Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[N:24][CH:25]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:29]1[CH2:30][CH:31]=[C:26]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][N:24]=2)[CH2:27][CH2:28]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: Fc1ccc(C2=CCNCC2)nc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H](N1CC=C(c2ccc(F)cn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 47.8 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.76 g, 3.0 mmol) and 5-fluoro-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (1.63 g, 9.3 mmol) were dissolved in acetonitrile (20 ml), and lithium perchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.63 g of the intended substance (yield 47.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[N:7]3[CH2:14][CH2:13][C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:8]3=[N:9][C:10]=2[CH:11]=1.[Cl:23][C:24]1[C:25]([O:27][C:28](=[O:31])[C:29]=1[Cl:30])=[O:26]>O1CCCC1>[CH:15](=[C:12]1[C:8]2=[N:9][C:10]3[CH:11]=[C:2]([NH:1][C:28](/[C:29](/[Cl:30])=[C:24](/[Cl:23])\[C:25]([OH:27])=[O:26])=[O:31])[CH:3]=[CH:4][C:5]=3[C:6](=[O:22])[N:7]2[CH2:14][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: C1CCOC1
Product: O=C(O)/C(Cl)=C(/Cl)C(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Reaction time: 3 h
Yield: 31.7 %

Procedure:
6-amino-3-benzylidene-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazoline-9-one (2 g) was reacted with 2,3-dichloro-maleic anhydride (3.46 g) in tetrahydrofuran (130 ml) under stirring at the reflux temperature for 3 hours. After cooling the solution was evaporated in vacuo to dryness: the residue was suspended in hot ethyl acetate and filtered. Crystallization from CH2Cl2 -ethyl acetate gave 1 g of (Z)-3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-2,3-dichloro-2-propenoic acid, m.p. 160°-165° C. (dec.),
Reaction SMILES: O=O.[C:3]([C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[C:14](\[CH3:17])/[CH2:15][OH:16])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>C1(C)C=CC=CC=1>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C@H:14]([CH3:17])[CH2:15][OH:16])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: C/C(=C\c1ccc(C(C)(C)C)cc1)CO
Agent: O=O
Solvent: Cc1ccccc1
Product: C[C@H](CO)Cc1ccc(C(C)(C)C)cc1
Yield: 99 %

Procedure:
A catalyst solution was prepared in a 50 ml of measuring flask in a glove box (O2 content <1 ppm) by dissolving 9.7 mg (0.02 mmol) of dichloro-bis-(1,5-cyclooctadiene)dirhodium and 21.9 mg (0.04 mMol) (R)-HOBIPHEP in 50 ml of toluene. 5 ml of this catalyst solution were added to a solution of 16.1 g (78.85 mmol) of (E)-3-(p-tert.butylphenyl)-2-methyl-2-propen1-ol [(E)-dehydroliliol] in 145 ml of toluene in a 500 ml autoclave. The hydrogenation was carried out at 100° , a constant pressure of 60 bar and while stirring intensively. The conversion was 99.9% after 21 hours. The pale yellow hydrogenation solution was rinsed from the autoclave and evaporated at 60°/17 mbar on a rotary evaporator. The residue was distilled at 140°/0.01 mbar. There were obtained 16.1 g (99.0%) of (S) -3-(p-tert.butylphenyl)-2-methyl-1-propanol [(S)-liliol], as a colourless oil with an enantiomeric purity of 96.2% e.e.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[NH:7]C(OC(C)(C)C)=O.O1CCOCC1>CC#N.Cl>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=1)[NH2:7]
Reactant: COC(=O)[C@H](O)CN(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: COC(=O)[C@H](O)CN(N)Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
