Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.FC1C=C2C(C(C3CCNCC3)=NN2C2C=CC=CC=2)=CC=1.Cl[CH2:47][CH2:48][CH2:49][CH:50]([C:58]1[CH:63]=[CH:62][C:61]([F:64])=[CH:60][CH:59]=1)[C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CC(C)CC(=O)C>[F:57][C:54]1[CH:53]=[CH:52][C:51]([CH:50]([C:58]2[CH:59]=[CH:60][C:61]([F:64])=[CH:62][CH:63]=2)[CH2:49][CH2:48][CH2:47][N:20]2[CH2:21][CH2:22][CH:17]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:7]=3)[CH2:18][CH2:19]2)=[CH:56][CH:55]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: Fc1ccc2c(C3CCNCC3)nn(-c3ccccc3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Fc1ccc(C(CCCN2CCC(c3nn(-c4ccccc4)c4cc(F)ccc34)CC2)c2ccc(F)cc2)cc1
Yield: 23.7 %

Procedure:
A stirred mixture, under nitrogen, of 6-fluoro-1-phenyl-3-(4-piperidinyl)-1H-indazole (1.5 g, 0.005 mol), the free base of Example 98, 4-chloro-1,1-bis-(4-fluorophenyl)butane (1.6 g, 0.0056 mol), Na2CO3 (0.6 g), a few crystals of KI and 4-methyl-2-pentanone (70 ml) was refluxed for 16 hours. The reaction was poured into H2O, and the aqueous mixture extracted with ethyl acetate. The ethyl acetate was washed (H2O), dried (MgSO4) and the solvent was concentrated to a liquid. The liquid was dissolved in anhydrous ether and HCl (g) was added to precipitate a gum. The supernatant ether was decanted, H2O was added to the gum, and the mixture was made basic with NH4OH. The basic suspension was extracted with ether, the extract washed (H2O), dried (MgSO4), and the solvent was concentrated to yield 0.64 g (24%) of a solid. This material was combined with 2.9 g of a compound from another run and recrystallized from isopropyl ether to yield 2.1 g of 3-[1-[4,4-bis(4-fluorophenyl)butyl-4-piperidinyl]-6-fluoro-1-phenyl-1H-indazole, mp 113°-115° C.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24]OS(C)(=O)=O)[O:21][C:20]4=[O:30])=[CH:15][C:14]=3[F:31])=[CH:9][N:8]=2)=[N:3]1.Cl.[CH3:33][NH:34][CH3:35]>CN(C)C=O>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@@H:22]([CH2:24][N:34]([CH3:35])[CH3:33])[O:21][C:20]4=[O:30])=[CH:15][C:14]=3[F:31])=[CH:9][N:8]=2)=[N:3]1
Reactant: CNC
Reactant: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](COS(C)(=O)=O)OC4=O)cc3F)cn2)n1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)C[C@@H]1CN(c2ccc(-c3ccc(-c4nnn(C)n4)nc3)c(F)c2)C(=O)O1
Temperature: 60 °C
Reaction time: 30 h
Yield: 79 %

Procedure:
In 5 ml of dimethylformamid was dissolved 100 mg of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyl oxazolidin-2-on prepared in the secondary step of the Example 24. The solution was added with 30 mg of dimethylamine hydrochloride at room temperature. The solution was stirred for 30 hours at the temperature of 60° C. And then the solution was extracted with ethyl acetate and the organic layer, thus separated, was washed with water and brine. The residue, prepared by dehydrating, filtering and concentrating the organic layer, was purified by column chromatography to provide the title compound 70 mg. Yield 76%.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][CH:16]([NH:18][CH3:19])[CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:28][C:29]1[CH:30]=[C:31]([CH2:36][C:37]([OH:39])=O)[CH:32]=[CH:33][C:34]=1[F:35]>>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][CH:8]([C:11]([N:13]3[CH2:14][CH:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH:16]([N:18]([CH3:19])[C:37](=[O:39])[CH2:36][C:31]4[CH:32]=[CH:33][C:34]([F:35])=[C:29]([F:28])[CH:30]=4)[CH2:17]3)=[O:12])[CH2:9][CH2:10]2)[CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Reactant: CNC1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Cc1ccc(F)c(F)c1)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(3,4-difluoro-phenyl)-N-methyl-acetamide was prepared from (1-cyclopropylmethyl-piperidin-4-yl)-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 3,4-difluorophenylacetic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light yellow oil. MS m/e: 564.3 [M]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:25][C:24]3[CH:23]=[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([O:35]C(C)(C)C)=[O:34])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[N:2]>Cl.O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:25][C:24]3[CH:23]=[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(C#N)cc(C(F)(F)F)c2)CC3)ccn1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(C(=O)O)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.9 %

