Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:5])=[O:4].[CH3:29][N:30]([CH3:35])[CH2:31][C:32](O)=[O:33].C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:32](=[O:33])[CH2:31][N:30]([CH3:35])[CH3:29])[CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:4])=[O:5]
Reactant: CN(C)CC(=O)O
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4OS(C)(=O)=O)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 4-[4-(5-{2-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidinium chloride (500 mg) in dimethylformamide (6 ml) under argon were added N,N-dimethylglycine (122 mg), diisopropylethylamine (582 mg) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 542 mg). The reaction mixture was stirred at room temperature for 18 hours. Then ice-cold sodium hydrogencarbonate solution was added thereto, the mixture was filtered, and the aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. This gave 2-(3-{2-[1-(N,N-dimethylglycyl)piperidin-4-yl]-1,3-thiazol-4-yl}-4,5-dihydro-1,2-oxazol-5-yl)phenyl methanesulphonate (310 mg, 55%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([N:10]([CH3:12])[CH3:11])[CH2:7][NH:6]1)=O.[NH3:13]>CO>[CH3:11][N:10]([CH3:12])[C@H:8]1[CH2:7][NH:6][C@H:5]([C:3]([NH2:13])=[O:2])[CH2:9]1
Reactant: COC(=O)[C@@H]1C[C@@H](N(C)C)CN1
Reactant: N
Solvent: CO
Product: CN(C)[C@H]1CN[C@H](C(N)=O)C1

Procedure:
A solution of (2S,4R)-4-dimethylamino-pyrrolidine-2-carboxylic acid methyl ester (Stage B.1, 225 mg) and 7 M ammonia in MeOH (7 mL) was stood for 18 h at it in a sealed vessel. Evaporation and trituration with Et2O gave the title compound as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]1[O:10][C:9]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:8]=2[O:7]1>>[CH2:2]([O:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][CH2:6][O:10][C:9]=2[CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCCCBr
Product: CCCCOc1ccc2c(c1)OCO2

