Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[I:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[I:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:19][CH:18]=1
Reactant: Oc1ccc(I)cc1
Reactant: COC(=O)CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCCCCCCCCCOc1ccc(I)cc1
Yield: 81.6 %

Procedure:
Methyl 11-bromoundecanoate (10 g, 35.8 mmmol), in acetone (150 ml) was treated with 4-iodophenol (7.88 g, 35.8 mmol) and potassium carbonate (9.88 g 71.6 mmol). The stirred reaction was heated at reflux for 48 h. The reaction was then allowed to cool and the reaction concentrated in vacuo to a gum. The reaction was then partitioned between ethyl acetate (150 ml) and water (150 ml). The ethyl acetate layer was separated dried, over sodium sulfate and concentrated in vacuo to solid. The solid was dissolved in diethyl ether (100 ml) and petroleum ether 60-80 C (100 ml) added. The solution was concentrated in vacuum to a volume of 100 ml. The solution was set aside and allowed to crystallise. The product was collected by filtration and dried in vacuum to give 12.22 g of solid. The mother liquors were concentrated to ˜20 ml and allowed to crystallise. A further 0.81 g of solid was collected by filtration. The two solids were combined to give the desired product (13.03 g, 86%) δH (CDCl3) 1.29-1.78 (16H, m, 3,4,5,6,7,8,9,10-CH2), 2.30 (2H, t, 2-CH2), 3.86 (3H, s, CO2CH3), 3.90 (2H, t, 11-CH2), 6.66 (2H, dd, 2,6-ArH), 7.53 (2H, dd, 3,5-ArH), δC(CDCl3) 24.90, 25.93, 29.09, 29.18, 29.30, 29.42, 34.07, 51.42, 68.06, 82.35, 116.90, 138.11, 158.98, and 174.33.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:5][C:3]=1[NH2:4].[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[N:30]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:4][C:3]2[CH:5]=[C:6]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][N:11]=3)[CH:7]=[CH:8][C:2]=2[Cl:1])=[O:35])[N:30]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Reactant: COc1cc2ncnc(Oc3ccc(Cl)c(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3ccc(Cl)c(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c3)c2cc1OC
Yield: 46.7 %

Procedure:
The title compound was prepared from 2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)aniline (100 mg, 0.3 mmol) and phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (140 mg, 0.4 mmol) using the procedure in Example 115C to give 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (80 mg, 0.14 mmol, 46%). 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.82 (s, 1H), 8.56 (s, 1H), 8.12 (d, 1H), 7.57-7.54 (m, 2H), 7.40-7.33 (m, 5H), 7.03 (dd, 1H), 6.34 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 2.37 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 587 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[N:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[CH3:13][O:11][C:10]([C:5]1[C:4]2[CH:3]=[N:2][NH:1][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cccc2[nH]ncc12
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cccc2[nH]ncc12
Temperature: 25 °C

Procedure:
Indazole-4-carboxylic acid (2.00 g, 12.3 mmol) was suspended in methanol (20 mL) and toluene (30 mL) at room temperature. A solution of 2 M trimethylsilyl diazomethane (12 mL, 24 mmol) in toluene was added slowly and the mixture was stirred at room temperature until the solution turned yellow. The reaction was quenched with concentrated acetic acid (5 mL) and the solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes to afford 1H-indazole-4-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[CH2:16]1[C:19]2([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][O:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:22]2[CH2:23][CH2:24][C:19]3([CH2:16][O:17][CH2:18]3)[CH2:20][CH2:21]2)=[O:15])=[CH:4][N:3]=1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Reactant: C1CC2(CCN1)COC2
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCC4(CC3)COC4)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 2-oxa-7-azaspiro[3.5]nonane by following the similar procedure as described for intermediate-11a.
