Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20]N(C5C=CC=CC=5)C4=O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[N:39]=[C:40]=[O:41].Cl>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:39]([C:33]5[C:32]([Cl:31])=[CH:37][CH:36]=[CH:35][C:34]=5[Cl:38])[C:40]4=[O:41])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Agent: Cl
Product: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1c(Cl)cccc1Cl

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by 2,6-dichlorophenyl isocyanate in Step 1 of the synthesis. The hydrochloride of the title compound melts at 237°-241° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]2[C:3](=[O:20])[N:4]([CH3:19])[C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8]2)=[O:24])=[CH:31][CH:32]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1ccc(Cl)cc1
Product: CC(C(=O)NCc1ccc(Cl)cc1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=489.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(4-chloro-benzyl)-malonamic acid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:18][CH2:17]1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH2:30]([N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22][N:19]2[CH2:18][CH2:17][CH:16]([O:15][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([C:9]4[CH:14]=[CH:13][N:12]=[CH:11][N:10]=4)[N:4]=3)[CH2:21][CH2:20]2)[CH2:29][CH2:28]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cn1c(OC2CCN(CCC3CCNCC3)CC2)nc(-c2ccncn2)cc1=O
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cn1c(OC2CCN(CCC3CCN(Cc4ccccc4)CC3)CC2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 710 %

Procedure:
To a mixture of 1-methyl-2-[1-(2-piperidin-4-yl-ethyl)piperidin-4-yloxy]-1H-[4,4′]bipyrimidinyl-6-one (40 mg, 0.10 mmol), benzaldehyde (16 mg, 0.15 mmol) and acetic acid (one drop) in 1,2-dichloroethane (0.5 ml) was added sodium triacetoxyborohydride (53 mg, 0.25 mmol). The mixture was stirred at room temperature overnight. The mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (eluent; hexane/ethyl acetate=20/80) to afford 2-{1-[2-(1-benzyl-piperidin-4-yl)ethyl]piperidin-4-yloxy}-1-methyl-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (35 mg, 0.71 mmol, 71%).
Reaction SMILES: [CH2:1](/[C:3](/[C:20]1[S:24][CH:23]=[C:22]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([C:37]([O:39][CH3:40])=[O:38])[C:30](=[CH:35][CH:36]=2)[C:31]([O:33][CH3:34])=[O:32])[CH:21]=1)=[CH:4]\[CH2:5][CH2:6][C:7]([CH2:18][CH3:19])([O:10][Si](CC)(CC)CC)[CH2:8][CH3:9])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1](/[C:3](/[C:20]1[S:24][CH:23]=[C:22]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([C:37]([O:39][CH3:40])=[O:38])[C:30](=[CH:35][CH:36]=2)[C:31]([O:33][CH3:34])=[O:32])[CH:21]=1)=[CH:4]\[CH2:5][CH2:6][C:7]([CH2:8][CH3:9])([OH:10])[CH2:18][CH3:19])[CH3:2]
Reactant: CC/C(=C\CCC(CC)(CC)O[Si](CC)(CC)CC)c1cc(COc2ccc(C(=O)OC)c(C(=O)OC)c2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC/C(=C\CCC(O)(CC)CC)c1cc(COc2ccc(C(=O)OC)c(C(=O)OC)c2)cs1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1.7 g (2.9 mmol) of dimethyl 4-[5-((E)-1,5-diethyl-5-triethylsilanyloxyhept-1-enyl)-3-thienylmethoxy]phthalate are dissolved in 50 mL of anhydrous THF. 3.5 mL (3.5 mmol) of tetrabutylammonium fluoride (1.0 M in THF) are added and the medium is stirred at 60° C. for 3 hours. After the usual treatment and purification on silica gel (eluent: 70 heptane/30 ethyl acetate), the desired product is obtained in the form of a yellow oil (m=710 mg; Y=51%).
Reaction SMILES: [O-2].[Ca+2:2].[CH2:3]([C:9](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]([OH:17])[C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].ClCCl>O>[OH:17][CH:10]([C:9](=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:11]([CH3:15])([CH3:16])[C:12]([O-:14])=[O:13].[OH:17][CH:10]([C:9](=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:11]([CH3:15])([CH3:16])[C:12]([O-:14])=[O:13].[Ca+2:2]
Reactant: CCCCCCC(=Cc1ccccc1)C(O)C(C)(C)C(=O)O
Agent: [Ca+2]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: CCCCCCC(=Cc1ccccc1)C(O)C(C)(C)C(=O)[O-]
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A 1 g (0.018 mole) quantity of calcium oxide was suspended in 100 mL of distilled water, and 4 g (0.013 mole) of 4-hexyl-3-hydroxy-2,2-dimethyl-5-phenyl-4-pentenoic acid was added to the suspension. After stirring for 4 days at room temperature, 50 mL of dichloromethane was added to the suspension and the mixture was stirred vigorously for 30 minutes. Another 50 mL of dichloromethane was added and the aqueous layer was separated. The aqueous phase was washed with 50 mL of dichloromethane, and the combined organic phase was evaporated to dryness to provide 4.8 g of crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].CO.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(C2C=NN=N2)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C2C=NN=N2)cc1C(=O)O
Reaction time: 8 h

Procedure:
Combine methyl 2-methoxy-5-(4H-triazol-4-yl)benzoate (56 mmol) and methanol (200 mL) and water (50 mL). Add 1 M aqueous solution of sodium hydroxide (62.5 mL, 62.5 mmol). Heat to reflux. After 8 hour, concentrate in vacuo to remove most of the solvent. Adjust the pH to about 1 to 2 using a 1 M aqueous hydrochloric acid solution, extract with dichloromethane. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 2-methoxy-5-(4H-triazol-4-yl)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH:49]([CH3:51])[CH3:50])=[CH:44][CH:43]=3)=[CH:38][C:37]=2[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:28][CH2:29]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:43]=[CH:44][C:45]([O:48][CH:49]([CH3:51])[CH3:50])=[CH:46][CH:47]=3)=[CH:38][C:37]=2[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:32]([F:34])([F:35])[F:33])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(OC(C)C)cc5)cc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(OC(C)C)cc5)cc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (130 mg, 0.164 mmol) in CH2Cl2 (4 mL) was added TFA (1 mL), and the reaction mixture was stirred at 25° C. for 12 h. The mixture was concentrated, and neutralized to pH 7-8 with saturated aqueous NaHCO3. The aqueous layer was extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a light yellow solid that is used without further purification.
Reaction SMILES: C([O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[N:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[N:14]=[C:13]1[CH2:22][N:23]1[C:27]2[CH:28]=[N:29][CH:30]=[CH:31][C:26]=2[N:25]([CH:32]2[CH2:34][CH2:33]2)[C:24]1=[O:35])(=O)C(C)(C)C.[OH-].[Li+]>C1COCC1.O>[Cl:21][C:17]1[N:16]=[C:15]2[N:14]=[C:13]([CH2:22][N:23]3[C:27]4[CH:28]=[N:29][CH:30]=[CH:31][C:26]=4[N:25]([CH:32]4[CH2:34][CH2:33]4)[C:24]3=[O:35])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][OH:7])[C:20]2=[CH:19][CH:18]=1
Reactant: CC(C)(C)C(=O)OCCCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=c1n(Cc2nc3nc(Cl)ccc3n2CCCCO)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 3 (0.29 g, 0.58 mmol) was dissolved in THF (15 mL) and lithium hydroxide (40 mg, 1.6 mmol) dissolved in water (5 mL) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured in water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography using dichloromethane and methanol. The title compound 14 was isolated as a white powder (200 mg, 80%). m/z=414 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:16]1[CH:46]=[CH:45][C:19]([O:20][C:21]2[N:35]=[C:34]([O:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)[CH:33]=[CH:32][C:22]=2[C:23]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:24])=[CH:18][CH:17]=1)#[N:15]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:23]([C:22]2[C:21]([O:20][C:19]3[CH:18]=[CH:17][C:16]([C:14]#[N:15])=[CH:46][CH:45]=3)=[N:35][C:34]([O:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)=[O:24])[CH2:27][CH2:28]1)=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(Oc2ccc(C(=O)NC3CCNCC3)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCC(NC(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Yield: 81 %

