Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH:12]C(=O)C)[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH3:25])[C:17]=2[F:26])[N:6]=1)=[O:4].C(Cl)(=O)C.O>CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH3:25])[C:17]=2[F:26])[N:6]=1)=[O:4]
Reactant: CCOc1c(Cl)ccc(-c2cc(NC(C)=O)c(Cl)c(C(=O)OC)n2)c1F
Solvent: CC(=O)Cl
Solvent: O
Solvent: CO
Product: CCOc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)OC)n2)c1F

Procedure:
To a solution of 4-acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-ethoxyphenyl)pyridine-2-carboxylic acid methyl ester (0.5 g, 0.0013 mol) in methanol (10 mL) was added acetyl chloride (1 mL) and the solution heated under reflux for 1 hour. Water (2 mL) was added and resulting solid collected and dried to give 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-ethoxyphenyl)pyridine-2-carboxylic acid methyl ester: mp 154-156° C.
Reaction SMILES: [SH:1][CH:2]([SH:17])[C:3]([SH:16])([SH:15])[C:4]([O:6][CH2:7][C:8]([CH2:13][OH:14])([CH2:11][OH:12])[CH2:9][OH:10])=[O:5].[CH2:18]=[C:19]1[O:23][C:21](=[O:22])[CH2:20]1>C(N(CC)CC)C.C(#N)C>[C:21]([O:14][CH2:13][C:8]([CH2:11][OH:12])([CH2:9][O:10][C:21](=[O:22])[CH2:20][C:19]([CH3:18])=[O:23])[CH2:7][O:6][C:4](=[O:5])[C:3]([SH:15])([SH:16])[CH:2]([SH:1])[SH:17])(=[O:22])[CH2:20][C:19]([CH3:18])=[O:23]
Reactant: C=C1CC(=O)O1
Reactant: O=C(OCC(CO)(CO)CO)C(S)(S)C(S)S
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC(CO)(COC(=O)CC(C)=O)COC(=O)C(S)(S)C(S)S
Temperature: 70 °C

Procedure:
To a solution of 20.0 g. (0.041 mol) of pentaerythritol tetramercaptopropionate in 20 g. of acetonitrile was added 7.9 g. (0.094 mol. 2.3 equiv.) of diketene. Upon addition of triethylamine catalyst (30 mg) an exotherm of 17° C. was observed. After 30 minutes the reaction mixture was warmed to 70° C. for an additional 30 minutes to ensure complete reaction. Solvent was removed on a rotary evaporator.
Reaction SMILES: C([S:4][CH:5]([CH2:11][C:12](=[O:26])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)C.O.S(=O)(=O)(O)O>C(O)C>[SH:4][CH:5]([CH2:11][C:12](=[O:26])[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(CC(=O)c1ccc(Oc2ccccc2)cc1)SC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(S)CC(=O)c1ccc(Oc2ccccc2)cc1
Yield: 82.1 %

Procedure:
3.72 g of ethyl 2-acetylthio-3-(4-phenoxybenzoyl)propionate were dissolved in 30 ml of ethanol, then 3 ml of distilled water and 1.2 ml of concentrated sulfuric acid were added, and the mixture was refluxed for 4 hours. The ethanol was removed by evaporation under reduced pressure. Diethyl ether was added to the residue, which was washed with water and dried over magnesium sulfate. The diethyl ether was distilled off and the residue was purified first by silica gel column chromatography, eluted with a mixture of hexane and diethyl ether, then by recrystallization from a mixture of hexane and diethyl ether to give 2.71 g of ethyl 2-mercapto-3-(4-phenoxybenzoyl)propionate.
Reaction SMILES: C[Mg]Cl.Cl.[O:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1>O>[OH:5][C:9]([CH3:8])([CH3:9])[CH2:8][C:7]1[CH:6]=[CH:7][C:7]([CH2:8][C:9]([OH:5])=[O:5])=[CH:6][CH:6]=1
Reactant: C1CCOC1
Agent: C[Mg]Cl
Agent: Cl
Solvent: O
Product: CC(C)(O)Cc1ccc(CC(=O)O)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The carboxylic acid of preparation 11 (18.26 g, 82.0 mmol) was dissolved in tetrahydrofuran (450 ml) and the solution cooled to 0° C. and treated dropwise with a solution of methylmagnesium chloride in tetrahydrofuran (82 ml, 246 mmol). The reaction mixture was allowed to warm to room temperature and left to stand for 18 hours. The reaction mixture was slowly diluted with water (80 ml) followed by 2M hydrochloric acid (120 ml, 240 mmol). The mixture was extracted with ethyl acetate (3×100 ml) and the organic extracts combined and washed with brine (3×50 ml). The ethyl acetate phase was dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:acetic acid (99.6:0:0.4 changing to 94.6:5:0.4) to yield the title product as a colourless solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:8][O:7]1)=[O:5])C.[OH-].[Na+:21]>O1CCCC1>[CH:14]1([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]2([C:4]([O-:5])=[O:3])[CH2:8][O:7]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1.[Na+:21]
Reactant: CCOC(=O)C1(CCCCCC2CCCCC2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])C1(CCCCCC2CCCCC2)CO1

