Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][OH:8].N1C=CC=CC=1.[C:22](Cl)(=[O:24])[CH3:23]>C1COCC1>[C:22]([O:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=1[O:2][CH3:1])(=[O:24])[CH3:23]
Reactant: COc1cc([N+](=O)[O-])ccc1OCCO
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])ccc1OCCOC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 2-(2-methoxy-4-nitrophenoxy)ethanol (5.5 g, 26 mmol) and pyridine (2.35 g, 30 mmol) in THF (140 mL) at 0° C. was acetyl chloride (2.33 g, 30 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, saturated aqueous CuSO4 solution, brine, dried over MgSO4, and concentrated to give 2-(2-methoxy-4-nitrophenoxy)ethyl acetate as a yellow solid (6 g, 91%).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C#[N:14]>CC(OC)(C)C>[OH:12][CH:10]([CH2:9][CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]#[N:14]
Reactant: CC(=O)CCSc1ccccc1
Reactant: C#N
Solvent: COC(C)(C)C
Product: N#CC(O)CCSc1ccccc1

Procedure:
9.01 g (50 mmol) of 4-phenylthio-2-butanone were dissolved in 30 ml of MTBE and treated with 1.0 g of ion exchanger Amberlyst A-21. After this, 9.8 ml (250 mmol) of HCN were added with stirring and the mixture was stirred at room temperature for 2 hours. The ion exchanger was filtered off and 0.05 g of citric acid was added to the solution. The solvent and HCN were stripped off in vacuo at 40° C. on a rotary evaporator. 9.5 g of (R/S)-2-hydroxy-4-phenylthiobutyronitrile (91.7% of theory) were found.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:31][CH:30]([CH3:32])[CH2:29][C@H:25]([NH:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([N:11]2[CH2:10][CH2:9][CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)=[CH:20][CH:19]=1)(=[O:23])=[O:22])[C:26]([OH:28])=[O:27]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)C[C@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Agent: Cl
Product: CC(C)C[C@H](NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1)C(=O)O

Procedure:
In a manner similar to Example 3(b), 4-phenyl-piperidine hydrochloride was condensed with (S)-2-(4-fluoro-benzenesulfonylamino)-4-methyl-pentanoic acid to give the title compound, %C,H,N found: 63.96, 6.96, 6.44.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[CH2:23][CH2:22]3)[C:17]([OH:19])=O)[C:10](=[O:29])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1.CC(C)N=C=NC(C)C.C(#N)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[CH2:23][CH2:22]3)[C:17]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=3)=[O:19])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCS(=O)(=O)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(CC2CCS(=O)(=O)CC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
768 mg (1.19 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)propanoic acid (racemate, purity 72%), 786 mg (4.76 mmol) of ethyl 4-aminobenzoate, 67.6 mg (476 μmol) of Oxima and 741 μl (4.76 mmol) of DIC in 11.5 ml of dimethylformamide were reacted according to General Method 5B. Preparative HPLC (acetonitrile/water gradient) gave the title compound. Yield: 331 mg (45% of theory)
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH3:13][NH:14][CH2:15][CH2:16][C:17]#[N:18].O>CN(C)C=O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([N:14]([CH2:15][CH2:16][C:17]#[N:18])[CH3:13])=[O:4]
Reactant: CNCCC#N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCC#N)C(=O)c1ccccc1N
Reaction time: 6 h

Procedure:
To Isatoic Anhydride (4.60 g, 28.2 mmol) in N,N-Dimethylformamide (30 mL) was added 3-Methylamino-propionitrile (3.00 mL, 32.1 mmol) and the reaction was stirred under an atmosphere of Nitrogen. After 6 h, the mixture was poured into 200 mL water, then extracted 3×100 mL DCM, washed with 100 mL satd. sodium bicarbonate, which was back extracted with 50 mL DCM. The combined organics were washed with brine (100 mL) and dried over sodium sulfate, then conc. in vacuo afforded 2-Amino-N-(2-cyano-ethyl)-N-methyl-benzamide as an oil in quantitative yield. 1H-NMR: 7.18 (dd, 1H, J=9.0, 9.0 Hz), 7.13 (d, 1H, J=7.3 Hz), 6.74 (m, 2H), 4.31 (br s, 2H), 3.76 (t, 2H, J=6.6 Hz), 3.15 (s, 3H), 2.75 (t, 2H, J=6.6 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>C(#N)C.N1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Cl)c1ccc(O)nc1
Temperature: 80 °C
Yield: 70.4 %

