Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[NH:30][C:31]([CH:33]1[CH2:35][CH2:34]1)=[NH:32]>>[CH:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][S:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:27][N:30]=2)[CH2:35][CH2:34]1
Reactant: N=C(NO)C1CC1
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: O=C(N1CCSCC1)N1CC(c2ccc(CC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
According to General Method 6A, 300 mg (0.720 mmol) of the compound from Example 45A and 79.3 mg (0.792 mmol) of N-hydroxycyclopropanecarboximidamide were reacted Yield: 160 mg (45% of theory)
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:3]=1[F:24].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:24])=[C:2]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:11]=2)[C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)cc2c1=O
Reactant: C1CNCCN1
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(N3CCNCC3)c(F)cc2c1=O

Procedure:
In the described fashion as Example 1(e), the above acid (7) (R6 =H, R=2,4-difluorophenyl), after reacting with piperazine, can give the described 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(piperazinyl)quinoline-3-carboxylic acid (9) ##STR19## R=2,4-difluorophenyl) and its hydrochloride salt.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[C:21]=1[O:22][CH3:23].[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29]([NH:14][C@H:12]([C:10]2[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]3[C:21]([O:22][CH3:23])=[C:4]([F:3])[CH:5]=[CH:6][C:7]=3[N:11]=2)[CH3:13])[N:28]=[CH:27][N:26]=1
Reactant: COc1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(F)ccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(-c3ccccc3)c12
Temperature: 90 °C
Yield: 67 %

Procedure:
To a solution of (S)-1-(6-fluoro-7-methoxy-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (160 mg, 0.44 mmol) in IPA (3 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (72 mg, 0.47 mmol) and DIPEA (229 μL, 1.34 mmol) and the reaction mixture heated at 90° C. for 72 hours. The reaction mixture was concentrated in vacuo and the resultant residue purified by prep HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 339 as a white solid (119 mg, 66%). 1H NMR 400 MHz δ (d6-DMSO): 7.80 (1H, s), 7.58 (1H, d, J=7.3 Hz), 7.55-7.47 (2H, m), 7.47-7.40 (3H, m), 7.39 (1H, dd, J=8.8, 4.0 Hz), 7.14 (2H, br s), 7.10 (1H, dd, J=12.2, 8.8 Hz), 5.24 (1H, quin, J=6.9 Hz), 3.32 (3H, d, J=0.7 Hz), 1.43 (3H, d, J=6.8 Hz), LCMS (Method K): RT=3.86 min, [M+H]+=404
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=1.CO.[BH4-].[Na+].Cl>O1CCCC1>[CH3:16][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Reaction time: 6 h
Yield: 97.2 %

Procedure:
A solution of 2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde (2.66 g, 7.68 mmol) in a mixed solvent of methanol (10 mL) and tetrahydrofuran (20 mL) was ice-cooled, sodium borohydride (90%, 0.323 g, 7.68 mmol) was added, and the mixture was stirred for 6 hr under nitrogen atmosphere. The reaction mixture was treated with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (2.60 g, yield 97%) as colorless crystals.
Reaction SMILES: CO.[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][C:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(O)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>[H][H].[Pd]>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc(F)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(F)cc2)CC1

Procedure:
To a methanol (10 mL) solution of 4-(4-fluorophenyl)-4-hydroxyazepane-1-carboxylic acid tert-butyl ester (100 mg) obtained in Example 352, 10% Pd—C (100 mg) was added, and the reaction solution was agitated in hydrogen stream at room temperature for 1 hour. Suction filtration of the reaction solution was carried out using celite after the reaction ended, and the filtrate was concentrated under reduced pressure. The obtained crude product of 4-(4-fluorophenyl)azepane-1-carboxylic acid tert-butyl ester was used for the next reaction, without further purifying.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:16]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:44])C(=O)C1>C(Cl)Cl>[Br:44][CH2:16][C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: OCc1nc2ccccc2n1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 217.1 %

