Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[N:26]1([C:32]2[N:37]=[CH:36][C:35]([NH:38][C:39]([C:41]3[N:42]([CH2:52][CH3:53])[C:43]4[C:48]([CH:49]=3)=[C:47]([O:50][CH3:51])[CH:46]=[CH:45][CH:44]=4)=[O:40])=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]([N:29]2[CH2:30][CH2:31][N:26]([C:32]3[CH:33]=[CH:34][C:35]([NH:38][C:39]([C:41]4[N:42]([CH2:52][CH3:53])[C:43]5[C:48]([CH:49]=4)=[C:47]([O:50][CH3:51])[CH:46]=[CH:45][CH:44]=5)=[O:40])=[CH:36][N:37]=3)[CH2:27][CH2:28]2)=[O:19])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c(C(=O)Nc2ccc(N3CCNCC3)nc2)cc2c(OC)cccc21
Reactant: O=C(O)[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1c(C(=O)Nc2ccc(N3CCN(C(=O)[C@H]4CC[C@H](C(=O)OCc5ccccc5)CC4)CC3)nc2)cc2c(OC)cccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of trans-cyclohexane-1,4-dicarboxylic acid mono-benzyl ester (50 mg, 0.16 mmol), CH2Cl2 (5 mL), and a catalytic amount of DMF was stirred under Ar, and oxalyl chloride (2M in dichloromethane, 200 μL, 0.4 mmol) was dripped into the mixture over 5 min. The mixture was stirred at room temperature and after 1.0 hr the reaction was concentrated to dryness. Benzene was added and the solution was evaporated to dryness again. The white-yellow solid was re-dissolved in 5 mL of CH2Cl2 and dripped, under Ar, into a solution of 1-ethyl-4-methoxy-1H-indole-2-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide (60.0 mg, 0.16 mmol), triethylamine (0.41 mg, 0.2 mmol) in 5 mL of CH2Cl2. The reaction was stirred at room temperature for 0.5 hr then concentrated and the residue was taken up in 50 mL of EtOAc and washed with 50 mL of saturated ammonium chloride, brine and dried with anhydrous sodium sulfate. The solvent was removed, and the crude product was purified by flash chromatography (hexanes:EtOAc), to afford the product trans-4-(4-{5-[(1-ethyl-4-methoxy-1H-indole-2-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid benzyl ester (35 mg, 37% yield) as a white solid. LCMS for C36H41N5O5 calcd. (m/e) 623, observed 624 (M+H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[C:34]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH:33]=[CH:32]2>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:42]2[CH2:43][CH2:44][N:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([Cl:28])[CH:30]=4)[N:35]=3)[CH2:40][CH2:41]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cc(Cl)ccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 6-chloro-2-piperazin-1-yl-quinoline.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].[Na].[CH:7]([Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11])=[CH2:8].C(O)(=O)C>>[C:1]([C:2]([CH3:4])([CH3:3])[CH2:8][CH2:7][Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11])#[N:5]
Reactant: CC(C)C#N
Reactant: C=C[Si](OC)(OC)OC
Agent: [Na]
Solvent: CC(=O)O
Product: CO[Si](CCC(C)(C)C#N)(OC)OC
Temperature: 103 °C
Yield: 72.9 %

