CH2:67]4)[CH:51]=[C:52]([C:54]4[CH:59]=[CH:58][C:57]([O:60][CH:61]([F:63])[F:62])=[CH:56][CH:55]=4)[N:53]=3)[CH2:45][CH2:44]2)[N:38]=[CH:37][N:36]=1>>[NH2:34][C:35]1[C:40]([C:41]([NH2:42])=[O:9])=[C:39]([N:43]2[CH2:48][CH2:47][CH:46]([C:49]3[N:50]([CH2:64][CH2:65][N:66]4[CH2:67][CH2:68][CH2:69]4)[CH:51]=[C:52]([C:54]4[CH:55]=[CH:56][C:57]([O:60][CH:61]([F:63])[F:62])=[CH:58][CH:59]=4)[N:53]=3)[CH2:45][CH2:44]2)[N:38]=[CH:37][N:36]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(OC(F)F)cc3)cn2CCN2CCC2)CC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: NC(=O)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(OC(F)F)cc3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-difluoromethoxy-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=513, obsd.=513).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:13]([C:22](O)=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:22](=[O:23])[C@@H:13]([NH:12][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([I:21])=[CH:19][CH:20]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Reactant: CCOC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](Cc2ccc(I)cc2)NC(=O)OC(C)(C)C)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 8, step 8.3, piperazine-1-carboxylic acid ethyl ester replacing piperazine-1-carboxylic acid butyl ester and Boc-Phe(4-I)-OH replacing intermediate 8.2.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16])=[C:2]=[O:3].[CH3:18][O:19][Si](C)(C)C>>[CH3:18][O:19][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:1]=[C:2]=[O:3]
Reactant: CO[Si](C)(C)C
Reactant: O=C=NCCCCCCCCCCCC(=O)Cl
Product: COC(=O)CCCCCCCCCCCN=C=O

Procedure:
0.1 mole 12-isocyanatododecanoic acid chloride was reacted as in Example 1 with 0.11 mole methoxytrimethyl silane at 75° C. until the acid chloride band at 1800 cm-1 had disappeared. The desired product was obtained after distillation.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]=O)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C(NCCCC)CCC.C1(=O)OC(=O)C2=CC=CC=C12.[N+:33]([CH:36](O)[CH3:37])([O-:35])=[O:34]>C(Cl)Cl>[CH2:8]1[O:7][C:6]2[CH:10]=[C:2]3[C:3]([CH:11]=[C:36]([N+:33]([O-:35])=[O:34])[CH2:37][O:1]3)=[CH:4][C:5]=2[O:9]1
Reactant: O=Cc1cc2c(cc1O)OCO2
Reactant: CC(O)[N+](=O)[O-]
Agent: O=C1OC(=O)c2ccccc21
Solvent: CCCCNCCCC
Solvent: ClCCl
Product: O=[N+]([O-])C1=Cc2cc3c(cc2OC1)OCO3
Temperature: 25 °C
Yield: 61.2 %

