Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][OH:17])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N+](=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N-]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][O:17][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C(c2ccc(Cl)c(Cl)c2)C1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)COCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
Under a nitrogen atmosphere at 80° C., to a solution of tert-butyl (6SR,7RS)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (600 mg) and rhodium acetate dimer (7 mg) in toluene (5 ml) was added dropwise a solution of ethyl diazoacetate (860 mg) in toluene (5 mL) over 10 min. The reaction mixture was stirred at the same temperature for 10 min. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (615 mg).
Reaction SMILES: FC1C=C(C[C@H](C2C([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=CN=C(NCCOC)N=2)NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C=C(F)C=1.Br[C:50]1[C:51]([C@@H:61]([NH:71][C:72](=[O:90])[CH2:73][N:74]2[C:82]3[C:81]([F:84])([F:83])[CH2:80][CH2:79][C:78]([F:86])([F:85])[C:77]=3[C:76]([CH:87]([F:89])[F:88])=[N:75]2)[CH2:62][C:63]2[CH:68]=[C:67]([F:69])[CH:66]=[C:65]([F:70])[CH:64]=2)=[N:52][C:53]([NH:56][CH2:57][CH2:58][O:59][CH3:60])=[N:54][CH:55]=1>>[F:89][CH:87]([F:88])[C:76]1[C:77]2[C:78]([F:86])([F:85])[CH2:79][CH2:80][C:81]([F:84])([F:83])[C:82]=2[N:74]([CH2:73][C:72]([NH:71][C@H:61]([C:51]2[C:50]([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=[CH:55][N:54]=[C:53]([NH:56][CH2:57][CH2:58][O:59][CH3:60])[N:52]=2)[CH2:62][C:63]2[CH:64]=[C:65]([F:70])[CH:66]=[C:67]([F:69])[CH:68]=2)=[O:90])[N:75]=1
Reactant: COCCNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Product: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (12E) was prepared according to the method presented for the synthesis of compound 11J of Example 11 utilizing 12D. 1H NMR (400 MHz, CD3OD) δ 8.80 (d, J=8.0 Hz, 1H), 8.05 (s, 1H), 7.47-7.29 (m, 2H), 7.21 (dd, J=10.7, 8.6 Hz, 1H), 6.97-6.61 (m, 2H), 6.44 (d, J=6.1 Hz, 2H), 5.22 (dd, J=14.9, 7.7 Hz, 1H), 5.05 (s, 2H), 3.89-3.51 (m, 4H), 3.41 (s, 3H), 3.02 (ddd, J=20.2, 13.2, 7.5 Hz, 2H), 2.66-2.28 (m, 4H). MS (m/z) 730.24 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]([NH:15][C@H:16]([C@@H:20]([OH:22])[CH3:21])[C:17]([OH:19])=O)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:14])[NH:15][C@H:16]2[C:17](=[O:19])[O:22][C@H:20]2[CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](O)[C@@H](NC(=O)OCCCCCC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCCCC1CCCCC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 39.6 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2R,3S)-2-(5-cyclohexylpentoxycarbonylamino)-3-hydroxy-butanoic acid (0.32 g, 1.02 mmol) in dry CH2Cl2 (30 mL), Et3N (0.43 mL, 3.08 mmol) and subsequently TBTU (0.39 g, 1.2 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy/AcOEt (from 100:0 to 0:100) to afford the title compound (0.12 g, 39%) as white solid. MS (ESI) m/z: 298 [M−H]+; (ESI) m/z: 296 [M−H]−. 1H NMR: δ 0.78-0.93 (m, 2H), 1.05-1.33 (m, 10H), 1.36 (d, J=6.4 Hz, 3H), 1.51-1.72 (m, 7H), 3.92-4.09 (m, 2H), 4.86 (dq, J=6.3 Hz, 1H), 5.42 (dd, J=6.1, 9.4 Hz, 1H), 8.20 (d, J=9.4 Hz, 1H).