Procedure:
3-tert-Butoxycarbonylamino-propionic acid (0.177 g, 0.91 mmol) and 2,6-bis-(4-cyano phenoxy)-N-piperidine-4-yl nicotinamide (0.4 g, 0.91 mmol) and other reagents as described in Example 9(e) were used to afford 0.45 g of the required product. Percentage purity (LCMS): 82.8%, (M+1)=610.1+1.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18])=[CH:11][CH:10]=1)([O-:8])=[O:7]>C1COCC1>[C:1]([NH:5][S:17]([CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1)(=[O:18])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1ccc(CCS(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
To a solution of tert-BuNH2 (15.6 mL, 148 mmol) in THF (50 mL) at 0° C., 2-(4-nitro-phenyl)-ethanesulfonyl chloride (WO 2006010079, 1.9 g, 7.6 mmol) was added portionwise. The resulting mixture was stirred for 24 h at RT. The solvent was removed in vacuo and the residue was taken up in DCM (50 mL) and cold 0.5 N HCl (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated to obtain 2-(4-nitro-phenyl)-ethanesulfonic acid tert-butylamide (1.3 g, 62%) which was used directly without further purification.
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH2:5][CH2:6][N:7]=1)[CH3:2].[CH2:8]=[O:9]>O>[OH:9][CH2:8][CH:1]([C:3]1[O:4][CH2:5][CH2:6][N:7]=1)[CH3:2]
Reactant: C=O
Reactant: CCC1=NCCO1
Solvent: O
Product: CC(CO)C1=NCCO1
Yield: 96 %

Procedure:
As an example, step A was conducted by reacting 2-ethyl-2-oxazoline (4 moles) having less than 1,000 ppm of water with paraformaldehyde (1 mole) at a reaction temperature of 100° C. for approximately 5.5 hours. The excess oxazoline reactant was removed along with water as "overheads" by fractional distillation of the reaction product, leaving the 2-(α-hydroxymethylethyl)-2-oxazoline in approximately 96 percent yield. Step C was then conducted by continuously adding the 2-(α-hydroxymethylethyl)-2-oxazoline to a stirred solution of sodium hydroxide in the mono-methyl ether of triethylene glycol at a temperature of from 100°-105° C. Under these conditions, the 2-isopropenyl-2-oxazoline and water were volatilized and recovered from the overheads. The product yield was approximately 98 percent of theory.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:8]=[C:7]([NH2:19])[N:6]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)Cl.O>[CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:18])=[O:28])[N:12]=3)=[CH:9][N:8]=[C:7]([NH2:19])[N:6]=2)[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2cnc(N)nc2CC2CC2)n1
Solvent: O
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2cnc(N)nc2CC2CC2)n1

