Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([NH:43][C:44]([N:46]2[CH2:51][CH2:50][CH:49]([C:52]3[C:53](=[O:62])[NH:54][C:55]4[C:60]([CH:61]=3)=[CH:59][CH:58]=[CH:57][CH:56]=4)[CH2:48][CH2:47]2)=[O:45])[C:13]([NH:15][C@H:16]([C:29](=[O:42])[N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)[CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.FC(F)(F)C(O)=O>ClCCl>[NH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([NH:15][C:13](=[O:14])[C@H:12]([NH:43][C:44]([N:46]1[CH2:51][CH2:50][CH:49]([C:52]2[C:53](=[O:62])[NH:54][C:55]3[C:60]([CH:61]=2)=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH2:48][CH2:47]1)=[O:45])[CH2:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[NH:9][N:8]=[CH:7]2)[C:29](=[O:42])[N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=2)[CH2:34][CH2:35]1
Reactant: Cc1cc(C[C@@H](NC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C[C@@H](NC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N[C@@H](CCCCN)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12
Reaction time: 1 h
Yield: 72 %

Procedure:
To a suspension of tert-butyl (S)-5-((R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanamido)-6-oxo-6-(4-(pyridin-4-yl)piperazin-1-yl)hexylcarbamate (230 mg, 0.27 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) at 0° C. After 1 h at room temperature, the solvent was removed under high vacuum and then dissolved in methanol. The free base of title compound was liberated by passing the methanolic solution over Strata-X—C-33μ cation polymeric sorbent followed by elution with 3.0 M ammonia solution in methanol to give N-((R)-1-((S)-6-amino-1-oxo-1-(4-(pyridin-4-yl)piperazin-1-yl)hexan-2-ylamino)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide as a white solid in 72% yield. 1H-NMR (CD3OD) δ 8.08-8.07 (m, J=2, 2H), 7.95 (s, 1H), 7.61 (d, J=10 Hz, 1H), 7.51-7.44 (m, 3H), 7.29 (d, J=10 Hz, 1H), 7.23-7.19 (m, 1H), 7.11 (s, 1H), 6.79-6.78 (m, 2H), 4.80-4.77 (m, 2H), 4.60-4.55 (m, 1H), 4.11-4.04 (m, 2H), 3.82-3.80 (m, 2H), 3.66-2.78 (m, 11H), 2.51 (s, 3H), 1.87-1.11 (m, 11H; MS (ESI) 747 (M+H); Rf=1.64.
Reaction SMILES: Cl[C@H:2]1[CH2:7][C@@H:6]([O:8][CH2:9][O:10][CH3:11])[CH2:5][N:4]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:3]1.[CH:22]1[C:32]2[CH2:31][O:30][C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[NH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1>>[CH3:11][O:10][CH2:9][O:8][C@H:6]1[CH2:5][N:4]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C@@H:2]([CH2:3][N:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:32]=3[CH2:31][O:30][C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]2=3)[CH2:7]1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COCO[C@@H]1C[C@H](Cl)CN(CCc2ccc(OC)cc2)C1
Product: COCO[C@@H]1C[C@H](CN2c3ccccc3COc3ccccc32)N(CCc2ccc(OC)cc2)C1

Procedure:
(3S, 5R)-(+)-3-chloro-5-(methoxymethoxy)-1-(4-methoxyphenethyl)piperidine was coupled with 5,11-dihydrodibenzo[b,e][1,4]oxazepine as described in Example 1 to give (+)-5,11-dihydro-5-[[(2R, 4R)-4-(methoxymethoxy)-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]dibenzo[b,e][1,4]oxazepine in 4.30 g (72.6%) yield as pale yellow oil.