Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][CH:27]=[C:26]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43]([OH:45])=O)=[CH:38][CH:37]=1.[NH2:46][C:47]1[CH:51]=[CH:50][O:49][N:48]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:49]1[CH:50]=[CH:51][C:47]([NH:46][C:43](=[O:45])[CH2:42][C:39]2[CH:38]=[CH:37][C:36]([O:35][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][CH:27]=3)=[CH:41][CH:40]=2)=[N:48]1
Reactant: COc1cc2nccc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Reactant: Nc1ccon1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(CC(=O)Nc4ccon4)cc3)c2cc1OC
Temperature: 60 °C
Yield: 14.6 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.226 g) and 2-hydroxypyridine N-oxide (0.131 g) were added in turn to a stirred mixture of 2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]acetic acid (0.2 g), 3-aminoisoxazole (0.064 g), diisopropylethylamine (0.226 g) and DMF (3 ml) at ambient temperature. The resultant mixture was stirred and heated to 60° C. for 16 hours. The mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘Xterra’ reversed-phase column (5 microns silica, 30 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetoliitrile as eluent. There was thus obtained the title compound (0.035 g); 1H NMR: (DMSOd6) 3.76 (s, 2H), 3.92 (s, 3H), 3.95 (s, 3H), 6.47 (d, 1H), 6.93 (d, 1H), 7.23 (d, 2H), 7.4 (s, 1H), 7.46 (d, 2H), 7.49 (s, 1H), 8.49 (d, 1H), 8.80 (d, 1H), 11.33 (br s, 1H); Mass Spectrum: M+H+ 406.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[C:10](C)=[N:11][CH:12]=[CH:13][C:14]=2N)=[N:6][CH:7]=1.[CH3:17][C:18](O)=O.[N:21](OC(C)(C)C)=O>C1COCC1>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[C:9]3[CH:14]=[CH:13][N:21]=[C:18]([CH3:17])[C:10]=3[N:11]=[CH:12]2)=[N:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Cc1nccc(N)c1Nc1ncc(F)cn1
Reactant: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: Cc1nccc2c1ncn2-c1ncc(F)cn1
Temperature: 100 °C
Yield: 76.5 %

Procedure:
A solution of N-(5-fluoropyrimidin-2-yl)-2-methylpyridine-3,4-diamine (0.50 g, 2.28 mmol) in THF (15 ml) and HOAc (0.14 ml, 2.51 mmol) was treated with t-butyl nitrite (0.45 ml, 3.42 mmol) and heated to 100° C. for 90 min. The reaction was concentrated, diluted with 1N NaHCO3, and extracted with DCM (50 mL×3). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2; EtOAc:Hex) gave the title compound (0.40 g, 77%). MS (ESI): mass calcd. for C10H7FN6, 230.07. m/z found, 231.1 [M+H]+.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5]([CH2:17][CH3:18])(CC)[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH:21]1[C:31]2C=C[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[C:26](=O)[C:25]=2[CH:24]=[CH:23][CH:22]=1.CO>CS(C)=O.[Cl-].[Na+].O>[N+:12]([C:9]1[CH:8]=[CH:7][C:6]([CH:5]=[C:17]2[C:18]3[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=3[CH:27]=[CH:26][C:25]3[CH:31]=[CH:21][CH:22]=[CH:23][C:24]2=3)=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: CCC(CC)(O[PH](=O)[O-])c1ccc([N+](=O)[O-])cc1
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(C=C2c3ccccc3C=Cc3ccccc32)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To 150 ml of dimethylsulfoxide, 3.60 g (about 90 mmol) of oily sodium hydride (about 60%) was added at room temperature. After the addition, the mixture was heated to the inner temperature of around 70° C. in an oil bath, and stirred under the same conditions for 1 hour. Thereafter, the reaction solution was cooled to room temperature, and then a solution of 25.1 g (92 mmol) of the diethyl-4-nitrobenzyl phosphonate and 10.0 g (48.6 mmol) of 5H-dibenzo[a,d]cyclohepten-5-one in 50 ml dimethyl sulfoxide was added dropwise thereto. After the addition was completed, the resulting mixture was stirred for 15 minutes at room temperature, and thereafter heated and stirred for 2 hours in an oil bath while keeping its internal temperature at 70 to 80° C. After the reaction was completed, the reaction mixture was cooled to room temperature, and then poured in about 1 liter of saturated brine, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To the residue thus obtained was added methanol, and the precipitated crystals were collected by filtration. The crystals were then recrystallized using a methanol/acetone mixed solvent to obtain 10.94 g of 5-(4-nitrobenzylidene)-5H-dibenzo[a,d]cycloheptene. Yield: 69.3%; m.p.: 151.5 to 152.