Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C@@H:15]1[C@:19]([Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([OH:20])[C@@H:18]([CH2:38][O:39][C:40]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[O:17][C@H:16]1[N:63]1[C:72]2[N:71]=[CH:70][N:69]=[C:67]([NH2:68])[C:66]=2[N:65]=[CH:64]1)=[O:7])#[N:2].[C:73](C1NN=NN=1)(=[O:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1.CC(C)=O.C(Cl)Cl>CCOC(C)=O>[C:73]([NH:68][C:67]1[C:66]2[N:65]=[CH:64][N:63]([C:72]=2[N:71]=[CH:70][N:69]=1)[C@@H:16]1[O:17][C@H:18]([CH2:38][O:39][C:40]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[C@@:19]([Si:21]([C:34]([CH3:35])([CH3:36])[CH3:37])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([OH:20])[C@H:15]1[O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:7])(=[O:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: O=C(c1ccccc1)c1nnn[nH]1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@H](OCCCCCNC(=O)OCCC#N)[C@@]2(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)[C@H](OCCCCCNC(=O)OCCC#N)[C@@]2(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of compound 54 (0.25 g, 0.25 mmol) and benzoyl-tetrazole (0.09 g, 0.50 mmol) in anhydrous CH2CN (0.5 mL) was stirred in a preheated bath at 65° C. for 1.5 h. After this time, the TLC (10% CH3COCH3/CH2Cl2) that the reaction was complete. The reaction mixture was cooled to room temperature and taken up in EtOAc (30 mL) washed with aq saturated sodium bicarbonate solution (2×15 mL) and water (15 mL) dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using 10% CH3COCH3/CH2Cl2 as the eluent and the appropriate fractions were combined and concentrated to give a colorless foam, yield (0.105 g, 50%). 1H NMR (CDCl3) d 11.21 (s, 1H), 8.58 and 8.56 (2s, 2H), 8.04 (d, 2H, J=7.3 Hz), 7.70-7.09 (m, 22H), 6.78 (d, 4H, J=8.0 Hz), 6.23 (d, 1H, J=4.6 Hz), 4.73-4.69 (m, 1H), 4.44-4.39 (m, 1H), 4.30-4.20 (m, 1H), 4.10 (t, 2H, J=6.1 Hz), 3.71 (s, 6H), 3.25-2.79 (m, 8H), 1.39-1.02 (m, 15H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][NH:29][C:30]([CH2:32][N:33]([CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH3:34])=[O:31]>>[CH3:28][NH:29][C:30]([CH2:32][N:33]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:40]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:41][CH:42]=1)[CH3:34])=[O:31]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CNC(=O)CN(C)Cc1ccc(N)cc1
Product: CNC(=O)CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-(methylcarbamoyl-methyl)-N-methyl-amino)-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C28H28N4O4
Reaction SMILES: CO.B(F)(F)F.[CH3:7]COCC.[CH3:12][N:13]1[C:17](=[O:18])[CH2:16][CH:15]([C:19]([OH:21])=[O:20])[CH:14]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:12][N:13]1[C:17](=[O:18])[CH2:16][CH:15]([C:19]([O:21][CH3:7])=[O:20])[CH:14]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN1C(=O)CC(C(=O)O)C1c1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C1CC(=O)N(C)C1c1ccccc1

Procedure:
To 400 ml. of methanol containing 25 ml. of boron trifluoride etherate was added 60 g of 1-methyl-5-oxo-2-phenylpyrrolidin-3-carboxylic acid and the solution refluxed for 8 hours. Concentration in vacuo provided an oil which was dissolved in chloroform. The chloroform solution was washed with a saturated sodium carbonate solution, a saturated sodium bicarbonate solution, water, a saturated sodium chloride solution and dried (Na2SO4). Titration and concentraion in vacuo provided 63 g. of an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:25])[CH3:26])[CH2:20][CH2:19]2)=[CH:3][C:2]([C:32]2[CH:33]=[C:28]([Cl:27])[C:29]([OH:44])=[C:30]([Cl:43])[CH:31]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure F, {6-bromo-4-[trans-4-(dimethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (45 mg, 0.110 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (38 mg, 0.135 mmol) to afford the desired product (32 mg, 58%) as a light yellow solid: NMR (500 MHz, CD3OD) δ 9.30 (s, 1H), 8.50 (s, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.78 (s, 2H), 4.47 (s, 1H), 3.45 (s, 1H), 2.91 (s, 6H), 2.85 (s, 1H), 2.51 (s, 2H), 2.31 (s, 2H), 1.91-1.74 (m, 4H), 1.31-1.18 (m, 4H); ESI MS m/z 498 [C27H29Cl2N3O2+H]+; HPLC 96.9% (AUC), tR=11.50 min.