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]1([CH2:39][NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>O.ClCCl>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([CH:17]=1)[C:14]([NH:40][CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(C(=O)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To solution of 8.5 parts of intermediate 18, namely 5-benzoyl-2-nitrobenzoic acid, in 66.5 parts of dichloromethane were added 5.3 parts of 1,1'-carbonylbis[1H-imidazole]. After stirring for 1 hour at room temperature, there were added 9.8 parts of benzenemethanamine. Stirring at room temperature was continued for 8 hours. The reaction mixture was diluted with 100 parts of water and acidified with HCl. The organic layer was separated, dried, filtered and evaporated. The residue was purified twice by column chromatography (silica gel; CHCl3 /CH3OH 98:2; CH3COOC2H5 /C6H5CH3 10:90). The eluent of the desired fractions was evaporated and the residue was crystallized from methylbenzene, yielding 8.1 parts (72.5%) of 5-benzoyl-2-nitro-N-(phenylmethyl)benzamide; mp. 167.4° C. (interm. 19).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[CH2:10])[CH2:7][CH:6]1[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].O[Li].O>CO.O>[C:15]([O:14][C:12]([NH:11][CH:6]1[CH2:7][C:8](=[CH2:10])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: C=C1CC(NC(=O)OC(C)(C)C)C(C(=O)OC)C1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: C=C1CC(NC(=O)OC(C)(C)C)C(C(=O)O)C1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution of 1.28 g of 35a in 30 ml of MeOH was added a solution of 0.42 g of LiOH.H2O in 10 ml of H2O and stirring was continued at 50° C. for 1 h. The solution was evaporated to approximately half of the volume, the aqueous layer was washed with Et2O, acidified with HCl, the suspension was filtered and the residue dried to give 1.13 g (93%) of the title compound 35b. MS: 242.4 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][C:8]([C:10]1[C:11]2[CH2:19][CH2:18][CH2:17][CH2:16][C:12]=2[S:13][C:14]=1[NH2:15])=[O:9])[CH3:6].O>N1C=CC=CC=1>[CH2:5]([O:7][C:8]([C:10]1[C:11]2[CH2:19][CH2:18][CH2:17][CH2:16][C:12]=2[S:13][C:14]=1[NH:15][C:1](=[O:3])[CH3:2])=[O:9])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1c(NC(C)=O)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (62 mL) was added dropwise to a stirred solution of 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (125 g) in pyridine (750 mL) on an ice bath. After stirring at room temperature for 30 minutes, the solution was poured into water (2.2 L). The resulting solid was collected by filtration and washed with water, and then was dried overnight at 55° C. to provide the title compound (140 g) as a colorless solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:9]([CH2:14][O:15][CH:16]([F:18])[F:17])[C:10]([O:12]C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.C(OCC)(=O)C>[CH2:19]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]([CH2:14][O:15][CH:16]([F:18])[F:17])[C:10]([OH:12])=[O:11])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
Methyl 2-dibenzylamino-3-difluoromethoxy-propionate (1.2 g, 3.43 mmol) was stirred with 1N LiOH (10.3 mL, 10.3 mmol) in THF (40 mL) at 50° C. for 2 hours and then stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and acidified with 1N HCl. The organic layer was dried with sodium sulfate and concentrated with silica gel. The product was purified by column chromatography, eluting with 10-50% ethyl acetate in hexanes, to give 2-(dibenzylamino)-3-(difluoromethoxy)propanoic acid (730 mg, 63.5%) as a white solid. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.26-7.42 (m, 10H), 6.29 (bt, 1H), 4.45 (dd, 1H), 4.28 (dd, 1H), 3.94 (q, 4H) and 3.85 (m, 1H).
