Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.NO.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[C:12](=[CH:18][N:19](C)C)[C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])=[C:7]([N:23]([CH2:28][CH3:29])[S:24]([CH3:27])(=[O:26])=[O:25])[CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:12]2[CH:18]=[N:19][O:14][C:13]=2[CH:15]2[CH2:17][CH2:16]2)=[O:22])=[C:7]([N:23]([CH2:28][CH3:29])[S:24]([CH3:27])(=[O:26])=[O:25])[CH:6]=1
Reactant: CCN(c1cc(Cl)ccc1C(=O)C(=CN(C)C)C(=O)C1CC1)S(C)(=O)=O
Agent: Cl
Agent: NO
Solvent: CCO
Product: CCN(c1cc(Cl)ccc1C(=O)c1cnoc1C1CC1)S(C)(=O)=O
Reaction time: 1 h
Yield: 22.9 %

Procedure:
Hydroxylamine hydrochloride (0.76 g) was added to a mixture of 1-[4-chloro-2-(N-ethyl-N-methylsulphonylamino)phenyl]-3-cyclopropyl-2-dimethylaminomethylenepropan-1,3-dione(3.83 g) in ethanol. The mixture was stirred for 1 hour and evaporated to dryness. The residue was dissolved in dichloromethane and washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography eluted with a mixture of cyclohexane, dichloromethane and ethyl acetate. The product was triturated with a mixture of ether and hexane and filtered to give 4-[4-chloro-2-(N-ethyl-N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole (0.81 g) as a white solid, m.p. 114°-115.8° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:14]1([N:22]=[C:23]=[O:24])[C:15]([CH3:21])=[CH:16][CH:17]=[CH:18][C:19]=1[CH3:20]>CN(C)C=O>[C:14]1([NH:22][C:23](=[O:24])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[C:15]([CH3:21])=[CH:16][CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2c(C)cccc2C)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 5 g of ethyl 2-aminothiazol-4-ylglyoxylate, 5.5 g of 2,6-xylyl isocyanate and 30 ml of dimethylformamide. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)([CH3:24])[CH3:23])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][C:33]1[C:34]([CH:40]=O)=[N:35][CH:36]=[C:37]([CH3:39])[CH:38]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:40][C:34]2[C:33]([CH3:32])=[CH:38][C:37]([CH3:39])=[CH:36][N:35]=2)[CH2:15][C:16]2[C:21]([C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)([CH3:24])[CH3:23])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ncccc2C(C)(C)c2ccc(F)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccc(F)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1

Procedure:
Using General Procedure B: Reaction of 4-({3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 with 3,5-dimethyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave 4-((3,5-dimethyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino)-piperidine-1-carboxylic acid tert-butyl ester as a white foam. 1H NMR (CDCl3) δ 1.25 (m, 3H), 1.43 (s, 9H), 1.61 (s+m, 8H), 2.24 (s, 3H), 2.28 (s, 3H), 2.39-2.47 (m, 3H), 3.35 (m, 1H), 3.66 (s, 2H), 4.02 (s, 2H), 6.87 (m, 4H), 7.19 (s, 2H), 7.82 (d, 1H, J=9.0 Hz), 8.10 (s, 1H), 8.51 (s, 1H). Deprotection with TFA using General Procedure F gave (3,5-dimethyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-piperidin-4-yl-amine as a pale yellow foam. 1H NMR (CDCl3) δ 1.56 (s+m, 9H), 1.76 (d, 2H, J=12.0 Hz), 2.21 (s, 3H), 2.28 (s, 3H), 2.52-2.67 (m, 3H), 3.18 (m, 1H), 3.41 (s, 2H), 3.57 (s, 2H), 6.83-6.90 (m, 4H), 7.20 (m, 2H), 7.82 (d, 1H, J=9.0 Hz), 8.09 (s, 1H), 8.49 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 17.9, 18.4, 27.9, 31.1, 41.9, 42.2, 53.4, 54.1, 54.5, 57.0, 114.9, 115.2, 127.1, 127.2, 131.3, 132.7, 133.8, 138.7, 143.1, 145.5, 146.3, 146.6, 154.4, 158.1, 159.3, 162.5. HPLC: 90%. ES-MS m/z 447 [M+H]+. Anal. Calcd. for C28H35N4F.0.2 CH2Cl2: C, 73.06; H, 7.70; N, 12.09. Found: C, 73.19; H, 7.79; N, 12.10.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][NH:28][CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33](=O)[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][N:28]([CH2:33][CH3:34])[CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3ccccc3)n12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CC(CC#N)(n2ccc(-c3cc4c(ccc5nnc(C)n54)n3Cc3ccccc3)n2)C1

