Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:51]([F:54])([F:53])[F:52])[C:28]3[CH:27]=[C:26]4[C:17]([O:18][C:19]5[CH:20]=[C:21](C(O)=O)[C:22](C(O)=O)=[CH:23][C:24]=5[C:25]4([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]([F:32])([F:31])[F:30])=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][C:10](C(O)=O)=[C:11](C(O)=O)[CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=CC=2)C=CC=1.Cl>O.[Cu]>[C:33]1([C:25]2([C:29]([F:31])([F:32])[F:30])[C:26]3[CH:27]=[C:28]4[C:15]([O:14][C:13]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[C:7]4([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:51]([F:52])([F:53])[F:54])=[CH:16][C:17]=3[O:18][C:19]3[C:24]2=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1cc2c(cc1C(=O)O)C(c1ccccc1)(C(F)(F)F)c1cc3c(cc1O2)Oc1cc(C(=O)O)c(C(=O)O)cc1C3(c1ccccc1)C(F)(F)F
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: FC(F)(F)C1(c2ccccc2)c2ccccc2Oc2cc3c(cc21)C(c1ccccc1)(C(F)(F)F)c1ccccc1O3
Yield: 14.5 %

Procedure:
A mixture of 20 g (0.03 mole) 12,14-Diphenyl-12,14-bis(trifluoromethyl) -12H,14H-5,7-dioxapentacene-2,3,9,10-tetracarboxylic acid, 25 g copper powder and 100 ml quinoline was refluxed vigorously for 4 hours. The cooled mixture was poured into a cold solution of 30 ml concentrated HCl in 300 ml water. The product was extracted with methylene chloride, and the extracts were passed through a column of alumina, and the eluate was stripped. The residue was stirred with methanol, and was filtered yielding 2.5 g (16 %) of a solid in two crops. The crude material melted at 203-213° C., in line with the presence of cis- and trans- isomers. The title compound was purified by vacuum sublimation at 0.6 Torr and 200° C., and melted then at 209-215° C. Analysis: Calc. for C34H20F6O2 : C 71.1; H 3.48, F 19.9; found: C 71.4; H 3.65; F 19.9 %. The mass spectrum showed presence of two isomers in about 2:1 ratio, and a parent peak at 574, with peaks at 505 and 436 m/e showing loss of one and two CF3 groups, respectively. The NMR spectrum had complex multiplets in the 7.2-7.35 and 6.9-7.1 ppm range (totaling 17 Hs), plus two pairs of broad singlets at 6.86+6.84 ppm (2H) and 6.32+6.22 ppm (1H). The coefficient of thermal expansion (CTE) was found to be 34 ppm (0-200° C.) by thermomechanical analysis (TMA) at 10° C. per minute.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CC(O)C.C(N(C(C)C)CC)(C)C>[Br:1][C:2]1[C:3]([OH:9])=[N:4][C:5]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Oc1nc(Cl)ncc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c(O)n2)CC1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A solution of 5-bromo-2-chloropyrimidin-4-ol (6.5 g, 31 mmol), tert-butyl piperazine-1-carboxylate (6.5 g, 35 mmol) in propan-2-ol (200 mL) and diisopropylethylamine (10 mL) was stirred at 80° C. overnight. The mixture was cooled to RT and then concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate:petroleum ether (100:1) to give tert-butyl 4-(5-bromo-4-hydroxypyrimidin-2-yl)piperazine-1-carboxylate (9 g, 80%) as a yellow solid. MS (ES+) C13H19BrN4O3 requires: 358, 360, found: 303, 305 [M+H-56]+.
Reaction SMILES: B#B.[CH2:3]([NH:10][C:11](=O)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([C:28]([O:30][CH3:31])=[O:29])[CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][NH:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:15][C:16]=1[C:28]([O:30][CH3:31])=[O:29])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cc(CCC(=O)NCc2ccccc2)ccc1OCc1ccccc1
Agent: B#B
Solvent: C1CCOC1
Product: COC(=O)c1cc(CCCNCc2ccccc2)ccc1OCc1ccccc1

