Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([CH2:8][Cl:9])=[O:7])[CH3:2].C(OCC)(OCC)O[CH2:13][CH3:14]>S(=O)(=O)(O)O>[Cl:9][CH2:8]/[C:6](/[O:7][CH2:13][CH3:14])=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:10]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C(/CCl)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl-4-chloroacetoacetate (5.0 g), triethyl orthoformate (4.5 g) and concentrated sulfuric acid (2 drops) was stirred at room temperature for 48 hours under a nitrogen atmosphere. The excess triethyl orthoformate was removed on a rotavap and the residue was dissolved in toluene (~20 mL) and a small amount of p-toluene sulfonic acid was added and refuxed for three hours. The mixture was diluted with ethyl acetate (~20 mL) and washed with aqueous sodium bicarbonate and brine; dried over anhydrous sodium sulphate and the solvent removed on a rotavap to obtain the title compound.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]([CH3:8])[CH3:7]>CO>[C:12]([O:11][C:9]([N:5]([CH2:4][C:3]([OH:16])=[O:2])[CH:6]([CH3:8])[CH3:7])=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)C(C)C
Solvent: CO
Product: CC(C)N(CC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.9 %

Procedure:
To a solution of (N-t-butoxycarbonyl-N-isopropyl-amino)-acetic acid methyl ester (5.59 g, 24.2 mmol) in a mixture of methanol (112 ml) and distilled water (56 ml) was added 1M aqueous sodium hydroxide solution (37 ml) in an ice bath, and the mixture was stirred at room temperature for 7 hours. After checking the completion of the reaction, Dowex-50W was added thereto in the ice bath to adjust the pH of the reaction mixture to 5 to 4. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give (N-t-butoxycarbonyl-N-isopropyl-amino)acetic acid (5.25 g) as a crude product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:27][C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:29])=[CH:18][CH:19]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCC(=O)c4ccccc4)cc3)cc12

Procedure:
2-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenoxy)-1-phenylethanone was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for Example 139, but using 2-bromo-1-phenylethanone. 1H NMR (Acetone-d6): δ 8.76 (s, 1H), 8.71 (s, 1H), 8.27 (d, 1H), 8.06 (d, 2H), 7.67 (t, 1H), 7.57 (t, 2H), 7.43 (s, 1H), 7.17 (d, 3H), 6.90 (d, 2H), 5.45 (s, 2H), 3.21 (t, 2H), 3.06 (t, 2H), 2.45 (s, 3H). LRMS [M+H]=448.2
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: Clc1ccc2cc[nH]c2c1
Product: Clc1ccc(-n2ccc3ccc(Cl)cc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-chloro-4-iodobenzene: ESMS m/e: 262.9 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[CH3:6][C:7]1([C:13]2([Li])C=CC=C2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C1COCC1>[CH3:6][C:7]1([CH2:13][Si:2]([CH:5]2[CH:9]=[CH:8][CH:7]=[CH:6]2)([CH3:4])[CH3:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: [Li]C1(C2(C)CCCCC2)C=CC=C1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CC1(C[Si](C)(C)C2C=CC=C2)CCCCC1
Yield: 57 %

Procedure:
Trimethylchlorsilane (29.1 g, 268 mmol) was slowly added to a solution of (1-methyl-cyclohexyl)cyclopentadienyllithium (43.34 g, 258 mmol) in THF (350 ml). After refluxing the mixture for 3,5 h, the solvent was removed in vacuo and the residue was distilled under reduced pressure to give (1-methylcyclohexyl)cyclopentadienyltrimethylsilane as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:12]([OH:17])(=[O:16])/[CH:13]=[CH:14]/[CH3:15].O.[OH-].[Na+]>C1(C)C=CC=CC=1>[N:7]1[C:8]2[C:3](=[C:2]([NH:1][CH:14]([CH3:15])[CH2:13][C:12]([OH:17])=[O:16])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccc2ncccc12
Reactant: C/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CC(=O)O)Nc1cccc2ncccc12
Yield: 51 %