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2[CH:22]=[CH:23][CH:24]=[N:25]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:25][CH:24]2[CH2:22][CH2:23]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(Br)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Bromo-benzoic acid (2.5116 g, 12.5 mmol) and HATU (5.2213 g, 13.7 mmol) were dissolved in DMF (40 mL). DIEA (4.572 mL, 26.2 mmol) was added, and the mixture was allowed to stir at ambient temperature for 15 minutes. Then cyclopropylamine (0.866 mL, 12.5 mmol) was added, and the reaction was stirred at ambient temperature overnight. The solvent was removed, and the crude was purified via silica gel chromatography to give the desired product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14]C)=[O:5].[CH2:16]([O:19]C1C=C(C)C(=C(C)C=1)N)[CH2:17][CH3:18].C(O)(=O)C.O.O.O.C([O-])(=O)C.[Na+]>O>[Br:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:14])=[CH:9][C:10]([O:19][CH2:16][CH2:17][CH3:18])=[CH:11][C:12]=1[CH3:13])=[O:5]
Reactant: CCCOc1cc(C)c(N)c(C)c1
Reactant: CCc1cccc(C)c1NC(=O)CCBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCOc1cc(C)c(NC(=O)CCBr)c(C)c1
Yield: 93 %

Procedure:
This compound was prepared analogously to 3-bromo-2'-ethyl-6'-methylpropionanilide of Example 11A from 20 g 4-propoxy-2,6-xylidine, 95 ml glacial acetic acid, 37 g sodium acetate trihydrate, 150 ml water 21.2 g 3-bromopropionyl bromide. The yield was 93% of recrystallized (methanol:water) material melting at 121.5°-122.5° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH3:21])[C:12]=2[CH3:22])[CH:5]=1.[Li+].[OH-]>CO.C1COCC1>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([S:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:23])=[O:2])=[C:12]([CH3:22])[N:13]2[CH3:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccc(Sc2c(C)n(C)c3cc(Cl)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Sc2cccc(C(=O)O)c2)c2ccc(Cl)cc2n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(6-Chloro-1,2-dimethyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.079 g, 0.23 mmol) was dissolved in MeOH:THF (1:1, 5 mL) and LiOH (2.30 mL, 1M aq., 2.3 mmol) was added. The reaction was stirred at room temperature overnight then submitted to aqueous workup procedure. Purification by preparatory HPLC (10-100% ACN in H2O) to yield the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1.[BH4-].[Na+]>CO>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)=[CH:2]1
Reactant: COc1ccc(CN)cc1
Reactant: O=Cc1ccoc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNCc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-Furaldehyde (5 mmol, 437 μL) and (4-methoxyphenyl)methanamine in MeOH (20 mL) was stirred at ambient temperature overnight then sodium borohydride (300 mg, 7.89 mmol) was slowly added. The resulting mixture was stirred at room temperature for 15 minutes and quenched with NaOH (1 N, aq). Methanol was removed in vacuo and the resulting slurry was redissolved in ethyl acetate then, washed with water, brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (Ethyl acetate:Hexanes 7:3) gave 1-(furan-3-yl)-N-(4-methoxybenzyl)methanamine as an oil. MS (M+H, 218.10); 1H NMR (400 MHz, CDCl3): δ, ppm: 3.64(s, 2H), 3.74(s, 2H), 3.80(s, 3H), 6.39(m, 1H), 6.86(m, 1H), 6.88(m, 1H), 7.23(m, 1H), 7.25(m, 1H), 7.35(m, 1H), 7.38(m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=1)[N:7](C(OC(C)(C)C)=O)[CH:6]=[C:5]2[CH:23]1[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[C:25]([CH3:32])([CH3:31])[CH2:24]1.[OH-].[Na+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:23]1[CH2:28][CH2:27][S:26](=[O:29])(=[O:30])[C:25]([CH3:32])([CH3:31])[CH2:24]1
Reactant: CCOC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C(C)(C)C3)cn(C(=O)OC(C)(C)C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CC(c2c[nH]c3c(C(=O)O)cc(Br)cc23)CCS1(=O)=O
Temperature: 80 °C
Yield: 94.5 %

Procedure:
1-(1,1-dimethylethyl) 7-ethyl 5-bromo-3-(2,2-dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-1,7-dicarboxylate (685 mg, 1.296 mmol) was placed in a flask and dissolved in methanol (6 mL) and water (3 mL). An aqueous solution of sodium hydroxide 6N in water (3.24 mL, 19.44 mmol) was added. The mixture was heated in a microwave for 30 mins at 80° C. The mixture was acidified with aqueous HCl 1N until pH=1, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and the solvent removed under vacuum to afford 490 mg of the title compound as a yellow powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][C:14]#[CH:15])[C:9]1=[O:16].[CH2:17]([SnH:21]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1(C)C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13]/[CH:14]=[CH:15]/[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[C:9]1=[O:16]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC[C@H]1C(=O)N(OC2CCCCO2)[C@H]1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: CCCC[Sn](/C=C/C[C@H]1C(=O)N(OC2CCCCO2)[C@H]1C)(CCCC)CCCC
Yield: 86.7 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(2-propyne-1-yl)-4-methylazetidin-2-one (1.32 g, 5.83 mmol) in 20 mL of toluene is added tributyltin hydride (1.70 g, 5.83 mmol) and AIBN (30 mg). The resulting solution is heated at reflux for 4 h then concentrated in vacuo. The reaction mixture is purified by silica gel chromatography (elution with 8:1 hexanes-ethyl acetate) to provide (3R,4S)-1-(2-tetrahydropyranyloxy)-3-((2E)-3-tributylstannyl-2-propene-1-yl)-4-methylazetidin-2-one as an oil (2.6 g, 87% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:18]=[CH2:19])[O:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4].O.[OH-].[Li+]>O1CCCC1.CO.O>[C:14]([O:13][C:11]([N:7]1[CH2:8][CH2:9][O:10][C:5]([CH:18]=[CH2:19])([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=CC1(C(=O)OC)CN(C(=O)OC(C)(C)C)CCO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CC1(C(=O)O)CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A solution of crude 2-vinyl-morpholine-2,4-dicarboxylic acid 4-tert-butyl ester 2-methyl ester (3.284 mmol) in tetrahydrofuran/methanol/water (50 mL, 2:2:1) was treated with lithium hydroxide monohydrate (413.3 mg, 9.852 mmol). After stirring at room temperature for 2 h, the volatiles were removed in vacuo and the residue was cooled to 0° C. and quenched with hydrochloric acid (1 M). The aqueous layer was extracted with dichloromethane (2×). The combined organics were filtered through a phase separator and the volatiles were removed in vacuo to provide the title compound (761.4 mg, 90% over 2 steps) as colorless needles. 1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9H), 3.31-3.42 (m, 1H), 3.45-3.61 (m, 2H), 3.87-3.94 (m, 2H), 4.02 (d, J=13.6 Hz, 1H), 5.44 (d, J=10.7 Hz, 1H), 5.60 (d, J=17.4 Hz, 1H), 5.85 (dd, J=17.4, 10.7 Hz, 1H).
Reaction SMILES: C([O:8]C(N1CCC[C@H]1C(NC(P(OC1C=CC=CC=1)(=O)OC1C=CC=CC=1)CC1C=CC(C#N)=CC=1)=O)=O)C1C=CC=CC=1.Br.N1(C(OCC2C=CC=CC=2)=O)CCC[C@H]1C(O)=O.[CH2:64]1[CH2:69][CH2:68][CH:67]([N:70]=[C:71]=[N:72][CH:73]2[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]2)[CH2:66][CH2:65]1>C(Cl)Cl.C(N(CC)CC)C>[C:71]([NH:70][CH:67]1[CH2:66][CH2:65][CH2:64][CH2:69][CH2:68]1)([NH:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1)=[O:8]
Reactant: N#Cc1ccc(CC(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Br
Agent: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.17 h
Yield: 52 %

Procedure:
Diphenyl 1-(N-Benzyloxycarbonyl-L-prolyl)amino-2-(4-cyanophenyl)ethanephosphonate {Cbz-Pro-(4-CN-Phe)P (OPh)2 }. To a cooled solution of the phosphonate 4-CN-PheP (OPh)2.HBr (0.41 g, 0.9 mmole) and Cbz-Pro-OH (0.25 g, 1.0 mmole) in 20 mL CH2Cl2 was added 0.14 mL triethyl amine. After stirring for 10 min, DCC (0.21 g, 1.0 mmole) was added and the mixture was stirred at 0° C. for 2 h and at r.t. for 24 h. During this period, dicyclohexylurea (DCU) formed, was removed by filtration and the filtrate was evaporated. The residue was dissolved in 50 mL ethyl acetate, filtered, the filtrate was washed with 50 mL 1N HCl, water, 6% NaHCO3, and water. The organic layer was dried, filtered, and evaporated to give crude product which was then recrystallized from ether to give white crystals, yield 52% (0.29 g); mp 131-132° C.; 1H NMR (DMSO) δ 8.75(m, 1H), 7.8-7.2(m, 19H), 5.06 (m, 2H), 4.95 (m, 1H), 4.6 (q, 1H), 4.2 (m, 1H), 3.5-3.1 (m, 3H), 2.0-1.4 (m, 4H); MS (FAB+) m/e 610 (M+1). Anal. (C34H32N3O6P) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH2:19])=[S:18])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21](I)[CH3:22]>>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[NH:19])[S:18][CH2:21][CH3:22])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NC(N)=S)cc1
