Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[N:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)[C:7]=2[CH:29]=1.[ClH:30].C(OCC)(=O)C>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:30].[ClH:30].[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:8]2[C:7]3[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[N:11]=[N:10][C:9]2=[O:12])[CH2:16][CH2:17]1
Reactant: COc1ccc2nnc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc2nnc(=O)n(CCN3CCC(N)CC3)c2c1

Procedure:
To a solution of 1,1-dimethylethyl (1-{2-[6-(methyloxy)-3-oxo-1,2,4-benzotriazin-4(3H)-yl]ethyl}-4-piperidinyl)carbamate (48 mg, 0.11 g mmol) in chloroform (2 ml) was added 4M HCl in 1,4-dioxane (2 ml). The reaction was stirred at rt for 1 h before evaporation and trituration with ethyl acetate to provide the desired compound as a yellow oil which was used without further purification (42 mg, 94%).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[CH2:22][C:21]([CH3:24])([CH3:23])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27]CC)=[O:26])[CH:19]=2)[NH:14]1)=[O:5].O.[OH-].[Li+].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[CH2:22][C:21]([CH3:24])([CH3:23])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=2)[NH:14]1)=[O:5]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NC(=O)c1ccccc1F)N2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(c2ccccc2NC(=O)c2ccccc2F)Nc2ccc(C(=O)O)cc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 2-(2-(2-fluorobenzamido)phenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (crude 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water (1.5 mL) at room temperature. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 2-[2-(2-fluoro-benzoylamino)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid. LC/MS m/e obsd. (ESI+) [(M+H)+] 419.30.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14].[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CS(C)=O.O>[CH2:17]([O:24][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 1.80 g, 45 mmol) was added to a solution of 4-fluoro-3-trifluoromethyl benzoic acid (4.162 g, 20 mmol) and benzyl alcohol (3.25 g, 30 mmol) in DMSO (50 mL). The mixture was stirred overnight at room temperature, poured into water (50 mL) and acidified with concentrated hydrochloric acid. The white precipitate was filtered off, dissolved in ethyl acetate (ca. 50 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/hexane. Yield: 4.252 g (72%). 1H-NMR (400 MHz, CDCl3) δ=5.37 (s, 2H), 7.32-7.48 (m, 6H), 8.12 (d, J=2.0 Hz, 1H), 8.18 (dd, J=8.6, 2.0 Hz, 1H), 13.16 (br s, 1H, —COOH). LRMS (FAB+): 91.1 (100),297.1 (18, [M+H]+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH2:27][CH2:28][CH3:29])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:16]2)[C@@H:12]([OH:30])[C@@H:11]1[OH:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1>CN(C=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH2:27][CH2:28][CH3:29])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[S:16]2)[C@@H:12]([O:30][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C@@H:11]1[O:31][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(CBr)cc1
Reactant: CCCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](OCc3ccc(OC)cc3)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
To a solution of tert-butyl (3aR,5R,6S,7R,7aR)-5-((tert-butyldimethylsilyloxy)methyl)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(propyl)carbamate (20 g, 42 mmol) in DMF (300 mL) was added sodium hydride (10 g, 417 mmol) at 15° C. in portions, followed by addition of 1-(bromomethyl)-4-methoxybenzene (33.8 g, 168 mmol). The resulting solution was stirred for 1.5 h at room temperature, quenched by addition of cold water (100 mL), and extracted with dichloromethane (5×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under vacuum to provide a residue, which was purified by silica gel column, eluted with 10-25% ethyl acetate in petroleum ether to give compound 18 as a yellow oil (20 g, 64.8%). (ES, m/z): 717.1; 1H NMR (300 MHz, CDCl3) δ 7.32-7.35 (d, J=8.7 Hz, 2H), 7.19-7.22 (d, J=8.7 Hz, 2H), 6.83-6.92 (m. 4H), 6.05-6.07 (d, J=6.9 Hz, 1H), 4.57-4.74 (m, 3H), 4.30-4.39 (m, 2H), 4.14-4.17 (t, J=4.2 Hz, 1H), 3.68-3.84 (m, 11H), 3.41-3.45 (m, 1H), 1.67-1.74 (m, 2H), 1.53 (s, 9H), 0.89 (s, 9H), 0.84 (m, 3H), 0.08 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:12]([CH2:41][OH:42])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@@H:20]([NH:32][C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:34])[CH2:21]C2C3C(=CC=CC=3)C=CC=2)=[O:19])(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:47].N1(C(N[C@@H](C[C:62]2[CH:71]=[CH:70][C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH:63]=2)C(O)=O)=O)CCOCC1.C1C=C2C(C=C(C[C@H](N)C(O)=O)C=C2)=CC=1.N1(C(N[C@@H](CC2C3C(=CC=CC=3)C=CC=2)C(O)=O)=O)CCOCC1.C1C=C2C=CC=C(C[C@H](N)C(O)=O)C2=CC=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:12]([CH2:41][OH:42])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@@H:20]([NH:32][C:33]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)=[O:34])[CH2:21][C:62]2[CH:71]=[CH:70][C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH:63]=2)=[O:19])(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:47]
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1)S(=O)(=O)c1ccc(N)c(Cl)c1
Reactant: O=C(O)[C@H](Cc1ccc2ccccc2c1)NC(=O)N1CCOCC1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: N[C@@H](Cc1cccc2ccccc12)C(=O)O
Agent: O=C(O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)N1CCOCC1)S(=O)(=O)c1ccc(N)c(Cl)c1
Yield: 25 %