(R)-3-[N-(4-Bromobenzyl)-N′-t-butoxycarbonyl-hydrazino]-2-hydroxy-propionic acid methyl ester (1.1 g, 2.8 mmol) was dissolved in MeCN (10 mL) and of 4N HCl in dioxane (6 mL, 20 mmol). The mixture was stirred at room temperature until deprotection was complete (1 hour). The precipitate was filtered and dried to yield the title compound (840 mg) as an HCl salt.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:32][C@@H:33]1[CH2:42][CH2:41][C:40]2[C:35](=[C:36]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH:37]=[CH:38][CH:39]=2)[CH2:34]1>CN(C)C=O>[CH3:49][N:46]1[CH2:47][CH2:48][N:43]([C:36]2[CH:37]=[CH:38][CH:39]=[C:40]3[C:35]=2[CH2:34][C@H:33]([NH:32][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[C:2]([CH3:1])[CH:3]=2)[CH2:42][CH2:41]3)[CH2:44][CH2:45]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N[C@@H]2CCc3cccc(N4CCN(C)CC4)c3C2)ccc1N1CCOCC1
Temperature: 75 °C
Reaction time: 15 h
Yield: 50 %

Procedure:
To a solution of 3-methyl-4-morpholinobenzoic acid (10 mg, 0.51 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 1,1'-carbonyldiimidazole (87 mg, 0.54 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.49 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added. The reaction was allowed to stir at ambient temperature for 15 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent gave 110 mg (50% yield) of the title compound as white crystals: mp 172-175° C.; [α]21D -47° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 448 (5, M+).
Reaction SMILES: [O:1]1[CH2:6][C:5](=S)[NH:4][C:3](=[O:8])[NH:2]1.[CH2:9]([NH2:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:9]([NH:27][C:5]1[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=1)[CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1NOCC(=S)N1
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Product: CCCCCCCCCCCCCC=CCCCNC1=NC(=O)NOC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 16.4 %

Procedure:
To 0.66 g (0.005 mole) of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione dissolved in 10 ml of freshly distilled dry dioxane is added 1.33 g (0.0051 mole) of oleylamine. The reaction mixture is stirred for 17 hours at room temperature and the crystalline material filtered, washed with additional dry dioxane and chloroform, and dried to give 0.3 g (16 percent) of 5-(4-octadecenylamino)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][NH:13][C:14]([C:16]2[CH:17]=[C:18]3[CH2:24][NH:23][C@@H:22]([CH:25]([CH3:27])[CH3:26])[C:19]3=[N:20][CH:21]=2)=[O:15])=[N:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[F:28][C:29]([F:39])([F:38])[C@H:30]1[CH2:35][CH2:34][C@H:33]([CH:36]=O)[CH2:32][CH2:31]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][NH:13][C:14]([C:16]2[CH:17]=[C:18]3[CH2:24][N:23]([CH2:36][C@H:33]4[CH2:32][CH2:31][C@H:30]([C:29]([F:28])([F:38])[F:39])[CH2:35][CH2:34]4)[C@@H:22]([CH:25]([CH3:26])[CH3:27])[C:19]3=[N:20][CH:21]=2)=[O:15])=[N:10][CH:11]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)nc1
Reactant: O=C[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C[C@H]2CC[C@H](C(F)(F)F)CC2)[C@H]3C(C)C)nc1
Temperature: 70 °C

Procedure:
To a solution of (S)-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (3.6 g, 9.25 mmol), trans-4-(trifluoromethyl)cyclohexane-1-carbaldehyde (3.3 g, 18.5 mmol) in anhydrous MeOH (100 mL) was added acetic acid dropwise until the pH was between 6 and 7. Sodium cyanoborohydride (1.7 g, 27.75 mmol) was added portionwise at rt. The mixture was heated to 70° C. for 1 h. Upon completion, the reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), then the organic phase was washed with water (3×100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 50% EtOAc in hexanes, gradient