Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([O:20][CH2:21][C:22]([OH:24])=[O:23])[C:10]([C:25](=[O:39])[NH:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH3:28])=[N:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:47](C)[C:48](OCC)=O>CC(C)=O>[CH2:47]([O:23][C:22](=[O:24])[CH2:21][O:20][C:11]1[C:10]([C:25](=[O:39])[NH:26][C@@H:27]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=2)[CH3:28])=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH3:48]
Reactant: CCOC(=O)C(C)Br
Reactant: C[C@@H](NC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1OCC(=O)O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(C(=O)N[C@H](C)c2ccc(C(F)(F)F)cc2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [E1] (156 mg, 0.28 mmol) in acetone was added potassium carbonate (26 mg) and ethyl 2-bromopropionate (11.7 ul, 0.10 mmol). The resulting suspension was stirred overnight at room temperature then partitioned between dichloromethane and brine. The organic phase was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica (2 g) silica, eluting with dichloromethane then ethyl acetate/heptane (1/1) to give 142 mg of {1-(2-Chloro-phenyl)-5-(4-chloro-phenyl)-3-[(R)-1-(4-trifluoromethyl-phenyl)-ethylcarbamoyl]-1H-pyrazol-4-yloxy}-acetic acid ethyl ester
Reaction SMILES: [Cl-].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][C:14]1[CH:39]=[CH:38][C:17]([CH2:18][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:16][CH:15]=1.[H-].[Na+].[OH:42][C:43]1[CH:50]=[CH:49][C:46]([CH:47]=O)=[CH:45][CH:44]=1>CN(C=O)C>[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[CH:47][C:46]2[CH:49]=[CH:50][C:43]([OH:42])=[CH:44][CH:45]=2)=[CH:38][CH:39]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: c1ccc([P+](Cc2ccc(OCc3ccc4ccccc4n3)cc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of (13.29 mmol) of 4-(2-quinolinylmethyloxy)benzyl triphenylphosphonium chloride in 100 ml of dry DMF under positive nitrogen atmosphere is cooled to 0° C. and 0.50 g (20.77 mmol), of an 80% NaH in oil dispersion is added in small portions. The suspension is aged for 15 minutes at 0° C. followed by 45 minutes at room temperature to assure complete anion formation. The flask is cooled to 0° C. and (13.29 mmol) of 4-hydroxybenzaldehyde in 20 ml of DMF is dropped in over a period of 15 minutes. The reaction is allowed to equilibrate to room temperature and stirred for 2 hours. The resultant mixture is poured into ice water and filtered. The precipitate is dissolved in CH2Cl2, dried, and concentrated in vacuo. The crude product is recrystallized from ether to give 4-(4-(2-quinolinylmethyloxy)styryl)-phenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])=[O:15])[C:12](=[O:23])[NH:11][C:10]([CH3:24])=[C:9]2[C:25]([O:27][CH3:28])=[O:26])=[CH:4][CH:3]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([NH2:48])[CH:43]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].Cl.CN(C)CCCN=C=NCC.C(Cl)Cl>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:43]=[C:44]([CH:45]=[CH:46][CH:47]=2)[NH:48][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][NH:16][C:14]([N:13]2[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:9]([C:25]([O:27][CH3:28])=[O:26])=[C:10]([CH3:24])[NH:11][C:12]2=[O:23])=[O:15])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)O)C1c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)Nc2cccc(C3CCN(C(=O)OC(C)(C)C)CC3)c2)C1c1ccc(F)cc1
Reaction time: 12 h
Yield: 33.2 %