Procedure:
This derivative was prepared from (1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-3-chloro-N-isobutyl-benzenesulfonamide (XII) (example 44, step B) as described in general procedure B using (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-2-yl-propionic acid. The latter derivative was prepared from L-2-naphthylalanine as described for the preparation of (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionic acid from L-1-naphthylalanine. The final product was obtained in 25% yield (51 mg).
Reaction SMILES: C([O:8][C:9]1[CH:28]=[C:27]([CH2:29][CH3:30])[CH:26]=[CH:25][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH3:23])(=[O:20])=[O:19])=[CH:14][C:13]=1[F:24])C1C=CC=CC=1.O1CCCC1>C(O)C>[CH2:22]([NH:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:25]=[CH:26][C:27]([CH2:29][CH3:30])=[CH:28][C:9]=2[OH:8])=[C:13]([F:24])[CH:14]=1)(=[O:19])=[O:20])[CH3:23]
Reactant: CCNS(=O)(=O)c1ccc(Oc2ccc(CC)cc2OCc2ccccc2)c(F)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1ccc(Oc2ccc(CC)cc2O)c(F)c1
Yield: 43.9 %

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for 4-(2-Benzyloxy-4-ethyl-phenoxy)-N-ethyl-3-fluoro-benzene sulfonamide (402 mg; 0.94 mmol) and tetrahydrofurane for ethanol (4 mL), the title compound (140 mg; 44%) was obtained as a clear oil, after purification on preparative TLC (dichloromethane).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[CH3:2].Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=2)[N:20]=1>C(O)C>[CH2:1]([N:3]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=2)[N:20]=1)[CH3:2]
Reactant: CCNCCc1ccc(NS(C)(=O)=O)cc1
Reactant: O=[N+]([O-])c1ccc2nc(CCl)ccc2c1
Solvent: CCO
Product: CCN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1ccc2cc([N+](=O)[O-])ccc2n1

