Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC=CC=1[C@H]1C(C)(C)COP(=O)([O-])O1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[C@@H:33]([NH3+:35])[CH3:34].C(N(CC)CC)C.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:47][CH:46]=1>C(#N)C.COC1C=CC(S(Cl)(=O)=O)=CC=1>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[C@@H:33]([NH:35][S:51]([C:48]1[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:50][CH:49]=1)(=[O:53])=[O:52])[CH3:34]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H]([NH3+])c1cc(F)ccc1-c1ccccc1F
Agent: COc1ccccc1[C@@H]1OP(=O)([O-])OCC1(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N[C@@H](C)c2cc(F)ccc2-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A stirred suspension of (1S)-1-(2′,4-difluoro-1,1′-biphenyl-2-yl)ethanaminium (4R)-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphinan-2-olate 2-oxide (2.53 g, 5.0 mmol) in acetonitrile (50 mL) was treated sequentially with triethylamine (1.39 mL, 10 mmol) and 4-methoxybenzenesulfonyl chloride (1.04 g, 5.05 mmol). The progress of the reaction was monitored by LCMS. After eight hours, approximately 5% of the starting amine was still present. An additional aliquot of 4-methoxybenzenesulfonyl chloride (52 mg, 0.25 mmol, 5 mole %) was added, and the reaction was stirred at ambient temperature for an additional 16 hours. Monitoring by LCMS indicated complete formation of a single product. The solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with a 5% aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with a 2 N hydrochloric acid solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a residue. The residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butylether in hexane, to afford N-[(1S)-1-(2′,4-difluoro-1,1′-biphenyl-2-yl)ethyl]-4-methoxybenzenesulfonamide (1.8 g, 89%, 99.2% ee), m.p. 133-135° C.;
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1>[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(I)cc1
Yield: 90 %

Procedure:
2 mM of p-nitrophenol are reacted overnight with 2 mM of p-iodo benzoic acid chloride in the presence of 2 mM of triethylamine in 20 ml of THF. The solvent is evaporated and the residue is taken up in chloroform and washed with 1N HCl, then with water. The solution is dried over MgSO4. It is purified on a chromatography column (silica; eluant CHCl3 -hexane 85/15 v/v). Yield: 90%.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O)[CH3:14].[F-].[K+]>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]>[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:14]
Reactant: N#Cc1ccc(Br)c([N+](=O)[O-])c1
Reactant: CCOc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Product: CCOc1ccccc1-c1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 50 mL round-bottom flask was charged with 4-bromo-3-nitrobenzonitrile (1.0 g 4.4 mmol), 2-ethoxyphenylboronic acid (731 mg, 4.4 mmol), Pd2(dba)3 (18 mg, 0.022 mmol) and potassium fluoride (786 mg, 13.5 mmol). The reaction vessel was evacuated and filled with argon. Dry THF (300 mL) was added followed by the addition of P(t-Bu)3 (0.11 mL, 10% wt. in hexane). The reaction mixture was stirred at room temperature for 30 min., and then heated at 80° C. for 16 h. After cooling to room temperature, the resulting mixture was filtered through a Celite pad and concentrated. 2′-Ethoxy-2-nitrobiphenyl-4-carbonitrile was isolated as a yellow solid (1.12 g, 95%). 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.20 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.41 (t, J=8.4 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 3.91 (q, J=7.2 Hz, 2H), 1.12 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 154.9, 149.7, 137.3, 137.2, 134.4, 131.5, 130.4, 128.4, 125.4, 121.8, 117.6, 112.3, 111.9, 64.1, 14.7; HPLC ret. time 2.43 min, 10-100% CH3CN, 5 min gradient; ESI-MS 269.3 m/z (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH:14]([CH3:16])[CH3:15])[CH2:3]1.[CH3:17][Mg]Br>C1COCC1>[OH:1][C:2]1([CH3:17])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[C@H:4]([CH:14]([CH3:16])[CH3:15])[CH2:3]1
