Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC=CC=1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O.[Cl:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[O:19][C:20]1[CH:21]=[C:22]([NH2:38])[C:23]([NH2:37])=[CH:24][C:25]=1[O:26][C:27]1[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=1>CO>[Cl:16][C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[O:19][C:20]1[C:25]([O:26][C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=2)=[CH:24][C:23]2[NH:37][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=3)=[N:38][C:22]=2[CH:21]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2Cl)cn1
Reactant: O=Cc1ccccn1
Solvent: CO
Solvent: Nc1ccccc1
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2Cl)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
0.26 ml of 1 M methanol solution of aniline and pyridine-2-carboxaldehyde (1/1) was added to a methanol (1 ml) solution of 35 mg of 4-(2-chlorophenoxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in (step 1), and the reaction liquid was stirred overnight at 60° C. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, and then dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[O:26])=[CH:20][C:19]=1[N:39]1[CH2:48][C:47]2[C:42](=[N:43][C:44](S(C)(=O)=O)=[N:45][CH:46]=2)[N:41]([CH3:53])[C:40]1=[O:54]>CN1CCCC1=O.C(OCC)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][CH:28]=2)=[O:26])=[CH:20][C:19]=1[N:39]1[CH2:48][C:47]2[C:42](=[N:43][C:44]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:14][CH3:15])=[CH:12][CH:11]=3)=[N:45][CH:46]=2)[N:41]([CH3:53])[C:40]1=[O:54]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CN1C(=O)N(c2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Agent: Cl
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2cc(NC(=O)c4ccc(-c5ccccc5)cc4)ccc2Cl)C3)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 35 %

Procedure:
0.1 g 4-(2-Diethylamino-ethoxy)-phenylamine were dissolved in 1 mL N-methylpyrrolidinone (NMP) and cooled to 0° C. 300 μl of a solution of aqueous HCl in diethyl ether were added and stirred for 45 min. Biphenyl-4-carboxylic acid [4-chloro-3-(7-methanesulfonyl-1-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-amide was dissolved in 2 ml NMP and added to the aforementioned solution and the reaction mixture was heated at 120° C. for 24 h. The reaction was quenched by addition of 5 mL of a saturated solution of sodium carbonate and the aqueous phase was extracted with dichloromethane. The organic phase was dried over sodium sulfate and the solvent was evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol) to give the title product in 35% yield.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)=[O:11].C(=O)(O)[O-].[Na+]>COCCO.O.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>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:15]1[CH:16]=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][CH:14]=1
Reactant: OCc1ccccc1Br
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: O=Cc1ccc(-c2ccccc2CO)cc1
Yield: 69.7 %

Procedure:
i)—To a solution of 2-bromo-benzylalcohol (5 g, 26.7 mmol) in 2-methoxyethanol/water (30 ml, 1/1) were added 4-formylphenylboronic acid (6 g, 40.0 mmol) and sodium bicarbonate (4.4 g, 52.4 mmol) under a nitrogen atmosphere. After (Ph3P)4Pd (1.54 g, 1.34 mmol) was added, the reaction mixture was heated under reflux for 17 h. After cooling, the mixture was filtered over dicalite and the residue was washed with water and ethyl acetate. The product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate concentrated under reduced pressure. Column chromatography afforded 2′-hydroxymethyl-biphenyl-4-carbaldehyde (3.95 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:17]4[CH2:18][CH2:19][CH:14]([CH:15]=[CH:16]4)[CH:13]2[C:12](=[O:20])[N:11]([CH3:21])[C:10]3=[O:22])[CH:5]=[CH:6][C:7]=1[Cl:8]>Cl.C(OCC)(=O)C.[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:17]4[CH2:16][CH2:15][CH:14]([CH2:19][CH2:18]4)[CH:13]2[C:12](=[O:20])[N:11]([CH3:21])[C:10]3=[O:22])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)C2C3C=CC(CC3)C2(c2ccc(Cl)c(Cl)c2)C1=O
Agent: O=[Pt]
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1C(=O)C2C3CCC(CC3)C2(c2ccc(Cl)c(Cl)c2)C1=O
Yield: 91.9 %