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C@H:3]1[O:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>ClCCl.CN(C1C=CC=CN=1)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:13]([O:12][C@@H:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C@H:2]1[O:1][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[O:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)CC(=O)O[C@@H]1C=Cc2ccccc2[C@H]1O
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)O[C@@H]1C=Cc2ccccc2[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 89.6 %

Procedure:
To a dried round bottom flask, 7 (270 mg, 0.98 mmol), imidazole (134 mg, 1.96 mmol), dimethylaminopyridine (6 mg, 0.05 mmol) were dissolved in dichloromethane (4 mL). Tert-butyldimethylsilyl chloride (222 mg, 1.47 mmol) was then added portionwise and allowed to react for 24 hours. The reaction was then quenched with water, extracted with dichloromethane, dried over Na2SO4 and concentrated in vacuo. Flash chromatography (10% ethyl acetate in hexanes) gave a colourless oil 8 (343 mg, 90%). Rf 0.48 on silica gel (10% ethyl acetate:hexanes. IR (KBr, cm−1) 2983 (w), 1731 (s), 1453 (w), 1370 (m), 1150 (s), 1031 (m); 1H NMR (400 MHz, CDCl3) δ 7.41-7.39 (1H, m), 7.24-7.22 (2H, m), 7.07-7.05 (1H, m), 6.47 (1H, dd, J=9.9, 1.8 Hz), 5.83 (1H, dd, J=9.7, 2.7 Hz), 5.60 (1H, ddd, J=9.3, 2.9, 2.0 Hz), 5.00 (1H, dd, J=9.3, 0.5 Hz), 4.22-4.15 (2H, m), 3.40 (2H, dd, J=19.6, 16.0 Hz), 1.57 (1H, s), 1.25 (3H, t, J=7.1 Hz), 0.92 (9H, s), 0.13 (3H, s), 0.09 (3H, s); 13C NMR (400 MHz, CDCl3) δ 166.3, 166.2, 136.2, 132.1, 129.4, 128.0, 127.9, 126.5, 125.9, 125.7, 76.4, 71.6, 61.6, 41.7, 25.8, 18.1, 14.0, −4.3, −4.5. HRMS calcd for C17H21O5Si (M+-C4H9): 333.1158. Found: 333.1149.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH3:13][Mg]Br.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:12])[CH3:13]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)C(=O)Nc2ccc(Br)cc21
Temperature: 25 °C
Yield: 28.7 %

Procedure:
A solution of 5-bromoisatin (5.0 g, 22 mmol) in dry THF (50 cm3) under N2 was cooled to 0° C. and treated drop-wise with methyl magnesium bromide (3M in diethylether, 14.7 cm3, 44 mmol) and the mixture was allowed to warm up-to room temperature. The reaction was poured into sat. ammonium chloride solution, then extracted into EtOAc (×3). The combined organic layers were then washed with water, brine, dried (MgSO4) and evaporated. The residue was then purified by column chromatography (SiO2, EtOAc:hexane, gradient elution) to afford 5-bromo-3-hydroxy-3-methyl-1,3-dihydro-indol-2-one (1.53 g, 6.32 mmol, 29%): 1H NMR (DMSO-d6) δ 1.38 (s, 3H), 5.99 (s, 1H), 6.77 (d, 1H, J=1.7 Hz), 7.38 (s, 1H, br); MS ((−) ESI) m/z 240/242 (M)−.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][CH:13]=[C:9]3[N:8]=[C:7]([CH2:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[CH:6]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.CN([CH:31]=[O:32])C>>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:31]=[O:32])=[C:9]3[N:8]=[C:7]([CH2:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1cccc(Cc2cc(NC3CC3)n3nccc3n2)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc(Cc2cc(NC3CC3)n3ncc(C=O)c3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To 3-((7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile (69 mg, 0.24 mmol) in DMF (0.6 mL), POCl3 (130 μL, 1.4 mmol) was added at room temperature. After the addition was complete, the reaction was stirred for 1 hour at room temperature. Then, the reaction was quenched by addition to ice cold 6N NaOH. The mixture was diluted with water and the solid was collected by filtration. The solid was washed several more times with water then dried under vacuum overnight. The product, 3-((7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile, was collected as a solid in 37% yield. LCMS (M+1=318)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:10]2=[O:19])=[CH:5][CH:4]=1)[CH3:2].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[C:22](=[O:23])[CH2:21][N:16]1[CH2:17][CH2:18][C:11]2([C:10](=[O:19])[N:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:13][CH2:12]2)[CH2:14][CH2:15]1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: CCc1ccc(N2CCC3(CCNCC3)C2=O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(N2CCC3(CCN(CC(=O)c4ccc(Cl)cc4Cl)CC3)C2=O)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
