Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:34][CH3:35]>>[CH3:32][N:31]([CH3:33])[CH:28]1[CH2:27][CH2:26][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:2]3[N:7]=[C:6]([C:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[NH:10][CH:9]=4)[C:5]([CH3:17])=[CH:4][N:3]=3)=[C:20]([O:34][CH3:35])[CH:21]=2)[CH2:30][CH2:29]1
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1N
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (INTERMEDIATE 1) and 1-(4-amino-3-methoxyphenyl)-N,N-dimethylpiperidin-4-amine (INTERMEDIATE 28).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(O)(C(F)(F)F)=O.[C:29](Cl)(Cl)=[S:30].[OH-].[Na+]>O>[CH:17]([C:5]1[CH:4]=[C:3]([O:20][CH3:21])[C:2]([N:1]=[C:29]=[S:30])=[CH:16][C:6]=1[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1N=C=S
Yield: 31.7 %

Procedure:
To a solution of 5-(5-amino-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.100 g, 0.4 mmol) in 1 ml H2O and TFA (0.040 g, 0.4 mmol) was added thiophosgene (0.040 g, 0.4 mmol). After 1 h the mixture was neutralized with 2 M NaOH and extracted with CH2Cl2. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 5-(2-isopropyl-5-isothiocyanato-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (0.042 g, 36%) as brown foam [MH]+=334.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=2[CH3:39])=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:33][C:32]=2[CH3:39])=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.7 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]-triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl-]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-ylethyl)-amide as a yellow solid (53 mg, 41%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([CH2:17][NH:18][C@H:19]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:20](O)=[O:21])=[C:11]2[C:10]([C:28]([O:30][CH3:31])=[O:29])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:42]2[CH:43]=[CH:44][CH:45]=[N:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CN1CCOCC1>C1COCC1>[CH:41]1([NH:46][C:20](=[O:21])[C@H:19]([NH:18][CH2:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:9]=[C:10]([C:28]([O:30][CH3:31])=[O:29])[C:11]=23)[CH2:23][C:24]([F:25])([F:27])[F:26])[CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@H](CC(F)(F)F)C(=O)O)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@H](CC(F)(F)F)C(=O)NC3CCCC3)c12
Temperature: 43 °C
Reaction time: 36 h

Procedure:
To (R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-4,4,4-trifluorobutanoic acid was added THF (2 mL), HATU (94 mg, 0.246 mmol), cyclopentanamine (70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). The resulting suspension was stirred at 43° C. for 36 h to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C24H31F3N4O5, 513; found, 513.6.
Reaction SMILES: C(OC1C=CC(CCCl)=C([NH:18][C:19]([C:21]2[O:22][C:23]3C=CC(N)=C[C:24]=3[CH:25]=2)=[O:20])C=1)C1C=CC=CC=1.CC[N:33]=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:25]([CH2:21][C:19]([NH2:18])=[O:20])[CH2:24][C:23]([NH2:33])=[O:22]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1ccc2oc(C(=O)Nc3cc(OCc4ccccc4)ccc3CCCl)cc2c1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CCCC(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 524.9 %

Procedure:
To the 2-(4-benzyloxy-2-(5-aminobenzofuran-2-carboxamido)phenyl)ethyl chloride (0.243 mmol) was added the N-[(N-BOC-(4-aminobutyl)-N-methylpyrrole-4-(N-methylimidazole-2-carboxamido)-2-carboxamido)]glutaramide monocarboxylic acid (0.133 g, 0.258 mmol), EDCI (0.093 g, 0.486 mmol) and 1-hydroxybenzotriazole hydrate [HOBT] (0.033 g, 0.244 mmol) which was then dissolved in DMF (15 mL). Dissolution was aided by sonication and the suspension stirred under nitrogen at room temperature for two days with the flask covered with foil. At that time, the DMF was removed via kugelrohr apparatus (0.1 mm Hg, 60° C.). The resulting oil was dissolved in CHCl3, washed with water (1×75 mL), then with brine (1×75 mL) and dried over sodium sulfate. It was then filtered and concentrated under reduced pressure to yield the product N-[(N-BOC-(4-aminobutyl)-N-methylpyrrole-4-(N-methylimidazole-2-carboxamido)-2-carboxamido)]-N-[5-(3-benzyloxy-2-(2-chloroethyl)phenyl)benzofuran-2-carboxamido)]glutarodiamide as a brown oil (0.166 g, 68% yield). Rf=0.40 (10% MeOH/CHCl3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>CN(C)C=O>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:15][C:3]1[C:2]([Cl:1])=[C:13]([Cl:14])[C:6]2[S:7][C:8]([CH2:10][CH2:11][CH3:12])=[CH:9][C:5]=2[CH:4]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CCCc1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cc2cc(OCC(=O)OCC)c(Cl)c(Cl)c2s1
Reaction time: 72 h
Yield: 58.9 %

Procedure:
A mixture of 11.5 g of 6,7-dichloro-5-hydroxy-2-n-propylbenzo[b]thiophene, 8.82 g of ethyl bromoacetate, 7.52 g of potassium carbonate, 135 ml of 2-butanone and 9 ml of dimethylformamide is stirred for 3 days. The reaction mixture is filtered and 100 ml of water and 100 ml of ether are added. The layers are separated and the aqueous layer is extracted 2 times with 100-ml portions of ether. The combined organic layers are dried, filtered and the filtrate is evaporated to give an oil which crystallizes from hexane. Recrystallization from ether-hexane gives 9 g of ethyl[ (6,7-dichloro-2-n-propylbenzo[b]thien-5-yl)oxy]acetate, mp 62°-63°.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH2:11]([CH:13]1[NH:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15][S:14]1)[CH3:12]>[OH-].[Na+]>[C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7]([N:17]1[CH:16]([C:18]([OH:20])=[O:19])[CH2:15][S:14][CH:13]1[CH2:11][CH3:12])=[O:8])(=[O:3])[CH3:2]
Reactant: CCC1NC(C(=O)O)CS1
Reactant: CC(=O)SCC(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC1SCC(C(=O)O)N1C(=O)C(C)CSC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Acetylthio-2-methylpropanoic acid chloride (5.4 g. prepared from 3-acetylthio-2-methylpropanoic acid and thionyl chloride, b.p. 80°) and 2 N sodium hydroxide (15 ml.) are added to a solution of 2-ethyl-4-thiazolidinecarboxylic acid [Z.Naturforschg, 17b, 765 (1962)] (5.2 g.) in normal sodium hydroxide (30 ml.) chilled in an ice-water bath. After three hours stirring at room temperature, the mixture is extracted with ether, the aqueous phase is acidified and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to yield 3-(3-acetylthio-2-methylpropanoyl)-2-ethyl-4-thiazolidinecarboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[C:46]1(=O)[O:50][CH2:49][CH2:48][CH2:47]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[OH:50][CH2:49][CH2:48][CH2:47][C:46]1[NH:45][C:44]2[CH:43]=[CH:42][CH:41]=[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])[C:2]=2[N:1]=1
Reactant: O=C1CCCO1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CCCO)nc12
Yield: 42 %

Procedure:
A solution of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (150 mg), butyrolactone (628 mg) and p-toluenesulfonic acid (139 mg) was heated at 100° C. for 4 hours. The reaction mixture was diluted with chloroform and washed with aqueous sodium hydrogen carbonate. The extract was dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (10% methanol in chloroform) and then preparative thin-layer chromatography (chloroform/methanol=20/3) to give 4-[2-(3-hydroxypropyl)-1H-benzimidazol-4-yl]carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (70 mg).
Reaction SMILES: [K].CC(C)([O-])C.[N+:7]([C:10]1[CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].Cl[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C)C=O>[N+:7]([C:10]1[CH:11]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:14][C:15]=1[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([O-:9])=[O:8]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
2.6 g of potassium-tert.butoxide are placed in 45 ml of dimethylformamide and at an internal temperature of −5° C. 1.3 ml of 3-nitro-trifluorotoluene and 1.5 ml of tert.butyl chloroacetate in 1 ml of dimethylformamide are added dropwise. The mixture is stirred for another 5 minutes and the solution is then poured onto ice water and the precipitate formed is suction filtered.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:13]([CH3:16])(=[O:15])=[O:14])=[N:6][CH:7]=1.[Cl:17][CH:18]([Cl:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][CH:25]=1)=[O:20].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1CCCC1=O>[Cl:17][CH:18]([Cl:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:7]=[N:6][C:5]([CH:8]3[CH2:12][CH2:11][CH2:10][N:9]3[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][CH:3]=2)=[CH:28][CH:29]=1)=[O:20]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CS(=O)(=O)N1CCCC1c1ccc(Br)cn1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)N1CCCC1c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: 80 °C
Yield: 19.9 %

Procedure:
A mixture of 5-bromo-2-(1-(methylsulfonyl)pyrrolidin-2-yl)pyridine (100 mg, 0.328 mmol), 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)-phenyl)-propan-2-yl)acetamide (145 mg, 0.328 mmol) and tris(2-furyl)phosphine (15.5 mg, 0.066 mmol) is dissolved in N-methylpyrrolidinone (1.6 mL) and deoxygenated. Tris(dibenzyliden-eacetone) dipalladium(0) (30.5 mg, 0.033 mmol) is then added and the mixture is heated to 80° C. overnight. The mixture is then cooled and purified by preparative hplc (Prep HPLC=Waters, Column=Gemini NX C18 21×150 mm 5 um, MP A=0.1% trifluoroacetic acid in water MP B=acetonitrile, Gradient 10% B to 50% in 10 min holding for 2 min, 20 mL/min.) Fractions are dried on rotovap and freeze-dried with 1,4-dioxane to give the title compound (33 mg): 1H NMR (400 MHz, DMSO-d6) 1.9-2.0 (m, 2H), 2.0-2.1 (m, 1H), 2.3-2.4 (m, 1H), 3.0 (s, 3H), 3.5-3.6 (m, 2H), 4.15-4.35 (m, 1.5H), 4.45 (t, 0.5H), 4.55-4.65 (m, 0.5H), 4.7-4.75 (m, 0.5H), 4.9-5.0 (m, 2H), 6.5 (s, 1H), 7.5 (d, 2H), 7.65 (d, 1H), 7.75 (d, 2H), 8.2 (dd, 1H), 8.6 (d, 1H), 8.85 (d, 1H). m/z (Cl) M+H 504+506.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O)([O-])=O.[H][H]>[Ni].C(O)C>[F:20][C:19]([F:22])([F:21])[C:17]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][NH:1][C:4]=2[CH:18]=1
Reactant: [H][H]
Reactant: O=Cc1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: FC(F)(F)c1ccc2c(c1)NCc1ccccc1O2

Procedure:
A solution of 55 parts of the ether obtained in the preceding paragraph in 800 parts of ethanol was hydrogenated over Raney nickel catalyst at room temperature and atmospheric pressure. When hydrogen uptake ceased, the catalyst was removed by filtration and the ethanol solvent was evaporated. The residue was then dissolved in 500 parts by volume of hexane, filtered, and then cooled. There was then obtained yellowish-white crystals which were separated by filtration to give 8-(trifluoromethyl)10,11,-dihydrodibenz -[b,f][1,4]oxazepine melting at about 86°-88° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)cc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
Trans-methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.18 g, 3.08 mmol) (from example 134, step 1) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.123 g, 3.08 mmol) dissolved in water (1.7 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.2 mL, 3.26 mmol) was added over 1 min and stirring continued at −40° C. for 2 h. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Crude trans-methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.1 g, 101%) was isolated as a pale orange foam. 1H NMR (500 MHz, cdcl3) δ 1.43-2.15 (m, 4H), 2.66-3.23 (m, 4H), 3.39-3.79 (m, 3H), 4.04-4.41 (m, 1H), 4.45-4.78 (m, 1H), 5.67 (s, 1H), 6.73-6.90 (m, 2H), 7.03-7.37 (m, 1H). MS m/z 353 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24](O)=[O:25])[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][O:29][C:30](=[O:40])[CH:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:32]>CN(C)C=O>[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:32][C:24](=[O:25])[C@H:12]([CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)C(N)Cc1ccccc1
Reactant: O=C(N[C@H](C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O
Yield: 82.2 %

Procedure:
The process of Example 1 was repeated except that 357 mg (1.00 mmol) of N-benzyloxycarbonyl-(β-benzyl)-L-aspartic acid, and 431 mg (2.00 mmol) of D,L-phenylalanine methyl ester hydrochloride were used. As a result, 426 mg (yield of 82.1%) of N-benzyloxycarbonyl-(β-benzyl)-L-aspartyl-L-phenylalanine methyl ester having an [α]D25 = -12.5 (C=1.0 dimethylformamide) were obtained.
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:10][CH:11]([CH3:15])[C:12](O)=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([O:9][C:12](=[O:13])[CH:11]([SH:10])[CH3:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(S)C(=O)O
Reactant: OC1CCCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(S)C(=O)OC1CCCCCCC1

