Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:6]([CH3:33])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[O:22][C:23]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=4[C:25]=3[CH3:26])=[O:20])=[CH:14][C:13]=2[F:32])[C:9]=1[CH3:10].[OH-].[Na+].Cl>O1CCOCC1.O.O>[F:32][C:13]1[CH:14]=[C:15]([NH:18][C:19]([C:21]2[O:22][C:23]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=3[C:25]=2[CH3:26])=[O:20])[CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:9]([CH3:10])=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:6]([CH3:33])=[N:7]1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(NC(=O)c3oc4ccc(F)cc4c3C)cc2F)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(Cc2ccc(NC(=O)c3oc4ccc(F)cc4c3C)cc2F)c(C)c1CC(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To a solution of 5-fluoro-3-methyl-1-benzofuran-2-carboxylic acid (194 mg, 1 mmol) in 5 mL dimethylformamide is added diisopropylethylamine (0.516 mL, 3 mmol) and HATU (399 mg, 1.05 mmol) is added. After stirring at room temperature for 25 minutes dimethylformamide (1 mL) and then intermediate [1-(4-amino-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester (291 mg, 1 mmol) is added. Subsequently diisopropylethylamine (0.344 mL, 2 mmol) and dimethylformamide (2 mL) is added, and the mixture is stirred at room temperature for 48 hours. Then ethyl acetate and water are added and the precipitate is filtered off. The organic layer is extracted twice with acetic acid (1 N), once with an aqueous solution of NaHCO3 (5% by weight) and twice with water, dried over MgSO4. The solvent is removed by evaporation in vacuo. The residue is purified by MPLC (dichloromethane/methanol 96:4) to yield 120 mg of (1-(2-fluoro-4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+=468; TLC: Rf=0.72 (dichloromethane/methanol 9:1, silicagel 60 F254)). b) To a solution of (1-(2-fluoro-4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)-amino]-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (119 mg, 0.26 mmol) in dioxane/water (7 mL/7 mL) is added an aqueous solution of NaOH (1 M, 2.3 mL) and the mixture is stirred at room temperature for 12 hours and at 60° C. for 2 hours. The mixture is diluted with water, acidified with hydrochloric acid (1 M, 1 mL) and extracted with ethyl acetate. The organic layer is dried over MgSO4, the solvent evaporated in vacuo, the residue is crystallized with diisopropyl ether and the precipitate is isolated by filtration to yield 69 mg of the title compound (ESI mass spectrum: [M+H]+=454; Retention time HPLC: 0.90 min (method D)).
Reaction SMILES: S([C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[CH:13][CH:12]=1)(C1C=CC(C)=CC=1)(=O)=O.[CH:37]([NH2:40])([CH3:39])[CH3:38]>>[CH:37]([NH:40][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:28])=[O:29])=[CH:13][CH:12]=1)([CH3:39])[CH3:38]
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)c2ccc(S(=O)(=O)c3ccc(C)cc3)c3c2C(=O)c2ccccc2C3=O)cc1
Product: Cc1ccc(S(=O)(=O)c2ccc(NC(C)C)c3c2C(=O)c2ccccc2C3=O)cc1
Yield: 76 %

Procedure:
1-(isopropylamino)-4-tosylanthraquinone was prepared by reaction of 1,4-ditosylanthraquinone with isopropyl amine. The isolated and purified reaction product has the structure illustrated below (where "Ts" is ##STR9## The yield was 76% and the m.p. 164°-165.5° C.; mass spec m/e 435 (M+), 420 (M-CH3), 280 (M-C7H7SO2), 238(280-C3H7 +H), 210 (238-CO), 182 (210-CO), 155 (C7H7SO2), 91 (C7H7); 1H-NMR (CD2Cl2)δ9.97 (br s, 1H), 8.19-8.10 (m, 2H), 7.85-7.67 (m, 4H), 7.27-6.97 (m, 4H), 4.02-3.68 (m, 1H), 2.30 (s, 3H), 1.38, 1.31 (d, 6H); IR (Nujol) 1180 cm-1 (symmetrical SO2 stretch), 890 cm-1, 860, 820, 780 (S--O--C stretch); UV/VIS max (Xylenes) 500 nm (ε6660).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[N:10]=[C:9]([C:11](OC)=[O:12])[CH:8]=[CH:7][CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:15][N:2]([CH2:3][C:5]1[N:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=1)[CH3:1]
Reactant: COC(=O)c1cccc(C(=O)N(C)C)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(CO)n1
Reaction time: 8 h
Yield: 32.1 %

