Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[CH:20]=[CH:21][N:22]=[C:23]2[C:28]=1[N:27]=[C:26]([O:29][CH3:30])[CH:25]=[CH:24]2>>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[N:27]=3)[N:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCCNCC1
Reactant: COc1ccc2nccc(Br)c2n1
Product: COc1ccc2nccc(N3CCCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
According to procedure F and starting from [1,4]diazepane-1-carboxylic acid benzyl ester and 8-bromo-2-methoxy-[1,5]naphthyridine the title compound was isolated as a brown oil (4.18 g, 62%).
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[C:14]([C:19](O)=[O:20])=[CH:15][C:16]([F:18])=[CH:17][C:11]=2[N:10]=1.[CH3:23][C:24]1([CH3:38])[O:28][C@@H:27]([CH2:29][O:30][C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH2:26][O:25]1>>[F:22][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([C:19]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([O:30][CH2:29][C@H:27]4[CH2:26][O:25][C:24]([CH3:38])([CH3:23])[O:28]4)[CH:32]=3)=[O:20])[C:12]=2[N:13]=1
Reactant: O=C(O)c1cc(F)cc2nc(-c3ccccc3C(F)F)[nH]c12
Reactant: CC1(C)OC[C@H](COc2cccc(N)c2)O1
Product: CC1(C)OC[C@H](COc2cccc(NC(=O)c3cc(F)cc4[nH]c(-c5ccccc5C(F)F)nc34)c2)O1
Yield: 48 %

Procedure:
2-(2-(difluoromethyl)phenyl)-5-fluoro-1H-benzo[d]imidazole-7-carboxylic acid (145; 250 mg, 0.82 mmol) was coupled with (S)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)aniline 146 (prepared as described for 133 in Example 33, steps 1-2, except using (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane in step 1) as outlined earlier. (S)-2-(2-(Difluoromethyl)phenyl)-N-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-6-fluoro-1H-benzo[d]imidazole-4-carboxamide 147 was obtained in 48% yield (200 mg). MS (ESI) calcd for C27H24F3N3O4: 511.17; found: 512 [M+H].
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:29])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH2:27][CH3:28])[N:6]=2.[CH3:30][C:31]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([CH3:34])[CH2:32][OH:33]>>[CH2:27]([C:19]1[N:18]([C:7]2[N:6]=[C:5]3[C:10]([N:11]=[C:3]([CH2:2][N:38]4[CH2:39][CH2:40][CH:35]([C:31]([CH3:34])([CH3:30])[CH2:32][OH:33])[CH2:36][CH2:37]4)[N:4]3[CH3:29])=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=1)[CH3:28]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(C)(CO)C1CCNCC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)CO)CC3)n(C)c2n1

Procedure:
Following General Procedure E for amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 2-methyl-2-(piperidin-4-yl)propan-1-ol were reacted to give 341. LCMS: M+H+=533.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=O.N1CCCCC1.C(O)=O.[CH3:23][C:24](=[O:29])[CH2:25][C:26](=[O:28])[CH3:27]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:25]([C:24](=[O:29])[CH3:23])[C:26](=[O:28])[CH3:27])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CC(=O)CC(C)=O
Reactant: CS(=O)(=O)c1ccc(C=O)cc1F
Solvent: C1CCNCC1
Solvent: O
Solvent: O=CO
Product: CC(=O)C(=Cc1ccc(S(C)(=O)=O)c(F)c1)C(C)=O
Temperature: 20 °C

Procedure:
To a solution containing 0.93 g 3-fluoro-4-methylsulfonylbenzaldehyde, 0.05 ml piperidine and 0.02 ml formic acid in 20 ml DMF was added 1.04 ml 2,4-pentanedione with stirring at 20° C. The solution was stirred overnight at 20° C. and poured into water. The product was extracted with ethyl acetate and washed with water and evaporated to dryness in vacuo. The residue was crystallized from methanol, yield 0.48 g (30%), mp. 140-143° C. 1H-NMR (DMSO-d6, 400 MHz): 2.28 (s, 3 H, CH3), 2.50 (s, 3 H, CH3), 3.36 (s, 3 H, CH3), 7.47 (m, 1 H, Ar), 7.93 (m, 2 H, Ar), 7.76 (s, 1 H, CH).
Reaction SMILES: [N:1]1([CH2:6][CH:7]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH2:16])=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:16][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH:7]([CH2:17][O:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(COCC(Cn2ccnc2)OCCCCCC(N)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(COCC(Cn2ccnc2)OCCCCCCN)cc1
Temperature: 25 °C