Procedure:
Starting from commercially available bromobutane and sesamol the title compound is obtained as colorless oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Sc1ccccc1
Reactant: O=C(CBr)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(CSc1ccccc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a suspension of 2-bromo-1-(2-fluorophenyl)ethanone (3.0 g) and potassium carbonate (2.0 g) in ethanol (30 mL) was added dropwise thiophenol (1.4 mL) at 0° C. The mixture was stirred at room temperature for 8 hr, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=15:1) to give the title compound as a pale-yellow solid (yield 2.2 g, yield 64%).
Reaction SMILES: N1C(C)=CC=CC=1C.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[C:11]=1[N:18]1[C:22](=[O:23])[CH2:21][C:20]([NH:24][C:25]2[CH:30]=[C:29]([NH:31][C:32](=[O:46])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:28]=[CH:27][C:26]=2[Cl:47])=[N:19]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:52](Cl)(=[O:54])[CH3:53].Cl>ClCCl>[Cl:17][C:12]1[CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]([Cl:9])[C:11]=1[N:18]1[C:22](=[O:23])[CH:21]=[C:20]([NH:24][C:25]2[CH:30]=[C:29]([NH:31][C:32](=[O:46])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:28]=[CH:27][C:26]=2[Cl:47])[N:19]1[C:52](=[O:54])[CH3:53]
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)n2C(C)=O)c1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
1.07 g (0.01 mole) of lutidine is added to a solution of 30.7 g (0.05 mole) of 1-(2,4,6-trichlorophenyl)-3-(2-chloro-5-myristoylaminoanilino)-2-pyrazolin-5-one and 8 g (0.06 mole) of anhydrous aluminium chloride in 100 ml of dichloromethane. The solution is cooled to 10° C and 5.90 g (0.075 mole) of acetylchloride are added. 8 g (0.075 mole) of lutidine divided into 4 portions of 2 g each (one portion every 15 min) are added in a total period of time of 1 h, the temperature being kept below 10° C. The reaction mixture is stirred for 2 h more and then poured out into 1 l of 1N aqueous hydrochloric acid. The dichloromethane layer is washed until free from acid, dried, and concentrated by evaporation. The product is agitated with methanol.
Reaction SMILES: ClC(Cl)C(O)=O.[C:7]([O:10][C@@H:11]1[C@@H:15]([CH3:16])[O:14][C@@H:13]([N:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:12]1)(=[O:9])[CH3:8].C1(N=C=NC2CCCCC2)CCCCC1.[C:42]([CH:47]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:44][CH2:45][CH3:46])=[O:43]>CS(C)=O.N1C=CC=CC=1>[C:7]([O:10][C@@H:11]1[C@@H:15](/[CH:16]=[CH:47]/[C:42]([O:44][CH2:45][CH3:46])=[O:43])[O:14][C@@H:13]([N:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:12]1)(=[O:9])[CH3:8]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](C)O2)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(Cl)Cl
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: CCOC(=O)/C=C/[C@H]1O[C@@H](n2cc(CC)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
1.9 g of dichloroacetic acid were added to a mixture of 8.95 g of 3'-O-acetyl-2',5'-dideoxy-5-ethyluridine and 18.6 g of dicyclohexylcarbodiimide in 75 ml of dimethyl sulfoxide. The mixture was stirred at room temperature for 24 hours. 1.2 ml of pyridine and 10.5 g of carbethoxymethylenetriphenylphosphorane were added and the mixture was stirred at room temperature for an additional 24 hours. The solvent was removed in vacuo and the residue was dissolved in 300 ml of ethyl acetate. The solution was washed with 300 ml of water, dried over anhydrous sodium sulfate and evaporated to give a yellow oil. This oil was subjected to flash chromatography on a column of silica gel using 5% methanol/dichloromethane for the elution. The product was recrystallized from ethanol to give 7.3 g of trans-3'-O-acetyl-2',5'-dideoxy-5'-(ethoxycarbonylmethylene)-5-ethyluridine in the form of a white solid of melting point 132°-133° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:19][CH3:20])[C:10]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]#[C:15][CH3:16])=[O:11])[CH:5]=[N:6][CH:7]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.C(OCC)C.[Cu]Cl>[CH3:21][Si:22]([C:25]#[C:26][C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:19][CH3:20])[C:10]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]#[C:15][CH3:16])=[O:11])[CH:5]=[N:6][CH:7]=1)([CH3:24])[CH3:23]
Reactant: CC#CC(C)(C)NC(=O)C(CC)Oc1cncc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Cu]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1cncc(C#C[Si](C)(C)C)c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
2-(5-Bromo-3-pyridyloxy)-N-(4-methylpent-2-yn-4-yl)butyramide (0.40 g), trimethylsilylacetylene (0.24 ml), copper (I) chloride (0.015 g) and palladium dichloride bis(triphenyl)phosphine (0.030 g) in dry triethylamine (4 ml) were sealed in a glass tube and heated to 90° C. for 3 hours. The mixture was cooled to ambient temperature and stored for 18 hours. Further trimethylsilylacetylene (0.24 ml) and palladium dichloride bis(triphenyl)-phosphine (0.030 g) were added and the mixture re-heated in the sealed tube for another 5.5 hours. The reaction mixture was cooled to ambient temperature, stored for 72 hours, diluted with diethyl ether and washed with water (three times). The organic phase was separated, dried over magnesium sulphate and evaporated under reduced pressure to give a dark yellow gum, ca. 0.4 g, containing the required product, which was used in the next Stage without further purification.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[Ca+2].[I:26]Cl>CO>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:26])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: COc1cc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 71.4 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.50 g, 5.22 mmol) in methanol (70 mL) was treated with CaCO3 (1.06 g, 10.44 mmol) followed by a solution of ICl (1.70 g, 10.44 mmol) in methanol (10 mL), and stirred overnight at 20 C. The product mixture was filtered, concentrated, dissolved in EtOAc (200 mL), extracted twice with 5% aqueous sodium bisulfite (100 mL), once with brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 1.54 g of a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.55 (m, 1 H), 6.57 (m, 1 H), 3.86 (s, 3 H), 3.80 (m, 1 H), 3.60-3.30 (m, 2 H), 3.20-2.80 (m, 4 H), 1.30 (m, 3 H). MS calculated for C14H15F3INO2+H: 414, observed: 414.
Reaction SMILES: [N:1]#[C:2]Cl.[CH:4]1[C:14]2[CH:13]=[CH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:2]([N:9]1[C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[CH:12]=[CH:13][C:14]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]1=2)#[N:1]
Reactant: N#CCl
Reactant: C1=Cc2ccccc2Nc2ccccc21
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: N#CN1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6 g of cyanogen chloride are introduced within 1 hour into a solution, heated to 80°, of 9.64 g of 5H-dibenz[b,f]azepine and 1 g of benzyltriethylammonium chloride in 40 ml of toluene. The reaction mixture is stirred for a further 5 hours at 80°; it is then cooled to room temperature and washed with 40 ml of 2 N sodium hydroxide solution; the organic phase is separated, and is then evaporated to dryness in vacuo to obtain 5-cyano-5H-dibenz[b,f]azepine, which is identical to the product obtainable according to Example 1; m.p. 107°-108°; yield 6.2 g (56.9% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[NH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH3:31].BrC1C=CC(F)=C(C2N=C(NC3C=CN=CC=3)C3C(=NC=CN=3)N=2)C=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:6]([C:8]2[N:17]=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[CH3:31])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2N2CCCC2)nc2nccnc12
Reactant: Cc1cnccc1N
Agent: Fc1ccc(Br)cc1-c1nc(Nc2ccncc2)c2nccnc2n1
Product: Cc1cnccc1Nc1nc(-c2cc(Br)ccc2N2CCCC2)nc2nccnc12