Procedure:
A 10-mL RB-flask was charged with 4-{[(6-(4-fluorophenyl)-5-(methoxycarbonyl)-4-methyl-2-oxo-3,6-dihydro-1(2H)-pyrimidinyl)carbonyl]amino}butanoic acid (77.0 mg, 0.189 mmol), tert-butyl-4-[3-(amino)phenyl]-1-piperidinecarboxylate (52.2 mg, 0.189 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (0.567 mmol, 87.8 mg), 4-dimethylaminopyridine (11.5 mg, 0.0945 mmol) in DMF:DCM (0.2:2.0 mL) at room temperature. The reaction mixture was stirred for 12 h and water (10.0 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with CHCl3 (3×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed (silica, hexanes:EtOAc 9:1) to afford the desired product (40.9 mg, 33.2%): 1H NMR (400 MHz, CDCl3) δ 8.03 (m, 3H), 7.57 (s, 1H), 7.36-7.28 (m, 3H), 7.27-7.22 (m, 1H), 6.97-6.89 (m, 3H), 6.72 (s, 1H), 3.72 (s, 3H), 3.47-3.37 (m, 2H), 2.42 (s, 3H), 2.37-2.29 (m, 2H), 1.98-1.91 (m, 2H), 1.86-1.75 (m, 2H), 1.72-1.54 (m, 7H), 1.48 (s, 9H); ESMS m/e: 652.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([OH:17])[C:11]([CH3:19])([CH3:18])[CH2:10]2)[N:5]=[C:4]([N:20]2[C:25]([CH3:27])([CH3:26])[CH2:24][CH2:23][CH2:22][C:21]2([CH3:29])[CH3:28])[N:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O>[O:33]1[CH2:34][CH2:35][N:30]([C:2]2[N:7]=[C:6]([O:8][CH:9]3[CH2:10][C:11]([CH3:19])([CH3:18])[N:12]([OH:17])[C:13]([CH3:15])([CH3:16])[CH2:14]3)[N:5]=[C:4]([N:20]3[C:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][CH2:24][C:25]3([CH3:27])[CH3:26])[N:3]=2)[CH2:31][CH2:32]1
Reactant: C1COCCN1
Reactant: CC1(C)CC(Oc2nc(Cl)nc(N3C(C)(C)CCCC3(C)C)n2)CC(C)(C)N1O
Solvent: O
Product: CC1(C)CC(Oc2nc(N3CCOCC3)nc(N3C(C)(C)CCCC3(C)C)n2)CC(C)(C)N1O

Procedure:
5 g of 2-chloro-4-(1-hydroxyl-2,2,6,6-tetramethylpiperidin-4-oxy)-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 36) are stirred under reflux with 50 ml of morpholine for 3 hours. After cooling to 20°, 200 ml of water are added and the precipitate is filtered off. After recrystallization from petroleum ether, the above product is obtained as reddish crystals which melt at 153°-157°.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C:10]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>O1CCOCC1>[CH3:19][C:16]1[CH:17]=[CH:18][C:10]2[NH:9][C:2](=[O:3])[O:13][C:12](=[O:14])[C:11]=2[CH:15]=1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Yield: 94.1 %

Procedure:
Trichloromethyl chloroformate (36.27 mL, 300 mmol) was added to a stirred solution of Compound 10 (41.3 g, 273 mmol) in dry dioxane at room temperature and the solution was refluxed for 4 h. The solution was cooled in ice bath and the solids formed were filtered. The solids were washed by ether and dried under vacuum at room temperature to yield 45.5 g (94%) of white solids. M.P. 257° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 7.06 (d, J=8.6 Hz, 1H), 7.56 (dd, J=8.6, 1.8 Hz, 1H), 7.71 (d, J=1.1, 1H), 11.63 (s, 1H). EIMS (neg. mode) m/z 176 (M−1), 152 (M+23). Anal. (C9H7NO3) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[N:22]1([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([C:35]3[CH:40]=[CH:39][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:36]=3)=[O:34])[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:38]3[CH:39]=[CH:40][C:35]([C:33]([N:30]4[CH2:29][CH2:28][CH:27]([N:22]5[CH2:23][CH2:24][CH2:25][CH2:26]5)[CH2:32][CH2:31]4)=[O:34])=[CH:36][CH:37]=3)=[CH:14][C:6]1=2
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2c(F)ccc(F)c2Cl)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 36 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (42 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a pale yellow foam (36% yield). M.p. 93-95° C., LCMS: m/z=553.00 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.75-1.85 (m, 5H), 1.87-2.04 (m, 2H), 2.22-2.33 (m, 1H), 2.88-3.08 (m, 2H), 3.28-3.33 (m, 2H), 3.52-3.58 (m, 2H), 3.82-3.90 (m, 1H), 4.53 (s, 1H), 4.90 (bs, 1H), 6.96-7.02 (m, 1H), 7.17 (s, 1H), 7.18-7.20 (m, 1H), 7.42 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 7.75 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].O1CCCCC1[N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1>>[Cl:18][C:15]([F:17])([F:16])[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:19]=[CH:20][C:21]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[C:2]([C:36]3[NH:35][N:34]=[CH:38][CH:37]=3)[CH:3]=2)=[CH:9][CH:10]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 8 using (R)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxypyrrolidin-1-yl)benzamide (Stage 20.1) and 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester to afford an off-white solid. UPLC-MS (Condition 3) tR=0.99 min, m/z=449.0 [M+H]+, m/z=493.0 [M+formic acid-H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.79 (m, 1H) 1.80-1.92 (m, 1H) 2.72 (d, J=10.88 Hz, 1H) 3.03-3.18 (m, 2H) 3.19-3.30 (m, 1H) 4.19 (br. s, 1H) 4.77-4.92 (m, 1H) 6.22-6.42 (m, 1H) 6.76-6.93 (m, 1H) 7.31 (d, J=8.56 Hz, 2H) 7.45-7.81 (m, 1H) 7.83-7.95 (m, 4H) 10.12 (s, 1H) 12.71-13.12 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)=[CH:5][CH:4]=1.[I-:16].[Na+]>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][I:16])=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: COc1ccc(CCCCCCBr)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1ccc(CCCCCCI)cc1

