Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].II.CO>O1CCCC1>[CH3:11][NH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CNCCCc1ccccc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCCCc1ccccc1
Temperature: 7 °C
Yield: 53 %

Procedure:
N-(3-Phenylpropyl)formamide (5.70 g, 34.9 mmol) was dissolved in tetrahydrofuran (50 ml) and added dropwise to a suspension of sodium borohydride (1.58 g, 41.91 mmol) in tetrahydrofuran (100 ml), which was cooled to 7° C. A solution of iodine (4.42 g, 17.46 mmol) in tetrahydrofuran was added dropwise, while the temperature was kept at 7° C. After the addition was finished, the reaction mixture was warmed to reflux for 16 h. The reaction mixture was cooled to 7° C., and methanol (250 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in 20% aqueous sodium hydroxide solution (250 ml) and tert-butyl methyl ether (100 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using dichicromethane/methanol/25% aqueous ammonia (100:10:1) as eluent to give 2.76 g of N-methyl-N-(3-phenylpropyl)amine.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[Cl:18][CH2:19][C:20](=[O:25])[CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[Cl:18][CH2:19][C:20](=[O:25])[CH2:21][C:22]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)=[O:23]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: O=C(Cl)CC(=O)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 104.3 %

Procedure:
After 191.2 g (1.25 mol) of p-nitrobenzyl alcohol is dissolved in 250 ml of methylene chloride, 98.8 g of pyridine is added, and the mixture is cooled to -5° to 0° C. A solution of 193.75 g (1.25 mol) of γ-chloroacetoacetyl chloride (γ-CAC) in 431 ml of methylene chloride is added at the same temperature over an hour and, after completion of the addition, the mixture is stirred for 30 minutes. The resulting pyridine hydrochloride is filtered off. The filtrate and washings are combined and washed with 2 l-portions of water. The organic layer is dried over sodium sulfate and the solvent is then distilled off to give 354 g of p-nitrobenzyl γ-chloroacetoacetate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([CH:23]=1)[C:20](O)=[O:21])=[O:14].C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.[CH3:56][N:57]1[CH2:62][CH2:61][N:60]([C:63]2[CH:68]=[CH:67][C:66]([NH:69][C:70]3[N:75]=[CH:74][C:73]([NH2:76])=[CH:72][N:71]=3)=[CH:65][CH:64]=2)[CH2:59][CH2:58]1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([C:20]([NH:76][C:73]2[CH:74]=[N:75][C:70]([NH:69][C:66]3[CH:65]=[CH:64][C:63]([N:60]4[CH2:59][CH2:58][N:57]([CH3:56])[CH2:62][CH2:61]4)=[CH:68][CH:67]=3)=[N:71][CH:72]=2)=[O:21])[CH:23]=1
Reactant: CN1CCN(c2ccc(Nc3ncc(N)cn3)cc2)CC1
Reactant: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccc2F)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccc2F)cc1C(=O)Nc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 16×100 mm vial was charged with 5-((2-fluoro-5-(trifluoromethyl)phenyl)carbamoyl)-2-methylbenzoic acid 36 (0.100 g, 0.293 mmol), dichloromethane (3 mL), diisopropylethylamine (0.200 ml, 1.15 mmol), 1-hydroxybenzotriazole (0.0396 g, 0.293 mmol), EDC.HCl (0.0562 g, 0.293 mmol), and N2-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,5-diamine (0.0875 g, 0.308 mmol), and the mixture stirred at room temperature for 24 hours. The reaction mixture was purified via column chromatography on silica gel (gradient elution with 0 to 20% methanol in dichloromethane) to afford N1-(2-fluoro-5-(trifluoromethyl)phenyl)-4-methyl-N3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)isophthalamide 37 as a light yellow solid. MS m/z found 608 [MH+]; calc. for C31H29F4N7O2=607.60.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]2[C:24]([O-:26])=[O:25])=[CH:5][CH:4]=1.COC1C=CC(C2C3C(=CC=CC=3)C(C3C=CC=CC=3)=C2C(OCC)=O)=CC=1>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)[O-])cc1
Agent: [Pd]
Agent: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Reaction time: 24 h

Procedure:
Ethyl (1RS, 2SR, 3SR)-1-(4-Methoxyphenyl)-3-phenylindane-2-carboxylate. To a solution of ethyl (RS)-1-(4-methoxyphenyl)-3-phenylindene-2-carboxylate (5.75 g, 15 mmol) in EtOAc (150 ml) was added 5% palladium on activated carbon (600 mg). The resulting suspension was stirred under an atmosphere of H2 for 1 d, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH2:22]([O:24][C:25]([C:27]1([NH:32][C:33]([CH:35]2[CH2:39][CH:38]([O:40][C:41]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=[CH:43][N:42]=3)[CH2:37][NH:36]2)=[O:34])[CH2:29][CH:28]1[CH:30]=[CH2:31])=[O:26])[CH3:23].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH2:22]([O:24][C:25]([C:27]1([NH:32][C:33]([CH:35]2[CH2:39][CH:38]([O:40][C:41]3[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH:44]=[CH:43][N:42]=3)[CH2:37][N:36]2[C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[O:34])[CH2:29][CH:28]1[CH:30]=[CH2:31])=[O:26])[CH3:23]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nccc3ccccc23)CN1)C(=O)OCC
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN1CCOCC1
Product: C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc2nccc3ccccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.6 %

Procedure:
2(S)-tert-butoxycarbonylamino-8-nonenoic acid (purchased from RSP Amino Acids)(1.0 g, 3.68 mmol) dissolved in 100 mL of DMF was treated sequentially with 1-{[4-(isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester, bis hydrochloride (1.46 g, 3.68 mmol), N-methyl morpholine (1.4 mL, 12.9 mmol), and HATU (PE biosystems) (1.68 g, 4.42 mmol). The reaction mixture was stirred at rt under N2 for 24 h, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give 2.2 g of the crude product. Flash chromatography (20–50% ethyl acetate/hexane) gave 1.9 g (79%) of 1-{[1-(2-tert-butoxycarbonylamino-non-8-enoyl)-4-(isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester as a glassy colorless solid:
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:19][C:13]3=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:20]=1)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([NH2:31])=[O:30]>CN(C)C=O>[CH3:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]2[O:19][C:13]3=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=[C:12]3[CH2:11][C:10]=2[CH:20]=1)[C:3]([O:5][CH2:28][C:29](=[O:30])[NH2:31])=[O:4]
Reactant: Cc1ccc2c(n1)Oc1ccc(C(C)C(=O)O)cc1C2
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)Oc1ccc(C(C)C(=O)OCC(N)=O)cc1C2
Temperature: 80 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 2.7 g of α,2-dimethyl-5H-[1]benzopyrano [2,3-b]pyridine-7-acetic acid in 15 ml of dimethylformamide are added 0.8 g of potassium carbonate and 1.1 g of 2-chloroacetamide, and stirred at 80° C. for 1 hour under a nitrogen atmosphere. The reaction mixture is poured into ice water, and the precipitated crystals are collected by filtration, washed with water, and then recrystallized from ethanol to obtain 2.7 g of carbamoylmethyl α,2-dimethyl-5H-[1]benzopyrano [2,3-b]pyridine-7-acetate as white crystals having a melting point of 175° to 177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](N)=[O:10])=[CH:4][CH:3]=1.N([O-])=O.[Na+].Cl.C(Cl)(Cl)Cl>O.F[B-](F)(F)F.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)Nc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C=Nc1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
4-Chlorophenyl urea (8.5 parts) and a solution of sodium nitrite (6.9 parts) in water (10 parts) were added over 6 hours to a mixture of conc. hydrochloric acid (10.3 parts) chloroform (130 parts) and tetra-n-butyl ammonium fluoroborate (10% by weight based on 4-chlorophenyl urea) at -10° to -5° C. The mixture was stirred for a further 15 minutes then the stirrer stopped and layers allowed to separate. No solid was present at this stage. 5 mls of the organic layer was taken for analysis and the remainder kept cold until required.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.[C:32](#[N:35])[CH2:33]O>CO>[CH3:1][N:2]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)[CH2:33][C:32]#[N:35]
Reactant: N#CCO
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Solvent: CO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CC#N)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-methylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) in methanol (10 ml) is added glycolonitrile (50%, 0.19 ml) and the mixture is stirred at room temperature for 20 minutes, and then refluxed for 30 minutes. Thereto is added additional glycolonitrile (0.5 ml) and the mixture is refluxed for 5.5 hours. The reaction solution is concentrated and to the resulting residue is added ethyl acetate. The precipitated crystal is collected by filtration, and recrystallized from acetonitrile to give 5-(N-methyl-N-cyanomethylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.32 g) as colorless needles, m.p. 227°-228° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:26]2[O:30][N:29]=[C:28]([C:31]([OH:33])=O)[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:54][CH2:55]1)[CH2:47][NH:46][C:31]([C:28]1[CH:27]=[C:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:30][N:29]=1)=[O:33]
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)on1
Temperature: 10 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
HOBt (44.6 mg, 0.33 mmol) and DIPEA (136.7 mg, 1.06 mmol) were added to a stirred solution of 5-phenyl-isoxazole-3-carboxylic acid (50 mg, 0.27 mmol) in DMF (1.0 mL). The reaction mixture was then cooled to 10° C. and EDCI.HCl (63.3 mg, 0.33 mmol) was added, followed by the addition 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone (as TFA salt) (113.5 mg, 0.27 mmol). Then resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with water and the product extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. The crude product thus obtained was purified by column chromatography using neutral alumina as stationary phase and 100% ethyl acetate as the eluent to afford 5-phenyl-isoxazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide as a solid in 20.3% yield. LC-MS purity: 98.075%, 1H NMR (DMSO-D6): δ 8.6 (s, 1H), 7.9 (m, 2H), 7.7 (m, 2H), 7.65 (m, 1H), 7.5 (m, 3H), 7.4 (s, 1H), 4.1 (m, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.1 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:7]2[C:8](=[O:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:3].[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](N)[N:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:7]3[C:8](=[O:16])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:3])[N:26]=[CH:25][N:24]=1
Reactant: Cc1cccc2nc(C(C)N)c(-c3ccccc3)c(=O)n12
Reactant: N#Cc1c(N)ncnc1N
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2nc(C(C)Nc3ncnc(N)c3C#N)c(-c3ccccc3)c(=O)n12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(1-aminoethyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.178 g, 0.637 mmol) and 4,6-diaminopyrimidine-5-carbonitrile (0.090 g, 0.67 mmol) in butan-1-ol (4 mL) was added diisopropylethyl amine (0.33 mL, 1.91 mmol). After stirring at 120° C. for 3 h, the solution was loaded onto silica gel and purified by MPLC (eluted with a gradient of 0-8% MeOH in DCM) to afford 4-amino-6-(1-(6-methyl-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)ethylamino)pyrimidine-5-carbonitrile as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (d, J=6.65 Hz, 3 H) 2.91 (s, 3 H) 5.09 (quin, J=6.85 Hz, 1 H) 6.97 (d, J=7.04 Hz, 1 H) 7.03 (d, J=7.24 Hz, 1 H) 7.32 (br. s., 2 H) 7.35-7.50 (m, 6 H) 7.72 (dd, J=8.80, 6.85 Hz, 1 H) 7.98 (s, 1 H) Mass Spectrum (ESI) m/e=398.1 (M+1). The racemic mixture (0.210 g) was separated by chiral separation using SFC to give 2 fractions. First-eluting enantiomer on AD-H column: 4-amino-6-(((1S)-1-(6-methyl-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.26 (d, 3 H) 2.90 (s, 3 H) 5.09 (qd, J=6.89, 6.72 Hz, 1 H) 6.97 (d, J=6.85 Hz, 1 H) 7.04 (d, J=7.34 Hz, 1 H) 7.33 (br. s., 2 H) 7.35-7.50 (m, 6 H) 7.71 (dd, J=8.93, 6.97 Hz, 1 H) 7.97 (s, 1H) Mass Spectrum (ESI) m/e=398.1 (M+1). Second-eluting enantiomer on AD-H column: Concentration of product fractions gave a solid that was triturated in water and filtered to afford 4-amino-6-(((1R)-1-(6-methyl-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile as a light yellow solid. Mass Spectrum (ESI) m/e=398.1 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:22])[O:15][C@:14]2([CH3:21])[CH2:16][C@@H:17]([CH2:19][OH:20])[O:18][CH:13]2[O:12]1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([O:20][CH2:19][C@H:17]1[O:18][CH:13]2[C@:14]([CH3:21])([O:15][C:11]([CH3:22])([CH3:10])[O:12]2)[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)OC2O[C@H](CO)C[C@@]2(C)O1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC1(C)OC2O[C@H](COC(=O)c3ccccc3)C[C@@]2(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.6 %

