Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[C:15](/[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)\[CH3:16])=[CH:8][CH:7]=1)C.C(O)C>[OH-].[Na+].Cl.C(OCC)(=O)C>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:19]=[CH:18][C:17](/[C:15](/[CH3:16])=[CH:14]/[CH2:13][O:12][C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:30])=[O:3])=[CH:11][CH:10]=3)=[CH:22][CH:21]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(Br)cc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C/C(=C\COc1ccc(CC(=O)O)cc1)c1ccc(-c2ccc(Br)cc2)cc1
Yield: 55.6 %

Procedure:
(E)-{4-[3-(4′-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic acid ethyl ester (example 24) (210 mg, 0.58 mmol) was suspended in 1N NaOH (1.16 mL) and ethanol (5 mL) and stirred for 24 h at room temperature. The mixture was diluted with 1N HCl (1.16 mL) and ethyl acetate (10 mL). The aqueous layer was separated and extracted with ethyl acetate (30 L) The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to give 141 mg (55%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:21]>O.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:16]=[O:21])=[O:17])=[CH:11][C:10]=1[CH2:18][OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=CC(=O)c1ccc(OCc2ccccc2)c(CO)c1

Procedure:
1-(4-Benzyloxy-3-hydroxymethylphenyl)ethanone (10.4 g) was added portionwise to a stirred solution of selenium dioxide (5.5 g) in water (0.9 ml) and dioxan (100 ml) at 60°. The mixture was stirred under reflux for 4 hours, filtered whilst hot and allowed to cool. The solid was collected and recrystallised from dioxan as a dimer, mp 180°-181° (7.7 g). (d6DMSO) 5.13 (1H, s), 4.94 (1H, s), 4.72 (2H, s), 3.42 (1H, d, J=10 Hz), 3.24 (1H, d, J=10 Hz), 2.72 (1H, m), 2.54 (5H, m), 2.04 (1H, m), 1.46 (1H, m).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=2)[C:22]1=[O:34])(=O)C.Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:49]=[CH:48][N:47]([CH2:50][CH3:51])[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1>>[C:30]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:34])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:36]3[CH:37]=[C:38]([NH:44][C:45]4[CH:49]=[CH:48][N:47]([CH2:50][CH3:51])[N:46]=4)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=3)[C:6]=1[CH2:5][OH:4])[CH2:29]2)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCn1ccc(Nc2cc(Br)cn(C)c2=O)n1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Product: CCn1ccc(Nc2cc(-c3cccc(N4Cc5cc(C(C)(C)C)ccc5C4=O)c3CO)cn(C)c2=O)n1

Procedure:
Following the same general procedure as described for 105, reaction of 103f (556 mg, 1.20 mmol) with 106a (300 mg, 1.00 mmol) gave a 20% (101 mg) yield of 106 as a white solid: mp 175-177° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 8.01 (d, 1H, J=2.0 Hz), 7.73 (d, 1H, J=7.5 Hz), 7.71 (s, 1H), 7.62 (dd, 1H, J=8.0, 1.0 Hz), 7.52 (d, 1H, J=2.5 Hz), 7.49 (t, 1H, J=7.5 Hz), 7.42 (dd, 1H, J=7.5, 1.0 Hz), 7.36 (dd, 1H, J=7.5, 1.0 Hz), 7.25 (d, 1H, J=2.0 Hz), 6.06 (d, 1H, J=2.0 Hz), 4.94 (s, 2H), 4.89 (t, 1H, J=5.0 Hz), 4.35 (d, 2H, J=5.0 Hz), 3.98 (q, 2H, J=7.5 Hz), 3.58 (s, 3H), 1.37 (s, 9H), 1.31 (t, 3H, J=7.5 Hz); MS (ESI+) m/z 512.3 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:14]([O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([CH2:2][OH:1])[CH:12]=[CH:11]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccc2cc(O)ccc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCc1ccc2cc(OCc3ccccc3)ccc2c1
Reaction time: 24 h