Reaction SMILES: Cl.CN.C1COCC1.[CH:9]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)([CH3:11])[CH3:10].[C:19]([BH3-])#[N:20].[Na+]>C(O)(=O)C.C(O)C>[CH:9]([N:12]1[CH2:17][CH2:16][CH:15]([NH:20][CH3:19])[CH2:14][CH2:13]1)([CH3:11])[CH3:10]
Reactant: CC(C)N1CCC(=O)CC1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC1CCN(C(C)C)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a stirred mixture of methylamine hydrochloride (2.62 g, 38.8 mmol), THF (30 ml), ethanol (15 ml), N-isopropyl-4-piperidinone (3.0 ml, 20.2 mmol), and acetic acid (3.60 ml) was added sodium cyanoborohydride (30 ml, 1 molar solution in THF, 30 mmol), and the mixture was stirred at 60° C. for 6 hours and then at room temperature overnight. The mixture was concentrated under reduced pressure, water (50 ml) and potassium carbonate (47.0 g) were added, and the mixture was extracted with ethyl acetate (6×50 ml). The combined extracts were dried over magnesium sulphate and concentrated, to yield 3.78 g (quant.) of the title compound as an oil, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH2:15][CH2:16][O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[N:21]=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][C:3]=1[C@H:30]([NH:35][S@@](C(C)(C)C)=O)[C:31]([F:34])([F:33])[F:32].Cl>CO>[NH2:35][C@@H:30]([C:3]1[CH:4]=[CH:5][C:6]([C:8]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH2:15][CH2:16][O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[N:21]=[CH:20][CH:19]=3)[N:9]=2)=[CH:7][C:2]=1[Cl:1])[C:31]([F:33])([F:32])[F:34]
Reactant: COc1ccc2c(OCCn3nc(-c4ccc([C@H](N[S@](=O)C(C)(C)C)C(F)(F)F)c(Cl)c4)ccc3=O)ccnc2c1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(OCCn3nc(-c4ccc([C@H](N)C(F)(F)F)c(Cl)c4)ccc3=O)ccnc2c1

Procedure:
A solution of (R)—N—((S)-1-(2-chloro-4-(1-(2-(7-methoxyquinolin-4-yloxy)ethyl)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (170 mg, 279 μmol) in MeOH (4 mL) was stirred with 5 N HCl (4 mL) at 23° C. for 18 hours. The solvents were then largely removed under reduced pressure and residue partitioned between 9:1 CHCl3/IPA (20 mL) and aqueous pH adjusted to 14 with NaOH (5 M, 4 mL). The aqueous layer was further extracted with 9:1 CHCl3/IPA (2×10 mL). The combined organics were then dried over MgSO4, concentrated, and purified on silica (12 g) eluting with 0>5% NH3 in MeOH (2 M)/DCM. Product was isolated as a white fluffy solid from lyophilized 50% ACN/water. MS (ESI pos. ion) m/z: 506 (MH+); calc'd for C24H20ClF3N4O3: 505. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.93 (s, 3 H) 4.74 (t, J=4.27 Hz, 2 H) 4.92 (t, J=4.52 Hz, 2 H) 5.18 (q, J=7.36 Hz, 1 H) 7.14 (d, J=10.04 Hz, 1 H) 7.21-7.28 (m, 1 H) 7.40 (d, J=6.53 Hz, 1 H) 7.49 (s, 1 H) 7.87-7.96 (m, 3 H) 8.05 (d, J=9.03 Hz, 1 H) 8.14 (d, J=10.04 Hz, 1 H) 8.97 (d, J=6.02 Hz, 1 H). 13C NMR (101 MHz, DMSO-d6) δ ppm 48.21, 54.49, 66.32, 99.81, 113.27, 118.38, 122.46, 123.30, 124.68, 128.27, 128.39, 129.30, 132.34, 134.84, 140.24, 145.85, 157.66, 161.35 19F NMR (376 MHz, DMSO-d6) δ ppm −73.63 (s, 3 F).