Procedure:
Aldehyde (2a) (6 g, 36.14 mmol) was dissolved in 300 ml of CH2Cl2 along with 3.1 ml of dibutylamine (18.16 mmol) and 10.72 g of phthalic anhydride in a two necked flask equipped with a Dean-Stark trap, a condenser and a dropping funnel. Nitroethanol (7 ml 97.69 mmol) was added dropwise over a period of 18 hours, while the solution was stirred at reflux. After addition, the reaction was stirred for an additional 24 hrs. The flask was then cooled to room temperature, filtered and the solution extracted with 2 M NaOH (300 ml×3) and brine (100 ml), then dried over MgSO4. The solvent was then evaporated to leave a concentrated solution which was passed through a short column of silica to remove dark polar impurities. The isolated material was recrystallized from methanol to give 4.89 g (61% yield) of the title compounds as red needles: mp 139° C.; 1H-NMR (CDCl3) δ 5.20 (s, 2, ArOCH2), 6.02 (s, 2, OCH2O), 6.49 (s, 1, ArH), 6.69 (s, 1, ArH), 7.75 (s, 1, ArCH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:20][CH2:21][N:22]2[CH2:25][CH:24]([N:26]3[CH2:31][CH2:30][CH:29]([F:32])[CH2:28][CH2:27]3)[CH2:23]2)[CH2:10][N:11](C)[C:12](=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[Cl:8].FC1C=CC(C(CCN2CC(N3CCSCC3)C2)CN(C)C(=O)OC(C)(C)C)=CC=1>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:20][CH2:21][N:22]2[CH2:25][CH:24]([N:26]3[CH2:31][CH2:30][CH:29]([F:32])[CH2:28][CH2:27]3)[CH2:23]2)[CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C[C@@H](CCN1CC(N2CCC(F)CC2)C1)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: CN(CC(CCN1CC(N2CCSCC2)C1)c1ccc(F)cc1)C(=O)OC(C)(C)C
Product: CNC[C@@H](CCN1CC(N2CCC(F)CC2)C1)c1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
The compound was synthesized in an analogous way to that of Method 3e but using tert-butyl {(2S)-2-(3,4-dichlorophenyl)-4-[3-(4-fluoropiperidin-1-yl)azetidin-1-yl]butyl}methylcarbamate rather than tert-butyl [2-(4-fluorophenyl)-4-(3-thiomorpholin-4-ylazetidin-1-yl)butyl]methylcarbamate (yield, 100%). 1H NMR (500 MHz, CD3OD): 1.9-2s 2.4 (m, 6H), 2.7 (s, 3H), 3.1-5.1 (cm, 15H), 7.4 (d, 1H), 7.7 (m, 2H), LCMS: m/z 389 (M+1)+.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1.[OH-].[K+].C1C2C(CCCC2)CCC1>[Cu].C(Cl)(Cl)Cl>[I:27][C:24]1[CH:25]=[CH:26][C:21]([N:8]2[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]2=3)=[CH:22][CH:23]=1
Reactant: Brc1ccc(I)cc1
Reactant: c1ccc2c(c1)Nc1ccccc1-c1ccccc1-2
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCC2CCCCC2C1
Solvent: ClC(Cl)Cl
Product: Ic1ccc(N2c3ccccc3-c3ccccc3-c3ccccc32)cc1
Temperature: 200 °C
Yield: 52.1 %

Procedure:
Eighteen point two (18.2) grams (75 mmol) of 9H-tribenz[b,d,f]azepin, 63.7 g (225 mmol) of 1-bromo-4-iodo-benzene, 5.0 g (90 mmol) of potassium hydroxide, and 2.0 g (31 mmol) of a copper powder were mixed with 50 ml of decalin and stirred by heating under a nitrogen gas current for about one week at outer temperature of 200° C. After the temperature of the reaction solution was lowered to near room temperature, chloroform was added thereto, and the solution was filtered through Celite to remove insoluble matters. Water was added to the filtrate, and the solution was subjected to extraction. The obtained concentrated reaction product was purified by silica gel column chromatography to obtain 17.4 g of 9-(4-iodophenyl)-tribenz[b,d,f]azepin (yield: 52%, a small amount of 4-bromophenyl compound was contained).
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1C=C[CH:13]=[CH:12][CH:11]=1>>[NH:10]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH:1]=[CH:13][CH:12]=[CH:11]1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccncc1
Product: C1=CNc2ccccc2C=C1

Procedure:
As described for Example 1, 5 mmol of 4- (2-methylbenzoyl)amino!benzoyl chloride is reacted with 5 mmol of 5,6-dihydro-7H-pyrimido 5,4-d! 1!benzazepine in pyridine to give the product as a solid.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.C([O-])(=O)C.[NH4+:10].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH:13]1[C:14]([CH:2]([NH2:10])[C:1]([OH:5])=[O:4])=[CH:15][CH:16]=[C:11]([OH:17])[CH:12]=1
Reactant: Oc1ccccc1
Reactant: O=CC(=O)O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Product: NC(C(=O)O)c1ccc(O)cc1
Yield: 28.9 %

Procedure:
30 g of an aqueous 40% glyoxylic acid solution are added to 70 ml of water, and 37.5 g of ammonium acetate and 22.5 g of phenol are added thereto under stirring. The mixture is stirred at room temperature for 41 hours. The crystalline precipitates are collected by filtration under cooling, and then successively washed with water and methanol. 7.8 g of DL-p-hydroxyphenylglycine are thereby obtained as white crystals. Yield: 28.9%, M.p. 225°-228° C. (decomp.).
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:19])[NH:11][C:12]3[C:17]/2=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)/[CH:3]=1.[F:20][C:21]1[N:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])/[C:9]/2=[C:4]1/[O:5][C:6]([CH3:8])([CH3:7])[C:2]([C:24]2[CH:25]=[N:26][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:3]/1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1Br
Reactant: OB(O)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1c1ccc(F)nc1
Temperature: 65 °C
Yield: 47 %