Reactant: CC(C)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)[C@@H]1CC(C)(O)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2S)-4-oxo-2-(propan-2-yl)pyrrolidine-1-carboxylate (500 mg, 2.2 mmol) in THF (10 mL) at −78° C. was added methylmagnesium bromide (1.65 mL, 4.95 mmol) dropwise. The reaction was stirred at −78° C. for 2 hours before warming to room temperature and stirring for an additional 2 hours. The reaction was quenched by slowly adding saturated aqueous ammonium chloride at 0° C. The mixture was acidified with HCl (1 N) and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-80% ethylacete/hexanes, linear gradient) to afford tert-butyl (2S)-4-hydroxy-4-methyl-2-(propan-2-yl)pyrrolidine-1-carboxylate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](O)=[O:11].ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[BH4-].[Na+]>O1CCCC1.CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: OCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a mixture of indole-2-carboxylic acid (2.0 g, 12 mmol), N,N-dimethylformamide (10 mL), tetrahydrofuran (20 mL) and N-hydroxysuccinimide (1.5 g, 13 mmol) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.9 g, 15 mmol), and the mixture was stirred overnight at room temperature. 0.5 M Aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated. Tetrahydrofuran (20 mL) and sodium tetrahydroborate (1.9 g, 50 mmol) were added to the residue under ice-cooling, and the mixture was stirred at room temperature for 6 hrs. 0.5 M Aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5:1) to give the title compound. yield 56%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.BrC1C=CC(F)=CC=1.[Mg].[C:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)(=[O:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)([OH:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(=O)c1ccc(-c2ccncc2)cc1
Agent: Fc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(O)(c1ccc(F)cc1)c1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
A solution of 4-fluorophenylmagnesium bromide (prepared from 7.6 ml (0.070 mol) 4-bromofluorobenzene and 3.40 g (0.14 mol) magnesium turnings) in tetrahydrofuran (150 mL) was added to a suspension of 4-(4-acetylphenyl)pyridine (9.85 g, 0.050 mol) in tetrahydrofuran (50 mL) at 0°. The mixture was stirred for 30 min at 0° and for 30 min at room temperature, then was poured into saturated aqueous ammonium chloride. The mixture was extracted with ether, the organic phase was washed with water and brine, then was dried over magnesium sulfate and concentrated. The residue was recrystallized (1-chlorobutane) to give 1-(4-fluorophenyl)-1-[4-(4-pyridyl)phenyl]ethanol colorless needles (10.0 g, 68%). MP 166-170°; NMR (CDCl3) 8.60 (d, 2H), 7.60-7.40 (8H), 7.00 (t, 2H), 2.00 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 200 °C
Yield: 42.7 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (457 mg, 3.0 mmol, prepared according to Thibault, C. et al. Org. Lett. 2003, 5, 5023) and 2-fluoro-4-nitrophenol (706 mg, 4.5 mmol), and N,N-diisopropylethylamine (580 mg, 4.5 mmol) in 1-methyl-2-prolidinone (NMP) (3 mL) was heated at 200° C. under microwave irradiation for 1.0 h. The mixture was diluted with ethyl acetate (150 mL), washed with sat. aq. KH2PO4 solution, and Na2CO3 (aq. 1 M), dried over Na2SO4. The product was purified by flash column chromatography (silica gel, eluting with CH2Cl2 to 30% EtOAc/CH2Cl2) to afford a brown solid (350 mg, 43%). MS(ESI+) m/z 274 (M+H)+.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9][C@H:2]1[C:3](N(OC)C)=[O:4].OS([O-])(=O)=O.[K+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[C:12]([N:1]1[CH2:11][CH2:10][CH2:9][C@H:2]1[CH:3]=[O:4])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O

Procedure:
10 mmol of 30 was dissolved in 20 ml of absolute ether at 0° C. 12.5 mmol lithiumalanate was added. After 7 min of stirring 10 ml of a saturated KHSO4 solution was added drop wise. Then the mixture was diluted by adding 50 ml of ether and the organic layer was separated. This was washed by 1N HCl, water, saturated NaHCO3 solution, brine and dried. 30 (1.43 g, 5.54 mmol), LiAlH4 (0.26 g, 6.92 mmol)
