Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:23][CH2:22][N:21]([C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=4[F:32])[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)(C)(C)C>C(O)=O>[Cl:31][C:27]1[C:26]([F:32])=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([N:21]1[CH2:20][CH2:19][C:18]([CH2:17][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:10][C:9]3[CH:8]=[CH:7][NH:6][N:5]=3)[N:16]=2)([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:23][CH2:22]1)=[O:33]
Reactant: CCOC(=O)C1(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)c2cccc(Cl)c2F)CC1
Solvent: O=CO
Product: CCOC(=O)C1(Cc2cccc(Nc3cc[nH]n3)n2)CCN(C(=O)c2cccc(Cl)c2F)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
207 mg of ethyl 4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzoyl)piperidine-4-carboxylate was dissolved in 3 ml of formic acid at room temperature, followed by stirring the reaction mixture at 100° C. for 8 hours. The reaction mixture was cooled to room temperature, and concentrated in vacuo. The resulting residue was basified with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The resulting ethyl acetate solution was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=10/1) to give the title compound as a colorless oil.
Reaction SMILES: B.O1CCCC1.[CH2:7]([O:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[C:14]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:13]=1)[CH2:8][CH2:9][CH3:10].CO>O1CCCC1>[CH2:7]([O:11][C:12]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)=[C:14]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[N:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C#N
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1CN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Borane-tetrahydrofuran (1.0M in tetrahydrofuran, 1.5 mL, 0.0016 mole) was added by syringe to a solution of 2-butoxy-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile (Example 14) (0.68 g, 0.0016 mole) in tetrahydrofuran (100 mL). After stirring at room temperature for 1 hour the solution was heated to reflux for 20 hours. Additional borane-tetrahydrofuran (2.4 mL) was added in three portions over the next 3 hours to the hot solution and stirred for 1 hour before cooling to room temperature. Methanol (20 mL) was added and the solution was concentrated to an oily solid. The product was purified by silica gel chromatography. Anal. Calc. C23H25N2 O3SF·0.5M H2O: C, 63.14; H, 5.99; N, 6.40. Found: C, 63.31; H, 5.94; N, 6.29.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+]([O-])(O)=O.[N+:18]([O:21][CH2:22][CH2:23][NH2:24])([O-:20])=[O:19]>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:24][CH2:23][CH2:22][O:21][N+:18]([O-:20])=[O:19])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: CC(=O)Oc1ccc(C(=O)NCCO[N+](=O)[O-])cc1
Yield: 74.6 %

Procedure:
Starting from 0.113 mole of 4-acetoxybenzoic acid chloride and 0.110 mole of 2-nitrooxy-ethylamine nitrate, and operating substantially as described in the preceding Example, 22 g of the title compound were obtained. M.p. 95°-97° C. (ethyl ether).
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1>CO>[NH:2]([C:6]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:5])[NH2:3]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 90.09 %

Procedure:
Hydrazine hydrate was added to a solution of terephthalic acid monomethyl ester (1 g, 5.5 mmol) in MeOH (10 mL) and stirring was continued for 1 hr. The reaction mixture was concentrated to afford 900 mg (90.09% Yield) of 4-hydrazinocarbonyl-benzoic acid. p-Toluene sulfonic acid (48 mg, 0.277 mmol) was added to a solution of 4-hydrazinocarbonyl-benzoic acid (500 mg, 2.77 mmol) in triethylorthoformate (7.5 mL, 44.0 mmol) and stirring was continued with heating at 100° C. for 3 hrs. The reaction mixture was diluted with water, the solid was collected to afford 200 mg (37.9% Yield) of 4-[1,3,4]oxadiazol-2-yl-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([OH:21])[CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.Br[CH2:30][CH:31]([CH3:33])[CH3:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([O:21][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CC(C)CBr
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1O
Product: CC(C)COc1cc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)ccc1CS(C)(=O)=O
Yield: 33.5 %

