Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O)=[O:3].ClCCl.[CH3:24][S:25]([OH:28])(=[O:27])=[O:26].II>CCCCCCC.C(OCC)(=O)C.O>[CH3:24][S:25]([OH:28])(=[O:27])=[O:26].[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:4]([C:2]([NH2:1])=[O:3])[NH2:5])=[CH:15][CH:16]=1
Reactant: Cc1ccc(CN(NC(=O)OC(C)(C)C)C(N)=O)cc1
Agent: CS(=O)(=O)O
Agent: II
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(CN(N)C(N)=O)cc1
Temperature: 32.5 °C
Yield: 98.6 %

Procedure:
A 22-L 4-neck flask was equipped with an overhead stirring apparatus, warming/cooling bath, thermometer probe, condenser, and 500-mL addition funnel. The flask was charged with 2-(Aminocarbonyl)-2-(4-methylphenylmethyl)-hydrazine carboxylic acid, 1,1-dimethylethyl ester (1100 g, 3.94 moles) and dichloromethane (12 L). The mixture was warmed to 30-35° C. to completely dissolve all solids, then cooled to 25-30° C. and methanesulfonic acid (MsOH) (398 g, 4.14 moles) was added over 30 min. The water bath was replaced with a heating mantle and the reaction solution was heated at reflux for 12-20 hours, and, monitored by TLC analysis (Ethyl Acetate 100%; I2, Rf(sm)=0.3, Rf(prod)=0.1) When complete, the reaction mixture was diluted with heptane (4000 mL), cooled to 10-20° C., and stirred for 30 min. After filtration, the cake was washed with heptane (2×1000 mL) and dried in vacuo at 35-45° C., to afford the title compound as a white solid (1070 g, 98.6%). 1H NMR (DMSO-d6, 300 MHz): δ 1.35 (s, 9 H), 2.26 (s, 1 H), 4.45 (br s, 2 H), 6.06 (s, 2 H), 7.10 (s, 4 H), 8.88 (br s, 1 H); Anal. Calcd. for C10H17N3O4 S,: C, 43.62; H, 6.22; N, 15.26; S, 11.64. Found: C, 43.33; H, 6.21; N, 14.97.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH:7]([CH3:9])[CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:4]1.[NH2:18][C:19]1[C:27]([Cl:28])=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([O:29][CH2:30][CH3:31])[CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[NH2:18][C:19]1[C:27]([Cl:28])=[CH:26][C:22]([C:23]([NH:1][CH2:2][CH:3]2[O:8][CH:7]([CH3:9])[CH2:6][N:5]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[CH2:4]2)=[O:24])=[C:21]([O:29][CH2:30][CH3:31])[CH:20]=1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC1CN(Cc2ccccc2Cl)CC(CN)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccccc2Cl)CC(C)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
To a solution of 2-aminomethyl-4-(2-chlorobenzyl)-6-methylmorpholine (2.2 g) in dichloromethane (50 ml), 4-amino-5-chloro-2-ethoxybenzoic acid (1.9 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.7 g) are added. The reaction mixture is stirred at 25° C. for 4 hours, washed successively with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is chromatographed on silica gel with ethyl acetate-hexanechloroform (1:1:1) to give the title compound (2.6 g) as an oil.
Reaction SMILES: [Cl:1]C1C=C2C(C=CN2)=CC=1.[C:11]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20](OC(F)(F)F)[CH:21]=2)[N:16]([CH2:28][C:29]([OH:31])=[O:30])[CH:15]=1)(=[O:13])[CH3:12]>>[C:11]([C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:1])=[CH:20][CH:21]=2)[N:16]([CH2:28][C:29]([OH:31])=[O:30])[CH:15]=1)(=[O:13])[CH3:12]
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: CC(=O)c1cn(CC(=O)O)c2cc(Cl)ccc12