Procedure:
Selective reduction of the amide group in 3-(4-benzyloxy-3-methoxycarbonyl-phenyl)-propionic acid N-benzylamide using diborane in tetrahydrofuran for a reaction time of 48 hours at a temperature of 20°-25° yields N-[3-(4-benzyloxy-3-methoxycarbonyl-phenyl)-propyl]benzylamine, which, in the form of the crude product, is converted by means of hydrogen in the presence of palladium-on-charcoal catalyst (50%), in methanol as the solvent, at a temperature of 15°-20° to N-[3-(4-hydroxy-3-methoxycarbonylphenyl)-propyl]-benzylamine with a melting point of 75°-77° (from isopropanol).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH3:14])[C:12]=2[OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21](O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]C.[NH2-].[Li+]>>[CH:1]1([C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])=[O:18])[CH:10]=[C:11]([CH3:14])[C:12]=2[OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCc1cc(C)c(O)c(C2CCCCC2)c1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: [Li+]
Agent: [NH2-]
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C)c(O)c(C2CCCCC2)c1
Temperature: 150 °C

Procedure:
27.6 g of methyl 3-(3-cyclohexyl-4-hydroxy-5-methylphenyl)propionate and 27.1 g of octadecanol are heated, under nitrogen, to 80° C. as described in Example 2. After the addition of 0.1 g of lithium amide, the reaction mixture is heated for 10 hours at 150° C. The methanol forming is continuously distilled off. The yield is 30.2 g of crude product which is in the form of a yellowish oil and can be purified by column chromatography.
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].[CH3:8][CH:9]([CH2:12][CH2:13][CH3:14])[CH:10]=[O:11]>ClCCl>[N:1]([C:10]([CH:9]([CH2:12][CH2:13][CH3:14])[CH3:8])=[O:11])=[N+:2]=[N-:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCC(C)C=O
Solvent: ClCCl
Product: CCCC(C)C(=O)N=[N+]=[N-]
Temperature: 25 °C

Procedure:
Under Ar, a mixture of azidotrimethylsilane (1.15 g, 9.98 mmol) and chromic anhydride (998 mg, 9.98 mmol) was stirred at room temperature till homogeneous solution. The solution of 2-methylpentanal (500 mg, 4.99 mmol) in 5 mL of dichloromethane was added. The mixture was stirred another 5 hours, and then filtered through silica gel. The filtrate was concentrated to give the crude material. FT-IR 2135.80 cm−1, 2110.9 cm−1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:16][C:17]([F:27])([F:26])C1C=C(C=CC=1)CBr.[Mg].C(OCC)(=O)C(OCC)=O>>[F:16][C:17]([F:27])([F:26])[C:7]1[CH:2]=[C:3]([CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1cccc(C(F)(F)F)c1
Yield: 78 %