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-pyrrolidin-1-yl-phenyl)pteridin-4-one 110 and 4-amino-3-methylpyridine following the procedure described for 4-(4-pyridylamino)-2-(5-bromo-2-fluorophenyl)pteridine 1 (LCMS analysis).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.S(=O)(=O)(O)[OH:15].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:15])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=Cc1cc(Cl)cc2c1OCCO2
Reactant: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cc(Cl)cc2c1OCCO2
Temperature: 5 °C
Yield: 77.2 %

Procedure:
7-Chloro-2,3-dihydro-1,4-benzodioxine-5-carbaldehyde (6.25 g, 31.4 mmol) was dissolved in acetone (150 mL) and the solution was then cooled to 5° C. A solution of CrO3 in sulfuric acid (4 M in 4 M H2SO4, 12.5 mL, 50 mmol) was added dropwise over 2 min and the mixture was refluxed for 30 min. Water (150 mL) was added and then most of the acetone was removed by evaporation. The mixture was extracted with ether (150 mL) and the organic solution was then extracted with a solution of NaOH (0.5 M, 150 mL). The aqueous solution was acidified with 2 M hydrochloric acid and then extracted with ether (150 mL). The organic solution was washed with brine and dried over Na2SO4. The solvent was removed by evaporation and the residue treated with CH2Cl2. After filtration and drying there was obtained 5.2 g (77%) of 7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid. 1H NMR (400 MHz, acetone-d6): 4.3-4.4 (m, 4H), 7.1 (d, 1H), 7.3 (d, 1H), 11-12 (b, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][C:14](=[O:22])[CH2:15][CH2:16]N(CC)CC)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(OC1C=C(CCCC(=O)C=C)C=CC=1)(=O)C.[CH3:40][CH:41]1[C:45](=[O:46])[CH2:44][CH2:43][C:42]1=[O:47].CO>[OH-].[K+].C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][C:14](=[O:22])[CH2:15][CH2:16][C:41]2([CH3:40])[C:45](=[O:46])[CH2:44][CH2:43][C:42]2=[O:47])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC(C)=O)c1
Reactant: CC1C(=O)CCC1=O
Agent: C=CC(=O)CCCc1cccc(OC(C)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)Oc1cccc(CCCC(=O)CCC2(C)C(=O)CCC2=O)c1

Procedure:
Reflux a mixture of 6-(m-acetoxyphenyl)-1-diethylaminohexan-3-one and 6-(m-acetoxyphenyl)hex-1-en-3-one (1 g), with 2-methylcyclopentane-1,3-dione (1.5 g) in 0.12% methanolic potassium hydroxide (6 cc) for 18 hours. Remove methanol (2 cc) under reduced pressure and add chloroform (60 cc). Wash the solution in turn with dilute sulfuric acid (25 cc), saturated potassium bicarbonate solution, and brine; dry and evaporate the solvent. The product (0.8 g) is the adduct 2-(6-m-acetoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione in admixture with some of the corresponding free phenol; infrared absorption: 2.86 to 3.08 (broad low-intensity band), 5.71, 5.81, 5.85, and 8.26 μ.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:6](=[O:16])[CH2:5]2.[C:17]([O:21][C:22](=[O:28])[NH:23][CH2:24][C@H:25]1[CH2:27][O:26]1)([CH3:20])([CH3:19])[CH3:18].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:28])[NH:23][CH2:24][C@H:25]([OH:26])[CH2:27][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:6](=[O:16])[CH2:5]2)([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Reactant: Nc1cc(F)c2c(c1)CC(=O)N2CC1CC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2CC1CC1