Procedure:
was prepared from 6-chloro-1H-indole in a similar manner as described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. Brown solid. MS: 252 [M+H]+, 274 [M+Na]+; tR (HPLC conditions k): 2.89 min.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH3:29])[N:23]=4)=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[C:4]2[CH2:30][CH2:31][CH2:32][C:3]=12.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(C(F)(F)F)=O>CC(O)CC.[OH-].[Na+].O.CCOC(C)=O>[CH3:29][NH:28][C:24]1[N:23]=[C:22]([C:21]2[C:16]([O:15][C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:5]4[N:6]=[N:7][C:2]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[C:3]5[CH2:32][CH2:31][CH2:30][C:4]=45)=[CH:10][CH:11]=3)=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:27]=[CH:26][N:25]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4c3CCC4)cc2)n1
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCC(C)O
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(N4CCCCC4)c4c3CCC4)cc2)n1
Temperature: 125 °C

Procedure:
To a mixture of 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine (0.200 g, 0.449 mmol) and piperidine (0.310 ml, 3.14 mmol) in 2 mL 2-butanol was added TFA (0.173 ml, 2.24 mmol). The reaction became slightly homogeneous and then solid. The solid was heated to 125° C. for 24 h, showing a small amount of conversion. The reaction was heated to 135° C. for 3 days. The brown, homogeneous reaction was allowed to cool, and was diluted with 2N NaOH, water, and EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting solid was adsorbed onto 2 g silica gel and purified by chromatography (0-100% 90/10 DCM/MeOH in DCM) to give N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(piperidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-amine as an off-white solid. MS m/z=495 [M+H]+. Calc'd for C28H30N8O: 494.6.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]2[CH2:19][O:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:20]=[N+:21]=[N-:22].[Na+].C(OC)=O.CO>O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]([OH:18])[CH2:19][N:20]=[N+:21]=[N-:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCCCCCCOCC2CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: COC=O
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCC(O)COCCCCCCCCc1ccccc1
Yield: 96.7 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 2.4 g of 8-phenyloctyloxymethyloxirane (prepared as described in Preparation 64), 2.97 g of sodium azide, 20 ml of methyl formate and 80 ml of an 8:1 by volume mixture of methanol and water were used, to give 2.7 g of the title compound having an Rf value of 0.29 (on silica gel thin layer chromatography, using a 1:5 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH:1]1([C:4]2[CH:33]=[CH:32][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:19][N:18]([C:20]([C:22]5[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:17]4)=[CH:12][C:11]=3[O:30][CH3:31])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)(Cl)Cl>[CH3:41][S:42]([O:29][CH2:28][C:26]1[CH:25]=[CH:24][N:23]=[C:22]([C:20]([N:18]2[CH2:17][CH:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:7]4[CH:32]=[CH:33][C:4]([CH:1]5[CH2:3][CH2:2]5)=[CH:5][CH:6]=4)=[C:11]([O:30][CH3:31])[CH:12]=3)[CH2:19]2)=[O:21])[CH:27]=1)(=[O:44])=[O:43]
Reactant: COc1cc(C2CN(C(=O)c3cc(CO)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(C2CN(C(=O)c3cc(COS(C)(=O)=O)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of {3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidin-1-yl}-(4-hydroxymethylpyridin-2-yl)-methanone (4.0 g) prepared in (6) in chloroform (80 mL) were added triethylamine (3.0 mL) and methanesulfonyl chloride (1.5 mL) at 0° C. The reaction mixture was stirred at RT for 30 min. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure. Hexane was added to the residue. The precipitated solid was collected on a filter and dried to give the title compound (4.6 g, 99%).
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:19][S:20](O)(=[O:22])=[O:21].C(Cl)(Cl)Cl.[Cl-].[Na+]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:13]1[CH:14]=[CH:15][C:16]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCCCCCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 24.6 grams (0.1 mole) of n-dodecylbenzene in 150 ml of carbon tetrachloride was added with stirring 34.8 grams (0.3 mole) of chlorosulfonic acid over a 1-hour period. The reaction was exothermic with the temperature rising to 27° C. Stirring was continued for 4 hours after which the reaction mixture was carefully poured onto 1 liter of cracked ice with vigorous stirring. Chloroform (200 ml) was added and the aqueous layer was saturated with sodium chloride. The chloroform layer was separated, washed two times with 500 ml of saturated aqueous sodium chloride solution, dried over Molecular Sieves 4A and filtered. The solvent was removed in vacuo, and the resulting residue was recrystallized from 100 ml of hexane. The dried product weighed 22.6 grams and melted at 33°-35° C.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([CH2:10][C:11]([NH2:13])=[O:12])#[N:9].C1(=O)CCCCC1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[C:1]1(=[C:10]([C:8]#[N:9])[C:11]([NH2:13])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCC(N)=O
Reactant: Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=C1CCCCC1
Solvent: CC(=O)O
Product: N#CC(C(N)=O)=C1CCCCC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
600 ml of toluene, 200 g of cyanoacetamide, 193 g of cyclohexanone, 15 g of ammonium acetate and 24 g of acetic acid are placed in a 2 litre flask equipped with a mechanical stirrer, thermometer and Dean-Stark trap connected to a condenser, under nitrogen flow. The mixture is heated under reflux, simultaneously separating the water by distilling the water-toluene azeotrope. The separated water is collected in the Dean-Stark trap and removed at suitable time intervals. After 2 hours, on completion of the azeotropic distillation, it is cooled to 70° C., washed with 400 ml of a saturated sodium bicarbonate solution and cooled to 15° C. The precipitated solid is filtered off, washed with 70 ml of toluene, then 70 ml of water and dried in an oven at 40° C. under vacuum. 213 g of 2-cyclohexylidene-2-cyanoacetamide are obtained.
Reaction SMILES: C([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][C:12]3[C:18]([Br:19])=[C:17]([Br:20])[S:16][C:13]=32)[CH2:9]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].ClC(OC(Cl)C)=O>ClC(Cl)C.CO>[Br:20][C:17]1[S:16][C:13]2[CH:14]3[CH:10]([CH2:11][C:12]=2[C:18]=1[Br:19])[CH2:9][NH:8][CH2:15]3
Reactant: Brc1sc2c(c1Br)CC1CN(Cc3ccccc3)CC21
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(Cl)Cl
Product: Brc1sc2c(c1Br)CC1CNCC21
Temperature: 22 °C
Reaction time: 1 h

