Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn].[Cl:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][C:4]=1[N+:14]([O-])=O.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(NC1C=CC=CC=1)(=O)C>Cl.C(O)(=O)C.O>[C:17]([NH:14][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=1[Cl:2])[CH:7]=[CH:8][C:9]([OH:11])=[O:10])(=[O:19])[CH3:18]
Reactant: O=C(O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)Nc1ccccc1
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C=CC(=O)O)ccc1Cl
Temperature: 45 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Tin II chloride dihydrate (103 g, 0.46 mol) was dissolved in concentrated HCl (120 mL). Warming was necessary to obtain a clear solution. 4-Chloro-3-nitrocinnamic acid (25 g, 0.11 mol) was added portionwise with stirring. After about 20% of the starting material had been added, the mixture was warmed with a heat gun to 45° C. to initiate reaction. The rate of addition was controlled to maintain a temperature of 65-75° C. Cooling with a water bath was used to prevent the temperature exceeding 80° C. After the addition was complete and reaction started to subside, the mixture was transferred to an oil bath at 65° C. for 1 h. The mixture was cooled to room temperature. The solid was filtered, washed with 2 M HCl, (60 mL) and sucked dry. The filter cake was dried in a vacuum oven for 1 h, then in air overnight, to give about 34 g crude product. This material was suspended in acetic acid (100 mL) with stirring and acetic anhydride (100 mL, 1.1 mol) was added in one portion. The temperature rose to 35° C. After the initial exotherm subsided, the mixture was stirred in an oil bath at 110° C. for 2 h, but did not dissolve. LCMS showed complete conversion to the desired acetanilide. The solution was cooled and water (50 mL) was added cautiously. The mixture was concentrated to about 200 mL. More water (100 mL) and 2 M HCl (50 mL) were added. The precipitate was filtered, washed with water and dried to give 3-acetamido-4-chlorocinnamic acid (25.0 g, 95%).
Reaction SMILES: [C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:36])=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[C:21](=[O:34])[N:20]([CH3:35])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:75][N:76]1[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]1>O.CN(C)C=O>[C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([N:79]5[CH2:80][CH2:81][N:76]([CH3:75])[CH2:77][CH2:78]5)=[O:30])=[CH:32][CH:33]=4)[C:21](=[O:34])[N:20]([CH3:35])[CH:19]=3)[C:13]=2[CH3:36])=[O:10])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)O)cc2)n1
Reactant: CN1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)N3CCN(C)CC3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
A solution of 4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-benzoic acid (7) (80 mg; 0.16 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (69 mg; 0.16 mmol), N,N-diisopropylethylamine (0.09 mL; 0.48 mmol), and N,N-dimethylformamide (1 mL) was stirred at room temperature for 0.5 hr. N-Methylpiperazine (80 mg; 0.8 mmol) was added and the mixture was stirred at room temperature for 16 hr. Water (30 mL) was added and the mixture was extracted with ethyl acetate (3×60 mL). The combined organic extracts were washed with water (2×30 mL) and brine (1×30 mL), dried over magnesium sulfate, and evaporated under reduced pressure. The residue was slurried with diethyl ether and filtered to give 4-tert-butyl-N-(2-methyl-3-{4-methyl-6-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5-oxo-4,5-dihydro-pyrazin-2-yl}-phenyl)-benzamide (8) as a cream solid (50 mg), MS 593.35 (M+H)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17]>O1CCOCC1.O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[CH:7]=1
Reactant: NCC(O)CO
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1c(NCC(O)CO)cc(Cl)cc1NCC(O)CO