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:19]=[CH:18][C:12]([O:13][CH:14]2[CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[CH3:22][C:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.O>O1CCCC1>[CH3:22][C:23]([NH:26][C:27]([N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([C:8]([F:7])([F:20])[F:21])=[CH:19][CH:18]=2)[CH2:17]1)=[O:28])([CH3:25])[CH3:24]
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Reactant: CC(C)(C)N=C=O
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 18 h
Yield: 79 %

Procedure:
A stirred slurry of 6.2 g (0.02 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine oxalate in 60 ml of tetrahydrofuran was treated with 2 g (0.022 mole) of 1,1-dimethylethyl isocyanate and after 0.5 hr 5 ml of triethylamine was added. The reaction slurry quickly turned to a pale yellow solution which was stirred for 18 hr, then treated with 10 ml of water. After 20 min, the tetrahydrofuran portion was separated, dried over magnesium sulfate and concentrated on a rotary evaporator. The solid residue was recrystallized from isopropyl ether to yield 5 g (79.0%) of fine white crystals, m.p. 145°-146° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])=[CH:8][CH:7]=1)[CH3:2].Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:13](=[O:21])[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:20][C:24]2=[O:26])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2ccccc2N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [4-(2-amino-benzoylamino)-phenyl]-acetic acid ethyl ester (14.2 g, 47 mmol) and triphosgene (0.5 eq, 7.03 g, 23.5 mmol) in DCM (200 ml) is treated with DIPEA (2 eq, 16.5 ml, 94 mmol) dropwise via dropping funnel while stirring at RT. After 1 hour, the reaction mixture is diluted with DCM and washed with saturated aqueous NaHCO3. The separated organic layer is washed with distilled water (2×), dried over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained as pure white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:18]1(=[O:25])(=[O:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:21]3[CH2:22][CH2:23][S:18](=[O:25])(=[O:24])[CH2:19][CH2:20]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2ccc(N3CCS(=O)(=O)CC3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and tetrahydro-2H-1,4-thiazine 1,1-dioxide. Brown solid. MS (m/e): 353.0 ([M+H]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH3:10]
Reactant: Fc1ccc(S)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CSc1ccc(F)cc1Cl
Reaction time: 8 h
Yield: 101.6 %

Procedure:
To a stirred mixture of 2-chloro-4-fluorobenzenethiol (65 g, 0.403 mol) and potassium carbonate (54 g, 0.39 mol) in DMF (450 mL) was added drop wise CH3I (24.96 mL, 0.442 mol) at room temperature and the mixture was stirred overnight. The reaction mixture was diluted with water (200 mL) and extracted with ethyl ether (150 mL×3), the combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to give (2-chloro-4-fluorophenyl)(methyl)sulfane (70 g, 98%) as a yellow liquid. To a solution of (2-chloro-4-fluorophenyl)(methyl)sulfane (66 g, 0.37 mol) in dichloromethane (1600 mL) was added 3-chloroperoxybenzoic acid (85% purity, 157 g, 0.77 mol) in portions, and the mixture was stirred at room temperature for 2 h. The mixture was washed with aq. saturated sodium sulfite solution (600 mL). The organic phase was separated and sequentially washed with aq. sodium bicarbonate solution (250 mL×2) and water (250 mL), dried over Na2SO4 and evaporated under reduced pressure