Procedure:
N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide (50 mg, 0.12 mmol) was treated with 1-bromo-2-methylpropane (26 μl, 0.24 mmol) via procedure U to yield 19 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-isobutoxy-4-(methylsulfonylmethyl)benzamide. MS (Q1) 473 (M)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:30])([CH3:29])[CH:21]([C:23]1[O:24][C:25]([CH3:28])=[N:26][N:27]=1)[NH2:22]>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:22][CH:21]([C:23]3[O:24][C:25]([CH3:28])=[N:26][N:27]=3)[C:20]([CH3:19])([CH3:29])[CH3:30])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nnc(C(N)C(C)(C)C)o1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: Cc1nnc(C(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(C)(C)C)o1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2,2-dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)propan-1-amine (example 174b) as starting materials and isolated (128 mg, 81%); MS (ESI, m/z): 413.6 (M+H+).
Reaction SMILES: Cl.[C:2](Cl)([CH3:5])([CH3:4])[CH3:3].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:2]([C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: Clc1ccccc1
Reactant: CC(C)(C)Cl
Agent: Cl
Product: CC(C)(C)c1ccc(Cl)cc1
Temperature: 30 °C
Yield: 98.7 %

Procedure:
To 16.9 g of chlorobenzene was added 1.5 g of ferric chloride, and hydrogen chloride gas was blown into the mixture for minutes. Then, 46 g of tert-butyl chloride was added dropwise to the mixture at 30° C. over a period of 1 hour. The mixture was maintained at 30° C. for 2 hours. The reaction mixture was washed with an aqueous solution of sodium carbonate and then with water, and evaporated under reduced pressure to give 25 g of 4-tertbutylchlorobenzene (bp.: 113° C./28 mmHg).
Reaction SMILES: [C:1]1([CH2:9][NH2:10])[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.CCCCCC.[C:17]([N:21]=[C:22]=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([NH:21][C:22](=[O:23])[NH:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([CH2:9][NH2:10])=[CH:2][CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: NCc1ccc(CN)cc1
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)NC(=O)NCc1ccc(CN)cc1
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a solution of 2.7 g p-xylylenediamine in 100 ml methylene dichloride, was added slowly with stirring 10 ml of a n-hexan solution containing 990 mg t-butyl isocyanate under ice cooling. Stirring was continued at room temperature for two hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography, giving 1 g of 4-(3-t-butylureidomethyl)-1-aminomethylbenzene.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([F:15])([F:14])[C:11]([OH:16])=[C:10](C(OCC)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:23]1CCOCC1>>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([OH:16])([OH:23])[C:12]([F:14])([F:15])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C(O)C(F)(F)CN(Cc2ccccc2)C1
Reactant: C1COCCO1
Agent: Cl
Product: OC1(O)CCN(Cc2ccccc2)CC1(F)F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 1-benzyl-5,5-difluoro-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylate (5.0 g) and conc. hydrochloric acid (40 mL) in 1,4-dioxane (15 mL) was stirred at 80° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and diluted with ethyl acetate, and the mixture was adjusted to pH-9 with saturated aqueous sodium carbonate solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with dichloromethane to give the title compound (1.40 g).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:5][C:4]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[C:38](=[O:39])[C:37]4[N:29]([C:30]5[C@@H:31]6[CH2:40][C@H:34]([C:35]=5[CH:36]=4)[CH2:33][CH2:32]6)[CH2:28][CH2:27]3)[C:21]=2[CH:41]=[O:42])=[CH:3]1.[BH4-].[Na+]>CO>[OH:42][CH2:41][C:21]1[C:22]([N:26]2[CH2:27][CH2:28][N:29]3[C:30]4[CH:31]5[CH2:40][CH:34]([C:35]=4[CH:36]=[C:37]3[C:38]2=[O:39])[CH2:33][CH2:32]5)=[N:23][CH:24]=[CH:25][C:20]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6[C@H]6CC[C@@H]7C6)C5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6C6CCC7C6)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A solution of 167h (120 mg, 0.21 mmol) in methanol (20 mL) was added NaBH4 (24 mg, 0.63 mmol). The mixture was stirred at 20° C. for 2 h. The reaction was quenched with water and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 167 (98 mg, 83%) as a yellow solid. MS-ESI: [M+H] 567.3. 1H NMR (500 MHz, DMSO-d6) δ 8.48 (d, J=5.0 Hz, 1H), 8.19 (s, 1H), 8.05 (d, J=2.5 Hz, 1H), 7.40 (s, 1H), 7.32 (d, J=5.0 Hz, 1H), 6.53 (d, J=5.5 Hz, 1H), 5.89 (s, 1H), 4.98 (t, J=5.0 Hz, 1H), 4.48-4.30 (m, 3H), 4.27-4.22 (m, 2H), 3.92-3.91 (m, 2H), 3.86-3.84 (m, 1H), 3.60 (s, 3H), 3.52-3.33 (m, 3H), 3.29 (ps, 1H), 2.79-2.77 (m, 2H), 2.35 (s, 3H), 1.87-1.76 (m, 3H), 1.60-1.59 (m, 1H), 1.09-0.91 (m, 2H).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].N.[CH2:9](Br)[CH:10]=[CH2:11].[Cl-].[NH4+]>>[CH3:6][C:5](=[O:7])[CH2:4][C:1](=[O:3])[CH2:2][CH2:11][CH:10]=[CH2:9]
Reactant: CC(=O)CC(C)=O
Reactant: C=CCBr
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: C=CCCC(=O)CC(C)=O
Reaction time: 0.5 h
Yield: 48 %