Procedure:
To a mixture of 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one (3.24 g, 10.0 mmol), 6-fluoropyridin-3-ylboronic acid (1.8 g, 12 mmol) in THF (150 mL), was added a solution of potassium carbonate (13.8 g, 100 mmol) in water (20 mL). The resulting mixture was deoxygenated by bubbling nitrogen through the reaction mixture for 3 minutes and palladium(O) tetrakis(triphenylphosphine) (578 mg, 5 mol %) was then added. The reaction mixture was heated at 65° C. for 18 hours. The reaction was cooled to room temperature and ethyl acetate (500 mL) added. The organic phase was washed with water (100 mL×2), dried over sodium sulfate, and evaporated to give the crude product, which was purified first by silica gel column chromatography (5% CH3OH/CH2Cl2 elution) and then by titration with ethyl acetate. The resulting product was isolated by filtration and dried under vacuum to provide 5-fluoro-3-[4-(6-fluoro-pyridin-3-yl)-5,5-dimethyl-5H-furan-(2E)-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (1.6 g, yield 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12]C(C)=O)[C:9]([S:16]([CH2:18][CH3:19])=[O:17])=[CH:8][C:4]=1[C:5]([OH:7])=O.CC(C)=O.ClC(OCC(C)C)=O.[CH:32]1([CH2:38][N:39]2[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O.C(N(CC)CC)C>[CH:32]1([CH2:38][N:39]2[CH2:43][CH2:42][CH:41]([NH:44][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([S:16]([CH2:18][CH3:19])=[O:17])[C:10]([NH2:12])=[CH:11][C:3]=3[O:2][CH3:1])[CH2:40]2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CCS(=O)c1cc(C(=O)O)c(OC)cc1NC(C)=O
Reactant: NC1CCN(CC2CCCCC2)C1
Agent: CC(C)COC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCS(=O)c1cc(C(=O)NC2CCN(CC3CCCCC3)C2)c(OC)cc1N
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
8.5 g of 2-methoxy-4-acetamino-5-ethylsulphinyl benzoic acid, 70 ml of acetone, 10 ml of water and 3 g of triethylamine are placed in a 250 ml flask fitted with an agitator, a thermometer and a dropping funnel. The solution is cooled to about 0° C., after which 4.2 g of isobutyl chloroformate is poured in drop by drop. It is agitated for 45 minutes at 0° C. then 6 g of 1-cyclohexylmethyl-3-amino-pyrrolidine is dripped in. It is reacted for 2 hours at room temperature, 50 ml of water is added and the acetone is evaporated under vacuum. 10 ml of soda and 50 ml of water are added to the aqueous residue and it is heated to reflux for 5 hours then cooled. The suspension is extracted twice with 50 ml of methylene chloride, and the organic phase is dried over magnesium sulphate and filtered. The filtrate is evaporated dry under vacuum, and the residue is dissolved in 70 ml of hot ethyl acetate. The product is re-crystallised by cooling and filtered. It is washed with a little ether and dried in an oven at 50° C.
Reaction SMILES: O1CCCC1.B.N1CCCCC1.CS(O)(=O)=O.[O:18]=[C:19]([N:33]1[CH2:38][CH2:37][N:36]2[C:39]([C:42]([F:45])([F:44])[F:43])=[N:40][N:41]=[C:35]2[CH2:34]1)[CH:20]=[C:21]([NH2:32])[CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31].N>O>[O:18]=[C:19]([N:33]1[CH2:38][CH2:37][N:36]2[C:39]([C:42]([F:45])([F:44])[F:43])=[N:40][N:41]=[C:35]2[CH2:34]1)[CH2:20][CH:21]([NH2:32])[CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: B
Agent: CS(=O)(=O)O
Agent: N
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCNCC1
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
In a 250 mL round bottom flask 1.0 M Borane tetrahydrofuran (37 mL) was taken. It was cooled to −10° C. and piperidine (3.14 g) was added dropwise at −10 to 5° C. After 30 min. methanesulfonic acid (6.0 mL) was added dropwise at −10 to 5° C. over a period of 15-30 min. Separately, 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (5.0 g) was added in small portions into the reaction mixture, keeping the temperature between −10 to −5° C. It was stirred for 1 h at −10 to −5° C. Reaction mixture was poured into cold water. It was basified by adding aq. ammonia solution. Product was extracted in an ethyl acetate. The organic layer was collected. It was washed with water and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-4.1 g, % Y-81.0%, % Purity by HPLC-84.5%).
Reaction SMILES: [BH4-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH:11]1[CH3:17])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]>C(O)C>[C:3]([N:10]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][C@@H:11]1[CH3:17])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H]1C[C@H](O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
213 mg (5.6 mmol) of NaBH4 were added portionwise at 0° C. to a solution of 1.0 g (4.7 mmol) 1-boc-2-methyl-piperidin-4-on in 10 mL of ethanol. The mixture was stirred at room temperature for 2 h. The solvent was removed by distillation and the remainder was dissolved in water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried over Na2SO4. After filtration the solvent was removed by distillation and the crude product was purified by column chromatography (n-heptane/ethyl acetate 1/1) to yield 367 mg (36%) of the cis-isomer 18 and 205 mg (20%) of the trans-isomer 19 in addition to 97 mg (10%) mixture of both isomers.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=1[OH:9].N(CCO)CCO.Cl>CC(C)=O.O>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=1[OH:9])=[O:4]
Reactant: Nc1cc(O)ccc1O
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: O
Solvent: OCCNCCO
Solvent: CC(C)=O
Product: O=C(CCl)Nc1cc(O)ccc1O