Procedure:
6-[2-(1H-Imidazol-1-yl)-1[[4-methoxyphenyl]methoxy]methyl]ethoxy]hexanamide (Example 20, 0.3 g, 0.0008 mol) in dry tetrahydrofuran (2 ml) was added to a stirred suspension of lithium aluminium hydride (0.5 g, 0.013 mol) in dry tetrahydrofuran (10 ml) under a nitrogen atmosphere. The resulting suspension was stirred under reflux for 24 hours cooled to room temperature and the residual lithium aluminium hydride destroyed using ethyl acetate (15 ml) followed by dilute sodium hydroxide solution (2N, 20 ml), the resulting solution was filtered and the filter cake was washed with ethyl acetate (50 ml), the organic layer was separated, dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica gel, ethylacetate to 10% methanol in ethyl acetate) to yield the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17](=S)[CH2:18][C:19](=O)[CH3:20])=[O:4].[F:23][C:24]([F:29])([F:28])[CH2:25][NH:26][NH2:27]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:26]([CH2:25][C:24]([F:29])([F:28])[F:23])[N:27]=[C:19]([CH3:20])[CH:18]=1)=[O:4]
Reactant: NNCC(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1CC(F)(F)F

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-cyclopropylmethanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 445c) was reacted with 2,2,2-trifluoroethylhydrazine (CAS Reg. No. 5042-30-8) to give the title compound as brown solid. MS (ESI): m/z=409.9 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([NH:13][C:14]([C:16]3[C:17]4[CH:24]=[N:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[C:18]=4[CH:19]=[N:20][CH:21]=3)=[O:15])[CH2:12][CH2:11]2)[CH:5]=1.[NH3:33].CO>>[C:3]([C:4]1[CH:5]=[C:6]([C:10]2([NH:13][C:14]([C:16]3[C:17]4[CH:24]=[N:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[C:18]=4[CH:19]=[N:20][CH:21]=3)=[O:15])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)(=[O:2])[NH2:33]
Reactant: COC(=O)c1cccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)c1
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc(C2(NC(=O)c3cncc4c3cnn4-c3ccc(F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 78 h

