Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16]C=CC=3)N=2)=[CH:7][CH:6]=1.C(OC1C=CC(C(O)=O)=C([F:42])C=1)C1C=CC=CC=1>>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([N:3]([O:2][CH3:1])[CH3:24])=[O:23])=[C:10]([F:42])[CH:9]=1)[C:13]1[CH:22]=[CH:21][CH:20]=[CH:15][CH:16]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1F
Product: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1F

Procedure:
Following the procedure for the preparation of N-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide but substituting 4-Benzyloxy-2-fluoro-benzoic acid provided the title compound. MS: (M+H m/z=290.2).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.O>CN(C)C=O>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][C:16]([F:30])([F:31])[F:15])=[CH:19][CH:20]=3)[CH2:29][CH2:28]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCN(c2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 7 h
Yield: 104.2 %

Procedure:
Mixture of (R)-2-chloro-1-(2-methyl-2-oxiranylmethyl)-4-nitroimidazole (2.50 g, 11.5 mM) obtained in example 7 and 4-(4-trifluoromethoxyphenyl)piperazine (3.11 g, 12.6 mM) in N,N-dimethylformamide (25 ml) was stirred at 70° C. for 7 hours. The temperature of reaction mixture was turned back to a room temperature, water was added and extracted twice with ethyl acetate. The organic layers were combined, washed with water three times, dried on anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure, there was obtained (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxyphenyl)piperazin-1-yl]propan-2-ol (5.55 g, yield: 100%) of slightly yellow oily product.
Reaction SMILES: [CH3:1]N(C)C=O.[CH:6]([O:9][C:10](=[O:47])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([CH2:41][N:42]([CH:44]=[O:45])[CH3:43])[CH:37]=3)[NH:32][C:31]2=[O:46])=[CH:26][CH:25]=1)[NH:12][C:13](=[O:22])[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>O.C(O)(=O)C>[CH:6]([O:9][C:10](=[O:47])[C@H:11]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([CH2:41][N:42]([CH:44]=[O:45])[CH3:43])[CH:37]=3)[N:32]([CH3:1])[C:31]2=[O:46])=[CH:28][CH:29]=1)[NH:12][C:13](=[O:22])[C:14]1[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=1[Cl:20])([CH3:8])[CH3:7]
Reactant: CC(C)OC(=O)[C@H](Cc1ccc(-n2c(=O)[nH]c3ccc(CN(C)C=O)cc3c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: CN(C)C=O
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)OC(=O)[C@H](Cc1ccc(-n2c(=O)c3cc(CN(C)C=O)ccc3n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 23 °C
Yield: 94 %