Procedure:
N-Ethyl-4-methanesulphonamidophenethylamine (see Preparation 9(C)--1.7 g, 7.0 mmole) and 2-chloromethyl-6-nitroquinoline (0.78 g, 4.1 mmole) were heated at reflux temperature in ethanol (50 ml) for 4 hours. The solvent was then evaporated and the residue was diluted with aqueous sodium bicarbonate and extracted with methylene chloride. The organic layer was dried (MgSO4), evaporated and the residue was purified by column chromatography on silica eluting with methylene chloride. The product-containing fractions were combined and evaporated to give the title compound as an oil, yield 0.56 g.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([NH:16][NH:17][C:18]([C@H:20]2[CH2:26][CH2:25][C@@H:24]3[CH2:27][N:21]2[C:22](=[O:33])[N:23]3[O:28][S:29]([OH:32])(=[O:31])=[O:30])=[O:19])=[O:15])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([NH:16][NH:17][C:18]([C@H:20]2[CH2:26][CH2:25][C@@H:24]3[CH2:27][N:21]2[C:22](=[O:33])[N:23]3[O:28][S:29](=[O:30])(=[O:31])[OH:32])=[O:19])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)NNC(=O)[C@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NNC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O)[C@@H]1CCCNC1
Yield: 79 %

Procedure:
By using the procedure described in Step-4 of Example-1 above, and by using tetrabutylammonium salt of trans-3-[N′-(6-sulfooxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(R)-piperidin-1-carboxylic acid tert-butyl ester (24 gm, 0.032 mmol), dichloromethane (60 ml) and trifluoroacetic acid (60 ml) to provide the title compound in 10 gm quantity as a white solid, in 79% yield.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:22][C:23]1([CH3:36])[NH:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1>>[CH3:22][C:23]1([CH3:36])[N:28]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[C:9]([C:12]4[NH:20][C:19]5[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=5[CH:13]=4)[CH:8]=[CH:7][CH:6]=3)[N:11]=2)[CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Product: CC(C)(C)OC(=O)N1CCN(c2cnc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C(C)(C)C1
Temperature: 120 °C
Yield: 16 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 100 mg, 0.354 mmol) and tert-butyl 3,3-dimethylpiperazine-1-carboxylate (152 mg, 0.709 mmol), heating at 120° C. for 1 d. Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% ACN/water with 0.1% TFA) provided tert-butyl 3,3-dimethyl-4-(8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)piperazine-1-carboxylate (16% yield). MS (ESI, pos. ion) m/z: 477.2 (M+1).
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[C:25](=O)[NH2:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[C:25]#[N:26])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(N)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCCC1C#N
Temperature: -5 °C
Yield: 97.4 %

Procedure:
Acetonitrile (220 mL) and DMF (3.82 mL, 49.4 mmol) were added to a 500 mL round bottom flask equipped with stir bar. Cooled the mixture down to −5° C. and to it added oxalyl chloride (24.7 mL, 49.4 mmol, 2 M dichloromethane). The resulting mixture was stirred for 15 min. This was followed by addition of solution of 2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (9.4 g, 41.2 mmol) in acetonitrile (50 mL) and pyridine (8.3 mL, 103 mmol). Reaction mixture was left stirring at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (300 mL). The organic phase was successively washed with water (300 mL) and brine (200 mL), dried (sodium sulfate), filtered and concentrated in vacuo to isolate the title compound (8.44 g, 97%) as a yellow solid. 1H-NMR (CDCl3), δ(ppm): 5.23 (bs, 1H), 4.03 (bs, 1H), 2.93 (t, 1H), 1.75 (m, 5H), 1.46 (m, 10H).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][CH3:21])=[C:16]1[N:22]=[C:23]([NH2:25])[S:24][C:15]1=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][CH3:21])=[C:16]1[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:15]1=[CH:14][CH:13]=3)=[O:6])([CH3:2])[CH3:3]
Reactant: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc4sc(N)nc4c3c12
Reactant: CC(=O)OC(C)=O
Product: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc4sc(NC(C)=O)nc4c3c12