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([OH:12])=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43]O)[CH2:38][CH2:37]1>C(Cl)(Cl)Cl>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:37][CH2:38][N:39]([CH2:42][CH2:43][O:11][C:10]([C:4]23[CH2:5][CH:6]4[CH2:9][CH:2]([CH2:1][CH:8]2[CH2:7]4)[CH2:3]3)=[O:12])[CH2:40][CH2:41]1
Reactant: COc1ccccc1N1CCN(CCO)CC1
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1N1CCN(CCOC(=O)C23CC4CC(CC2C4)C3)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of hexahydro-2,5-methanopentalene-3a[1H]-carboxylic acid (0.6 g, 3.6×10-3 mol) in 25 ml of chloroform un der a dry nitrogen atmosphere was added carbonyldiimidazole (0.58 g, 3.6×10-3 mol). The resulting solution was stirred at ambient temperature for three hours, during which time a gas (CO2) was evolved. A solution of 2-[1-(2-methoxyphenyl)-4-piperazinyl]ethanol (0.86 g, 3.6×10-3 mol) in 25 ml of chloroform was then added, and the resulting reaction mixture was stirred under nitrogen at ambient temperature for two days. The mixture was diluted to 150 ml with chloroform, washed with three-one hundred ml portions of water, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator. The desired product (TLC on silica using a 30% methanol in ethyl acetate solvent system, RF=0.60) was isolated by gravity chromatography on silica gel and converted to the hydrochloride salt with isopropanolic HCl (0.82 g, 44% yield), mp.=207°-208° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8]1\[CH2:9][C@@H:10]2[C@H:14]([CH2:15]\1)[C@H:13](/[CH:16]=[CH:17]/[CH:18]([OH:25])[CH:19]([F:24])[CH2:20][CH2:21][CH2:22][CH3:23])[C@H:12]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:11]2)([OH:3])=[O:2]>C(O)(C)C>[C:1]([CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8]1\[CH2:9][C@@H:10]2[C@H:14]([CH2:15]\1)[C@H:13](/[CH:16]=[CH:17]/[C:18](=[O:25])[CH:19]([F:24])[CH2:20][CH2:21][CH2:22][CH3:23])[C@H:12]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:11]2)([OH:3])=[O:2]
Reactant: CCCCC(F)C(O)/C=C/[C@H]1[C@H]2C/C(=C/CCCC(=O)O)C[C@H]2C[C@H]1OC1CCCCO1
Solvent: CC(C)O
Product: CCCCC(F)C(=O)/C=C/[C@H]1[C@H]2C/C(=C/CCCC(=O)O)C[C@H]2C[C@H]1OC1CCCCO1
Reaction time: 0.5 h

Procedure:
(1S,2S,3R,5S)-(E)-7-(4-Carboxybutylidene)-2-[4(RS)fluoro-3(RS)-hydroxy-(E)-1-octenyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (13') (0.140 g) was subjected to Jones oxidation between -15 ° C. and -20 ° C. The mixture was stirred for 30 minutes, isopropyl alcohol was added to the mixture, and the resultant was treated by a usual work-up. The obtained crude product was purified on column chromatography (hexane/ethyl acetate=6/1-5/1) to give (1S,2S,3R,5S)-(E)-7-(4-carboxybutylidene)-2-[4(RS)-fluoro-3-oxo-(E)-1-octenyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (14') as a colorless oily product. Yield: 0.106 g (76%)
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:23]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br)([O-:25])=[O:24]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[N+:23]([O-:25])=[O:24])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (319 mg) in DMF (5 mL) was added potassium carbonate powder (491 mg) I) and 2-nitrobenzyl bromide (768 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (5%-35% EtOAc/hexanes), followed by dissolution in CH2Cl2 and trituration with hexanes to yield the title compound as orange solid.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20](OC)(=[O:25])[CH2:21][C:22]([CH3:24])=O>>[CH2:1]([NH:13][CH2:14][CH2:15][N:16]1[C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[N:19][CH2:18][CH2:17]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNCCNCCN
Reactant: COC(=O)CC(C)=O
Product: CCCCCCCCCCCCNCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 271.1 g (1 mole) of N-dodecyldiethylenetriamine and 116.1 g (1 mole) of methyl acetoacetate. After 18 g of water and 32 g of methanol had been distilled off at 140° to 150° C., there was obtained 4-dodecylaminoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one in slight red liquid.