Procedure:
6-(4-Methoxyphenyl)hexyl iodide [VIa; Ar is 4-CH3OC6H4, R is H] was prepared from 16.3 g. of 6-(4-methoxyphenyl)hexyl bromide (Preparation C10) and 9.93 g. of sodium iodide in 325 ml. of 2-butanone, to give 19.3 g. of product as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][OH:11].O.[OH-].[Na+]>>[N:1]1([CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: OCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCCN1CCCCC1

Procedure:
Combine piperidine (18.01 g, 0.212 mol), 3-chloro-1-propanol (10 g, 0.106 mol) and water (3.2 g, 0.18 mol) and heat on a steam-bath for ˜5 hours. Add sodium hydroxide (6.35 g, 0.16 mol) to the cooled solution and heat the resulting mixture on a steam-bath for ˜30 minutes. Add water, separate the organic layer, and extract the aqueous layer with dichloromethane, twice. Combine the organic layers and wash with water, dry with sodium sulfate and evaporate the solvent to give the final, desired compound. The final compound may be purified by chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH3:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:28]([N:36]2[CH2:48][CH2:47][C:46]3[N:45]4[C:40]([CH2:41][CH2:42][CH2:43][CH2:44]4)=[CH:39][C:38]=3[C:37]2=[O:49])=[N:29][CH:30]=[CH:31][C:32]=1B(O)O)(=[O:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:36]2[CH2:48][CH2:47][C:46]3[N:45]4[C:40]([CH2:41][CH2:42][CH2:43][CH2:44]4)=[CH:39][C:38]=3[C:37]2=[O:49])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH3:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: CN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CN(C)C4)cn3)c(=O)n(C)c2)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Temperature: 100 °C
Yield: 37 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 5-bromo-1-methyl-3-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)pyridin-2(1H)-one 239c (140 mg, 0.40 mmol), 244c (230 mg, 0.60 mmol), Pd(dppf)Cl2 (20 mg, 0.020 mmol), K3PO4 (180 mg, 0.80 mmol), sodium acetate•3 water (120 mg, 0.80 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified on silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 244d as a yellow solid (90 mg, 43%). MS-ESI: [M+H]+ 608.3
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH2:23]O>>[Cl:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH2:23][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: Cc1ccc(CO)c(Cl)c1
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(Cl)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-chloro-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.35 (3H, s), 5.30 (2H, s), 5.80 (1H, d, J=1.6 Hz), 7.10 (1H, d, J=8.4 Hz), 7.25 (1H, d, J=3.2 Hz), 7.40 (2H, dd, J=1.2 Hz, 5.2 Hz), 7.58 (1H, d, J=2.4 Hz), 8.06 (1H, s), 8.71 (1H, d, J=5.2 Hz). [M+H] Calc'd for C17H13ClN4O, 325. Found, 325.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCOc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(OCCCC(=O)O)cc2)CC(C)(C)C1
Yield: 84.1 %