Reaction SMILES: [O:1]1[C:9]2[CH2:8][CH2:7][N:6]([S:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)(=[O:12])=[O:11])[CH2:5][C:4]=2[CH:3]=[CH:2]1.C[O-].[Na+].O>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.CO>[C:16]1([CH:17]=[CH:17][C:16]2[CH:19]=[CH:20][CH:13]=[CH:14][CH:15]=2)[CH:19]=[CH:20][C:13]([S:10]([N:6]2[CH2:7][CH2:8][C:9]3[O:1][CH:2]=[CH:3][C:4]=3[CH2:5]2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(S(=O)(=O)N2CCc3occc3C2)cc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(=O)(c1ccc(C=Cc2ccccc2)cc1)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.377 g (1.294 mmol) of 4-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-ylsulfonyl)benzaldehyde and 0.60 g (1.55 mmol) of benzyltriphenylphosphonium chloride in 30 ml of methanol, 0.30 g (1.55 mmol) of 28% sodium methoxide in methanol was added dropwise at room temperature, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane/ethyl acetate=3/1) to yield 5-(stilbene-4-sulfonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine as a mixture of the (E) and (Z)-isomers.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Br[CH2:14][C:15]1[C:19]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[NH:18][S:17](=[O:25])(=[O:24])[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1>CO>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:16]2[S:17](=[O:25])(=[O:24])[NH:18][C:19]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[C:15]=2[CH2:14][NH:5][CH2:4][CH2:3][F:2])=[CH:31][CH:30]=1
Reactant: NCCF
Reactant: O=S1(=O)NC2(CCCC2)C(CBr)=C1c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=S1(=O)NC2(CCCC2)C(CNCCF)=C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-fluoroethylamine hydrochloride (1.08 g, 10.9 mmol; prepared as described in J. Med. Chem. 9 (1966), 892-911) in 30 mL of absolute MeOH was treated with triethylamine (2.50 mL, 1.76 g, 17.4 mmol) at 0° C. Solid 4-bromomethyl-3-(4-chlorophenyl)-2,2-dioxo-2-thia-1-aza-spiro[4.4]non-3-ene (1.64 g, 4.35 mmol; described during the preparation of Intermediate 6) was added. The resulting mixture was stirred for 16 h at ambient temperature and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol as eluent to yield the title intermediate. Yield: 1.00 g (64%); MS (IS): 359.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])P(OC)(OC)=O.CC1(C)[O:26][C:25](=O)[CH:24]=[C:23]([CH3:28])O1.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]1[C:23]([CH3:28])=[CH:24][C:25](=[O:26])[N:11]1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:19]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COC(=O)C1C(C)=CC(=O)N1C(=O)OC(C)(C)C
Temperature: 23 °C
Yield: 86.2 %