to 100%), then further purified by a chiral column using the following conditions: instrument: Berger MultiGram™ SFC, Mettler Toledo Co, Ltd; column: AD 300 mm×50 mm, 10 μm; mobile phase: A: supercritical CO2, B: iPrOH (0.05% diethylamine), A:B=60:40 at 200 mL/min; column temp: 38° C.; nozzle pressure: 100 bar; nozzle temp: 60° C.; evaporator temp: 20° C.; trimmer temp: 25° C.; wavelength: 220 nm. Isomer SFC tR=2.28 min in 12 min chromatography was isolated as the major isomer, which was then further purified by reverse-phase HPLC to give (S)-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-7-isopropyl-6-((trans-4-(trifluoromethyl)cyclohexyl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (2, HCl salt) as a light yellow solid. LC-MS tR=0.69 min in 1 min chromatography, MS (ESI) m/z 553.1 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 9.12 (s, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.36-8.32 (m, 2H), 7.75 (d, J=8.0 Hz, 1H), 5.16 (d, J=15.6 Hz, 1H), 4.89-4.87 (m, 2H), 4.73 (d, J=15.2 Hz, 1H), 3.42-3.34 (m, 3H), 3.31-3.28 (m, 2H), 2.58-2.51 (m, 1H), 2.20-1.90 (m, 6H), 1.50-1.39 (m, 2H), 1.33 (d, J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H), 1.24-1.20 (m, 2H), 1.10 (d, J=6.8 Hz, 3H). HCl preparative HPLC method mobile phase A: water with 0.05% HCl; mobile phase B: CH3CN; flow rate: 80 mL/min; detection: UV 220 nm/254 nm; column: Phenomenex Gemini C18 (250 mm×50 mm×5 μm); column temperature: 30° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:25][C:26](=[NH:37])[C:27]1[CH:32]=[CH:31][C:30]([S:33](=[O:36])(=[O:35])[NH2:34])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]4[O:23][N:37]=[C:26]([C:27]5[CH:28]=[CH:29][C:30]([S:33]([NH2:34])(=[O:35])=[O:36])=[CH:31][CH:32]=5)[N:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)cc1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) (171 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a yellow solid (150 mg, 58%). MS (EI) 520.0 [(M)+]; mp 296° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:11]([Cl:13])=[CH:10][CH:9]=[C:8]3[C:14](=[O:20])[CH:15]([N:17]=[N+]=[N-])[CH2:16][C:6]([C:7]=23)=[CH:5]1)(=[O:3])[CH3:2].Cl>C(OC(=O)C)C.C(O)C>[ClH:13].[C:1]([N:4]1[C:12]2[C:11]([Cl:13])=[CH:10][CH:9]=[C:8]3[C:14](=[O:20])[CH:15]([NH2:17])[CH2:16][C:6]([C:7]=23)=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1cc2c3c(ccc(Cl)c31)C(=O)C(N=[N+]=[N-])C2
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)n1cc2c3c(ccc(Cl)c31)C(=O)C(N)C2

Procedure:
Into a stirred solution of 1-acetyl-4-azido-8-chloro-3,4-dihydrobenz[cd]-indol-5(1H)-one (3.5 g., 0.012 mole) in ethylacetate-ethanol (1:1) (200 ml.), containing 4 gm. of 6 N hydrochloric acid and 0.5 g. of 10% palladium on carbon catalyst, is bubbled a stream of hydrogen gas. After 2.5 hours the product which has separated is recovered by filtration. The yield of crude product which contains some of the catalyst is 2.6 g. (72%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]1([C:49]([N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][O:52]2)=[O:50])[CH2:42][C@@H:41]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:67][CH2:68][CH2:69][C:70]([OH:72])=[O:71].C([BH3-])#N.[Na+].Cl>O1CCOCC1.O.O>[C:70]([CH2:69][CH2:68][CH2:67][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@@:40]1([C:49]([N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][O:52]2)=[O:50])[CH2:42][C@@H:41]1[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:12])[CH3:13])([OH:72])=[O:71]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