Procedure:
Into a 100 ml reaction flask equipped with reflux condenser, thermometer, hot plate, spin bar and heating mantle are placed 12.8 grams of cyclooctanol; 22 grams of 2-mercaptopropionic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and maintained at reflux for a period of 10 hours. At the end of the reaction mass, the reaction product is washed with one 25 ml volume of water and dried over anhydrous sodium sulfate. The reaction mass is then distilled on a micro distillation column yielding the compound having the structure: ##STR98##
Reaction SMILES: IC.[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([O:33][CH3:34])=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[C:24]([CH3:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1.[C:39]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([O:33][CH3:34])=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([O:29][CH3:39])=[C:24]([CH3:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H](Cc1cc(C)c(O)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](Cc1cc(C)c(OC)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
19 μL (0.30 mmol) iodomethane were added to a solution of 100 mg (0.20 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 2 mL DMF and the mixture was stirred for 15 min at RT. Then 131 mg (0.40 mmol) Cs2CO3 was added and the reaction solution was heated to 50° C. for 3 h. The precipitate was filtered, the filtrate was evaporated down to 1 mL down and combined with 3 mL water. The precipitate was suction filtered, dried and further reacted without purification.
Reaction SMILES: [CH3:1][C:2]([S:5](Cl)=[O:6])([CH3:4])[CH3:3].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][C:10]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]3)[C:26]([Cl:28])=[CH:27][C:20]=2[N:19]=1.O>C(Cl)Cl>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:14][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[CH:11][C:10]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:29]3[CH2:30][CH2:31][CH:32]([C:35]([F:37])([F:36])[F:38])[CH2:33][CH2:34]3)[C:26]([Cl:28])=[CH:27][C:20]=2[N:19]=1
Reactant: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Reactant: CC(C)(C)S(=O)Cl
Solvent: ClCCl
Solvent: O
Product: Cn1c(Nc2cc(CNS(=O)C(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-methylpropane-2-sulfinic acid chloride (83 mg, 0.59 mmol) in DCM (2 mL) was added dropwise to a solution of 4-chloro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzylamine (265 mg, 0.56 mmol), TEA (113 mg, 1.12 mmol) and DCM (3 mL) at 0° C. under Ar. The mixture was stirred at rt overnight, poured into H2O and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Crystallization from DCM/PE gave the sub-title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:14][CH:13]=2)=[N:6][C:7]=1[C:8]([NH:10][NH2:11])=[O:9].[NH2:23][C:24]1[N:29]=[C:28]([C:30](O)=[O:31])[CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]([CH3:19])[CH3:20])=[O:17])=[CH:21][CH:22]=2)=[N:6][C:7]=1[C:8]([NH:10][NH:11][C:30]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:23])[N:29]=1)=[O:31])=[O:9]
Reactant: Nc1cccc(C(=O)O)n1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(=O)c3cccc(N)n3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-[5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl]-N,N-dimethyl-benzamide (100 mg, 0.3163 mmol) and 6-aminopyridine-2-carboxylic acid (43.69 mg, 0.3163 mmol) in DMF (1.000 mL) weas treated with triethylamine (32.01 mg, 44.09 μL, 0.3163 mmol) then warmed slightly. The mixture was cooled to room temperature and then treated with (benzotriazol-1-yloxy-dimethylamino-methylene)-dimethyl-ammonium tetrafluoroborate (121.9 mg, 0.3796 mmol) and stirred at room temperature overnight. The mixture was poured dropwise onto water (5 ml) with rapid stirring, stirred at room temperature for 1 h then filtered to give a wet paste which was dried under high vacuum at 100° C. overnight. Used directly in the next step without purification.
Reaction SMILES: NC1C2SC=C(C3C=C(NC(NC(C)C)=O)C=CC=3)C=2N=C(NC2C=C(OC)C(OC)=C(OC)C=2)N=1.[NH2:37][C:38]1[CH:39]=[C:40]([C:44]2[C:48]3[N:49]=[C:50]([Cl:54])[N:51]=[C:52]([NH2:53])[C:47]=3[S:46][CH:45]=2)[CH:41]=[CH:42][CH:43]=1.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>>[NH2:53][C:52]1[C:47]2[S:46][CH:45]=[C:44]([C:40]3[CH:39]=[C:38]([NH:37][S:56]([CH3:55])(=[O:58])=[O:57])[CH:43]=[CH:42][CH:41]=3)[C:48]=2[N:49]=[C:50]([Cl:54])[N:51]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(-c2csc3c(N)nc(Cl)nc23)c1
Agent: COc1cc(Nc2nc(N)c3scc(-c4cccc(NC(=O)NC(C)C)c4)c3n2)cc(OC)c1OC
Product: CS(=O)(=O)Nc1cccc(-c2csc3c(N)nc(Cl)nc23)c1
Yield: 93.9 %

Procedure:
The target compound (360 mg, 93% yield) was prepared in the same manner as the synthesis of the compound of Example 12, using 7-(3-aminophenyl)-2-chlorothieno[3,2-d]pyrimidin-4-amine (300 mg, 1.08 mmol) and methanesulfonyl chloride (94 μL, 1.19 mmol).