Procedure:
A mixture of 8.0 g of the above dicarboximide, 0.8 g of platinum oxide and 3 drops of concentrated hydrochloric acid in 150 ml of ethyl acetate was hydrogenated in a Parr apparatus. The reaction mixture was filtered and the filtrate was concentrated in vacuo giving 7.4 g of 3a-(3,4-dichlorophenyl)hexahydro-2-methyl-4,7-ethano-1H-isoindole-1,3(2H)-dione as straw colored crystals, mp 126°-134° C.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[S:31][C:32]5[CH:38]=[C:37]([C:39]([NH:41][CH2:42][C:43]([O:45]C)=[O:44])=[O:40])[CH:36]=[CH:35][C:33]=5[N:34]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1.[Li+].[OH-]>O.O1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:17])([F:18])[F:19])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[S:31][C:32]5[CH:38]=[C:37]([C:39]([NH:41][CH2:42][C:43]([OH:45])=[O:44])=[O:40])[CH:36]=[CH:35][C:33]=5[N:34]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1
Reactant: COC(=O)CNC(=O)c1ccc2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CNC(=O)c1ccc2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Reaction time: 2 h

Procedure:
Methyl 2-(2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxamido)acetate was subjected to a solution of 4N LiOH in water (2 mL) and dioxane (2 ml) and stirred for 2 hours. The solvent was reduced in vacuo and the mixture diluted with 5% citric acid (10 ml) and extracted with ethyl acetate (2×8 mL). The organics were combined and dried (MgSO4) then evaporated in vacuo. The product was purified with flash silica chromatography with methanol/dichloromethane with a 0-40% gradient to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[O-].[Na+].[CH:17](OCC)=[O:18]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:17]=[O:18])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC=O
Reactant: COc1ccc(CC#N)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(C(C#N)C=O)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a stirred solution of 3,4-dimethoxyphenyl acetonitrile (8.86 g, 50 mmol) in diethyl ether (150 mL) was added sodium methoxide (2.97 g, 55 mmol) and ethyl formate (4.04 mL, 50 mmol) in diethyl ether (50 mL) solution. The reaction mixture was stirred at room temperature for 24 hrs. A solid was precipitated. The mixture was filtered and the solid was collected and washed with diethyl ether. The solid was dissolved in water (50 mL). 10% acetic acid was then added dropwise to the solution. A white precipitation was formed and the mixture was filtered again. The while solid was washed with water and collected to afford 2-(3,4-dimethoxy-phenyl)-3-oxo-propionitrile (8.0 g, 78% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[Cl-].[CH3:18][O:19]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([CH:18]=[O:19])[CH2:5][CH2:4]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(C=O)CC1

Procedure:
46 mmol (10.0 g) of 4-dimethylamino-4-phenylcyclohexanone were dissolved in toluene. This solution was added dropwise at 70° C. to a suspension of 138.1 mmol, (47.33 g) methoxymethyl triphenylphosphonium chloride and 138.1 mmol (25.82 g) potassium tert.-butylate. The mixture was stirred for a few more hours at 70° C., hydrolysed with water and extracted using EE. The combined organic phases were washed with saturated NaCl solution, dried over sodium sulphate and concentrated. The resultant brown resin was chromatographed using silica gel. The desired aldehyde is obtained as a cis/trans-mixture.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.N1C=CC=CC=1.[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26](Cl)=[O:27])[C:24]1([CH3:30])[CH3:29]>C(Cl)Cl>[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26]([O:13][CH2:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:7]=2)=[O:27])[C:24]1([CH3:29])[CH3:30]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: OCc1cccc(-c2ccsc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 5.2 %