Procedure:
To a solution of 6-hydroxy methyl-naphthalen-2-ol (16) (1 equi.) and benzyl bromide (2) (1 equi.) in DMF (3 mL/mmole), cesium carbonate (1.25 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (20% THF/hexanes) and recrystallization from EtOAc-Hexane (1:2) afforded (6-benzyloxy-naphthalen-2-yl)-methanol (17) a white solid (88%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:28][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:28][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([NH:27][C:29](=[O:31])[CH3:30])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Agent: Cl
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 39 %

Procedure:
To a solution of 2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydro-benzo[b]thieno[2,3-d]oxepin-8-amine HCl salt (0.2 g, 0.464 mmol) in 10 ml of dried DCM was added TEA (0.32 mL, 2.3 mmol). The mixture was stirred at 0° C. for 20 min and 0.2 ml of acetic anhydride was added. After stirred for 10 min, the solution was quenched with water and evaporated to the crude product, which was purified by preparative TLC to give 115 (80 mg, 39%). 1H NMR (DMSO-d6, 400 MHz): δ 10.02 (s, 1H), 8.81 (s, 1H), 7.79-7.15 (m, 7H), 6.54 (s, 1H), 4.16 (t, J=4.8 Hz, 2H), 2.95 (t, J=4.8 Hz, 2H), 1.99 (s, 3H). MS: (ESI+) 437.1
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[NH2:39])[N:3]=1.C(O)(=O)C.[CH:44](=O)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C([BH3-])#N.[Na+]>CO>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[NH:39][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:3]=1
Reactant: COc1ccc(COc2cccc(N)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c(N)n2)cc1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(COc2cccc(NCc3ccccc3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C#N)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a cooled (0° C.), stirred solution of tert-butyl 3-(2-amino-6-{2-amino-6-[(4-methoxybenzyl)oxy]phenyl}-3-cyano-4-pyridinyl)-1-piperidinecarboxylate (0.30 g, 0.566 mmol) in methanol (10 mL) including acetic acid (0.03 g, 0.566 mmol) was added benzaldehyde (0.08 mL, 1.133 mmol) followed by sodium cyanoborohydride (0.04 g, 0.566 mmol), and the stirring was continued at 0° C. for 3 hrs. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give tert-butyl 3-(2-amino-6-{2-(benzylamino)-6-[(4-methoxybenzyl)oxy]-phenyl}-3-cyano-4-pyridinyl)-1-piperidinecarboxylate as a yellow amorphous (0.299 g, yield; 85%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.CN(C)C(N(C)C)=N.[CH2:20]([OH:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29].[N+:31]([C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([N+]([O-])=O)[C:35]=1[C:36]#[N:37])([O-:33])=[O:32]>>[OH:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:38]1[CH:39]=[CH:40][CH:41]=[C:34]([N+:31]([O-:33])=[O:32])[C:35]=1[C:36]#[N:37]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCCCCCCCCCO
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCCCCCCCCCO)cccc1[N+](=O)[O-]
Yield: 30.7 %

Procedure:
Prepared as in Example 274c (except DBU was replaced with 1,1,3,3-tetramethylguanidine) from 1,9-nonanediol and 2,6-dinitrobenzonitrile in 30.7% yield. MS 307 (MH+).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C@@H:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C([O-])(=O)C.[Na+]>>[O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C@@H:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC[C@H]1[C@@H](CC(=O)OC)CC[C@H]1O
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CCCCC[C@@H]1C(=O)CC[C@@H]1CC(=O)OC
Yield: 94.9 %