Procedure:
100 mg of 2-amino-10-ethyl-thiazolo[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester is suspended in 10 ml of acetic anhydride and heated for 15 minutes to 80° C. After cooling, the settled precipitate is filtered off and recrystallized from ethyl acetate. 51 mg of 2-acetamido-10-ethyl-thiazolo[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester with a melting point of 208-210° C. is obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[C:12]2[CH2:13][CH2:14][CH2:15][C:16](=[O:18])[NH:17][C:11]=2[CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[OH:6][C:7]1[C:12]2[CH2:13][CH2:14][CH2:15][C:16](=[O:18])[NH:17][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2c1CCCC(=O)N2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C1CCCc2c(O)cccc2N1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
10 ml of DMF are added to 65 g of anhydrous aluminum chloride with vigorous stirring, and cooling if necessary. 13.5 g (0.07 mole) of 6-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one are introduced in portions into the resulting melt, and the contents of the flask are then heated to 110°-140° C., left at this temperature for 10 minutes, and thereafter stirred for a further 30 minutes without additional heating. The contents of the flask are then poured into ice water, the sand-colored precipitate formed is filtered off and the filtrate is re-extracted repeatedly with ether. The ether phases are combined, dried and concentrated on a rotary evaporator. The residue is recrystallized from an acetone/cyclohexane/ethyl acetate mixture in the presence of animal charcoal. 6.3 g of 6-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (51% yield), of melting point 244°-245° C., are obtained.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1)=O.[NH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>C(#N)C>[CH3:15][C:2]1[N:18]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]2=[N:16][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1
Reactant: CC(Br)C(=O)c1ccc2oc(=O)[nH]c2c1
Reactant: Cc1ccnc(N)c1
Solvent: CC#N
Product: Cc1ccn2c(C)c(-c3ccc4oc(=O)[nH]c4c3)nc2c1
Yield: 25.1 %

Procedure:
A solution of 5-(2-bromopropionyl)-2-benzoxazolinone (5.4 g) and 2-amino-4-picoline (6.5 g) in acetonitrile (100 ml) was refluxed for an hour. The reaction mixture was evaporated in vacuo and the residue was poured into a suspension of water and ethyl acetate with stirring. The resultant mixture was acidified to pH 0.8 with 10% hydrochloric acid and stirred for 20 minutes at ambient temperature. The resultant precipitate was collected by filtration. The product was suspended in a mixture of water and ethyl acetate and the resultant mixture was adjusted to pH 8.0 with 20% potassium carbonate. The precipitate was collected by filtration and washed with water and ethyl acetate. The precipitate was recrystallized from an aqueous tetrahydrofuran to afford 5-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)-2-benzoxazolinone (1.4 g). mp. 276°-280° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]1[NH:14][C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([CH3:22])=[CH:17][C:16]=3[N:10]1[C:9]2=[O:23])([O-:3])=[O:2].[O:24]=[C:25]([CH2:32]Cl)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[C:27]([CH2:26][C:25](=[O:24])[CH2:32][N:14]1[C:11]2=[N:12][C:13]3[C:8]([C:9](=[O:23])[N:10]2[C:16]2[CH:17]=[C:18]([CH3:22])[C:19]([CH3:21])=[CH:20][C:15]1=2)=[CH:7][CH:6]=[CH:5][C:4]=3[N+:1]([O-:3])=[O:2])([O:29][CH2:30][CH3:31])=[O:28]
Reactant: Cc1cc2[nH]c3nc4c([N+](=O)[O-])cccc4c(=O)n3c2cc1C
Reactant: CCOC(=O)CC(=O)CCl
Product: CCOC(=O)CC(=O)Cn1c2cc(C)c(C)cc2n2c(=O)c3cccc([N+](=O)[O-])c3nc12

Procedure:
6-(3-Carboethoxy-2-oxopropyl)-4-nitro-8,9-dimethylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 4-nitro-8,9-dimethylbenzimidazo[2,1-b]quinazolin-12(6H)one and ethyl 3-oxo-4-chlorobutyrate.
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]([NH:13][NH2:14])([CH3:12])([CH3:11])[CH3:10].[CH3:15][O:16][C:17](=[O:28])[C:18]([C:23]([CH:25]1[CH2:27][CH2:26]1)=O)=[CH:19]N(C)C>C(O)C>[CH3:15][O:16][C:17]([C:18]1[CH:19]=[N:14][N:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:23]=1[CH:25]1[CH2:27][CH2:26]1)=[O:28]
Reactant: COC(=O)C(=CN(C)C)C(=O)C1CC1
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1cnn(C(C)(C)C)c1C1CC1
Yield: 36.3 %