Procedure:
α-chloroacetylchloride (10.1 g, 0.128 mole) was added dropwise under stirring at room temperature to the 2-aminohydroquinone (4.16 g, 0.128 mole) in dry acetone (400 ml) and diethanolamine (2.04 ml, 0.128 mole). The reaction mixture was poured into water and hydrochloride acid (2,000 ml, pH 1), then extracted with ethylacetate (500 ml). The solvent was evaporated to dryness and the solid residue (4.20 g, 80%) was used without any further purification. The structure of the 2-(α-chloroacetamido)-hydroquinone was confirmed by NMR analysis.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[O:12][C:13]2[C:19]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]([CH3:31])[C:21]3=[O:32])=[C:18]([F:33])[CH:17]=[C:16]([Cl:34])[C:14]=2[N:15]=1>CN(C)C=O>[Cl:34][C:16]1[C:14]2[N:15]=[C:11]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:12][C:13]=2[C:19]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]([CH3:31])[C:21]2=[O:32])=[C:18]([F:33])[CH:17]=1
Reactant: Oc1ccccc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(Cl)oc23)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3nc(Oc4ccccc4)oc23)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of 2.0 grams (51 mmole) of 60% sodium hydride (in mineral oil) in 25 mL of N,N-dimethylformamide is cooled in an ice bath, and a solution of 5.3 grams (56.3 mmoles) of phenol in 25 mL of N,N-dimethylformamide is added dropwise during a five minute period. To this is added a solution of 20.3 grams (51 mmole) of 3-(2,4-dichloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione (as prepared in Example 24) in 25 mL of N,N-dimethylformamide. Upon completion of the addition the reaction mixture is allowed to warm to ambient temperature, where it stirs for about 18 hours. After this time the reaction mixture is concentrated under reduced pressure, yielding 3-(4-chloro-6-fluoro-2-phenoxybenzoxazol-7-yl]-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[NH:13][C:14]3[C:19]([C:20]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[CH:5]2.CC([O-])=O.[K+].[Br:31]Br>CC(O)=O.O>[Br:31][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:12]1[NH:13][C:14]3[C:19]([C:20]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8]2
Reactant: CCCCCc1c(-c2ccc3cc(O)ccc3c2)[nH]c2ccccc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCc1c(-c2ccc3c(Br)c(O)ccc3c2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
To a stirred solution of 2-(6-hydroxy-2-naphthyl)-3-pentyl-1H-indole (1.27 g, 3.85 mmol) in HOAc (25 mL) at 0° C. was added KOAc (0.453 g, 4.62 mmol). The reaction was stirred at this temperature for 10 min., and then a solution of Br2 (0.218 mL, 4.24 mmol) in HOAc (5 mL) was added dropwise to it over a period of ˜10 min. The reaction mixture was allowed to warm to rt and stirred for 4 h. The reaction mixture was then diluted with H2O (50 mL) and extracted with EtOAc (200 mL). The organic layer was washed with brine (20 mL) and then dried (Na2SO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 30% EtOAc:petroleum ether gradient) to afford the product (0.782 g, 50%) as a solid (inseparable mixture of mono- and di-bromo-substituted analogs which were separated in the next step); monobrominated compound: mass spectrum [(−) ESI], m/z 406/408 (M−H)− and dibrominated analog: mass spectrum [(−) ESI], m/z 486 (M−H)−.