Procedure:
This ester (2.85 g) was then oxidized by means of PCC, in the presence of sodium acetate, in a manner analogous to the method described in Example 1 d), to yield 2.68 g of the desired methyl (+)-(1R)-cis-3-oxo-2-pentyl-1-cyclopentaneacetate (colorless oil; purity 98.5%; yield 92.7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][OH:22])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:30][C:31]#[N:32].[Cl-].[NH4+]>C(OCC)(=O)C.O.CN(C)C=O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][O:22][CH2:30][C:31]#[N:32])[C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCO)CC1
Reactant: N#CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOCC#N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.7 g, 4.7 mmol), tetrahydrofuran (70 mL), and dimethylformamide (8 mL). Cool in an ice bath. Add with stirring, sodium hydride (0.28 9, 60% in oil, 7.0 mmol). After 3 hours, warm to ambient temperature. After 30 minutes, again cool in an ice bath and add bromoacetonitrile (1.12 g, 9.36 mmol). Warm to ambient temperature. After 18 hours, again cool in an ice bath and add a saturated aqueous solution of ammonium chloride (5 mL) and then water (5 mL). Concentrate the reaction mixture in vacuo to remove most to the tetrahydrofuran and dilute with dichloromethane (150 mL). Extract three times with water, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give 1-(t-butoxycarbonyl)-4-(1-(2-cyanomethyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.38 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[O:9][C:10]3[C:16]([O:17]C)=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH2:4][CH2:3]1.Br.[OH-].[Na+]>>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[O:9][C:10]3[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH2:4][CH2:3]1
Reactant: COc1cccc2cc(C3CCN(C)CC3)oc12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(c2cc3cccc(O)c3o2)CC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A mixture of 1-methyl-4-(7-methoxy-2-benzofuranyl)piperidine (5.6 g) and 48% HBr (40 mi) was stirred at 120° C. for 30 minutes. After cooling to room temperature, the mixture was neutralized with 10% sodium hydroxide solution and extracted with 1:1 ethyl acetate/1-butanol. The organic extract was washed with brine, concentrated and the resulting oil was chromatographed (silica gel, eluting with 20% MeOH/DCM and 0.5% NH4OH) to afford 1.9 g of 1-methyl-4-(7-hydroxy-2-benzofuranyl)piperidine.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10](C3C=NC=C(C(F)(F)F)C=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.N1(CCN2C=C([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([O:54][CH3:55])[CH:49]=3)N=C2C2CCNCC2)CCC1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([O:54][CH3:55])[CH:49]=3)[N:9]=[C:8]2[CH:22]2[CH2:23][CH2:24][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:26][CH2:27]2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(OC)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 4-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-methoxypyridine instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=463, obsd.=463).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=O.Cl.[NH2:37][CH2:38][CH2:39][N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42].C[O-].[Na+]>CCO>[CH3:44][S:41]([N:40]([CH3:45])[CH2:39][CH2:38][NH:37][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[CH:8]2)=[O:2])(=[O:43])=[O:42]
Reactant: COC(=O)c1nc(-c2ccccc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CN(CCN)S(C)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(CCNC(=O)c1nc(-c2ccccc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O)S(C)(=O)=O
Temperature: 140 °C
Yield: 49 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3,8-diphenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (39 mg, 0.084 mmol), N-(2-amino-ethyl)-N-methyl-methanesulfonamide HCl salt (80 mg, 0.42 mmol), and NaOMe (23 mg, 0.42 mmol) in EtOH (3 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and 0.1 M HCl. The organic layer was washed with brine and dried over MgSO4. After evaporating the solvent, the residue was purified by silica gel chromatography (10-100% EtOAc/hexanes+2% AcOH) to give 24 mg of the title compound as a light yellow solid. MS: (+) m/z 583.32 (M+1).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.Cl[CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.O>CN(C)C=O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reactant: ClCCCN1CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)c1cnc2c(OCCCN3CCCCC3)cccc2c1Nc1ccccc1C
Yield: 26.9 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were dissolved in dry dimethylformamide (100 ml) at 80° , then 1-(3-chloropropyl)piperidine hydrochloride (4.0 g, 20 mmol) added and stirred for I hour. The mixture was poured into water, extracted with ether, and the extracts dried and evaporated. Chromatography (silica gel, 3-5% methanolic ammonia in dichloromethane) and recrystallisation from ether/petroleum ether gave 3-butyryl-4-(2-methylphenylamino)-8-(3-piperidinopropoxy)quinoline (1.2 g, 27%), m.p. 76°-78°.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]([N:24]([CH:51]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:25][CH2:26][N:27]([CH2:38][CH2:39][C:40]2[C:48]3[S:47][C:46](=[O:49])[NH:45][C:44]=3[C:43]([OH:50])=[CH:42][CH:41]=2)C(=O)OCC2C=CC=CC=2)=[O:23])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>ClCCl.C(O)(=O)C>[CH2:1]([NH:8][C:9](=[O:10])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]([N:24]([CH:51]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:25][CH2:26][NH:27][CH2:38][CH2:39][C:40]2[C:48]3[S:47][C:46](=[O:49])[NH:45][C:44]=3[C:43]([OH:50])=[CH:42][CH:41]=2)=[O:23])=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)c1ccc(CCNCCC(=O)N(CCN(CCc2ccc(O)c3[nH]c(=O)sc23)C(=O)OCc2ccccc2)C2CCCCCC2)cc1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(NCc1ccccc1)c1ccc(CCNCCC(=O)N(CCNCCc2ccc(O)c3[nH]c(=O)sc23)C2CCCCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The product from step iv) (0.106 g) was dissolved in dichloromethane (1.5 mL) and cooled to 0° C. Hydrobromic acid in acetic acid (33%, 0.6 mL) was added dropwise. The reaction mixture was stirred for 2 h then concentrated and azeotroped with toluene (×3) and methanol (×3). The crude material was purified by reverse phase HPLC (75-5% of 0.2% aqueous TFA in acetonitrile) to afford the product as a white solid (0.027 g).
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(C4C=CC=C(F)C=4)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:33]([CH2:36][CH:37]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[C:45]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[CH:47]=3)[C:39]=2[O:38]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[F:52][C:48]1[CH:47]=[C:46]([C:45]2[C:39]3[O:38][CH:37]([CH2:36][NH2:33])[CH2:41][C:40]=3[CH:42]=[CH:43][CH:44]=2)[CH:51]=[CH:50][CH:49]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3cccc(F)c3)c2O1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(F)c4)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Product: NCC1Cc2cccc(-c3cccc(F)c3)c2O1
Yield: 81 %

