Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1O)([O-:9])=[O:8]>>[CH:1]1([O:6][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N+:7]([O-:9])=[O:8])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: OC1CC=CC1
Reactant: O=[N+]([O-])c1ccccc1O
Product: O=[N+]([O-])c1ccccc1OC1CC=CC1

Procedure:
Cyclopent-3-en-1-ol was reacted with o-nitrophenol to yield 2-cyclopent-3-en-oxynitrobenzene; which was reduced to the corresponding aniline; then reacted with 5-methyl-N-chloromethyl-2-pyrrolidone to form the corresponding 5-methyl-N'-methylene-2-pyrrolidonyl derivative.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C#N)ccc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1cc(CN)ccc1Br
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3-methyl-benzonitrile (commercially available) (15 g) in diethyl ether (150 ml) under an argon atmosphere was added a solution of lithium aluminum hydride in diethyl ether (1M) (150 ml) at ambient temperature. The reaction mixture was stirred at 40° C. for 2 hours. Then the reaction mixture was cooled to 0° C. and quenched by successive addition of water (10.5 ml), aqueous sodium hydroxide (20% w/w) (7.5 ml) and water (37.5 ml). The phases were separated. The organic phase was filtered through a plug of silica gel and the filtrate concentrated to give 4-bromo-3-methyl-benzylamine (15.11 g) as a yellow oil. 1H-NMR (400 MHz, CDCl3): 7.47 (d, 1H), 7.19 (s, 1H), 6.98 (d, 1H), 3.80 (s, 2H), 2.39 (s, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6](O)[CH:7]([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O>[CH3:8][CH:7]([CH3:9])[CH:6]([C:5]1[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][CH:4]=1)[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CC(C)C(O)c1ccc(O)cc1
Reactant: C1COCCN1
Solvent: O
Product: CC(C)C(c1ccc(O)cc1)N1CCOCC1
Yield: 34.7 %

Procedure:
A mixture of 4-hydroxy-α-isopropylbenzyl alcohol (1.0 g; 0.006 mol) morpholine (1.3 g; 0.015 mol) and water (1.3 ml) is refluxed under a nitrogen atmosphere for 23 hours, and then poured into water (~20 ml). The aqueous solution is extracted with 30 ml of ether, the ethereal solution dried over magnesium sulfate, and concentrated to give 0.97 g of crude product (69% of theory). Recrystallization of the crude product from methylene chloride affords pure title compound (490 mg 35%): mp 142°-143° C.; IR (Nujol) 3300 (s), 2940 (s), 1610 (m), 1595 (m) cm-1 ; NMR (CDCl3) δ0.75 and 0.92 (a pair of d, J=7 Hz, 6 H, two methyls), 1.8-2.4 (m, 1 H, isopropyl methine proton), 2.3-2.5 (m, 4 H, two methylene groups adjacent to the nitrogen atom), 2.94 (d, J=8 Hz, 1 H, benzylic proton), 3.6-3.9 (m, 4 H, two methylene groups adjacent to the oxygen atom), 3.9-6.2 (broad s, 1 H, phenoxy proton) and 6.75 and 7.05 ppm (AB quartet, J=8 Hz, 4 H, aromatic). Anal. Calcd for C14H21NO2 : C, 71.45; H, 8.95; N, 5.95. Found: C, 71.07; H, 8.64; N, 6.01.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1.[CH:20]([O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=1[C:26](O)=[O:27])([CH3:22])[CH3:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH2:14][N:13]([C:26]([C:25]2[CH:29]=[C:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=[CH:32][C:24]=2[O:23][CH:20]([CH3:22])[CH3:21])=[O:27])[CH2:12][CH2:11]3)=[CH:18][CH:19]=1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Fc1ccc(COc2ccc3c(c2)CCNC3)cc1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(OCc3ccc(F)cc3)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 6-(4-fluoro-benzyloxy)-1,2,3,4-tetrahydro-isoquinoline (CA [620606-78-2]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 498.4 (M+H+).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([N:24]1[C:29](=[O:30])[CH:28]=[CH:27][NH:26][C:25]1=[O:31])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([N:24]1[C:29](=[O:30])[CH:28]=[CH:27][N:26]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:25]1=[O:31])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(c1ccccc1)n1c(=O)cc[nH]c1=O
Reactant: O=C(OCCCCCO)c1ccccc1
Product: O=C(OCCCCCn1ccc(=O)n(C(=O)c2ccccc2)c1=O)c1ccccc1
Yield: 50 %