Procedure:
A solution of give tert-butyl 4-{[7-({[3-cyano-5-(trifluoromethyl)phenyl]-amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}pyridine-2-carboxylate (0.750 g, 1.40 mmol) in 2M HCl in dioxane (15 mL) was allowed to stir at rt overnight and then evaporated to give 4-{[7-({[3-cyano-5-(trifluoromethyl)phenyl]amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}pyridine-2-carboxylic acid (0.788 g), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1C(CCC)C(=O)C(CCC)[C:4](=[O:15])[C:3]=1[NH:16][C:17]([CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=O.[OH-].[K+].Cl.[CH2:32]([OH:34])C>>[CH2:2]([N:1]1[C:4](=[O:15])[C:3]2[N:16]=[C:17]([CH:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)[NH:1][C:2]=2[N:16]([CH2:17][CH2:19][CH3:20])[C:32]1=[O:34])[CH2:3][CH3:4]
Reactant: CCCC1C(=O)C(NC(=O)C2CCc3ccccc3C2)=C(N)C(CCC)C1=O
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCCn1c(=O)c2nc(C3CCc4ccccc4C3)[nH]c2n(CCC)c1=O
Temperature: 70 °C

Procedure:
Dissolve 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2-amino-4,6-dioxo-3,5-dipropylcyclohex-1-enyl)amide (2.0 g, 5.2 mmol) in ethanol (50 ml), add 15% potassium hydroxide (50 ml) and heat to 70° C. for 4 hours. After cooling to 0° C., acidify the reaction with concentrated hydrochloric acid (13 ml). Add water (100 ml) and collect the resulting precipitate by suction filtration. Purify the white solid by flash chromatography (50% ethyl acetate/hexane) and triturate with 5% diethyl ether/hexane to provide, after drying under vacuum at 120° C. for 30 minutes the title compound (1.04 g), m.p. 202°-204° C.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:8][F:9])([OH:7])[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH2:15](O)[CH3:16]>>[CH2:15]([O:5][C:4](=[O:6])[C:3]([CH2:8][F:9])([OH:7])[CH2:2][F:1])[CH3:16]
Reactant: CCO
Reactant: O=C(O)C(O)(CF)CF
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(O)(CF)CF
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude 3-fluoro-2-fluoromethyl-2-hydroxy-propionic acid (17 g) was dissolved in ethanol (400 ml) and H2SO4 (98%, 30 g) was added. The reaction mixture was refluxed for 16 h. The reaction mixture was cooled to ambient temperature and filtered. The solution was carefully treated with 30 g solid Na2CO3 and the resulting mixture was stirred for 30 min at room temperature. 400 ml DCM were added and the mixture was filtered. The solution was concentrated (50° C., 150 mbar) and further purified by distillation (82° C., 20 mbar) to give a colorless liquid.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][CH:16]=1.O>CN(C)C=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
tert-Butyldimethylchlorosilane (1.13 g) and imidazole (513 mg) were added to a solution of 4-(4-bromophenyl)butan-1-ol (1.15 g) in N,N-dimethylformamide (35 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1→50:1→20:1) to give the title compound (1.78 g, quant.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].[C:22]([O:27][CH2:28][CH3:29])(=[O:26])[C:23]#[C:24][CH3:25].C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:21][CH:24]([CH2:23][C:22]([O:27][CH2:28][CH3:29])=[O:26])[CH2:25][N:20]=1)=[CH:15]2)(=[O:7])=[O:8]
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 60 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
A solution of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (4.3 g), ethyl but-2-ynoate (3.2 mL) and tributylphosphine (3.2 mL) in tetrahydrofuran (40 mL)-toluene (40 mL) was stirred at room temperature for 2 days. ethyl but-2-ynoate (1.6 mL) was added to the reaction solution again, and the mixture was stirred at 60° C. for 2 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-4:6) to give the title compound (1.6 g, yield: 28%) as a pale-brown oil.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[N:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[CH:26])=[N:23][CH:24]=2)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[C:26][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[N:6][CH:7]=3)=[N:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: OCCCc1ccc(I)cn1
Product: OCCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cn1

