Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2=[N:6][C:7]([S:10][CH3:11])=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:13].[CH2:14](Br)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[CH3:1][C:2]1[N:12]=[C:5]2[N:6]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]([S:10][CH3:11])=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:13]
Reactant: BrCCc1ccccc1
Reactant: CSc1ccc2c(C)c(C)[nH]c2n1
Solvent: CC#N
Product: CSc1ccc2c(C)c(C)nc-2n1CCc1ccccc1
Yield: 13.5 %

Procedure:
A refluxing solution of 2,3-dimethyl-6-mehylthiopyrrolo[2,3-b]pyridine (100 mg, 0.5 mmol) in 5 ml CH3CN was treated with five portions of phenethyl bromide (85 μl, 1.2 mmol), one each 24 h. The solvent was evporated and the residue chromatographed (silica, CH2Cl2 saturated with NH3 /diethyl ether/petroleum ether; 5/2/3) affording 20 mg (13%) pure title compound.
Reaction SMILES: [Br:1][C:2]1([C:9](Cl)=[O:10])[CH:6]([Br:7])[C:5]([Br:8])=[CH:4][S:3]1.[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14].[OH-].[Na+]>O1CCOCC1.O>[Br:1][C:2]1([C:9]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])=[O:10])[S:3][CH:4]=[C:5]([Br:8])[CH:6]1[Br:7]
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)C1(Br)SC=C(Br)C1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)C1(Br)SC=C(Br)C1Br)C(=O)O
Yield: 60.4 %

Procedure:
15.3 g 2,3,4-tribromothiophene carboxylic acid chloride in 60 ml dioxane are reacted in a manner analogous to Example 89 with 34.56 g L-alanine and 3.20 g NaOH in 60 ml H2O. After workup, 10.5 g (60.1% of theory) N-(2',3',4'-tribromothenoyl)-L-alanine with a melting point of 175°-179° C. are obtained.
Reaction SMILES: [NH2:1][C:2](=[N:6][OH:7])[CH2:3][S:4][CH3:5].[Cl:8][CH2:9][C:10](Cl)=[O:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:1][C:2](=[N:6][O:7][C:10]([CH2:9][Cl:8])=[O:11])[CH2:3][S:4][CH3:5]
Reactant: O=C(Cl)CCl
Reactant: CSCC(N)=NO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSCC(N)=NOC(=O)CCl
Reaction time: 1 h
Yield: 61.5 %

Procedure:
1-Amino-1-hydroxyimino-2-methylthioethane (11.32 g, 94.2 mmol) was suspended in dry chloroform (60 mL) under nitrogen. A solution of chloroacetyl chloride (7.5 mL, 94.2 mmol) in chloroform (20 mL) was added dropwise. After stirring for 1 hour, a solution of triethylamine (15.8 mL, 113 mmol) in chloroform (20 mL) was added dropwise. The reaction mixture was stirred for 15 minutes, then washed with water (2×70 mL), dried over sodium sulfate, concentrated in vacuo, and dried under vacuum to yield 11.4 g (62% yield) of 1-amino-1-((chloromethyl)carbonyloxy)imino-2-methylthioethane, as a brown semi-solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH2:7])=[N:2]1.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][N:19]([C:22]2[S:23][C:24]([C:28](O)=[O:29])=[C:25]([CH3:27])[N:26]=2)[C:18](=[O:31])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][C:28]([C:24]2[S:23][C:22]([N:19]3[CH:20]=[CH:21][C:16]([O:15][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:17][C:18]3=[O:31])=[N:26][C:25]=2[CH3:27])=[O:29])=[N:2]1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: NCc1cc[nH]n1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cc[nH]n1
Yield: 43 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (1H-pyrazol-3-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 43% yield: 1H NMR (300 MHz, DMSO-d6) δ 12.63 (br s, 1H), 8.74-8.54 (m, 2H), 7.63-7.31 (m, 6H), 6.38 (dd, J=8.1, 2.5 Hz, 1H), 6.22 (d, J=2.5 Hz, 1H), 6.13 (d, J=1.0 Hz, 1H), 5.15 (s, 2H), 4.37 (d, J=5.6 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 422.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=[C:5]2[NH:4][CH:3]=1.[ClH:15]>O1CCOCC1>[ClH:15].[Br:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=[C:5]2[NH:4][CH:3]=1
Reactant: COC(=O)c1cnc2c(Br)c[nH]c2c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cnc2c(Br)c[nH]c2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
To a solution of methyl 3-bromo-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (2.90 g, 11.4 mmol) in 1,4-dioxane (30 mL) was added 6 N aqueous hydrochloric acid (18.9 mL, 114 mmol). The reaction was heated to 90° C. and stirred overnight. The reaction was cooled to room temperature and concentrated to dryness to afford the title compound (2.76 g, quantitative). 1H NMR (400 MHz, DMSO-d6, δ): 12.31 (br. s., 1 H), 8.91 (d, J=1.8 Hz, 1 H), 8.37 (s, 1 H), 8.14 (d, J=1.6 Hz, 1 H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:14]=[C:13]([CH3:33])[N:12]=1.O>COCCOCCOC>[CH3:33][C:13]1[N:12]=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:14]=1
Reactant: Cc1cc(NCCOCCCc2cccnc2)c([N+](=O)[O-])c(Cl)n1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: Cc1cc(NCCOCCCc2cccnc2)c([N+](=O)[O-])c(Oc2ccccc2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 129.4 %