to give a yellow solid. The crude product was re-crystallized from ether (200 mL) to give the title compound (33.1 g, 43%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[Br:16][C:17]1[CH:28]=[CH:27][C:20]([C:21](N(C)OC)=[O:22])=[CH:19][CH:18]=1.O>C1COCC1>[Br:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]([C:6]2[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([F:1])[CH:7]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Reactant: COc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc(Br)cc2)cc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a stirred solution of 2-fluoro-4-bromoanisole (3.03 g, 14.8 mmol) in anhydrous THF (100 mL) was added n-butyllithium (1.6 M in hexanes, 10.2 mL, 16.3 mol) dropwise at −78° C. The reaction mixture was stirred for 1 h and 80 (4.02 g, 16.3 mmol) dissolved in THF (20 mL) was added dropwise. The reaction mixture was warmed to −20° C. over 1 h, water (100 mL) was added, and the volatiles were removed under reduced pressure. The mixture was extracted with ether (3×100 mL) and the combined extracts were washed with water (100 mL) and brine (100 mL). The mixture was dried over MgSO4 and concentrated. The residue was chromatographed on silica gel (20:1 to 5:1 hexanes:EtOAc) to afford 2.35 g (51%) of 81 as a white crystalline solid. 1H NMR (400 MHz, CDCl3): δ 3.97 (s, 3H), 7.01 (t, J=8.4 Hz, 1H), 7.55-7.62 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[F:16]C1C=C(C=CC=1)C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:16])[CH:7]=1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: O=Cc1cccc(F)c1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1cccc(F)c1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methylester but using 3-fluorobenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:26])[CH3:25])[N:16]=[CH:17][C:10]=2[N:9]([CH3:32])[C:8]1=[O:33])=O.O.O[Li].O>C1COCC1.CC(=O)OCC>[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH3:26])[CH3:25])[N:16]=[CH:17][C:10]=2[N:9]([CH3:32])[C:8]1=[O:33]
Reactant: CC(C)CCc1c(-c2ccccc2C(C)C)ncc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CCc1c(-c2ccccc2C(C)C)ncc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
To a solution of 3-(5-isopentyl-6-(2-isopropylphenyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (10 mg, 0.022 mmol in THF (0.5 mL) and water (0.5 mL) was added LiOH.H2O (1.8 mg, 0.044 mmol). The reaction was stirred at RT for 30 min then diluted with EA (5 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-5-isopentyl-6-(2-isopropylphenyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (2.2 mg, 23.6% yield) as a white solid. 1H NMR (CDCl3) δ: 8.66 (s, 1H), 7.41 (d, J=3.8 Hz, 2H), 7.26-7.23 (m, 1H), 7.11 (d, J=7.5 Hz, 1H), 4.28 (t, J=6.1 Hz, 2H), 3.72 (s, 3H), 3.65-3.54 (m, 2H), 3.35 (td, J=11.8, 4.5 Hz, 1H), 3.14 (t, J=6.6 Hz, 1H), 2.69 (d, J=11.9, 4.4 Hz, 1H), 2.53-2.40 (m, 1H), 2.04-1.91 (m, 2H), 1.45 (d, J=12.9, 6.4 Hz, 1H), 1.38-1.32 (m, 1H), 1.19 (d, J=6.9 Hz, 3H), 1.14 (dd, J=7.1, 4.8 Hz, 1H), 1.10 (d, J=6.8 Hz, 3H), 0.72 (d, J=6.6 Hz, 3H), 0.65 (d, J=6.6 Hz, 3H). LCMS: MH+ 424 and TR=3.102 min.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@@H:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]3[C@@H:18]([C:26]([OH:28])=[O:27])[O:17]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:29](OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>CO>[CH3:29][O:27][C:26]([C@@H:18]1[C@@H:19]2[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]2)[C@H:16]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][CH:14]=[N:15][C:7]=3[NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[O:17]1)=[O:28]
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(NC3CCCC3)ncnc21
Solvent: CO