Reaction SMILES: [Br:1]C1CC2C(=CC=CC=2F)C1=O.[Cl:13][C:14]1[C:22]([Cl:23])=[C:21]2[C:17]([CH2:18][CH2:19][C:20]2=[O:24])=[CH:16][CH:15]=1>[Cu](Br)Br.O1CCOCC1>[Br:1][CH:19]1[CH2:18][C:17]2[C:21](=[C:22]([Cl:23])[C:14]([Cl:13])=[CH:15][CH:16]=2)[C:20]1=[O:24]
Reactant: O=C1CCc2ccc(Cl)c(Cl)c21
Reactant: O=C1c2cccc(F)c2CC1Br
Agent: Br[Cu]Br
Solvent: C1COCCO1
Product: O=C1c2c(ccc(Cl)c2Cl)CC1Br

Procedure:
The 2-bromo-6,7-dichloro-1-indanone is prepared as in Example 14 for the preparation of 2-bromo-4-fluoro-1-indanone but starting with 7.42 g of 6,7-dichloro-1-indanone, 21.8 g of copper bromide and 240 ml of dioxane. After purification by silica column chromatography with an ethyl acetate-cyclohexane mixture (10-90 by volume) as eluent, 6.79 g of 2-bromo-6,7-dichloro-1-indanone are obtained which melt at 103° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:19][CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[C:15]([F:14])([F:24])[F:25])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1ccccc1C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccc3C(F)(F)F)ccc12
Yield: 5.1 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (100 mg, 0.385 mmol), 2-(trifluoromethyl)benzylamine (0.31 mL, 0.424 mmol), Pd2(dba)3 (35 mg, 0.0385 mmol), rac-BINAP (81 mg, 0.120 mmol) and NaOt-Bu (92 mg, 0.963 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2-trifluoromethyl-benzylamino)-2H-phthalazin-1-one (7 mg) as a white solid, 1H (400 MHz, CDCl3) δ: 4.63 (s, 2H), 6.84 (d, 1H), 6.97 (m, 1H), 7.35 (m, 1H), 7.43 (d, 1H), 7.47 (t, 2H), 8.09 (d, 1H), 10.15 (s, 1H) ppm. m/z (M+1) 353.97.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1([CH3:32])[CH2:10][CH2:9][CH:8]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:7]1([CH3:31])[CH3:30].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[C:14]([SiH2:13][O:12][C:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:8]1[CH2:9][CH2:10][C:6]([CH:5]=[CH:4][CH2:3][OH:2])([CH3:32])[C:7]1([CH3:31])[CH3:30])([CH3:15])([CH3:16])[CH3:17]
Reactant: COC(=O)C=CC1(C)CCC(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)C1(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C1CCC(C)(C=CCO)C1(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Intermediate (5) (11.12 g, 23.92 mmol) in CH2Cl2 (150 mL ) at −78° C. was added dropwise diisobutylaluminium hydride (1.5 M solution in toluene; 63.8 mL, 95.67 mmol) over a period of 30 minutes. After stirring at −78° C. for 2 hours, the reaction mixture was allowed to warm to −55° C. over a period of 2 hours and the reaction was quenched by the addition of a 2 N K-Na-tartrate solution (100 mL). H2O (400 mL) was added and the aqueous layer was extracted with Et2O (4×150 mL). The combined organic layers were dried over anhydrous MgSO4, the solvent removed in vacuo and the resulting residue was purified over silica (n-hexane/ethyl acetate, 85:15) to afford 10.34 g (99% yield) of the desired intermediate (6) as a colourless oil which was characterized as follows:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[CH:9]=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH3:16][O:17][CH:18]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:9]=[C:18](\[O:17][CH3:16])/[C:19]([O:21][CH3:22])=[O:20])[CH:11]=[CH:12][C:13]=1[OH:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(C=O)ccc1O
Reactant: COC(=O)C(OC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOc1cc(/C=C(\OC)C(=O)OC)ccc1O
Temperature: 40 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
4.0 g (20.6 mmol) of 3-butoxy-4-hydroxybenzaldehyde and 13.25 g (30.9 mmol) of (methoxy(methoxycarbonyl)methyl)triphenylphosphonium chloride are suspended in 40 ml of tetrahydrofuran. 6 ml (42 mmol) of triethylamine are added and then the reaction medium is stirred at 40° C. for 16 hours. The reaction medium is filtered and then the solvents are evaporated. 50 ml of diethyl ether are added and the mixture is stirred at ambient temperature for 10 minutes and then filtered. After evaporation of the solvents, the residue is taken up in a heptane/ethyl acetate 8/2 mixture and then filtered through a silica patch (2 cm). 5.3 g of methyl (Z)-3-(3-butoxy-4-hydroxyphenyl)-2-methoxyacrylate are obtained after evaporation of the solvents.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([NH2:40])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and (S)-3-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH2:13][CH2:12][N:11]([CH:14]([C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=2)=[O:34])[S:15][C@H:16]2[N:19]([CH2:20]O)[C:18](=[O:22])[C@H:17]2[NH:23][C:24](=[O:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]1=[O:46])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.S(Cl)(Cl)=O>O1CCCC1>[CH:1](=[N:8][N:9]1[CH2:13][CH2:12][N:11]([C@@:14]2([C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[S:15][C@H:16]3[N:19]([C:18](=[O:22])[C@H:17]3[NH:23][C:24](=[O:32])[CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:20]2)[C:10]1=[O:46])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N(CO)[C@@H]1SC(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(N=Cc2ccccc2)C1=O
