Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:33][C:34]([CH3:39])([CH3:38])[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:32][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:35](=[O:36])[C:34]([F:33])([CH3:39])[CH3:38])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1([C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:23])[CH2:21][CH2:20]1)=[O:18]
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: CC(C)(F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(F)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (250 mg, 0.565 mmol) and 2-fluoro-2-methylpropanoic acid (108 mg, 1.02 mmol) in anhydrous CH2Cl2 (30 mL) was added HATU (323 mg, 0.85 mmol) and DIPEA (2.5 mL) under N2. This reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was poured into water (100 mL), extracted with ethyl acetate (3×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. This crude product was purified by silica gel chromatography to give N-(2,5-difluoro-4-((2-(2-fluoro-2-methylpropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (128 mg, 43% yield). 1H-NMR (400 MHz, Methanol-d4): δ 8.21-8.17 (m, 2H), 7.73 (d, J=2.4 Hz, 1H), 7.54-7.51 (m, 2H), 7.23 (dd, J=10.8, 7.2 Hz, 1H), 7.08-7.04 (m, 2H), 6.75 (dd, J=5.6, 2.4 Hz, 1H), 1.76-1.69 (m, 4H), 1.62 (s, 3H), 1.56 (s, 3H); MS (ESI): m/z 531.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[NH:29][CH2:30][C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:29]([C:23]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])[CH2:30][C:31]3[N:32]=[N:33][N:34]([CH3:36])[N:35]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Cc1cccc(C)c1NCc1nnn(C)n1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2c(C)cccc2C)[C@H]1O
Yield: 29 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (300 mg, 1.1 mmol) obtained in step 1 of example 2 and N-(2,6-dimethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (153 mg, yield: 29%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8](O)[CH2:7][CH2:6]2.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]2[C:9]([CH:8]=[CH:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: OC1CCc2cc(C(F)(F)F)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2c(c1)CC=C2
Yield: 96.2 %

Procedure:
A mixture of 5-(trifluoromethyl)indan-1-ol (1.6 g, 7.9 mmol) and p-toluenesulfonic acid (0.02 g, 0.1 mmol) in toluene (20 mL) was refluxed through a Dean-Stark trap for about 3 h. The solution was concentrated in vacuo and the residue was purified by flash chromatography on silica eluting with 5% EtOAc/hexane to afford the desired product as an oil (1.4 g, 96%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:13][NH2:14])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10].[F:15][C:16]([F:34])([F:33])[C:17](=O)[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[CH:29][S:30][CH:31]=2)=[CH:23][CH:22]=1)=O>>[Cl:2][C:3]1[CH:4]=[C:5]([N:13]2[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[N:28]=[CH:29][S:30][CH:31]=4)=[CH:25][CH:26]=3)=[CH:18][C:17]([C:16]([F:34])([F:33])[F:15])=[N:14]2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: CS(=O)(=O)c1ccc(NN)cc1Cl
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(-c2cscn2)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cscn3)cc2)cc1Cl

Procedure:
The title compound was prepared according to the procedure of Example 60 using [3-chloro-4-(methylsulfonyl)phenyl]hydrazine hydrochloride from step 1 of Example 155 instead of [3-fluoro-4-(methylsulfonyl)phenyl]hydrazine hydrochloride, 4,4,4-trifluoro-1-[4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione from step 3 of Example 82 instead of 4,4,4-trifluorro-1-[4-(2-furyl)phenyl]-1,3-butanedione.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][N:8]1[CH:12]=[N:11][N:10]=[CH:9]1.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.Cl>CS(C)=O>[F:21][C:20]([F:23])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([NH:7][N:8]2[CH:12]=[N:11][N:10]=[CH:9]2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: Nn1cnnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(Nn2cnnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
3.36 Grams of potassium tert-butoxide was added to 15 ml of anhydrous dimethylsulfoxide and the mixture was stirred for 30 minutes at room temperature. Next, 2.52 g of 4-amino-4H-1,2,4-triazole was added to the solution. After the reaction mixture was stirred for 15 minutes at room temperature, 1.64 g of 4-fluorobenzotrifluoride was added thereto and the mixture was stirred for further 30 minutes at room temperature. Ice-water was added to the reaction mixture, which was then neutralized with a diluted hydrochloric acid. The crystals as precipitated out were collected by filtration to give 1.93 g of 4-[(4-trifluoromethylphenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][NH2:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:16](=O)[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1>CO>[OH:1][C:2]1[C:3]([C:12]([NH:14][N:15]=[CH:16][C:17]2[O:21][CH:20]=[CH:19][CH:18]=2)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=Cc1ccco1
Reactant: NNC(=O)c1cc2ccccc2cc1O
Solvent: CO
Product: O=C(NN=Cc1ccco1)c1cc2ccccc2cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A four neck flask (2 liters) equipped with a thermometer, a reflux condenser and a stirrer was charged with 101 g (0.5 mol) of 3-hydroxy-2-naphthohydrazide and 1.5 liter of methanol, and 57.6 g (0.6 mol) of furfural was dropwise added thereto in 30 minutes while stirring at room temperature. After heating under reflux for 5 hours, the reaction liquid was cooled down to 20° C. or lower, and crystal was filtered off. The crystal was washed with a small amount of methanol and then dried under reduced pressure, whereby the intended compound (slightly yellow crystal) was obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.C(O)(=O)C(O)=O.O[CH2:12][C@@H:13]1[C@H:18]([CH2:19][CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16][N:15]([CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:14]1.O>C(Cl)(Cl)Cl>[Cl:3][CH2:12][C@@H:13]1[C@H:18]([CH2:19][CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16][N:15]([CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:14]1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3CO)c2c1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3CCl)c2c1
Temperature: 60 °C