Procedure:
A mixture of 5-aminoquinoline (9.9 g, 0.069 mol) and crotonic acid (8.9 g, 0.103 mol) in toluene (35 ml) was stirred at reflux for 48 h. The reaction mixture was allowed to cool to ambient, added to water (500 ml) and the pH adjusted to 9 to 10 by the addition of 2N sodium hydroxide. The reaction mixture was screened and the filtrate extracted with diethyl ether (3×100 ml). The pH of the aqueous layer was first adjusted to pH2 with concentrated HCl and then to pH7 with calcium hydroxide. The precipitate which formed was collected by filtration, washed first with water (200 ml) and then with acetone (200 ml) before being dried to give 8.1 g of a cream solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[Br:21]Br>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Br:21])[CH:12]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)c2ccc(OC)c(Br)c2)cc1
Temperature: 25 °C

Procedure:
To the solution of 4-(4-methoxy-benzoyl)-benzoic acid methyl ester (3.4 g, 12.6 mmol) in dichloromethane (10 mL) is added bromine (2.4 g, 15.1 mmol). The solution is stirred at room temperature till the starting material is gone. Then the mixture is diluted with dichlormethane, washed with 1N NaOH, water, brine, dried, and purified with column chromatography to give the titled compound as a yellow solid: 4.42 g (100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[S:59][C:60]([CH3:67])=[C:61]([S:63](Cl)(=[O:65])=[O:64])[N:62]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:63]([C:61]1[N:62]=[C:58]([NH:57][C:54](=[O:56])[CH3:55])[S:59][C:60]=1[CH3:67])(=[O:64])=[O:65])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(=O)Nc1nc(S(=O)(=O)Cl)c(C)s1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1nc(NC(C)=O)sc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (130 mg) was reacted with 2-acetylamino-5-methyl-thiazole-4-sulfonyl chloride (54 mg) to furnish (S)-2-({(S)-7-(2-acetylamino-5-methyl-thiazole-4-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (LCMS m/z: 965) according to General Procedure E. The title compound (16 mg) was prepared by the hydrolysis of (S)-2-({(S)-7-(2-acetylamino-5-methyl-thiazole-4-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (20 mg) using General Procedure B. LCMS (m/z): 952.
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:31](=[O:40])[N:32]([CH2:36][CH2:37][CH2:38][F:39])[CH2:33][CH2:34][CH3:35])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH2:10][C:11]([C:31](=[O:40])[N:32]([CH2:36][CH2:37][CH2:38][F:39])[CH2:33][CH2:34][CH3:35])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCN(CCCF)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCC)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CCCF)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCC)cc3)cc2N=C(N)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
The crude product from Step E was then taken up in 2 mls of dichloromethane and 1 ml of TFA, and stirred at room temperature for one hour. The mixture was concentrated under reduced pressure and the resulting crude product was taken up in DCM (10 mls) and concentrated ammonium hydroxide (5 mls) and stirred at room temperature for 15 minutes, then extracted with dichloromethane. The extracts were dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM/0.5% NH4OH) afforded 17 mgs (36%) of ethyl 4-((1E,4E)-2-amino-4-((3-fluoropropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.09-8.14 (m, 2H), 7.70-7.74 (m, 2H), 7.52-7.55 (m, 1H), 7.32-7.41 (m, 2H), 6.87 (m, 1H), 5.11 (br s, 1H), 4.57-4.63 (m, 1H), 4.46-4.52 (m, 1H), 4.37-4.45 (m, 2H), 3.57-3.73 (m, 2H), 3.42-3.55 (m, 2H), 2.82 (s, 2H), 1.99-2.15 (m, 2H), 1.62-1.76 (m, 2H), 1.38-1.45 (m, 3H), 0.89-0.98 (m, 3H); m/z (APCI-pos) M+1=452.2.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[CH3:9][C:10]1[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[O:19][CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCC(=O)OC(C)C)ccc1[N+](=O)[O-]

Procedure:
In a similar manner to Example 2, starting material step (b), isopropyl bromoacetate (13.9 ml), 3-methyl-4-nitrophenol (15 g), anhydrous potassium carbonate (16.25 g) and acetone (500 ml) were reacted to give isopropyl 3-methyl-4-nitrophenoxyacetate (22.2 g) as an off-white solid: NMR Spectrum (DMSO-d6) 1.22 (6H, d), 2.54 (3H, s), 4.89 (2H, s), 5.00 (1H, m), 6.96 (1H, dd), 7.04 (1H, d), 8.03 (1H, d); Mass Spectrum m/Z 254 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1.[CH3:13][Mg]Cl>C1COCC1>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]([CH3:13])[OH:7])=[C:4]([F:12])[CH:3]=1
Reactant: C[Mg]Cl
Reactant: COc1cc(C=O)c(F)cc1Cl
Solvent: C1CCOC1
Product: COc1cc(C(C)O)c(F)cc1Cl
Temperature: 25 °C
Yield: 95.6 %