Procedure:
Mix 6-hydroxy-nicotinic acid (14 g, 101 mmol) and pyridine (0.41 mL, 0.49 mmol) in acetonitrile (60 mL). Heat the mixture at 80° C. for 30 min. Add thionyl chloride (7.6 mL, 104 mmol) and continue heating at 80° C. for an additional 1.5 h. Cool to room temperature (reaction solidifies). Filter off the solid using a minimal amount of cold acetonitrile. Dry the solid in vacuo to obtain the desired intermediate as a tan solid (11.2 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[N:4]=[C:5]1[C:10](=[N:11]2)[C:9]2[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=2[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]1=2.F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1.CS(C)=O.C(O[K])(C)(C)C>O>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([N:4]2[C:3]3[C:12](=[CH:13][CH:14]=[CH:15][C:2]=3[NH2:1])[NH:11][C:10]3[C:9]4[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=4[C:7]4[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=4[C:5]2=3)=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: Nc1cccc2nc3c4ccccc4c4ccccc4c3nc12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cccc2c1N(c1ccc([N+](=O)[O-])cc1)c1c(c3ccccc3c3ccccc13)N2
Reaction time: 24 h

Procedure:
While agitating 10.0 g (34 mmol) of 10-aminodibenzo(A,C)phenazine, 4.8 g (34 mmol) of 4-fluoronitrobenzene and 500 ml of dimethylsulfoxide, 19.4 g (173 mmol) of t-butoxy potassium was gently added. After completion of the addition, the reaction container was charged with nitrogen, followed by agitation at room temperature for 24 hours. After completion of the reaction, 500 ml of water was added while cooling, after which the reaction solution was filtered to obtain a filtration residue. The thus obtained residue was washed with methanol to obtain the intended product.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:16][CH2:17][OH:18])[CH:9]=[C:8]2[C:19]1[N:27](S(C2C=CC(C)=CC=2)(=O)=O)[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=1>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:16][CH2:17][OH:18])[CH:9]=[C:8]2[C:19]1[NH:27][C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]=1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCO)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CCO)c2cc1OC
Yield: 36.4 %

Procedure:
1.65 ml of a 5N aqueous potassium hydroxide solution are added to a solution of 0.18 g of 2-{5,6-dimethoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]indol-1-yl}ethanol in 10 ml of methanol, at a temperature in the region of 20° C. The reaction medium is refluxed for 4 hours. After cooling, the solid formed is filtered off through sintered glass, and washed twice with 3 ml of methanol and then five times with 5 ml of water. The solid is purified by flash-pack chromatography (silica, 95/05 by volume dichloromethane/methanol as eluents). 0.045 g of 2-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]ethanol is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26](O)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@H:7]2[CH2:31][CH3:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.[N:38]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH2:38])=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@H:7]2[CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(N)=O)c4c3OCC4)nc2N1C1CCCC1
Yield: 90.6 %

