Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[CH3:4][C:5]([CH3:30])([O:7][C:8]([NH:10][C@H:11]([C:22]([NH:24][C@@H:25]([C:27]([OH:29])=O)[CH3:26])=[O:23])[CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=1[CH3:21])=[O:9])[CH3:6].CN1CCOCC1.[C:38]1([CH2:44][CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CCOC(C)=O>[CH3:4][C:5]([CH3:6])([O:7][C:8]([NH:10][C@H:11]([C:22]([NH:24][C@@H:25]([C:27]([NH:47][CH2:46][CH2:45][CH2:44][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:29])[CH3:26])=[O:23])[CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=1[CH3:21])=[O:9])[CH3:30]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)O
Reactant: NCCCc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCCCc1ccccc1
Temperature: -45 °C
Reaction time: 8 h

Procedure:
A CH2Cl2 solution (100 ml) of the title compound from Example 9, (16.6 g, 43.6 mmole) was charged with 4.4 g (43.6 mmoles) of NMM and cooled to -45° C. To this solution was added 5.7 g (43.6 mmole) of IBCF and the mixture warmed to 10° C. The solution was then cooled to -25° C. before adding 7.4 g (54.5 mmole) of 3-phenylpropylamine. After allowing the reaction to warm to room temperature and stand overnight, it was diluted with 300 ml of EtOAc and extracted with three 100 ml portions of 0.5N KHSO4. The combined aqueous washes were extracted with 100 ml of EtOAc and this extract was combined with the original organic phase. The combined organic was then washed with one 150 ml portion of brine before drying it over Na2SO4. All solvent was removed under reduced pressure to give the title product as a foam. This material was chromatographed to give 10 g (46%) of a compound identical to diastereomer S of Example 3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][NH2:11])=[C:4]([F:12])[CH:3]=1.[F:13][CH:14]([F:23])[C:15]([NH:17][C:18](=O)[O:19]CC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:18](=[O:19])[NH:17][C:15]([CH:14]([F:23])[F:13])=[N:11]2)=[C:4]([F:12])[CH:3]=1
Reactant: COc1cc(NN)c(F)cc1Cl
Reactant: CCOC(=O)NC(=O)C(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: COc1cc(-n2nc(C(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 12.2 %

Procedure:
To a stirred mixture of 8.0 g (0.042 mole) of 4-chloro-2-fluoro-5-methoxyphenylhydrazine and 8.4 g (0.05 mole) of ethyl difluoroacetylcarbamate in 120 mL of xylene was added 2.1 g of phosphorus pentoxide. After complete addition the mixture was heated at reflux for one hour. While still hot, the reaction mixture was decanted from a dark residue into a clean flask. This residue was washed with xylene and the wash was combined with the decanted reaction mixture. The resultant mixture was stirred at room temperature for one hour. A precipitate formed and was removed by filtration and saved for later purification. The filtrate was extracted with three 150 mL portions of an aqueous 10% sodium hydroxide solution. The basic washes were combined and extracted with xylene. During the extraction an oil formed a third phase in the bottom of the separatory funnel and was removed from the other two phases. The basic aqueous phase was separated from the organic phase and filtered through a celite pad. The filtrate was washed with two portions of diethyl ether and acidified with concentrated hydrochloric acid. The acidified aqueous mixture was stirred at room temperature forming a brown precipitate. Collection of the precipitate by filtration yielded 1.5 g of 1-(4-chloro-2-fluoro-5-methoxyphenyl)-3-difluoromethyl-4,5-dihydro-1,2,4-triazol-5(1H)-one. The precipitate which was previously saved for purification was stirred in 70 mL of an aqueous 10% sodium hydroxide solution. The basic mixture was filtered through a celite pad to remove insoluble materials. The filtrate was acidified with concentrated hydrochloric acid producing a white solid. This solid was collected by filtration to yield an additional 0.7 g of product (mp 188°-190° C.).
Reaction SMILES: CC(O[C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)C.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.[C:27](O)(=O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]C.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Nc1ccccn1
Product: CCCCCCCCCCN[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The acylated phenylalanine anilide imprint molecule was synthesized in three steps. (1) N-α-t-BOC-L-phenylalanine was coupled with 2-aminopyridine using DCC to give N-α-t-BOC-L-phenylalanine-2-aminopyridine. (2) The α-amine was then deprotected with TFA to give N-α-L-phenylalanine-2-aminopyridine. (3) To create a compound having the properties of a surfactant, the free amine was then acylated with decanoic acid using DCC to give N-α-decyl-L-phenylalanine-2-aminopyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.[CH2:13]=[C:14](B(O)O)[CH3:15].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Br:12][C:4]1[CH:3]=[C:2]([C:14]([CH3:15])=[CH2:13])[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=1
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Reactant: C=C(C)B(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: C1COCCO1
Solvent: O
Product: C=C(C)c1cc(Br)cc(C(C)(C)C)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 1,3-dibromo-5-(tert-butyl)benzene (2.92 g, 10 mmol) in dioxane (20 mL) was added Pd(PPh3)4 (3.0 g, 2.6 mmol), prop-1-en-2-ylboronic acid (1.0 g, 12 mmol), K2CO3 (2.8 g, 20 mmol) and H2O (1 mL) under N2. The resulting mixture was stirred at 90° C. overnight, concentrated and purified by CC (hexane) to give compound P24a (2.5 g, 100%; 80% by GC/MS) as a liquid.
Reaction SMILES: [Cl:1]C1C(S(C2C=CC=CC=2)(=O)=O)=CC=C(CCC2C=CC(F)=CC=2F)N=1.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)(=[O:45])=[O:44])=[CH:39][N+:38]=1[O-]>>[Cl:1][CH:36]([C:37]1[CH:42]=[CH:41][C:40]([S:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)(=[O:45])=[O:44])=[CH:39][N:38]=1)[CH2:35][C:29]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=1[F:27]
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)[n+]([O-])c1
Reactant: O=S(=O)(c1ccccc1)c1ccc(CCc2ccc(F)cc2F)nc1Cl
Product: O=S(=O)(c1ccccc1)c1ccc(C(Cl)Cc2ccc(F)cc2F)nc1