Procedure:
Under a nitrogen atmosphere, isobutyronitrile (297.4 grams, 4.3 moles) and sodium metal spheres (9.9 grams, 0.43 moles) were added to a flask as described in Example 6. The contents of the flask were heated to 103° C with stirring and vinyltrimethoxysilane (637.8 grams, 4.3 moles) was added. After removing the heat source, the temperature of the flask contents was maintained at 100° C. to 107° C. by the rate of addition of the vinyltrimethoxysilane. After adding all of the vinyltrimethoxysilane, the flask contents were heated to 150° C. for one hour to ensure complete reaction. A sample taken for infra-red analysis showed no signs of any absorption attributable to a vinyl group on silicon. The infra-red spectrum was entirely consistent with the proposed structure and indicated a high state of purity. After cooling to room temperature, 25.8 grams (0.43 moles) of glacial acetic acid was added to neutralize any residual basic material. The reaction product was filtered and vacuum distilled (boiling point, 76° C. to 77° C. at 0.3 mm Hg) to yield 681.4 grams (73% yield after distillation) of 3-cyano-3-methylbutyltrimethoxysilane, as characterized by 1H and 13C NMR spectroscopy.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].Cl.[CH3:10][NH:11][CH3:12].[CH2:13]=O.Cl>C(O)(C)C>[CH3:10][N:11]([CH3:13])[CH2:12][CH2:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CNC
Reactant: C=O
Reactant: CC(=O)c1cccs1
Agent: Cl
Solvent: CC(C)O
Product: CN(C)CCC(=O)c1cccs1

Procedure:
An example of a method known for producing N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine is reacting 2-acetylthiophene with a dimethylamine hydrochloride in isopropanol in the presence of paraformaldehyde and hydrochloric acid to give 2-thienyl 2-dimethylaminoethyl ketone, and reducing this ketone with sodium borohydride in ethanol (Japanese Unexamined Patent Publication No. 1995-188065).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19])[CH2:6]2)=[O:4].C(N(CC)CC)C.Cl[S:39][N:40]([CH:46]([CH3:48])[CH3:47])[C:41](=[O:45])[O:42][CH2:43][CH3:44]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([N:20]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[S:39][N:40]([CH:46]([CH3:48])[CH3:47])[C:41]([O:42][CH2:43][CH3:44])=[O:45])=[O:19])[CH2:6]2)=[O:4]
Reactant: CCOC(=O)N(SCl)C(C)C
Reactant: COC(=O)C12CCc3ccccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N(SN(C(=O)N1CC2(C(=O)OC)CCc3ccccc3C2=N1)c1ccc(C(F)(F)F)cc1)C(C)C
Temperature: 25 °C
Yield: 85.7 %

Procedure:
To a solution of the title compound of Step B (2.0 g, 4.8 mmol) in 5 0 ml methylene chloride cooled to 0° C. was added triethylamine (1.0 g, 0.01 mol) and ethyl (chlorosulfenyl) (1-methylethyl)carbamate from Step D (1.4 g, 7.7 mmol). The mixture was allowed to warm to room temperature andstirred for one hour. The crude mixture was purified by silica column chromatography using ether-hexane (1:2) as eluent. The title compound (2.38 g) was obtained in about 90% purity (mp: 130°-134° ). Extraction of the product with ether-hexane (2:1) gave 1.8 g of highly pure material mp: 139°-140° C.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH3:6])C.[Li+].[OH-]>C1COCC1.CO.O>[Cl:15][C:10]1[CH:9]=[C:8]([NH:7][CH:5]([CH3:6])[C:4]([OH:16])=[O:3])[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: CCOC(=O)C(C)Nc1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Yield: 82.1 %