Procedure:
A mixture of 0.1 mole (22.6 g) of 2,4,6-trichloro nitrobenzene and 54.7 g of 3-amino-1,2-propanediol in 20 ml of dioxan was refluxed for 4 hours followed by evaporation of the dioxan under reduced pressure. The oil obtained was diluted in about 300 ml of water. The desired product was obtained using HPLC in two stages. About 200 ml of the aqueous solution of the product containing 3-amino-1,2-propanediol were injected onto a C18RD chromatographic column (Instrument: Waters Prep 500). The desired product was eluted using 35% methanol-65% water solution. After evaporation of the fractions containing the desired product, a dry extract was obtained which was recrystallized from 96° alcohol. The product melted at 146° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1>CS(C)=O.O>[S:19]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:8]1[N:6]2[N:7]=[C:2]([NH:32][C@H:33]3[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Clc1ccc2ncc(-c3cc4ncccc4s3)n2n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: O[C@H]1CC[C@H](Nc2ccc3ncc(-c4cc5ncccc5s4)n3n2)CC1
Temperature: 100 °C

Procedure:
To a solution of 6-chloro-3-(thieno[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazine (40 mg, 0.139 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (20 mg, 0.139 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (0.695 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 40 mg of the yellow solid, 79%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH3:8][C:9]1[N:14]=[C:13]([SH:15])[N:12]=[C:11]([OH:16])[CH:10]=1.C(N(CC)CC)C>C(O)C>[CH3:8][C:9]1[N:14]=[C:13]([S:15][CH2:2][C:3]2[CH:7]=[CH:6][S:5][CH:4]=2)[N:12]=[C:11]([OH:16])[CH:10]=1
Reactant: BrCc1ccsc1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2ccsc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.7 %

Procedure:
A mixture of 3-(bromomethyl)thiophene (360 mg, 2.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (242 mg, 1.7 mmol), and triethylamine (280 μL, 2.0 mmol) in absolute ethanol (10 mL) was stirred at room temperature for 2 days. The solid residue was removed by filtration. The filtrate was recovered and evaporated under reduced pressure. The solid product was suspended in water (20 mL). The solid material was recovered by filtration, washed with water (2×15 mL) and hexanes (3×15 mL), and dried in vacuo, affording the title compound (80 mg, 20% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.39 (s, 2H), 6.02 (s (br), 1H), 7.12 (dd, 1H, J=1.3 Hz, 3.5 Hz), 7.47 (m, 2H); M+ 239; HPLC purity: 96.1%.
Reaction SMILES: Cl[C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[Na+].[SH-:11]>C(O)C>[SH:11][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [SH-]
Reactant: O=c1cccccc1Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1cccccc1S
Temperature: -70 °C
Reaction time: 2 h

Procedure:
A solution of 2-chloro-2,4,6-cycloheptatrien-1-one [2.82 g, described by T. Nozoe et al., Proc. Japan Acad., 28, 483 (1952)] in ethanol (20 ml) is added dropwise to a suspension, cooled to -70° C, of sodium sulfhydrate (2.2 g) in ethanol (20 ml). The mixture is stirred at -70° C for two hours, allowed to warm to room temperature and stirred at room temperature for 1 hour. The mixture is filtered and the filtrate is evaporated. The residue is suspended in water, the mixture is acidified to pH2 with 10% hydrochloric acid and extracted with ethyl acetate. The organic extract is dried and evaporated. The residue is dissolved in benzene and subjected to chromatography on silica gel. Th eluates are evaporated to give the title compound, mp 55° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=3[CH3:17])[CH2:26][CH2:27]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3C)CC2)nn1C(C)(C)C