Procedure:
After 30 minutes, a powdery complex compound produced by mixing acetylacetone (15 g; 10.15 mol) with ammonia was gradually added to the solution. The mixture was stirred for about 1 hour, and then allyl bromide (18.2 g; 0.15 mol) was added to it. After stirring 1 hour, the solution was neutralized with solid ammonium chloride (15 g) and ammonia was removed by vaporiation. The reaction mixture was treated by the conventional method. The resulting oily product was distilled under a reduced pressure to obtain 10.1 g of 7-octene-2,4-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20](O)=[O:21])[C:6]2=[O:17].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:47][OH:48].O>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20](=[O:21])[NH:47][OH:48])[C:6]2=[O:17]
Reactant: NO
Reactant: CCOc1cc([C@@H](CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc([C@@H](CC(=O)NO)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a solution of (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid (1.3 g, 2.8 mmol) in tetrahydrofurane (10 ml) was added carbonyldiimidazole (0.7 g, 4.2 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added hydroxylamine HCl salt (0.4 g, 5.6 mmol). The resulted mixture was stirred at room temperature for 4 hours. Water (20 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was added ethyl acetate (30 ml). The mixture was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulted oil was stirred with ether (5 ml) for 2 hours and filtered to give (1R)-cyclopropanecarboxylic acid {7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (1.2 g, 86%): mp 142-144° C.; 1HNMR (DMSO-d6): δ 0.87-0.89 (m, 4H, c-CH2), 1.28-1.33 (t, J=7.5 Hz, 3H, OCH2CH3), 1.78-1.83 (m, 1H, c-CH), 2.85-2.91 (m, 2H, CH2CO), 3.73 (s, 3H), 4.00 (t, J=7.5 Hz, 2H, OCH2CH3), 4.11 (d, J=17 Hz, 1H, NCHH), 4.60 (d, J=17 Hz, 1H, NCHH), 5.53-5.69 (m, 1H, CHN), 6.92-6.94 (m, 3H, Ar), 7.58 (d, J=10 Hz, 1H, Ar), 8.26 (d, J=10 Hz, 1H, Ar), 8.84 (s, 1H), 10.46 (s, 1H), 10.57 (s, 1H); 13C NMR (DMSO-d6): δ 8.4, 8.5, 15.2, 15.9, 35.4, 46.2, 52.2, 55.9, 64.3, 74.6, 112.4, 112.7, 119.7, 119.8, 121.5, 131.7, 132.9, 136.4, 140.2, 148.4, 149.1, 166.3, 167.6, 172.4; Anal. Calcd. for C26H28ClN3O7+0.5H2O: C, 58.01; H, 5.48; N, 8.46; Found: C, 57.97; H, 5.29; N, 8.53, H2O, 1.5.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][S:28]([CH3:27])(=[O:30])=[O:29])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(C)(=O)=O)c1
Reaction time: 48 h
Yield: 82.3 %