Procedure:
To a stirred solution of (1-phenyl-1H-benzoimidazol-2-yl)methanol (240 mg, 1.02 mmol) and triphenylphospine (295 mg, 1.12 mmol) in DCM (10 mL) was added NBS (200 mg, 1.12 mmol) and the mixture was stirred at RT for 3 h. Volatiles were evaporated under reduced pressure and the residue was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) affording 2-Bromomethyl-1-phenyl-1H-benzoimidazole as a colourless oil (0.636 g, quantitative yield). LCMS: RT 3.31 min [M+H]+ 386.8/388.8
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[ClH:10].[O:11]1CC[CH2:13][CH2:12]1>C(O)C>[ClH:10].[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1CCOC1
Agent: Cl
Solvent: CCO
Product: CCOC(=N)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
A solution of 4-fluorobenzonitrile (50 g) in tetrahydrofuran (300 mL) and ethanol (60.5 mL) at 0° C. was saturated with anhydrous hydrogen chloride gas and the resulting solution was allowed to stand overnight. The solvent was evaporated and the resulting solid was collected and washed with ether to provide ethyl 4-fluorobenzimidate hydrochloride as a white solid (20 g); NMR: 8.27 (m,2), 7.51 (m,2), 4.63 (q,2), 1.47 (t,3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24](=C)[CH2:25][CH3:26])[C:5]2=[CH:4][CH:3]=1.[O:29]=[O+][O-]>CO.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24](=[O:29])[CH2:25][CH3:26])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CCC(=O)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (300 mg, 0.72 mmol) prepared in example 80b in methanol and dichloromethane (1:1, 50 mL) at −78° C. was passed a stream of ozone until the color of the solution turned blue. The reaction mixture was degassed with nitrogen, then methyl disulfide (5 mL) was added. The reaction was slowly warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was purified by chromatography (EtOAc:CH2Cl2=1:1) to give the racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-propionylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 160 mg, 50%)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[N:12][N:5]2[C:6](=[O:11])[C:7]=1[N+:8]([O-])=O.C(O)(=O)C>CN(C)C=O.[C].[Pd]>[NH2:8][C:7]1[C:6](=[O:11])[N:5]2[N:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:19][CH:20]=3)[S:14][C:4]2=[N:3][C:2]=1[NH2:1]
Reactant: CC(C)(C)c1ccc(-c2nn3c(=O)c([N+](=O)[O-])c(N)nc3s2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(-c2nn3c(=O)c(N)c(N)nc3s2)cc1
Yield: 79.6 %

Procedure:
2.75 g of 7-amino-2-(4-tert-butylphenyl)-6-nitro-5H-[1,3,4] thiadiazolo[3,2-a]pyrimidin-5-one was dissolved in 200 ml of warmed dimethylformamide, and 20 ml of acetic acid and 2.0 g of 5% palladium-carbon were added to the solution. Catalytic reduction was carried out at a temperature of 40° to 60° C. After the calculated amount of hydrogen was absorbed, the catalyst was removed by filtration while hot, and the filtrate was concentrated under reduced pressure. The precipitate formed was separated by filtration to obtain 2.0 g of 6,7-diamino-2-(4-tert-butylphenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as yellow needles.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:17]3[CH2:23][CH2:22][NH:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>>[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:17]3[CH2:23][CH2:22][N:21]([C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:31]([F:30])=[CH:32][CH:33]=4)[CH2:20][C:18]=3[N:19]=2)=[CH:12][CH:13]=1)=[O:6])[CH3:3]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2ccc(F)cc2)C3)cc1

Procedure:
The compound ru was prepared following the general procedure described in Example 5 by reacting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride salt with 4-Fluorobenzoic acid chloride: LC-MS m/z=505 (M+H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[CH3:28][C:29]1([CH3:44])[CH2:34][N:33]([CH3:35])[CH2:32][CH2:31][N:30]1[CH2:36][C:37]1[N:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:28][C:29]1([CH3:44])[CH2:34][N:33]([CH3:35])[CH2:32][CH2:31][N:30]1[CH2:36][C:37]1[N:42]=[CH:41][C:40]([NH:43][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:5])=[CH:39][CH:38]=1
Reactant: CN1CCN(Cc2ccc(N)cn2)C(C)(C)C1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4(C)C)nc3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 6-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (Step 114.1), 1.5 equiv of trimethyl aluminum, stirring the reaction mixture for 2 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 563.2 [M+H]+; tR=3.36 min (System 1); TLC: Rf=0.22 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Cl:1][CH:2]=[C:3]([O:10]C1C=CC=CC=1)[C:4]([CH3:9])([CH3:8])[CH:5]([CH3:7])[CH3:6].C(O)=O.Cl>C(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)C(C)(C)C(=CCl)Oc1ccccc1
Agent: Cl
Solvent: O=CO
Solvent: ClCCl
Product: CC(C)C(C)(C)C(=O)CCl
Yield: 77 %