Procedure:
The general method described in Part E of Example 80 was used with the following modifications. A solution of phenol (1.45 g, 15.4 mmol) in diglyme (10 mL) was added to a cooled mixture of the sodium hydride dispersion (0.59 g, 14.7 mmol) in diglyme (15 mL), and the addition flask was rinsed twice with diglyme (5 mL), which was added to the reaction. A solution of (2-chloro-6-methyl-3-nitropyridin-4-yl)-{2-[3-(pyridin-3-yl)propoxy]ethyl}amine (4.9 g, 14 mmol) was added, and the reaction was heated at 60° C. for 20 hours. Additional reagent prepared from phenol (0.50 g, 5.3 mmol) and 60% sodium hydride (0.21 g, 5.3 mmol) in diglyme was added, and the reaction was heated at 60° C. for 2.5 hours. The reaction was allowed to cool to room temperature and slowly added to 800 mL of water and stirred for one hour to form a bright yellow solid. The solid was isolated by filtration and washed with hexane (50 mL) to provide 7.4 g of (6-methyl-3-nitro-2-phenoxypyridin-4-yl)-{2-[3 -(pyridin-3-yl)propoxy]ethyl}amine as a yellow solid contaminated with water.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].I.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[NH:22])SC)=[CH:14][CH:13]=1)#[N:11]>O.C(O)C>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[NH:22])[NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:16][CH:17]=1)#[N:11]
Reactant: NCCC(=O)O
Reactant: CSC(=N)Nc1ccc(C#N)cc1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(NC(=N)NCCC(=O)O)cc1
Yield: 64.1 %

Procedure:
A mixture of 4.18 g (47 mmol) of β-alanine, of 1,88 g (47 mmol) of sodium hydroxide in 20 cm3 of water and of 15 g (47 mmol) of N-(4-cyanophenyl)-S-methylisothiourea hydroiodide in 100 cm3 of 95% ethanol is heated to reflux for 5 hours. The precipitate formed is filtered, then dissolved in 150 cm3 of 1N aqueous sodium hydroxide solution. The solution obtained is washed with ethyl acetate (3×50 cm3), then neutralized to pH 7 by a concentrated HCl solution. The precipitate obtained is filtered, washed with hot absolute ethanol, then recrystallized in water. 7 g (yield 65%) of N-[4-cyanophenylamino(imino)methyl]-3-aminopropanoic acid, having a melting point of 233°-235° C., are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Cl)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27](=[O:28])[N:26]([CH2:29][CH2:30][CH3:31])[C:25]([CH3:32])=[N:24]2)=[CH:19][CH:18]=1.[I-].[K+].C1(O)CCCCC1.C(=O)([O-])O.[Na+]>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]2[CH2:13][CH2:14][N:16]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[C:27](=[O:28])[N:26]([CH2:29][CH2:30][CH3:31])[C:25]([CH3:32])=[N:24]4)=[CH:21][CH:22]=3)[CH2:2][CH2:3]2)=[CH:6][CH:7]=1
Reactant: CCCn1c(C)nn(-c2ccc(N)cc2)c1=O
Reactant: COc1ccc(N(CCCl)CCCl)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: OC1CCCCC1
Solvent: O
Product: CCCn1c(C)nn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Yield: 44 %

Procedure:
A mixture of 25 parts of N,N-bis(2-chloroethyl)-4-methoxybenzenamine, 23.2 parts of 2-(4-aminophenyl)-2,4-dihydro-5-methyl-4-propyl-3H-1,2,4-triazol-3-one, 2 parts of potassium iodide and 200 parts of cyclohexanol was stirred and refluxed for 5 hours using a water-separator. The reaction mixture was cooled and neutralized with a sodium hydrogen carbonate solution. The product was filtered off and dissolved in trichloromethane. The solution was filtered over silica gel and the solvent was evaporated. The residue was crystallized from 1-butanol, yielding 18 parts (44%) of 2,4-dihydro-2-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-5-methyl-4-propyl-3H-1,2,4-triazol-3-one; mp. 202.2° C. (int. 22).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][O:29]2)[N:17]=[CH:16][N:15]=1>CN(C=O)C>[O:29]1[CH2:30][CH2:31][CH2:32][CH:28]1[CH2:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:17]=[CH:16][N:15]=[C:14]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:19]=1
Reactant: Nc1cccc(CS(N)(=O)=O)c1
Reactant: Clc1cc(-c2ccccc2OCC2CCCO2)ncn1
Solvent: CN(C)C=O
Product: NS(=O)(=O)Cc1cccc(Nc2cc(-c3ccccc3OCC3CCCO3)ncn2)c1
Temperature: 85 °C

Procedure:
A mixture of (3-amino-phenyl)-methanesulfonamide (0.18 g, 0.62 mmol) and 4-chloro-6-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-pyrimidine (0.115 g, 0.62 mmol) in DMF (3 mL) was stirred at 80-90° C. till the reaction completion (TLC control), then evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel yielding (3-{6-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 82) as white solid.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)=[O:44])=[N:41][CH:42]=1>>[CH:46]1([NH:45][C:43]([C:40]2[N:39]=[CH:38][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:42][N:41]=2)=[O:44])[CH2:48][CH2:47]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=C(NC1CC1)c1ncc(Br)cn1
Product: C[C@@H](c1ccc(-c2cnc(C(=O)NC3CC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-one and 5-bromo-N-cyclopropylpyrimidine-2-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.167 min, m/z=515.2; 1H NMR (CDCl3) 0.65 (m, 2H), 0.87 (m, 2H), 1.09 (m, 6H), 1.51 (m, 3H), 2.26 (m, 2H), 2.31 (m, 2H), 2.43 (m, 3H), 2.83 (m, 1H), 2.98 (m, 1H), 5.67 (m, 1H), 7.06 (m, 1H), 7.25 (m, 7H), 8.02 (m, 1H), 8.89 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccccc2Cl)CC1
Yield: 91 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 3.15 (s, 4H), 3.79 (s, 4H), 4.15 (s, 3H), 6.99-7.06 (m, 2H), 7.23-7.45 (m, 4H), 7.74-7.79 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:17][Si:18]([CH3:34])([CH3:33])[CH2:19][CH2:20][O:21][CH2:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH2:32])[CH:30]=2)[CH:25]=[N:24]1.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:14][C:13]([F:16])([F:15])[CH2:12][NH:11][C:4]1[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([NH:32][C:29]2[CH:30]=[C:31]3[C:26]([CH:25]=[N:24][N:23]3[CH2:22][O:21][CH2:20][CH2:19][Si:18]([CH3:34])([CH3:33])[CH3:17])=[CH:27][CH:28]=2)[N:3]=1
Reactant: C[Si](C)(C)CCOCn1ncc2ccc(N)cc21
Reactant: FC(F)(F)CNc1nc(Cl)nc2ccoc12
Agent: [Pd]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ncc2ccc(Nc3nc(NCC(F)(F)F)c4occc4n3)cc21
Temperature: 110 °C
Yield: 74.8 %

Procedure:
2-Chloro-N-(2,2,2-trifluoroethyl)furo[3,2-d]pyrimidin-4-amine (1.56 g, 6.20 mmol) and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-amine (1.797 g, 6.82 mmol) were dissolved in 1,4-dioxane (10 mL). RuPhos (0.296 g, 0.620 mmol), Pd2dba3 (0.568 g, 0.620 mmol, Alfa) and K2CO3 (1.714 g, 12.40 mmol) were added. The tube was evacuated and purged with N2 (3×), and the mixture was heated at about 110° C. for about 5 h. The mixture was cooled to rt and filtered. The filter cake was washed with DCM (3×25 mL). The filtrate was washed with saturated aqueous NaCl (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 2:1 hexanes/EtOAc) to give N4-(2,2,2-trifluoroethyl)-N2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)furo[3,2-d]pyrimidine-2,4-diamine (2.22 g, 75%): LC/MS (Table 2, Method h) Rt=2.26 min; MS m/z: 479 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([OH:14])=[O:13].[CH:16](NC(=NC(C)C)OC)(C)C>C(O)C>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[O:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([O:14][CH3:16])=[O:13]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C1\CCOC1=O
Reactant: COC(=NC(C)C)NC(C)C
Solvent: CCO
Product: COC(=O)[C@@H]1[C@H](/C=C2\CCOC2=O)C1(C)C
Yield: 28.8 %