Procedure:
To a solution of 4′-(cyclopropylmethyl)-2-(methylthio)-4,5′-bipyrimidin-2′-amine (4a) (2.17 g, 7.14 mmol) in DCM (14.29 ml) was added m-CPBA (1.761 g, 7.14 mmol). Immediately after the addition of m-CPBA, the reaction completion was observed. The reaction mixture was diluted with DCM and water. The organic layer was washed with saturated sodium bicarbonate and brine, dried with sodium sulfate, and concentrated in vacuo. The crude residue was purified by Biotage flash chromatography [100 g SNAP column, eluted with 1-15% MeOH/DCM] to obtain the desired product as a slightly pale yellow solid (1.47 g, 71% yield). MS (ES+): m/z=290.4/291.5 (100/10) [MH+]. HPLC: tR=0.76 min over 3 min. Purity: 100% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][OH:7])=[CH:4][CH:3]=1.[N:10]([C:13]1[N:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:16]=[C:15]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:14]=1)=[C:11]=[O:12]>C1COCC1>[F:24][C:21]([F:22])([F:23])[CH2:20][O:19][C:17]1[CH:16]=[C:15]([O:25][CH2:26][C:27]([F:28])([F:29])[F:30])[N:14]=[C:13]([NH:10][C:11](=[O:12])[N:6]([C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[OH:7])[N:18]=1
Reactant: O=C=Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reactant: ONc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)N(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
To a solution of 4-chloro-N-hydroxyaniline (0.423 g, 2.95 mmol (prepared according to the procedure of Rondestwedt Jr., C. S. and Johnson, T. A. Synthesis 1977, p850-851) in THF (10 mL) was added the 2-isocyanato-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (2.0 g, 6.3 mmol) in THF (10 mL) and the mixture stirred at room temperature for 12 h. The mixture was concentrated in vacuo to give a brown solid. This solid was purified by reverse phase column chromatography (CH3CN/H2O) to afford 64 as a dark brown gum (448 mg, 36% yield): ESI/MS 461 (M+H), 459 (M−H); 1H NMR (DMSO-d6): δ 11.04 (S, 1H, 9.51 (S, 1H), 7.63 (d, 2H, J=6.6 Hz), 7.41 (d, 2H, J=6.6 Hz), 6.30 (s, 1H), 5.05 (m, 4H).
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=S)#[N:2].C(N=C(NC1C=CC=CC=1)N[C@@H]1C2C=C(C#N)C=CC=2OC(C)(C)[C@H]1O)#N.[C:40]([C:43]1[CH:44]=[CH:45][C:46]2[O:51][C:50]([CH3:53])([CH3:52])[CH:49]([OH:54])[CH:48]([NH2:55])[C:47]=2[CH:56]=1)(=[O:42])[CH3:41].Cl.CN(C)CCCCCN=C=N>CN(C)C=O>[C:40]([C:43]1[CH:44]=[CH:45][C:46]2[O:51][C:50]([CH3:53])([CH3:52])[C@@H:49]([OH:54])[C@H:48]([NH:55][C:4]([NH:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:3][C:1]#[N:2])[C:47]=2[CH:56]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)c1ccc2c(c1)C(N)C(O)C(C)(C)O2
Reactant: N#CNC(=S)Nc1ccccc1
Agent: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=NC#N)Nc2ccccc2)[C@@H]1O
Agent: CN(C)CCCCCN=C=N
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)[C@@H](NC(=NC#N)Nc1ccccc1)[C@H](O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of N-cyano-N'-phenylthiourea (0.98 g, 5.5 mmol, compound of Example 3, part A) and 6-acetyl-3,4-dihydro-2,2-dimethyl-3-hydroxy-4-amino-2H-1-benzopyran (1.0 g, 4.25 mmol, prepared according to Evans et al., J. Med. Chem., 1983, 26, 1582 and J. Med. Chem., 1986, 29, 2194) in dimethylformamide (6 ml) under argon was treated with 1-(3-dimethylaminopropyl)-2-ethylcarbodiimide hydrochloride (1.1 g, 5.5 mmol). The reaction was stirred at room temperature for 2 hours and then partitioned between 10% citric acid and ethyl acetate. The aqueous phase was reextracted with ethyl acetate and the combined extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was crystallized from ethyl acetate to yield the title compound (0.43 g), m.p. 182°-184° C.: 1H NMR (DMSO-d6) δ 9.45 (s, 1H), 7.82 (m, 3H), 7.44 (s, 3H), 7.25 (s, 1H), 6.96 (d, J=9.0 Hz, 1H), 6.0 (s, 1H), 5.1 (m, 1H), 4.15 (m, 1H), 3.8 (s, 1H), 2.61 (s, 3H), 1.52 (s, 3H), 1.29 (s, 3H); 13C NMR (CDCl3) δ 196.2, 159.3, 156.6, 137.6, 129.7, 129.1, 128.4, 124.7, 123.5, 123.3, 117.2, 116.6, 80.0, 71.2, 52.3, 26.7, 26.3, 18.6; IR (KBr) 3412.3, 2978.3, 2935.8, 2179.7, 1670.5, 1602.9, 1577.9, 1493.0, 1359.9, 1271.2, 1126.5 cm-1.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:27]=[C:26]([CH2:28][NH2:29])[O:25][N:24]=1>>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:29][CH2:28][C:26]2[O:25][N:24]=[C:23]([O:22][CH3:21])[CH:27]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(CN)on1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: COc1cc(CNC(=O)c2cnc(OCC(F)(F)F)c(C3CCCC3)c2)on1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (135 mg, 0.47 mmol) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) (60.16 mg, 0.47 mmol) as starting materials; off white solid (59 mg, 37.8%). MS (ESI): 400 (M+H)+.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:21]2[N:25](C(OC(C)(C)C)=O)[C:24]3[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:23]=3[N:22]=2)=[N:11][C:12]([NH:15][C:16](=[O:20])[CH2:17][C:18]#[N:19])=[CH:13][N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:20])[CH2:17][C:18]#[N:19])=[N:11][C:10]=1[C:21]1[NH:25][C:24]2[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:23]=2[N:22]=1
Reactant: Cc1ccc2nc(-c3nc(NC(=O)CC#N)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n(C(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2nc(-c3nc(NC(=O)CC#N)cnc3N)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.5 %