Procedure:
Triethylamine (4.8 mL, 34.2 mmol) and tert-butyl hydrazine hydrochloride (1.4 g, 11.4 mmol) were added sequentially to a solution of crude 2-cyclopropanecarbonyl-3-dimethylamino-acrylic acid methyl ester (2.4 g, 11.4 mmol) in ethanol (24 mL). The resulting suspension was mixed well and divided equally into two 25 mL Personal Chemistry Microwave Process Tubes (Biotage AB, Sweden). The tubes were sealed with a septum and submitted to 150 W microwave irradiation using a Personal Chemistry Microwave Synthesis System (Biotage AB, Sweden) at 160° C. for 30 minutes. The reaction mixtures in the two tubes were combined and ethanol was evaporated under reduced pressure. The remaining mixture was partitioned between dichloromethane and water, and the water phase was extracted three times with dichloromethane. The organic phases were combined, concentrated in vacuo, and purified by silica chromatography eluting with a gradient of 10-20% ethyl acetate/hexanes, then 20% ethyl acetate/hexanes to give 1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (921 mg, 36%). LRMS m/z calcd for C12H18N2O2 (M+H) 223.1, found 223.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:7](=[O:19])[NH:6][CH2:5]2.[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:22][CH2:21]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:27]3[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=3[CH3:31])[C:24]([NH:23][CH:20]3[CH2:21][CH2:22]3)=[O:41])=[CH:11][CH:10]=2)[CH2:5][NH:6][C:7]1=[O:19]
Reactant: O=C1NCc2cc(Br)ccc2N1c1ccccc1Cl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(c1)CNC(=O)N2c1ccccc1Cl

Procedure:
To a stirred mixture of 6-bromo-1-(2-chlorophenyl)-3,4-dihydroquinazolin-2(1H)-one (0.1993 g, 0.5903 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.2134 g, 0.7084 mmol) and Pd(PPh3)4 (0.03411 g, 0.02952 mmol) was added 1,2-dimethoxyethane (5.000 ml) followed by 2N Na2CO3(aq) (0.7379 ml, 1.476 mmol) under nitrogen. The mixture was heated to reflux for 24. After cooling, the mixture was filtered through a short path of Celite and the filter cake was washed with EtOAc (3×10 mL). The combined organic layers were concentrated to give a crude product, which was purified using flash column chromatography (50% EtOAc in hexanes to 100% EtOAc) to afford 3-(1-(2-chlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)-N-cyclopropyl-4-methylbenzamide as a white solid. MS m/e 432 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6]P(OCC)(OCC)=O)=[O:5].CC([O-])(C)C.[K+].[CH3:21][C:22]1([CH3:37])[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[C:28]2[CH:27]=[C:26]([C:34](=O)[CH3:35])[CH:25]=[CH:24][C:23]1=2>C1COCC1>[CH2:2]([O:3][C:4](=[O:5])/[CH:6]=[C:34](/[C:26]1[CH:25]=[CH:24][C:23]2[C:22]([CH3:37])([CH3:21])[CH2:31][CH2:30][C:29]([CH3:32])([CH3:33])[C:28]=2[CH:27]=1)\[CH3:35])[CH3:1]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 0.25 h

Procedure:
7.30 ml of phosphonoacetic acid triethyl ester were dissolved in 100 ml of abs. THF. 3.90 g of KOtBu were added at 0° C. and the mixture stirred for 15 minutes at this temperature. 4.20 g of 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone, dissolved in 30 ml of THF, were added dropwise within 30 minutes at room temperature and stirring continued at 40° C. for 16 hours. The reaction mixture was then poured onto crashed ice/NH4Cl, extracted with EtOEt, washed with brine and H2O, and dried over Na2 SO4. Evaporation of the solvent, followed by flash chromatography (silica gel, hexane/AcOEt=97:3) yielded 3.70 g of (E)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-but-2-enoic acid ethyl ester as yellowish oil (GC-purity 98%).