Procedure:
A mixture of 2-(3,4-dichloro-phenylamino)-propionic acid ethyl ester (10.0 g, 38.1 mmol) and LiOH (2.74 g, 114 mmol) in THF/MeOH/water 2:1:1 (100 mL) was heated at reflux for 3 h, then after cooling poured onto water and extracted with TBME. The organic phase was extracted twice with 1 M aq. sodium hydroxide solution. The aqueous phases were combined, acidified to pH 2-3 by addition of 37% aq. HCl solution, and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and evaporated to produce the title compound (7.32 g, 82%). Light yellow solid, MS: 233.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)C=O>[CH2:24]([O:17][C:4]1[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[N:7]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of methyl 5,7-dichloro-4-oxo-1,4-dihydroquinoline-2-carboxylate (3 g) in dry dimethyl-formamide (20 ml) was added potassium carbonate (6.1 g) followed by benzyl bromide (1.44 ml) and the mixture stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3×100 ml), the organic layers were combined and washed with water (2×100 ml), 1M hydrochloric acid (1×100 ml), brine (2×100 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure and the crude product purified by column chromatography to give methyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (2.8 g). δ (360 MHz, DMSO-d6) 3.95 (3H, s, OCH3), 5.48 (2H, s, CH2), 7.35 (1H, d, p-ArH), 7.38 (2H, t, m-ArH), 7.46 (2H, d, o-ArH), 7.59 (1H, s, 3-H), 7.83 (1H, d, 6-H) and 8.11 (1H, d, 8-H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1.Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1)[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25]
Reactant: O=C(CCl)N1CCCCC1
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCCCC1)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
Note: For the preparation of the starting material compound 1, see Example 147. To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]cyclohexane-1,4-diamine (90 mg, 0.30 mmol, 1.00 equiv) in DMF (10 mL) was added 2-chloro-1-(piperidin-1-yl)ethan-1-one (72 mg, 0.45 mmol, 1.50 equiv) and potassium carbonate (83 mg, 0.60 mmol, 2.00 equiv) at room temperature under nitrogen. The resulting solution was stirred overnight at ambient temperature. After completion of the reaction, the solids were removed by filtration and the filtrate was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (7.0% CH3CN up to 55.0% in 19 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[methyl[4-([7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino)cyclohexyl]amino]-1-(piperidin-1-yl)ethan-1-one (18.4 mg) as a white solid. MS (ES, m/z): 428 (M+H+); 1H NMR (400 MHz, CD3OD): δ 8.23 (s, 1H), 4.08-4.09 (m, 1H), 3.54-3.59 (m, 4H), 3.39 (s, 2H), 3.08 (t, 2H, J=6.8 Hz), 2.99 (t, 2H, J=6.8 Hz), 2.54-2.59 (m, 3H), 2.34 (s, 3H), 2.16-2.19 (m, 2H), 1.94-1.97 (m, 2H), 1.45-1.70 (m, 10H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[N:12]([CH3:14])[CH3:13])([O-:8])=[O:7].CN(C)[CH:20]=[O:21]>>[N+:6]([C:9]1[CH:10]=[C:11]([N:12]([CH3:13])[CH3:14])[CH:15]=[CH:16][C:17]=1[CH:20]=[O:21])([O-:8])=[O:7]
Reactant: CN(C)c1cccc([N+](=O)[O-])c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
720 parts of phosphorus oxychloride is added at 25°C to a solution of 498 parts of m-nitrodimethylaniline in 1800 parts by volume of dimethylformamide. The mixture is then heated within 1 hour to 75° to 80°C and stirred at this temperature for six hours. After the solution has cooled it is poured into 6000 parts of ice-water. The precipitate is suction filtered, washed and recrystallized from acetone. 385 parts (66% of theory) of 2-nitro-4-dimethylaminobenzaldehyde having a melting point of 115° to 116°C is obtained. ##SPC14##
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.C(OC([NH:33][CH2:34][CH2:35]Br)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH2:33][CH2:34][CH2:35][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH3:12])[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:25])[C:22]2=[O:23]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCN)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
N-Cyclopropyl-3-(6-hydroxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (0.621 g), 2-(tert-butoxycarbonylamino)ethyl bromide (0.5 g), potassium carbonate (2.06 g), and potassium iodide (0.025 g) were stirred in DMF (10 ml) at 60° C. for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water (5×), brine (2×), dried (magnesium sulfate) and concentrated. The resulting solid was dissolved in a solution of 4N HCl in dioxane (4 ml) and methanol (3 ml) and stirred at room temperature for 16 hours. The precipitate was collected by filtration and washed with ethyl acetate. Purification by column chromatography on an ion exchange column (isolute SCX-2 column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) washing with methanol initially and then eluting with a 99:1 mixture of methanol and aqueous ammonia solution gave 3-[6-(2-aminoethoxy)-4-oxoquinazolin-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide (AZ12278502) (0.343 g) as a white solid; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.69 (m, 2H), 1.81 (broad s, 2H), 2.14 (s, 3H), 2.87 (m, 1H), 2.93 (t, 2H), 4.08 (m, 2H), 7.52 (m, 2H), 7.59 (s, 1H), 7.73 (d, 1H), 7.84 (s, 1H), 7.91 (d, 1H), 8.19 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 379.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:10][CH:9]=2)[C:5]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:4][N:3]=1.[Br:26][CH2:27][C:28](=[O:31])[CH2:29][CH3:30]>>[Br-:26].[NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:12][CH:13]=2)[C:5]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:4][N+:3]=1[CH2:27][C:28](=[O:31])[CH2:29][CH3:30]
Reactant: CCCCc1nnc(N)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCC(=O)CBr
Product: CCCCc1n[n+](CC(=O)CC)c(N)n1Cc1ccc(-c2ccccc2C#N)cc1
Product: [Br-]