Procedure:
Prepared by the method of Example 93, using {3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (8.5 mg, 0.020 mmol, from Example 90) in DCM (0.4 mL), and acetaldehyde (5.6 μL, 0.10 mmol, Aldrich), followed by sodium triacetoxyborohydride (13 mg, 0.060 mmol). Yield: (6.7 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[CH2:7][C:8](O)=[O:9].S(Cl)([Cl:17])=O>>[CH3:1][C:2]1[C:3]2[C:4](=[CH:11][CH:12]=[CH:13][CH:14]=2)[S:5][C:6]=1[CH2:7][C:8]([Cl:17])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CC(=O)O)sc2ccccc12
Product: Cc1c(CC(=O)Cl)sc2ccccc12

Procedure:
A mixture of 2.0 g of 3-methylbenzo[b]thiophene-2-acetic acid and 19.4 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.25 g of the desired product as a residue.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[C:13]1=[O:24])(=[O:4])[CH3:3].C1C(C(N)=O)=CN(CC2C=CC=CC=2)C=C1>>[C:2]([C:5]1[CH:10]([CH2:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]2=[O:24])[CH:9]=[CH:8][N:7]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[CH:6]=1)(=[O:4])[CH3:3]
Reactant: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3cccc([N+](=O)[O-])c3)cc1C(C)=O)C2=O
Agent: NC(=O)C1=CN(Cc2ccccc2)C=CC1
Agent: [Br-]
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3cccc([N+](=O)[O-])c3)C=C1C(C)=O)C2=O

Procedure:
The title compound 159 is prepared according to the procedure reported in Example 39.1 with compound 123 (60 mg, 0.12 mmol) and BNAH (25 mg, 1 equiv) as reactants. Yellow solid. (Yield 20.8 mg, 39%).
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:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=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:33]4[CH:34]=[CH:35][C:30]([OH:29])=[CH:31][CH:32]=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: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(Br)s2)N1c1ccccc1
Reactant: OB(O)c1ccc(O)cc1
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3ccc(O)cc3)s2)N1c1ccccc1
Yield: 56.5 %

Procedure:
(3R,4S)-4-(5-Bromo-2-thienyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (69.8 mg, 0.152 mmol) was coupled with 4-hydroxyphenyl boronic acid (25.2 mg, 0.183 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-(4-hydroxyphenyl)-2-thienyl]-1-phenylazetidin-2-one (40.7 mg, 56% yield) as a clear foam; Rf 0.39 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.64-7.60 (m, 4H), 7.56-7.48 (m, 5H), 7.33-7.27 (m, 2H), 7.25-7.20 (m, 2H), 7.07 (d, J=8.6 Hz, 2H), 6.81 (br s, 1H), 5.14 (d, J=2.3 Hz, 1H), 5.00-4.95 (m, 1H), 3.57-3.50 (m, 1H), 2.29-2.11 (m, 4H) ppm; MS [M+H]+ 474.0.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl-].[Al+3].[Cl-].[Cl-].[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH3:17].C([O-])([O-])=O.[Na+].[Na+]>C(=S)=S>[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
A mixture of 16 g (0.11 mol) phthalic anhydride, 30 g (0.22 mol) aluminum chloride and 12 g (0.10 mol) isopropylbenzene in 120 mL carbon disulfide was refluxed for 7 h in a water bath. The carbon sulfide was then removed by distillation. A dilute HCl solution (100 mL, 1.2N) was then added slowly to the remaining residue. The aqueous phase was decanted to yield a sticky solid. Na2CO3 aqueous solution (500 mL, 15%) was added slowly to the residue which resulted in considerable foaming. The solution was heated and the resultant solution was filtered to remove the undissolved material. The filtrate was acidified with conc. HCl to give an oily layer which was extracted with diethylether. The diethylether layer was dried with MgSO4, filtered and then the diethylether was removed by rotary evaporation to yield a cream-colored solid. The product was recrystallized from a 33/66 (v/v) mixture of toluene and pentane (17 g, 64%) mp 126°-127° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Product: Clc1cc(-c2ccccc2)nc(Cl)n1