Procedure:
A solution of 6-(N,N-dimethylcarbamyl-2-carbomethoxypyridine (20.3 g; 97.5 mmoles) [prepared in Step A] in 200 ml of tetrahydrofuran was added to a suspension of lithium aluminum hydride (9.6 g; 0.25 moles) in 500 ml of tetrahydrofuran. The mixture was stirred and heated at reflux temperature under a nitrogen atmosphere for 3 hours then left at ambient temperature overnight. The mixture was decomposed with a saturated aqueous solution of Na2SO4, filtered, dried and evaporated under reduced pressure. The residue was placed on 275 g of aluminum oxide and eluted with methylene chloride. The appropriate fractions were combined and evaporated to give 5.2 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[N:12][O:13][CH2:14][C:15]([OH:17])=O)[CH2:7][CH:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:5][C:4]=2[N:3]=1.S(Cl)(Cl)=O.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C(Cl)Cl>[N:34]1([C:15](=[O:17])[CH2:14][O:13][N:12]=[C:8]2[CH2:7][CH:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:5][C:4]3[N:3]=[C:2]([NH2:1])[N:11]=[CH:10][C:9]2=3)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: C1COCCN1
Reactant: Nc1ncc2c(n1)CC(c1ccccc1-c1ccccc1)CC2=NOCC(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Nc1ncc2c(n1)CC(c1ccccc1-c1ccccc1)CC2=NOCC(=O)N1CCOCC1

Procedure:
The title compound was prepared from (2-amino-7-biphenyl-2-yl-7,8-dihydro-6H-quinazolin-5-ylideneaminooxy)-acetic acid (compound 54) by treating with thionyl chloride followed by amidation using morpholine and triethylamine in DCM.
Reaction SMILES: C(Br)(=O)C.[CH:5]1([C:8]2[C:9]([C:18]([C:20]3[CH:21]=[C:22]([CH:25]=[C:26]([CH3:28])[CH:27]=3)[C:23]#[N:24])=[O:19])=[N:10][C:11]([O:16]C)=[N:12][C:13]=2[O:14]C)[CH2:7][CH2:6]1>>[CH:5]1([C:8]2[C:13](=[O:14])[NH:12][C:11](=[O:16])[NH:10][C:9]=2[C:18]([C:20]2[CH:21]=[C:22]([CH:25]=[C:26]([CH3:28])[CH:27]=2)[C:23]#[N:24])=[O:19])[CH2:7][CH2:6]1
Reactant: COc1nc(OC)c(C2CC2)c(C(=O)c2cc(C)cc(C#N)c2)n1
Agent: CC(=O)Br
Product: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C2CC2)c1
Temperature: 60 °C
Yield: 77.6 %