Solvent: O=S(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
In 420 ml of anhydrous tetrahydrofuran was dissolved 30.00 g of (3R,4R)-4-[1-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-1-(p-nitrobenzyloxycarbonyl)methylthio]-1-hydroxymethyl-3-phenylacetamidoazetidin-2-one. To the solution were added, with ice cooling, 6.72 ml of 2,6-lutidine and 3.95 ml of thionyl chloride in this order. The mixture was stirred at room temperature for 10 minutes. The insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 600 ml of anhydrous tetrahydrofuran. To the solution was added 13.6 ml of N,O-bis(trimethylsilyl)acetamide. The mixture was stirred at room temperature for 15 minutes and cooled to -60° C. To the reaction mixture were added, at -40° C. or below, 40.4 ml of hexamethylphosphoric triamide and 69.6 ml of tetrahydrofuran solution containing lithium bis(trimethylsilyl)amide (0.8 mmol/ml), in this order. The temperature of the mixture was elevated to -15° C. in 1 hour. To the reaction mixture was added 3.16 ml of acetic acid while maintaining the temperature at -15° C. The mixture was added to a mixed solvent consisting of 500 ml of water and 500 ml of ethyl acetate. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with diluted hydrochloric acid of pH 2.0, mixed with 200 ml of water, and adjusted to pH 7.0 with an aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: n-hexane/ethyl acetate=1/1 to 2/1) to obtain 13.32 g (yield: 45.7%) of (3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamido-4-thia- 1-azabicyclo[3.2.0]heptane.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[NH:11]([C:13]1[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)[NH2:12]>CN1C(=O)CCC1>[I:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]2[N:11]([C:13]3[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=3)[N:12]=[CH:4][C:3]=12
Reactant: NNc1cccc(S(N)(=O)=O)c1
Reactant: O=Cc1c(I)ccnc1F
Solvent: CN1CCCC1=O
Product: NS(=O)(=O)c1cccc(-n2ncc3c(I)ccnc32)c1
Temperature: 185 °C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
To a 45 mL pressure bottle was added 2-fluoro-4-iodonicotinaldehyde (1.05 g, 4.18 mmol), 3-hydrazinylbenzenesulfonamide (800 mg, 4.27 mmol), and anhydrous NMP (15 mL). The reaction mixture was flushed with argon, securely capped, and heated at 185° C. for 6.5 h. The reaction mixture was cooled to room temperature and slowly added to a rapidly stirred solution of diethyl ether (430 mL). The resulting solid material was filtered and the pale yellow Et2O filtrate was allowed to stand for 18 h at room temperature. The yellow crystals precipitated out and were collected by vacuum filtration to give 425 mg (16.42%) of the title compound as a yellow solid as a “dot” 2 NMP complex by proton NMR. LC/MS (Condition B): ret. T=3.2 min, (M+H)+ 400.83. 1H NMR (500 MHz, DMSO-d6) δ 7.56 (s, 2 H) 7.78-7.84 (m, 2 H) 7.89-7.92 (m, 1 H) 8.37-8.42 (m, 2 H) 8.57 (dt, J=4.81, 2.33 Hz, 1 H) 8.75 (s, 1 H). Second and third crops of yellow solid (300 mg, 11.7%; 246 mg, 9.4%) were identical to the first crop of material.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([C:13]1[N:14]=[CH:15][N:16]2[C:21](=[O:22])[N:20]([CH3:23])[N:19]=[N:18][C:17]=12)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:23][N:20]1[C:21](=[O:22])[N:16]2[CH:15]=[N:14][C:13]([C:11]3[O:12][C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][N:10]=3)=[C:17]2[N:18]=[N:19]1
Reactant: Cn1nnc2c(C(=O)NNC(=O)c3ccccc3)ncn2c1=O
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1nnc2c(-c3nnc(-c4ccccc4)o3)ncn2c1=O

Procedure:
N′-Benzoyl-3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbohydrazide (0.03 mmol), carbon tetrabromide (0.06 mmol) and triphenylphosphine (0.06 mmol) were stirred in DCM (0.5 mL) for 3 hours. The crude reaction mixture was purified by column chromatography, eluting with 10% MeCN/DCM, to give the title compound. δH (DMSO-d6) 9.06 (1H, s), 8.11 (2H, m), 7.67 (3H, m), 3.93 (3H, s).