Procedure:
To a stirred solution of 1.0 g (0.005 mol) of 3-(3-thienyl)phenylmethanol and 0.5 g (0.005 mol) of pyridine in 25 mL of methylene chloride was added in one portion 1.2 g (0.005 mol) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride in 5 mL of methylene chloride. The reaction mixture was stirred at ambient temperature for 17 hours, then transferred to a separatory funnel, and diluted with 200 mL of methylene chloride. The solution was washed with 200 mL of aqueous 2 N hydrochloric acid, 200 mL of a saturated aqueous solution of sodium chloride, 200 mL of a cold aqueous 2 N solution of sodium hydroxide, and finally, 200 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was subjected to medium pressure liquid chromatography using petroleum ether:ethyl acetate (55:1) as the eluent. The appropriate fractions were combined and subjected to distillation under reduced pressure using a Kugelrohr distilling system to give 0.1 g of 3-(3-thienyl)-phenylmethyl cis-3-(2,2-dichloroetheny)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH2:36][CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[C:33]([OH:35])=O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].[S:43]1[CH:47]=[CH:46][N:45]=[C:44]1[NH2:48]>CN(C=O)C>[CH3:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH:32]([CH2:36][CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[C:33]([NH:48][C:44]2[S:43][CH:47]=[CH:46][N:45]=2)=[O:35])=[CH:30][CH:31]=1)(=[O:24])=[O:25]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
EDCI (80 mg, 420 μmol) and HOBt (56 mg, 420 μmol) were added to a stirred solution of 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionic acid (Preparation 41, 100 mg, 320 μmol) in anhydrous DMF (6 mL). After 15 min, the solution was treated with thiazol-2-ylamine (38 mg, 380 μmol). The mixture was stirred at 20° C. for 16 h, before being concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and saturated aqueous Na2CO3. The organic layer was washed with 1M HCl and dried (MgSO4). Filtration and solvent evaporation yielded the title compound: RTA=3.16 min; m/z (ES+)=436.2 [M+MeCN+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([SH:27])[CH:23]=[CH:24][C:25]=1[Cl:26].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:27][C:22]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(Cl)c(Cl)c2)CC1

Procedure:
4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (11.18 g) and 3,4-dichlorothiophenol (6.15 ml) were stirred together in acetonitrile (200 ml) and potassium carbonate (8.86 g) was added. The mixture was heated at reflux for 18 hours after which water was added and the resulting mixture extracted with dichloromethane. The organic extracts were combined, washed with water, dried (MgSO4) and evaporated to give the sub-title compound (14.58 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.C(N(CC)CC)C.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([O:23][C:24]([NH:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ncc(C=O)s1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=Cc1cnc(NC(=O)OCc2ccccc2)s1
Yield: 63.5 %

Procedure:
1 g (7.8 mmol) of 2-amino-5-formyl-1,3-thiazole was dissolved in 25 ml of tetrahydrofuran and 1.35 ml (9.36mmol) of triethylamine and 1.33 ml (9.36 mmol) of benzylchloroformate were added at 0° C. under stirring. After 8 hours at room temperature the solvent was evaporated, the residue redissolved with methylene chloride and washed with saturated tartaric acid and then with water. The solvent was dried over anhydrous sodium sulfate and evaporated. The residue was purified by chromatography on silica gel using cyclohexane-ethylacetate as eluent to give 1.3 g (65% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:9]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=c1cc(O)cc[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1cc[nH]c(=O)c1)c1ccccc1
Yield: 44 %

Procedure:
50 ml of a solution of 1.00 g of 4-hydroxy-2-pyridone and 1.35 ml of benzoyl chloride in pyridine was refluxed for 6 hours. After the pyridine was distilled off, the residue was mixed with water. The precipitate was recovered by filtration and was washed with a small amount of ethanol to obtain 0.86 g of the title compound in a yield of 44%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2.[F:20][CH:21]([F:25])[C:22](O)=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[F:20][CH:21]([F:25])[C:22]([NH:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=3[I:1])[NH:11]2)=[CH:16][CH:15]=1)=[O:23]
Reactant: COc1nccc(I)c1-c1cc2ccc(N)cc2[nH]1
Reactant: O=C(O)C(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1nccc(I)c1-c1cc2ccc(NC(=O)C(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
A solution of 2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (30 mg, 0.08 mmol) in CH2Cl2 (5 mL) was added 2,2-difluoroacetic acid (12 mg, 0.12 mmol) and HATU (47 mg, 0.12 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded 2,2-difluoro-N-[2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-acetamide (24 mg, 67%) as a white solid. MH+ 443.9.
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([O:16][CH3:17])=[C:10]([CH3:18])[C:9]=1[CH:19]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[CH3:6][O:7][C:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([O:16][CH3:17])=[C:10]([CH3:18])[C:9]=1[CH:19]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]
Reactant: COc1c(C)c(C)c(OC)c(C(CCCCCC(=O)O)c2cccnc2)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(OC)c(C(CCCCCCO)c2cccnc2)c1C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a stirred tetrahydrofurane solution (40 ml) of 7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-(3-pyridyl)heptanoic acid (3.0, 7.8 mmol) prepared in the Reference Example 11 was added lithium aluminum hydride (450 mg, 11.9 mmol) under ice-cooling. The reaction mixture was allowed to rise to room temperature and stirred for 30 min. After that water was carefully added to the reaction mixture and the product was extracted with ethylacetate. The extract was washed with water, dried, and evaporated in vacuo to yield 7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-(3-pyridyl)heptanol (2.3 g, 79.6%) as, an oil, after chromatography of the crude product on silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:16][C:17]([C:19]1[O:20][C:21]([CH2:24]Cl)=[CH:22][CH:23]=1)=[O:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:21]3[O:20][C:19]([C:17]([OH:18])=[O:16])=[CH:23][CH:22]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COC(=O)c1ccc(CCl)o1
Product: O=C(O)c1ccc(COc2ccc(-c3ccc(Br)cc3)cc2)o1