Procedure:
The hydrolysis procedure described for 11 (example 5, step 3) was used. A solution of ethyl 4-({4-[(4-fluorophenyl) (3,3,5,5-tetramethylcyclohexylidene) methyl]phenyl}oxy) butanoate) (12) (0.665 g, 1.47 mmol) in THF/EtOH (1:1, 10 mL) was treated with 1 N NaOH (5 mL, excess) at 70° C. for 1 h. The reaction mixture was cooled and poured into 20% aqueous HCl (40 mL). Standard work-up followed by purification afforded 0.525 g (84%) of the title compound 13 as a white foam. 1H NMR (300 MHz, DMSO-d6): δ12.13 (br s, 1H), 7.15 (d, J=6.6 Hz, 2H), 7.12 (d, J=9.6 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 3.94 (t, J=6.3 Hz, 2H), 2.37 (t, J=7.2 Hz, 2H), 1.93 (s, J=2H), 1.89 (s, 2H), 1.76 (quintet, J=6.3 Hz, 2H), 1.27 (s, 2H), 0.89 (s, 12H). LCMS (ESI): m/z 423 (M−H)−. Anal. Calcd for C27H33FO3, C, 76.39, H, 7.83, F, 4.47. Found: C, 76.30, H, 7.90, F, 4.52.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16][CH:17]=[O:18])[CH:6]=[C:7]([CH2:14]Br)[CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH3:2].[P:20]([O:29]C(C)C)([O:25][CH:26]([CH3:28])[CH3:27])[O:21][CH:22]([CH3:24])[CH3:23]>>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16][CH:17]=[O:18])[CH:6]=[C:7]([CH2:14][P:20]([O:25][CH:26]([CH3:28])[CH3:27])([O:21][CH:22]([CH3:24])[CH3:23])=[O:29])[CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH3:2]
Reactant: CCOC(=O)C(C=C(CBr)CCOC(C)=O)NC=O
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)C(C=C(CCOC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 19 h

Procedure:
8.7 g (25 mmol) of 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 21 ml (75 mmol) of triisopropyl phosphite (90%) are heated to from 80° to 90° C. and stirred for 19 hours under a pressure of approximately 100 mbar. The excess triisopropyl phosphite is distilled off and the evaporation residue is chromatographed on 150 g of silica gel with first ethyl acetate and then ethyl acetate/ethanol (9: 1) as eluants. 6-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[O:14][CH2:13][O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.Cl.[OH-].[Na+]>O1CCCC1>[O:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([B:16]([OH:21])[OH:17])[C:15]=2[O:14][CH2:13]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cccc2c1OCO2
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: OB(O)c1cccc2c1OCO2
Temperature: 25 °C
Yield: 69.1 %

Procedure:
nBuLi (2.5M in hexanes, 2.38 mL, 5.97 mmol) was dropwise added to a solution of 4-bromo-1,3-benzodioxole (1 g, 4.97 mmol) and triisopropyl borate (1.49 mL, 6.47 mmol) in 50 mL of dry tetrahydrofuran at −78° C. under argon. The reaction was maintained at that temperature for 3 hours, then warmed up to room temperature and cooled back to 0° C. immediately. The solution was acidified to pH=2 with HCl 2N and neutralized to pH=7 with NaOH 2N, it was then extracted with ethyl acetate (3×25 ml), the organic solution was washed with brine, dried over sodium sulphate and the solvent removed under reduced pressure to yield the title compound (570 mg, 69%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][NH:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:16].[NH4+].[Cl-]>[Fe]>[NH2:32][C:30]1[CH:29]=[CH:28][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:11]#[C:12][CH2:13][NH:14][C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[O:16])=[C:2]([F:1])[CH:31]=1
Reactant: O=C(NCC#Cc1cnccc1Oc1ccc([N+](=O)[O-])cc1F)N1CCC[C@H]1CN1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1ccc(Oc2ccncc2C#CCNC(=O)N2CCC[C@H]2CN2CCCC2)c(F)c1