Procedure:
Benzoyl chloride (1.92 mL, 0.0166 mol) was added to a solution of ((5S,6aR)-2,2,6a-trimethyl-dihydro-5H-furo[3,2-d][1,3]dioxol-5-yl)methanol (from step 8) (2.72 g, 0.0138 mol) in 20 mL of anhydrous pyridine at 0° C. To this mixture 5 mol % of DMAP was added and stirred at room temperature for 3 h. Pyridine was removed under vacuum; the residue was diluted with ethyl acetate and washed with 1N HCl, saturated NaHCO3 and brine. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The compound was purified via column chromatography using hexane and ethyl acetate as a gradient mixture to give 4.1 g of the title compound (97% yield).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.Cl.[CH2:40]([O:42][C:43](=[O:46])[CH2:44][NH2:45])[CH3:41]>C1COCC1>[CH2:40]([O:42][C:43](=[O:46])[CH2:44][NH:45][C:14]([C@@H:13]1[CH2:12][S:11][C@H:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[N:9]1[C:7](=[O:8])[CH2:6][CH2:5][S:4][C:1](=[O:3])[CH3:2])=[O:16])[CH3:41]
Reactant: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O
Reactant: CCOC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)[C@@H]1CS[C@H](c2ccccc2O)N1C(=O)CCSC(C)=O
Yield: 81.6 %