Procedure:
Under argon, 2,4,6-trichloropyrimidine (7.28 g, 40 mmol), phenylboronic acid (4.9 g, 40 mmol), tetrakis(triphenylphosphine)palladium (1.39 g, 1.2 mmol), toluene (120 mL) and an aqueous solution of 2M sodium carbonate (60 mL) were sequentially added and heated to reflux for eight hours.
Reaction SMILES: C[NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])=S.[N:17]#CN.[Pb]>>[CH3:16][C:12]1[N:13]=[CH:14][NH:15][C:11]=1[CH2:10][S:9][CH2:8][CH2:7][CH2:6][NH:5][C:3](=[NH:17])[NH2:2]
Reactant: CNC(=S)NCCCSCc1[nH]cnc1C
Reactant: N#CN
Agent: [Pb]
Product: Cc1nc[nH]c1CSCCCNC(=N)N
Yield: 17.5 %

Procedure:
The reaction of N-methyl-N'-[3-((4-methyl-5-imidazolyl)methylthio)propyl]thiourea (5.9 g.) with lead cyanamide (17.5 g.) by a procedure similar to that described in Example 3(b) afforded N-cyano-N'-methyl-N"-[3-((4-methyl-5-imidazolyl)methylthiopropyl]guanidine (0.91 g.), m.p. 156°-158°, following chromatography on silica gel with successive elution by chloroformethyl acetate (1:1), ethyl acetate and ethyl acetate isopropyl alcohol (5:1) and final recrystallisation from isopropyl alcohol-ether. (Found: C, 49.5; H, 7.0; S, 12.0. C11H18N6S requires: C, 49.6; H, 6.8; S, 12.0).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][N:9]=1.O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH2:7][C:8]1[N:9]=[CH:10][C:11]([CH2:12][OH:13])=[CH:15][CH:16]=1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
At 0° C., lithiumaluminium hydride (1.7 g) was added to a THF solution (58 mL) of 6-amino-nicotinic acid (2.0 g), and stirred overnight at room temperature. Sodium sulfate 10 hydrate was added to the reaction liquid at 0° C. to stop the reaction, and this was dried with anhydrous sodium sulfate. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain (6-amino-3-pyridinyl)methanol (1.7 g) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 77 %

Procedure:
A suspension of 5-chloropyrimidin-2-one (1.202 g) and 2-bromo-4'-chloroacetophenone (2.114 g) in triethylamine (2 ml) and ethanol (20 ml) was stirred at ambient temperature for 75 mins. The resulting suspension was filtered, the solid was washed with water then crystallised from acetone to give the title pyrimidinone (1.973 g,); m.p. 216°-218°; λmaxEtOH 252 nm (ε 22360), 233 nm (ε 2080), λinf 288 nm (ε 1530).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:11])[CH3:10])[CH2:5][CH2:4]1.[H-].[Na+].[Si]([O:21][CH2:22][C:23]1[C:24]([F:36])=[C:25]([C:29]2[CH:30]=[N:31][C:32](Cl)=[N:33][CH:34]=2)[CH:26]=[CH:27][CH:28]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CCOC(C)=O.O.C1COCC1>[F:36][C:24]1[C:23]([CH2:22][OH:21])=[CH:28][CH:27]=[CH:26][C:25]=1[C:29]1[CH:34]=[N:33][C:32]([O:1][CH2:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9](=[O:11])[CH3:10])[CH2:7][CH2:8]2)=[N:31][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-c2cnc(Cl)nc2)c1F
Reactant: CC(=O)N1CCC(CO)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(COc2ncc(-c3cccc(CO)c3F)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
1-[4-(Hydroxymethyl)piperidin-1-yl]ethan-1-one (200 mg) and THF (4 ml) were mixed, and NaH (70 mg) was added thereto, followed by stirring at room temperature for 10 minutes. 5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-chloropyrimidine (200 mg) was added to the reaction mixture, followed by stirring at room temperature for 1 hour, and then 1M TBAF/THF (1.2 ml) was added thereto, followed by stirring at room temperature. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc/CHCl3/MeOH) to obtain 1-{4-[({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)methyl]piperidin-1-yl}e than-1-one (167 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[C:8]1([CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][C:16](O)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)CCl>ClCCl>[C:19]1([CH:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:15][C:16]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1CNCCN1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1CN(C(=O)CC(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of piperazin-2-one (100 m g, 1 mmol), 3,3-diphenylpropanoic acid (226 mg, 1 mmol) was added EDC (382 mg, 2 mmol) in dichloromethane (5 mL). The solution was stirred at room temperature overnight and concentrated in vacuo. The residue was diluted with EtOAc, and the mixture was washed consecutively with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (2:98 MeOH/DCM) to give the desired 4-(3,3-diphenylpropanoyl)piperazin-2-one product (compound 4) (246 mg, 80%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][CH2:24]OS(C)(=O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:24][CH2:23][C:13]1[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:16][C:12]=1[CH3:11])[CH:5]=[O:6]
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: O=Cc1ccc(O)c(F)c1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1F

Procedure:
In analogy to the procedures described in examples 114 b], c] and d], 3-fluoro-4-hydroxy-benzaldehyde was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester [PCT Int. Appl. (2000) WO0008002] to give 3-fluoro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde. Treatment of 3-fluoro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde with (benzyloxycarbonyl-ethoxy-methyl)-triphenyl-phosphonium chloride (prepared in analogy to the procedure described for the synthesis of (benzyloxycarbonyl-methoxy-methyl)-triphenyl-phosphonium chloride in example 114 a]) then gave 2(Z,E)-ethoxy-3-{3-fluoro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid benzyl ester, which was hydrogenated to yield [rac]-2-ethoxy-3-{3-fluoro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:14][C:13]3[C:12](=O)[NH:11][CH:10]=[N:9][C:8]=3[CH:7]=2)=[CH:2]1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:23])=O>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:14][C:13]3[C:12]([Cl:23])=[N:11][CH:10]=[N:9][C:8]=3[CH:7]=2)=[CH:2]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(-c3ccsc3)sc12
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ncnc2cc(-c3ccsc3)sc12
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of 6-(3-thienyl)-3H-thieno[3,2-d]pyrimid-4-one (218, 74 mg, 0.32 mmol) in phosphorus oxychloride (2 mL) under N2 was heated at reflux for 1 hour. The resulting solution was allowed to cool to room temperature, poured into a saturated aqueous solution of sodium bicarbonate to neutralize and then extracted with ethyl acetate. The organic layer was washed with water followed by saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to yield 6-(3-thienyl)-4-chlorothieno[3,2-d]pyrimidine (65 mg, 81% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:6][N:5]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(C)cc2)c(N)n1
Reactant: CC(=O)N1CCC(N)CC1
Product: CC(=O)N1CCC(Nc2ncc(C(=O)c3ccc(C)cc3)c(N)n2)CC1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-p-tolyl-methanone (Example 354) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(4-methyl-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 354.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][NH:4][C:3]=1/[CH:15]=[C:16]1\[C:17](=[O:35])[NH:18][C:19]2[C:24]\1=[C:23]([C:25]1[CH:26]=[C:27]([CH2:31][C:32]([OH:34])=O)[CH:28]=[CH:29][CH:30]=1)[CH:22]=[CH:21][CH:20]=2.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH:40][C:32](=[O:34])[CH2:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:24]=2/[C:16](=[CH:15]/[C:3]2[NH:4][CH:5]=[C:6]([C:7]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)=[O:8])[C:2]=2[CH3:1])/[C:17](=[O:35])[NH:18]3)[CH:26]=1
Reactant: Cc1c(C(=O)N2CCOCC2)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc(CC(=O)O)c3)c21
Reactant: CN(C)CCN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1c(C(=O)N2CCOCC2)c[nH]c1/C=C1\C(=O)Nc2cccc(-c3cccc(CC(=O)NCCN(C)C)c3)c21

