Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH2:18]([N:25]1[C@@H:30]2[C@H:31]([C:33]#[N:34])[CH2:32][C@@:26]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:27]([OH:35])[CH2:28][CH2:29]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl>[CH2:18]([N:25]1[C@@H:30]2[C@H:31]([C:33]#[N:34])[CH2:32][C@@:26]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:27]([O:35][C:6](=[O:7])[C:5]1[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=1)[CH2:28][CH2:29]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](OC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.8 %

Procedure:
3,5-Bis(trifluoromethyl)benzoyl chloride (2.76 g, 10 mmol) was added dropwise to an ice-cold solution of (1R*,2R*,5S*,6R*)-8-benzyl-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 31; 3 g, 9.4 mmol), triethylamine (2 g, 20 mmol) and 4-N,N-dimethylaminopyridine (200 mg, 1.6 mmol) in dichloromethane (30 ml). The mixture was stirred at room temperature for 20 hours. The mixture was concentrated in vacuo then partitioned between ethyl acetate and brine. The organics were separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel eluting with 10 and 20% ethyl acetate/iso-hexanes to afford the title compound (4.87 g, 93%).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7]>C1(C)C=CC=CC=1>[CH2:5]([CH:4]([C:3]([CH2:4][CH2:5][CH2:6][CH3:7])=[O:8])[C:3]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH3:7]
Reactant: CCCCC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCC(=O)C(CCC)C(=O)OCC
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A mechanically stirred suspension of sodium hydride (16.2 g of 60% dispersion in mineral oil) in 400 mL of anhydrous toluene was treated dropwise with ethyl pentanoate (50.0 g) at room temperature under nitrogen atmosphere. Upon completion of the addition, the reaction mixture was refluxed for 5 h and then cooled to room temperature, quenched by pouring onto a mixture of ice and 10% aqueous hydrochloric acid, and extracted with chloroform. The combined organic phases were washed with aqueous solution of potassium bicarbonate, then with water, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator, and distilled in vacuum to give 32.0 g (79%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]([CH3:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([NH:34][C@H:35]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH3:43])(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: C[C@H](NS(=O)(=O)c1ccccc1Br)C(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: C[C@H](NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared using analogous conditions to those described in Example 571 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine and (S)-tert-butyl 2-(2-bromophenylsulfonamido)propanoate. MS (ESI): mass calcd. for C23H25FN4O4S, 472.16; m/z found, 473.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.65 (d, J=1.1, 2H), 8.08 (dd, J=8.0, 1.2, 1H), 7.66 (m, 1H), 7.61-7.49 (m, 2H), 7.37 (m, 3H), 3.66 (q, J=107.2, 1H), 1.34 (s, 9H), 1.26 (d, J=7.2, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[O:13]>C(#N)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:22])=[O:21])=[O:25])[N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Temperature: 25 °C

Procedure:
To 37 g of 2-amino-4,6-dimethylpyrimidine in 500 ml of anhydrous acetonitrile was added 67 g of 2-methoxycarbonylbenzenesulfonyl isocyanate with stirring at ambient temperature. The resulting mixture was thereafter stirred for sixteen hours and then filtered to remove the desired product which had precipitated as a white solid, m.p. 198°-202°. It showed infrared absorption peaks at 1750, 1700, 1600 and 1550 cm-1, consistent for the desired compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[C:5]([F:9])=[CH:4][N:3]=1.C(O)(=[O:12])C.O>>[F:9][C:5]1[C:6]([I:8])=[CH:7][C:2](=[O:12])[NH:3][CH:4]=1
Reactant: CC(=O)O
Reactant: Fc1cc(I)c(F)cn1
Solvent: O
Product: O=c1cc(I)c(F)c[nH]1
Reaction time: 8 h
Yield: 99 %

