Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][CH:9]2O)=[CH:5][CH:4]=1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:20][NH2:21].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl.C(OCC)(=O)C>[F:15][C:16]([F:29])([F:30])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=1)[CH2:20][NH:21][CH2:9][C:10]1[CH:11]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OC1OCc2ccc(C(F)(F)F)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OCc1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
6-Trifluoromethyl-1,3-dihydro-isobenzofuran-1-ol (4.12 g) is dissolved in 1,2-dichloroethane (75 ml), and thereto are added 3,5-bis-trifluoromethyl-benzylamine (5.89 g), triacetoxy-sodium borohydride (9.0 g) and acetic acid (2.3 ml), and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=7:3→1:1) to give {2-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-4-trifluoromethyl-phenyl}-methanol (7.06 g). MS (m/z): 432 [M+H]+
Reaction SMILES: [CH:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]C1.[OH2:11].[OH-].[Li+].Cl>C1COCC1.CO.O>[CH:6]1([C:1]([S:7]([NH2:10])(=[O:8])=[O:9])=[O:11])[CH2:3][CH2:4][CH2:5]1
Reactant: O
Reactant: NS(=O)(=O)C1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)C(=O)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of intermediate 5 from Example 344 (700 mg, 2.7 mmol) in THF (90 mL), methanol (50 mL) and water (12 mL) mixture, lithium hydroxide monohydrate (1700 mg, 2.0 mmol) was added. The reaction mixture was stirred at rt. for overnight. Then it was acidified with 1N HCl solution to pH=3 to 5. Extracted with ethyl acetate (2×20 mL) and the organic layers were combined and dried (MgSO4). Evaporation of solvent gave thick colorless oil as product (intermediate 7) (0.58, 88% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)[CH3:2].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[C:24]3=[N:25][S:26](=[O:30])(=[O:29])[CH2:27][CH2:28][N:23]3[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C@@H:19]3[C:24]4=[N:25][S:26](=[O:30])(=[O:29])[CH2:27][CH2:28][N:23]4[CH2:22][CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=S1(=O)CCN2CCC[C@H](c3ccc(O)cc3)C2=N1
Reactant: CCc1ccc(B(O)O)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2ccc([C@H]3CCCN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
A mixture of (4-ethylphenyl)boronic acid (1.34 g), (9R)-9-(4-hydroxyphenyl)-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (500 mg), diacetoxycopper (648 mg), triethylamine (1.24 mL), and powdered 4A MS (1.50 g) in DMF (20 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc-IPE to give the title compound (53.0 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:19][C:18]([CH2:42][C:43]#[N:44])([N:20]4[CH:24]=[C:23]([C:25]5[C:26]6[CH:33]=[CH:32][N:31](COCC[Si](C)(C)C)[C:27]=6[N:28]=[CH:29][N:30]=5)[CH:22]=[N:21]4)[CH2:17]3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:5][CH:4]=[N:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[CH2:19][C:18]([CH2:42][C:43]#[N:44])([N:20]4[CH:24]=[C:23]([C:25]5[C:26]6[CH:33]=[CH:32][NH:31][C:27]=6[N:28]=[CH:29][N:30]=5)[CH:22]=[N:21]4)[CH2:17]3)[CH2:14][CH2:15]2)(=[O:9])=[O:8])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1S(=O)(=O)N1CCC(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1S(=O)(=O)N1CCC(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
To a solution of {1-{1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (56 mg, 0.1 mmol) in methylene chloride (1.5 mL) was added trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in 2 mL of a methanol solution containing 20% ethylenediamine. After being stirred at room temperature for 1 hour, the mixture was purified by HPLC (method B) to give 20 mg (64.5%) of {1-{1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. LC-MS: 507.2 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 12.08 (brs, 1H), 8.72 (d, 1H), 8.62 (s, 1H), 8.34 (s, 1H), 7.55 (d, 2H), 6.99 (d, 1H), 6.75 (s, 1H), 3.95 (s, 3H), 3.62 (dd, 2H), 3.45 (dd, 2H), 3.40 (m, 2H), 3.25 (s, 2H), 3.19 (m, 1H), 2.75 (m, 2H), 1.70 (m, 2H), 1.25 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[CH3:13][C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=1.CN(C)C=O.ClCCl>C(#N)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:23]3[CH2:24][CH2:25][N:20]([C:18]4[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[N:19]=4)[CH2:21][CH2:22]3)[C:7]=2[CH:8]=1