Procedure:
Reaction of 3-amino-5-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-4H-1,2,4-triazole (from Example 1, Step D) with 1-bromo-2-butanone according to the procedure of Example 1, Step E, gave a quantitative yield of the title compound as a white solid, mp 221°-224° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[C:11]([O:19][C@@H:20]([C@H:22]3[CH2:26][NH:25][C:24](=[O:27])[CH2:23]3)[CH3:21])[CH:10]=2)O1.Br[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[F:37][C:36]([F:39])([F:38])[C:33]1[CH:34]=[CH:35][C:30]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[C:11]([O:19][C@@H:20]([C@H:22]3[CH2:26][NH:25][C:24](=[O:27])[CH2:23]3)[CH3:21])[CH:10]=2)=[N:31][CH:32]=1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncccc12)[C@H]1CNC(=O)C1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1cc(-c2ccc(C(F)(F)F)cn2)cc2ncccc12)[C@H]1CNC(=O)C1
Yield: 62.1 %

Procedure:
500 mg (R)-4-{(R)-1-[7-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinolin-5-yloxy]-ethyl}-pyrrolidin-2-one (325 mg 2-Bromo-5-trifluoromethyl-pyridine, 46 mg Bis(triphenylphosphine)palladium(II) chloride, 1.96 mL 2N aqueous sodium carbonate and 10 mL DMF were heated at 80° C. for 18 hours. The reaction was partitioned between DCM and NaHCO3 (sat aq) then the organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by MPLC using a Hept/EtOAc/MeOH gradient to give 326 mg of (R)-4-{(R)-1-[7-(5-Trifluoromethyl-pyridin-2-yl)-quinolin-5-yloxy]-ethyl}-pyrrolidin-2-one as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.F[C:21](F)(F)C(OC(=O)C(F)(F)F)=O.CI>CO>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH3:21])[C:3]([C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CI
Solvent: CO
Product: CNc1cc(Cc2ccc(F)cc2)cnc1C(=O)OC

Procedure:
This compound was prepared from methyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate as described in Example 89, Steps 9-10 by reacting with trifluoroacetic anhydride, followed by alkylation with methyl iodide and subsequent deprotection upon heating in the presence of MeOH.
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6][N:5]([C:8](OC(C)(C)C)=O)[CH2:4][CH2:3]1.Cl.ClC1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>Cl.O1CCOCC1>[CH3:1][C:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3][CH2:4][N:5]([C:8]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C1(C)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-tert-Butyl 4-ethyl 4-methylpiperidine-1,4-dicarboxylate (500 mg, 1.84 mmol) obtained in Step 1 was dissolved in 4N hydrochloric acid/1,4-dioxane (4 ml), and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethanol (18.4 ml). 4-Chloropyridine hydrochloride (276 mg, 1.84 mmol) and triethylamine (2.57 ml, 18.4 mmol) were added thereto, and the reaction mixture was stirred at 170° C. overnight in a sealed tube. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate 95:5-10:90) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44]>C(Cl)Cl.C(O)C>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44].[C:28]([O:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:19]=[CH:20][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CCCCCCCCCC(=O)Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCCC(=O)OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 0.33 h