Procedure:
(3-{3-[1-[3-Methyl-4-(morpholine-4-carbonyl)-1H-pyrrol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-4-yl}-phenyl)-acetic acid (117.6 mg, 0.25 mmol) was coupled with N,N-dimethylethylenediamine (2 eq.), EDC (1.5 eq.) and HOBt (1 eq.) in DMF (1 mL) using the general amidation procedure to give 117.3 mg of the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[S:6][CH2:5][CH2:4][O:3]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)CC(O)=O.CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:3][CH2:4][CH2:5][S:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]
Reactant: CC1(CC(=O)Nc2ccccc2)OCCS1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)O
Agent: O=C(O)CC(=O)O
Solvent: Cc1ccccc1
Product: CC1=C(C(=O)Nc2ccccc2)SCCO1
Yield: 73.5 %

Procedure:
Cis-2-methyl-N-phenyl-1,3-oxathiolane-2-acetamide-3-oxide, prepared from 0.1 moles of 2-methyl-N-phenyl-1,3-oxathiolane-2-acetamide as prepared in Example 1, was placed with toluene (100 g), tetrabutylammonium bromide (a phase transfer catalyst) (0.32 g, 0.001 g mole) and malonic acid (pKa =2.83, 0.41 g, 0.004 g mole) in a 1 L three-necked round bottom flask equipped with a mechanical stirrer, a thermometer and a Dean-Stark trap for the efficient removal of evolved water of reaction. The reaction mixture so prepared was placed under a vacuum equivalent of 300 mm of Hg and heated at 72°-75° C. for 1 hour. Methanesulfonic acid (0.19 g, 0.002 g mole) was then added to the reaction mixture, the vacuum was increased to 200 mm Hg and heating was continued at 72°-75° C. for an additional hour. The reaction mixture was then cooled to 55°-60° C. and washed successively with 100 mL portions of 5% aqueous sodium hydroxide solution and water. The resulting organic layer was then decanted and concentrated, and after isolation and drying, yielded a total of 17.3 g of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxanilide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([CH3:20])([CH3:19])[CH2:16][C:17](=[O:18])[C:11]2=[CH:10][C:9]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.C1(N[S:50]([C:53]([F:56])([F:55])[F:54])(=[O:52])=[O:51])C=CC=CC=1>CN(C=O)C>[F:54][C:53]([F:56])([F:55])[S:50]([O:18][C:17]1[C:11]2[C:12](=[N:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[C:9]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[CH:10]=2)[O:14][C:15]([CH3:20])([CH3:19])[CH:16]=1)(=[O:52])=[O:51]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: CC1(C)CC(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)C=C(OS(=O)(=O)C(F)(F)F)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2O1
Reaction time: 0.08 h

Procedure:
To the product of Example 3 (0.47 g, 1.2 mmol) in DMF (9 mL) at −78° C., was added 1 M LiHMDS in THF (1.3 mL, 1.3 mmol) and the reaction was stirred for 5 min. N-phenyl trifluoromethanesulfonamide (0.47 g, 1.3 mmol) was added and the reaction was allowed to come to rt. The reaction was stirred an additional 15 min, concentrated and the residue was purified by flash chromatography on silica gel gradient eluted with 0-20% EtOAc in hexane to afford the title compound. Step B: 7-(2-Chlorophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-4-pyridin-4-yl-2H-pyrano[2,3-b]pyridine