Reactant: Cc1cccc(N2CCNCC2)n1
Reactant: Clc1ccc2scc(CBr)c2c1
Solvent: ClCCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cccc(N2CCN(Cc3csc4ccc(Cl)cc34)CC2)n1
Temperature: 25 °C

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene (1 mmol, maybridge chemical) and 1-(6-methyl-2-pyridinyl)piperazine (1 mmol) were combined in 2 mL of acetonitrile and 1 mL of dimethylformamide and stirred at 25° C. for 5 minutes. The mixture was heated briefly to dissolve any solids and allowed to cool to 25° C. The mixture was monitored by thin layer chromatography until disappearance of starting residue. The mixture was poured into dichloromethane and washed with dilute aqueous ammonium hydroxide. The organic phase was dried over sodium sulfate, filtered, and the filtrate concentrated. The residue was purified by flash chromatography with dichloromethane/methanol/saturated aqueous ammonia to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 2.29 (s, 3H), 3.31 (m, 6H), 3.45 (m, 2H), 3.74 (s, 2H), 6.48 (d, 1H, J=7.5 Hz), 6.57 (d, 1H, J=7.8 Hz), 7.38–7.42 (m, 2H), 7.71 (s, 1H), 8.02 (d, 1H, J=7.8 Hz), 8.06 (d, 1H, J=1.5 Hz); MS (DCI/NH3) m/z 358.1 (M+H)+.
Reaction SMILES: C(C1C=C(CCC2C=CN3C(=O)C(/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=C(N4CCOCC4)N=C3C=2)SC=1)C.[CH:32]([O:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:41]2[N:42]=[C:43]3[CH:53]=[C:52]([C:54]([NH:56][C:57]4[S:58][CH:59]=[C:60]([C:62]([CH3:65])([CH3:64])[CH3:63])[N:61]=4)=[O:55])[CH:51]=[CH:50][N:44]3[C:45](=[O:49])[C:46]=2C=O)[CH2:36]1)=[O:33]>>[C:62]([C:60]1[N:61]=[C:57]([NH:56][C:54]([C:52]2[CH:51]=[CH:50][N:44]3[C:45](=[O:49])[C:46](/[CH:24]=[CH:25]/[C:26]([O:28][C:52]([CH3:54])([CH3:53])[CH3:51])=[O:27])=[C:41]([N:37]4[CH2:38][CH2:39][CH2:40][C@@H:35]([O:34][CH:32]=[O:33])[CH2:36]4)[N:42]=[C:43]3[CH:53]=2)=[O:55])[S:58][CH:59]=1)([CH3:65])([CH3:64])[CH3:63]
Reactant: CC(C)(C)c1csc(NC(=O)c2ccn3c(=O)c(C=O)c(N4CCC[C@@H](OC=O)C4)nc3c2)n1
Reactant: CCc1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCOCC4)nc3c2)c1
Product: CC(C)(C)OC(=O)/C=C/c1c(N2CCC[C@@H](OC=O)C2)nc2cc(C(=O)Nc3nc(C(C)(C)C)cs3)ccn2c1=O
Yield: 100 %

Procedure:
Reactions were performed in the same manner as in Example 1, (J) by using (3R)-1-[8-({[4-(tert-butyl)-1,3-thiazol-2-yl]amino}carbonyl)-3-formyl-4-oxo-4H-pyrido-[1,2-a]pyrimidin-2-yl]hexahydro-3-pyridinyl formate (277 mg, 0.5723 mmol), and the resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=100:1→70:1→50:1) to obtain 559 mg (100% or more) of the title compound as a brown oily substance in a mixture with byproducts.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][P:25]([CH3:29])(=[O:28])[CH2:24][CH2:23]3)=[CH:18][C:17]=2[O:30][CH3:31])=[N:4][C:5]([NH:8][CH2:9]C2SC=CC=2)=[N:6][CH:7]=1.[F:32][C:33]1[CH:45]=[CH:44][C:36]([CH2:37][N:38]2[CH:42]=C[C:40](N)=[CH:39]2)=[CH:35][CH:34]=1>>[Cl:1][C:2]1[C:3]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][P:25]([CH3:29])(=[O:28])[CH2:24][CH2:23]3)=[CH:18][C:17]=2[O:30][CH3:31])=[N:4][C:5]([NH:8][C:9]2[CH:40]=[CH:39][N:38]([CH2:37][C:36]3[CH:35]=[CH:34][C:33]([F:32])=[CH:45][CH:44]=3)[CH:42]=2)=[N:6][CH:7]=1
Reactant: Nc1ccn(Cc2ccc(F)cc2)c1
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nc(NCc2cccs2)ncc1Cl
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nc(Nc2ccn(Cc3ccc(F)cc3)c2)ncc1Cl

Procedure:
The compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine (as described in Example 47) with 1-(4-fluorobenzyl)-1H-pyrrol-3-amine.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:36]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)=[CH:35][C:34]6[C:33](=[O:43])[NH:32][CH:31]=[CH:30][C:29]=6[N:28]=5)=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)=[N:12][N:13]=2)=[CH:5][CH:4]=1>Cl>[OH:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([CH:14]3[CH2:15][CH2:16][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27]5[C:36]([C:37]6[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=6)=[CH:35][C:34]6[C:33](=[O:43])[NH:32][CH:31]=[CH:30][C:29]=6[N:28]=5)=[CH:25][CH:26]=4)[CH2:18][CH2:19]3)=[N:12][N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nnc(C3CCN(Cc4ccc(-c5nc6cc[nH]c(=O)c6cc5-c5ccccc5)cc4)CC3)[nH]2)cn1
Agent: Cl
Product: O=c1[nH]ccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccc(O)nc6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 120 °C

Procedure:
2-[4-({4-[5-(6-Methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}methyl)phenyl]-3-phenyl-1,6-naphthyridin-5(6H)-one (300 mg, 0.5 mmol) was dissolved in 6 M aqueous HCl (10 mL) and heated at 120° C. for 16 h. The solvents were evaporated under vacuum and the yellow residue was dried under high vacuum for 16 h to give 2-[4-({4-[5-(6-hydroxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]piperidin-1-yl}methyl)phenyl]-3-phenyl-1,6-naphthyridin-5(6H)-one. NMR (MeOD): δ 9.16 (1H, bs), 8.61 (1H, bs), 8.28 (1H, bs) 7.91-6.85 (12H, bm), 4.52 (2H, bs), 3.61-3.38 (6H, bm), 2.15 (3H, bm). m/e (m+1): 556.1.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]=[CH2:18])=[C:12]([OH:19])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl.CCN(CC)CC>[C:1]([NH:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]=[CH2:18])=[C:12]([O:19][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCc1ccc(C(NC(C)=O)C(=O)OC)cc1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCc1ccc(C(NC(C)=O)C(=O)OC)cc1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of methyl α-(acetylamino)-3-hydroxy-4-(2-propenyl)benzeneacetate from Preparation 6 (1.5 g, 5.7 mmol) in CHCl3 (20 ml) and Et3N (1 ml) is treated with benzoyl chloride (1.0 g, 7.1 mmol). The resulting solution is stirred at room temperature for 4.5 hours. The reaction mixture is concentrated and the residue partitioned between EtOAc and saturated aqueous NaHCO3. The organic phases are combined, dried (MgSO4) and concentrated. The residue is purified by silica gel chromatography (50% EtOAc/Heptane). An oil of methyl α-(acetylamino)-3-[(phenylcarbonyl)oxy]-4-(2-propenyl)benzeneacetate is obtained (2.1 g, quantitative).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>C(OCC)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH:16]([O:18][S:21]([CH3:20])(=[O:23])=[O:22])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(O)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2RS,3RS)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (11 g) was dissolved in a mixture of ethyl acetate (200 ml) and methylene chloride (50 ml), to which triethylamine (6.21 ml) was added under ice-cooling. Then, methanesulfonyl chloride (3.46 ml) was added dropwise to the mixture over the period of 3 minutes under ice-cooling and stirring. After the addition, the resultant solution was stirred for 45 minutes at room temperature. Thereafter, water (100 ml) was added to the solution to separate the organic layer. The organic layer was washed with water, dried over anhydrous magnesium sulfate and distilled off to remove the solvent under reduced pressure, obtaining (2RS,3RS)-2-(2,4-difluorophenyl)-3-methanesulfonyloxy-1-(1H-1,2,4-triazol-1-yl)-2-butanol as an oil. Thus obtained compound was dissolved in methanol (200 ml), to which a sodium methylate methanolic solution (8.84 g, 28%) was added under ice-cooling. The resultant solution was stirred for 30 minutes at room temperature. The solvent was removed under reduced pressure, and the residue was extracted with ethyl acetate (200 ml) and water (100 ml). The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and distilled off the solvent under reduced pressure. The residue was purified by a silica gel column chromatography (ethyl acetate-methylene chloride=4:1) and crystallized from hexane to give (2RS,3SR)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (8.3 g) as colorless crystals which was a single diastereomer.