Procedure:
There was added, to 21.26 L of N,N-dimethylformamide (DMF), 5.445 kg of Nα-(2,6-dichlorobenzoyl)-4-{6-(N-formyl-N-methylamino-methyl)-quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl ester, the resulting mixture was stirred at 23° C. and in a nitrogen gas stream to dissolve the isopropyl ester compound. Then 2.46 kg of potassium carbonate and 2.491 kg of methyl p-toluene-sulfonate were added to the resulting solution and the mixture was stirred with heating at 55 to 65° C. After the confirmation of the progress of the N-methylation reaction by HPLC, 2.14 kg of acetic acid was added to the mixture and subsequently the mixture was stirred with heating at 50° C. for one hour. To the reaction solution, there was dropwise added 10.9 L of water, followed by the addition of 6 g of seed crystals and stirring of the mixture at 50° C. for 2 hours. To the resulting slurry, there was further added 10.9 L of water, the mixture was cooled to 25° C. and stirred overnight. The precipitates thus obtained were recovered by the filtration using a centrifuge and the resulting cake was washed with 21.8 kg of water. The resulting wet crystals were dried under reduced pressure at 60° C. to thus give 5.235 kg of the title compound as a white crystalline solid (yield: 94%).
Reaction SMILES: [CH3:1][Si:2]([CH3:56])([CH3:55])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([O:41][CH2:42][CH2:43][O:44][CH3:45])([C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35])[CH2:30][CH2:29]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:62]([O:64][CH2:65][CH3:66])=[CH2:63])CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][Si:2]([CH3:56])([CH3:55])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([O:41][CH2:42][CH2:43][O:44][CH3:45])([C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35])[CH2:30][CH2:29]2)[C:9]=1[C:62]([O:64][CH2:65][CH3:66])=[CH2:63]
Reactant: COCCOC(=O)C1(OCCOC)CCC(c2nc3c(-c4cnn(-c5ccccc5)c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1c(C2CCC(OCCOC)(C(=O)OCCOC)CC2)nc2c(-c3cnn(-c4ccccc4)c3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
A mixture of 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate (300 mg, 0.343 mmol), tributyl(1-ethoxyvinyl)tin (0.348 mL, 1.03 mmol), Pd(PPh3)4 (39.6 mg, 0.034 mmol) in dioxane (3.5 mL) was stirred at 100° C. under Ar for 16 h. The reaction mixture was passed through a short SiO2/KF (9:1) plug (eluting with EtOAc) to remove the majority of Tin species. After evaporating, the crude product was purified by a SiO2 column (0-30%, EtOAc/Hexanes, Rf=0.65 in 50% EtOAc) to afford 2-methoxyethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(2-methoxyethoxy)cyclohexanecarboxylate as a pale yellow oil (258 mg, 87%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH:15]([CH:21]([CH3:23])[CH3:22])[C:16]([O:18]CC)=[O:17].O>C(O)C>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH:15]([CH:21]([CH3:23])[CH3:22])[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)C(Nc1ccc(C(F)(F)F)cc1Cl)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To 0.60 grams of sodium hydroxide dissolved in 10 ml of ethanol was added 3.30 g of the above ester. The mixture was stirred at room temperature for 4 hours, after which water was added, and the mixture was washed with toluene. The organic phase was discarded. The product was acidified, extracted into ether, washed with water, dried and solvent removed to yield 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid, m.p. 132°-135°, in 90% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([OH:36])=O)([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:51]1([S:54]([NH2:57])(=[O:56])=[O:55])[CH2:53][CH2:52]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:57][S:54]([CH:51]5[CH2:53][CH2:52]5)(=[O:56])=[O:55])=[O:36])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (42), (80 mg, 0.147 mmol) and carbonyldiimidazol (48 mg, 0.295 mmol) in dry THF (25 mL) was stirred at reflux under nitrogen for 3 h. Then, the reaction mixture was cooled down to room temperature and cyclopropylsulfonamide (54 mg, 0.442 mmol) and DBU (52 mg, 0.34 mmol) were added. The resulting solution was stirred at 50° C. for 48 h. Then, the reaction mixture was partitioned between AcOEt ethyl acetate and water. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2/EtOAc, 95:05) to give the title product contaminated with cyclopropylsulfonamide. This solid was triturated 10 min in water and filtered, washed with water, dried under high vacuum, triturated again in diethylether and filtered to give 37 mg (39%) of the title product 43 as a white powder: m/z=647 (M+H)+; 1H-NMR (CDCl3): 10.40 (br s, 1H), 7.95 (d, J=9.1 Hz, 1H), 7.55 (s, 1H), 7.15 (s, 1H), 7.10 (dd, J=9.12 Hz, 2.4 Hz, 1H), 6.90 (d, J=2.4 Hz, 1H), 5.85 (br s, 1H), 5.65 (dd, J=18.2 Hz, 8.0 Hz, 1H), 5.15 (t, J=10.0 Hz, 1H), 4.8 (t, J=7.2 Hz, 1H), 4.10 (dd, J=11.3 Hz, 3.8 Hz, 1H), 3.9 (s, 3H), 3.60-3.70 (m, 1H), 3.6 (d, J=11.3 Hz, 1H), 3.10-3.20 (m, 1H), 2.90-3.00 (m, 1H), 2.85 (s, 3H), 2.4-2.6 (m, 3H), 1.90-2.20 (m, 3H), 1.25-1.60 (m, 7H), 0.90-1.10 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[NH:23][CH:22]([C:27]3[C:35]([Br:36])=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH:21]3[CH2:37][CH:38]=[CH:39][CH:20]3[C:19]=2[CH:18]=1)(C)(C)C>ClCCl>[Br:36][C:35]1[C:27]([CH:22]2[CH:21]3[CH2:37][CH:38]=[CH:39][CH:20]3[C:19]3[CH:18]=[C:17]([CH2:16][CH2:15][NH2:14])[CH:26]=[CH:25][C:24]=3[NH:23]2)=[CH:28][C:29]2[O:33][CH2:32][O:31][C:30]=2[CH:34]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc2c(c1)C1C=CCC1C(c1cc3c(cc1Br)OCO3)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ccc2c(c1)C1C=CCC1C(c1cc3c(cc1Br)OCO3)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Trifluoroacetic acid (1.2 mL) was added dropwise to a solution of {2-[4-(6-bromo-benzo[1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethyl}-carbamic acid tert-butyl ester (0.15 g, 0.3 mmol) in dichloromethane (1.5 mL), and stirred at rt for 1 h. The reaction mixture was diluted with dichloromethane (15 mL) and washed with cold saturated NaHCO3. Organic layer dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by preparative silica gel chromatography using 20% MeOH/DCM and gave the product as a colorless solid (0.115 g, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([CH3:18])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[C:27]#[CH:28]>CC(C)=O>[C:26]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([CH3:18])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1)#[C:27][CH3:28]
Reactant: Cc1c(-c2ccccc2)oc2cc(O)ccc2c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1