Procedure:
The product from step g) (605 mg, 1.46 mmol) in dichloroethane (7 ml) was treated with powdered K2CO3 (806 mg, 5.84 mmol) and 1-chloroethyl chloroformate (Ace-Cl) (632 μl, 5.84 mmol) at 80° C. for 16 hours. Next, the reaction was cooled, filtered and concentrated providing an oily residue. This oily residue was diluted with anhydrous MeOH (15 ml) and stirred for 1 hour at 22° C. The solvent was concentrated and the crude residue was purified by preparative LC/MS providing title compound. 1H NMR (300 MHz, CD3OD, ppm) 2.65-2.75 (m, 1H); 3.05-3.30 (m, 2H); 3.32-3.80 (m, 4H); 4.10-4.28 (br m, 1H); MS calculated for C9H9Br2NS+H 324, observed 322, 324, 326.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][N:15]2[C:38](=[O:49])[CH:39]([NH:44][C:45]([O:47][CH3:48])=[O:46])[C:40]([CH3:43])([CH3:42])[CH3:41])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:48][O:47][C:45]([NH:44][CH:39]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:38]([N:15]1[CH2:16][CH:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:21]=2)[CH2:18][CH:14]1[C:12]([NH:11][C:6]1([C:4]([OH:5])=[O:3])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:13])=[O:49])=[O:46]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)C(NC(=O)OC)C(C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)C(NC(=O)OC)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 1-{[1-(2-methoxycarbonylamino-3,3-dimethyl-butyryl)-4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropane-carboxylic acid ethyl ester (410 mg, 0. 52 mmol) in THF (20 mL), methanol (11.5 mL) and water (3.8 mL) mixture, lithium hydroxide monohydrate (328 mg, 7.82 mmol) was added. The reaction mixture was stirred at rt for overnight. Then it was acidified with 1N HCl solution and concentrated. The residue was extracted with EtOAc twice and the organic layers were combined. Then it was dried (MgSO4) and concentrated to give an off-white solid. (230 mg, 69% yield). 1H NMR (400 MHz, CD3OD) δ 1.02 (s, 9H), 1.43 (dd, J=9.54, 5.14 Hz, 1H), 1.68 (dd, J=8.07, 5.14 Hz, 1H), 2.17 (m, 1H), 2.57 (m, 1H), 2.75 (m, 1H), 3.34 (s, 3H), 4.03 (s, 3H), 4.06 (m, 1H), 4.18 (s, 1H), 4.60–4.70 (m, 2H), 4.88 (m, 1H), 5.08 (dd, J=10.39, 1.59 Hz, 1H), 5.25 (dd, J=17.36, 1.71 Hz, 1H), 5.77–5.87 (m, 2H) 7.38 (dd, J=9.29, 2.20 Hz, 1H), 7.50 (m, 1H), 7.62 (m, 1H), 7.69–7.78 (m, 3H), 8.03–8.07 (m, 2H), 8.36 (d, J=9.20 Hz, 1H). LC-MS (retention time: 2.177 min.), MS m/z 645 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][S:23]2(=[O:29])=[O:28])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12]CC1C=CC=CC=1)=[O:5])[CH3:2].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][S:23]2(=[O:28])=[O:29])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[OH:12])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1O
Yield: 82.6 %