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (187 mg, 0.43 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (138 mg, 0.43 mmol) were dissolved in 40 mL of anhydrous dichloromethane followed by the addition of diisopropylethylamine (0.2 mL, 0.95 mmol), stirred until the solution became clear, followed by the addition of 5 mL of a solution of (cis-exo)-2-methyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-amine 5k (60 mg, 0.43 mmol) in dichloromethane, and stirred for another 2 hours. The resulting solution was added with 30 mL of dichloromethane, washed with dilute aqueous ammonia (20 mL), water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (cis-exo)-N-2-methyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]-7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 5 (170 mg, yield: 71.0%) as a white solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:24])([F:23])[C:8]([N:10]1[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]3[C:17]=2[C:12](=[CH:13][CH:14]=[CH:15]3)[CH2:11]1)=[O:9]>C(Cl)(Cl)Cl>[F:24][C:7]([F:6])([F:23])[C:8]([N:10]1[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:16]3[C:17]=2[C:18](=[CH:20][CH:21]=[CH:22]3)[CH2:19]1)=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1Cc2cccc3cccc(c23)C1)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(N1Cc2cccc3c(S(=O)(=O)Cl)ccc(c23)C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Chlorosulfonic acid (40 mmol) is added dropwise to a cold (0° C.) solution of 2,3-dihydro-2-trifluoroacetyl-1H-Benz[de]isoquinoline (8 mmol) in chloroform (800 mL). The resulting solution is stirred at 0° C. for 30 minutes. The cold bath is then removed and the solution is stirred at room temperature for 1 hour then cautiously poured into ice-water. The organic layer is separated, dried over magnesium sulfate and concentrated to afford the title compound. The crude product can be purified by recrystallization or chromatography.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15](I)[C:14]([O:18][CH2:19][CH2:20][OH:21])=[C:13]([Br:22])[CH:12]=1)[CH3:8].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31].C(Cl)Cl>O.Cl.O1CCOCC1>[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([C:27]2[CH:28]=[CH:29][C:30]([F:31])=[C:25]([Cl:24])[CH:26]=2)[C:14]([O:18][CH2:19][CH2:20][OH:21])=[C:13]([Br:22])[CH:12]=1)[CH3:8]
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(I)c1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Reaction time: 0.08 h

Procedure:
To a stirred solution of K2CO3 (4.99 g, 36.1 mmol) in 18 mL H2O was added 145 mL dioxane, 3-bromo-4-(2-hydroxyethoxy)-5-iodobenzoic acid ethyl ester (5.0 g, 12.04 mmol), and 3-chloro-4-fluorophenylboronic acid (2.1 g, 12.04 mmol) at room temperature. This mixture was stirred for 5 min then degassed twice. Then [1,1í-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with CH2Cl2 (49 mg, 0.06 mmol) was added. The reaction was stirred for three hours then 98 mg, 0.12 mmol, of the catalyst was added. The reaction was allowed to stir for five days at room temperature before being worked up in the following manner. The reaction was diluted with 1N HCl and H2O and extracting with EtOAc three times. The combined organic extracts were dried over Na2SO4 and filtered. Removal of the solvent in vacuo gave crude material which was subjected to prep HPLC to yield 2 g, 35.5% of the bis arylated product 1H NMR (CDCl3) δ1.40 (t, J=8.18 Hz, 3H); 1.945 (s, 1H); 3.712 (m, 4H); 4.36 (q, J=8.18 Hz, 2H); 7.19-7.23 (m, 1H); 7.40-7.45 (m, 1H); 7.60-7.65 (dd, J=8.18 Hz, 2.73 Hz, 1H); 7.91 (d, J=2.73 Hz, 1H); 8.24 (d, J=2.73 Hz, 1H); and 860 mg, 17.1% of the mono arylated product 1H NMR (CDCl3) δ1.29 (bs, 1H); 1.41 (t, J=8.18 Hz, 3H); 3.40 (m, 4H); 4.40 (q, J=8.18 Hz, 2H); 7.20-7.28, (m, 2H); 7 454-7.545 (m, 2H); 7.69 (dd, J=8.18 Hz, 2.73 Hz, 2H); 8.013 (s, 1H); and 38% recoveredSM.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[NH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.N1C2C(=CC=CC=2)C=C1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](OC)=[O:38])=[CH:29]1>>[S:15]1[CH:16]=[CH:17][N:18]=[C:14]1[NH:13][C:37]([C:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:28]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=2)[CH:29]=1)=[O:38]
Reactant: Nc1nccs1
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: CC(=O)Nc1ccc(CCl)cc1
Agent: c1ccc2[nH]ccc2c1
Product: CC(=O)Nc1ccc(Cn2cc(C(=O)Nc3nccs3)c3ccccc32)cc1