Procedure:
Acetyl bromide (1 mL, excess) was added to 3-(5-cyclopropyl-2,6-dimethoxy-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (31 mg, 0.096 mmol). The reaction was heated to 60° C. for 1 hour. The reaction was concentrated down and purified (silica gel, 20-80% EtOAc/hexane) to give white solid (22 mg, 77%). LC-MS shows 294.0 (M−1). 1H NMR (300 MHz, CDCl3): δ 8.04 (s, 1H), 7.97 (s, 1H), 7.75 (s, 1H), 2.50 (s, 3H), 1.17 (m, 1H), 0.56 (m, 2H), 0.49 (m, 2H).
Reaction SMILES: N(O[CH2:4][CH2:5][CH2:6][CH3:7])=O.N[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:10]=1[C:11](O)=O.C1CC=CC=1>ClCCl.CC(C)=O>[N+:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:9]2[C:10]=1[CH:11]1[CH2:7][CH:6]2[CH:5]=[CH:4]1)([O-:20])=[O:19]
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Reactant: CCCCON=O
Agent: C1=CCC=C1
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2c1C1C=CC2C1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
In a three necked flask equipped with thermometer, dropping funnel and cooler with a bubbler, tertio-butyl nitrite (5.77 ml, 1.77 eq, 48.6 mmol) is dissolved in dichloromethane (30 ml) and heated to reflux while a solution of cold 2-amino-6-nitro-benzoic acid (5 g, 1 eq, 27.5 mmol) and cyclopentadiene (40.7 ml, 18 eq, 0.49 mol) in acetone (20 ml) is added dropwise. Care should be taken regarding gas evolution. After refluxing for 18 hours, the reaction is cooled down to ambient temperature before being filtrated through a silica pad and evaporated. The crude mixture is purified by chromatography column (silica gel, elution with a gradient from pure cyclohexane to a mixture of ethyl acetate:cyclohexane 1:12. 3 grams of 5-nitro-1,4-dihydro-1,4-methano-naphthalene are then obtained (58% yield). 1H NMR (CDCl3) 7.7 ppm, 1H, dd, J=0.7 and 8.4 Hz; 7.45 ppm, 1H, dt, J=7.3 and 0.7 Hz; 7.07 ppm, 1H, dd, J=7.3 and 8.4 Hz; 6.9-6.86 ppm, 2H, m; 4.86 ppm, 1H, bs; 4.02 ppm, 1H, bs; 2.38 ppm, 1H, dt, J=7.7 and 1.5 Hz; 2.3 ppm, 1H, dt, J=7.4 and 1.5 Hz.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:21][C@H:22]1[NH:27][C@@H:26]([CH3:28])[CH2:25][N:24]([C:29]([C:31]2[C:32]([CH3:38])=[C:33]([CH:36]=O)[NH:34][CH:35]=2)=[O:30])[CH2:23]1>C(O)C.N1CCCCC1>[CH3:28][C@H:26]1[NH:27][C@@H:22]([CH3:21])[CH2:23][N:24]([C:29]([C:31]2[C:32]([CH3:38])=[C:33]([CH:36]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:34][CH:35]=2)=[O:30])[CH2:25]1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3cccc(C(F)(F)F)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 27 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 4[(cis)3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-{4((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (34.3 mg, 27%).
Reaction SMILES: C1(N(C2C=CC=CC=2)C(OC(=O)C2C=CC(CN3C4C(=CC=C(NC(=O)C(CC)CCCC)C=4)C=C3)=C(OC)C=2)=O)C=CC=CC=1.[CH:47]1([O:52][C:53]([NH:55][C:56]2[CH:57]=[C:58]3[C:62](=[CH:63][CH:64]=2)[N:61]([CH3:65])[N:60]=[C:59]3[CH2:66][C:67]2[CH:76]=[CH:75][C:70]([C:71]([O:73]C)=[O:72])=[CH:69][C:68]=2[O:77][CH3:78])=[O:54])[CH2:51][CH2:50][CH2:49][CH2:48]1>>[CH:47]1([O:52][C:53]([NH:55][C:56]2[CH:57]=[C:58]3[C:62](=[CH:63][CH:64]=2)[N:61]([CH3:65])[N:60]=[C:59]3[CH2:66][C:67]2[CH:76]=[CH:75][C:70]([C:71]([OH:73])=[O:72])=[CH:69][C:68]=2[O:77][CH3:78])=[O:54])[CH2:48][CH2:49][CH2:50][CH2:51]1
Reactant: COC(=O)c1ccc(Cc2nn(C)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Agent: CCCCC(CC)C(=O)Nc1ccc2ccn(Cc3ccc(C(=O)OC(=O)N(c4ccccc4)c4ccccc4)cc3OC)c2c1
Product: COc1cc(C(=O)O)ccc1Cc1nn(C)c2ccc(NC(=O)OC3CCCC3)cc12

Procedure:
Using a similar procedure to that described in part (d) of Example 1, except starting from the ester (Y) instead of the ester (C), 4-[5-(cyclopentyloxycarbonyl)amino-1-methylindazol-3-ylmethyl]-3-methoxybenzoic acid (U) was obtained as a white solid (95%); mp 216°-217° C.
Reaction SMILES: CO[C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:10][CH2:9][C:8]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1c(N)ccc2c1CCC(NCC(F)(F)F)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Yield: 70 %