Product: CCSC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Yield: 85 %

Procedure:
Using the compound obtained in Example 50 as a starting material and also using ethyl iodide as a reagent, the same procedure of Example 29 gave the titled compound (yield, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>>[Cl-:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N+:16]2[CH:17]=[CH:18][N:14]([CH3:13])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: Cn1ccnc1
Reactant: ClCCCCc1ccc(Cl)cc1
Product: Cn1cc[n+](CCCCc2ccc(Cl)cc2)c1
Product: [Cl-]

Procedure:
Combine 6.1 g (0.03 mole) 1-chloro-4-(4-chlorobutyl)benzene with 2.5 g (0.03 mole) 1-methyl-1H-imidazole and heat at 120° C., following the course of the reaction by thin-layer chromatography on silica gel (methanol:1M sodium chloride, 95:5). At the completion of the reaction, cool and triturate with ether, collect the solid and recrystallize from 50 ml hot acetone to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCCCCC.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: Cc1cc(Cl)ccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Br)c(CBr)c1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
20.5 g (100 mmol) of 2-bromo-5-chlorotoluene was dissolved in 200 ml of carbon tetrachloride, 0.2 g (1 mmol) of AIBN and 19.6 g (110 mmol) of N-bromosuccinimide were added thereto, the resulting mixture was refluxed for 2 hours and cooled to room temperature. The reaction mixture was washed with 50 ml of water twice and with 50 ml of a brine solution, dried over anhydrous MgSO4, and distilled under a reduced pressure to obtain an oil containing a small amount of the starting material. The oil was dissolved in 20 ml of hexane, and recrystallized at room temperature to obtain 22.7 g (yield 80%) of 2-bromo-1-bromomethyl-5-chlorobenzene.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[CH2:11][NH:10][CH:9]([C:12]([OH:14])=O)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[O:15]([CH2:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[C:1]([O:5][N:6]=[C:7]1[CH2:11][N:10]([C:23](=[O:24])[CH2:22][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:9]([C:12]([NH:29][CH:26]2[CH2:28][CH2:27]2)=[O:14])[CH2:8]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC(C)(C)ON=C1CNC(C(=O)O)C1
Reactant: NC1CC1
Product: CC(C)(C)ON=C1C[C@@H](C(=O)NC2CC2)N(C(=O)COc2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylic acid, phenoxyacetyl chloride, and cyclopropylamine the title compound was obtained in 73% purity by LC/MS. MS(ESI+): m/z=374.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC.[Br:29]N1C(=O)CCC1=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:29][CH2:18][C:16]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1)=[O:17]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CCC(=O)N1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(CBr)c1cc([N+](=O)[O-])ccn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
Tetrakis(triphenylphosphine) palladium(0) (0.364 g, 0.315 mmol) was added to a solution containing 2-chloro-4-nitropyridine (1 g, 6.31 mmol) and Tributyl(1-ethoxyvinyl)tin (2.149 ml, 6.31 mmol) in Toluene (12.61 ml). In a capped vial, the reaction was heated to 110° C. for overnight. LC/MS verified that the vinyl enolate intermediate formed. The reaction was cooled to room temperature, filtered thru a plug of Celite and the filtrate concentrated. The resulting residue was diluted with THF (20 mL) and water (2 mL). The reaction mixture was cooled to 0° C. and N-Bromosuccinimide (1.347 g, 7.57 mmol) was added. The reaction was stirring for 1 hour and warmed to room temperature. The reaction was diluted with ethyl acetate and washed with water. Separated organics, dried with MgSO4, filtered and concentrated. Purified using combiflash using 0% to 20% ethyl acetate in hexanes to afford 2-bromo-1-(4-nitropyridin-2-yl)ethanone (1.1 g, 4.49 mmol, 71.2% yield) as a light purple oil. 1H NMR (CDCl3) δ: 4.81 (s, 2H), 7.24 (m, 1H), 7.80 (m, 1H), 8.66 (m, 1H).