Procedure:
The title compound was prepared as described for B4 using 3-trifluoromethylbenzyl bromide (2.5 g, 10.46 mmol), magnesium (0.280 g, 11.50 mmol) and diethyl oxalate (3.06 g, 20.92 mmol). The product was isolated in the form of colorless oil in 78% yield and use instantly in next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[C:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([OH:27])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:31]3[CH:32]=[CH:33][C:28]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(=O)O)cc3)c1)N2
Yield: 76.9 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (4.0 g, 10.3 mmol), 4-carboxyphenylboronic acid (2.5 g, 15.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.1 mmol) in dioxane (10 mL) was added 2 M sodium carbonate solution in water (10 mL, 20 mmol). The resulting mixture was subjected to microwave irradiation for 60 min at 110° C. The mixture was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate solution (30 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 2-(4′-carboxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.4 g, 80%) as a white solid: LC/MS m/e calcd for C27H27NO4 (M+H)+: 430.52, observed: 430.1.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:22]([F:25])([F:24])[F:23])=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].CC(O)=O>C1COCC1>[F:25][C:22]([F:24])([F:23])[C:15]1[CH:14]=[C:13]2[C:12](=[C:21]3[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]3)[NH:11][S:8](=[O:10])(=[O:9])[C:3]1[C:2]2=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1ccc(C(F)(F)F)c2cccnc12
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(cc(C(F)(F)F)c3cccnc23)-c2ccccc21
Yield: 12.2 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-(5-trifluoromethyl-quinolin-8-yl)-benzenesulfonamide (Intermediate 281) (230 mg, 0.63 mmol), t-butyl nitrile (111 mg, 0.94 mmol) and AcOH:THF (2.3 ml: 2.3 ml) gave the title compound (27 mg, 12%) after purification by column chromatography with DCM/MeOH (99.7:0.3) as the eluent.
Reaction SMILES: [CH:1]1([C@H:4]([NH:11][C:12]([C:14]2[C:23]3[C:18](=[C:19](F)[CH:20]=[CH:21][CH:22]=3)[C:17](=[O:25])[N:16]([NH:26][CH2:27][CH3:28])[C:15]=2[CH3:29])=[O:13])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.N([O-])=[O:31].[Na+]>CN(C)C=O>[CH:1]1([C@H:4]([NH:11][C:12]([C:14]2[C:23]3[C:18](=[C:19]([OH:31])[CH:20]=[CH:21][CH:22]=3)[C:17](=[O:25])[N:16]([NH:26][CH2:27][CH3:28])[C:15]=2[CH3:29])=[O:13])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=N[O-]
Reactant: CCNn1c(C)c(C(=O)N[C@H](c2ccccc2)C2CC2)c2cccc(F)c2c1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNn1c(C)c(C(=O)N[C@H](c2ccccc2)C2CC2)c2cccc(O)c2c1=O
Temperature: 220 °C

Procedure:
A mixture of 2-ethylamino-8-fluoro-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ((S)-cyclopropyl-phenyl-methyl)-amide (47.0 mg, 0.119 mmol, sodium nitrite (80.0 mg, 1.16 mmol), and N,N-dimethylformamide (0.2 mL) was heated under microwave irradiation at 220° C. for 60 min. Partitioned between EtOAc and water (4×10 ml), then combined aqueous phases were extracted with ether (15 ml), which was washed with water (4×10 ml). The combined organic solution was concentrated in vacuo, and purified by flash chromatography (with a gradient of heptane-ethylacetate) to give 2-ethylamino-8-hydroxy-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ((S)-cyclopropyl-phenyl-methyl)-amide as a yellow solid.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:19])([F:18])[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][NH:13]2.Cl.CN(C)CCCN=C=NCC.[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[C:36]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[N:35]=[C:34]1[CH2:46][C:47]([O-])=[O:48].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[C:36]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[N:35]=[C:34]1[CH2:46][C:47](=[O:48])[N:13]1[C:14]2[C:10](=[C:9]([C:8]([F:7])([F:18])[F:19])[CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:12]1
Reactant: FC(F)(F)c1cccc2c1CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(CC(=O)N2CCc3c2cccc3C(F)(F)F)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.2 %

Procedure:
3 ml of pyridine, 94 mg of 4-trifluoromethyl-2,3-dihydro-1H-indole and 153 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 138 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 3 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 16 hours. After the addition of 50 ml of water and extraction with ethyl acetate (3×15 ml), the organic phases are combined and then washed with water (2×15 ml), and a saturated aqueous sodium chloride solution (15 ml), and then dried over magnesium sulfate, filtered through sintered glass, and concentrated under reduced pressure. The solid obtained is washed with diethyl ether (5 ml) and then dried, so as to give 64 mg of 3-methyl-6-(morpholin-4-yl)-2-{2-oxo-2-[4-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one in the form of a pink solid, the characteristics of which are the following:
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:51]([N:58]1[CH2:62][CH:61]([C:63]2[CH:68]=[CH:67][C:66]([Cl:69])=[C:65]([Cl:70])[CH:64]=2)[CH:60]([CH:71](O)[CH3:72])[CH2:59]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>C1COCC1>[CH2:51]([N:58]1[CH2:62][CH:61]([C:63]2[CH:68]=[CH:67][C:66]([Cl:69])=[C:65]([Cl:70])[CH:64]=2)[CH:60]([CH:71]([O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)[CH3:72])[CH2:59]1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: N#Cc1ccc(O)nc1
Reactant: CC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(C#N)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (1.97 g) in THF (300 mL) at 0° C. were added 6-hydroxy-nicotinonitrile (0.61 g, 5.1 mmol) and then DBAD (1.10 g). After 5 minutes was added (RS)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (1.20 g, 3.4 mmol, described herein above). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:4) yielded 1.02 g (66%) of the title compound as a colorless oil. ES-MS m/e: 452.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:4]([OH:9])[C:5]([F:8])=[CH:6][CH:7]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([O:9][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:3]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCBr
Reactant: CCCCCCOc1c(F)ccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCOc1c(F)ccc(F)c1OCCCCCC
Yield: 69.6 %