Procedure:
A solution of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-5-benzyloxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (4.05 g, 9.61 mmol) in a mixture of ethanol (250 ml) and ethyl acetate (250 ml) was hydrogenated over 10% palladium on activated carbon (0.9 g) and under 1 atmosphere of hydrogen for 1 h. The catalyst was then filtered and the solvent was evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate gave 2.63 g (82% yield) of the title ester as white crystals; mp 186–189° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.42 (3H, t, J=7.0 Hz, CH3), 1.6–1.63 (1H, m, CH), 2.3–2.6 (3H, m, CH2 and CH), 3.2 (1H, m, CH), 3.55–3.75 (2H, m, CH2), 3.65 (3H, s, NCH3), 3.95–4.05 (1H, m, CH), 4.44 (2H, q, J=7.0 Hz, OCH2). HRMS (FAB POS) calculated for C12H18N3O6S [M+H+]: 332.091632. found: 332.092342.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[C:13]([F:22])[C:12]=2F)[CH2:5][CH2:4]1.[F:27][C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.Cl.CCN(C(C)C)C(C)C>CC#N>[F:1][C:2]([F:25])([F:26])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[C:13]([F:22])[C:12]=2[N:30]2[CH2:31][CH2:32][C@@H:28]([F:27])[CH2:29]2)[CH2:7][CH2:8]1
Reactant: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(F)c1F
Reactant: F[C@@H]1CCNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1c([N+](=O)[O-])cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(N2CC[C@@H](F)C2)c1F

Procedure:
The sub-title compound is prepared in analogy to procedure 6a from N-(trans-4-trifluoromethyl-cyclohexyl)-2,3-difluoro-4-methylamino-5-nitro-benzoic acid amide (200 mg, 0.52 mmol), (R)-3-fluoropyrrolidine×HCl (72 mg, 0.57 mmol), DIPEA (0.76 mL, 4.4 mmol) and MeCN (5 mL). Yield: 230 mg. HPLC Rt=1.52 min (method A). MS m/z: 451 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>CN(C)C=O.ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH:15][C:26]([CH:23]1[CH2:25][CH2:24]1)=[O:27]
Reactant: NCCCc1c(Cl)ccc2c1CCO2
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCCCc1c(Cl)ccc2c1CCO2)C1CC1
Reaction time: 0.33 h
Yield: 50 %

Procedure:
A mixture of 3-(5-chloro-2,3-dihydro-benzofuran-4-yl)-propylamine hydrochloride (142 mg), dimethylformamide (5 drops), triethylamine (0.64 ml) and dichloromethane (5 ml) was stirred in ice for 20 minutes. Cyclopropanecarbonyl chloride (66 mg) was added and stirring continued for 5 hours. The mixture was purified by chromatography on silica eluting with ethyl acetate/hexane (1:1) to give the title compound as a white solid (80 mg).
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1NCCc2nc(O)ccc21
Product: O=C1NCCc2nc(Cl)ccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
A mixture of 2-hydroxy-7,8-dihydro-6H-[1,6]naphthyridin-5-one (17 g, 73.1 mmol) in phosphorus oxychloride (30 mL) was stirred at 100° C. for 8 h. The solvent was evaporated in vacuo. The mixture was basified with a saturated solution of NaHCO3 and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; petroleum ether/EtOAc 1/1). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-chloro-7,8-dihydro-1,6-naphthyridin-5(6H)-one (4.81 g, 36%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].[Cl-].[Al+3].[Cl-].[Cl-].COC1C=C(C(C2C=CC(OC)=CC=2)=CC#N)C=CC=1OC>>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([C:6]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=2)=[O:7])[CH:19]=[CH:18][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: COc1ccccc1OC
Agent: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2)c1
Yield: 71.9 %

