Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:20][CH:21]([Cl:29])[C:22]([Cl:28])([S:24](Cl)(=O)=O)[CH3:23]>C(Cl)(Cl)Cl>[Cl:20][CH:21]([Cl:29])[C:22]([Cl:28])([S:24][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH3:23]
Reactant: CCS(=O)(=O)Nc1ccccc1
Reactant: CC(Cl)(C(Cl)Cl)S(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N(SC(C)(Cl)C(Cl)Cl)c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred, cooled solution of 18.5 g. of N-phenyl ethane sulfonamide in 10.1 g. of triethylamine and 200 ml. of chloroform was added at a temperature below 10° C. a solution of 1,1,2-trichloropropane-2-sulfonyl chloride (21.4 g.) in 50 ml. of chloroform. During the addition, an exothermic reaction took place. When the addition was complete, the mixture was allowed to cool to room temperature. The product was washed twice with water, dried over sodium sulfate and filtered and stripped. A viscous red oil was formed which on evaporation with benzene yielded a solid product of 29.6 g. (92% of theory), m.p. 85°-86° C.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:18].[C:19](=N)(OCC)[CH3:20]>C(O)C>[ClH:18].[ClH:18].[N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]3[NH:16][C:19]([CH3:20])=[N:17][C:12]=3[CH:11]=2)[CH:7]([CH3:8])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)C(c1ccc(N)c(N)c1)n1ccnc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: Cc1nc2cc(C(C(C)C)n3ccnc3)ccc2[nH]1
Reaction time: 3 h
Yield: 44 %

Procedure:
A mixture of 6.2 parts of 4-[1-(1H-imidazol- 1-yl)-2-methylpropyl]-1,2-benzenediamine, 6.5 parts of ethyl ethanimidate hydrochloride and 80 parts of ethanol was stirred for 3 hours at reflux temperature. After evaporation to dry, the residue was taken up in water and sodium carbonate. The product was extracted three times with 120 parts of trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in a mixture of 2-propanone and ethanol. The salt was filtered off and crystallized from a mixture of ethanol and 2-propanone. The product was filtered off and dried, yielding 4 parts (44%) of 5-[1-(1H-imidazol-1yl)-2-methylpropyl]-2-methyl-1H-benzimidazole dihydrochloride.monohydrate; mp. 214.8° C. (comp. 22).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6][NH2:7])[CH3:2].C(N(CC)CC)C.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:7]([S:47]([C:44]2[CH:43]=[CH:42][C:41]([O:40][CH3:39])=[CH:46][CH:45]=2)(=[O:49])=[O:48])[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:8])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CCN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a solution of β-alanine ethyl ester (154 mg, 1 mmol) in anhydrous methylene chloride (7 mL) at room temperature was added triethyl amine (101 mg, 1 mmol) and 4-chlorobenzaldehyde (155 mg, 1.1 mmol). After being stirred for 0.5 h, sodium triacetoxyborohydride (318 mg, 1.5 mmol) was added and the reaction mixture was stirred for additional 1 h at room temperature, followed by the addition of 4-methoxybenzenesulfonyl chloride (207 mg, 1 mmol) and triethyl amine (152 mg, 1.5 mmol). The resulting mixture was stirred for 18 h, quenched with 10% citric acid (10 mL) and, after 30 min, extracted with methylene chloride (2×30 mL). Two phases was separated and the organic layers was washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (2/1: hexanes/ethyl acetate) to give ethyl 3-[(4-chlorobenzyl)-(4-methoxybenzenesulfonyl)-amino]-propionate (44 mg, 0.1 mmol).
Reaction SMILES: C([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)(=O)C.[C:16]([O:19]O)(=[O:18])[CH3:17]>C(O)(=O)C>[C:16]([O:19][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1ccc(OC(C)C(=O)O)cc1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(OC(C)C(=O)O)cc1
Reaction time: 9 h
Yield: 91.4 %

Procedure:
To a solution of 2-(4-acetylphenoxy)propanoic acid (5.08 g, 24.4 mmol) in acetic acid (20 mL) is added purified peracetic acid (16%, 15.80 g, 33.3 mmol) over 30 minutes. The reaction mixture is stirred under reflux at 55° C. to 60° C. and 60-64 mm Hg for 9 hours. The solution is rotovapped and vacuumed to remove the acetic acid. The product obtained is 5.0 g of 2-(4-acetoxyphenoxy)propanoic acid (yield 91%): m.p. 102° C., 1H NMR (CDCl3, delta 1.63 (d, J=7.0 Hz, 3H), 2.26 (s, 3H), 4.85 (q, J=7.0 Hz, 1H), 7.10 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14]([OH:16])=O)=[O:7])=[CH:4][CH:3]=1.Cl.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([OH:7])[C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:14](=[O:16])[N:28]2[CH2:27][C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:30][CH:29]=2)=[CH:17][CH:18]=1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)C1=C(C(=O)c2ccc(Cl)cc2)CCCC1
Agent: Cl
Product: O=C1C2=C(CCCC2)C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 44.4 %

Procedure:
The named compound was synthesised from, 2-(4-chlorobenzoyl)cyclohex-1-enecarboxylic acid (1.00 g, 3.78 mmol) and 4-nitrobenzylamine hydrochloride (0.78 g, 4.16 mmol) using General Procedure B, purified by chromatography (Biotage SP4; 30% EtOAc/petrol) and obtained as a yellow solid (0.67 g, 44%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([C:12]1[CH:17]=[CH:16][C:15](SC)=[CH:14][CH:13]=1)=[CH:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].OO.[S:23](=[O:26])(O)[O-:24].[Na+].[CH:28](O)=O>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([C:12]1[CH:17]=[CH:16][C:15]([S:23]([CH3:28])(=[O:26])=[O:24])=[CH:14][CH:13]=1)=[CH:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)C(=CC1CCCC1)c1ccc(SC)cc1
Reactant: O=S([O-])O
Reactant: O=CO
Agent: OO
Agent: [Na+]
Product: CCOC(=O)C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of the isomeric mixture of 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-acrylic acid ethyl ester [58.93 g, 0.203 mol, (E):(Z)=1.44:1] in formic acid (203 mL) was cooled to 0° C. and then slowly treated with a 30% aqueous hydrogen peroxide solution (62.2 mL, 0.609 mol). The reaction mixture was stirred at 0° C. for 30 min then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was cooled back to 0° C. and then slowly treated with a saturated aqueous sodium bisulfite solution (1 L). The reaction mixture was then extracted with ethyl acetate (2×700 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×700 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-acrylic acid ethyl ester (65.02 g, 99%) as a yellow oil consisting of a 1.63:1 mixture of (E):(Z) isomers. The material was used without further purification and characterization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].O=S(Cl)[Cl:16]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-fluoro-4-nitrobenzoic acid (30 g, 162.0 mmol) in toluene (500 mL) was added SOCl2 (35 mL, 486 mmol). The reaction was heated to 110° C. at which point the reaction became homogeneous. The reaction was stirred at 110° C. for 3 h. The reaction had not gone to completion so an additional portion of SOCl2 (10 mL) was added. The reaction was stirred for an additional 3 h. A small amount of starting material remained thus a final portion of SOCl2 (10 mL) was added and the reaction was heated for 2 h. The resulting green solution was cooled to room temperature and allowed to stand over night. The reaction mixture was filtered and concentrated in vacuo. Toluene (300 mL) was added to the resulting oil and removed under reduced pressure (2×). The product was used without further purification.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:17])[CH2:15][CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([O:7][C:1]2[CH:2]=[CH:3][C:4]([C:1](=[O:7])[CH2:2][CH3:3])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1)(=[O:17])[CH2:15][CH3:16]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1ccc(Oc2ccc(C(=O)CC)cc2)cc1

Procedure:
Diphenyl ether (67 grams) was mixed with about 79 grams of propionyl chloride and 109 grams of aluminum chloride in about 150 ml of carbon disulfide. The product, 4-propionylphenyl ether, was isolated by hydrolysis of the mixture and conventional recrystallization techniques.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=2)O)[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:37]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=2)[Cl:37])[N:7]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OC(c1cccc(Br)n1)c1cccc(Br)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClC(c1cccc(Br)n1)c1cccc(Br)n1
Reaction time: 8 h

Procedure:
To the solution of bis(6-bromopyridin-2-yl)methanol (1.07 g, 3.11 mmol) in CCl4 (15 mL) and CH2Cl2(15 mL) was added triphenylphophine (1.14 g, 4.36 mmol) and stirred overnight. The mixture was concentrated and the residue was purified by silica gel chromatography (5-10% EtOAc in hexane) to give 2-bromo-6-[(6-bromopyridin-2-yl)(chloro)methyl]pyridine. LRMS m/z (M+H) Calcd: 362.5, found: 362.8.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:18]=[C:17]([CH2:19][CH:20]([O:22][CH3:23])[CH3:21])[CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13][NH2:14].Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][N:26]=1>C1(C)C=CC=CC=1>[CH3:8][C:9]1[CH:18]=[C:17]([CH2:19][CH:20]([O:22][CH3:23])[CH3:21])[CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13][NH:14][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][N:26]=1
Reactant: COC(C)Cc1ccc(OCCN)c(C)c1
Reactant: Clc1ncnc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(C)Cc1ccc(OCCNc2ncnc3ccccc23)c(C)c1
Reaction time: 3 h
Yield: 63.5 %

Procedure:
1.0 g of triethylamine and 2.2 g of 2-[2-methyl-4-(2-methoxypropyl)phenoxy]ethylamine were added to 1.7 g of 4-chloroquinazoline dissolved in 50 ml of toluene. The mixture was then heated under reflux, whilst stirring, for 3 hours. At the end of this time, the reaction product was washed with water and dried over anhydrous sodium sulfate. Toluene was removed by distillation under reduced pressure. The oily product thus obtained was subjected to column chromatography (Wakogel C-200, eluted with a 1:1 by volume mixture of toluene and ethyl acetate) to isolate the product, and the crystals obtained were recrystallized from hexane, to give 2.2 g of the title compound as a colorless crystalline powder, melting at 95°-97° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1B(O)O)([CH3:9])[CH3:8].Br[C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:32][CH2:31][C@@H:30]([CH2:33][NH:34][C:35](=[O:56])[C:36]3[CH:41]=[CH:40][C:39]([C:42]4[O:43][C:44]5[C:50]([CH:51]([CH3:53])[CH3:52])=[CH:49][C:48]([C:54]#[N:55])=[CH:47][C:45]=5[N:46]=4)=[CH:38][CH:37]=3)[CH2:29]2)=[N:26][CH:27]=1.O>C1(C)C=CC=CC=1.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(O)C>[C:54]([C:48]1[CH:49]=[C:50]([CH:51]([CH3:53])[CH3:52])[C:44]2[O:43][C:42]([C:39]3[CH:40]=[CH:41][C:36]([C:35]([NH:34][CH2:33][C@@H:30]4[CH2:31][CH2:32][N:28]([C:25]5[CH:24]=[CH:23][C:22]([C:12]6[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=6[O:10][CH:7]([CH3:9])[CH3:8])=[CH:27][N:26]=5)[CH2:29]4)=[O:56])=[CH:37][CH:38]=3)=[N:46][C:45]=2[CH:47]=1)#[N:55]
Reactant: Cc1ccc(OC(C)C)c(B(O)O)c1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@@H]4CCN(c5ccc(Br)cn5)C4)cc3)oc12
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(OC(C)C)c(-c2ccc(N3CC[C@@H](CNC(=O)c4ccc(-c5nc6cc(C#N)cc(C(C)C)c6o5)cc4)C3)nc2)c1
Temperature: 150 °C
Yield: 75.6 %