A mixture of 320 mg (1.24 mmol) 2-(4-ethylphenyl)-2,8-diazaspiro[4.5]decan-1-one, 431 mg (1.61 mmol) 2-bromo-1-(2,4-dichlorophenyl)ethanone and 376 mg (3.72 mmol) triethylamine in 50 mL DCM was stirred at 22° C. for 16 h. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 435 mg (79%) of the title compound as orange solid. MS m/e: 445.2 [M+H]+.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:20])=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)(=O)C.O.[CH2:22](O)[CH3:23].C(Br)C>[OH-].[Na+]>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[C:10]([C:15]([OH:17])=[O:16])=[CH:11][N:12]2[CH2:22][CH3:23])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cnc2cc(NC(C)=O)ccc2c1O
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCBr
Product: CCn1cc(C(=O)O)c(=O)c2ccc(N)cc21

Procedure:
4.6 Grams of ethyl 7-acetamido-4-hydroxy-3-quinolinecarboxylate are dissolved in 15 ml of 10% NaOH, 60 ml of H2O and 100 ml of ethanol, and 5 ml of ethyl bromide are added. The mixture is left under reflux for 4 hours, then the excess of ethyl bromide and ethanol is evaporated off, and 10 ml of 10% NaOH are then added. The mixture is heated under reflux for 2 hours, allowed to cool, acidified with HCl, filtered and treated with ethanol at 70° C. The product is filtered off and recrystallized in a dimethylformamide/water (1:1) mixture. 1.0 Gram of a solid is obtained, of melting point 304°-307° C.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:8]2[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:4][CH:3]=1.[CH:34]([N-]C(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:17])[CH3:18])=[CH:13][CH:14]=3)[C:9]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:8]2[CH:26]([CH3:34])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1c(Sc2ccccc2)c2cc(C(C)C)ccc2n1Cc1ccc(Cl)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1c(Sc2ccccc2)c2cc(C(C)C)ccc2n1Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Example 6, Step 1, but using ethyl 1-(p-chlorobenzyl)-3-phenylthio -5-(i-propyl)-indole-2-acetate (Example 10, Step 1) as the starting material, lithium diisopropylamide as base, and tetrahydrofuran as solvent, ethyl 1-(p-chlorobenzyl)-α-methyl-3-phenylthio-5-(i-propyl)-indole-2-acetate was prepared.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][OH:6].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].O>CN(C=O)C>[O:6]([CH2:5][CH2:4][CH2:3][C:2]#[CH:1])[Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCCCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
5.00 g (59.4 mmol) of pent-1-yn-5-ol were dissolved in 50 ml of dry DMF, and 10.10 g (149 mmol, 2.5 eq.) of imidazole and 9.40 g (62.4 mmol, 1.1 eq.) of TBS-Cl were added. After 12 hours of stirring at RT, 250 ml of water were added and the mixture was extracted with 3×150 ml of MTBE. The organic phase was washed 3× with in each case 100 ml of water and then dried over MgSO4. Purification by column chromatography gave 11.10 g (53.5 mmol, 90%) of 5-(tert-butyldimethylsiloxy)pent-1-yne as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.[CH:15]1([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26]([CH:23]3[CH2:22][CH2:21][N:20]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:25][CH2:24]3)=[CH:34][CH:33]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1(N)CCCCC1
Reactant: O=C(O)c1ccc(C2CCN(C3CCCC3)CC2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCNC(=O)C1(NC(=O)c2ccc(C3CCN(C4CCCC4)CC3)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (0.74 mmol), 4-(1-cyclopentyl-piperidin-4-yl)-benzoic acid hydrochloride (0.74 mmol), HOBT (0.74 mmol), WSCD (0.74 mmol) and triethylamine (0.74 mmol) are dissolved in DMF (5 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 233-234° C., Rf=0.34 (CH2Cl2/MeOH (with 3N NH3)=9:1) is obtained.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([SiH2:17][O:18][C:19]([CH3:38])([CH3:37])[C:20]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:21]=1[S:22][C:23]1[C:24]([CH2:35]O)=[CH:25][CH:26]=[CH:27][C:28]=1[N:29]2[CH3:34])([CH3:16])([CH3:15])[CH3:14].[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:13]([SiH2:17][O:18][C:19]([CH3:38])([CH3:37])[C:20]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:21]=1[S:22][C:23]1[C:24]([CH2:35][N:43]3[C:39](=[O:49])[C:40]4[C:41](=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:42]3=[O:44])=[CH:25][CH:26]=[CH:27][C:28]=1[N:29]2[CH3:34])([CH3:14])([CH3:16])[CH3:15]