Procedure:
3,6-Difluoro-2-hexyloxyphenol (25 g, 0.11 mol) was dissolved in dry, distilled ethanol (350 ml) under a stream of nitrogen. 1-Bromohexane (45.35 g, 0.275 mol, 2.2 eq) and potassium carbonate (75.1 g, 0.54 mol, 5.5 eq) were added and the reaction mixture was stirred vigorously under reflux for 2 days. Dichloromethane (300 ml) was added to the orange reaction mixture, which was then filtered through a bed of celite to remove the potassium carbonate. The filtrate was washed with water (3×100 ml), and dried with magnesium sulphate. Removal of the solvent in vacuo yields 24.07 g of pale brown oil. This was distilled under reduced pressure to yield a colourless oil (18.82 g, 80%), bp 102° C., 0.2 mbar; (Found: C, 68.8; H, 9.05. C18H28O2F2 requires C, 68.76; H, 8.98; O, 10.18; F, 12.08%); vmax(film)/cm−1 2956 and 2860 (C—H aliph), 2361 (C═C); δH(300 MHz; CDCl3) 0.90 (3H, t, 3J(H,H)=7 Hz, —CH3), 1.33 (4H, m, 2×—CH2—), 1.46 (2H, septet, 3J(H,H)=7 Hz, —CH2CH2CH2O—Ar), 1.76 (2H, quintet, 3J(H,H)=7 Hz, —CH2CH2CH2O—Ar), 4.08 (2H, t, 3J(H,H)=7 Hz, —CH2CH2O—Ar), 6.73 (2H, dd, 3J(H,F)=14.5, 4J(H,F)=7.2 Hz, C5,6H); δC(75 MHz 1H{BB}, INEPT; CDCl3) 14.41 (CH3), 23.01 (CH2), 25.87 (CH2), 30.45 (CH2), 31.98 (CH2), 74.99 (CH2), 110.15 (CH, dd, 2J(C,F)=17.7, 3J(C,F)=4.3 Hz, C5,6), 141.94 (C, dd, 2J(C,F)=11.0, 3J(C,F)=7.0 Hz, C2,3), 153.12 (C, dd, 1J(C,F)=244.2, 4J(C,F)=3.6 Hz, C1,4); m/z (FAB+); 314 (M+, 99%), 146 (M+-alkoxy chains, 100%), 85 (79), 55 (40%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1.CCN(CC)CC>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)[N:7]=1
Reactant: Nc1ccc2c(c1)NC(=O)C2
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1Cc2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (3.51 g; 16.2 mmol) in THF (100 mL) was added a solution of ZnCl2 (1M in ether; 16.2 mL). After 15 minutes 6-aminooxindole (2 g; 13.5 mmol) was added in small portions, followed by the dropwise addition of Et3N (1.63 g; 16.2 mmol) in 10 mL of THF. The reaction was then stirred at RT overnight. Following removal of the solvent under reduced pressure, the crude reaction was triturated from methanol and the product filtered off as a yellow solid 2.2 g (50% yield). 1H NMR (DMSO-d6, 400 MHz) δ 3.40 (s, 2H), 7.13 (d, J=8.3 Hz, 2H), 7.20 (d, J=7.9 Hz; 1H), 7.27 (br s, 1H), 8.75 (s, 1H), 10.41 (s, 1H), 10.62 (s, 1H); HPLC ret. time: 5.933 min. LRMS (M+) 329.1, 331.0.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:13]=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCCCCCCCCCN.[BH4-].[Na+]>CO>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:13][OH:14])[CH:15]=[CH:16][C:17]=1[Cl:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C=O)ccc1Cl
Agent: CCCCCCCCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCc1cc(CO)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-chlorobenzaldehyde from step 3 of Amine 10 synthesis (1 eq.) in methanol (0.14 M) was added sodium borohydride (5 eq.). The resulting mixture was stirred at RT 3 h. The reaction was quenched by the addition of sat. aq. NH4Cl and then extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded an colorless oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19]([OH:21])=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.C[CH2:27][N:28](C(C)C)[CH:29]([CH3:31])[CH3:30].[I-].[K+].CNC(C)C.[N-]=C=O>CC(N(C)C)=O.C(Cl)Cl>[CH:29]([N:28]([CH3:27])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19]([OH:21])=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1)([CH3:31])[CH3:30]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(OCCCl)cc2c1=O
Agent: CNC(C)C
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(OCCN(C)C(C)C)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-[7-(2-chloroethoxy)-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoic acid (504 mg), DIPEA (0.7 ml), potassium iodide (332 mg) and N-methylisopropylamine (0.42 ml) in DMA (4 ml) was heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 120° C. for 30 minutes. The mixture was diluted with methylene chloride (25 ml), isocyanate resin (CombiZorb) (7.67 g) was added and stirred at room temperature for 18 hours. The resin was removed by filtration and the filtrate was washed with water. The aqueous phase was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to yield 3-[7-{2-[isopropyl(methyl)amino]ethoxy}-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoic acid as a pale brown solid (110 mg); NMR Spectrum: (DMSOd6) 1.00 (m, 6H), 2.15 (s, 3H), 2.30 (s, 3H), 2.45 (s, 1H), 2.85 (m, 2H), 4.15 (m, 2H), 6.70 (m, 1H), 7.20 (m, 1H), 7.40 (m, 1H), 7.55 (m, 1H), 7.70 (m, 2H), 7.80 (m, 1H), 7.95 (m, 1H); Mass Spectrum: M+H+ 395.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2[NH:17][C:16]([C:18]([F:21])([F:20])[F:19])=[N:15][C:14]=2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.C(N(CC)CC)C>C(#N)C>[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2[N:17]([C:1](=[O:3])[CH3:2])[C:16]([C:18]([F:21])([F:19])[F:20])=[N:15][C:14]=2[C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(Cl)cc(-c2[nH]c(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)n1c(C(F)(F)F)nc(-c2ccc(S(C)(=O)=O)cc2)c1-c1cc(C)cc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.9 %