Reaction SMILES: [C:1]12[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=1[S:8][C:7]1[C:6](=[O:14])[NH:5][N:4]=[CH:3][C:2]2=1.[C:15]([O:18][CH2:19][C:20]1[C:25]([Br:26])=[CH:24][C:23]([F:27])=[CH:22][C:21]=1Br)(=[O:17])[CH3:16].CNCCNC.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I.O1CCOCC1>[C:15]([O:18][CH2:19][C:20]1[C:21]([N:5]2[C:6](=[O:14])[C:7]3[S:8][C:9]4[CH2:10][CH2:11][CH2:12][CH2:13][C:1]=4[C:2]=3[CH:3]=[N:4]2)=[CH:22][C:23]([F:27])=[CH:24][C:25]=1[Br:26])(=[O:17])[CH3:16]
Reactant: O=c1[nH]ncc2c3c(sc12)CCCC3
Reactant: CC(=O)OCc1c(Br)cc(F)cc1Br
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)OCc1c(Br)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Temperature: 100 °C
Yield: 20 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-6-one (1 g, 4.85 mmol), 2,6-dibromo-4-fluorobenzyl acetate 197c (4.8 g, 14.6 mmol), copper(I) iodide (553 mg, 2.9 mmol), N1,N2-dimethylethane-1,2-diamine (512 mg, 5.82 mmol), Cs2CO3 (3.2 g, 9.7 mmol), and 1,4-dioxane (50 mL). The system was evacuated and then refilled with N2. A reflux condenser was attached to the flask, and the reaction mixture was heated at 100° C. for 16 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 5:1 petroleum ether/ethyl acetate to afford 341a as a yellow solid (437 mg, 20%). MS: [M+H]+ 451.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:19]([NH:21][N:22]([CH2:33][C@@H:34]([CH3:37])[CH2:35][CH3:36])S(C1C=CC(C)=CC=1)(=O)=O)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Mg]>>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:38][CH:39]([CH3:40])[CH3:41])[C:19]([NH:21][NH:22][CH2:33][C@@H:34]([CH3:37])[CH2:35][CH3:36])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC[C@H](C)CN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C)cc1
Agent: [Mg]
Product: CC[C@H](C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
A mixture of 0.325 g of (E)-2(R)-[1(S)-(tert.-butoxycarbonyl)-4-phenyl-3-butenyl)-4-methyl-2′-(2(S)-methylbutyl)-2′-(p-toluenesulphonyl)valerohydrazide and 0.135 g of magnesium powder was placed in a sonic bath for 1.5 hours. The methanol was evaporated and the residue was partitioned between diethyl ether and potassium hydrogen sulphate solution. The ethereal layer was washed in sequence with potassium hydrogen sulphate solution, 5% sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (5:1) for the elution. There was obtained 0.146 g of (E)-2(R)-[1(S)-(tert.-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-2′-(2(S)-methylbutyl)valerohydrazide in the form of a white solid.