Procedure:
3.6 cm3 of thionyl chloride were added dropwise, at a temperature in the region of 20° C., to a stirred solution of 2.9 g of (3R,4R)-3-hydroxymethyl4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine oxalate in 20 cm3 of chloroform. The mixture was heated for 2 hours at a temperature in the region of 60° C. and then, after cooling, was poured onto 50 cm3 of water to which 250 g of ice had been added. After separating by settling from the chloroform phase, the mixture was extracted with 100 cm3 of dichloromethane. 5 g of sodium hydrogencarbonate were added to the aqueous phase, which was then extracted with 2 times 200 cm3 of dichloromethane. The organic extracts were dried over magnesium sulfate, filtered, and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40°. 1.3 g of (3R,4R)-3-chloromethyl-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine were obtained in the form of an oil with a brown color.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([OH:19])([C:15]([F:18])([F:17])[F:16])/[CH:4]=[CH:5]\[CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][CH2:10][CH:11]=[O:12].C(N(CC)CC)C.[CH2:29]([Si:31](Cl)([CH2:34][CH3:35])[CH2:32][CH3:33])[CH3:30]>C1COCC1.CN(C)C1C=CN=CC=1>[F:1][C:2]([F:20])([F:21])[C:3]([O:19][Si:31]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:29][CH3:30])([C:15]([F:17])([F:18])[F:16])/[CH:4]=[CH:5]\[CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][CH2:10][CH:11]=[O:12]
Reactant: CC(C)(C/C=C\C(O)(C(F)(F)F)C(F)(F)F)CCCC=O
Reactant: CC[Si](Cl)(CC)CC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCCC=O)(C(F)(F)F)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of 6.73 g of (Z)-10,10,10-trifluoro-9-hydroxy-5,5-dimethyl-9-trifluoromethyl-dec-7-enal in 67 ml of THF was added at 22° subsequently 2.55 g of triethylamine, 0.128 g of 4-dimethylamino pyridine and 3.92 g of triethylsilyl chloride and the solution was stirred at 22° for 1.5 h after which time g.l.c. indicated completion of the reaction. The suspension was evaporated, the residue dissolved in dichloromethane and washed with 0.1 N of aqueous hydrochloric acid and with sat. aqueous NaCl. The organic layer was dried over MgSO4, evaporated and the residue was chromatographed over silica with hexane/AcOEt 15:1 to give 7.50 g of the pure (99%, g.l.c.) title compound as a colorless liquid. IR (neat): 1729s (C═O), 1661w (C═C). MS (EI): 405/10 M−C2H5).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]=1[CH2:25][Br:26])=[O:5])[CH3:2].C(OC(C1C=C(C2C=CC([F:43])=CC=2)N(C2C=CC(F)=CC=2)C=1C)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([F:43])=[CH:21][CH:20]=2)[C:7]=1[CH2:25][Br:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccc(F)cc2)c1C
Reactant: CCOC(=O)c1c(Br)c(-c2ccc(F)cc2)n(-c2ccccc2)c1CBr
Product: CCOC(=O)c1c(Br)c(-c2ccc(F)cc2)n(-c2ccc(F)cc2)c1CBr

Procedure:
Prepared in analogy to that of 4-bromo-2-bromomethyl-5-(4-fluoro-phenyl)-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester from 1,5-Bis-(4-fluoro-phenyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester. The title compound, ESI MS (m/z): 418 (M−HBr+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:9]=1)[CH:5]=[O:6].S(Cl)([Cl:18])(=O)=O>ClCCl>[Cl:18][C:3]1[C:2]([OH:1])=[CH:9][C:8]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: COCCCc1cc(O)cc(C=O)c1
Solvent: ClCCl
Product: COCCCc1cc(O)c(Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-hydroxy-5-(3-methoxypropyl)benzaldehyde from the previous step (I eq.) in dichloromethane (0.2 M) was added sulfuryl chloride (1 eq.). The resulting reaction mixture was then stirred at RT for 18 h. The volatiles were removed in vacuo and purification of the crude product thus obtained by way of column chromatography (SiO2, Hex→3:2 (v/v) Hex:EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:26]([F:27])=[CH:25][C:6]2[O:7][C:8]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:9]=3[C@H:10]3[C@H:15]([NH:16][C:17](=[O:19])[CH3:18])[CH2:14][CH2:13][CH2:12][N:11]3[C:5]=2[CH:4]=1)#[N:2].C1C(=O)N([Cl:35])C(=O)C1>>[Cl:35][C:4]1[C:5]2[N:11]3[CH2:12][CH2:13][CH2:14][C@@H:15]([NH:16][C:17](=[O:19])[CH3:18])[C@@H:10]3[C:9]3[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:8]=3[O:7][C:6]=2[CH:25]=[C:26]([F:27])[C:3]=1[C:1]#[N:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)N[C@@H]1CCCN2c3cc(C#N)c(F)cc3Oc3cccc(F)c3[C@@H]12
Product: CC(=O)N[C@@H]1CCCN2c3c(cc(F)c(C#N)c3Cl)Oc3cccc(F)c3[C@@H]12
Yield: 62.7 %

Procedure:
Preparation analogous to Example 3 from (−)-(cis)-N-(7-cyano-8,14-difluoro-1,3,4,14b-tetrahydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)acetamide (0.277 g, 0.75 mmol) and NCS (0.10 g, 0.75 mmol). The crude compound was purified by HPLC to give the title compound (0.19 g, 62%). 1H-NMR (600 MHz, DMSO) 1.46-1.57 (m, 4H), 1.64 (m, 1H), 1.72 (m, 1H), 1.92 (m, 1H), 3.27 (m, 1H), 3.53 ( m, 1H), 4.31 (d, J=11.6, 1H), 4.38 (m, 1H), 7.05 (m, 1H), 7.11 (d, J=8.7, 1H), 7.33 (m, 1H), 7.64 (d, J=9.8, 1H), 7.81 (br-d, J=9.8, 1H). e.e.=100%, Rf=17.8 min. (chiralpak OD-H 25*0.46 cm, heptane:ethanol=9:1). (MIM)=403. [α]D20=−207° (c=1.0025, THF).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][CH:7]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:6]1=[O:34])(=O)[CH3:2].Cl.[NH2:36][OH:37]>C(O)C.C(OC(C)C)(C)C>[OH:37][N:36]=[C:1]([CH3:2])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:8][CH:7]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:6]1=[O:34]
Reactant: CC(=O)CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Reactant: NO
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CC(CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)=NO
Temperature: 25 °C
Reaction time: 40 h
Yield: 42.3 %

Procedure:
A mixture of (3RS)-1-acetylmethyl-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1, 4-benzodiazepine-2-one (0.42 g), hydroxylamine hydrochloride (62.5 mg) in ethanol (20 ml) was stirred at room temperature for 40 hours. The mixture was evaporated to dryness and the residue was subjected to column chromatography on silica gel with an eluent of a mixture of chloroform and methanol (40:1). The fractions containing the objective product were combined and evaporated to give a pale green oil, which was pulverized in diisopropyl ether to afford (3RS)-1-(2-hydroxyiminopropyl)-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1, 4-benzodiazepine-2-one (177 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([NH2:12])[C@H:9](OS(C)(=O)=O)[C@H:8]([O:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:7]=1)=[O:5])C.C(N)CN>C(O)C>[CH2:20]([CH:19]([O:18][C@H:8]1[C@@H:9]2[C@H:10]([NH:12]2)[CH2:11][C:6]([C:4]([OH:3])=[O:5])=[CH:7]1)[CH2:22][CH3:23])[CH3:21]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@@H](OS(C)(=O)=O)[C@H](N)C1
Solvent: NCCN
Solvent: CCO
Product: CCC(CC)O[C@@H]1C=C(C(=O)O)C[C@H]2N[C@@H]21
Yield: 92.3 %

Procedure:
A yellowish solution of 0.87 g (2.5 mmol) (3R,4S,5R)-5-amino-3-(1-ethyl-propoxy)-4-methanesulfonyloxy-cyclohex-1-enecarboxylic acid ethyl ester and 0.17 ml (2.5 mmol) of ethylenediamine in 4.4 ml ethanol was heated to reflux for 1 hour. The resulting suspension was evaporated in a rotary evaporator to dryness and the residue was suspended in 5 ml ethyl acetate, extracted with 2 ml aqueous 1M NaHCO3 solution, dried over Na2SO4, filtered and evaporated in a rotary evaporator at reduced pressure to dryness to yield 0.52 g (82%) of (1R,5R,6S) 5-(1-ethyl-propoxy)-7-aza-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethy as a yellow oil. IR (film): 3312, 2966, 2936, 2877, 1715, 1660, 1464, 1254, 1083, 1057, 799 cm−1; MS (EI, 7o eV)): 253 (M+), 224, 208, 182, 166, 110 m/z.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:6]([O:8][C:9](=[O:13])[CH2:10][N+:11]#[C-:12])[CH3:7]>>[CH2:6]([O:8][C:9]([CH:10]1[CH:1]([CH:2]=[CH:3][CH3:4])[O:5][CH:12]=[N:11]1)=[O:13])[CH3:7]
Reactant: C/C=C/C=O
Reactant: [C-]#[N+]CC(=O)OCC
Product: CC=CC1OC=NC1C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of crotonaldehyde with isocyanoacetic acid ethyl ester in a manner analogous to that described in Example 1 yields 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of the 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester analogously to Example 1, 2-formylamino-3-hydroxy-4-hexenoic acid ethyl ester is obtained. Reaction of the 2-formylamino-3-hydroxy-4-hexenoic acid ethyl ester with thionyl bromide and subsequent treatment with triethyl phosphite in a manner analogous to that described in Example 1 (12 hours) yields E-2-formylamino-5-diethylphosphono-5-methyl-3-pentenoic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH:10]([F:12])[F:11])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>CCCCCC>[CH2:26]([O:25][C:23]([C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[C:3]=1[O:9][CH:10]([F:11])[F:12])=[O:24])[CH3:27]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(F)c1OC(F)F
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1cccc(F)c1OC(F)F)C(=O)OCC
Temperature: 120 °C
Yield: 85 %

Procedure:
A mixture of 22.4 g (0.127 mole) of 3-fluoro-2-difluoromethoxyaniline obtained as described above and 27.4 g (0.127 mole) of diethyl ethoxymethylenemalonate was heated at 120° C. for 5 hours. The mixture was cooled to room temperature, n-hexane was added thereto, and the mixture was filtered. Products collected by filtration was washed with n-hexane and dried to obtain 37.5 g of N-(2,2-diethoxycarbonylvinyl)-3-fluoro-2-difluoromethoxyaniline as white powder.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=S)[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CO[CH:19](OC)[CH:20]([NH2:22])[CH3:21].S(=O)(=O)(O)O.[OH-].[Na+]>C(O)CCC>[CH3:21][C:20]1[N:22]=[C:10]2[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[NH:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[N:9]2[CH:19]=1
Reactant: COC(OC)C(C)N
Reactant: S=C1Nc2ccccc2Nc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: Cc1cn2c(n1)-c1ccccc1Nc1ccccc1-2
Yield: 40 %

Procedure:
in a 250-ml., three-neck flask fitted with a condenser, is heated to reflux 6.25 g. of 5,10-dihydro-11H-dibenzo-[b,e][1,4]diazepine-11-thione (30.0 mmol.) and 10.8 g. of aminopropionaldehyde dimethyl acetal (90.0 mmol.) in 60 ml. of n-butanol, during 2 hours. An additional 60 ml. of n-butanol is added and the mixture is refluxed overnight (22 hours). At this point, 60 ml. of n-butanol is distilled from the reaction mixture and refluxing is maintained for an additional 18 hours. On cooling, 2.0 g. of crude starting material is obtained. This is added to the reaction mixture along with an additional 5.4 g. of aminopropionaldehyde acetal (40.0 mmol.) and heating is maintained over a weekend (65 hours). On cooling and removal of the solvent in vacuo, 10 g. of brown oil is obtained. The oil is dissolved in 80 ml. of concentrated sulfuric acid and stirred at room temperature under nitrogen for 10 hours. The reaction mixture is then poured into ice and carefully neutralized with 50% aqueous sodium hydroxide solution. The basic aqueous solution is extracted thoroughly with chloroform. The combined chloroform extracts are washed with brine, dried over anhydrous potassium carbonate and concentrated in vacuo. The resulting oil is taken up in ethyl acetate, treated with activated charcoal and filtered. On concentrating and cooling the filtered solution, 3.2 g. of 2-methyl-9H-dibenzo[b,f]imidazo[1,2-d][1,4]diazepine is obtained in 2 crops (yield 40%) of melting point 232°-236° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[N:6][CH:7]=1.CCN(CC)CC.[CH:25](O)([CH3:27])[CH3:26]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:25]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[N:6][CH:7]=1)([CH3:27])=[CH2:26]
Reactant: CC(C)O
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Product: C=C(C)c1ccc(C(=O)OCc2ccccc2)nc1
Temperature: 80 °C

Procedure:
A mixture of benzyl 5-bromopicolinate (2.92 g, 10 mmol), potassium isopropenyl trifluoroborate (3.05 g, 21 mmol), Pd(dppf)Cl2 (445 mg, 0.54 mmol), and Et3N (1.4 mL) in isopropyl alcohol (20 mL) was degassed with N2 and heated at 80° C. for 7 h. The mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with H2O, 5% citric acid, sat.NaHCO3 (aq.) and brine, then dried (MgSO4) and concentrated. The product benzyl 5-isopropenylpicolinate (1.27 g) was obtained by silica gel chromatography (elution with 0-16% EtOAc/Hex).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:17])[C:6](=[O:16])[NH:7]2.CO[CH:20]1[CH2:24][CH2:23][CH:22](OC)O1>>[N:1]1([C:2]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]3[C:3]=2[NH:4][C:5](=[O:17])[C:6](=[O:16])[NH:7]3)[CH:20]=[CH:24][CH:23]=[CH:22]1
Reactant: Nc1cc(C(F)(F)F)cc2[nH]c(=O)c(=O)[nH]c12
Reactant: COC1CCC(OC)O1
Product: O=c1[nH]c2cc(C(F)(F)F)cc(-n3cccc3)c2[nH]c1=O

Procedure:
12.2mmol of 5-amino-7-trifluoromethyl-2,3(1H,4H)-quinoxalinedione were reacted with 12.2 mmol of 2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][C@H:21]([C:26]([NH2:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24]>CS(C)=O>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:20][C@H:21]([C:26]([NH2:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(N)=O
Solvent: CS(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 ml 0.1M veronal-Na/HCl buffer, pH 8.3/50% (v/v) DMSO, containing 100 mM Boc-Phe-OCam, 300 mM H-Leu-NH2 and 100 μM trypsinogen is agitated at room temperature under pH control. After 3 hours, the reaction is stopped as described in Example 3. The yield is analytically determined with HPLC to be 93% of theory.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1.Br[C:28]1[N:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:31]=[CH:30][C:29]=1[CH3:39].COCCOC.C([O-])([O-])=O.[Cs+].[Cs+]>O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:28]3[N:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:31]=[CH:30][C:29]=3[CH3:39])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2[nH]c(=O)[nH]c2c1
Reactant: Cc1cnn(-c2ccccc2)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1cnn(-c2ccccc2)c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 130 °C
Yield: 12 %

Procedure:
6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (30 mg, 0.084 mmol) and 5-bromo-4-methyl-1-phenyl-1H-pyrazole (30 mg, 0.13 mmol) was added to a solvent mixture of 1,2-dimethoxyethane (2 ml) and water (1 ml). To the above mixture were added PEPPSI-Ipr (5.4 mg, 0.008 mmol) and Cs2CO3 (83 mg, 0.25 mmol). The reaction mixture was heated at 130° C. in microwave reactor for 30 mins. The reaction mixture was then filtered and organic solvent was evaporated and the residue was purified with Prep HPLC (0-100% CH3CN/H2O) to afford 3.9 mg product 6-(3,5-dimethylisoxazol-4-yl)-4-(4-methyl-1-phenyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one (yield=12%).