Procedure:
Using the procedure of Example 17, 3.9 g of (1R,cis) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylic acid and 3.5 g of methyl N,N'-diisopropylcarbamimidate were reacted to obtain 1.2 g of methyl (1R,cis) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-furanylidene)-methyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+43°±2.5° (c=0.5% in ethanol).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([NH2:20])[CH:13]=1>O1CCCC1>[NH2:20][C:14]1[CH:13]=[C:12](/[CH:11]=[CH:10]/[CH2:9][OH:8])[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COC(=O)/C=C/c1ccc(OC)c(N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(/C=C/CO)cc1N
Reaction time: 0.25 h
Yield: 26 %

Procedure:
A solution of lithium aluminum hydride (1 M in THF, 4 mL) was added at 0° C. to a solution of (E)-3-(3-amino-4-methoxy-phenyl)-acrylic acid methyl ester (400 mg) in tetrahydrofuran (10 mL) and the resulting mixture was stirred for 15 minutes. The reaction mixture was then quenched by addition of a saturated aqueous solution of ammonium chloride, the resulting mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was separated and the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 90 mg of (E)-3-(3-amino-4-methoxy-phenyl)-prop-2-en-1-ol without further purifications.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[C:7]([C:13]([O:15]C)=O)=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:5]=1[C:32](OC)=O)([CH3:3])[CH3:2].[Br-].[CH2:37]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:38][CH2:39][CH2:40]C.C(OCC)(=O)C.FC(F)(F)C(O)=O>CC#N>[CH:10]([C:8]1[C:7]([CH2:13][OH:15])=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:5]([CH:32]=[CH:37][CH2:38][CH2:39][CH3:40])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:9]=1)([CH3:11])[CH3:12]
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c(C(C)C)cc(C(C)C)c(C(=O)OC)c1-c1ccc(F)cc1OCc1ccccc1
Agent: [Br-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCC=Cc1c(C(C)C)cc(C(C)C)c(CO)c1-c1ccc(F)cc1OCc1ccccc1
Reaction time: 0.33 h

Procedure:
The desired compound was prepared from dimethyl 3,5-diisopropyl-2′-benzyloxy-4′-fluoro-1,1′-biphenyl-2,6-dicarboxylate (Example 246, Step D) by the procedure described in Example 241, Steps F-I (using pentyl triphenylphosphonium bromide in Step H). The pure product obtained was a clear oil (4.73 g, 52% over 4 steps). 1H NMR (300 MHz, CDCl3): δ 0.67-0.78 (m, 3H), 1.09-1.34 (m, 14H), 1.66-1.88 (m, 3H), 3.16-3.46 (m, 2H), 4.29-4.44 (m, 2H), 4.88-5.04 (m, 2H), 5.27-5.41 (m, 1H), 5.94-6.01 (m, 1H), 6.69-6.78 (m, 2H), 7.00-7.06 (m, 3H), 7.22-7.26 (m, 3H), 7.35 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.18, 14.52, 22.89, 23.05, 24.39, 24.64, 24.94, 25.11, 25.38, 29.73, 30.50, 30.66, 31.68, 35.85, 60.78, 71.07, 71.45, 102.25, 102.59, 108.08, 108.37, 122.33, 122.54, 127.11, 127.22, 127.92, 128.11, 128.51, 129.16, 132.70, 132.83, 133.39, 134.06, 135.96, 136.96, 137.29, 137.35, 147.48, 147.63, 147.79, 156.90, 156.93, 163.26 (d, J=246.6 Hz, 1C). FAB-MS: calculated for C31H37O2F 460; found 460 (M+). Anal. calc for C31H37O2F: C, 80.83; H, 8.10. Found: C, 80.91; H, 8.01. Rf=0.34 (9:1 hexanes:ethyl acetate). HPLC: (C-18, A=0.05% aqueous trifluoroacetic acid, B=CH3CN; linear gradient: 80%-100% B over 20 min; 254 nm, 1 mL/min): R.T. 14.8 min (37.7 area %), 15.2 min (56.0 area %); 93.7% purity (cis- and trans-).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:16])=[CH:10][C:11]=2[N+:13]([O-:15])=[O:14])[CH2:6][CH2:5]1)(=O)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:16][C:9]1[CH:8]=[C:7]2[C:12](=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1)[NH:4][CH2:5][CH2:6]2
Reactant: CC(=O)N1CCc2cc(Br)cc([N+](=O)[O-])c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(Br)cc2c1NCC2
Yield: 96 %