Procedure:
The title compound (50%) was prepared as described in example 15 but using the alcohol 20 instead of 14 in the coupling reaction with N3-benzoyluracil.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([N:16]2[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[N:31][C:30](Cl)=[CH:29][N:28]=1)=[O:26].CCN(CC)CC>O1CCOCC1>[CH3:23][O:24][C:25]([C:27]1[N:28]=[CH:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([C:11]3[N:10]=[N:9][C:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[C:13]([CH3:14])[C:12]=3[CH3:15])[CH2:17][C@H:18]2[CH3:22])=[N:31][CH:32]=1)=[O:26]
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCN[C@H](C)C2)c1C
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Yield: 75.3 %

Procedure:
A mixture of compound 47 (6.0 g, 20.27 mmol), 5-chloropyrazine-2-carboxylic acid methyl ester (5.3 g, 30.30 mmol), Et3N (6.2 g, 60.60 mmol) and dioxane (100 mL) is heated to reflux overnight. Solvent is removed. Saturated NH4Cl solution is added and extracted with EtOAc. The organic layer is concentrated to afford the crude product that is purified by chromatography on silica gel (EtOAc/heptane: 50%˜100%) to give the title compound (6.6 g, 76%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]C(=O)OC(C)(C)C)=[CH:18][CH:17]=1)=[O:3].Cl.CCOCC>C(Cl)Cl>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][NH:14][C:9]2[C:8]3[C:13](=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=[CH:6][CH:7]=3)[N:12]=[CH:11][N:10]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CNc2ncnc3c(C(N)=O)cccc23)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: NC(=O)c1cccc2c(NCc3ccc(N)cc3)ncnc12
Yield: 95 %

Procedure:
The title compound was prepared as light yellow solid in 95% yield by treating tert-butyl [4-({[8-(aminocarbonyl)quinazolin-4-yl]amino}methyl)phenyl]carbamate with 2N HCl/ether in DCM overnight. The precipitate was filtered, washed with ether and dried. Mass: M+H+: 294.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:22])=[C:18]([F:21])[CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:22])=[C:18]([F:21])[CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)c(F)cc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)c(F)cc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-Chloro-5-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1O.C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[O:12]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:10]1[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][CH:7]=1
Reactant: O=C(O)Cc1ccc(CO)cc1
Reactant: Nc1ccccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: OCc1ccc(Cc2nc3ccccc3o2)cc1
Temperature: 180 °C
Reaction time: 72 h
Yield: 20.8 %

Procedure:
A mixture of (4-hydroxymethyl-phenyl)-acetic acid (5.0 g, 30.1 mmol) and 2-amino-phenol (6.6 g, 60.2 mmol) was heated at 180° C. for 3 h. The crude residue was cooled and then dissolved in THF (50 mL). The resulting solution was treated with carbonyldiimidazole (3.7 g, 22.5 mmol) and stirred at 80° C. for 72 h. The reaction mixture was then partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was dried (MgSO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 80% EtOAc in hexanes) followed by a second silica gel flash chromatography (0% to 10% CH3OH in CH2Cl2) afforded a colorless oil. The crude oil was then partitioned between EtOAc (200 mL) and 1 N NaOH (200 mL). The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound as a colorless oil (1.5 g, 20%). MS (ESI): mass calcd. for C15H13NO2, 239.09; m/z found, 240.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.70-7.68 (m, 1H), 7.49-7.46 (m, 1H), 7.40-7.35 (m, 4H), 7.33-7.29 (m, 2H), 4.69 (br d, J=4.5 Hz, 2H), 4.28 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25]>O1CCCC1>[F:8][C:6]1[C:5]([Br:9])=[CH:4][C:3]2[N:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:24](=[O:25])[NH:1][C:2]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(F)cc2N)CC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(F)c(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-[(2-amino-4-fluoro-5-bromophenyl)amino]-1-piperidinecarboxylate (D44) (0.83 g, 2.1 mmole) was dissolved in anhydrous tetrahydrofuran (20 ml) and carbonyl diimidazole (0.51 g, 3.2 mmole) was added in portions over 15 minutes. The mixture was stirred at rt for 1 hr and the at reflux temperature for 18 hrs. The cooled mixture was concentrated to dryness under vacuum and the residue purified by silica gel chromatography eluting with 15-100% ethyl acetate in n-pentane to afford the title compound as a buff solid, 0.54 g, 51% LC/MS—85% m/e 412/414 (MH−).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Yield: 83.6 %

Procedure:
At 100° C., 167.0 g of 4-hydroxy-3-nitrobenzaldehyde, 311.0 g of potassium carbonate, and 211.0 g of benzyl chloride are agitated in 2 l of dimethylformamide for 16 hours. The resultant reaction mixture is poured into 10 l of water, the thus-separated solid product is filtered off and recrystallized from ethanol, yielding 215.0 g of 4-benzyloxy-3-nitrobenzaldehyde, mp 100°-102° C.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:26]=[C:25]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:33]>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:23]2[CH:24]=[C:25]([S:27]([CH:30]([CH3:31])[CH3:32])(=[O:28])=[O:29])[CH:26]=[CH:21][C:22]=2[CH3:33])[CH:11]=1)#[N:16]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)C(C)C)cc1Br
Product: Cc1ccc(S(=O)(=O)C(C)C)cc1C#Cc1cc(C#N)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 2-bromo-4-(isopropylsulfonyl)-1-methylbenzene (Intermediate 64), the title compound was obtained as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[C:12]2=[O:29])=[CH:7][CH:6]=1.[CH3:30][NH2:31].[I-].[Na+]>C(#N)C>[CH3:30][NH:31][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[C:12]2=[O:29])=[CH:7][CH:6]=1
Reactant: CN
Reactant: O=c1n(-c2ccc(OCCBr)cc2)ccn1-c1ccc(Oc2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CNCCOc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1

Procedure:
A solution of 1-[4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in acetonitrile (1 ml) was left to stand with methylamine (1M in THF, 1 ml) and sodium iodide (5 mg) and 24 hours. The reaction solution was filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 401.47 (C24H23N3O3); MS (ESI): 402 ([M+H]+), was obtained as hydroformate in this way.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[N:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:25]=[N:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:27]=[N:26][CH:25]=[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)[CH:23]=4)[N:19]=[C:15]3[CH:14]=[N:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2cncc(Br)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cncc3nc(N)nn23)cc1
Product: CN1CCN(c2cncc(Nc3nc4cncc(-c5ccc(S(C)(=O)=O)cc5)n4n3)c2)CC1
Yield: 4 %

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]-[5-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine and 1-(5-bromo-pyridin-3-yl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as an off-white lyophilate
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1>>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:22]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]=[CH:24][CH:23]=4)=[CH:18][CH:19]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(CN2CCN(c3ccccc3)CC2)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: Clc1ccc2c(Nc3ccc(CN4CCN(c5ccccc5)CC4)cc3)ccnc2c1

Procedure:
In the manner given in Example 1C, 1-phenyl-4-[(4-aminophenyl)methyl]piperazine and 4,7-dichloroquinoline are reacted together at reflux to give 4-[[4-[[4-phenyl-1-piperazinyl]methyl]phenyl]amino]-7-(chloro)quinoline.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[NH:29]([CH2:33][CH2:34][CH2:35][N:36]1[C:40]([SH:41])=[N:39][N:38]=[N:37]1)[C:30]([NH2:32])=[NH:31]>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH3:27])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][S:41][C:40]4[N:36]([CH2:35][CH2:34][CH2:33][NH:29][C:30]([NH2:32])=[NH:31])[N:37]=[N:38][N:39]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1csc(N)n1
Reactant: N=C(N)NCCCn1nnnc1S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCCNC(=N)N)CS[C@H]12)c1csc(N)n1
Temperature: -20 °C
Yield: 59.1 %