Procedure:
A solution of 3-(1-{[1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-cyclopropyl)-benzoic acid methyl ester (70.0 mg, 0.163 mmol) in a 7M solution of ammonia in methanol (1.00 mL, 7.00 mmol) is stirred at 120° C. in a sealed pressure tube. After 78 hours, the reaction vessel is cooled to room temperature, vented and opened. The reaction mixture is concentrated in vacuo, and the resulting residue is purified by silica gel chromatography eluting with a gradient of 0-10% methanol in methylene chloride to afford the title compound a solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[C:19]([CH2:26][CH3:27])=[N:20][CH:21]=[CH:22][C:23]=1[CH2:24][CH3:25]>CN(C=O)C>[CH2:26]([C:19]1[C:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[C:23]([CH2:24][CH3:25])[CH:22]=[CH:21][N:20]=1)[CH3:27]
Reactant: CCc1ccnc(CC)c1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccnc(CC)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (839 mg, 5.9 mmol) was dissolved in anhydrous DMF (30 mL), and then potassium carbonate (2.45 g, 17.7 mmol) and 3-(bromomethyl)-2,4-diethylpyridine (7.1 mmol) in DMF (10 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 3-10% DCM/MeOH to afford 2-{[(2,4-diethylpyridin-3-yl)methyl]sulfanyl-6-methylpyrimidin-4-ol (966 mg, 56% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.14-1.22 (m, 6H), 2.22 (s, 3H), 2.68 (q, J=7.5 Hz, 2H), 2.82 (q, J=7.5 Hz, 2H), 4.48 (s, 2H), 6.05 (bs, 1H), 7.08 (d, J=5.1 Hz, 1H), 8.32 (d, J=5.1 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:30][CH:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>>[CH3:30][CH:31]([S:33]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)(=[O:35])=[O:34])[CH3:32]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
[(R)-1-(Propane-2-sulfonyl)-pyrrolidin-3-yl]-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and propane-2-sulfonyl chloride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH2:24][C:25]4([OH:33])[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]4)=[CH:18][C:17]=3[CH3:34])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38].CO.[OH-].[Na+].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH2:24][C:25]4([OH:33])[CH2:26][CH2:27][S:28](=[O:32])(=[O:31])[CH2:29][CH2:30]4)=[CH:18][C:17]=3[CH3:34])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:35][CH2:36][C:37]([OH:39])=[O:38]
Reactant: CCOC(=O)CCc1ccc(NCc2cccc(-c3c(C)cc(OCC4(O)CCS(=O)(=O)CC4)cc3C)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCC2(O)CCS(=O)(=O)CC2)cc(C)c1-c1cccc(CNc2ccc(CCC(=O)O)c(F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
To a mixture of ethyl 3-(2-fluoro-4-[({4′-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl)methyl)amino]phenyl}propanoate (1.99 g, 3.40 mmol), methanol (24 mL) and tetrahydrofuran (7 mL) was. added 1 M aqueous sodium hydroxide solution (10.2 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and concentrated under reduced pressure to evaporate the organic solvent. The residue was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1-hexane/ethyl acetate=1/1) and recrystallized from ethyl acetate-hexane to give the title compound (1.47 g, yield 78%) as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([O:9]CCCC)=[CH2:8].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:44]1[CH:52]=[CH:51][C:47]([C:48]([OH:50])=[O:49])=[C:46]([CH3:53])[CH:45]=1.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)CCC>[C:7]([C:44]1[CH:52]=[CH:51][C:47]([C:48]([OH:50])=[O:49])=[C:46]([CH3:53])[CH:45]=1)(=[O:9])[CH3:8]
Reactant: C=COCCCC
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCCCO
Product: CC(=O)c1ccc(C(=O)O)c(C)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
16.6 g (120 mmol) of potassium carbonate, 30.1 g (300 mmol) of n-butyl vinyl ether, 44.9 mg (0.2 mmol) of palladium acetate and 0.247 g (0.6 mmol) of 1,3-bis(diphenylphosphino)propane were added to a suspension solution of 21.5 g (100 mmol) of 4-bromo-2-methylbenzoic acid and 64.5 g of n-butanol. After degassing and nitrogen-purging inside of the reactor, the mixture was refluxed for 5 hours. After cooling the reaction solution to 80° C., n-butanol and n-butyl vinyl ether were distilled off under reduced pressure. After adding 172 g of toluene and 108 g of water, the mixture was neutralized by adding 15.6 g (150 mmol) of concentrated hydrochloric acid, and the water phase was separated. The obtained toluene solution was analyzed by a quantitative analysis method using HPLC. A content of 4-acetyl-2-methylbenzoic acid was 16.9 g (yield 95%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]([N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1)([CH3:11])[CH3:10].[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH:9]([N:12]1[C:16]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:15][CH:14]=[N:13]1)([CH3:11])[CH3:10]
Reactant: CC(C)n1cccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccnn1C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a cold (−78° C.) solution of LDA (prepared from n-BuLi (7.99 mL, 1.6 M, 1.1 eq) and diisopropylamine (1.82 mL, 1.1 eq)) in THF, a solution of 1-isopropyl-1H-pyrazole (1.28 g, 11.6 mmol) in THF was added dropwise while keeping the temperature below −70° C. At the end of the addition, the mixture was stirred at −78° C. for 30 min. Tributyltin chloride (3.44 mL, 1.1 eq) was then added dropwise while keeping the temperature below −70° C. At the end of the addition, the mixture was stirred for 1 h at −78° C. and for 2 h at r.t. The solvent was removed in vacuo and the crude oil was dissolved into AcOEt. The organic phase was washed with water and dried over Na2SO4. The solution was concentrated in vacuo to afford a yellow oil (3.82 g, 82%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20][NH:21][CH:22]2[CH2:24][CH2:23]2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:26])=[C:7]([F:25])[CH:8]=2)[N:3]=1>C(O)C.O.C(OC(C)C)(C)C>[CH:22]1([N:21]2[C:2]3[N:3]=[C:4]4[CH:5]=[C:6]([F:26])[C:7]([F:25])=[CH:8][C:9]4=[CH:10][C:11]=3[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20]2)[CH2:24][CH2:23]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Solvent: CC(C)OC(C)C
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Temperature: 20 °C
Yield: 74.9 %