Procedure:
Sodium carbonate (100 μl, 2M aqueous), (2-isopropoxy-5-methylphenyl)boronic acid (39 mg), and N-{[(3R)-1-(5-bromopyridin-2-yl)pyrrolidin-3-yl]methyl}-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (EXAMPLE 85, 27 mg) were dissolved in toluene (2.1 ml), water (0.6 ml) and ethanol (0.3 ml). To this solution was added tetrakis(triphenylphosphine)palladium(0) (9 mg). The mixture was heated to 150° C. for 25 min via microwave, and then cooled and concentrated. The residue was dissolved in dichloromethane, and purified via flash chromatography on a Biotage Horizon, 40 M column, eluting with 1 column volume of 100% hexanes, followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volumes, followed by 4 column volumes of 100% ethyl acetate to provide the title compound (23 mg, 74%). Mass spectrum (ESI) 614.6 (M+2). 1H NMR (500 MHz, CDCl3): δ 8.37 (d, J=2.3 Hz, 1H), 8.34 (d, J=8.2 Hz, 2H), 7.95 (d, J=8.2 Hz, 2H), 7.94 (s, 1H), 7.72 (dd, J=8.6 Hz, 2.3 Hz, 1H), 7.52 (s, 1H), 7.09 (s, 1H), 7.04 (dd, J=8.4 Hz, 2.1 Hz, 1H), 6.87 (d, J=8.2 Hz, 1H), 6.43 (d, J=8.7 Hz, 2H), 4.40 (sept, J=6.1 Hz, 1H), 3.79 (m, 2H), 3.73 (m, 1H), 3.51 (m, 3H), 3.41 (m, 1H), 2.76 (sept, J=6.9 Hz, 1H), 2.32 (s, 3H), 2.27 (m, 1H), 1.91, (m, 1H), 1.46 (d, J=6.8 Hz, 6H), 1.24 (d, J=5.9 Hz, 6H).
Reaction SMILES: [N:1]([CH2:4][C:5]([OH:7])=O)=[N+:2]=[N-:3].C(N(CC)CC)C.[C:15]1([CH:21]=[CH:22][CH:23]=[N:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[N:1]([C@H:4]1[C@@H:23]([CH:22]=[CH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:24]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:5]1=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(=O)O
Reactant: COc1ccc(N=CC=Cc2ccccc2)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N2C(=O)[C@@H](N=[N+]=[N-])[C@H]2C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
2-Azidoacetic acid (24.26 g) is dissolved in 100 ml of methylene chloride and cooled in an ice bath. To this solution is added 48.57 g of triethylamine and 14.24 g of N-(3-phenyl-2-propenylidene)-4-methoxyaniline dissolved in 250 ml of methylene chloride. To the resulting solution is added 50.41 g of trifluoroacetic anhydride dropwise over a one hour period. After stirring for one hour in an ice bath, the mixture is warmed to room temperature and stirred for about 16 hours. The mixture is then diluted with 250 ml of methylene chloride and washed with water (750 ml), 5% sodium bicarbonate solution (two 750 ml portions), and 1N HCl solution (750 ml). The organic layer is dried over anhydrous sodium sulfate and stripped of solvent to give a solid. The crude product is recrystallized from ethyl acetate to give 11.39 g of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.Cl.[CH3:20][O:21][C:22](=[O:31])[C@H:23]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH2:24]>CO.C(Cl)Cl>[CH3:20][O:21][C:22](=[O:31])[C@H:23]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:24][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and L-histidine methyl ester dihydrochloride (Sigma), the title compound was prepared as a solid (mp=195-197° C.). The reaction was monitored by tlc (Rf=0.29 in 10% CH3OH/CH2Cl2).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15](Cl)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:18][CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.Cl>C(O)(C)C>[OH2:18].[C:1]1([C:7]2[N:16]=[C:15]([N:21]3[CH2:22][CH2:23][CH:19]([OH:18])[CH2:20]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([C:7]2[N:16]=[C:15]([N:21]3[CH2:22][CH2:23][CH:19]([OH:18])[CH2:20]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: OC1CCNC1
Agent: Cl
Solvent: CC(C)O
Product: O
Product: OC1CCN(c2nc(-c3ccccc3)nc3ccccc23)C1
Yield: 72.9 %

Procedure:
A mixture containing 12 g (0.05 mole) of 2-phenyl 4-chloroquinazoline, 4.3 g (0.05 mole) of 3-hydroxy pyrrolidine and 150 ml of isopropanol was refluxed for 11/2 hrs. The resulting reaction mixture was filtered. The filtrate was adjusted to pH 10 with sodium hydroxide and concentrated under reduced pressure to dryness. The semi-solid residue was recrystallized twice with hot water, a white crystalline solid was obtained. The white crystalline solid was dissolved in aqueous solution adjusted to pH=3 with hydrochloric acid and reprecipitated by adjusting to pH=7.5 using sodium hydroxide. This white crystalline solid was filtered and recrystallized with hot water to yield 7.3 g of the title compound, m.p. 180°-182° C.
Reaction SMILES: C(OC(C1OC(CC(C([NH:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)C)C(OC(C)(C)C)=O)=CC=1)=O)C.[Si:34]([O:41][CH2:42][CH:43]([CH2:47][C:48]1[O:49][C:50]([C:53](=[O:61])[NH:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:51][CH:52]=1)[CH:44](O)[CH3:45])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][NH:22][CH:44]([CH3:45])[CH:43]([CH2:42][O:41][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35])[CH2:47][C:48]1[O:49][C:50]([C:53](=[O:61])[NH:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[CH:51][CH:52]=1
Reactant: CCOC(=O)c1ccc(CC(C(=O)OC(C)(C)C)C(C)NCc2ccc3ccccc3c2)o1
Reactant: CC(O)C(CO[Si](C)(C)C(C)(C)C)Cc1ccc(C(=O)Nc2ccccc2)o1
Product: CC(NCc1ccc2ccccc2c1)C(CO[Si](C)(C)C(C)(C)C)Cc1ccc(C(=O)Nc2ccccc2)o1