Procedure:
R5X=N-(4-chloromethylphenyl)-acetamide; NH2A=2-aminothiazole; Indole starting material=methyl indole 3-carboxylate
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[CH:8]=[C:7]([NH:11][CH3:12])[N:6]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[F:20])[C:5]2=[O:21])[CH2:3][CH2:2]1.[CH3:22][CH:23]([C:27]([OH:29])=O)[C:24]([OH:26])=O.C(OC(=O)C)(=O)C.CC(C)=O>O>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:27]([OH:29])=[C:23]([CH3:22])[C:24](=[O:26])[N:11]([CH3:12])[C:7]=3[N:6]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[F:20])[C:5]2=[O:21])[CH2:2][CH2:3]1
Reactant: CNc1cc(=O)n(C2CC2)c(=O)n1-c1ccc(I)cc1F
Reactant: CC(C(=O)O)C(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: Cc1c(O)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Under a nitrogen atmosphere, to 3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6-methylamino-1H-pyrimidine-2,4-dione 52 (34.4 g) and 2-methyl-malonic acid 54 (15.2 g) was added acetic anhydride (34.4 ml), and the mixture was stirred with heating at 100° C. for 3 hrs. After allowing to cool to 50° C., acetone (68.8 ml) was added dropwise, and the mixture was stirred as it was for 30 min. Water (172 ml) was further added dropwise, and the mixture was stirred for 1 hr. After allowing to cool to room temperature with stirring, the precipitated crystals were collected by filtration and dried to give crude crystals (37.7 g, LC purity 91%) of 3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 55. Isopropanol (92.0 ml) was added to the obtained crude crystals (30.7 g), and the mixture was stirred at room temperature for 4 hrs. The crystals were collected by filtration and dried to give 3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 55 (25.9 g, yield from 76, 58%) as pale-yellow crystals.
Reaction SMILES: CO[CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10](COC)[CH:11]=1)[CH:7]=[CH2:8].[CH2:15]([Cl:17])Cl.B(Cl)(Cl)[Cl:19].[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl.CO>[Cl:19][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH2:15][Cl:17])[CH:11]=1)[CH:7]=[CH2:8]
Reactant: ClCCl
Reactant: ClB(Cl)Cl
Reactant: C=Cc1cc(COC)cc(COC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: C=Cc1cc(CCl)cc(CCl)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 54 %

Procedure:
Subsequently, 2.76 g (14.4 mmol) of 3,5-bis(methoxymethyl)styrene was dissolved in 30 ml of carbon tetrachloride in a reaction vessel of 200 ml, then 40 ml of methylene chloride solution containing 1.0 M boron trichloride was added dropwise at 0° C., and further agitated at 0° C. for 12 hours. After treating the excess boron trichloride by adding methanol to the reaction liquid, the resultant was poured into 150 ml of 5% NaOH solution (added with 100 g of ice). The organic layer was aliquoted and dried with anhydrous magnesium sulfate. Residues obtained by the removal of solvent were purified by silica gel column chromatography to obtain 1.57 g (7.81 mmol) of the target 3,5-bis(chloromethyl)styrene as a transparent liquid. Yield was 54%.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([OH:14])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:26][O+](C)C.O>ClCCl>[CH2:1]([S:8][C:9]1[N:13]=[C:12]([O:14][CH3:26])[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1nc(SCc2ccccc2)nn1-c1ccccc1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1nc(SCc2ccccc2)nn1-c1ccccc1
Reaction time: 18 h
Yield: 51.5 %

Procedure:
3-Benzylthio-5-hydroxy-1-phenyl-1,2,4-triazole (15 g) in dichloromethane (60 ml) was treated with trimethyloxonium tetrafluoroborate (15.7 g) and allowed to stand for 18 hours at room temperature. The reaction mixture was poured into water (200 ml) and the aqueous layer was washed with dichloromethane (2×100 ml). The dried organic layer was evaporated and then purified by column chromatography (silica/petroleum ether:ether), to give 8.1 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:22]([O:23][CH3:24])=[CH:21][C:6]2[CH:7]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:8][N:9]([N:12]=O)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[C:25]([OH:28])(=[O:27])[CH3:26].[OH2:29]>[Zn]>[C:22]([OH:23])(=[O:29])/[CH:3]=[CH:26]\[C:25]([OH:28])=[O:27].[NH2:12][N:9]1[CH2:8][CH:7]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[CH:21]=[C:22]([O:23][CH3:24])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11][CH2:10]1
Reactant: CC(=O)O
Reactant: COc1cc2c(cc1OC)C(Oc1ccccc1)CN(N=O)CC2
Reactant: O
Agent: [Zn]
Product: COc1cc2c(cc1OC)C(Oc1ccccc1)CN(N)CC2
Product: O=C(O)/C=C\C(=O)O
Reaction time: 3 h