Procedure:
A solution of tert-butoxycarbonylamino-(dimethoxy-phosphoryl)-acetic acid methyl ester (20.0 g, 67 mmol, 1 equiv), 2,2,6-trimethyl-[1,3]dioxin-4-one (43.96 ml, 47.8 g, 336 mmol, 5.0 equiv), and 2,6-lutidine (11.71 ml, 10.77 g, 101 mmol, 1.5 equiv) in toluene (200 ml) was heated at reflux for 16 h. The reaction mixture was allowed to cool to 23° C. and was concentrated. The residue was purified by flash column chromatography (5% ethyl acetate-dichloromethane initially, grading to 8% ethyl acetate-dichloromethane) to give 3-methyl-5-oxo-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (14.74 g, 86%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]([C:17](Cl)=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:22]([O:24][C:25](=[O:27])[NH2:26])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:27])[NH:26][C:17]([CH:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:18])[CH3:23]
Reactant: CCOC(N)=O
Reactant: O=C(Cl)C1c2ccccc2Oc2c1cccc2C(F)(F)F
Product: CCOC(=O)NC(=O)C1c2ccccc2Oc2c1cccc2C(F)(F)F

Procedure:
The title compound, white solid, m.p.=196-198° C., MS: m/e=365 (M+) was prepared in accordance with the general method of example 36 from 4-trifluoromethyl-9H-xanthene-9-carbonyl chloride and carbamic acid ethyl ester.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].C1COCC1.[CH3:12][N:13]1[C:17]([N:18]2[CH2:24][C:23](=O)[CH2:22][C@@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:20][CH2:19]2)=[C:16]([N+:34]([O-:36])=[O:35])[CH:15]=[N:14]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]=[C:23]1[CH2:24][N:18]([C:17]2[N:13]([CH3:12])[N:14]=[CH:15][C:16]=2[N+:34]([O-:36])=[O:35])[CH2:19][CH2:20][C@H:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]1
Reactant: CC(C)(C)[O-]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CC[C@H](NC(=O)OC(C)(C)C)CC(=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C1C[C@@H](NC(=O)OC(C)(C)C)CCN(c2c([N+](=O)[O-])cnn2C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
Methyl triphenylphosphonium bromide (3.09 g, 8.49 mmol) was suspended in toluene (25 mL). Potassium tert-butoxide (1.0 mol/L) in THF (7.07 mL, 7.074 mmol) was added and the mixture turned bright yellow. It was stirred at room temperature for 4 h, then tert-butyl N-[(4S)-1-(2-methyl-4-nitro-pyrazol-3-yl)-6-oxo-azepan-4-yl]carbamate (1000 mg, 2.83 mmol) (second eluting peak in the chiral separation) in 5 mL toluene was added. The mixture was stirred at RT for 30 min, quenched with saturated ammonium chloride, and extracted with EA 3×. The combined organic layers were concentrated and the residue was purified via silica gel column chromatography (0-100% EA/heptane) to give tert-butyl N-[(4R)-6-methylene-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl]carbamate (699 mg, 70%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.Br[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.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:1][C:2]1[N:7]=[C:6]([NH:8][C:19]2[C:20]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=[CH:17][CH:18]=2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Brc1cccc2ccccc12
Reactant: Cc1cnc(Cl)nc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cnc(Cl)nc1Nc1cccc2ccccc12

Procedure:
To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol) in 1,4-dioxane (40 mL) was added 1-bromonaphthalene (227 mg, 1.1 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 183 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1×100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 27, was used for next reaction without further purification.
Reaction SMILES: CC(NC(=O)/C=C/C=[CH:11]/[C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[C:22](Br)Br)=[CH:17][CH:16]=1)C(C)C.C([Li])CCC.[OH2:31]>O1CCCC1>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C@@H:13]2[CH2:14][C@H:12]2[CH2:11][OH:31])=[CH:16][CH:17]=1)#[CH:22]
Reactant: CC(C)C(C)NC(=O)/C=C/C=C/[C@@H]1C[C@H]1c1ccc(C=C(Br)Br)cc1
Reactant: O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1ccc([C@@H]2C[C@H]2CO)cc1

Procedure:
(±)-Trans-2-[4-(2,2-dibromoethenyl)phenyl]cyclopropylmethanol (1.43 g) (prepared as in example 16) in dry tetrahydrofuran under nitrogen at -40° was treated with n-butyllithium (8.1 ml) After 4 hours at 25° water was added and the mixture worked up in the usual manner. Purification by chromatography (silica ether/hexane) gave (±)-trans-2-(4-ethynylphenyl)cyclopropane methanol (0.62 g). NMR 1H: 7.41(2H,d), 6.90(2H,d), 3.30(2H,d), 2.95(1H,s), 2.59(1H,s), 1.85(1H,m), 1.34(1H,m), 0.90(2H,m).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][Si:11]([CH3:17])([CH3:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[CH3:17][Si:11]([CH3:16])([O:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1)[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1