Procedure:
2,5-Difluoro-4-iodopyridine (500 mg, 2.08 mmol) was suspended in acetic acid:water (2:1, 30 mL). The mixture was heated to reflux and stirred at this temperature overnight. The reaction was concentrated to dryness to afford the title compound as a yellow solid (491 mg, 99.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.02 (d, J=5.07 Hz, 1H) 7.69 (d, J=2.34 Hz, 1H).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:14])([CH3:13])[C:8]1[O:9][CH:10]=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:16]>O1CCCC1.[Cl-].[NH4+]>[Br:16][C:10]1[O:9][C:8]([C:7]([CH3:14])([CH3:13])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[N:12][CH:11]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ncco1
Reactant: BrC(Br)(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)c1ncc(Br)o1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(tert-Butyl-dimethyl-silanyloxymethyl)-oxazole) (0.35 g, 1.643 mmol) in dry tetrahydrofuran (8 mL) is added n-Butyl litihum (0.26 g, 4.107 mmol) drop wise under nitrogen atmosphere at −78° C. then stirred at −40° C. for 2 hours. The reaction mixture is again cooled to −78° C. then added carbontetrabromide (1.36 g, 4.107 mmol) and stirred to room temperature for 14 hours. Reaction mixture is diluted with saturated ammonium chloride solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography eluting 2% Ethyl acetate in hexane to afford the crude title compound (0.18 g), which is used in the next step without purification. LC-MS (m/z): [M+H]=294.2.
Reaction SMILES: [P:1]([O:5][CH2:6][C@@H:7]([OH:14])[C@@H:8]([OH:13])[C@@H:9]([OH:12])[CH:10]=[O:11])([O-:4])([O-:3])=[O:2].[Ba+2]>O>[P:1]([O:5][CH2:6][C@@H:7]([OH:14])[C@@H:8]([OH:13])[C@@H:9]([OH:12])[CH:10]=[O:11])([OH:3])([OH:4])=[O:2]
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)COP(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: O
Product: O=C[C@H](O)[C@H](O)[C@H](O)COP(=O)(O)O
Reaction time: 840 h
Yield: 43.7 %

Procedure:
This complex was made by adding 1.0 grams of barium D-ribose-5-phosphate to 4.08 ml of 0.67 M cis-[Pt(NH3)2 (H2O)2 ](NO3)2. The reaction flask was stoppered with a porous plug, and the reaction mixture was stirred for 35 days. After that time, the water-insoluble blue-black product which had formed was isolated and washed by the method described in Example 5, yielding 0.275 grams of the above-identified complex.
Reaction SMILES: [C@@H:1]12[CH2:10][C@@H:5]([CH2:6][C:7](=[O:9])[NH:8]1)[CH2:4][CH2:3][C@@H:2]2[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][CH:14]=[N:15][C:16]=2[NH:20]C(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[C@@H:1]12[CH2:10][C@@H:5]([CH2:6][C:7](=[O:9])[NH:8]1)[CH2:4][CH2:3][C@@H:2]2[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][CH:14]=[N:15][C:16]=2[NH2:20]
Reactant: O=C1C[C@H]2CC[C@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)[C@H](C2)N1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@H]1CC[C@@H]2CC(=O)N[C@H]1C2
Temperature: 25 °C
Reaction time: 19 h
Yield: 95.5 %

Procedure:
A 500 ml round-bottomed flask was loaded with 8.2 g of benzoyl-A lactam 15a (22 mmol) and 250 ml of dry methanol. The suspension was heated until 15a had completely dissolved. A solution of 1.62 g of NaOMe in 5.5 l of MeOH was then added and the mixture was stirred at room temperature for 19 h. The resulting suspension was filtered and the precipitate was washed with Et2O. The filtrate was neutralized by addition of ion-exchange resin (Amberlite IR-120, H+ form). The resin was filtered off and the solvent was removed under reduced pressure. The residue was dissolved in 4 ml of MeOH and precipitated by addition of 30 ml of Et2O. The precipitate was filtered and the combined precipitates were dried in vacuo to afford 5.8 g of 15b (21 mmol, 97%), which was sufficiently pure for further reactions. An analytical sample was obtained by crystallization from MeOH/H2O.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][C:15]1[C:16](B(O)O)=[CH:17][S:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[C:16]1[C:15]([CH3:14])=[CH:19][S:18][CH:17]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Reactant: Cc1cscc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cscc2C)c(OC)c1
Temperature: 25 °C