Procedure:
A stirred suspension of 5.27 g of ethyl 2-(2-chloro-6,7-difluoroquinoline-3-carbonyl)-3-cyclopropylaminoacrylate in 2.22 g of 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) and 120 cm3 of ethanol is heated at a temperature close to 75° C. for 35 minutes. After cooling to about 20° C., the reaction mixture is taken up in 100 cm3 of water and extracted once with 100 cm3 and twice with 50 cm3 of trichloromethane. The combined organic extracts are washed with 3 times 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (20 kPa) at a temperature close to 20° C. The dry extract obtained is taken up in 30 cm3 of diisopropyl ether, drained and recrystallized from a mixture of 75 cm3 of ethanol and 75 cm3 of dimethylformamide. 3.57 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 229°-230° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[CH3:11][C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:17]([C:15]3[S:16][C:12]([CH3:11])=[CH:13][CH:14]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: Cc1ccc(C=O)s1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: Cc1ccc(C2C3=C(CC(C)(C)CC3=O)NC3=C2C(=O)CC(C)(C)C3)s1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 5-methyl-2-thiophenecarboxaldehyde in an analogous manner to that described in Example 1 to give 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(5-methyl-2-thienyl)-1,8(2H,5H)-acridinedione. Crystallization from ethyl acetate/methanol gave a beige crystalline solid of melting point 266-268° C. (decomposition).
Reaction SMILES: [C:1]([C:4]#[CH:5])([CH3:3])=[CH2:2].C([Li])CCC.[CH:11]([CH:13]=[CH2:14])=[O:12].[NH4+].[Cl-]>CCCCCC.O1CCCC1>[CH3:2][C:1](=[CH2:3])[C:4]#[C:5][CH:11]([OH:12])[CH:13]=[CH2:14]
Reactant: C#CC(=C)C
Reactant: C=CC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CC(O)C#CC(=C)C
Temperature: 25 °C

Procedure:
10 g Isopropenylacetylene are taken up in abs. tetrahydrofuran and under an inert gas 94.5 ml of 1.6M solution of n-butyllithium in hexane added dropwise at -20°. The mixture is then cooled to -78° and 8.5 g of acrolein added dropwise. The reaction mixture is warmed to room temperature, poured into saturated aqueous NH4Cl and repeatedly extracted with ether. The organic phase is washed, dried and concentrated in vacuum. An oil is obtained.
Reaction SMILES: C(O)=[O:2].OO.[C:6]12(C)[C:12](C)(C)[CH:9]([CH:10]=[CH:11]1)[CH2:8][CH:7]2[S:15]([O-:18])(=[O:17])=[O:16].CC1C=CC=C(C)[NH+]=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>>[OH:2][CH:10]1[CH:11]2[CH:6]3[CH:7]([CH2:8][CH:9]1[CH2:12]3)[S:15](=[O:18])(=[O:17])[O:16]2
Reactant: O=CO
Reactant: CC1(C)C2C=CC1(C)C(S(=O)(=O)[O-])C2
Agent: Cc1cccc(C)[nH+]1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Product: O=S1(=O)OC2C(O)C3CC2C1C3
Temperature: 10 °C
Reaction time: 21 h