Procedure:
The product was obtained analogously to Example 7.1e starting from 3-(5-iodopyridin-2-yl)propan-1-ol and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 0.80 g (74% of theoretical); C21H17ClN2O (M=348.825); calc.: molpeak (M+H)+: 349/351 (Cl); found: molpeak (M+H)+: 349/351 (Cl); HPLC-MS: 8.24 minutes (method A).
Reaction SMILES: NC1SC2C3C(CC=2C=1[C:14]([NH2:16])=[O:15])=CC=CC=3.FC(F)(F)C(O)=O.[NH2:24][C:25]1[S:29][C:28]2[C:30]3[C:35]([CH2:36][CH2:37][C:27]=2[C:26]=1[C:40]([NH2:42])=[O:41])=[CH:34][CH:33]=[C:32]([O:38][CH3:39])[CH:31]=3>>[CH3:39][O:38][C:32]1[CH:31]=[C:30]2[C:35]([CH2:36][CH2:37][C:27]3[C:26]([C:40]([NH2:42])=[O:41])=[C:25]([NH:24][C:14]([NH2:16])=[O:15])[S:29][C:28]=32)=[CH:34][CH:33]=1
Reactant: COc1ccc2c(c1)-c1sc(N)c(C(N)=O)c1CC2
Reactant: NC(=O)c1c(N)sc2c1Cc1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)-c1sc(NC(N)=O)c(C(N)=O)c1CC2

Procedure:
The title compound was prepared by the same procedure as Example 2 except 2-amino-4H-indeno[1,2-b]thiophene-3-carboxylic acid amide was replaced with 2-amino-8-methoxy-4,5-dihydro-naphtho[1,2-b]thiophene-3 carboxylic acid amide trifluoroacetate to give the above title compound as brown solid. ESMS m/z: 318 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[CH3:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[CH3:35].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:31]1[CH:32]=[CH:33][C:34]([CH3:35])=[C:29]([CH3:28])[CH:30]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1ccc(C)c(C)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 3,4-dimethylphenylboronic acid (82.5 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(3,4-dimethyl-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a slight yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]([F:20])([F:19])[C:16](=[O:18])[CH3:17]>CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]([OH:18])([CH3:17])[C:15]([F:20])([F:19])[F:14])=[CH:3][CH:4]=1
Reactant: CC(=O)C(F)(F)F
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 62.4 %