Procedure:
To a solution of 363 mg of sodium 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4-carboxylate and 241 mg of 1-(3-guanidinopropyl)-5-mercapto-1H-tetrazole in 10 ml of DMF was added 800 mg of ethyl o-phenylenephosphate under stirring at -20° C. The reaction mixture was stirred at -20° C. to 0° C. for 60 minutes and subjected to a column chromatography on silica gel (100 g), being washed with acetonitrile and eluted with acetonitrile/water (4:1). The eluate was concentrated under reduced pressure and subjected to a column chromatography on XAD-II (150 ml), being washed with water and eluted with 20% aqueous ethanol. The eluate was concentrated under reduced pressure and then lyophilized to give 294 mg of the title compound as a colorless powder.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][NH:13][C@H:14]1[CH2:33][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([O:29]CCC)=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3>>[CH3:12][N:13]([C:9](=[O:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:14]1[CH2:33][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([OH:29])=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3
Reactant: O=C(Cl)COc1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)COc1ccccc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from phenoxyacetyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 393.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]([C@H:7]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([I:21])[CH:15]=2)[CH2:12][C@H:11]2[N:22]([CH3:23])[C@@H:8]1[CH2:9][CH2:10]2)=[O:6].N([O-])=O.[Na+].[N-:28]=[N+:29]=[N-].[Na+].Cl>CC(O)=O.O>[ClH:1].[CH3:3][O:4][C:5]([C@H:7]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]=[N+:28]=[N-:29])=[C:16]([I:21])[CH:15]=2)[CH2:12][C@H:11]2[N:22]([CH3:23])[C@@H:8]1[CH2:9][CH2:10]2)=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(N)c(I)c2)C[C@@H]2CC[C@H]1N2C
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@H]1[C@@H](c2ccc(N=[N+]=[N-])c(I)c2)C[C@@H]2CC[C@H]1N2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of 3β-[3'-iodo-4'-aminophenyl]tropan-2β-carboxylic acid methyl ester dihydrochloride (1a) (90 mg, 0.1902 retool) in 1 mL of AcOH (3M) was added an aqueous solution of NaNO2 (17.3 mg, 0.2661 mmol, in 0.5 mL of H2O) at 0° C. After 30 min at this temperature NaN3 (19 mg, 0.2754 mmol) in 0.5 mL of H2O was added dropwise to the reaction mixture and stirred for 30 min at 0° C. then 30 min at room temperature. After removal of all solvent by evaporation, the residue was dissolved in CHCl3 and washed with H2O. The organic layer was dried over MgSO4 and concentrated to give an oil which was converted to HCl salt to yield 64 mg (72.7%) of 3β-[3'-iodo-4'-azidophenyl]tropan-2β-carboxylic acid methyl ester hydrochloride (1b) as a yellowish solid: mp 140°-143° C.; [α] 25 -97.4° (c 0.115), MeOh); 1H NMR (250 MHz, CDCl3) δ 1.51-1.73 (m, 3) 2.07-2.16 (m, 2), 2.19 (s, 3, NCH3) 2.47 (m, 1), 2.80-2.93 (m, 2), 3.32 (m, 1, H-5), 3.51 (s, 3, OCH3), 3.54 (m, 1, H-1), 7.01 (d, 1, J-7.7, ArH), 7.28 (dd, 1, J=7.77, J=1, ArH), 7.60 (d, 1, J=1, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a mixture of 0.51 g of 2,6-dichloro-4-(3,3,-dichloro-2-propenyloxy)phenol, 0.27 g of potassium carbonate and 20 ml of N,N-dimethylformamide was added dropwise a solution of 0.29 g of m-chlorobenzyl chloride dissolved in 5 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 7 hours, the reaction mixture was poured into ice-water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.50 g of 3,5-dichloro-4-(3-chlorobenzyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (69% yield), m.p. 87.0° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:19])=O)[N:12]=2)[CH:4]=1)[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[N:12]=2)[CH:4]=1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCc1cc(-c2cccc(C(=O)O)n2)c(C)[nH]c1=O
Product: CCc1cc(-c2cccc(C(=O)N3CCCC3)n2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-6-carboxylic acid and pyrrolidine to afford the title compound. MS: m/e=312 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](C=O)[S:5][C:6]=1[N+:7]([O-:9])=[O:8].[Cl-].[NH4+].[CH:14]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])OCC>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])[S:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1cc(Br)c([N+](=O)[O-])s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(OCC)c1cc(Br)c([N+](=O)[O-])s1
Temperature: 60 °C
Reaction time: 14 h
Yield: 81.2 %

Procedure:
To a solution of 4-bromo-5-nitrothiophene-2-carbaldehyde (Int. 65) (6.981 g, 29.6 mmol) in EtOH (50 ml), ammonium chloride (0.475 g, 8.87 mmol) and triethyl orthoformate (7.39 ml, 44.4 mmol) were added, and the resulting solution was stirred at 60° C. for 14 hours. Additional triethyl orthoformate (7.39 ml, 44.4 mmol) was added, and the mixture was vigorously refluxed for further 2 days. The solvent was evaporated under vacuum and the crude was partitioned between water and EtOAc. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by chromatography on silica gel cartridge (petroleum ether/EtOAc=9/1) to afford 3-bromo-5-(diethoxymethyl)-2-nitrothiophene (Int. 66) (7.456 g, 24.04 mmol).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:34]([O:36]C)=[O:35])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:18][C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1.CO.[OH-].[Na+]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:34]([OH:36])=[O:35])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:18][C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN1CCOCC1)Cc1ccccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN1CCOCC1)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
The crude methyl 14-cyclohexyl-6-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate was dissolved in THF/MeOH (1:1) and to that solution an excess of NaOH (1N) was added. The solution was stirred at RT overnight. The solvent was evaporated in vacuo. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (20%).