Procedure:
Methyl 4-bromo-3-methoxybenzoate (Combi-Blocks, 2.50 g; 10.20 mmol) and 4-methyl-3-thiopheneboronic acid (1.59 g; 11.22 mmol), potassium carbonate (7.04 g; 51 mmol), tetrakis(triphenylphosphine)palladium(0) (1.17 g; 1.02 mmol) were mixed in toluene (10 mL) and water (10 mL) under N2 atmosphere. The reaction mixture was degassed with N2 for 10 min and was heated under reflux for 3 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene. The filtrate was concentrated under vacuum to afford brown oil. It was taken in EtOAc and the organic layer was washed with a saturated aqueous solution of NaHCO3, water and brine. It was dried over MgSO4, filtered off and concentrated under vacuum giving a brown oil. LC/MS (Method A): 262.8 (M+1-1)+. HPLC (Method A) Rt 4.79 min (Purity: 63.0%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:7].[BH4-].[Na+]>CO.O>[C:11]([O:10][C:8]([N:6]([CH2:5][CH2:4][CH2:3][OH:2])[CH3:7])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)CCN(C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(CCCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of N-t-butoxycarbonyl-N-methyl-β-alanine methyl ester (3.911 g) in methanol (20 ml) and water (20 ml) was added sodium borohydride (6.81 g) portionwise at 4° C. and the mixture was stirred at room temperature for 3 hours. The solution was concentrated in vacuo, and the residue was portioned between ethyl acetate (100 ml) and 0.5N hydrochloric acid (100 ml). The separated organic layer was washed with 0.5N hydrochloric acid (100 ml), water (100 ml), aqueous sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml) successively,and dried over magnesium sulfate. Evaporation of the solvent gave 3-(N-t-butoxycarbonyl-N-methylamino)propanol (2.48 g) as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH:16]([CH3:25])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH3:25][CH:16]([O:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C:3]([OH:4])=[O:2])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc2ccccc2c1OC(C)COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(COc1ccccc1)Oc1c(C(=O)O)ccc2ccccc12
Reaction time: 16 h
Yield: 79.9 %

Procedure:
To 0.47 g of 1-(1-methyl-2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid methyl ester in 5 ml of THF and 2 ml methanol were added 10 ml of 2 M aqueous sodium hydroxide. After 16 h at room temperature and 2 h at reflux the organic solvents were removed in vacuo. The residue was treated with 2 M hydrochloric acid, and three times extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate, concentrated and dried in vacuo to yield 0.36 g of 1-(1-methyl-2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:33][C@H:34]([C:42]([NH2:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:42]([CH:34]([NH:33][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:43])[NH2:44]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)C(Cc1ccccc1)NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with phenylalaninamide (38 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 47 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12]C(=O)C)[CH2:4][CH2:3]1.Cl>O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH2:12])[CH2:4][CH2:3]1
Reactant: CC(=O)NC1CCC(=O)c2ccccc21
Agent: Cl
Solvent: O
Product: NC1CCC(=O)c2ccccc21

Procedure:
A mixture of 41.4 g. of crude N-(1,2,3,4-tetrahydro -4-oxo-1-naphthyl)acetamide, 300 ml. of concentrated hydrochloric acid and 250 ml. of water is stirred and heated at reflux overnight. The mixture is decanted, filtered, and the cooled filtrate is extracted with 300 ml. of chloroform. The aqueous solution is evaporated to dryness in vacuo to afford 26.55 g. of the title product.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].COCCOC.Cl.Cl[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[N:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([CH2:31][C:32]2[CH:37]=[N:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cc1ccc(CCl)cn1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(C)nc2)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a solution of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.00 g) in a mixed solvent of DME (30.0 mL)-water (10.0 mL) were added 5-(chloromethyl)-2-methylpyridine hydrochloride (1.22 g), tetrakis(triphenylphosphine)palladium(0) (0.38 g) and sodium carbonate (2.11 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. The reaction mixture was allowed to be cooled to room temperature, water and ethyl acetate were added thereto, and the mixture was partitioned. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.57 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:39])=[C:11]([N:16]4[CH2:20][CH2:19][C@@:18]([CH2:23][N:24](CC5C=CC=CC=5)CC5C=CC=CC=5)([CH2:21][F:22])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:40])[C:6]([C:41]([OH:43])=[O:42])=[CH:5]2)[CH2:3][CH2:2]1.O.NN>C(O)C.[OH-].[Na+].[C].[Pd]>[NH2:24][CH2:23][C@@:18]1([CH2:21][F:22])[CH2:19][CH2:20][N:16]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:40])[C:6]([C:41]([OH:43])=[O:42])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:39])[CH2:17]1
Reactant: COc1c(N2CC[C@](CF)(CN(Cc3ccccc3)Cc3ccccc3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: [Pd]
Agent: NN
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1c(N2CC[C@@](CN)(CF)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 4 h

