Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:29]=[C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[N:31]1[CH2:40][CH2:41][C:42]1([CH:45]=O)[CH2:44][CH2:43]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:45][C:42]1([CH2:41][CH2:40][N:31]2[C:30](=[O:29])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]2=[O:39])[CH2:44][CH2:43]1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC1(CCN2C(=O)c3ccccc3C2=O)CC1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(CN(CC2(CCN3C(=O)c4ccccc4C3=O)CC2)C2CCCc3cccnc32)nc2ccccc21
Yield: 29.5 %

Procedure:
Using General Procedure B: Reaction of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.269 g, 0.70 mmol) and 1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropanecarboxaldehyde (0.25, 1.03 mmol) with NaBH(OAc)3 (0.433 g, 2.04 mmol) in CH2Cl2 (7 mL) for 6 hours followed by purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2—CH3OH—NH4OH) followed by radial chromatography on silica gel (1 mm plate, 100:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.125 g (29%) of 2-{[{1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropylmethyl}-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester as a white foam.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[C:29]([CH3:37])[CH:28]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:33]([C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][C:29]=4[CH3:37])(=[O:34])=[O:35])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cc1cc(F)ccc1S(=O)(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(F)cc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-fluoro-2-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: C(OC(=O)C)C.Cl.C(OCC)(=O)C.C(OC(=O)[NH:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH3:45])[C:40](=[O:46])[CH:39]=[CH:38]2)[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)(C)(C)C>CO>[NH2:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH3:45])[C:40](=[O:46])[CH:39]=[CH:38]2)[CH2:24][C:25]1[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=1
Reactant: Cn1c(=O)ccc2cc(OCCCN(CCNC(=O)OC(C)(C)C)Cc3ccncc3)ccc21
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1c(=O)ccc2cc(OCCCN(CCN)Cc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A 4N-hydrogen chloride ethyl acetate solution(0.22 ml) was added to an ethyl acetate solution (3 ml) of (2-{[3-(1-Methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)-propyl]-pyridin-4-ylmethyl-amino}-ethyl)-carbamic acid tert-butyl ester (137 mg), and the mixture was stirred at room temperature overnight. 5N-Ammoia methanol solution(1 ml) was added to the reaction mixture, and the generated insoluble matter was separated by filtration. The filtrate was condensed under reduced pressure to give the title compound(85.7 mg) as an colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH2:29][CH2:28][CH2:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1>[CH3:37][S:38]([O:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH2:29][CH2:28][CH2:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:10][CH:9]=1)(=[O:7])=[O:6])(=[O:40])=[O:39]
Reactant: COc1ccc2[nH]c(=O)c3c(c2c1-c1ccc(S(=O)(=O)NCCO)cc1)CCC3
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]c(=O)c3c(c2c1-c1ccc(S(=O)(=O)NCCOS(C)(=O)=O)cc1)CCC3
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.6 %

Procedure:
To a stirred solution of N-(2-hydroxyethyl)-4-(8-methoxy-4-oxo-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinolin-9-yl)benzenesulfonamide (230 mg, 0.555 mmol) and triethylamine (168 mg, 1.66 mmol) in anhydrous tetrahydrofuran (10 mL) was added methane sulfonyl chloride (88 mg, 0.666 mmol). The reaction mixture was stirred for 20 h at room temperature. After this time the reaction mixture was filtered to remove a white precipitate, which was washed with tetrahydrofuran (30 mL). The filtrate was concentrated under reduced pressure to an orange solid. The residue was purified by flash chromatography to afford the desired product as a brown solid (141 mg, 51%). ESI MS m/z 493 [C22H24N2O7S2+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH:17]([NH:21][C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[N:29]2)=[CH:26][CH:27]=1)[CH2:18][CH2:19][CH3:20])[C:5]([NH:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[O:6].C(=O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH:17]([NH:21][C:22]1[CH:23]=[N:24][C:25]([N:28]2[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[N:29]2)=[CH:26][CH:27]=1)[CH2:18][CH2:19][CH3:20])[C:5]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:6]
Reactant: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)OC)cc1F
Agent: O=C=O
Product: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1F

Procedure:
The title compound was prepared by a method analogous to that described for Example 109, using Isomer 2 of methyl 3-(3-fluoro-4-(1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoate in Step C. 1H NMR (400 MHz, CD3OD, δ): 8.57 (s, 1H), 7.77 (s, 1H), 7.63 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.43-7.46 (m, 2H), 7.34-7.38 (m, 1H), 6.94 (d, J=8.4 Hz, 1H), 4.66 (t, J=7.2 Hz, 1H), 3.48 (t, J=7.2 Hz, 2H), 2.50 (t, J=6.8 Hz, 2H), 1.67-1.82 (m, 2H), 1.29-1.48 (m, 2H), 0.89 (t, J=7.6 Hz, 3H). MS (M+1) 494.2. Chiral SFC: Chiralpak AD-3, 4.6×50 mm, 3 μm. Modifier: 0.05% DEA. Gradient: 95% CO2/5% ethanol linear to 60% CO2/40% ethanol over 3.0 minutes. Flow: 4 mL/min. Retention time: 1.42 minutes, 99% ee (Isomer 2).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH:5]1[C:10]2[C:11]3[C:22](=[O:23])[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:12]=3[O:13][C:14](=O)[C:9]=2[CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[O:13]=[C:14]1[C:9]2[C:10](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:11]2[C:22](=[O:23])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:12]=2[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CCCN
Reactant: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Solvent: ClC(Cl)Cl
Product: CCCn1c2c(c3ccccc3c1=O)C(=O)c1ccccc1-2
Yield: 56 %

Procedure:
Propylamine (0.3 mL, 3 mmol) was added to a stirred solution of benz[d]indeno[1,2-b]pyran-5,11-dione (2) (0.49 g mmol) in CHCl3 (10 mL). The red solution stirred overnight before CHCl3 (75 mL) was added and the mixture washed with H2O (3×20 mL) and brine (1×20 mL), dried (MgSO4), and concentrated under reduced pressure to give a yellow-orange solid (0.32 g, 55%): mp 166-167° C.; IR (neat) 2967, 1660, 1502, 1427, 1317, 1193, 959 cm−1; 1H NMR (CDCl3, 300 MHz) δ8.69 (d, 1H, J=8.0 Hz), 8.33 (d, 1H, J=9.0 Hz), 7.70 (td, 1H, J=9.0, 3.0 Hz), 7.62 (d, 1H, J=6.2 Hz), 7.40 (m, 4H), 4.46 (t, 2H, J=8.0 Hz), 1.92 (m, 2H), 1.12 (t, 3H, J=7.4 Hz); CIMS m/z (relative intensity) 290 (MH+, 100). Anal. Calcd for C19H15NO2: C, H, N.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][C:7](O)=[N:8][CH:9]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O.CCN(C1C=CC=CC=1)CC>>[C:1]([C:4]1[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][C:7]([Cl:18])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nc(O)ncc1C(C)=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CCOC(=O)c1nc(Cl)ncc1C(C)=O
Temperature: 25 °C

Procedure:
A mixture of ethyl 5-acetyl-2-hydroxy-4-pyrimidinecarboxylate (2.91 g, 13.8 mmol), phosphoryl chloride (11 ml, 118.0 mmol) and diethylaniline (3 ml, 18.0 mmol) is heated to reflux under N2 for 45 min, after which it is cooled to RT and worked up. The residue is distilled, then dissolved in a small amount of methylene chloride and set aside to crystallize. The solid is then filtered, rinsed with methylene chloride and dried to give ethyl 5-acetyl-2-chloro-4-pyrimidinecarboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:3]=1.[Br:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[Br:21][C:22]1[CH:27]=[C:26]([C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]3[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1
Reactant: OB(O)c1cccc(Br)c1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.3) (2.0 g, 6.46 mmol) and commercially available 3-bromo-benzene-boronic acid (1.43 g, 7.12 mmol) according to the general procedure IIb. Obtained as a white solid (0.89 g, 32%). MS (ISP) 430.1 [(M+H)+]; mp 148.5° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:9][C:8]2=1)#[N:4].Cl[CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C)C=O.C(OCC)(=O)C>[C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=1)[C:13]1[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:9][C:8]2=1)#[N:4]
Reactant: Fc1cccnc1CCl
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(C#N)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2ncccc2F)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
Suspend sodium hydride (60% suspension in mineral oil, 114 mg, 1.64 mmol) in dimethylformamide (7 mL) and cool to 0° C. Add a solution of N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 3) (385 mg, 1.37 mmol) in dimethylformamide (3.5 mL). After several minutes, warm the reaction to room temperature, and stir for 30 min, after which time add 2-chloromethyl-3-fluoro-pyridine (Preparation 60). Stir the reaction overnight and then dilute with ethyl acetate (100 mL). Wash the reaction mixture sequentially with brine (3×75 mL), water (75 mL), and brine (75 mL). Separate the organic layer, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Purify using flash chromatography [silica gel, gradient from 0:100 to 20:80 (90:10:1 dichloromethane:methanol:concentrated ammonium hydroxide):dichloromethane] to provide 184 mg (38%) of the title compound as an off-white solid. m.p.=213-216° C.; MS: m/z 391 [C23H23FN4O+1]+; 1H NMR (300 MHz, DMSO-d6): δ 8.29-8.31 (m, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.71-7.78 (m, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.38-7.44 (m, 2H), 5.56 (s, 2H), 3.99-4.04 (m, 1H), 2.73-3.00 (m, 3H), 2.49-2.55 (m, 1H), 2.37 (septet, J=6.8 Hz, 1H), 1.96-2.00 (m, 1H), 1.76-1.83 (m, 1H), 1.01 (d, J=6.8 Hz, 6H).
Reaction SMILES: [C:1]1(=O)[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[C:1]1(=[N:17][OH:18])[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCc2c1ccc1ccccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1CCCc2c1ccc1ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,2,3,4-tetrahydrophenanthren-1-one (1.0 g, 5.1 mmol) in pyridine was added hydroxylamine hydrochloride (0.69 g, 10.0 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo. Water was added to the residue, which was then filtered and dried to provide the oxime.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:50]1(C(OC(C)(C)C)=O)[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:50]6[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCCNCC4)c3)c2C)c1
Reaction time: 3 h
Yield: 36 %

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) along with 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (48 μL, 0.00024 mol) and sodium triacetoxyborohydride (68 mg., 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The crude product was taken up in 1,2-dichloroethane (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on a Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a pale brown colored solid [40.6 mg (36%)]. LC-MS m/z 743.9 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[CH:16][CH:15]=1.[OH-].[Na+].O>[Br-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([CH3:24])([CH3:23])[CH2:21][O:22][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:6]=2)=[CH:18][CH:19]=1
Reactant: FCCOc1cccc(CCl)c1
Reactant: CC(C)(CO)c1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(COCc1cccc(OCCF)c1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A mixture consisting of 2.0 g of 3-(2-fluoroethoxy)benzyl chloride, 2.3 g of 2-(4-chlorophenyl)-2-methylpropyl alcohol, 0.5 g of triethylbenzylammonium bromide and 5 g of a 50% aqueous solution of sodium hydroxide was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and poured into water. Toluene was added, and the mixture was fully stirred. The toluene layer was separated, washed with water and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure. The resulting crude ether was purified by silica gel (100 g) column chromatography (developing solvent: toluene) to give 2.9 g of the desired 3-(2-fluoroethoxy)benzyl 2-(4-chlorophenyl)-2-methylpropyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][CH:15]([C:27](O)=[O:28])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].O[N:31]=[C:32]([NH2:36])[CH:33]([CH3:35])[CH3:34]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:14][CH:15]([C:27]3[O:28][N:36]=[C:32]([CH:33]([CH3:35])[CH3:34])[N:31]=3)[CH2:16][N:17]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:18]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:10])[F:12]
Reactant: Cc1cc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)ccc1OC(F)(F)F
Reactant: CC(C)C(N)=NO
Product: Cc1cc(C2CC(c3nc(C(C)C)no3)CN(C(=O)N3CCOCC3)C2)ccc1OC(F)(F)F

Procedure:
500 mg (1.15 mmol) of the compound from Example 167A and 130 mg (1.27 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 1. Yield: 286 mg (51% of theory)
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:53])([CH3:52])[C:29]([F:51])([F:50])[C@:30]([C:33]3[CH:38]=[C:37]([C:39]4[S:40][C:41]5[CH:47]=[C:46]([Cl:48])[CH:45]=[CH:44][C:42]=5[N:43]=4)[CH:36]=[CH:35][C:34]=3[F:49])([CH3:32])[N:31]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O.Cl>C(OCC)C>[ClH:48].[Cl:48][C:46]1[CH:45]=[CH:44][C:42]2[N:43]=[C:39]([C:37]3[CH:36]=[CH:35][C:34]([F:49])=[C:33]([C@:30]4([CH3:32])[C:29]([F:50])([F:51])[C:28]([CH3:53])([CH3:52])[O:27][CH2:26][C:25]([NH2:24])=[N:31]4)[CH:38]=3)[S:40][C:41]=2[CH:47]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4nc5ccc(Cl)cc5s4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC1(C)OCC(N)=N[C@](C)(c2cc(-c3nc4ccc(Cl)cc4s3)ccc2F)C1(F)F
Yield: 104.9 %