Procedure:
238 g (1 mol) of 1-chloro-2-phenoxy-3,3,4-trimethyl-pent-1-ene are stirred with 500 g of formic acid and 50 g of concentrated hydrochloric acid for 2 hours at 80° C. The mixture is diluted with methylene chloride, and is washed once with water and four times with dilute sodium hydroxide solution. After the mixture has been dried over sodium sulphate, the solvent is stripped off in vacuo, and the residue is distilled over a column. 125 to 135 g (77-83% of theory) of 1-chloro-3,3,4-trimethyl-pentan-2-one of boiling point 88°-93° C./16 mbar are obtained. ##STR17##
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]1[N:17]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:19][C:20](=[O:21])[C:9]1=[CH:8]2.I[CH3:28]>CN(C)C=O>[CH3:28][N:19]1[C:20](=[O:21])[C:9]2[C:10](=[N:11][C:12]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:4][CH3:3])=[C:14]([O:15][CH3:16])[CH:13]=3)[N:17]=[C:18]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CI
Reactant: CCOC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)n1C
Temperature: 0 °C

Procedure:
Sodium hydride (470 mg. of 50% in oil, 0.011 mole) is added to a slurry of ethyl 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate (3.3 g., 0.01 mole) in N,N-dimethylformamide (75ml.). The mixture is stirred and heated on a steambath for ten minutes and then at room temperature for a half hour. It is cooled in an ice-bath and iodomethane (2.1 g., 0.015 mole) added dropwise over a 30 minute period. Following completion of addition, the mixture is stirred for an additional 15 minutes in an ice-bath and then for a half-hour at room temperature. The reaction mixture is poured into ice-water (200 ml.) and the resulting solid filtered off, air-dried, and recrystallized from ethanol to give 2.1 g. of yellow crystals (61.2%); m.p. 211.5°C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.C[O:11][C:12](=O)[C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:18][C:13]=1[C:12](=[O:11])[NH:8]2
Reactant: Nc1nccc(Cl)c1I
Reactant: COC(=O)c1cc(OCCN2CCOCC2)ccc1B1OC(C)(C)C(C)(C)O1
Product: O=c1[nH]c2nccc(Cl)c2c2ccc(OCCN3CCOCC3)cc12
Yield: 6.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 1 using 4-chloro-3-iodopyridin-2-amine (65 mg, 0.26 mmol) and 5-(2-morpholin-4-yl-ethoxy)-2-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-benzoic acid methyl ester (110 mg, 0.28 mmol) to provide 222 (6 mg, 6% yield) as a white solid. LC-MS (M+H=360, obsd.=360).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[N:25][NH:26][N:27]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][N:25]1[N:26]=[N:27][C:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[N:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CCCCN1Cc1ccccc1
Reactant: Fc1ccc(-c2nn[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2nnn(CC3CCCCN3Cc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Benzyl-2-bromomethylpiperidine (2.1 g), 5-(4-fluoro-phenyl)-2H-tetrazole (1.28 g) and potassium carbonate (6 g) were combined in xylene (100 ml) containing diisopropylethylamine (7 ml) and boiled for 16 h. The reaction mixture was cooled to room temperature, filtered, solvent removed at reduced pressure and the residue column chromatographed (silica gel; diethyl ether/petroleum ether 40:60 eluant) to give after combining appropriate fractions and removing solvent at reduced pressure the title compound 10.44 g.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O.O>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:20][CH2:19]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 122 °C
Reaction time: 24 h
Yield: 53.6 %