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 200 mg, 0.735 mmol) in dichloromethane (5 ml) at room temperature was added pyridine (0.15 ml, 1.84 mmol) then dropwise over 5 minutes methanesulfonylchloride (0.11 ml, 158 mg, 1.38 mmol). The mixture was stirred for 48 h, concentrated in vacuo and the residue was purified by silica (10 g) column chromatography eluting with 90:10:1 ethyl acetate:methanol:ammonia solution (0.880), then in 80:20:1 ethyl acetate:methanol:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (212 mg, 82%).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: COC(=O)CBr
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(NC(C)=O)cc1
Temperature: 25 °C

Procedure:
4-Acetaminophenol (1.51 g), potassium carbonate (1.38 g) and methyl bromoacetate (1.0 ml) were combined in acetone (40 ml) and heated to reflux for 5 hours. The mixture was allowed to cool to room temperature, filtered and evaporated. The residue was dissolved in ethyl acetate, washed with water and then with brine then dried, filtered and evaporated to give the subtitle compound (2.32 g).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[C:20]2[C:19]([C:21]([O:23]CCN(C)C)=[O:22])=[C:18]3[C:13]([CH:14]=[C:15]4[CH:32]=[CH:31][CH:30]=[CH:29][C:16]4=[CH:17]3)=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:3]>[OH-].[Na+].CO>[CH3:3][N:2]([CH2:4][CH2:5][O:6][C:7]1[C:20]2[C:19]([C:21]([OH:23])=[O:22])=[C:18]3[C:13]([CH:14]=[C:15]4[CH:32]=[CH:31][CH:30]=[CH:29][C:16]4=[CH:17]3)=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:1]
Reactant: CN(C)CCOC(=O)c1c2cc3ccccc3cc2nc2cccc(OCCN(C)C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCOc1cccc2nc3cc4ccccc4cc3c(C(=O)O)c12
Yield: 31.9 %

Procedure:
A solution of N,N-dimethylaminoethyl 2-(N,N-dimethylamino)ethoxy-benz[b]acridine-12-carboxylate (86 mg, 0.20 mmol ) in 4N sodium hydroxide (7.3 ml) and methanol (22 ml) was stirred at 65° C. for 1 hour and at 35° C. for 15 hours. The reaction mixture was evaporated under reduced pressure to dryness. The residue was washed with water (5 ml) and air-dried, yielding 2-(N,N-dimethylamino)ethoxy-benz[b]acridine-12-carboxylic acid (23 mg, 32%). Rf 0.3 (silica gel, chloroform/methanol/water 65:25:4). MS (FAB, Glycerol Matrix): m/z 361 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([OH:19])[N:9]=1.Br[CH2:21][CH2:22][O:23][CH3:24]>O>[Cl:7][C:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([O:19][CH2:21][CH2:22][O:23][CH3:24])[N:9]=1
Reactant: COCCBr
Reactant: Oc1cc2c(Cl)cccc2c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCOc1cc2c(Cl)cccc2c(Cl)n1
Temperature: 50 °C
Yield: 86.5 %

Procedure:
Potassium carbonate (646 mg, 4.67 mmol) was added to a solution of 1,5-dichloroisoquinolin-3-ol (500 mg, 2.336 mmol) and 1-bromo-2-methoxyethane (357 mg, 2.57 mmol) and heated to 50° C. for 3 hrs. After 3 hrs the reaction was diluted with water and extracted with EtOAc (2×). The organic layer was washed with water followed by brine, dried over MgSO4, filtered and evaporated to give the crude product 1,5-dichloro-3-(2-methoxyethoxy)isoquinoline (550 mg, 87% yield), which was used as is in the next step. MS: MS m/z 272.1(M++1).
Reaction SMILES: [Na].Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[N:6]=[C:5]([S:17][CH2:18][CH3:19])[C:4]=1[C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)=[O:21].CCCCCC.[CH3:37][OH:38]>>[CH2:18]([S:17][C:5]1[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[O:21])=[C:3]([O:38][CH3:37])[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[N:6]=1)[CH3:19]
Reactant: CO
Reactant: CCSc1nc2cc(C(F)(F)F)ccc2c(Cl)c1C(=O)NCc1cccc(F)c1
Agent: [Na]
Solvent: CCCCCC
Product: CCSc1nc2cc(C(F)(F)F)ccc2c(OC)c1C(=O)NCc1cccc(F)c1
Temperature: 60 °C
Yield: 38 %