Procedure:
2-chloro-6-[2-(2,4-difluorophenyl)ethyl]-3-(phenylsulfonyl)pyridine and the title compound were prepared from 2-[2-(2,4-difluorophenyl)ethyl]-5-(phenylsulfonyl)pyridine 1-oxide according to the method of Example 29 Step 2, separating the products by dry flash column chromatography using toluene-5% ethyl acetate/toluene. m/z (ES+) 394, 396 [MH+].
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)O1.Br[C:32]1[CH:43]=[CH:42][C:35]([C:36]([NH:38][CH:39]2[CH2:41][CH2:40]2)=[O:37])=[C:34]([F:44])[CH:33]=1>>[CH:39]1([NH:38][C:36]([C:35]2[CH:42]=[CH:43][C:32]([C:9]3[CH:10]=[CH:11][C:12]4[O:16][C:15]([CH:17]5[CH2:18][CH2:19][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]5)=[N:14][C:13]=4[CH:29]=3)=[CH:33][C:34]=2[F:44])=[O:37])[CH2:41][CH2:40]1
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Reactant: O=C(NC1CC1)c1ccc(Br)cc1F
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(=O)NC5CC5)c(F)c4)ccc3o2)CC1
Yield: 7 %

Procedure:
Following the General Procedure-3, the titled compound (20 mg) was prepared from Intermediate 14 (250 mg, 0.61 mmol) and 4-bromo-N-cyclopropyl-2-fluorobenzamide (156 mg, 0.61 mmol) as an off-white solid. M.P.: 162-165° C. MS (m/z): 466.3 [M+H]+.
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][NH2:29])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C(O)C>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][NH:29][C:5]2[C:6](=[O:18])[C:7](=[O:17])[C:8]=2[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Reactant: CC(C)(C)c1ccc(CCN)cc1
Solvent: CCO
Product: COc1ccc(-c2c(NCCc3ccc(C(C)(C)C)cc3)c(=O)c2=O)cc1
Yield: 81.3 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and 4-tert-butyl-phenethylamine (0.216 g, 1.22 mmol) in ethanol (2 mL) were converted to the title compound (0.180 g, 81%) m.p.: 258.1-260.2° C.; 1H NMR (DMSO-d6) δ 9.07(br t,1H), 7.97(ABq,2H), 7.29(ABq,2H), 7.14(d,2H), 7.09(d,2H), 3.87(m,2H), 3.83(s,3H), 2.84(t,2H), 1.23(s,9H); IR (KBr) 3160, 2950, 1775, 1720, 1580, 1425, 1350, 1300, 1250, 1180, 1020, 840 cm−1; MS (m/z) 364 [M+H+].
Reaction SMILES: N1C=CC=CC=1.O[CH2:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[CH:11]=[CH:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[Cl:27][CH2:8][C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=1[CH:11]=[CH:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1C=CCOc1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: ClCc1ccccc1C=CCOc1ccccc1
Reaction time: 1 h