Procedure:
The suspension is prepared by using 1.78 g of (2R,4R)-3-(S-acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid, 0.51 g of N-methylmorpholine and 0.68 g of isobutyl chlorocarbonate. To the suspension the solution of 0.7 g of glycine ethyl ester hydrochloride and 0.51 g of N-methylmorpholine dissolved in aqueous THF is added, and treated in the same manner as Example 10 to give 1.8 g (82%) of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=3)[C:16]([S:26]([CH3:28])=[O:27])=[CH:15]2)=[N:12][CH:13]=1.Cl.[CH3:30][NH:31][C:32]1([CH2:35][OH:36])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:31]([C:32]4([CH2:35][OH:36])[CH2:34][CH2:33]4)[CH3:30])=[O:25])[CH:21]=3)[C:16]([S:26]([CH3:28])=[O:27])=[CH:15]2)=[N:12][CH:13]=1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Reactant: CNC1(CO)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CN(C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1)C1(CO)CC1

Procedure:
Prepared from 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid and (1-(methylamino)cyclopropyl)methanol hydrochloride under use of HATU as reagent. White solid. Yield: 42 mg
Reaction SMILES: [CH2:1]([C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]([C:15]([O:17]CC)=O)=[C:6]([CH:20]=[CH2:21])[N:5]=1)[CH2:2][CH3:3].[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.C(N(C(C)C)C(C)C)C.O>CC(N(C)C)=O>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([N:22]2[CH2:21][CH2:20][C:6]3[N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=3[C:15]2=[O:17])[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C=Cc1nc(CCC)c(C(=O)OCC)cc1C(=O)OCC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCCc1nc2c(cc1C(=O)OCC)C(=O)N(C1CCN(C(=O)OC(C)(C)C)CC1)CC2
Temperature: 135 °C
Reaction time: 4.5 h
Yield: 72.7 %

Procedure:
A mixture of diethyl 2-propyl-6-vinylpyridine-3,5-dicarboxylate (9.00 g), tert-butyl 4-aminopiperidine-1-carboxylate (7.42 g) and N-ethyl-N-isopropylpropan-2-amine (8.09 mL) in DMA (45 mL) was stirred at 130 to 140° C. for 4.5 hours. The mixture was poured into water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with brine twice, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was passed through a silica gel-pad (hexane/ethyl acetate), and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (10.0 g).
Reaction SMILES: [F:1][CH:2]([F:4])Cl.[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[CH:9]=[C:8]([CH3:13])[N:7]=1>O.[OH-].[Na+].O1CCOCC1>[NH2:5][C:6]1[N:11]=[C:10]([O:12][CH:2]([F:4])[F:1])[CH:9]=[C:8]([CH3:13])[N:7]=1
Reactant: Cc1cc(O)nc(N)n1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(OC(F)F)nc(N)n1

Procedure:
Gaseous difluorochloromethane is introduced, over a period of 12 hours at a temperature of 70° to 75° C., into a solution of 62.5 g of 2-amino-4-hydroxy-6-methyl-pyrimidine in 500 ml of water, 100 ml of 40% sodium hydroxide solution and 100 ml of dioxane. There are added during this time, in each case at intervals of 1 hour and in equal portions, a total of 160 g of solid sodium hydroxide. The organic phase is separated, and concentrated to about 1/10 of its volume; the residue is poured into water, and the solid substance which has precipitated is removed. The yield is 39.9 g of 2-amino-4-difluoromethoxy-6-methyl-pyrimidine, m.p. 136° to 137° C. (compound No. 1.1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1C=CC=CC=1.N1CCCCC1>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: O=Cc1cc2ccccc2s1
Reactant: O=C(O)CC(=O)O
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1cc2ccccc2s1

Procedure:
To a mixture of 1-benzothiophene-2-carbaldehyde, malonic acid (1.5 equiv) and pyridine (2.5 equiv) was added piperidine (0.1 equiv). The mixture was heated to reflux for 6 h, cooled and poured into H2O and filtered. Air drying over night gave the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[NH:14][C:13](=[O:16])[CH:12]=[N:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>>[O:16]=[C:13]1[CH:12]=[N:11][C:10]2[N:9]=[CH:8][CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[C:23]([O:22][C:21]([F:20])([F:32])[F:33])[CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[C:15]=2[NH:14]1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccnc3ncc(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3ncc(=O)[nH]c23)c1)c1cccc(OC(F)(F)F)c1
Yield: 20 %

Procedure:
Method G1 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-trifluoromethoxybenzoyl chloride to afford the title compound as a white solid (35 mg, 20%).