Procedure:
1.5 g of 2-(5-cyclohexylpentyl)-oxirane-2-carboxylic acid ethyl ester are stirred for 2 hours at room temperature with 5,6 ml of 1 N sodium hydroxide solution and 5 ml of tetrahydrofuran. The mixture is concentrated to half its volume and the fatty gleaming plates of the title compound which have been precipitated are filtered off.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:29]=[C:28]([CH2:30][N:31]4[CH2:36][CH2:35][CH:34]([C:37]([OH:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]4)[CH:27]=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:3][CH2:2]1.[CH2:41]([N:43]1[C:51](I)=[C:50]2[C:45]([CH:46]=[CH:47][CH:48]=[CH:49]2)=[N:44]1)[CH3:42]>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].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>[CH2:41]([N:43]1[C:51]([C:11]2[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[C:8]3[N:29]=[C:28]([CH2:30][N:31]4[CH2:32][CH2:33][CH:34]([C:37]([OH:40])([CH3:39])[CH3:38])[CH2:35][CH2:36]4)[CH:27]=[CH:26][C:9]=3[N:10]=2)=[C:50]2[C:45]([CH:46]=[CH:47][CH:48]=[CH:49]2)=[N:44]1)[CH3:42]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1
Reactant: CCn1nc2ccccc2c1I
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CCn1nc2ccccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
To a degassed solution of 2-(1-((4-morpholino-2-(tributylstannyl)pyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol (0.13 g) and 2-ethyl-3-iodo-2H-indazole (1.05 eq) in 1,4-dioxane (1.5 mL) was added copper(I) thiophene-2-carboxylate (1 eq) and tetrakis(triphenylphosphine)palladium(0) (0.05 eq). The reaction was microwaved at 140° C. for 30 minutes and then loaded onto Biotage isolute scx-2 catridge and eluted with 2M ammonia in Methanol. The crude material was purified by reverse phase HPLC to afford 36.6 mg of 136. MS (Q1) 516.3 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25].Cl>ClCCl>[C:24]([O:17][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:16][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(C(=O)c2cc(Br)ccc2O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)cc1C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16.75 h

Procedure:
To a yellow solution of 229 mg (0.8 mmol) of 5-bromo-2-hydroxy-4′-methylbenzophenone (Compound K) in 15 mL of dichloromethane (under a blanket of argon) was added 0.07 mL (69 mg, 0.9 mmol) of pyridine followed by 0.07 mL (74 mg, 0.9 mmol) of acetyl chloride. The resultant reaction mixture was stirred at ambient temperature overnight (16.75 hours), poured into 10% HCl (aq.) solution and extracted with ethyl acetate. The layers were separated and the aqueous phase was washed with ethyl acetate. The organic phases were combined and then sequentially washed with sat. NaHCO3 (aq.) solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. Purification by flash chromatography (silica, 20% ethyl acetate in hexane) gave the title compound as a clear, colorless oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:38][C:39]([CH3:41])=O>>[CH:39]([N:19]1[CH2:18][CH2:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)([C:22]#[N:23])[CH2:21][CH2:20]1)([CH3:41])[CH3:38]
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCNCC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)N1CCC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CC1
Yield: 58 %