Procedure:
To a suspension of 1-fluoro-3-nitrobenzene (3.77 mL, 35.4 mmol) and potassium carbonate (10 g, 71 mmol) in DMSO (30 mL) was added 1-methyl piperazine (59 mL, 53.2 mmol). The mixture was stirred at 122° C. for 24 hours. After cooing down, the mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried with sodium sulfate (Na2SO4), and concentrated in vacuo to afford an orange oil. Recrystallization from EtOAc/hexanes gave 4.2 g of 1-(4-methyl-piperazin-1-yl)-3-nitrobenzene, which was reduced via hydrogenation to give the title compound (beige solid, 3 g). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.04 (t, J=8.0 Hz, 1H), 6.38 (dd, J=2.3, 8.2 Hz, 1H), 6.26 (t, J=2.2 Hz, 1H), 6.22 (dd, J=2.3, 8.2 Hz, 1H), 3.60 (br, 2H), 3.18 (t, J=4.9 Hz, 4H), 2.55 (t, J=4.9 Hz, 4H), 2.34 (s, 3H).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:7]=2[CH2:6]1)(=O)C.[OH-].[Na+]>CO.O>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:8]2[CH2:9][CH2:10][CH2:11][C@@H:5]([OH:4])[CH2:6][C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)C[C@H](OC(C)=O)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)C[C@H](O)CCC2
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of (R)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl acetate (136 g) in methanol (1.36 l) was added dropwise a solution of sodium hydroxide (46.4 g) in water (232 ml) at ambient temperature. The reaction mixture was stirred for 1 hour and evaporated in vacuo. The residue was partitioned between ethyl acetate (1.1 l) and brine (550 ml). The organic layer was washed with 1N hydrochloric acid solution (550 ml), 1N aqueous sodium hydroxide solution (550 ml), and brine (550 ml), dried over magnesium sulfate, and evaporated in vacuo to give (R)-3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ol (108.96 g) as a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:37][CH2:36][N:11]2[C:12](=[O:35])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=1[CH3:30])=[CH:15][C:14]=3[C:31]([F:34])([F:33])[F:32])=O)(C)(C)C.[ClH:38]>C(OCC)C>[ClH:38].[CH3:30][C:20]1[CH:21]=[C:22]([O:25][C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:35])[N:11]3[CH2:36][CH2:37][NH:8][CH2:9][C@H:10]32)=[C:14]([C:31]([F:34])([F:32])[F:33])[CH:15]=1
Reactant: Cc1cc(OC(F)(F)F)ccc1-c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(OC(F)(F)F)ccc1-c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-trifluoromethoxyphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (11 mg, 0.022 mmol) was added diethyl ether (2 mL) and saturated aqueous hydrochloric acid (1 mL). After 15 min of stirring, the reaction was concentrated, diluted with water and lyopholized to give (R)-1,3,4,10b-tetrahydro-9-(2-methyl-4-trifluoromethoxyphenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one hydrochloric acid salt (9.7 mg, 97%) as a white solid. MS (ESI) 431.3 (M−Cl).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:12]C(=O)C)(=[O:11])[CH3:10]>>[C:9]([OH:12])(=[O:11])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccccc1
Product: O=C(O)C=Cc1ccccc1
Yield: 19 %

Procedure:
Kalnin, Helv. Chim. Acta 11, 977 (1928) describes various salts as catalysts. 1 mol of benzaldehyde and 1.5 mol of acetic anhydride are refluxed at 180° C. for 8 hours with 0.65 mol of catalyst. The yields of cinnamic acid are, following work-up, for potassium acetate 72%, for potassium carbonate 59%, for sodium carbonate 40%, for sodium acetate 39%, for sodium phosphate 36%, for potassium phosphate 20% and for potassium sulphide 32%. As well as potassium and sodium salts, amines are also possible as catalysts. For 0.33 mol of triethylamine, the yield is 19%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH3:15])[CH2:12][N:11]([C:27](Cl)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:37][N:38]([CH3:47])[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[CH3:15])[CH2:12][N:11]([C:27]([N:44]3[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][N:38]([CH3:47])[CH3:37])[CH2:42][CH2:43]3)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Reactant: CN(C)CCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(C(=O)N2CCN(CCN(C)C)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a stirred solution of (3RS,4SR)-3-(3,4-dichloro-phenyl)-4-[(RS)-1-(4-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine-1-carbonyl chloride (58 mg, 0.12 mmol) in CH2Cl2 (2 ml) were added Et3N (0.02 mL, 0.15 mmol) and dimethyl-(2-piperazin-1-yl-ethyl)-amine (0.03 mL) (commercially available). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH3, 9/4/1) to yield 46 mg (63%) of the title compound as light yellow oil. ES-MS m/e: 587.3 (M+H+).