Procedure:
Zinc dust (9 g) was added to a solution of 7,8-dimethoxy-3-nitroso-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine (10 g) in 150 ml of 2:1 acetic acid/water. After stirring at ambient temperate for three hours, the reaction mixture was filtered, stirred with ice and basified with ammonium hydroxide. The oil which had separated was extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride solution, and thereafter dried (anhydrous magnesium sulfate), filtered and concentrated to 10 g brown oil. This was eluted through silica with ethyl acetate via high performance liquid chromatography to yield 8.6 g white solid, mp 98°-100°. This solid was again eluted through silica with 5% methanol in dichloromethane via high performance liquid chromatography to yield 6 g white solid, mp 107°-109°. A three gram portion was converted to the maleate salt in 10% methanol/ether to yield 3.3 g white solid, mp 132°-134°.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)=[CH:9][CH:8]=1.[OH-].[Na+].CN(C)[CH:26]=[O:27]>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[C:16]3[CH:26]=[O:27])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(-c2ccc3[nH]ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(-c3ccc(Br)cc3)cc12
Temperature: 25 °C

Procedure:
In a 100-ml round-bottom flask is placed 2.8 mL of dimethylformamide (2.74 g, 3.74 mmol). The flask and the content was cooled in an ice-salt bath for about 0.5 hour and 0.86 mL (1.44 g, 94 mmol) of freshly distilled phosphorusoxychloride is subsequently added with stirring to the dimethylformamide dropwise. Then a solution of 1.0 g of 32 (85 mmol) in 1 mL of dimethylformamide is added to the above solution slowly. After the addition, the temperature of the solution is brought to 40° C. and allowed to stir for an hour. At this time, 1N NaOH (10 mL) was added to the reaction mixture dropwise. The resulting mixture is heated rapidly to the boiling point and allowed to cool to room temperature. The resulting precipitate is collected on a filter and the solid was further washed with water. Compound 33 obtained from this procedure was pure enough for the next reaction. MS (Es+ve) m/z 300, (Es−ve) m/z 298.
Reaction SMILES: [CH2:1]([N:8](C)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])C1C=CC=CC=1>[Pd].CO>[CH3:1][NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17]
Reactant: CN(CCNC(=O)OC(C)(C)C)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
A mixture of tert-butyl 2-(benzyl(methyl)amino)ethylcarbamate (1.20 g, 4.54 mmol), 10% Pd/C (0.90 g) and MeOH (60 mL) was stirred under a H2 atmosphere (0.8 MPa, RT, 16 h). The mixture was filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel, eluting with saturated N3 in MeOH-DCM (0-10%) to afford tert-butyl 2-(methylamino)ethylcarbamate as a colorless oil (0.54 g, 68.3%). 1HNMR (CDCl3): δ 3.25 (m, 2H, CH2), 2.7 (m, 2H, CH2), 2.49 (s, 3H, CH3), 1.49 (s, 9H, CH3).
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][CH3:6])[CH3:3].[C:7]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[C-]#N.[K+].[CH3:16][N:17](C)C1(C#N)CCCC1>O>[CH2:2]([N:4]([CH2:5][CH3:6])[C:7]1([C:16]#[N:17])[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:3]
Reactant: CCNCC
Reactant: O=C1CCCC1
Reactant: CN(C)C1(C#N)CCCC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CCN(CC)C1(C#N)CCCC1
Yield: 62 %

Procedure:
The title compound (2.06 g, 62%) was prepared from diethylamine hydrochloride (2.14 g, 20 mmol), cyclopentanone (1.68 g, 20 mmol) and potassium cyanide (1.30 g, 20 mmol) in water (10 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 1.11 (6H, t, J=7 Hz), 1.78-1.88 (6H, m), 2.22 (2H, m), 2.71 (4H, q, J=7 Hz).