Procedure:
The title compound was prepared by the reduction of (S)-N-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carboxamide (50 mg, 0.11 mmol) in a manner similar to that of Step E of Example 35 using Fe (powder, 67 mg, 1.21 mmol), NH4Cl (128 mg, 2.42 mmol). The product (36 mg, 75%) was obtained as a yellow oil which was used directly in the subsequent step. MS(ESI+): m/z 438.30 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:18]([N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:19])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.NN>C(O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:18]([NH2:20])[CH3:19])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1cc2ccc(F)cc2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: C[C@H](N)c1cc2ccc(F)cc2nc1-c1ccccn1
Temperature: 90 °C
Yield: 70.6 %

Procedure:
To a slurried 2-((S)-1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (2.1 g, 5.3 mmol) in anhydrous ethanol (15 mL) was added NH2NH2 (0.85 g, 26 mmol) dropwise over 5 minutes. The reaction mixture was heated to 90° C. for 30 min and cooled to rt. The reaction mixture was filtered and washed with EtOAc. The resulting EtOAc solution was washed with water, brine and dried over Na2SO4. Removal of solvents gave a tan oil of (S)-1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethanamine (1 g, 71%). Mass Spectrum (ESI) m/e=468 (M+1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]2)=[CH:13][CH:12]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: OCCN1CCNCC1
Product: OCCN1CCN(Cc2ccc(F)cc2)CC1

Procedure:
The title compound was synthesized by using 2-(1-piperazinyl)ethanol and p-fluorobenzyl chloride according to the same process as in Preparation Example 4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2.[Li]CCCC.CON(C)[C:20](=[O:24])[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: CCCC(=O)N(C)OC
Reactant: Cn1ccc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc2c(ccn2C)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 57.4 %

Procedure:
To a solution of 5-bromo-1-methyl-1H-indole (9.8 g, 46.7 mmol) in THF (40 mL) was added n-BuLi (2.5M in hexanes, 22.3 mL, 55.8 mmol, 1.2 eq) at −78° C. dropwise over 15 min. The mixture was stirred for 30 min at −78° C. before a solution of N-methoxy-N-methylbutyramide (7.35 g, 56.0 mmol, 1.2 eq) in THF (10 mL) was added. After stirred at −78° C. for 10 min, the reaction was quenched with saturated aqueous NH4Cl. The resulting mixture was extracted by ether (3×30 mL) and combined organic layers were dried over Na2SO4. The crude product was purified by flash chromatography (0-10% EtOAc in hexanes) to give the title compound (5.40 g, 26.8 mmol, 57%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14]1[NH:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:57]=[CH:56][C:34]5[NH:35][C:36]([C@@H:38]6[CH2:42][C@H:41]([CH3:43])[CH2:40][N:39]6[C:44](=[O:55])[C@@H:45]([N:49]([C:51]([O:53][CH3:54])=[O:52])[CH3:50])[CH:46]([CH3:48])[CH3:47])=[N:37][C:33]=5[CH:32]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:18]=1)=O)(C)(C)C.[ClH:58].O1CCOCC1>CO>[ClH:58].[CH3:54][O:53][C:51](=[O:52])[N:49]([CH3:50])[C@H:45]([C:44]([N:39]1[CH2:40][C@@H:41]([CH3:43])[CH2:42][C@H:38]1[C:36]1[NH:35][C:34]2[CH:56]=[CH:57][C:31]([C:28]3[CH:29]=[CH:30][C:25]([C:22]4[CH:23]=[CH:24][C:19]([C:17]5[N:18]=[C:14]([C@@H:9]6[CH2:10][C@H:11]([CH3:13])[CH2:12][NH:8]6)[NH:15][CH:16]=5)=[CH:20][CH:21]=4)=[CH:26][CH:27]=3)=[CH:32][C:33]=2[N:37]=1)=[O:55])[CH:46]([CH3:48])[CH3:47]
Reactant: COC(=O)N(C)[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)n5)cc4)cc3)ccc2[nH]1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)N(C)[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6C[C@H](C)CN6)n5)cc4)cc3)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-2-{4-[4′-(2-{(2S,4S)-1-[(S)-2-(methoxycarbonyl-methyl-amino)-3-methyl-butyryl]-4-methyl-pyrrolidin-2-yl}-1H-benzoimidazol-5-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (115 mg, 0.1486 mmol) in methanol is added 4M HCl in dioxane (0.632 mL, 2.526 mmol). The reaction mixture is stirred at room temperature for 1 hour and concentrated to dryness. The title product is used as such in the next step.