Procedure:
To a solution 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propanol (1.81 6.5 mmol) triethylamine (0.9 g, 9.0 mmol) in DCM (45 ml) was added decanoyl chloride (1.5 g, 7.8 mmol) dropwise at room temperature. The mixture was stirred for 20 minutes, then concentrated down to a crude solid. The solid was extracted into EtOAc (20 ml), and the insoluble salts were filtered. The EtOAc was removed. The crude oil was purified by flash choursomatography (Sorbsil C-30, 30 g; eluted with MeOH:DCM). The oil thus obtained (254 g, 90%) was converted to a fumarate salt with fumaric acid (670 mg) in ethanol. The crystals collected weighed 1.61 g, m.p.=100-102° C.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH3:15])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])CC.[CH2:16]=[O:17].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.C(N([CH2:35][CH3:36])CC)C>N1C=CC=CC=1>[OH:17][CH2:16][C:5]([O:4][CH2:1][CH2:35][CH3:36])([CH3:15])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[O:7]
Reactant: C=O
Reactant: CCCOC(C)C(=O)c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCOC(C)(CO)C(=O)c1ccc(Cl)cc1
Yield: 433.6 %

Procedure:
To 10 g (44 mmole) of 2-propoxy-4'-chloropropiophenone (Example 96c) in 10 g of pyridine was added 1.7 g (57 mmole) of paraformaldehyde and 0.4 g of a 40% methanolic solution of benzyltrimethylammonium hydroxide (Triton® B). After warming at 70° C. for two hours an additional 1.0 g of paraformaldehyde and 1.0 g of triethylamine was added. After heating for an additional two hours the mixture was partitioned between diethyl ether and dilute aqueous hydrochloric acid. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield 11 g of the crude title compound mixed with starting material.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][C:8]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16][C:7]=2[N:6]2[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=[C:5]12.[N:25](OCCC(C)C)=[O:26].O>CS(C)=O.C(O)(=O)C>[OH:26][N:25]=[C:16]1[C:7]2[N:6]3[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=[C:5]3[C:4](=[O:3])[NH:9][C:8]=2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]1=2
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1ccccc1C3
Reactant: CC(C)CCON=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn2c3c([nH]c(=O)c2n1)-c1ccccc1C3=NO
Reaction time: 18 h

Procedure:
0.34 g of sodium hydride is added to 1 g of ethyl 4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate in solution in 20 ml of anhydrous dimethyl sulphoxide, while the temperature of the reaction mixture is maintained below 20° C. 0.44 ml of isoamyl nitrite is then added and stirring is continued for 18 hours at the same temperature. The reaction mixture is then poured into iced water and the solution is acidified with 15 ml of acetic acid. The precipitate formed is filtered off, washed with water, with acetone and then with methanol and finally dried under reduced pressure (1 mm Hg; 0.13 kPa) to produce 0.25 g of 10-hydroxyimino-4,5-dihydro-4-oxo-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylic acid in the form of a brown powder whose melting point is higher than 260° C. (1H spectrum in DMSO, T=300K, δ in ppm (200 MHz), mixture of the syn and anti isomers: Major isomer: between 7.30 and 7.50 (2H, m, CH arom.), 7.62 (1H, s, CH arom.), 7.82 (1H, d, J=7 Hz, CH arom.), 8.00 (1H, s, CH arom.), 8.20 (1H, d, J=7 Hz, CH arom.), 12.7 (1H, s, NH), 13.0 (1H, s, OH), Minor isomer: between 7.30 and 7.50 (2H, m, CH arom.), 7.51 (1H, s, CH arom.), 7.70 (1H, d, J=7 Hz, CH arom.), 7.88 (1H, d, J=7 Hz, CH arom.), 8.58 (1H, s, CH arom.), 12.7 (1H, s, NH), 13.2 (1H, s, OH)).