Procedure:
A mixture of 7-hydroxy-3-methylflavone (2.52 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.78 g, 0.015 mol) and acetone (100 mL) was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 2.32 g of a product with the following characteristics: m.p. 179-180° C.; 1H NMR (CDCl3) δ: 2.15 (s, 3H), 2.69 (m, 1H), 4.8 (s, 2H), 6.95-8.25 (m, 8H).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].[CH2:12](OS(OCC)(=O)=O)[CH3:13].C(N(CC)CC)C>ClCCl>[C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O:3][CH2:12][CH3:13])=[O:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=Cc1ccccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a 3-neck 500 ml round-bottom flask equipped with a magnetic stirrer, reflux condenser and addition funnel was added 2-carboxybenzaldehyde (30.00 g, 0.200 moles), diethylsulfate (33.92 g, 0.220 moles) and 150 ml of dichloromethane under nitrogen. The mixture was heated to reflux and triethylamine (30.36 g, 0.300 moles) was added at such a rate to maintain a brisk reflux. After the addition was complete, the solution was heated at reflux for 1 hour and then allowed to cool to room temperature and stirred overnight. The mixture was then washed with water (1×50 ml), 1.0N hydrochloric and solution (1×50 ml), saturated sodium bicarbonate solution (1×50 ml), saturated sodium chloride solution (1×50 ml), dried over magnesium sulfate and concentrated in vacuo to give 21.0 g of the product as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][CH2:14][CH2:15][CH:16]=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCCCC1CC(c2ccc(F)cc2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCCC2CC(c3ccc(F)cc3)=NO2)CC1
Yield: 63.7 %

Procedure:
4-[3-(4-Fluorophenyl)-4,5-dihydroisoxazol-5-yl]butanal (22.6 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.262 mmol) and diisopropylethylamine (26.9 μL, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 22.8 mg (70.4%) of the target compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]([C:6]1[C:7]([O:31][CH2:32][CH3:33])=[N:8][N:9]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=2[Cl:30])[C:10]=1[N:11]1C(=O)C2=CC=CC=C2C1=O)=[O:5].O.NN>C(O)C>[NH2:11][C:10]1[N:9]([C:22]2[C:23]([Cl:30])=[CH:24][C:25]([Cl:29])=[CH:26][C:27]=2[Cl:28])[N:8]=[C:7]([O:31][CH2:32][CH3:33])[C:6]=1[C:4](=[O:5])[C:3]1[CH:34]=[CH:35][CH:36]=[CH:37][C:2]=1[Cl:1]
Reactant: CCOc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N2C(=O)c3ccccc3C2=O)c1C(=O)c1ccccc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(=O)c1ccccc1Cl