Procedure:
Treatment of (±)-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.68 g, 4.22 mmol) with sodium azide (1.09 g, 16.88 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.107 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.95 g (81%) of (±)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 200-202° C., Anal. calcd. for C15H14FNOHCl: C, 64.4; H, 5.4; N, 5.01. Found: C, 63.93; H, 5.48; N, 4.73.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=3)=[O:25])=[CH:19][C:18]=1[F:38])[CH:12]=[CH:11]2)(C)(C)C.C(OC(=O)C)C.Cl>C(OCC)(=O)C>[ClH:33].[NH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=3)=[O:25])=[CH:19][C:18]=1[F:38])[CH:12]=[CH:11]2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(ccn2-c2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccc2c(ccn2-c2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 178 %

Procedure:
In 2 mL of ethyl acetate, 104 mg (0.18 mmol) of (1-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]-2-fluorophenyl}-1H-indol-5-yl)carbamic acid tert-butyl ester was dissolved, and 2 mL of a 4N hydrogen chloride ethyl acetate solution was added thereto and the mixture solution was stirred at room temperature for one hour. The reaction solution was concentrated and the obtained product was triturated with ethyl acetate to obtain 80 mg (86%) of 1-[4-(5-aminoindol-1-yl)-3-fluorophenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride (Table 1, Compound No. 17).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:15]=2)[CH2:12][C:11]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:10]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:26][CH2:25][CH2:24][N:23]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:22][CH2:21]3)[CH:15]=2)[CH2:12][C:11]([C:27]([F:33])([F:32])[C:28]([F:30])([F:31])[F:29])=[N:10]1
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(N3CCCNCC3)c2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.3 %

Procedure:
1-(2-Chloro-phenyl)-5-[3-(homopiperazin-1-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Step 1, triethylamine (41.0 uL, 0.30 mmol) and methanesulfonyl chloride (8.1 mg, 0.07 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 3 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 3.4 mg of the titled compound as a yellow liquid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH3:20][O:21][CH2:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:27]4[CH2:26][CH2:25][NH:24][CH:23]([CH2:22][O:21][CH3:20])[CH2:28]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: COCC1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: COCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Yield: 46.3 %

Procedure:
A mixture of 0.6 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1.4 g of 2-(methoxymethyl)piperazine in 4 ml of pyridine was heated at 120°-130° C. under argon in a pressure bottle for 18 hours. The solvent was removed and the residue was chromatographed and the crude product triturated with methanol and ether, giving 370 mg of the desired product as white crystals, mp 215°-216° C.