Procedure:
A solution of 1-nitro4-(1,1,2,2-tetramethyl-1-silapropoxy)benzene (7.8 g, 30.8 mmol) (from Example 19a supra) and 10% Pd/C (0.70 g) (Aldrich) in ethyl acetate (100 mL) was hydrogenated for 1 day. The reaction mixture was filtered though Celite® and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate/hexanes (1:9 V/N)) to afford 4-(1,1,2,2-tetramethyl-1-silapropoxy)phenylamine. (Yield 6.7 g, 97%).
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.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[C:17]=1[CH:18]=[O:19].N(CC(O)=O)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([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)[C:17]=1[CH:18]=[O:19]
Reactant: O=c1[nH]ncc2c3c(sc12)CCCC3
Reactant: O=Cc1c(Br)cccc1Br
Agent: CNCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=Cc1c(Br)cccc1-n1ncc2c3c(sc2c1=O)CCCC3
Temperature: 100 °C
Yield: 60.1 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (20 mL), 8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-6-one 117c (618 mg, 3.0 mmol), 2,6-dibromobenzaldehyde (1980 mg, 7.5 mmol), CuBr (215 mg, 1.5 mmol), sarcosine (267 mg, 3.0 mmol), and K2CO3 (828 mg, 6.0 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 16 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 130a (702 mg, 60%) as a yellow solid. MS: [M+H]+ 389.0
Reaction SMILES: [N+](=[CH:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N-].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([OH:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1>CCOCC>[O:14]=[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][O:25][S:22]([C:19]1[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Reactant: CCCCCCCCCC(=O)C=[N+]=[N-]
Solvent: CCOCC
Product: CCCCCCCCCC(=O)COS(=O)(=O)c1ccc(Cl)cc1
Yield: 75.3 %

Procedure:
A 1.2 g quantity of 1-diazo-2-undecanone is dissolved in 50 ml of ether, and 1.6 g of p-chlorobenzenesulfonic acid is slowly added to the solution at room temperature. The mixture is stirred until no nitrogen is evolved. The reaction mixture is washed with water, and the ethereal layer is dried over anhydrous sodium sulfate and distilled in a vacuum to remove the solvent. The residue is recrystallized from ether/petroleum ether to give 1.62 g of 2-oxoundecyl-p-chlorobenzene sulfonate (Compound 68), m.p. 51° to 51.5° C. Yield 75.3%.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[C:7]1[CH2:17][OH:18].[CH3:19]I.[Cl-].[NH4+]>O1CCCC1>[CH3:3][O:4][CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[C:7]1[CH2:17][O:18][CH3:19]
Reactant: CI
Reactant: COCn1cc(-c2ccccc2)cc1CO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCc1cc(-c2ccccc2)cn1COC
Reaction time: 0.25 h
Yield: 62.4 %

Procedure:
Sodium hydride (400 mg 1.83 mmol, 60%) was added to a solution of (1-methoxymethyl-4-phenyl-1H-pyrrol-2-yl)-methanol (420 mg, 2.08 mmol) in tetrahydrofuran (15 mL) at 0° C. and stirred for a further 15 min. Methyl iodide (517 mg, 3.66 mmol) was added and the reaction mixture stirred for 12 h. The mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1,2-bis(methoxymethyl)-4-phenyl-pyrrole (300 mg, 72%) as a brown liquid.
Reaction SMILES: Cl[Sn]Cl.[CH2:4]([O:6][C:7]([N:9]1[C:13]2[CH2:14][N:15]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)(=[O:19])=[O:18])[CH2:16][C:12]=2[C:11]([NH:27][C:28](=[O:45])[C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[C:31]([N+:42]([O-])=O)[CH:30]=2)=[N:10]1)=[O:8])[CH3:5]>C(O)C.Cl>[CH2:4]([O:6][C:7]([N:9]1[C:13]2[CH2:14][N:15]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)(=[O:19])=[O:18])[CH2:16][C:12]=2[C:11]([NH:27][C:28](=[O:45])[C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[C:31]([NH2:42])[CH:30]=2)=[N:10]1)=[O:8])[CH3:5]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCN(C)CC3)c([N+](=O)[O-])c2)c2c1CN(S(=O)(=O)c1cccc(F)c1)C2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCN(C)CC3)c(N)c2)c2c1CN(S(=O)(=O)c1cccc(F)c1)C2
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a solution of 360 mg (1.91 mmol, 5 eq.) of SnCl2 in 3 mL of ethanol at 60° C. were added a solution of 230 mg (0.39 mmol) of 5-(3-fluoro-benzenesulfonyl)-3-[4-(4-methyl-piperazin-1-yl)-3-nitro-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester in 2 mL of ethanol and 2 mL of concentrated hydrochloric acid. After 2 hours, the solvent was removed under reduced pressure, the residue was treated with saturated sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic phase dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by flash column chromatography, using dichloromethane-methanol 9:1 as eluant, to give 120 mg (54% yield) of 3-[3-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3-fluoro-benzenesulfonyl)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:8][C:9]1[CH:15]=[C:14]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:12][C:10]=1[NH2:11])=[O:5])[CH3:2].[Cl:30][C:31]1[CH:32]=[C:33]2[CH2:45][CH2:44][C@@H:43]([CH2:46][C:47](O)=[O:48])[N:35]3[C:36](=[O:42])[C:37](=[O:41])[NH:38][C:39]([CH:40]=1)=[C:34]23>C(O)(=O)C.C(OCC)(=O)C>[Cl:30][C:31]1[CH:32]=[C:33]2[CH2:45][CH2:44][C@@H:43]([CH2:46][C:47](=[O:48])[NH:11][C:10]3[CH:12]=[CH:13][C:14]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:15][C:9]=3[CH2:8][CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:35]3[C:36](=[O:42])[C:37](=[O:41])[NH:38][C:39]([CH:40]=1)=[C:34]23
Reactant: CCOC(=O)C(CCc1cc(CNC(=O)OC(C)(C)C)ccc1N)C(=O)OCC
Reactant: O=C(O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23)C(=O)OCC
Yield: 78.3 %