Reaction SMILES: [C:1]([CH:5]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:6]C(O)=O)([CH3:4])([CH3:3])[CH3:2].CC([O-])=O.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([CH:5]1[CH2:10][CH2:11][C:12](=[O:13])[CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C(CCCO)CC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)C1CCC(=O)C1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A suspension of the 3-tert-butyl-6-hydroxyhexanoic acid (1 g, 4.95 mmol), anhydrous NaOAc (0.321 g, 3.91 mmol) and acetic anhydride was refluxed for 5 hours during which time the solution mixture turned black. After the reaction mixture was cooled to room temperature, the formed acetic acid and remaining acetic anhydride were removed on a rotary evaporator and then under high vacuum. The residue was then dissolved in ethyl acetate, filtered through a plug of celite to remove the precipitate NaOAc, and concentrated in vacuo to give the crude product of 3-tert-butylcyclopentanone (0.557 g, 58%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].[Li]CCCC.CN(C)[CH:27]=[O:28]>O1CCCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:27]=[O:28])=[C:3]([C:16]([F:19])([F:18])[F:17])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc(OCc2ccccc2)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccccc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described in example 8 c], 1-bromo-2-trifluoromethyl-4-(phenylmethoxy)-benzene was treated with n-BuLi and N,N-dimethylformamide in dry tetrahydrofuran to yield 4-benzyloxy-2-trifluoromethyl-benzaldehyde as colorless liquid.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[Mg].Br[C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1.[CH2:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C:16]1=[O:24]>C1COCC1.CCOCC>[C:7]1([C:16]2([OH:24])[CH2:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15]2)[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: O=C1Cc2ccccc2C1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)cc(C2(O)Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A suspension of anhydrous cerium chloride (43.88 g, 178.1 mmol) in THF (250 mL) was stirred at room temperature for 2 hours under nitrogen. A solution of 3,5-m-xylenylmagnesium bromide (178 mmol, prepared from magnesium (4.33 g, 178.1 mmol) and 5-bromo-m-xylene (24.2 mL, 178.1 mmol) in ether (60 mL) was added at 0° C. and stirred for 3.5 h. A solution of 2-indanone (14.21 g, 107.7 mmol) in THF (20 mL) was added at the same temperature. After stirring at 0° C. for 3 h, the mixture was allowed to warm to room temperature and kept at ambient temperature for 12 h. It was then treated with 5% aqueous hydrochloric solution. The solution was extracted with diethyl ether (4*200 mL). All etheral layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulphate and concentrated to give the crude product. 2-Indanone was distilled out at 80° C. (0.3 mm Hg). The residue was washed with pentane (50 mL) to yield 21.57 g of 2-(3,5-xylenyl)-2-indanol in solid form.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[I:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1.CN1CCOCC1.ClC(OCC(C)C)=O>[I:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:10](=[O:12])[CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[CH:17][CH:16]=1
Reactant: NCc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)NCc1ccc(I)cc1
Reaction time: 0.5 h
Yield: 118.8 %

Procedure:
To a solution of N-Boc-glycine (325 mg) in tetrahydrofuran (3 mL), N-methylmorpholine (1.0 mL) and isobutyl chloroformate (244 μL) were added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, 4-iodobenzylamine hydrochloride (250 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain tert-butyl (2-((4-iodobenzyl)amino)-2-oxoethyl)carbamate (R4, 430 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:27][CH:28]=[C:29](I)[C:24]=4[O:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].[CH2:46]([O:53][C:54](=[O:62])[NH:55][CH2:56][CH2:57][B-](F)(F)F)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[K+].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:27][CH:28]=[C:29]([CH2:57][CH2:56][NH:55][C:54]([O:53][CH2:46][C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)=[O:62])[C:24]=4[O:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(I)c2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Reactant: O=C(NCC[B-](F)(F)F)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(CCNC(=O)OCc2ccccc2)c2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 95 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
A mixture of bis(1,1-dimethylethyl) (3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodofuro[3,2-c]pyridin-4-yl)imidodicarbonate (302 mg, 0.413 mmol), potassium benzyl-N-[2-(trifluoroboranuidyl)ethyl]carbamate (90 mg, 0.316 mmol), palladium(II) acetate (9 mg, 0.040 mmol), RuPhos (38 mg, 0.081 mmol), and cesium carbonate (403 mg, 1.237 mmol) in Toluene (3 mL) and Water (1 mL) was degassed with Nitrogen for 10 minutes. The 25 mL vial was then capped and it was stirred vigorously at 95° C. for 16 hours. LCMS showed complete consumption of starting material and good conversion to the desired product, along with a 23% peak corresponding to the de-iodo byproduct. It was cooled, diluted with ethyl acetate (15 mL), and washed with a mixture of water (5 mL) and saturated aqueous NaHCO3 (10 mL). The aqueous phase was back-extracted with EtOAc (15 mL), and the combined organic phases were washed with brine (1×15 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 40 g SiO2, 5%-70% EtOAc in hexanes gradient over 55 minutes) to give bis(1,1-dimethylethyl) {3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-({[(phenylmethyl)oxy]carbonyl}amino)ethyl]furo[3,2-c]pyridin-4-yl}imidodicarbonate (149 mg, 0.190 mmol, 46.1% yield) as an off-white foam. LC/MS (ES) m/z=783.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.CC([N:26]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:41][CH2:40][NH:39][CH2:38]2)=[CH:33][CH:32]=1)C(=O)[O-])(C)C>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:39]2[CH2:40][CH2:41][CH:37]([C:34]3[CH:35]=[CH:36][C:31]([CH2:30][NH2:26])=[CH:32][CH:33]=3)[CH2:38]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(C)(C)N(Cc1ccc(C2CCNC2)cc1)C(=O)[O-]
Product: NCc1ccc(C2CCN(c3c(F)c(N)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)cc1

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.95 g, 3.2 mmol) and 1,1-dimethylethyl[[4-(3-pyrrolidinyl)phenyl]methyl]carbamate, a procedure analogous to that given in Example 6 provided the title compound (0.75 g) as a yellow solid, mp 225°-227° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:24]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:23][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH3:2].[OH-].[Na+]>C(O)C.Cl>[CH2:1]([C:3]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C:24]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:23][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH3:2]
Reactant: CCOC(=O)CCc1ccccc1OCCCOc1cc(OCc2ccccc2)c(-c2ccc(F)cc2)cc1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCOc1ccccc1CCC(=O)O
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution of 375 mg of ethyl 3-(2-(3-(2-ethyl-4-(4-fluorophenyl)-5-benzyloxyphenoxy)propoxy)phenyl)propionate in 25 mL of ethanol was mixed with 5 mL of 5.0N sodium hydroxide and stirred 16 hours. The mixture was diluted with 1.0N hydrochloric acid and extracted with 3:1 dichloromethane/isopropanol. The organic phase was washed with saturated sodium chloride, dried over sodium sulfate, and evaporated in vacuo providing the desired title product in 93% yield. NMR.