Procedure:
47.4 g (0.6 mol) of pyridine was added to a solution which had been obtained by adding 500 ml of chloroform to 120 g (0.5 mol) of o-hydroxymethylphenoxy methylstyrene. 71.4 g (0.6 mol) of thionyl chloride was dropwise added to the mixture with stirring while keeping the temperature at 3° to 4° C. in an ice bath. The mixture was stirred at the same temperature for 1 hour and then at a temperature of 30° C. for 1 hour. After being washed with water, the mixture was dried by sodium sulfate. The chloroform was removed from by distillation under reduced pressure to obtain a yellow liquid as the desired product.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15](=[O:35])[CH:16]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:36][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15](=[O:35])[CH:16]([NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The product of part (c) was heated under reflux with tri-n-butyltin hydride (51.12 g) in toluene for 20 hours. The reaction was cooled and purified by column chromatography on silica using ethyl acetate/petroleum ether (1:4) to yield the title compound as a white solid (37.1 g), mp 138°-140° C.: found: C, 59.23; H,4.90; N, 5.28; C26H24F6N2O3 requires C, 59.09, H, 4.96; N, 5.30%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:5][CH:4]=1)#[N:2].C([BH3-])#N.[Na+].Cl>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)CCCc2c[nH]cn2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(C2CCCc3cncn32)cc1
Reaction time: 2 h

Procedure:
A solution of 0.24 g of 1-(p-cyanophenyl)-4-(4-imidazolyl)-1-butanone in 20 ml of methanol at room temperature is treated with 0.2 g of sodium cyanoborohydride. The pH is adjusted and maintained at 5.5-6.0 by addition of concentrated hydrochloric acid. The reaction mixture is stirred for 2 h, adjusted to pH 2, and evaporated to dryness. The residue is taken up in methylene chloride and washed with saturated sodium bicarbonate. The organic layer is dried over sodium sulfate and evaporated to yield 5-(p-cyanophenyl)5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.
Reaction SMILES: C([N:8]1[CH2:30][CH2:29][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][C@@H:17]([C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)[CH3:18])[C:10]=2[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[F:28][C:25]([F:26])([F:27])[C:22]1[N:21]=[CH:20][C:19]([C@H:17]([NH:16][C:15]2[C:10]3[CH2:9][NH:8][CH2:30][CH2:29][C:11]=3[N:12]=[CH:13][N:14]=2)[CH3:18])=[CH:24][CH:23]=1
Reactant: C[C@@H](Nc1ncnc2c1CN(Cc1ccccc1)CC2)c1ccc(C(F)(F)F)nc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](Nc1ncnc2c1CNCC2)c1ccc(C(F)(F)F)nc1
Reaction time: 15 h
Yield: 98.7 %

Procedure:
A mixture of (R)-6-benzyl-N-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (3.55 g, 8.59 mmol), 10% palladium on charcoal (740 mg), and methanol (60 mL) were stirred under hydrogen (1 atm) for 15 h. The catalyst was filtered off through Celite and the filter cake was washed with MeOH (3×30 mL). The filtrate was concentrated to obtain an off-white foam (2.74 g, 98% yield).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]([NH2:21])=[CH:19][C:18]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[N:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.N1C=CC=CC=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[C:36]([F:43])[C:35]=1[F:44].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CO.O>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]([NH:21][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([F:33])=[C:35]([F:44])[C:36]=3[F:43])=[O:42])=[CH:19][C:18]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[N:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=C=Nc1ccc(F)c(F)c1F
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-n2nc(-c3cccs3)cc2N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c(F)c1F)Nc1cc(-c2cccs2)nn1-c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 72.7 %