Procedure:
(S)-1-Cyclopropyl-7-(3-(N,N-dibenzylaminomethyl)-3-fluoromethylpyrrolidin-1-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (19.58 g) was dissolved in ethanol (300 ml), and 10% palladium-carbon (3.9 g) and hydrazine hydrate (5.0 g) were added. The mixture was refluxed with stirring for 4 hours. The precipitated crystals were dissolved in a 2N aqueous solution of sodium hydroxide. The mixture was filtrated to remove the catalyst. After concentration, water (100 ml) was added and the pH of the solution was adjusted to 7 with dilute hydrochloric acid. The precipitated crystals were collected by filtration to give the object compound, melting point 188°-190° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:15]=[CH:16][C:17]([O:23][CH3:24])=[CH:18][C:19]=3[O:20][C:21](=[O:22])[C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[CH3:24][O:23][C:17]1[CH:16]=[CH:15][C:14]2[C:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]=3[C:21](=[O:22])[O:20][C:19]=2[CH:18]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CN(Cc1ccccc1)CC3
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Yield: 48.2 %

Procedure:
A solution of 3-benzyl-8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one (8.2 g, 26 mmol) in 150 mL of methanol and 100 mL of tetrahydrofuran is hydrogenated at room temperature over a palladium on carbon catalyst (0.85 g) for 18 hours. The catalyst is filtered and the filtrate evaporated. Recrystallization of the residue from acetonitrile with a small amount of added water gives 2.9 g (49%) of product; mp 179°-181° C.
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd]>[C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: O=C1CCC(=Cc2ccccc2)CC1
Agent: [Pd]
Product: OC1CCC(Cc2ccccc2)CC1

Procedure:
In an alternate method, when n is the bridging group --CH2 --, the 8-phenylmethylene-1,4-dioxaspiro[4.5]decane is treated with acetic acid and water as previously described, yielding the corresponding 4-phenylmethylenecyclohexanone. The cyclohexanone is then reduced with hydrogen gas in the presence of 10% palladium on charcoal (Degussa type), yielding the corresponding 4-phenylmethylcyclohexanol, which is in turn treated with sodium dichromate and sulfuric acid in water, affording the 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 3 provides a detailed description of how this reaction is conducted.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[CH3:55][C:56]([O:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)([CH3:58])[CH3:57]>CN(C)C(=O)C>[CH3:58][C:56]([O:59][CH:60]1[CH2:61][CH2:62][N:63]([C:4]([C:3]2[CH:7]=[C:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)[CH:9]=[CH:10][CH:2]=2)=[O:6])[CH2:64][CH2:65]1)([CH3:55])[CH3:57]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CC(C)(C)OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)CC1
Reaction time: 0.08 h

Procedure:
To 20 ml vial was added 3-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid (1b) (50 mg, 0.178 mmol). To this was added N,N-dimethylacetamide (2 mL) and triethylamine (70 μL, 0.445 mmol). This mixture was allowed to stir for 5 mins before addition of O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate, this solution was also allowed to stir for a further 5 minutes. A solution of 4-[(2-methylpropan-2-yl)oxy]piperidine hydrochloride (35 mg, 0.178 mmol) in N,N-dimethylacetamide (1 mL) and triethylamine (25 μl, 0.179 mmol) was then added and the reaction left to stir at ambient temperature for 2 hours before being purified by preparative HPLC to afford the desired compound; m/z (LC-MS, ESI+), RT=1.74 (M+H 420.4).
Reaction SMILES: [Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[C-:14]#[N:15].[Na+].C(O)(=O)C>C(O)C.O>[Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]([OH:9])[C:14]#[N:15]
Reactant: [C-]#N
Reactant: O=Cc1cccc(OC=C(Cl)Cl)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: N#CC(O)c1cccc(OC=C(Cl)Cl)c1
Yield: 91.9 %

Procedure:
To the combined solutions of 30 g of 3-(2,2-dichlorovinyloxy)benzaldehyde in 320 ml of ethanol and 15 g of NaCN in 30 ml water are added 39 ml of acetic acid dropwise at 0°-5° C. in the course of 1 hour. The resultant solution is stirred for 1 hour at 20°-25° C. and subsequently diluted with 1000 ml of H2O. The product is extracted with toluene, washed and evaporated, to yield 31 g of 3-(2,2-dichlorovinyloxy)mandelonitrile. The crude product can be processed without further purification.