Procedure:
20 mg (0.95 mmol) sodium were added to methanol (6 ml) at RT. Once the sodium had completely dissolved, a solution of 210 mg (0.47 mmol) 4-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-7-(trifluoromethyl)-quinoline-3-carboxamide (example 122) in MeOH (2 ml) was added at RT. The mixture was then heated for 30 min at 60° C. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with water and extracted with EE. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 9:1) of the residue yielded 80 mg (0.18 mmol, 38%) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methoxy-7-(trifluoromethyl)-quinoline-3-carboxamide. MS: m/z 439.1 [M+H]+.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:30]([O:37][C:38](=[O:49])[N:39]([C@H:41]1[CH2:46][CH2:45][C@H:44]([CH:47]=O)[CH2:43][CH2:42]1)[CH3:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:30]([O:37][C:38](=[O:49])[N:39]([CH:41]1[CH2:46][CH2:45][CH:44]([CH:47]=[CH:2][O:3][CH3:4])[CH2:43][CH2:42]1)[CH3:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@H](C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=CC1CCC(N(C)C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A supension of 128.6 g (375 mmol) of (methoxymethyl)triphenylphosphonium chloride in 540 ml THF was treated at −8° C. with 43.1 g (375 mmol) potassium tert-butoxide. The red solution was stirred 30 min at 0° C. and cooled (−20° C.), then 82.6 g (300 mmol) of trans-(4-Formyl-cyclohexyl)-methyl-carbamic acid benzyl ester in 240 ml THF were dropped in (60 min). The reaction was warmed to RT and stirred for 2 h, washed with aqueous saturated NaHCO3 (540 ml). The water phase was extracted with 0.5 l TBME, the combined organic phases were oxidized with 16 ml of hydrogen peroxide solution (35%), mixed with water (150 ml). The organic solvent was evaporated, the residue was extracted with MeOH (350 ml)/hexane (2×2000 ml). The hexane was washed twice with 500 ml MeOH/water (7/3), dried (Na2SO4) and evaporated to give 81.7 g (90%) of trans-(2E/Z) [4-(2-Methoxy-vinyl)-cyclohexyl]-methyl-carbamic acid benzyl ester, MS: 303(M).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:4]=2[CH:3]=1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:27].C(N(CC)CC)C>C(Cl)Cl>[C:14]([O:13][C:11]([N:9]1[CH2:10][C:4]2[CH:3]=[C:2]([NH:1][C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])[CH:24]=[CH:23][C:5]=2[CH:6]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:7][CH2:8]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)Cc2cc(N)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)Cc2cc(NC(=O)OCc3ccc([N+](=O)[O-])cc3)ccc21
Reaction time: 5 h

Procedure:
To a stirring solution of methyl 2-{8-amino-2-[(tert-butyl)oxycarbonyl]-1H,3H,4H,5H-benzo[e]azepin-5-yl}acetate (1 eq) in methylene chloride (0.1 M) was added 4-nitrobenzyl chloroformate (1.1 eq) and triethylamine (5 eq) at room temperature. After stirring for 5 hr, the reaction mixture was diluted with methylene chloride. The organic phase was washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/Hexane). EI-MS m/z 514 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]1[NH:11][C:10](=[O:12])[CH2:9][CH:8]1[C:13]([F:16])([F:15])[F:14].F[B-](F)(F)F.[CH3:22][O+](C)C>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]1[CH:8]([C:13]([F:16])([F:14])[F:15])[CH2:9][C:10]([O:12][CH3:22])=[N:11]1
Reactant: C[O+](C)C
Reactant: O=C1CC(C(F)(F)F)C(CC2OCCO2)N1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(CC2OCCO2)C(C(F)(F)F)C1

Procedure:
The product material from Example 223 B is treated with trimethyloxonium tetrafluoroborate in DCM by the method of Example 3 to yield 2-[(1,3-dioxolan-2-yl)methyl]-3,4-dihydro-5-methoxy-3-(trifluoromethyl)-2H-pyrrole as a mixture of diastereomers.