Procedure:
To a solution of 1-(3-((t-butyldimethylsilyloxy)methyl)phenyl)-3-(thiophen-2-yl)-1H-pyrazol-5-amine (available from ethyl 3-(5-amino-3-(thiophen-2-yl)-1H-pyrazol-1-yl)benzoate using general method C followed by protection with TBSCl) (0.5 g, 1.3 mmol) in THF (3 mL) was added pyridine (0.10 g, 1.3 mmol) and 1,2,3-trifluoro-4-isocyanatobenzene (0.27 g, 1.6 mmol). The reaction mixture was stirred at room temperature for 22 hours. Water was added and the solid was filtered, washed with H2O and dried under vacuum to obtain the crude product. To a solution of the crude product in THF was added TBAF (1.6 mL, 1.0 M). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. Ethyl acetate was added into the residue and then 1N—HCl (5 drops) was added. The organic layer was washed with water, dried (Na2SO4) and evaporated under reduced pressure to obtain the crude product. The crude was dissolved in methanol and the solid filtered and dried under vacuum to yield 1-(1-(3-(hydroxymethyl)phenyl)-3-(thiophen-2-yl)-1H-pyrazol-5-yl)-3-(2,3,4-trifluorophenyl)urea (0.42 g, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.13 (brs, 1H), 8.99 (s, 1H), 7.85 (m, 1H), 7.4-7.6 (m, 6H), 7.28 (m, 1H), 7.11 (dd, J=3.6, and 4.8 Hz, 1H), 6.86 (s, 1H), 5.39 (t, J=6.0 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H); MS (EI) m/z: 445.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[S:23][C:22]2[CH2:21][CH2:20][NH:19][CH:18]([CH3:24])[C:17]=2[C:16]=1[F:25]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[S:23][C:15]([F:14])=[C:16]([F:25])[C:17]=4[CH:18]3[CH3:24])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2sc(F)c(F)c21
Product: CC1c2c(sc(F)c2F)CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,3-difluoro-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)C.[O-]CC.[Na+].Br[CH2:20]/[CH:21]=[CH:22]/[CH2:23]Br.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:23][CH:22]1[CH:21]=[CH2:20])=[O:11])[CH3:2]
Reactant: BrC/C=C/CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 168.5 %

Procedure:
93.4 g (583 mmol) of malonic acid diethyl ester and 1000 mL of toluene were added into a four-necked flask (2 L), and thereafter, 223 mL (569 mmol) of a 20% sodium ethoxide ethanol solution was added thereto as a base. The obtained mixture was stirred at room temperature for 1.5 hours, and 59.4 g of trans-1,4-dibromo-2-butene (278 mmol; a reagent manufactured by Sigma-Aldrich) was then added to the reaction solution. The obtained mixture was stirred at room temperature for 2 hours, and 109 mL (278 mmol) of a 20% sodium ethoxide ethanol solution was then added to the reaction solution. The obtained mixture was stirred at room temperature for 1 hour, and 29.1 g of trans-1,4-dibromo-2-butene (136 mmol; a reagent manufactured by Sigma-Aldrich) was then added to the reaction solution. The mixture was stirred at room temperature for 4 hours, and 347 mL of a 1 M sodium hydroxide aqueous solution was then added to the reaction solution. The mixture was stirred for 14 hours, and an organic layer was then separated. Subsequently, the organic layer was washed with 132 mL of water twice, and was then dried over anhydrous sodium sulfate. The resultant was filtrated, and the obtained filtrate was concentrated at 40° C. under reduced pressure, so as to obtain 99.3 g of 1,1-di-ethoxycarbonyl-2-vinylcyclopropane in the form of a crude product of a light yellow oily substance. This crude product contained 83.2 g of 1,1-di-ethoxycarbonyl-2-vinylcyclopropane (yield: 94.9%). However, this crude product did not contain a malonic diethyl ester.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:26][CH2:27][F:28])[C:10]1=[O:29])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[F:28][CH2:27][CH2:26][N:11]1[C:12]2[C:17](=[CH:16][C:15]([F:20])=[C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:13]=2)[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:29]
Reactant: O=c1c2cc(F)c(N3CCCC3)cc2n(CCF)c(=O)n1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(CCF)c(=O)n1O
Yield: 128.5 %