Procedure:
The title compound (45 mg, 58%) was prepared from 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile, acetone and sodium triacetoxyborohydride similarly to the procedure used for example 54. 1H NMR (400 MHz, CD3OD) 61.12 (d, 6H), 1.81-1.84 (m, 4H), 1.99-2.14 (m, 6H), 2.58-2.69 (m, 8H), 2.82 (m, 1H), 3.02 (d, 2H), 4.04 (t, 2H), 6.96 (d, 2H), 7.42 (d, 2H). HRMS ESI+ m/z 356.2691 [MH]+.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)[C:9](=[O:25])[N:8]([CH2:26][CH3:27])[C:7]=2[N:6]=[C:5]1[Cl:28])[CH:2]=[CH2:3].Cl>C(O)C>[CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][OH:17])[C:9](=[O:25])[N:8]([CH2:26][CH3:27])[C:7]=2[N:6]=[C:5]1[Cl:28])[CH:2]=[CH2:3]
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2CC
Agent: Cl
Solvent: CCO
Product: C=CCn1c(Cl)nc2c1c(=O)n(CCCO)c(=O)n2CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 136.2 %

Procedure:
To a solution of 7-allyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-8-chloro-3-ethyl-1H-purine-2,6(3H,7H)-dione (3.8 g, 8.92 mmol) in ethanol (20 mL) was added concentrated HCl (2 mL). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with brine and dried over sodium sulfate, and concentrated to give 7-allyl-8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (3.8 g) as yellow oil, which was used without purification. LCMS retention time 0.999 min; LCMS MH+ 313.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:12]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:12]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[CH:14][C:15]([CH2:18][N:3]2[C:2](=[O:1])[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4]2)=[CH:16][CH:17]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(=O)n(Cc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
A mixture of methyl 6-hydroxynicotinate (3 g), 4-biphenylylmethyl bromide (5.8 g), potassium carbonate (8.2 g), and DMF (30 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially and concentrated. The resulting crystals were washed with diisopropylether and recrystallized from ethyl acetate/hexane to obtain the titled compound (5.1 g).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)=[O:26])[CH2:21][CH2:20]1>>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH2:20][CH2:21][N:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([N:5]3[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]3(=[O:10])=[O:9])=[CH:29][CH:28]=2)=[O:26])[CH2:23][CH2:24]1
Reactant: CC(C)[C@H]1CCS(=O)(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@@H](C(C)C)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 4.2 %

Procedure:
Using (R)-3-isopropylisothiazolidine 1,1-dioxide (300 mg) described in Preparation Example 8 and [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (420 mg) described in Preparation Example 108 and by the reaction and treatment in the same manner as in Example 1, the title compound (19 mg) was obtained.
Reaction SMILES: C([CH:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:15][C:14]=1[CH:28]([CH3:30])[CH3:29])[C:9]([O-:11])=[O:10])C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH:28]([C:14]1[CH:15]=[C:16]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)[CH:17]=[CH:18][C:13]=1[O:12][CH2:8][C:9]([OH:11])=[O:10])([CH3:30])[CH3:29]
Reactant: CC(C)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC(Cc1ccccc1)C(=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of benzyl[2-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate (0.238 g) in ethanol (10 mL) was added 10% palladium-carbon (0.05 g), and the mixture was stirred at room temperature for 2 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to afford the title compound (0.156 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH3:31])[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][CH3:31])[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: CCn1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-ethylpyrazole.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:11][CH2:10][N:9]1[CH2:30][C:31]([NH:33][O:34]C1CCCCO1)=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>CO.O1CCOCC1>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:28])([F:29])[F:27])=[N:19]3)[CH2:11][CH2:10][N:9]1[CH2:30][C:31]([NH:33][OH:34])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN(CC(=O)NOC3CCCCO3)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(CC(=O)NO)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Reaction time: 16 h
Yield: 99 %