Procedure:
A stirred solution of 10.4 g of 4-chloro-2-fluoro-5-methoxybenzaldehyde in 150 mL of anhydrous THF was cooled in a dry ice-acetone bath and treated with 35 mL of a 3M solution of methyl magnesium chloride in THF over a period of one minute. The ice bath was removed and the mixture allowed to warm to room temperature. After warming, the solution was slowly poured into ice water. The water slurry was extracted three times with diethyl ether, the ether extracts dried and concd to afford a crude oil. Crystallization from hexanes yielded 10.8 g (95.6%) of 4-chloro-2-fluoro-5-methoxy-α-methyl-benzenemethanol: mp 68.5°-69.5° C. This benzenemethanol intermediate was dissolved in 100 mL of acetone, cooled in an ice water bath and treated dropwise with 50 mL of freshly prepared Jones'reagent (prepared from 6.7 g of CrO3, 6 mL of H2SO4 and 50 mL of water), keeping the temperature below 10° C. After stirring for 2 hrs., the solution was diluted with water and extracted three times with methylene chloride. The organic extracts were dried and concd to give a crude product. Recrystallization from methanol yielded 9.66 g (90.3%) of 1-(4-chloro-2-fluoro-5-methoxyphenyl) ethanone as a white solid: mp 96.5-98.5 ° C.; 1HNMR (CDCl3) δ 2.50 (d, 3H, 5.4 Hz), 3.80 (s, 3H), 7.10 (d, 1H, 10.1 Hz), 7.30 (d, 1H, 6.3 Hz).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:46]=[CH:47][C:48]([Cl:51])=[N:49][CH:50]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:50]=[N:49][C:48]([Cl:51])=[CH:47][CH:46]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(Cl)nc3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 5-amino-2-chloropyridine according to procedure B followed by deprotection yielded the title compound as an off-white foam. MS (ESI): m/z=390.2/392.2 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18](O)[C:13]=3[C:12]3[CH:22]=[C:23]([Cl:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:28]>P(Cl)(Cl)(Cl)=O.ClCCl>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([Cl:28])[C:13]=3[C:12]3[CH:22]=[C:23]([Cl:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ncc2c(c1O)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ncc2c(c1Cl)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
A solution of 9-benzenesulfonyl-3-chloro-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (1.9 g, 4.94 mmol) and phosphorus pentachloride (3.1 g, 14.8 mmol) in phosphorus oxychloride (8 mL) was heated at 105° C. for 2 hours. The reaction mixture was cooled to ambient temperature and then the solvent removed in-vacuo to afford a residue. The resultant residue was dissolved in dichloromethane (300 mL) and then the solution was diluted with ice/water (300 mL). The layers were separated and the aqueous layer further extracted with dichloromethane. The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The resultant residue was triturated with diethyl ether and dried to afford the title compound as a tan solid (1.17 g, 59%). 1H NMR (400 MHz, CDCl3): 9.81 (s, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H), 8.26-8.22 (m, 2H), 7.66-7.66 (m, 1H), 7.53-7.53 (m, 2H).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:38](=[O:39])[C:37]5[CH:36]=[CH:35][C:34]([N:31]6[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]6)=[CH:42][CH:41]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: CN1CCN(c2ccc(C(=O)N[C@H]3CC[C@H](CCN4CCC(c5cccc6c5CCO6)CC4)CC3)cc2)CC1

Procedure:
The title compound, white solid (106 mg, 80%), MS (ISP) m/z=531.3 [(M+H)+], mp 241° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-(4-methyl-piperazin-1-yl)-benzoic acid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[N:19]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[C:26]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:18]=[C:17]2[CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)#[N:27]
Reactant: CS(=O)(=O)n1cc(C2CCN(C(=O)OCc3ccccc3)CC2)c2cc(C#N)ccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)n1cc(C2CCNCC2)c2cc(C#N)ccc21
Reaction time: 2 h
Yield: 97 %