Procedure:
Into a three-necked flask having an inner volume of 300 mL equipped with a stirrer, a thermometer and a dropping funnel, the whole amount of “Aqueous Solution D” obtained above was charged, and cooled down to 10° C. 99% Formic acid (10.8 g, 0.232 mol) was weighed into a dropping funnel, and added dropwise to the reaction system so that the inner temperature of the reaction system was maintained in a range of 11 to 15° C. After that, the inner temperature was raised up to 50 to 52° C. by heating, and then 30% hydrogen peroxide aqueous solution (18.69 g, 0.165 mol) weighed and contained in another dropping funnel was added dropwise to the reaction system over 3 hours. After completion of the dropping, the inner temperature of the reaction system was also maintained at around 50° C. After 21 hours from completion of the dropping, the reaction liquid was analyzed by HPLC to confirm that conversion ratio of 2,6-dimethylpyridinium 5-bornene-2-sulfonate was 98.4%. After cooling down the reaction liquid to 15° C., sodium sulfite was added slowly to the reaction system so that the inner temperature of the reaction system was maintained in a range of 15 to 18° C. until a starch paper did not detect hydrogen peroxide. Subsequently, sodium hydrogen carbonate was added slowly to adjust pH of the reaction liquid at 7.0 so that the inner temperature of the reaction system was maintained in a range of 17 to 20° C. The reaction liquid was extracted with ethyl acetate (100 g) twice, the resultant organic layers were combined, and washed with water (25 g), then concentrated under the reduced pressure until the amount of the liquid became 37.4 g. Isopropyl ether (21.0 g) was added to the resultant concentrated liquid in a heated state at 50° C., then the mixture was cooled down to 5° C. at a rate of about 10° C./hour, to precipitate crystal of the product. After filtering the precipitated crystal, the filtered out crystal was washed with isopropyl ether (6.0 g) at 5° C., and dried at 40° C. for hours under the reduced pressure, to obtain 2-hydroxy-4-oxa-5-thiatricyclo[4.2.1.03,7]nonane 5,5-dioxide (7.86 g, purity: 98.1%, 0.041 mol). It should be noted that, yield of the product from 5-norbornene-2-sulfonyl chloride was 46.8%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]=1)[CH3:2].[CH3:17][NH:18][CH2:19][CH2:20][CH3:21].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([N:18]([CH3:17])[CH2:19][CH2:20][CH3:21])=[O:10])[CH:6]=1)[CH3:2]
Reactant: CCCNC
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
Mix 5-hydroxymethyl-isophthalic acid monoethyl ester (3.3 g, 14.7 mmol), N-methyl propylamine (1.5 mL, 14.7 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.8 g, 14.7 mmol), and 1-hydroxtbenzotriazole hydrate (2.0 g, 14.7 mmol) in dichloromethane (40 mL) and DMF (4 mL). Stir at room temperature for 3 h. Concentrate and redissolve in ethyl acetate (150 mL). Wash with aqueous sodium bicarbonate solution, aqueous ammonium chloride solution, water, saturated aqueous sodium chloride, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with ethyl acetate and hexanes) to give the title compound (2.5 g, 61%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([O:11]N2C(=O)CCC2=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:20]1.C(N(CC)CC)C>ClCCl>[OH:28][CH2:27][CH2:26][CH2:25][CH:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])[CH2:20]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: OCCCC1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC(CCCO)C1
Reaction time: 18 h
Yield: 87.3 %

Procedure:
1-({[(Phenylmethyl)oxy]carbonyl}oxy)-2,5-pyrrolidinedione (8.70 g), 34.9 mmol) was added portionwise to a stirred mixture of 3-(3-piperidinyl)-1-propanol (5.02 g, 35 mmol) and triethylamine (5 ml, 3.63 g, 35.9 mmol) in dichloromethane (100 ml) at room temperature. The resultant mixture was allowed to stand at room temperature for 18 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate (100 ml). The organic phase was dried (MgSO4), filtered and evaporated. The sample was purified by chromatography on silica (100 g cartridge loaded in dichloromethane) using a gradient of 0-100% ethyl acetate-cyclohexane over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a colourless liquid (8.45 g).
Reaction SMILES: [C:1]12[C:11](=[O:12])[O:10][C:8](=[O:9])[C:2]=1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2>C(OC(=O)C)(=O)C>[C@@H:2]12[C:8](=[O:9])[O:10][C:11](=[O:12])[C@@H:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2
Reactant: O=C1OC(=O)C2=C1CCCCC2
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)[C@@H]2CCCCC[C@H]12

Procedure:
Hydrogenation of this anhydride using platinic oxide in acetic anhydride according to the procedure set forth in Coll. Czech. Chem. Comm., Vol. 26, p. 262 (1961) yields (cis)-1,2-cycloheptanedicarboxylic anhydride. Treatment with water and recrystallization gives (cis)-1,2-cycloheptanedicarboxylic acid.