Procedure:
The intermediate 2-((S)-2-benzyl-4-(8-methoxy-2-(trifluoromethyl)quinolin-5-yl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acetamide (130 mg, 0.23 mmol) was dissolved in MeOH (5 mL) and water (1 mL) and treated with a 4 N HCl solution in dioxane (250 mL). The resulting mixture was allowed to stir for 16 h after which time the reaction was evaporated to a small volume and partitioned between EtOAc (20 mL) and water (10 mL). The solution was adjusted to pH ˜7 with a saturated aqueous NaHCO3 solution and the organic portion further washed with brine (2×5 mL), dried over Na2SO4, filtered, and evaporated to afford the title compound as a yellow solid (108 mg, 97%). LC/MS (Method A) 5.16 min, [M+1]+ 475.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[C:30]([OH:31])=[CH:29][C:27]([NH2:28])=[C:26]([F:32])[CH:25]=1>CC(O)CC>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:28][C:27]3[CH:29]=[C:30]([OH:31])[C:24]([Cl:23])=[CH:25][C:26]=3[F:32])=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CCC(C)O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ccnc2cc1OCc1ccccc1
Yield: 43.4 %

Procedure:
Using an analogous procedure to that described for the synthesis of Example 11, 7-benzyloxy-4-chloro-6-methoxyquinoline hydrochloride (336 mg, 1 mmol), (prepared as described for the starting material in Example 3), was reacted with 4-chloro-2-fluoro-5-hydroxyaniline (178 mg, 1.1 mmol), (as described in EP 61741 A2), in 2-butanol (15 ml) to give 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxyquinoline hydrochloride (200 mg, 43%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C@H:7]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9](=[O:17])[C@@H:8]2[CH2:18][CH2:19][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[OH:21])=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C@@H:20]([OH:21])[CH2:19][CH2:18][C@@H:8]2[C@@H:7]([C:5]3[S:6][C:2]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([OH:29])[CH:35]=4)=[CH:3][CH:4]=3)[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]2=[O:17])=[CH:23][CH:24]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(Br)s2)N1c1ccccc1
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(O)c3)s2)N1c1ccccc1
Yield: 83.6 %

Procedure:
(3R,4S)-4-(5-Bromo-2-thienyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (90.2 mg, 0.196 mmol) was coupled with 3-hydroxyphenyl boronic acid (32.2 mg, 0.233 mmol) under standard Suzuki conditions illustrated by Example 42. Purification by chromatography (12 g silica gel, 15% to 100% ethyl acetate-hexane) afforded (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(3-hydroxyphenyl)-2-thienyl]-1-phenylazetidin-2-one (77.6 mg, 84% yield) as a clear foam; Rf 0.36 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CD3OD) δ 7.31-6.93 (m, 14H), 6.70 (ddd, J=8.0, 2.3, 1.0 Hz, 1H), 4.89-4.88 (m, 1H), 4.64-4.59 (m, 1H), 3.77 (br s, 2H), 3.25-3.21 (m, 1H), 1.97-1.83 (m, 4H) ppm; MS [M−OH]+ 456.0.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@@H:10]([O:12][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](O)COCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 179.8 %