Product: COC(=O)[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Yield: 74.2 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-(6-cyclopentylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (3.018 g) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.66 g) in methanol (120 ml) was heated under reflux for 17 h. The resulting mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (150 ml). The solution was washed with 0.5 M aqueous citric acid solution (3×25ml) and brine (50 ml), dried (magnesium sulphate), and evaporated in vacuo to give a white foam. Purification by column chromatography on silica gel, eluting with ethyl acetate:cyclohexane (1:1), gave the title compound as a white solid (2.32 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)[CH3:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1.[ClH:38].C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)C>[ClH:38].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:43])[NH2:27])=[CH:22][CH:21]=4)[CH3:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C#N)cc1)n2C)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1cccnc1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:42]=[CH:43][CH:44]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([CH2:27][C@H:28]([O:33][CH3:34])[C:29]([F:32])([F:31])[F:30])[C:24]([N:35]=CN(C)C)=[C:23]([F:40])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11][C:10]1=[O:41])([CH3:4])([CH3:3])[CH3:2]>[Cl-].[Cl-].[Zn+2].CCCCCC.CCOC(C)=O>[NH2:35][C:24]1[C:25]([CH2:27][C@H:28]([O:33][CH3:34])[C:29]([F:31])([F:32])[F:30])=[CH:26][C:21]([CH2:20][C@H:13]2[C@H:12]3[C@@H:17]([N:9]([CH2:8][C:7]4[CH:42]=[CH:43][CH:44]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=4)[C:10](=[O:41])[O:11]3)[CH2:16][S:15](=[O:19])(=[O:18])[CH2:14]2)=[CH:22][C:23]=1[F:40]
Reactant: CO[C@@H](Cc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N=CN(C)C)C(F)(F)F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CO[C@@H](Cc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N)C(F)(F)F

Procedure:
The title compound was prepared in analogous manner as described for example 1n) from N′-[4-[(3aR*,7S*,7aS*)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-fluoro-6-((S)-3,3,3-trifluoro-2-methoxy-propyl)-phenyl]-N,N-dimethyl-formamidine and ZnCl2 to yield a yellow oil: TLC (hexane-EtOAc 2:1) Rf=0.22; HPLC RtA=2.40 min; ESIMS [M+H]+=587.
Reaction SMILES: [NH2:1][C:2]1([CH2:20][CH3:21])[CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9](=[O:19])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][N:14]=3)[N:12]=[C:3]12.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30](O)=[O:31])[CH:25]=1.COC1N=CC=CC=1C(O)=O>>[CH2:20]([C:2]1([NH:1][C:30]([C:26]2[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[CH:28][N:27]=2)=[O:31])[CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9](=[O:19])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][N:14]=3)[N:12]=[C:3]12)[CH3:21]
Reactant: CCC1(N)CCCCn2c1nc(-c1ccncn1)cc2=O
Reactant: COc1ccnc(C(=O)O)c1
Agent: COc1ncccc1C(=O)O
Product: CCC1(NC(=O)c2cc(OC)ccn2)CCCCn2c1nc(-c1ccncn1)cc2=O
Yield: 31 %

Procedure:
By analogy with the method described in example 13 (step 13.5), using (+/−) 10-amino-1 0-ethyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one and 4-methoxy-pyridine-2-carboxylic acid in place of (+)10-amino-10-methyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one and 2-methoxy nicotinic acid, 37 mg (31%) of the compound was obtained as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=3)[N:18]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[CH:17]=2)=[O:15])=[N:10][CH:9]=1)C.C1(CN2C3C(=CC=C(F)C=3)C(C(NC3SC=C(SCC(O)=O)N=3)=O)=C2)CC1>>[CH:30]1([CH2:29][N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:16]([C:14]([NH:13][C:11]3[S:12][C:8]([S:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:9][N:10]=3)=[O:15])=[CH:17]2)[CH2:31][CH2:32]1
Reactant: CCOC(=O)CCSc1cnc(NC(=O)c2cn(CC3CC3)c3cc(C(F)(F)F)ccc23)s1
Agent: O=C(O)CSc1csc(NC(=O)c2cn(CC3CC3)c3cc(F)ccc23)n1