Procedure:
The title compound was prepared by the same reactions as in Reference Example 1(3) and (4) by using (2RS,3SR)-3-(tert-butyldimethylsilyloxymethyl)-2-hydroxy-4-{5-(phenylcarbamoyl)-2-furyl}butane instead of tert-butyl (2RS,3SR)-2-{5-(ethoxycarbonyl)-2-furylmethyl}-3-hydroxybutanoate used as the starting material in Reference Example 1(3).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11](Br)=[CH:12][N:13]=2)[CH2:3]1.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].C(N(CC)CC)C>C1COCC1.CCOC(C)=O.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:12][N:13]=2)[CH2:3]1
Reactant: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)ncc(Br)c1=O
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
2-[2-(3-(R)-Amino-piperidin-1-yl)-5-bromo-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile (189 mg, 0.49 mmol), trimethylsilylacetylene (103 μL, 0.73 mmol), triphenylphosphine (4 mg, 0.02 mmol), and triethylamine (102 μL, 0.73 mmol) were stirred in THF (4 mL) in a flask purged with nitrogen. Dichlorobis(triphenylphosphine)palladium(I) (17 mg, 0.024 mmol) was added, and after 10 min copper iodide (2 mg) was added. The reaction stirred for 18 h at r.t. The solution was diluted with EtOAc, washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (5% MeOH/CHCl3) gave 168 mg (85%) of the title compound as a clear oil. MS (ES) [m+H] calc'd for C22H27N5OSi, 406; found 406.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([O:27][CH3:28])[C:12]2[CH2:18][N:17]([C:19](=O)[CH2:20][C:21](=O)[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15][C:13]=2[N:14]=1.N1C=CC=CC=1.[CH3:35][NH:36][NH2:37].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1>C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([O:27][CH3:28])[C:12]2[CH2:18][N:17]([C:19]3[N:36]([CH3:35])[N:37]=[C:21]([CH:22]([CH3:23])[CH3:24])[CH:20]=3)[CH2:16][CH2:15][C:13]=2[N:14]=1
Reactant: CNN
Reactant: COc1nc(-c2c(C)cccc2C)nc2c1CN(C(=O)CC(=O)C(C)C)CC2
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1nc(-c2c(C)cccc2C)nc2c1CN(c1cc(C(C)C)nn1C)CC2
Temperature: 125 °C

Procedure:
To a solution of 1-(2-(2,6-dimethylphenyl)-4-methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpentane-1,3-dione (5.92 g, 15.52 mmol) in THF (80 mL) was added pyridine (5 mL). the resulting solution was evenly divided into four microwave 20 mL vials. To each microwave via was added, methyl hydrazine (0.312 mL, 5.81 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (1.88 g, 4.66 mmol). The vials were immediately capped and heated to 125° C. for 10 min via microwave irradiation. The reaction vials were cooled to r.t. and the reaction mixtures were combined and diluted with brine. The mixture was extracted with DCM three times. The combined organic layers were dried over Na2SO4. After filtration and concentration, the resulting residue was purified via silica gel FCC ((1% MeOH in EtOAc):n-heptane=0 to 100%) to provide 2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.15-7.24 (m, 1 H), 7.05-7.12 (m, 2 H), 5.77 (s, 1 H), 4.00-4.04 (m, 2 H), 3.98 (s, 3 H), 3.70 (s, 3 H), 3.28 (t, J=5.8 Hz, 2 H), 3.05 (t, J=5.8 Hz, 2 H), 2.87 (dt, J=13.9, 6.9 Hz, 1 H), 2.12 (s, 6 H), 1.23 (d, J=7.1 Hz, 6 H). MS (ESI+) m/z 392.4 (M+H)+.