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](Cl)=[O:15].[OH-].[Na+]>O>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([N:1]1[CH2:3][CH2:2]1)=[O:15]
Reactant: C1CN1
Reactant: O=C(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1cccs1)N1CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a cooled (0° c) mixture of 338 parts of a solution of aziridine in water 0.875 N and 22 parts of sodium hydrogen carbonate are added dropwise, during a 45 minutes-period, 87 parts of 2-thiophenecarbonyl chloride while stirring vigorously. Upon completion, stirring is continued for 45 minutes without cooling. The reaction mixture is warmed to room temperature and alkalized with a diluted sodium hydroxide solution till pH 8 is reached. The product is extracted three times with trichloromethane. The combined extracts are washed with water, dried, filtered and evaporated, yielding 42 parts of 1-(2-thienylcarbonyl)aziridine as a residue.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[C:19]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)=[CH:22][CH:21]=1)#[N:18]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1ccc(OC(F)(F)F)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC(F)(F)F)cc1

Procedure:
(RS)-Methoxy-(4-trifluoromethoxy-phenyl)-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-(4-trifluoromethoxy-phenyl)-acetamide. Light blue semisolid. MS 365.2 ([M+H]+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][C:8]2=[O:19])[CH2:2]1.ON1C2C=CC=CC=2N=N1.[C:30](O)(=[O:34])[CH2:31][CH:32]=[CH2:33].N=C=N.C(O)C(N)(CO)CO.[N-]=C=O>>[C:30]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][C:8]2=[O:19])[CH2:2]1)(=[O:34])[CH2:31][CH:32]=[CH2:33]
Reactant: C=CCC(=O)O
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1C1CCCNC1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Product: C=CCC(=O)N1CCCC(n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-piperidin-3-yl-3,6-dihydroimidazo[4,5-d]-pyrrolo[2,3-b]pyridin-2(1H)-one (0.030M solution in N,N-dimethylformamide, 1.00 mL), 1-hydroxybenzotriazole (4.1 mg, 0.030 mmol), 3-but-enoic acid (0.50M solution in NMP, 0.080 mL), and PS-Carbodiimide (Argonaut technologies,50 mg) was agitated at ambient temperature for 16 hours. PS-Trisamine (Argonaut technologies, 50 mg), PS-Isocyanate (50 mg) was added and the reaction agitated at ambient temperature for a further 2 hours and filtered. The filtrate was concentrated to yield 1-(1-but-3-enoylpiperidin-3-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (9.7 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:22]([NH:24][CH3:25])=[O:23]>>[CH3:27][C:26]([CH3:29])([CH3:28])[C@H:21]([NH:20][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[N:8]=1)=[O:19])[C:22](=[O:23])[NH:24][CH3:25]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Product: CNC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(S(=O)(=O)CC(C)C)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351 b) and (2S)-2-amino-N,3,3-trimethyl-butanamide (CAN 89226-12-0) as starting materials. MS (EI): m/e=410.6 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:25])[CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[Cl:1][C:2]1[S:6][C:5]([CH:7]([OH:25])[CH:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(Cl)s1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)s1
Reaction time: 2 h

Procedure:
While stirring zinc chloride (6.47 g, 47.5 mmol) in diethyl ether (100 ml), sodium borohydride (3.59 g, 94.9 mmol) was added at room temperature, and the mixture was-stirred as it was for 2 hrs. The insoluble material of the mixture was removed by filtration (washed with diethyl ether) to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 3-(5-chloro-2-thienyl)-3-oxo-2-[4-(trifluoromethyl)benzyl]propionate (9.272 g, 23.73 mmol) in diethyl ether (50 ml) at room temperature, and the mixture was stirred as it was for 2 hrs. Dilute hydrochloric acid was added to the reaction solution by small portions to decompose excess zinc borohydride. The mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-3/1) to give the objective substance.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[CH:3]=1.[CH2:18]([NH2:23])[CH:19]([NH2:22])[CH2:20][CH3:21].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[NH2:22][CH:19]([CH2:20][CH3:21])[CH2:18][NH:23][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)[CH:3]=1
Reactant: CCC(N)CN
Reactant: Cc1cccc(Nc2cc(Cl)ncc2C#N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCC(N)CNc1cc(Nc2cccc(C)n2)c(C#N)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 6-chloro-4-[(6-methylpyridin-2-yl)amino]pyridine-3-carbonitrile (PrepEx 1.3) (38 mg, 0.16 mmol) in NMP (1 mL) was added butane-1,2-diamine (107 mg, 1.21 mmol) and N,N-diisopropylethylamine (0.163 mL, 0.932 mmol). The reaction mixture was heated to 100° C. After 16 hours, the reaction mixture was allowed to cool to room temperature, filtered, and purified directly via reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 6-[(2-aminobutyl)amino]-4-[(6-methylpyridin-2-yl)amino]pyridine-3-carbonitrile. MS ESI calc'd. for C16H21N6 [M+H]+ 297. found 297.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5].[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:4]([C:3]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:22])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: COc1cccc(N)c1C#N
Product: COc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N

Procedure:
Prepared as in Example 53a from 2-amino-6-methoxybenzonitrile and benzoyl isocyanate as light orange solid (118 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ3.94 (s, 3H), 6.98 (d, J=8 Hz, 1H), 7.54 (t, J=8 hz, 2H), 7.64 (t, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 8.04 (d, J=5.6 Hz, 2H), 11.35 (s, 1H), 11.51 (s, 1H). MS 295 (MH+).