Procedure:
5-(4′-Bromo-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid was prepared using general procedure A from 4-bromo-4′-hydroxybiphenyl (available from TCI America, Portland, Oreg.) and 5-chloromethylfuran-2-carboxylic acid methyl ester (available from Aldrich, Milwaukee, Wis., or from Maybridge plc, Tintagel, UK). Yield: 86 mg. Mass spectrum (ES) MH+=373.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:30]=[CH:29][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35]>>[C:34]([CH2:33][CH2:32][S:31][CH:22]1[C:21]2[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:29]=[CH:30][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:36])=[O:35]
Reactant: Cc1cccc2c1C(O)c1cc(OCc3ccc4ccc(Cl)cc4n3)ccc1OC2
Reactant: O=C(O)CCS
Product: Cc1cccc2c1C(SCCC(=O)O)c1cc(OCc3ccc4ccc(Cl)cc4n3)ccc1OC2

Procedure:
2-(7-Chloroquinolin-2-yl)methoxy-11-hydroxy-10-methyl-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][O:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:3][C:4]#[N:5].[ClH:18].[H][H]>CO.[Pd]>[ClH:18].[OH:1][C@H:2]([CH2:6][O:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:10])=[O:9])[CH2:3][CH2:4][NH2:5]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)CC#N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CCN)cc1
Reaction time: 20 h

Procedure:
To a solution of (S)-3-hydroxy-4-(p-toluenesulfonyloxy)butyronitrile (17.0 g) in methanol (120 ml), 10 wt. % Pd on carbon (3.0 g) and conc. hydrochloric acid (30 ml) were added. The mixture was stirred in a hydrogen atmosphere of 4. 0 kg/cm2 at room temperature for 20 hours. After filtrating off the catalyst, the mixture was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography (Wako Gel C200, an eluent: methanol/acetone (volume ratio of 3/7) to obtain pure (S)-3-hydroxy-4-(p toluenesulfonyloxy)butylamine hydrochloride (17.5 g). Yield, 89 %.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9](I)=[CH:8][N:7]3[C:13]=2[CH3:14])[CH2:3][CH2:2]1.C([Li])CCC.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.[OH-].[Na+]>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([B:24]([OH:25])[OH:23])=[CH:8][N:7]3[C:13]=2[CH3:14])[CH2:3][CH2:2]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1c(C2CC2)nc2ccc(I)cn12
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(B(O)O)cn12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-cyclopropyl-6-iodo-3-methylimidazo[1,2-a]pyridine (742 mg) in THF (25 ml) was added n-butyllithium (1.6 M in hexane, 6.2 ml) at −78° C. The mixture was stirred at −78° C. under N2 atmosphere for 30 min. After being stirred, boric acid triisopropyl ester (0.86 ml) was added to the reaction mixture at −78° C. The mixture was stirred at −78° C. under N2 atmosphere for 30 min and then at room temperature for 3 h. The mixture was poured into 1 M NaOH at 0° C. and washed with EtOAc. The aqueous layer was neutralized with 1 M HCl (to pH 7.0) and extracted with EtOAc/IPA. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting solid was washed with EtOAc/MeOH to give the title compound (176 mg) as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>ClCCl>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[C:17]([SiH2:16][O:15][C:14]([CH3:22])([CH3:21])[CH:11]1[CH2:12][CH2:13][N:8]([NH2:7])[CH2:9][CH2:10]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NN1CCC(C(C)(C)O[SiH2]C(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)C1CCN(N)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
[4-(t-Butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-carbamic acid t-butyl ester (100 mg, 290 μmol) was at 0° C. combined with dichloromethane (3 mL) and trifluoroacetic acid (3 mL) to give a light yellow solution. The reaction mixture was stirred for 2 h at 0° C. and subsequently concentrated in vacuo to give the title compound as yellow oil, which was used without further purification in the next step.