Procedure:
In an analogous procedure to Example 651, part c, 1-methoxy-N*7*-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide to yield N-((1R,2R)-2-{5-Chloro-2-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (456.46, 70% yield) as a beige foam. 1H-NMR (CDCl3) δ 7.92 (m, 2H), 7.27 (m, 1H), 6.88 (d, J=8.3 Hz, 1H), 5.40 (m, 2H), 3.90 (m, 1H), 3.72 (s, 3H), 3.24 (m, 4H), 2.81 (M, 4H), 2.66 (m, 1H), 2.49 (m, 1H), 2.22 (m, 2H), 2.08 (m, 2H), 1.36 (m, 6H). LC/MS (ESI+)=591 (M+H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[C:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:8]=2)[N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:20][C:15]1[CH:14]=[C:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[C:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:8]=3)[N:3]=[C:2]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[N:11]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: OB(O)c1cccnc1
Reactant: CN(C)CC#Cc1ccc2nc(Cl)nc(Nc3ccc(F)c(Cl)c3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C)CC#Cc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
In a 50 mL round-bottomed flask was added 2-chloro-N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)quinazolin-4-amine, (61 mg, 0.16 mmol), 3-pyridineboronic acid (25 mg, 0.20 mmol), K2CO3 (0.11 mg, 0.78 mmol) and PdCl2(PPh3)2, (5.5 mg, 7.8 mM) in dioxane (2 mL) to give a yellow suspension. The mixture was heated at reflux for 3 h under argon. After cooling to room temperature, water (10 mL) and ethyl acetate (10 mL) were added to the mixture to form a precipitate. The resulting precipitate was filtered through Celite. The filtrate was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with water (1×15 mL) and brine (1×15 mL) and then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with AcOEt/MeOH 1:0 to 9:1). The desired product was washed with CH2Cl2 to give 25 mg of N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)prop-1-ynyl)-2-(pyridin-3-yl)quinazolin-4-amine as a light brown solid in 37% yield. LCMS m/z=432 (M+1) (Method C) (retention time=1.86 ruin). 1H NMR (300 MHz, DMSO) δ 10.13 (s, 1H), 9.51 (s, 1H), 8.77-8.56 (m, 3H), 8.26 (dd, J=6.9, 2.5 Hz, 1H), 8.02-7.78 (m, 3H), 7.64-7.47 (m, 2H), 3.54 (s, 2H), 2.30 (s, 6H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[C:11]2[C:12](=[O:23])[N:13]([CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][C:10]=2[NH:9][CH:8]=1.O.[OH-].[Na+].CN(C)[CH:29]=[O:30]>>[CH3:6][C:7]1[C:11]2[C:12](=[O:23])[N:13]([CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][C:10]=2[NH:9][C:8]=1[CH:29]=[O:30]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.37 %

Procedure:
N,N-dimethylformamide (1.5 ml) was added slowly with phosphorus oxychloride (115 μl, 3.2 mmol) under an argon atmosphere while maintaining the temperature at 0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at room temperature, and cooled down to 0˜5° C. in an ice-water bath. A mixture of 3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (719 mg, 2.91 mmol) in 3 ml of N,N-dimethylformamide was added dropwise to the above solution. Upon completion of the addition, the mixture was stirred for 2 hours at 0° C., added with cold water (20 ml) and stirred for another 5 minutes. The resulting mixture was adjusted to pH 12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (30 ml×3). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with triethylamine: methanol:dichloromethane (1:20:500) as eluents to give 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (411 mg, 51.37%) as a brown oil which was used as such.
Reaction SMILES: Cl.Cl.ClC1C=CC(C2C3[C@@H]4CCNCC[C@@H]4NC=3C=CC=2)=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]1[C:33]2[C:34]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41][C:35]=3[NH:36][C:37]=2[CH:38]=[CH:39][CH:40]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]1[C:33]2[C@@H:34]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41][C@@H:35]3[NH:36][C:37]=2[CH:38]=[CH:39][CH:40]=1
Reactant: Clc1ccccc1Nc1cccc2[nH]c3c(c12)CCNCC3
Agent: Cl
Agent: Clc1ccc(-c2cccc3c2[C@@H]2CCNCC[C@@H]2N3)cc1
Product: Clc1ccccc1Nc1cccc2c1[C@@H]1CCNCC[C@@H]1N2