Product: O=C(O)CCSc1cnc(NC(=O)c2cn(CC3CC3)c3cc(C(F)(F)F)ccc23)s1

Procedure:
3-{2-[(1-Cyclopropylmethyl-6-trifluoromethyl-1H-indole-3-carbonyl)-amino]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester was hydrolysed according to the procedure given in the procedure for the synthesis of {2-[(1-cyclopropylmethyl-6-fluoro-1H-indole-3-carbonyl)-amino]-thiazol-4-ylsulfanyl}-acetic acid
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7](=[S:14])[C:8]3[C:9](=[CH:11][S:12][CH:13]=3)[NH:10][C:4]=2[CH:3]=1.O1CCOC[CH2:18]1.[OH-].[K+].COS([O-])(=O)=O>CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([S:14][CH3:18])[C:8]3[C:9](=[CH:11][S:12][CH:13]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: S=C1Nc2ccc(Cl)cc2Nc2cscc21
Reactant: C1COCCO1
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSC1=Nc2ccc(Cl)cc2Nc2cscc21
Reaction time: 3 h

Procedure:
To a stirred suspension of 0.7 g. of 6-chloro-4,9-dihydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-thione in 10 ml. of dioxane is added dropwise and simultaneously at 30°-40°C., a solution of 0.95 g. of potassium hydroxide in 10 ml. of methanol and 0.8 g. of methylsulfate. After addition is complete, the mixture is stirred for 3 hours, diluted with methanol and filtered. The filtrate is concentrated to 20 ml. and diluted with water. The precipitate is collected, washed with water and recrystallized from methanol-water to give yellow crystals, m.p. 152°-154°C.
Reaction SMILES: COC([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:18])=[CH:7][CH:6]=1)=O.[CH3:26][OH:27]>C(OCC)(=O)C>[CH3:26][O:27][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]([S:11][C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=1[C:19]([O:21][CH3:22])=[O:20])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20]
Reactant: COC(=O)c1ccc(SC2(C(=O)OC(C)(C)C)CCCCC2=O)cc1
Reactant: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC(Sc1ccccc1C(=O)OC)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
1 g (30.2 mmol) of 2-(4-methoxycarbonylphenylthio)-2-tert. butoxycarbonylcyclohexanone is dissolved, together with 0.37 g (3.3 mmol) of potassium tert. butylate, in 100 ml of methanol of reagent purity and the solutions is left to stand for 2 hours at room temperature. It is then diluted with 500 ml of ethyl acetate and the organic phase is washed with water and a saturated sodium chloride solution, dried with sodium sulphate and concentrated by evaporation. After drying in a high vacuum 11.3 g of an oily product are obtained, which is sufficiently pure to be used for further reactions.
Reaction SMILES: CS[C:3]([S:13][CH3:14])=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9]N=1)=[O:6].[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16].[CH3:24]C(C)([O-])C.[K+]>C1COCC1>[C:7]1([C:5](=[O:6])[CH:4]=[C:3]([S:13][CH3:14])[CH2:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH:24]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CSC(=CC(=O)c1ccccn1)SC
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Product: CSC(=CC(=O)c1ccccc1)CC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Ketene dithioacetal (Product A) (2.0 g, 0.0089 mol) was added to a solution of acetophenone (1.07 g, 0.0089 mol) and potassium tert-butoxide (2.0 g, 0.0178 mol) in dry THF (20 mL). The temperature of the reaction mixture was raised to 60° C. and the mixture was stirred for 1 hour during which time an orange-red precipitate formed. This was collected and added to an ice-cold HCl solution (4% acid) and the oily material which separated allowed to crystallize. The brown solid was collected and recrystallized from benzene: petroleum ether (b.p. 80°-100° C.) from which it separated as pale-yellow prisms: 1.8 g (70%), m.p. 106°-108° C.: IR (KBr)νCO 1680, 1630 cm-1 ; NMR (CDCl3)δ8.0-7.56 (m, 10, aromatic), 6.82 (s,1, vinylic), 4.64 (s,2,CH2), 2.59 (s,3,SCH3); M.+ 296 (7%).