Procedure:
10% Palladium on carbon (0.49 g) was added to a solution of 1-benzyloxycarbonyl-4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (0.98 g, 2.24 mmol) [prepared as described in Step 2 above] in 80% ethanol/tetrahydrofuran (10 ml) under an argon atmosphere. The reaction mixture was stirred under an atmosphere of hydrogen gas (1 atm) for 2 h. The reaction mixture was degassed, filtered through Celite and concentrated in vacuo to give 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (97%) as a white solid. This material was converted to N-hydroxy-1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]-piperidine-2-(R)-carboxamide by converting it to 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl chloride by following Example 16, Step 1, coupling the sulfonyl chloride with (R)-pipecolinic acid (L)-tartrate salt to give 1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (86%) by following Example 14, Step 6 and then converting the acid to the final compound by following Example 16, Steps 3 and 5; mp: 143.3-143.9° C.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])[O:13][CH:14]=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>C(Cl)Cl>[F:17][CH:15]([F:16])[C:12]1[O:13][CH:14]=[C:9]([OH:8])[C:10](=[O:18])[CH:11]=1
Reactant: O=c1cc(C(F)F)occ1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1cc(C(F)F)occ1O
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To an ice-salt cooled, clear solution of 5-benzyloxy-2-difluoromethyl-pyran-4-one (252 mg, 1 mmol) in CH2Cl2 (4 mL) was added dropwise a solution of 1.0 M BBr3 in CH2Cl2 (1 mL, 1 mmol) diluted with CH2Cl2 (1 mL). After 10 min, TLC analysis of the reaction mixture using a mixture of CH2Cl2 and MeOH (20/1, v/v) as eluant indicated consumption of the starting material. The reaction mixture was quenched with MeOH (5 mL), and evaporated to dryness. The residual oil was taken up in ethyl acetate (30 mL), and the organic layer was washed with brine (2×10 mL), dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated in vacuo to give a solid. The solid was triturated with ether, and was then collected by suction filtration. The title compound was obtained as an off-white solid (80 mg, 50% yield). The purity (peak area percent is 97.3%) of this material was analysed by HPLC Method 1 as described above.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@H:10]([O:48][CH2:49][C@H:50]([OH:54])[CH2:51][O:52][CH3:53])[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:53][O:52][CH2:51][C@@H:50]([OH:54])[CH2:49][O:48][C@H:10]1[C@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13][NH:8][CH2:9]1
Reactant: COC[C@@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: Cl
Solvent: CO
Product: COC[C@@H](O)CO[C@@H]1CNC[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2OC)cc1
Temperature: 25 °C

Procedure:
15.3 g (20.5 mmol) of (3S,4R,5R)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 70 ml of abs. methanol at 0° C., then 118 ml (236 mmol) of hydrochloric acid in methanol (2.0 molar) were added dropwise at 5° C. max. and thereafter the mixture was warmed to room temperature. After 22 hours the reaction mixture was poured into ice-cold sodium hydrogen carbon ate solution (1 l , 60 g sodium hydrogen carbonate) and the product was extracted three times with 500 ml dichloromethane, the organic phases were washed with distilled water, then dried over magnesium sulphate, filtered and concentrated in a water-jet vacuum. The thus-obtained crude product was chromatographed on silica gel with dichloromethane methanol (95/5). There were thus obtained 9.3 g (14.4 mmol), 70.2%, (R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol as colorless oil; MS: 646.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C#N)ccc1O
Reactant: BrCCCCBr
Product: COc1cc(C#N)ccc1OCCCCBr

Procedure:
The procedure is as for Example 53, Step A, using as substrate 4-hydroxy-3-methoxybenzonitrile and 1,4-dibromobutane.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:17][CH2:18][S:19][C:3]1=2.ClN1C(=O)CCC1=O>N1C=CC=CC=1>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:3][S:19][CH:18]=[C:17]12
Reactant: CCOC(=O)c1ccc2nc3c(c(=O)n2c1)SCC3
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2nc3cscc3c(=O)n2c1
Temperature: 0 °C

Procedure:
A mixture of ethyl 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno-[3,2-d]pyrimidine-7-carboxylate (0.4 g., 0.0014 mol) and N-chlorosuccinimide (0.9 g., 0.0014 mol) in pyridine (4 ml) is heated on a steam bath for 18 minutes. The reaction mixture is cooled and poured into a large volume of ice water. The precipitate is filtered, washed with water and dried. Recrystallization from ethanol gives the product (0.2 g.) mp 188°-190° C.