Procedure:
92 mg (94%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(2,3-dimethylphenyl)piperazine (43mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [OH:1][C@H:2]([CH2:32][OH:33])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[C:26][Si](C)(C)C)=[CH:21][C:20]=3[F:31])=[C:12]([F:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(Cl)Cl>C1COCC1>[OH:1][C@H:2]([CH2:32][OH:33])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][C:20]=3[F:31])=[C:12]([F:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1
Reactant: Cn1c(=O)c(F)c(Nc2ccc(C#C[Si](C)(C)C)cc2F)c2c(=O)n(C[C@H](O)CO)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#Cc1ccc(Nc2c(F)c(=O)n(C)c3ncn(C[C@H](O)CO)c(=O)c23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a mixture of (S)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-((trimethylsilyl)ethynyl)phenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 21A in THF (3 mL) was added 1M solution of TBAF (0.14 mL, 0.14 mmol, 1.75 eq). The reaction mixture was stirred at ambient temperature for 1 hour. The solvent was removed under vacuum and the residue was purified by flash chromatography with 2:8 MeOH:DCM to yield the desired product (S)-3-(2,3-dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 21) as an off-white solid (10 mg, 30% yield). 1H NMR (400 MHz, MeOD) δ ppm 3.54 (s, 1H) 3.60 (d, J=5.05 Hz, 2H) 3.72 (s, 3H) 3.75-3.83 (m, 1H) 3.93-4.00 (m, 1H) 4.41 (dd, J=13.52, 2.91 Hz, 1H) 7.11 (td, J=8.15, 5.68 Hz, 1H) 7.21-7.29 (m, 2H) 8.40 (s, 1H). [M+H] calc'd for C19H16F2N4O4, 403. found, 403.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:17][CH:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19](O)=[O:20])([CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:4].[CH3:26][NH:27][C:28](=[O:35])[C@H:29]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH2:30].O[C:37]1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:1][O:2][P:3]([CH2:17][CH:18]([C:19](=[O:20])[NH:30][C@H:29]([C:28](=[O:35])[NH:27][CH3:26])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:22][C:23]([CH3:37])([CH3:24])[CH3:25])([CH2:5][N:6]1[C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]2[C:10]1=[O:11])=[O:4]
Reactant: COP(=O)(CC(CC(C)C)C(=O)O)CN1C(=O)c2ccccc2C1=O
Reactant: CNC(=O)[C@@H](N)CC(C)C
Reactant: Oc1cccc2[nH]nnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)(C)C)CP(=O)(CN1C(=O)c2ccccc2C1=O)OC
Yield: 80.1 %

Procedure:
3.0 g of 2(RS)-[[(RS)-(methoxy)(phthalimidomethyl)phosphinyl]methyl]-4-methylvaleric acid were dissolved in 50 ml of tetrahydrofuran and 1.65 g of L-leucine N-methylamide and 2.2 g of hydroxybenzotriazole were added while stirring. After all of the solids had dissolved, 2.02 g of N,N'-dicyclohexylcarbodiimide were added and the mixture was stirred at room temperature overnight. The tetrahydrofuran was removed by evaporation, the residue was triturated with 100 ml of ethyl acetate and the mixture was filtered in order to remove dicyclohexylurea. The filtrate was washed twice with 50 ml of saturated sodium hydrogen carbonate solution each time, dried over anhydrous sodium sulfate and evaporated to give a yellow gum. This gum was purified by flash chromatography on silica gel using 5% methanol in ethyl acetate for the elution. There were obtained 3.32 g of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]-4-methylpentyl](phthalimidomethyl)phosphinic acid methyl ester in the form of a white foam.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13])[CH:2]=[CH2:3].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([BH3-])#N.[Na+].C(O)(=O)C.Cl>ClCCCl>[CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([NH:11][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]=1[C:12]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=1)=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)ccc(N)c1C(=O)c1ccc(C(C)C)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C=CCc1c(O)ccc(NCc2ccccc2)c1C(=O)c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 39 mg (0.13 mmol) (2-allyl-6-amino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanone and 13.34 μl (13 mmol) benzaldehyde in 1.3 ml 1,2-dichlorethane and 0.3 g molecular sieves (4 Å pore size) are added after 1 h 13 mg (0.18 mmol) sodium cyanoborohydride and 7.55 μl acetic acid (0.13 mmol). After stirring for 16 h at r.t. 1 M hydrochloric acid is added to destroy the excess of hydride equivalents. By adding 1 M NaOH the mixture is basified. The crude product obtained by extraction with dichloromethane is purified by reversed phase preparative chromatography.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[Si:8]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34](S(C)(=O)=O)[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[Si](OC[C@@H](N1C=CC(C2C=CN=C(S(C)(=O)=O)N=2)=CC1=O)C1C=CC(Cl)=C([F:60])C=1)(C(C)(C)C)(C)C>>[Si:8]([O:15][CH2:16][C@@H:17]([N:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH:7][C@@H:4]3[CH2:5][CH2:6][O:1][CH2:2][C@H:3]3[F:60])[N:33]=2)=[CH:28][C:27]1=[O:42])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: NC1CCOCC1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(F)c(Cl)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Product: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(F)c(Cl)c1)n1ccc(-c2ccnc(N[C@@H]3CCOC[C@H]3F)n2)cc1=O