Procedure:
A procedure similar to that described in Example 18-6) was performed with 2-(3,3-diethoxycarbonylpropyl)-4-tert-butoxycarbonylaminomethylaniline (559 mg, 1.37 mmol) and (S)-9-chloro-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (445 mg, 1.51 mmol) to give 735 mg of the title compound after silica gel column chromatography with 0.3% acetic acid/ethyl acetate (78%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[NH2:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl.CO>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:26][NH:25][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: NNc1cccnc1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNc1cccnc1
Yield: 6.4 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) and 3-hydrazinopyridine (0.077 g, 1.0 eq.) in EtOAc (10 mL). T3P (50% in EtOAc; 0.52 g, 1.2 eq.) and DIPEA (0.27 g, 2.0 eq.) were added under nitrogen atmosphere at −55 to −60° C. The progress of the reaction was followed by TLC analysis using 10% MeOH:CH2Cl2 as mobile phase and visualization under UV light. The reaction mixture was concentrated under reduced pressure (25° C., 20 mmHg) to afford 0.475 g of a crude solid. Purification was performed using Combi-Flash Column chromatography (with MeOH:CH2Cl2). The desired compound started eluting at 2.3% MeOH in CH2Cl2. The fractions containing the compound were combined and concentrated under reduced pressure (35° C., 20 mmHg) to afford 20.0 mg (yield: 6%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyridin-3-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.66 (s, 1H), 8.53 (s, 2H), 8.28 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.93-7.95 (m, 1H), 7.52-7.54 (d, J=10.4 Hz, 1H), 7.09-7.15 (m, 2H), 6.04-6.07 (d, J=10.4 Hz, 1H), LCMS for C18H13F6N6O [M+H]+ 443.33 found 443.19 (RT 2.19 min, purity: 99.60%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1)C.O.[NH2:17][NH2:18]>C(O)C>[NH:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[CH2:5][C:4]([NH:17][NH2:18])=[O:3]
Reactant: NN
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Solvent: CCO
Solvent: O
Product: NNC(=O)Cc1nc2ccccc2[nH]1
Yield: 76 %

Procedure:
15 g 1H-benzo[d]imidazole-2-acetic acid ethyl ester (0.074 mol), 100 mL anhydrous ethyl alcohol and 37 mL of 80% hydrazine hydrate were added to a three-necked bottle and reacted under reflux for 4 hours. A white solid was isolated. After sucking filtration, the filter cake was washed with ethanol. After drying, 10.7 g white solid was obtained. Yield: 76%, MS: 191(M+1).