Procedure:
5.05 g (17.7 mmol) of 1-acetyl-5-bromo-7-nitroindoline was dissolved into a mixed solution of 6 ml of ethanol and 40 ml of 6 N hydrochloric acid, followed by heating under reflux for 3 hours. After neutralizing by adding sodium carbonate thereto, the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel column chromatography, to give 4.13 g of 5-bromo-7-nitroindoline. 301 mg (1.24 mmol) of this compound was added to 10 ml of toluene, and then 580 mg (2.55 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added thereto. After heating under reflux for 3.5 hours while stirring, the insoluble matters were filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography, to give 252 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[N:9]([O-])=O.[Na+].OS(O)(=O)=O>S([O-])([O-])(=O)=O.[NH+]1NN=C2C=CC=CC=12.[NH+]1NN=C2C=CC=CC=12.O>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[N:9]1
Reactant: O=N[O-]
Reactant: Nc1ccccc1N
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: c1ccc2[nH]nnc2c1
Temperature: 205 °C
Yield: 98.2 %

Procedure:
108.0 g (1.0 mol) of o-diaminobenzene, 75.9 g (1.1 mol) NaNO2, 205 g water and 10.0 g (0.03 mol) benzotriazolium sulfate were charged to a pressure reactor. The reaction was heated to 205° C. for 4 hours. The reactor was cooled to 50° C. and neutralized to pH 6 with 50% H2SO4. The contents were poured into a preheated separatory funnel and separated. The resulting oil was dried overnight at 150° C. to yield 117 g (98%) of benzotriazole.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:17])([F:16])[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)C.[BH4-].[Na+]>C(O)C>[F:17][C:5]([F:16])([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)[CH2:4][OH:3]
Reactant: CCOC(=O)C(F)(F)c1ccc2ccccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(F)(F)c1ccc2ccccc2n1
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a solution of difluoroquinolin-2-yl acetic acid ethyl ester (2 g, 7.9 mmol) in ethanol (20 mL) was added NaBH4 (317 mg, 1.0 mmol) at 0° C. under N2. The mixture was stirred for 1 hour and then at room temperature for 1.5 hours. The solution was quenched with dilute HCl (0.1 N, 20 mL). The mixture was neutralized with saturated NaHCO3 solution and extracted with EtOAc (3*100 mL). The combined organic layer was dried over sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica gel (PE:EA=10:1) to give the title compound as a yellow solid (0.7 g, 44%). LC-MS (ESI+): m/e 210 (M+H)+, Rt: 0.75 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([C:35](O)=[O:36])[N:11]([C:16]([C:18]1[C:19]([NH:28][CH2:29][C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[N:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:22][CH:23]=1)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:38]1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>ClCCCl.CN(C=O)C>[NH2:38][C:35](=[O:36])[C@@H:10]([N:11]([C:16]([C:18]1[C:19]([NH:28][CH2:29][C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[N:20][C:21]([C:24]([CH3:26])([CH3:27])[CH3:25])=[N:22][CH:23]=1)=[O:17])[CH2:12][CH:13]([CH3:14])[CH3:15])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H](CNC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H](CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 61.3 %

Procedure:
3-[(tert-Butoxycarbonyl)amino]-N-({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)-N-(2-methylpropyl)-L-alanine (147 mg), 1H-1,2,3-benzotriazol-1-ol ammoniate (130 mg) and triethylamine (160 μl) were dissolved in 1,2-dichloroethane-DMF (3:1, 15 ml), WSC.HCl (163 mg) was added and the mixture was stirred at room temperature for 21 hr. The reaction mixture was concentrated under reduced pressure, and diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9) to ethyl acetate was concentrated under reduced pressure to give the object compound (90 mg).