Procedure:
1-((S)-2-(tert-Butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-((3S,4R)-3-fluorotetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one was prepared according to the general procedure of Example 2, Step A, substituting (3S,4R)-3-fluorotetrahydro-2H-pyran-4-amine for tetrahydro-2H-pyran-4-amine and (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one for (S)-1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one. m/z (APCI-pos) M+1=577.2, 579.2.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10].Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][C:22]1=[O:31]>C(#N)C>[CH2:7]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][N:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][C:22]2=[O:31])[CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCC1CCNCC1
Reactant: O=C1CCc2ccccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CCc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A suspension of NaH in mineral oil (55-60%) (712 mg) was added to a solution of 3,4-dihydro-1H-quinolin-2-one (2.0 g, 13.6 mmol) in N,N-dimethylformamide (50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. then 1-bromo-3-chloropropane (1.34 mL, 13.6 mmol) was added. The slurry was stirred for additional 16 h. at ambient temperature then water (50 mL) was added and the product was extracted with diethyl ether (2×50 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by flash-chromatography (eluent: dichloromethane) to give 1-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol). KI (2.5 g, 15 mmol), K2CO3 (2.1 g, 15 mmol) and 4-butylpiperidine (1.8 mL, 15 mmol) were added to a solution of 1-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at 60° C. for 16 h. The acetonitrile was evaporated in vacuo, water (50 mL) was added and the product was extracted with ethyl acetate (2×50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash-chromatography (eluent: ethyl acetate) gave the title product. Yield: 2.06 g, 58%. Oxalate-salt was prepared from oxalic acid (1.1 eq.) in acetone. HPLC-MS: M+1+=329.5 (UV/MS(%)=100/100). 1H NMR (400 MHz, CD3OD): δ=0.89 (3H, t), 1.12-1.36 (9H, m), 1.67 (2H, broad d), 1.83 (2H, quin.), 1.97 (2H, broad t), 2.41 (2H, t), 2.59 (2H, t), 2.84-2.96 (4H, m), 3.99 (2H, t), 7.02 (1H, broad t), 7.16 (1H, broad d), 7.20 (1H, broad d), 7.25 (1H, broad t). 13C NMR (CD3OD): δ 13.2, 22.8, 24.3, 25.0, 28.9, 31.6, 31.9 (2C), 35.6, 36.2, 40.1, 53.8 (2C), 55.9, 115.2, 123.2, 127.0, 127.4, 127.9, 139.1, 171.5
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)(=O)[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[F:31])[C:19]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:20].[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.CO>[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[F:31])[C:19]([NH:21][CH:22]1[CH2:23][CH2:24][N:25]([CH:1]([C:4]2[CH:13]=[C:12]3[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]3)=[CH:6][CH:5]=2)[CH3:2])[CH2:26][CH2:27]1)=[O:20]
Reactant: CC(=O)c1ccc2c(c1)NC(=O)CC2
Reactant: O=C(NC1CCNCC1)c1ccc(F)c(Cl)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(c1ccc2c(c1)NC(=O)CC2)N1CCC(NC(=O)c2ccc(F)c(Cl)c2)CC1
Temperature: 25 °C