Procedure:
5-Amino-1-cyclopropylmethyl-7-fluoro-1,3-dihydro-indol-2-one (1.00 g, 4.55 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (0.79 g, 4.55 mmol) and lithium trifluoromethanesulfonate (0.618 g, 4.55 mmol) in acetonitrile (20 ml) are heated at 90° C. for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% ethyl acetate/hexane) gives the title compound as a white solid. HPLC r.t. 4.35 min; MS for C20H28FN3O4 m/z 394.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:17][O:16][C:14]([C:12]1[CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH:11]=1)=[O:15]
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1=CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from Step A (9.8 g, 40.6 mmol) and DBU (9 mL, 60 mmol) in DCM (70 mL) was stirred at rt overnight. The mixture was cooled to 0° C. and washed with 1N HCl aqueous solution and brine, dried over Na2SO4. Evaporation and purification by column chromatography (eluent: 20% EtOAc in hexanes to 40%) gave the product as a white solid. 1H-NMR (400 MHz, CDCl3): δ 1.44 (s, 9H), 2.36-2.47 (m, 2H), 2.88-2.99 (m, 2H), 3.74 (s, 3H), 4.36 (br s, 1H), 4.71 (br s, 1H), 6.71-6.72 (m, 1H). LC/MS: C12H19NO4: m/z 264.0 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>CN(C=O)C.O>[Na+:18].[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:13][CH2:14][C:15]([O-:17])=[O:16])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(NCC(=O)[O-])cc1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-4-fluoro-5-nitrotoluene (2.080 g, 10.97 mmol, as prepared above) in DMF (11.0 mL) at 70° C., was added dropwise, a solution of sodium glycinate (1.065 g, 10.97 mmol, Aldrich, used as received) in water (11.0 mL). The resulting suspension was stirred overnight at 70° C., cooled to room temperature, and the resulting red solid was filtered, washed with acetone (35 mL), and dried under vacuum to give 1.005 g (37%) of the pure (1H NMR) title compound as a red powder; 1H NMR (DMSO-d6): δ 2.184 (s, 3H), 3.396 (d, 2H, J=4.2 Hz), 6.852 (s, 1H), 7.991 (s, 1H), 8.671 (s, 1H).
Reaction SMILES: F[C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:20][O-:21].[Na+].CO>>[CH3:20][O:21][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: C[O-]
Reactant: Fc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Agent: [Na+]
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Yield: 89 %

Procedure:
A solution of 7-fluoro-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (100 mg, 0.31 mmol) in 1 M sodium methoxide-methanol (30 mL) is stirred under reflux for 42 h. The resulting mixture is concentrated under reduced pressure, diluted with water and neutralized with dilute HCl to give 7-methoxy-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (92 mg, 89%) as a white solid. 1H NMR (DMSO) δ 10.22 (1H, brs), 9.57 (1H, s), 8.63 (1H, s), 8.19 (1H, s), 7.86 (1H, brd, J=7.9 Hz), 7.39 (1H, t, J=7.9 Hz), 7.35 (1H, dd, J=7.9, 1.5 Hz), 6.96 (1H, s), 4.00 (3H, s).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:7]([OH:8])[CH:6]=[CH:5][CH2:4]1.[C:9]([Si:13](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:13]([O:1][CH2:2][C@H:3]1[C@@H:7]([OH:8])[CH:6]=[CH:5][CH2:4]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC[C@@H]1CC=C[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@@H]1CC=C[C@@H]1O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of (1S,5S)-5-(hydroxymethyl)cyclopent-2-en-1-ol (1.14 g, 9.99 mmol) in DCM (50.0 mL) was added TEA (4.18 mL, 30.0 mmol) and DMAP (60.0 mg, 0.491 mmol). The solution was cooled to 0° C., tert-butylchlorodiphenylsilane (3.90 mL, 15.0 mol) was added and the mixture was stirred at rt for 2 h. TLC indicated complete conversion, and the reaction was quenched by addition of MeOH (1.00 mL). Concentration in vacuo and silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes afforded the title compound (2.88 g, 86%). LC/MS: Rt=2.51 min, ES+ 353 (AA standard).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][C:21]([O:23][CH2:24]Cl)=[O:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:26].[Na+]>CC(C)=O>[I:26][CH2:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][O:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCC(=O)OCI
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-propionate (2.05 g, 5.51 mmole) in dry acetone (50 ml) was added sodium iodide (4.12 g, 27.5 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl acetate water. The organic phase was washed with a 5% sodium thiosulfate solutions dried with sodium sulfate and evaporated under reduced pressure. Yield: 2.35 g=92%.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:5][C:6]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[N:7][C:8]=1[CH:9]([CH3:11])[CH3:10].C1(C)C=CC=CC=1.[C:32]1([PH2:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[O:39]CC)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O>[C:32]1([P:38](=[O:39])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:2][C:3]2[C:4]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:5][C:6]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[N:7][C:8]=2[CH:9]([CH3:11])[CH3:10])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CBr
Reactant: CCO[PH2](c1ccccc1)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CP(=O)(c1ccccc1)c1ccccc1
Reaction time: 9 h
Yield: 72.8 %

Procedure:
N-[5-bromomethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (10.0 g), toluene (100.0 mL), and diphenyl(ethoxy)phosphorane (6.2 g) were added to a reactor. The reaction mixture was stirred at 90˜100° C. for 9 hours and then water (80.0 mL) was added thereto. The separated organic layer was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1:1) to obtain diphenyl[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-ylmethyl]phosphine oxide as a white solid (9.4 g, yield 73%).