Procedure:
A suspension of 184 mg of the compound of Step D in 10 mL of ethanol was treated with 0.5 mL of 55% hydrazine hydrate and refluxed for 1 hour. Solids in the cooled reaction mixture were filtered off and discarded and the filtrate was evaporated to a gum which was triturated with ether and filtered. The filtrate was again evaporated to a foam which was shown to be 104 mg of the analytically pure title compound. Anal. Calcd. for C18H13O2N3Cl4 : C, 48.57; H, 2.94; N, 9.44. Found, C, 48.41; H, 2.52; N, 9.43.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH2:12]O)[CH:3]=1.C(N(CC)CC)C.S(Cl)([Cl:23])=O>ClCCl>[Cl:23][CH2:12][C:4]1[CH:3]=[C:2]([F:1])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: OCc1cc(F)c2c(c1)OCCO2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1cc(CCl)cc2c1OCCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
To a solution of (8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methanol (0.84 g, 4.55 mmol) and triethylamine (960 μl, 4.84 mmol) in dichloromethane (20 mL) was slowly added thionyl chloride (400 μl, 5.47 mmol) at 0° C. The solution was stirred at 0° C. for 15 min then at rt for 3 h. Dichloromethane (80 mL) was added and the solution was washed with water (40 mL), saturated aqueous sodium bicarbonate (40 mL) then brine (40 mL) and dried over sodium sulfate. Filtration and concentration gave 7-(chloromethyl)-5-fluoro-2,3-dihydro-1,4-benzodioxine (0.92 g, quantitative yield) as a brown oil. The chloride was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:20](O)=[O:21])=[CH:16][C:11]2=[N:10][N:9]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:39]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])(=[O:42])[NH:40][NH2:41]>C1COCC1>[C:39]([NH:40][NH:41][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:25]([CH3:26])=[C:17]([C:15]2[CH:14]=[CH:13][N:12]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:9][N:10]=[C:11]3[CH:16]=2)[CH:18]=1)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]
Reactant: Cc1ccc(C(=O)O)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Temperature: 50 °C

Procedure:
To a solution of 3-(3-(2-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-methylbenzoic acid (444 mg, 1.22 mmol) in 15 mL of THF at RT was added CDI (218 mg, 1.34 mmol). The resulting mixture was heated for 1 h at 50° C. The reaction mixture was then cooled to RT and tert-butyl carbazate (177 mg, 1.34 mmol) was added. The reaction mixture was again heated at 50° C. for 24 h. After the reaction mixture was concentrated to dryness, the residue was purified on the ISCO (40 g column, 50-100% EtOAc in Hexanes) to afford the title compound as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 478.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:10]=2)[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[N:3]=1.[H-].[Na+].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>CN(C=O)C>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:10]=2)[CH:5]=[C:4]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:24][CH:25]=2)[N:3]=1
Reactant: CCCCCCCCc1ccc2cc(-c3ccc(O)cc3)nc(F)c2c1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(-c2cc3ccc(CCCCCCCC)cc3c(F)n2)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 mmol of 1-fluoro-3-(4-hydroxyphenyl)-7-octylisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 8 mmol of 1-fluoro-3-[4-(octyloxy)phenyl]-7-octylisoquinoline.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.CC(C)([O-])C.[K+].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Cl>CN(C)C=O>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][O:9][CH:6]1[CH2:7][CH2:8][C:3]([N:2]([CH3:16])[CH3:1])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:5]1
Reactant: CN(C)C1(c2ccccc2)CCC(O)CC1
Reactant: Fc1cccc(CCl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccc2)CCC(OCc2cccc(F)c2)CC1
Temperature: 0 °C
Yield: 33.4 %

Procedure:
2.00 g of 4-dimethylamino-4-phenylcyclohexanol were dissolved in 20 ml of dimethylformamide; 1.13 g of potassium tert.-butoxide were added and stirring was carried out for 45 minutes, before 1.45 g of 3-fluorobenzyl chloride were added dropwise in the course of 15 minutes. After stirring overnight, the mixture was added to 25 ml of ice-water and extracted repeatedly with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The resulting crude product (2.71 g) was separated on silica gel with hexane/diethyl ether (V:V=1:1). 996 mg of [4-(3-fluorobenzyloxy)-1-phenylcyclohexyl]dimethylamine were obtained and, as described for Example 1, were converted into 720 mg of the corresponding hydrochloride with chlorotrimethylsilane and water in 2-butanone.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20](F)(F)F)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.BrC1C=CC2[C:31]3[N:32]=[C:33]([C:39](N)=[O:40])S[C:35]=3CCOC=2C=1.N1(CCNN)CCOCC1>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][CH2:20][N:32]5[CH2:33][CH2:39][O:40][CH2:35][CH2:31]5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: NNCCN1CCOCC1
Product: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3CCN3CCOCC3)nc1-2

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with (2-morpholin-4-yl-ethyl)-hydrazine to give 8-bromo-2-[2-(2-morpholin-4-yl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. MS(ESI+) 462.1/464.1.
Reaction SMILES: Br[C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:34]=[CH:35][C:36]([C:2]4[CH:6]=[N:5][N:4]([CH3:7])[C:3]=4[CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:37][CH:38]=3)=[CH:31][CH:32]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]
Reactant: Cn1ncc(Br)c1C(O)CCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: 1-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-phenyl-butan-1-ol and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.