Reaction SMILES: C([O:9][C@H:10]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:22][C:13]2[C:14]3[CH:15]=[N:16][NH:17][C:18]=3[C:19]([Cl:21])=[CH:20][C:12]=2[CH2:11]1)(=O)C1C=CC=CC=1.C1COCC1.[OH-].[Li+].O>>[Cl:21][C:19]1[C:18]2[NH:17][N:16]=[CH:15][C:14]=2[C:13]2[CH2:22][N:23]([CH2:26][C:27]([F:28])([F:30])[F:29])[C:24](=[O:25])[C@H:10]([OH:9])[CH2:11][C:12]=2[CH:20]=1
Reactant: O=C(O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1[C@H](O)Cc2cc(Cl)c3[nH]ncc3c2CN1CC(F)(F)F
Reaction time: 3 h
Yield: 53 %

Procedure:
(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl benzoate (7.00 g, 16.0 mmol) in THF (60.00 ml, 732 mmol) was added lithium hydroxide (0.766 g, 32.0 mmol) followed by water (6.0 ml, 333 mmol). After 3 h, the solvent was removed and the crude product was diluted with dichloromethane and neutralized with 1.0 M HCl. The organic phase was dried and the crude product was purified by flash chromatography using 70% EtOAc in hexane to give (R)-4-chloro-7-hydroxy-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3 H)-one in 53% yield. 1HNMR (500 MHz, CDCl3): in δ 8.12 (s, 1H), 7.16 (s, 1H), 5.18-5.14 (m, 2H), 4.55 (d, J=17 Hz, 1H), 4.30-4.28 (m, 1H), 4.27-4.24 (m, 1H), 3.86 (m, 1H), 3.46 (dd, J=5 Hz, J=1.5 Hz, 1H), 3.09 (dd, J=5 Hz, J=1.5 Hz, 1H), 1.52 (s, 9H), MS (ESI) 334 (M+H); Rf=1.49.
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:20]=[N:21][N:22]([C:24]3([CH2:28][C:29]#[N:30])[CH2:27][NH:26][CH2:25]3)[CH:23]=2)=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.O=[C:32]1[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.O1CCOCC1>C1COCC1>[F:1][C:2]1[C:3]([C:19]2[CH:20]=[N:21][N:22]([C:24]3([CH2:28][C:29]#[N:30])[CH2:27][N:26]([CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[CH2:25]3)[CH:23]=2)=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)c(F)cnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)c(F)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile.2[HCl] (3.10 g, 5.78 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (1.152 g, 5.784 mmol) and N,N-diisopropylethylamine (3.022 mL, 17.35 mmol) in THF (100.0 mL) was added sodium triacetoxyborohydride (2.452 g, 11.57 mmol). The mixture was stirred at room temperature for 2 hours and quenched with brine. The resulting solution was extracted with EtOAc (2 times). The combined extracts were washed with water, brine and dried over Na2SO4. After filtration and evaporation, the residue was purified by flash chromatography on silica gel eluting with 50-100% EtOAc/hexanes. The purified intermediate ([M+H]+=610.3) was dissolved in THF (50 mL). To the solution at 10° C. was added a 4.0 M solution of hydrogen chloride in 1,4-dioxane (50.0 mL, 200 mmol). The mixture was stirred at room temperature for 2 hours and concentrated to give 3.57 g of {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-piperidin-4-ylazetidin-3-yl}acetonitrile.3[HCl] as an off-white solid. LC/MS found: 510.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6), δ 9.41 (s, 1H), 8.81 (s, 1H), 8.72 (s, 1H), 8.35 (d, 1H), 8.32 (s, 1H), 7.85 (d, 1H), 7.00 (d, 1H), 5.63 (s, 2H), 4.93 (d, 2H), 4.55 (d, 2H), 3.78-3.60 (m, 1H), 3.55 (s, 2H), 3.51 (t, 2H), 3.47-3.37 (m, 2H), 2.79 (m, 2H), 2.11 (m, 2H), 1.80 (m, 2H), 0.81 (t, 2H), −0.12 (s, 9H).