Procedure:
tert-Butyl 2-(3-(bis(tert-butoxycarbonyl)amino)-6-(2-cyanoethanamido)pyrazin-2-yl)-6-methyl-1H-benzo[d]imidazole-1-carboxylate (isolated from Step 2) was dissolved in DCM (5 mL) and TFA (28.29 mg, 19.11 μL, 0.2481 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (8 mg, 10.5% Yield). 1H NMR (400.0 MHz, CDCl3) δ 2.4 (3H, s), 3.95 (2H, s), 7.15 (1H, d), 7.42-7.49 (1H, m), 7.52-7.58 (1H, m), 8.0 (1H, br s), 8.62 (1H, s), 10.55 (1H, s), 12.8 (1H, vbr s); MS (ES+) 308.0.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:37](C)(C)[O:38][SiH2]C(C)(C)C)([CH2:35][CH3:36])[CH2:33][CH3:34])[NH:9]1)=[O:7])(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>ClCCl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH2:35][CH3:36])([CH2:37][OH:38])[CH2:33][CH3:34])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CCC(CC)(CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C(C)(C)O[SiH2]C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(CO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 94 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[2-(tert-butyl-dimethyl-silanyloxymethyl)-2-ethyl-butyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 111b (1.8 g, 2.6 mmol) was reacted trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-ethyl-2-hydroxymethyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a light yellow solid (1.5 g, 94%).
Reaction SMILES: [Cl-].[CH2:2]([O:4][CH:5]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:3].CN(C)C(=N)N(C)C.[CH:38]([C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][CH:44]=[CH:43]2)=O>ClCCl>[CH2:9]([O:8][C:6](=[O:7])/[C:5](/[O:4][CH2:2][CH3:3])=[CH:38]/[C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][CH:44]=[CH:43]2)[CH3:10]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1ccc2[nH]ccc2c1)OCC
Reaction time: 16 h
Yield: 94.4 %

Procedure:
To a solution of 25.73 g of (1,2-diethoxy-2-oxoethyl)triphenyl phosphonium chloride in 200 ml of dichloromethane was added at 0° C. 8.0 ml of tetramethyl guanidine and the mixture was warmed to 22° C. The mixture was treated with 5.81 g of 5-formyl-indole and stirring was continued at 40° C. for 16 h. The mixture was treated again with 25.73 g of the Wittig salt and 8.0 ml of tetramethyl guanidine and stirring was continued at 40° C. for 24 h after which time the conversion was complete. The mixture was evaporated and the residue partitioned between AcOEt and water. The organic layer was dried, evaporated and the residue chromatographed on silica (n-hexane/AcOEt, 2:1) to give 9.80 g of the title compound as an oil which solidified on storing at 22° C. to give a pale yellow solid. MS: (M)+ 259.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[N:11][C:10]=2[C:23](O)=[O:24])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:30][C:31]1[S:32][CH2:33][CH2:34][N:35]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)=[N:11][C:10]=2[C:23]([NH:30][C:31]2[S:32][CH2:33][CH2:34][N:35]=2)=[O:24])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)O)cc1
Reactant: NC1=NCCS1
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)NC2=NCCS2)cc1

Procedure:
5-(4-Methoxyphenyl)-2-(3-nitrophenyl )imidazole-4-carboxylic acid, 1 M hydrochloric acid—ether solution, thionyl chloride and 2-aminothiazoline are reacted and treated in the same manner as in Example 1 to give 5-(4-methoxyphenyl)-2-(3-nitrophenyl)-N-(2-thiazolinyl)imidazole-4-carboxamide.