Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:43]=[C:44](B(O)O)[C:45]([F:48])=[N:46][CH:47]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])(=O)C.[K+]>C(O)C.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:44]3[CH:43]=[C:42]([CH2:41][N:38]4[CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36][CH2:37]4)[CH:47]=[N:46][C:45]=3[F:48])[CH:3]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Cl)nc(C)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)c(B(O)O)c2)CC1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)nc(C)n2)cc1
Temperature: 100 °C
Yield: 42.4 %

Procedure:
6-Chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (214.0 mg, 0.557 mmol), 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-ylboronic acid (Example 34, Step 3) (189 mg, 0.557 mmol), PdCl2(AmPhos)2 (Aldrich, St. Louis, Mo.) (19.74 mg, 0.028 mmol), and potassium acetate (164 mg, 1.672 mmol) in a mixture of ethanol (3.0 mL) and water (0.300 mL) was sparged with argon and then heated (microwave) at 100° C. in a 20 mL microwave vial for 20 min. The reaction mixture was then concentrated onto silica gel and chromatographically purified (ISCO, 24 g, 0 to 100% EtOAc/Hexanes) to provide tert-butyl 4-((5-(6-(bis(4-methoxybenzyl)amino)-2-methylpyrimidin-4-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (152.0 mg, 0.236 mmol, 42.4% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J=9.39, 2.15 Hz, 1H); 8.14 (s, 1H); 7.17 (d, J=7.82 Hz, 4H); 6.86 (d, J=8.61 Hz, 5H); 4.74 (br. s., 4H); 3.79 (s, 6H); 3.55 (s, 2H); 3.42 (t, J=4.69 Hz, 4H); 2.62 (s, 3H); 2.37-2.43 (m, 4H); 1.45 (s, 9H). 19F NMR (377 MHz, CDCl3) δ −71.01 (d, J=9.16 Hz, 1 F). m/z (ESI, +ve ion) 643.2 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:35])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:15]=2[CH3:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>ClCCl>[C:45]([CH:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH2:9][CH2:10][NH:11][C:12](=[O:35])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[C:15]=1[CH3:34])(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)c(CC(=O)NCCCNC1CCCCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)c(CC(=O)NCCC(NC1CCCCC1)C(C)=O)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.100 g (0.2 mmol) of N-(3-cyclohexylaminoprop-1-yl)-1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetamide in 1 mL of anhydrous dichloromethane was added 0.04 mL (0.24 mmol) of diisopropylethyl amine followed by 0.015 mL (0.2 mmol) of acetyl chloride. The reaction was stirred at room temperature for 20 hr then diluted with more dichloromethane (2 mL). The solution was washed with dilute aqueous citric acid (1 mL) before drying (Na2SO4), filtering and evaporating. The residue was purified by preparative HPLC to give the title compound. 1H NMR (CDCl3) δ 7.68 (2H, d), 7.39 (2H, d), 7.16 (1H, bt), 6.86 (1H, d), 6.79 (1H, d), 6.61 (1H, dd), 3.75 (3H, s), 3.57 (2H, s), 3.36 (1H, bt), 3.06 (4H, m), 2.33 (3H, s), 1.96 (3H, s), 0.9-1.8 (12H, m).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[I:11])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].Cl>C1COCC1.[OH-].[NH4+].CCOCC>[I:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCc1ccccc1I
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCc1ccccc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of 1-azidomethyl-2-iodo-benzene (6.1 g, 23.4 mmol) in anhydrous THF (100 mL) was added triphenylphosphine (6.8 g, 25.7 mmol) at 0° C. The reaction mixture was slowly warmed up to room temperature and stirred for 16 h. The mixture was diluted with ammonium hydroxide (20 mL) and stirred for 3 h. The mixture was then treated with 2M NaOH (30 mL) and stirred for 1 h. The reaction mixture was acidified to pH 2 by adding 3 M HCl. The mixture was diluted with ether and the layers were separated. The aqueous layer was basified to pH 9 by adding 2 M NaOH and then extracted with CH2Cl2 (×3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to yield an oily residue. The resulting residue was treated with ether and filtered. The filtrate was purified by silica gel column chromatography using 95:5 CH2Cl2:MeOH as an eluent to afford 5.4 g (80%) of 2-iodobenzylamine.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:37]=[CH:38][C:39]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:40]([CH:44]=1)[C:41](O)=[O:42].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[F:35][C:36]1[CH:37]=[CH:38][C:39]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:40]([C:41]([N:3]2[CH2:4][CH2:5][C@@H:6]3[C@@H:1]([N:8]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:7]3)[CH2:2]2)=[O:42])[CH:44]=1
Reactant: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN(c3cnc4ccccc4n3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-2-(3,8-Diaza-bicyclo[4.2.0]oct-8-yl)quinoxaline (Intermediate 3) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C23H20FN7O, 429.46; m/z found 430.1 [M+H]+. 1H NMR (CD3OD): 8.60-8.30 (m, 1H), 8.04-7.33 (m, 8H), 7.24-6.55 (m, 1H), 5.15-4.72 (m, 1H), 4.54-4.43 (m, 2H), 4.32-3.53 (m, 4H), 3.26-3.16 (m, 1H), 2.36-1.91 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](N)[CH2:25][NH2:26].[OH-].[Na+].Cl>>[NH:26]1[CH2:25][CH2:24][N:12]=[C:11]1[CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1]
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Product: Nc1cccc(CC2=NCCN2)c1
Temperature: 100 °C

Procedure:
A mixture of 30.7 mmol (5 g) of 3-nitrophenylacetonitrile and 30 mmol (7.2 g) of ethylenediamine para-toluenesulphonate is heated at 100° C. for 1 hour. After cooling to 20° C., the mixture is hydrolysed with 100 ml of a 5M aqueous solution of sodium hydroxide and then extracted with dichloromethane. The organic phases are dried over magnesium sulphate and concentrated. The residue obtained is converted into the hydrochloride by the action of an ethanolic HCl solution to yield the expected product.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])=[CH:21][CH:20]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[O:31])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Reactant: COc1ccc(-c2ocnc2C(=O)O)cc1
Product: COc1ccc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)cc1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(4-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.11 min; [M+H]+=429.03.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:2].C(N(CC)CC)C.[C:40]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:45]=[CH:44][C:43]([C:46](Cl)=[O:47])=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([N:24]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:46]([C:43]1[CH:44]=[CH:45][C:40]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:41][CH:42]=1)=[O:47])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(CCOc1ccc(OC(C)(C)C(=O)OCC)cc1)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(CCOc1ccc(OC(C)(C)C(=O)OCC)cc1)N(Cc1ccccc1)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.1 %

Procedure:
A sample of 2-benzylamino-4-[4-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenoxy]-butyric acid ethyl ester (490 mg, 1.10 mmol) was dissolved in 10 mL of methylene chloride followed by addition of triethylamine (0.31 mL, 2.21 mmol) and biphenyl-4-carbonyl chloride (287 mg, 1.33 mmol). The reaction was allowed to stir at room temperature for 12 hours then partitioned between additional methylene chloride (50 mL) and 0.1 N HCl (50 mL). The organic phase was dried over sodium chloride, then concentrated under reduced pressure to yield 687 mg (100%) of an oil. HPLC RT1=7.65 min; 1H NMR (400 MHz, CDCl3) δ7.60-7.20 (m, 14H), 6.77-6.46 (m, 4H), 4.91-4.45 (m, 2H), 4.19-3.66 (m, 7H), 2.78-2.12 (m, 2H), 1.49 (s, 6H), 1.25-1.22 (m, 6H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[Br:26][C:27]1[CH:28]=[C:29](I)[CH:30]=[C:31]([Br:33])[CH:32]=1.C(O)(C(F)(F)F)=O>C1COCC1.CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[C:25][C:29]2[CH:28]=[C:27]([Br:26])[CH:32]=[C:31]([Br:33])[CH:30]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: Brc1cc(Br)cc(I)c1
Reactant: C#CCCCCCc1cccc(OCCCC(=O)O)c1CCC(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCOc1cccc(CCCCCC#Cc2cc(Br)cc(Br)c2)c1CCC(=O)O
Temperature: 60 °C
Yield: 57.4 %

Procedure:
To a solution of 4-[2-(2-Carboxy-ethyl)-3-hept-6-ynyl-phenoxy]-butyric acid (250 mg, 0.72 mmol), 3,5-dibromoiodobenzene (preparation in J. Org. Chem. 2003, 68, 8750) (261 mg, 0.72 mmol), CuI (7 mg, 0.036 mmol) in THF (5 mL) and Et3N (5 mL) was added bis-(triphenylphosphine)palladium(II) dichloride (25 mg, 0.036 mmol). The reaction mixture was heated at 60° C. for 3 h. Then the reaction mixture was cooled down, a few drop of TFA was added and the resulting mixture was evaporated under vacuo. The crude material was purified by column chromatography using a gradient from EtOAc to 20% MeOH-EtOAc as eluant to give the title compound (240 mg, 60%) as a oil. HR-MS-EI(+): calculated for C26H28O5Br2(M+Na) 601.0195, found 601.0193.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=O)=[CH:5][CH:4]=1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:31])[CH3:30])[CH:24]=1.C(OC(=O)C)(=O)C.Cl>>[CH3:30][N:29]([CH3:31])[C:25]1[CH:24]=[C:23]([N:22]([CH3:32])[CH3:21])[CH:28]=[CH:27][C:26]=1[C:7]1([C:6]2[CH:18]=[CH:19][C:3]([N:2]([CH3:20])[CH3:1])=[CH:4][CH:5]=2)[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:13])[O:12]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)cc1
Temperature: 95 °C

Procedure:
A mixture of 2-(4-(dimethylamino)benzoyl)benzoic acid (26.8 g.), N,N.N', N'-tetramethyl-m-phenylenediamine (16.4 g.) and acetic anhydride (80 g.) was heated (to 95° C.) during one hour, cooled and poured into dilute hydrochloric acid. The resulting mixture was basified. Recrystallization of the resulting solid from a mixture of toluene and hexane afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)-phenyl)phthalide (I: X= Y4 = (CH3)2N, Y2 = Z4 = Z5 = Z6 = Z7 = H) (m.p. 190°-194° C.).
Reaction SMILES: C([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H: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][C@H:15]2[C:38](=[O:59])[NH:39][C@H:40]([C:45](=[O:58])[NH:46][C@@H:47]([CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[C:48](=[O:51])[NH:49][CH3:50])[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:13])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])C.[Li+].[OH-].Cl>C1COCC1.CO.O>[CH:52]1([C@H:47]([NH:46][C:45]([C@@H:40]([NH:39][C:38]([C@@H:15]2[CH2:16][C@H: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:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:18][C@H:14]2[C:12]([NH:11][C@:6]2([C:4]([OH:5])=[O:3])[CH2:8][C@H:7]2[CH:9]=[CH2:10])=[O:13])=[O:59])[C:41]([CH3:43])([CH3:42])[CH3:44])=[O:58])[C:48](=[O:51])[NH:49][CH3:50])[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)O
Reaction time: 48 h
Yield: 66.5 %

Procedure:
To a solution of compound 39 (20 mg, 0.025 mmol) in THF/MeOH/water 2:1:1 (2 mL) at 0° C. was added 1M LiOH (175 uL, 0.175 mmol) and the solution was allowed to attain room temperature and was stirred for 48 h. The solution was acidified to pH 3 with 1M HCl and was then evaporated and coevaporated with toluene. The crude product was purified by HPLC (MeOH/water 6:4+0.5% TFA followed by MeOH/water 4:1+0.2% TFA) to give compound 40 (13 mg, 67%) as a colorless solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)(O)[CH2:15][C:9]=2[CH:8]=[CH:7][C:6]=1[O:29][CH3:30])([CH3:3])[CH3:2]>C(O)(=O)C.O>[CH:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[CH:15][C:9]=2[CH:8]=[CH:7][C:6]=1[O:29][CH3:30])([CH3:3])[CH3:2]
Reactant: COc1cc(C2(O)CCCc3c(ccc(OC)c3OC(C)C)C2)cc(OC)c1OC
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C2=Cc3ccc(OC)c(OC(C)C)c3CCC2)cc(OC)c1OC
Yield: 95.1 %

Procedure:
A mixture of the SM (40) (1.1 g, 2.64 mmol) in 30 mL of acetic acid and 100 mL of water, taken in a 250 mL round bottom flask were refluxed for 12 h. The reaction mixture was cooled and extracted with dichloromethane (3×25 mL) and the combined organic phases were dried over magnesium sulfate. The solvent evaporated and the crude product was purified by flash column chromatography (10:90 ethylacetate:hexanes), to afford 1 g (95%) of 4-Isopropoxy-3-methoxy-8-(3,4,5-trimethoxy-phenyl)-6,7-dihydro-5H-benzocycloheptene as white crystals. Rf: 0.56 (60:40, Hex:EA)
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[O:4]=[C:5]([CH3:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=1.Cl>O1CCCC1.C(OCC)(=O)C.O.N1C=CC=CC=1>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([CH:6]([C:5](=[O:4])[CH3:14])[C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])=[O:21])=[C:18]([N+:25]([O-:27])=[O:26])[CH:17]=1
Reactant: O=C(Cl)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: -8 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Under a nitrogen atmosphere, to a suspension of 2.28 g of magnesium chloride in 50 mL of tetrahydrofuran was added 3.80 g of tert-butyl 3-oxobutanoate at room temperature. The mixture was cooled to −8° C., and 3.9 mL of pyridine was added thereto, followed by stirring at the same temperature for 30 minutes, warming to room temperature, and further stirring for 30 minutes. The mixture was cooled to −8° C., and a solution of 5.3 g of 4-bromo-2-nitrobenzoyl chloride in 20 mL of tetrahydrofuran was added thereto, followed by stirring at the same temperature for 1 hour, warming to room temperature, and further stirring for 1.5 hours. The mixture was poured into a mixture of water and ethyl acetate, and adjusted to pH 3 with concentrated hydrochloric acid. The aqueous layer was separated, and then the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 4.95 g of tert-butyl 2-(4-bromo-2-nitrobenzoyl)-3 -oxobutanoate.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[BH4-].[Na+].[C:33](O)(=O)[CH3:34]>>[F:30][C:2]([F:29])([F:1])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][N:12]([CH2:33][CH3:34])[CH2:11][CH2:10]1
Reactant: CC(=O)O
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCNCC2)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CCN1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Isomer A of 4-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-4-phenylazepane (3 mg), in glacial acetic acid (0.05 mL) was added sodium borohydride (2 mg) in two portions. After addition, the mixture was stirred at room temperature for overnight. The mixture was concentrated under vacuum. Then saturated sodium bicarbonate and dichloromethane was added to the mixture and the organic layer was separated. The aqueous layer was extracted with dichloromethane 2 times and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to give the product as a clear colorless sticky oil (1.8 mg, 56% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18](C=O)=[CH:17][CH:16]=1.[OH:23]OS([O-])=O.[K+].CCOC(C)=O>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([OH:23])=[CH:17][CH:16]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=S([O-])OO
Agent: COC(=O)c1ccc(OC)cc1
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To prepare methyl 4-methoxybenzoate, 4-methoxybenzaldehyde (100 mg) was dissolved in MeOH (10 mL), and OXONE (0.451 g) was added and stirred at room temperature for 18 hours with the reaction having a final volume (11 mL). The reaction was monitored by TLC or GC analysis. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (30 mL×3) and brine (30 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain methyl 4-methoxybenzoate in 19% yield and 4-methoxy phenol in 77% yield after purification by silica gel column chromatography.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:11][CH2:12][C@H:13]([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([Cl:28])[CH:21]=3)=[N:16]2)[CH3:14])=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[Cl:28][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][N:15]([C@H:13]([CH3:14])[CH2:12][NH:11][C:9]([C:7]3[NH:6][N:5]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:8]=3)=[O:10])[N:16]=2)[CH:25]=[CH:24][C:23]=1[C:26]#[N:27]
Reactant: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Yield: 87.3 %