50 mg (0.054 mmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate (Intermediate 16) were dissolved in 8 ml of dioxane/water, and 70 ml (0.108 mmol) of a 15% solution of 4-oxobutanoic acid in water were added. The reaction mixture was subsequently stirred at 100° C. for 1 h. After cooling to RT, 3.7 mg (0.059 mmol) of sodium cyanoborohydride were added and the mixture was adjusted to a pH of 3 by adding about 300 μl of 0.1 N hydrochloric acid. The reaction mixture was then stirred at 100° C. for a further 2 h. After cooling, another 70 ml (0.108 mmol) of the 15% 4-oxobutanoic acid solution were added and the reaction mixture was again stirred at 100° C. for 1 h. Then a further 3.7 mg (0.059 mmol) of sodium cyanoborohydride were added and about 300 μl of 0.1 N hydrochloric acid were subsequently used to adjust the pH back to 3. The reaction mixture was then stirred at 100° C. for another 2 h. In the event of conversion still being incomplete, this procedure was repeated for a third time. The reaction mixture was finally concentrated and the residue was purified by means of preparative HPLC. In this way, 32 mg (65% of theory) of the title compound were obtained in the form of a colourless foam.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][C:10]([C:13]3[C:22]4[C:17](=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:27]([F:30])([F:29])[F:28])[CH:14]=3)([OH:12])[CH2:9]2)C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[F:30][C:27]([F:28])([F:29])[C:15]1[CH:14]=[C:13]([C:10]2([OH:12])[CH2:11][NH:8][CH2:9]2)[C:22]2[C:17](=[C:18]([C:23]([F:24])([F:25])[F:26])[CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: OC1(c2cc(C(F)(F)F)nc3c(C(F)(F)F)cccc23)CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: OC1(c2cc(C(F)(F)F)nc3c(C(F)(F)F)cccc23)CNC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a stirred solution of 1-diphenylmethyl-3-(2,8-bis(trifluoromethyl)-4-quinolinyl)-3-azetidinol (690 mg, 1.37 mmol) in dichloroethane (20 mL), at 0° C., was added dropwise 1-chloroethyl chloroformate (0.18 mL, 1.2 eq), the mixture was stirred at 70° C. for 1 h and concentrated in vacuo. The residue was dissolved in MeOH (20 mL), stirred at room temperature for 17 h, concentrated in vacuo and the residue triturated with ether to give the title compound (351 mg, 69%) as a pale-yellow solid: mp 201° C. (dec); NMR δH (400 MHz, CDCl3) 4.44-4.45 (2H, m), 4.76-4.78 (2H, m), 7.95-7.99 (1H, m), 8.23 (1H, s), 8.38-8.42 (2H, m), 9.00 (1H, br s) and 9.47 (1H, br s); Anal. Calcd for C14H11ClF6N2O: C, 45.12; H, 2.97; N, 7.51. Found: C, 45.21: H, 3.29; N, 7.08.
Reaction SMILES: C1([Li])C=CC=CC=1.[Cl-].[C:9]1([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:13][CH:12]=[CH:11][CH:10]=1.[CH2:34]([N:38]([CH2:49][CH2:50][CH2:51][CH3:52])[C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[C:41]([O:47][CH3:48])[CH:40]=1)[CH2:35][CH2:36][CH3:37].O>O1CCCC1.C(OCC)(=O)C>[CH2:34]([N:38]([CH2:49][CH2:50][CH2:51][CH3:52])[C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[CH:14][C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[C:41]([O:47][CH3:48])[CH:40]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(OC)c1
Reaction time: 1.5 h
Yield: 89.2 %

Procedure:
In a stream of argon, to 20 ml of tetrahydrofuran was added 2.4 g of phenyllithium (19% solution in dibutylether) (5.43 mmol), and 1.95 g (4.94 mmol) of 2-thenyl triphenylphosphonium chloride was added thereto under ice cooling. Next, 1.3 g (4.94 mmol) of 4-dibutylamino-2-methoxybenzaldehyde was dissolved in tetrahydrofuran and added dropwise. The mixture was stirred under ice cooling for 1.5 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 1.51 g of an orange oily matter (yield: 89.2%).