Reactant: CN1c2cccc(CO)c2Sc2c1cccc2C(C)(C)O[SiH2]C(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1c2cccc(CN3C(=O)c4ccccc4C3=O)c2Sc2c1cccc2C(C)(C)O[SiH2]C(C)(C)C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
1.62 ml (10.34 mmol) of diethyl azodicarboxylate were slowly added dropwise while cooling with ice and under argon to a solution of 3.09 g (7.97 mmol) of [6-(tert-butyl-dimethyl-silanyloxymethyl)-10-methyl-phenothiazin-4-yl]-methanol, 1.76 g (11.9 mmol) of phthalimide and 2.30 g (8.75 mmol) of triphenylphosphine in 65 ml of tetrahydrofuran. The reaction mixture was stirred at 0° for 3 hours and then worked-up analogously to that described in Example 2.1.1.ea. The residue was chromatographed on 500 g of silica gel with toluene/ethyl acetate (19:1), whereupon, after crystallization from ethanol/ethyl acetate, 3.22 g (78.2%) of 2-[6-(tert-butyl-dimethyl-silanyloxymethyl)-10-methyl-phenothiazin-4-ylmethyl]-2,3-dihydro-1H-isoindole-1,3-dione were obtained as a light yellow solid of m.p. 195°-196°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:31]=1[CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:31]=1[CH2:32][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(OC)c(O)c1
Reactant: Cc1cccc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC)c(OCc2c(C)cccc2C)c1
Temperature: 25 °C

Procedure:
A solution of Ethyl 3-hydroxy-4-methoxybenzoate (Step A, 9.10 g, 46.4 mmol) and diisopropyl azodicarboxylate (DIAD, 10.23 g, 50 mmol) in dry THF (20 ml) was added drop wise to a solution of 2,6-Dimethylbenzyl alcohol (6.94 g, 51 mmol) and triphenylphosphine (TPP, 13.27 g, 50 mmol) in dry THF (60 ml) at 0° C. under argon. The reaction mixture was warmed to room temperature for 4 hours or until all the starting material is consumed, diluted with ether and washed with water (2×). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:16]=1[CH:17]=[O:18]>CC(C)=O>[CH:17]([C:16]1[CH:19]=[C:20]([CH3:24])[C:21]([CH3:23])=[CH:22][C:15]=1[O:14][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:18]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(O)c(C=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C)c(C)cc1C=O

Procedure:
0.808 ml of ethyl bromoacetate and 1 g of potassium carbonate were added to a solution of 838 mg of 2-hydroxy-4,5-dimethylbenzaldehyde (J. Chem. Soc. (1953) 820) in 150 ml of acetone. The suspension obtained was heated to reflux overnight and then filtered. The filtrate was concentrated. The crude product was isolated by extraction and purified by chromatography on silica gel and yielded 952 mg of ethyl (2-formyl-4,5-dimethyl-phenoxy)-acetate as a pale yellow solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=O)=[CH:12][CH:11]=1.[CH3:20][O:21][C:22](=[O:27])[C@H:23](CO)[NH2:24]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14]2[O:16][CH:17]=[C:23]([C:22]([O:21][CH3:20])=[O:27])[N:24]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: COC(=O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Product: COC(=O)c1coc(-c2ccc(-c3nc4ccccc4[nH]3)cc2)n1

Procedure:
Using essentially the same procedures described in Examples 23 and 24 and employing methyl 4-(1-H-benzimidazol-2-yl)benzoate and serine methyl ester as starting materials the title compound was obtained and identified by NMR and mass spectral analyses. 1HNMR (400 MHz, DMSO-d6): 3.86 (s, 3H), 7.22-7.24 (m, 2H), 7.62 (d, J=3.2 Hz, 2H), 8.19 (d, J=7.6 Hz, 2H), 8.36 (d, J=8 Hz, 2H), 9.02 (s, 1H), 13.1 (s, 1H). LCMS (ESI+) 319 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[NH:22]1[CH:26]=[N:25][C:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[N:23]1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:24]2[N:25]=[CH:26][N:22]([C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=4)[N:3]=3)[N:23]=2)[CH:28]=1
Reactant: c1cncc(-c2nc[nH]n2)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4cccnc4)n3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.2) (0.16 g, 0.5 mmol) and 3-(1H-[1,2,4]-triazol-3-yl)-pyridine [CAS-No. 23195-63-3] (0.075 g, 0.51 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.095 g, 44%). MS (ISP) 437.3 [(M+H)+]; mp 190° C.