Procedure:
(R)-3-acetyl-N-(2-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl)-1H-pyrazole-5-carboxamide (100 mg, 0.25 mmol) was treated with sodium borohydride using the method of Example 102. Thus, 87 mg (87%) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 1.37 (d, 3H), 1.46 (d, 3H), 3.52-3.72 (m, 2H), 4.63-4.84 (m, 2H), 5.40 (bs, 1H), 6.42 (bs, 1H), 6.95 (d, 1H), 7.87 (d, 1H), 7.99 (s, 2H), 8.09-8.22 (m, 2H), 13.0 (bs, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][C:20](=[O:22])[N:19]([N:23]([CH3:37])[CH:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=4)[CH2:26][CH2:25]3)[CH:18]([C:38]([O:40]C)=[O:39])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[OH-].[Na+].Cl>CO>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][C:20](=[O:22])[N:19]([N:23]([CH3:37])[CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=4)[CH2:28][CH2:29]3)[CH:18]([C:38]([OH:40])=[O:39])[CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2
Reactant: COC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1N(C)C1CCN(c2ccnc(C)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(N2CCC(N(C)N3C(=O)CN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(=O)O)CC2)ccn1
Yield: 84.1 %

Procedure:
A mixture of methyl 4-[(6-chloro-2-naphthyl)sulfonyl]-1-[methyl[1-(2-methyl-4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylate hydrochloride (0.22 g) obtained in Example 128 and a 1N aqueous solution of sodium hydroxide (1.4 ml) in methanol (4.0 ml) was stirred at 40° C. for 30 minutes. The reaction mixture was cooled, and the reaction system was adjusted at pH 5 with 1N hydrochloric acid, and then concentrated under reduced pressure. The residue was purified on a CHP-20 column (water→1% conc. aqueous ammonia-containing 25% aqueous solution of acetonitrile) to obtain the title compound (0.17 g) as a colorless powder.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:13]=[C:12]([NH2:14])[C:11]([Cl:15])=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].B(Br)(Br)Br.[OH-].[Na+].O>C(Cl)Cl>[NH2:14][C:12]1[CH:13]=[C:4]([OH:3])[C:5](=[CH:10][C:11]=1[Cl:15])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(Cl)c(N)cc1OC
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Nc1cc(O)c(C(=O)O)cc1Cl
Temperature: 25 °C

Procedure:
A suspension of 37 g (0.15 mol) of methyl 2-methoxy-4-amino-5-chlorobenzoate hydrochloride in 500 ml methylene chloride is stirred at 25° C. To this is added 600 ml (0.60 mol) of BBr3 in CH2Cl2 gradually until the ester dissolves. After 24 hours stirring a ppt. forms on the side of the flask. This mixture is poured into rapidly stirring ice water (700 ml). Aqueous NaOH (5.5N, 600 ml) is poured in to the flask to dissolve the ppt. The water organic layer forms a ppt. and this mixture is stirred and cooled in an ice bath and treated with the NaOH solution cautiously. The ppt. dissolves and the organic layer is separated. The aqueous layer is washed with CH2Cl2 (200 ml) and then cooled to 0° and treated with concentrated HCl with stirring. A colorless ppt. forms which is filtered, washed (H2O) and air dried to obtain 4-amino-5-chlorosalicylic acid which is used directly in the next step.