Reaction SMILES: [CH:1]1([C:4]2[NH:15][C:14](=O)[C:7]3[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc2cc(C3CC3)[nH]c(=O)c2n1
Product: CSc1ncc2cc(C3CC3)nc(Cl)c2n1
Temperature: 70 °C
Yield: 88 %

Procedure:
6-Cyclopropyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (Preparation 181, 180 mg 0.77 mmole) was stirred with phosphorus oxychloride (6 mL) and the reaction was heated at 70° C. for 2 hours before concentrating in vacuo. Ethyl acetate (20 mL) was added to the residue and the solution was cooled in ice. A little ice and then sodium bicarbonate solution (10 mL) was added. The mixture was shaken thoroughly and the aqueous layer separated. The organic layer was washed with sodium bicarbonate solution (10 mL), brine (5 mL), dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with 1:3 ethyl acetate:cyclohexane to afford the title compound (171 mg 88%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[O:4])[CH:16]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Brc1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2cccnc2)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A mixture of (3-(methoxycarbonyl)phenyl)boronic acid (600 mg, 3.33 mmol), 3-bromopyridine (479 mg, 3.0 mmol), K2CO3 (1.2 g, 9.0 mmol) and Pd(dppf)Cl2 (50 mg) in a solution of dioxane (10 mL) and H2O (2.5 mL) was stirred at 120° C. for 30 minutes with microwave heating under N2. The catalyst was then filtered and the filtrate concentrated. The residue was then purified by column chromatography to give the desired product and used directly in the next step. (630 mg Yield 90%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH:14]S(O)(=O)=O>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH:11]=[O:14]
Reactant: COc1c(C)ccc([N+](=O)[O-])c1Cl
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1c(C=O)ccc([N+](=O)[O-])c1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-chloro-2-methoxy-4-nitrotoluene (1.0 g, 5.0 mmol) in acetic acid (10 mL) and acetic anhydride (10 mL) was cooled to 5° C. and treated with 1 mL conc. H2SO4. Chromium trioxide (1.4 g, 14 mmol) was added in portions over 10 minutes while the reaction temperature was maintained at 0-5° C. After 30 minutes at this temperature, the mixture was poured onto ice-water (20 g) and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with brine, dried (sodium sulfate) and concentrated. The crude bis-acetate was combined with water (10 mL), ethanol (10 mL) and concentrated sulfuric acid (1 mL) and heated to reflux for 40 minutes. Upon cooling, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried (sodium sulfate) and concentrated. The crude mixture was chromatographed (10% ethyl acetate/hexanes) to give 3-chloro-2-methoxy-4-nitrobenzaldehyde (400 mg, 1.9 mmol): LC/MS (m/z=215).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2([C:19]([NH2:21])=[O:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[CH2:5][CH2:4]1.[N+:22]([O-])([OH:24])=[O:23].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[N+:22]([C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][C:9]([CH:6]3[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]3)([C:19]([NH2:21])=[O:20])[C:10]2=[O:18])=[CH:15][CH:14]=1)([O-:24])=[O:23]
Reactant: CN1CCC(C2(C(N)=O)Cc3ccccc3C2=O)CC1
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Product: CN1CCC(C2(C(N)=O)Cc3ccc([N+](=O)[O-])cc3C2=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To an ice cold solution of 2-(1-methyl-4-piperidyl)-1-oxo-2-indanecarboxamide hydrochloride (5.5 g, 0.0178 mol) in 27 mL of concentrated sulfuric acid was added dropwise over 5 minutes 2.20 g of 90% nitric acid dissolved in 6.8 mL of cold concentrated sulfuric acid. After the addition was complete, the solution was stirred at 0° C. for two hours and then was poured onto ice. The solution was made basic by the addition of solid sodium bicarbonate, and the mixture was extracted with three 100 mL portions of chloroform. The combined chloroform extracts were washed with water, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was recrystallized from absolute ethanol to give 4.42 g (78% yield)) of 6-nitro-2-(1-methyl-4-piperidyl)-1-oxo-2-indane carboxamide, mp 189°-190° C.