Procedure:
To a MeOH solution (15 mL) of the compound (206 mg) obtained in Step 51-2, the compound (560 mg) obtained in Step 51-3 and AcOH (327 mg), NaBH3CN (274 mg) was added at room temperature and the mixture was refluxed for 12 hours. After the reaction mixture was cooled to room temperature, NaBH3CN (274 mg) was added and the mixture was refluxed for 72 hours. After a saturated aqueous NaHCO3 solution was added, a water layer and an organic layer were separated. The water layer was extracted three times with CHCl3. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography [(silica gel 60 N, mobile phase: MeOH/CHCl3=0/100 to 20/80; v/v) and (Chromatorex NH, mobile phase MeOH/CHCl3=0/100 to 10/90; v/v) in this order] to obtain the titled compound (7 mg, a colorless solid).
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:5].[CH2:12]=O.[K].Cl>C(O)C.O>[C:4]([CH:6]([CH2:12][C:1]#[N:2])[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:5]
Reactant: [C-]#N
Reactant: C=O
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C#N)CC#N
Yield: 77.4 %

Procedure:
Potassium cyanide (13.0 g, 0.2M) was stirred in absolute ethanol and ethyl cyanoacetate (22.6 g, 0.2M) and paraformaldehyde (6.0 g, 0.2m) were added at ambient temperature. After 5 minutes the white suspension was heated under reflux conditions for 12 minutes, and the orange solution was evaporated to dryness in vacuo at below 25° C. to give a buff solid. The solid (the potassium salt) was dissolved in water (400 ml), acidified to pH 5 with 2M hydrochloric acid solution, giving a red oil. This mixture was extracted with dichloromethane and the extracts dried and evaporated to dryness in vacuo to give the title compound as a red oil (23.5 g), 1H NMR (CDCl3) d 4.3 (2H, q), 3.95 (1H, t), 3.0 (2H, d), 1.35 (3H, t); identical with an authentic sample. Distilled material had b.p. 132-136° C. at 0.5mmHg. Yield : 77%.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:21])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][NH:12]2)=[CH:8][CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:21])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][N:12]2[C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CC1(c2ccccc2)CNc2cc(Br)ccc21
Solvent: ClCCl
Product: CC(=O)N1CC(C)(c2ccccc2)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.2 %

Procedure:
Acetyl chloride (163 μL, 2.29 mmol) and TEA (313 μL, 2.29 mmol) were added to a solution of 6-bromo-3-methyl-3-phenyl-2,3-dihydro-1H-indole (600 mg, 2.1 mmol) in DCM (20 mL) at 0° C. The reaction was stirred for 45 minutes at room temperature and then quenched with 1 M aqueous HCl and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound (660 mg) as a yellow solid. MS: [M+H]+=330.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][OH:14].O[C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1>>[CH3:28][C:21]([O:20][C:19]1[CH:18]=[CH:17][C:16]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:30][CH:29]=1)([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1

Procedure:
Made from (5-methyl-2-phenyloxazol-4-yl)methanol [Overman, et al., J. Org. Chem. (1979), 44(13), 2323-25] and ethyl 2-(4-hydroxyphenoxy)-2-methylpropanoate (American Home Products, U.S. Pat. No. 3,795,691) via an analogous procedure to that reported for Example 2, Step A: 1H NMR (300 MHz, CDCl3) δ 8.03-8.09 (m, 2H), 7.45-7.52 (m, 3H), 6.94 (d, 2H), 6.88 (d, 2H), 4.99 (s, 2H), 4.37 (q, 2H), 2.47 (s, 3H), 1.60 (s, 6H), 1.33 (t, 3H).
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([NH:18][C:6](=[O:8])[CH2:5][C:4](=[O:3])[CH3:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)NCc1ccccc1

Procedure:
9 ml (0.05 mol) of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (diketene-acetone adduct) were added dropwise to a solution of 5.5 ml (0.05 mol) of benzylamine in 20 ml of toluene and the temperature was allowed to rise 70° C. The solution was refluxed for 2 h then the solvent was removed in vacuo. The crude product was triturated with ether obtaining 7.5 g of the title compound. M.p.=84°-86° C.