Procedure:
Acetyl chloride (50 mg, 0.6 mmol) was added to a cold (5° C.), stirred solution of Example 54 (150 mg, 0.3 mmol) and triethylamine (80 mg, 0.8 mmol) in acetonitrile (3 ml). The reaction was warmed to room temperature and stirred for 4 hours. The solvent was removed and the residue was purified by chromatography on silica gel using 20% ethyl acetate in toluene as the eluent to give 15 mg of the desired product as a crystalline solid: mp 257° C. Anal. Calc'd. for C20H16N2O3ClF3S (MW 456.87): C, 52.58; H, 3.53; N, 6.13; S, 7.02. Found: C, 52.21; H, 3.61; N, 5.95; S, 7.30.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.[CH:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[CH2:18].[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:18][CH2:17][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccncc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Product: CN1CCc2c(n(CCc3ccncc3)c3ccc(Cl)cc23)CC1
Temperature: 110 °C
Yield: 28 %

Procedure:
The title compound was prepared by following general procedure 4. 9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.42 mmol), tetra n-butyl ammonium chloride (6 mg, 0.025 mmol), 4-vinylpyridine (53 mg, 0.51 mmol) were taken into 50% NaOH (3 mL). The reaction mixture was heated overnight at 110° C. The reaction was monitored by TLC. After completion of reaction, the reaction mixture was extracted with ethyl acetate and water, the organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 40 mg of 9-chloro-3-methyl-6-(2-(pyridin-4-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).