Procedure:
Following the procedure for the preparation of (5aS*,10bS*)-10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole dihydrochloride, making non-critical variations, starting from N-(2-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-amine the title compound was prepared: 1H NMR (DMSO-d6) δ 1.68, 1.77, 1.93, 2.58, 2.73, 2.95, 5.62, 6.20, 6.77-6.82, 6.86, 6.94, 7.14, 7.37. HRMS (FAB) calcd for C18H20ClN3 (MH+) 314.1424, found 314.1422.
Reaction SMILES: O1CCCC1.[O:6]([CH2:13][C:14]([NH:16][CH:17]1[C:43](=[O:44])[N:19]2[C:20]([C:27]([O:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[C:21]([CH:25]=O)[CH2:22][S:23](=[O:24])[C@H:18]12)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:45][N:46]1[C:50]([CH:51]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:49][N:48]=[N:47]1.Cl>CO.C(OCC)(=O)C>[O:6]([CH2:13][C:14]([NH:16][CH:17]1[C:43](=[O:44])[N:19]2[C:20]([C:27]([O:29][CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:28])=[C:21]([CH:25]=[CH:51][C:50]3[N:46]([CH3:45])[N:47]=[N:48][N:49]=3)[CH2:22][S:23](=[O:24])[C@H:18]12)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cn1nnnc1C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S(=O)C1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1nnnc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S(=O)C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
To 130 ml of anhydrous tetrahydrofuran was added 5.35 g of benzhydryl 7-phenoxyacetamido-3-formyl-3-cephem-4-carboxylate-1-oxide, and, after cooling to -5°--10° C., further added 4.3 g of (1-methyl-1H-tetrazol-5-yl)methylenetriphenylphosphorane. The mixture was stirred at that temperature for 5 hours and poured into a mixture of ethyl acetate and ice-water. The resulting mixture was then made acidic with 10 ml of 5% hydrochloric acid. The organic layer was washed with five portions of a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave a solid residue. The residue was, after addition of approximately 30 ml of methanol, stirred at room temperature for 20 minutes and filtered leaving a precipitate. There was obtained 3.62 g of benzhydryl 7-phenoxyacetamido-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylate-1-oxide as a crystalline powder. The filtrate was evaporated under redueced pressure to dryness, and the obtained residue was developed through silica gel column with ethyl acetate to give 600 mg of the crystals additionally.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:11][Si:12]([C:15]#[C:16][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1ccc([N+](=O)[O-])cc1
Yield: 69.8 %

Procedure:
A mixture of p-bromonitrobenzene (2.02 g, 10 mmol), bis(triphenylphosphine)palladium(II) chloride (0.2 g, 0.3 mmol), and copper(1) iodide (0.05 g, 0.3 mmol) in 40 ml of N,N-diisopropylamine was degassed by freeze/pump/thaw technique (three times). Trimethylsilylacetylene (1.2 g, 12 mmol) was added and the mixture was refluxed for 12 hours. After removal of amine by rotary evaporation, the residue was dissolved in CH2Cl2 and washed with water. The organic layer was dried (Na2SO4), filtered, and rotary evaporated. The residue was purified by column chromatography (EtOAc/hexanes, 1:10) to afford 4-(trimethylsilylethynyl)nitrobenzene (1.53 g, 70%). (Procedure adapted from Takahashi, S; Kuroyama, Y; Sonogashira, K; Hagihara, N. Synthesis, 1980, 627.)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH2:28])[CH:18]=[CH:19][CH:20]=1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH:28][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: COc1cccc(-c2ccc(C)cc2N)c1
Product: COc1cccc(-c2ccc(C)cc2Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (0.065 g, 0.36 mmol) was reacted with the product from Example 217b (0.072 g, 0.34 mmol) for 96 h at 100° C. following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing a trifluoroacetic acid salt (0.102 gm, 64%). 1H NMR (300 MHz, DMSO-d6) ppm: 2.43 (s, 3H) 2.72 (s, 3H) 3.62 (s, 3H) 6.29 (d, J=7.35 Hz, 1H) 6.77 (dd, J=7.91, 2.02 Hz, 1H) 6.87-7.00 (m, 2H) 7.17 (t, J=7.91 Hz, 1H) 7.36 (s, 1H) 7.41-7.46 (m, 1H) 7.51-7.56 (m, 1H) 7.75 (d, J=8.46 Hz, 1H) 8.32 (d, J=7.35 Hz, 1H) 8.91 (d, J=8.82 Hz, 1H) 11.99-12.22 (s, 1H); MS (ESI+) m/z 356.0 (M+H)+; (ESI−) m/z 354.0 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:24]([NH:28][CH2:29][C:30]1[CH:42]=[CH:41][C:33]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:32]([CH3:43])[CH:31]=1)[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH2:24]([N:28]([CH2:29][C:30]1[CH:42]=[CH:41][C:33]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:32]([CH3:43])[CH:31]=1)[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: Cc1ccc(-c2cncc(Br)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(C)cc2)n1
Temperature: 100 °C
Yield: 8.3 %

Procedure:
A mixture of 2-bromo-6-(4-methylphenyl)pyrazine (0.25 g, 1 mmol), N,N-diisopropylethylamine (0.35 mL, 2 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.42 g, 1.5 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The reaction mixture was then allowed to come to room temperature and the residue dissolved in CH2Cl2 (30 mL), the organic extract was washed water (15 mL) and passed through a hydrophobic frit before concentrating in vacuo. Purification by Biotage™ chromatography (Silica, 40 g) eluting 1:19–1:4 EtOAc:cyclohexane afforded the title compound as a pale yellow oil (37 mg).