Procedure:
A 500 mL round-bottomed flask was charged with 1,4-dibromobenzene (30.27 g, 128 mmol, Sigma-Aldrich, St. Louis, Mo.) and 200 mL of ether. After cooling to −78° C., n-BuLi (59.0 mL, 2.5 M in hexanes, 148 mmol) was added. This mixture was stirred for 15 min at −78° C., then 1,1,1-trifluoro-2-propanone (24.2 mL, 257 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. Stirring was continued at −78° C. for 30 min then the mixture was quenched with 100 mL of saturated aqueous NH4Cl. The mixture was extracted with EtOAc (250 mL), dried (MgSO4) and concentrated to give an oil. Purification via column chromatography (330 g of silica, 0 to 30% EtOAc in hexanes) gave 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (21.50 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]#N)[C:6]([N+:12]([O-])=O)=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][NH:12][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(CC#N)n1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2[nH]ccc2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under a hydrogen pressure of 45 psi, 17.70 g (91.7 mmol) of the compound obtained in Step A and 2.5 g of palladium-on-carbon suspended in 300 ml of ethanol are stirred for 5 hours at room temperature. After filtration over Celite and evaporation, the residue is purified over silica gel (eluant: petroleum ether/ethyl acetate, 4:1) to yield the title product in the form of a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(Cl)c1OCc1ccccc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
To a stirring solution of 3-chloro-4-hydroxy-5-methoxybenzaldehyde (599 mg, 3.21 mmol) in DMF (5 mL) under nitrogen was added Cs2CO3 (1.10 g, 3.38 mmol) followed by benzyl chloride (0.40 mL, 3.48 mmol) and the mixture heated at reflux for 1 h. After allowing the mixture to cool to ambient temperature the reaction was quenched by the addition of aqueous NaOH (2N, 30 mL) and the mixture concentrated under vacuum. The residue was then partitioned between NaOH (2N, 30 mL) and EtOAc (50 mL) and the layers separated. The aqueous layer was then re-extracted with EtOAc (50 mL), the layers separated and the combined organic layer washed with brine and then concentrated under vacuum. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 10:1) afforded the title compound (632 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=2)[N:3]=1.[CH2:25]([CH:33]([CH2:36]O)[CH2:34][OH:35])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].S([O-])([O-])(=O)=O.[Na+].[Na+].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[C:7]([CH:8]2[O:35][CH2:34][CH:33]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:36][O:9]2)=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=2)[N:3]=1
Reactant: CCCCCCCCC(CO)CO
Reactant: CCCCCCCCOc1ccc(-c2ccc(C=O)c(F)n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(-c2ccc(C3OCC(CCCCCCCC)CO3)c(F)n2)cc1
Yield: 41.9 %

Procedure:
2.20 g (6.68 mmol) of 2-fluoro-3-formyl-6-(4-octyloxyphenyl)pyridine, 1.26 g (6.68 mmol) of 2-octylpropane-1,3-diol, 0.02g (0.10mmol) of p-toluenesulfonic acid and 3.00 g of sodium sulfate are stirred in 100 ml of toluene at room temperature for 68 hours. 0.14 ml (1.00 mmol) of triethylamine is then added, sodium sulfate is filtered off, the filtrate is concentrated, and the residue is purified by chromatography (silica gel, 9:1 hexane/ethyl acetate) and by recrystallization from acetonitrile, giving 1.40 g of 2-fluoro-3-(5-octyl-1,3-dioxane-2-yl)-6-(4-octyloxyphenyl)pyridine. ##STR63##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH2:23][O:24][CH:25]3[CH2:30]CCC[O:26]3)=[CH:21][N:22]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:43].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[C:25]([O:24][CH2:23][C:20]1[S:19][C:18]([C:16]2[NH:43][C:13]([CH:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:14][CH:15]=2)=[N:22][CH:21]=1)(=[O:26])[CH3:30]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OCc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)[nH]2)s1
Temperature: 110 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)-1-{5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-2-yl}hexane-1,4-dione (366 mg) in acetic acid (3.1 mL) was added ammonium acetate (773 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (103 mg, yield 31%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 523 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[OH:41])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]4[OH:41])(=[O:32])=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1O)c1ccccc1Br
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)N[C@@H]3CCCC[C@H]3O)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-bromo-N-((trans)-2-hydroxycyclohexyl)benzene-sulfonamide. MS (ESI): mass calcd. for C22H23FN4O3S, 442.15; m/z found, 443.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.51 (d, J=1.3, 2H), 8.17 (dd, J=8.0, 1.4, 1H), 7.64-7.59 (m, 1H), 7.57-7.51 (m, 1H), 7.44-7.31 (m, 4H), 5.30 (s, 2H), 4.83 (d, J=7.7, 1H), 3.78 (s, 1H), 3.20-3.11 (m, 1H), 1.72-1.65 (m, 1H), 1.57-1.10 (m, 8H).
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C:16]1[C:17]([CH3:23])=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1>>[OH:22][C:18]1[C:17]([CH3:23])=[C:16]([NH:15][C:12](=[O:13])[CH2:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1c(N)cccc1O
Product: Cc1c(O)cccc1NC(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (0.81) and 3-amino-2-methylphenol (0.5 g) to give the title compound as a white solid (0.5 g).