Procedure:
Deprotection of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(6-chloro-benzothiazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (26 mg, 35 μmol) with trifluoroacetic acid (27 μl, 349 μmol), treatment with hydrochloric acid and followed by trituration with diethyl ether yielded the (R)-5-[5-(6-Chloro-benzothiazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine hydrochloride (9 mg, 53% yield) as a white solid. MS (ISP): m/z=454.1 [M+H]+ and 456.1 [M+2+H]+.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:7]=[C:8]([N+]([O-])=O)[CH:9]=1)([O-])=O.[N+:17]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:8]1[CH:7]=[C:6]([C:13]([F:14])([F:15])[F:16])[CH:5]=[C:4]([O:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)[CH:9]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Product: O=[N+]([O-])c1cccc(Oc2cc(Oc3cccc([N+](=O)[O-])c3)cc(C(F)(F)F)c2)c1

Procedure:
In an example of the process (i), 3,5-dinitrobenzotrifluoride is condensed with m-nitrophenol in the presence of a base, in an aprotic solvent, to give 1,3-bis(3-nitrophenoxy)-5-trifluoromethylbenzene, which is then reduced to 1,3-bis(3-aminophenoxy)-5-trifluoromethylbenzene, in a high yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7](I)([CH3:9])[CH3:8].CS(C)=O.Br.[Br:16][C:17]1[CH:18]=[N:19][C:20]([OH:23])=[N:21][CH:22]=1>O>[Br:16][C:17]1[CH:18]=[N:19][C:20](=[O:23])[N:21]([CH:7]([CH3:9])[CH3:8])[CH:22]=1
Reactant: Oc1ncc(Br)cn1
Reactant: CC(C)I
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)n1cc(Br)cnc1=O
Temperature: 15 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
With cooling with ice, potassium carbonate (17 g, 123 mmol) and isopropyl iodide (4.56 mL, 45.7 mmol) were added to a dimethyl sulfoxide (150 mL) solution of 5-bromo-2-hydroxypyrimidine hydrobromide (9.0 g, 35.2 mmol), and stirred at 15° C. for 16 hours. Water was added to the reaction mixture, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, hexane/ethyl acetate=3/2) to obtain the entitled compound (2.34 g, 31%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[C:11]2[N:6]([CH2:7][CH2:8][CH2:9][CH:10]2[OH:13])[C:4](=[O:5])[C:3]=1[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[C:23]3[CH:24]=[CH:25][C:26]([F:31])=[CH:27][C:28]=3[O:29][N:30]=2)[CH2:18][CH2:17]1.C1OCCOCCOCCOCCOCCOC1.Br[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([O:58]CC)=[O:57].[H-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1>[F:31][C:26]1[CH:25]=[CH:24][C:23]2[C:22]([CH:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C:3]4[C:4](=[O:5])[N:6]5[CH2:7][CH2:8][CH2:9][CH:10]([O:13][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([OH:58])=[O:57])[C:11]5=[N:12][C:2]=4[CH3:1])[CH2:17][CH2:18]3)=[N:30][O:29][C:28]=2[CH:27]=1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Reactant: CCOC(=O)CCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCCCC(=O)O
Reaction time: 18 h

Procedure:
A solution of paliperidone (1.0 g, 2.34 mmol) in THF (15 mL), under argon, was treated with 18-Crown-6 (309.88 mg, 1.17 mmol), ethyl 6-bromohexanoate (628.76 μL, 3.52 mmol) and sodium hydride (60 w/w %, 937.80 mg, 23.45 mmol). After 18 h, the reaction mixture was poured into an aqueous saturated sodium bicarbonate solution (20 mL), and the aqueous layer was extracted with ethyl acetate (three times 20 mL). The aqueous layer was acidified with acetic acid and extracted with 2-methyl THF (three times 20 mL). The combined organic 2-methyl THF layers were dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC to give the title compound. ESI-MS (M+1) 541. 1H NMR: (CDCl3, 360 MHz): δ ppm 1.35-2.00 (m, 11H), δ 2.10-2.30 (m, 8H), δ 2.40-2.80 (m, 8H), δ 3.20-4.00 (m, 5H), δ 4.24-4.30 (m, 1H), δ 7.07 (td, J=8.97, 1.83 Hz, 1H), δ 7.24 (d, J=1.83 Hz, 1H), δ 7.76 (dd, J=8.60, 4.94 Hz, 1H).