Procedure:
(S)-1-hydroxy-2-tetrahydropyranyloxypropane (120 g, 0.75 mol) prepared according to the method of C. Malanga et al, Synthetic Communications, 12,(1), 67-70 (1982)) was dropwise added to sodium hydride (44.8 g, 1.87 mol) in tetrahydrofuran (400 ml) (hereinafter abbreviated to THF), followed by adding dimethylformamide (hereinafter abbreviated to DMF) (200 ml), agitating the mixture for 2 hours, dropwise adding benzyl bromide (140.8 g, 0.82 mol) at 30° C. or lower, agitating the mixture at room temperature for 6 hours, adding toluene, sufficiently agitating the mixture, washing the resulting organic layer with 2N-NaOH aqueous solution and then with water, drying it over anhydrous magnesium sulfate, distilling off toluene, adding to the resulting oily residue, (S)-1-benzyloxy-2-tetrahydropyranyloxypropane, pyridium p-toluenesulfonate (18 g) and ethanol (500 ml), heating the mixture to 70° C. for one hour, distilling off ethanol, adding toluene to the residue, sufficiently washing it with water, distilling off toluene, and distilling the residue to obtain (S)-1-benzyloxy-2-hydroxypropane (98 g)(b.p. 94.0° C./2.5 mmHg). A mixture of this (S)-1-benzyloxy-2-hydroxypropane (60 g, 0.36 mol) with anhydrous pyridine (300 g) was cooled with ice, followed by dropwise adding a solution of p-toluenesulfonyl chloride (75.8 g, 0.20 mol) in pyridine (70 ml) at 0° C., agitating the mixture at room temperature for 3 hours, adding toluene (800 ml), agitating the mixture, several times washing the resulting organic layer with water, drying it over anhydrous magnesium sulfate and distilling off toluene to obtain (S)-1-benzyloxy-2-(p-toluenesulfonyloxy)propane (115.2 g). On the other hand, a solution of 4-hydroxy-4'-octyloxybiphenyl (50 g, 0.17 mol) in THF (200 ml) was dropwise added to a mixture of sodium hydride (8.5 g, 0.35 mol) with THF (100 ml), followed by dropwise adding a solution of the above (S)-1-benzyloxy-2-(p-toluenesulfonyloxy)propane (64.5 g)(0.20 mol) in DMF (100 ml), agitating the mixture at 60° C. for 4 hours, allowing the mixture to cool down, adding toluene, agitating the mixture, washing with 6N-HCl, then with 2N-NaOH and further with water, drying over anhydrous magnesium sulfate, distilling off toluene, dissolving the residue in a mixture of ethanol (250 ml) with ethyl acetate (250 ml), adding Pd/C catalyst (10 g), agitating the mixture in hydrogen gas, filtering off the Pd/C, distilling off the solvent, and recrystallizing the residue from heptane (150 ml), to obtain (R)-4-(2'-hydroxy-1'-methyl)ethyloxy-4'-octyloxybiphenyl (m.p. 107.9° C.).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].[N:10]([O-])=O.[Na+]>Cl>[NH:7]([C:6]1[CH:8]=[CH:9][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[NH2:10]
Reactant: O=N[O-]
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Product: N#Cc1ccc(NN)cc1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 71006.4 %

Procedure:
To a cold solution of 4-cyanoaniline (6.0 g, 0.050 mol) in conc. HCl was added aq. solution of sodium nitrite (3.85 g, 0.055 mmol) at −15° C. The reaction mass was stirred at 0-10° C. for 15 minutes and filtered off to remove insolubles. The filtrate was added to stannous chloride in conc. HCl (24.0 g, 0.166 mmol). The reaction mass was stirred at −15° C. for 30 minutes. The reaction mass was filtered to afford 5.2 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 7.04 (d, 2H), 7.70 (d, 2H), 9.17 (br s, 1H), 10.66 (br s, 2H).
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][CH:11]([CH2:24][N:25](CC1C=CC=CC=1)[CH3:26])[CH2:12][CH2:13][CH2:14][N:15](CC1C=CC=CC=1)[CH3:16])C1C=CC=CC=1.[H][H]>[Pd]>[CH3:1][NH:8][CH2:9][CH2:10][CH:11]([CH2:24][NH:25][CH3:26])[CH2:12][CH2:13][CH2:14][NH:15][CH3:16]
Reactant: CN(CCCC(CCN(C)Cc1ccccc1)CN(C)Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: CNCCCC(CCNC)CNC
Reaction time: 48 h
Yield: 90 %

Procedure:
To a methanolic solution of N1,N6-Dibenzyl-3-[(benzyl-methyl-amino)-methyl]-N1,N6-dimethylhexane-1,6-diamine (1 g, 0.002 mol) was added 1 g of Pd/C. The solution was exposed to 2 bar of hydrogen and left to shake for 48 hours at ambient temperature. The reaction mixture was filtered through celite and concentrated at reduced pressure to yield a viscous oil. The structure was confirmed by NMR, yield ˜90%.