Procedure:
3,5-Dimethoxybenzoyl chloride (10.28 g, 51.24 mmol), 1,2-dimethoxybenzene (6.53 ml, 51.24 mmol), and aluminum chloride (7.52 g, 56.37 mmol) were treated in the same manner as described above for the synthesis of 3-(3,4-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (10% EtOAc in hexane gradient to 50% EtOAc in hexane in 50 min.) to give (3,4-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)-methanone as a light yellow solid (11.14 g, 72%); 1HNMR (DMSO-d6) δ 7.38-7.33 (m, 2H, Ar), 7.09 (d, J=8 Hz, 1H, Ar), 6.77 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.79 (s, 6H, 2OCH3). The product was carried over to the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](=[O:11])[NH:8][C:7]=2[CH:12]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].FC(F)(F)C(O)=O>O1CCCC1.CC#N.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](=[O:11])[N:8]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]=2[CH:12]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2oc(=O)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cn1c(=O)oc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
A solution of 5-(methyloxy)-1,3-benzoxazol-2(3H)-one (0.78 g, 4.7 mmol) dissolved in 5 mL of anhydrous tetrahydrofuran was added drop-wise to a mixture of sodium hydride (60% by weight in mineral oil, 0.21 g, 5.2 mmol) suspended in 10 mL of anhydrous tetrahydrofuran under argon. The mixture was allowed to stir at room temperature for 10 minutes and then ethyl bromoacetate (0.63 mL, 5.7 mmol) was added to the mixture and stirred vigorously for 18 hours before it was determined to be complete by LCMS (two Aquasil C 18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=1.5 min and m/e 252 [M+1]+. The reaction was quenched by adding 5 mL of a 4 M solution of hydrochloric acid in dioxane. After allowing the mixture to stir for one hour, all of the volatiles were removed by rotary evaporation, and the crude residue was purified by silica gel chromatography (40 g Redisep column, silica, 40 um, 60 Å, 35 mL/min, A: methylene chloride, B: methanol, B: 0% to 10% over 30 min; detection at 214 nm) to give ethyl [5-(methyloxy)-2-oxo-1,3-benzoxazol-3(2H)-yl]acetate (0.98 g, 3.9 mmol, 83%) of a pink oil. MS (ES) m/e 252 [M+1]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[C:15]2[C:9]([CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][CH:7]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].Cl>C(Cl)Cl>[Br:16][C:17]1[CH:18]=[C:19]([C:20]([C:8]2[C:9]3[C:15]([CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]([CH3:5])[CH:7]=2)=[O:21])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc2cccccc1-2
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C(=O)c2cccc(Br)c2)c2cccccc1-2
Reaction time: 0.25 h

Procedure:
Aluminum chloride (1.87 g) was added to a solution of 1-methylazulene (2 g) in methylene chloride (20 ml) at 0° C. and the mixture was stirred for 15 minutes. Then, a solution of 3-bromobenzoyl chloride (1.86 ml) in methylene chloride (5 ml) was added dropwise to the reaction mixture at 0° C. and the mixture was stirred for one hour. The reaction mixture was added to 10% aqueous solution of hydrochloric acid under cooling with ice and was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (3-bromophenyl)(3-methylazulen-1-yl)methanone (1.2 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:18])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[Br:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>CN(C)C=O>[Br:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:18])([CH3:3])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2
Reactant: BrCc1ccccc1Br
Reactant: CC1(C)c2ccccc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2N(Cc2ccccc2Br)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.7 g (0.243 mol) of NaH, 60% in mineral oil, are dissolved in 500 ml of dimethylformamide under protective atmosphere. 22.1 g (0.106 mol) of 9,9-dimethyl-9,10-dihydroacridine are dissolved in 500 ml of DMF and added dropwise to the reaction mixture. After 1 h at room temperature, a solution of 60.6 (242 mmol) of 2-bromobenzyl bromide in 500 ml of DMF is added dropwise. The reaction mixture is stirred at room temperature for 1 h, then poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene and recrystallised from toluene/n-heptane. The yield is 37 g (94%).