Procedure:
Twenty percent Pd/C (25 mg) was added to a solution of 3-benzyloxy-1-(2-fluoroethyl)-6-fluoro-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example E-4, 0.17 g, 0.4 mmol) in 50 mL of THF, this was shaken under 50 PSI of hydrogen for 14.5 hours. The mixture was filtered and concentrated to afford 0.16 g of a solid, which was triturated with ether and dried to give 0.07 g of the title compound as a solid, mp 228-230° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[NH2:12][C:13]1[C:22](Br)=[N:21][C:20]([Br:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].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>[NH2:12][C:13]1[C:22]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=2)=[N:21][C:20]([Br:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: OCc1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
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+]
Product: COC(=O)c1cc(Br)nc(-c2cccc(CO)c2)c1N
Yield: 72.5 %

Procedure:
A flask containing a mixture of 3-(hydroxymethyl)phenylboronic acid (0.88 g, 5.79 mmol), methyl 3-amino-2,6-dibromoisonicotinate (1.5 g, 4 8 mmol), tetrakistriphenylphosphine Pd(0) (0.335 g, 0.290 mmol), sodium carbonate (1.23 g, 11.6 mmol) was flushed with nitrogen and toluene (12 mL), and MeOH (4 mL) were added. The reaction was heated at reflux under nitrogen for 48 hr. It was partitioned between EtOAc and water and the organic phase was separated, washed with brine, dried with sodium sulfate, and the solvent removed. Chromatography (step gradient elution with DCM containing 0 to 15% EtOAc) afforded methyl 3-amino-6-bromo-2-(3-(hydroxymethyl)phenyl)isonicotinate (1.4 g, 4.2 mmol, 86% yield) as a yellow solid. MS (ESI) m/z 339.02 (M+H). 1H NMR (400 MHz, chloroform-d) δ ppm 7.80 (1H, s), 7.58 (1H, s), 7.40-7.55 (3H, m), 5.94 (2H, br. s.), 4.74 (2H, d, J=5.79 Hz), 3.92 (3H, s), 1.77 (1H, t, J=5.92 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[NH2:9][C:10]1[C:14]([C:15]#N)=[CH:13][NH:12][N:11]=1.[OH-].[NH4+]>>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:15]1[C:14]1[C:10]([NH2:9])=[N:11][NH:12][CH:13]=1
Reactant: Nc1ccccc1S
Reactant: N#Cc1c[nH]nc1N
Agent: [NH4+]
Agent: [OH-]
Product: Nc1n[nH]cc1-c1nc2ccccc2s1
Temperature: 200 °C
Yield: 40.5 %

Procedure:
A mixture of 2-aminobenzenethiol (100 mg, 0.8 mmol) and 3-aminopyrazole-4-carbonitrile (86 mg, 0.8 mmol) in 3 g of polyphosphoric acid was heated at 200° C. for 3 hours. The mixture was then poured into ice water and was neutralized with conc. Ammonium hydroxide solution. The resulting yellow solid was isolated by filtration and washed with cold water to yield the title compound (70 mg, 40%). MS (m/z, ES+): 217 (M+1, 100%); 1H NMR (300 MHz, ppm, DMSO-d6): δ 7.97 (d, 3J=7.8 Hz, 1H), 7.88 (s, 1H), 7.84 (d, 3J=8.0 Hz, 1H), 7.42 (m, 1H), 7.29 (m, 1H), 6.3 (br s, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[C:29]1([C:35]2[CH:39]=[CH:38][NH:37][N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O.Cl>[CH3:26][C:23]1[C:22]([CH2:27][N:37]2[CH:38]=[CH:39][C:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:36]2)=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1Cn1ccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-[4′-(4-Bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.132 g, 0.3 mmol) and 3-phenyl-1H-pyrazole (0.043 g, 0.3 mmol) were combined in DMF. Sodium hydride (60% in mineral oil; 0.014 g, 0.35 mmol) was added, and the reaction was stirred at room temperature for 1.5 hours. Once no starting material was seen by analytical LCMS, the mixture was diluted with EtOAc and 1N aqueous HCl. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with H2O and brine, and then dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound.