Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:5][CH2:4][S:3][C:2]1=[C:6]([C:26]([O:28][CH3:29])=[O:27])[C:7]([NH:9][C@@H:10]1[C:24](=[O:25])[N:12]2[CH:13]([C:18]([O:20]CC=C)=[O:19])[C:14]([CH3:17])([CH3:16])[S:15][C@H:11]12)=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[Na+:59].C(OCC)(=O)C>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>[S:3]1[CH2:4][CH2:5][S:1][C:2]1=[C:6]([C:26]([O:28][CH3:29])=[O:27])[C:7]([NH:9][C@@H:10]1[C:24](=[O:25])[N:12]2[CH:13]([C:18]([O-:20])=[O:19])[C:14]([CH3:17])([CH3:16])[S:15][C@H:11]12)=[O:8].[Na+:59]
Reactant: C=CCOC(=O)C1N2C(=O)[C@@H](NC(=O)C(C(=O)OC)=C3SCCS3)[C@H]2SC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])C(C)(C)S[C@H]12)=C1SCCS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Allyl 6β-[(1,3-dithiolan-2-ylidene)(methoxycarbonyl)acetamido]-2,2-dimethylpenam-3-carboxylate (459 mg, 1 mmol) was dissolved in 0.25N sodium 2-ethylhexanoate/ethyl acetate solution (4 mL), and treated with triphenylphosphine (30 mg) and tetrakis(triphenylphosphine)palladium(0) (30 mg). The reaction mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting precipitate was collected by filtration, washed with ethyl acetate and diethyl ether, and dried in vacuo to yield the title compound (368 mg, 84%) as a light yellow powder: 1H NMR (D2O) δ 1.40 and 1.50 (each 3H, s, C2 -(CH3)2), 3.25-3.45 (4H, m, SCH2CH2S), 3.69 (3H, s, OCH3), 4.13 (1H, s, C3 -H), 5.45-5.52 (2H, m, C5 -H and C6).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH:20]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]1)=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][N:14]1[CH2:15][CH2:16][N:17]([CH:20]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:18][CH2:19]1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccccc2c1CC(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]c2ccccc2c1CCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 52.4 %

Procedure:
A solution of 1.5 grams (0.003 mole) of N-(2-methylindol-3-ylacetyl)-N′-[bis(4-fluorophenyl)methyl]piperazine in 10.0 mL of anhydrous tetrahydrofuran was added to a stirred mixture of 0.4 gram (0.010 mole) of lithium aluminum hydride in 5.0 mL of anhydrous tetrahydrofuran. Upon completion of the addition the reaction mixture was heated to reflux, where it stirred for 2.5 hours. The reaction mixture was cooled to 0° C., and water was added, followed by 50 mL of aqueous 10% sodium hydroxide. The solution was warmed to ambient temperature and then extracted with ethyl acetate. The extract was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.7 gram of N-(2-methylindol-3-ylethyl)-N′-[bis(4-fluorophenyl)methyl]piperazine, mp 65-73° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](OCC)=[O:12])[CH:10]=1)[N:7](C(OC(C)(C)C)=O)[CH:6]=[C:5]2[CH:23]1[CH2:29][CH2:28][CH2:27][S:26](=[O:31])(=[O:30])[CH2:25][CH2:24]1.[OH-].[Na+].BrC1C=C2C(=C(C(O)=O)C=1)[NH:40]C=C2C1CCCS(=O)(=O)CC1.CCN=C=NCCCN(C)C.Cl.Cl.C1C=C2N=NN(O)C2=CC=1.O.N>CO.O.CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:40])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:23]1[CH2:29][CH2:28][CH2:27][S:26](=[O:31])(=[O:30])[CH2:25][CH2:24]1
Reactant: O=C(O)c1cc(Br)cc2c(C3CCCS(=O)(=O)CC3)c[nH]c12
Reactant: CCOC(=O)c1cc(Br)cc2c(C3CCCS(=O)(=O)CC3)cn(C(=O)OC(C)(C)C)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)cc2c(C3CCCS(=O)(=O)CC3)c[nH]c12
Temperature: 85 °C

Procedure:
To a solution of 1-(1,1-dimethylethyl) 7-ethyl 5-bromo-3-(1,1-dioxido-4-thiepanyl)-1H-indole-1,7-dicarboxylate (273 mg, 0.53 mmol) in methanol (3 mL) and water (1.6 mL) was added 6 M aqueous sodium hydroxide (1 mL). The mixture was heated to 85° C. for 2 h, after which time a clear yellow solution was obtained. The mixture was cooled to rt, concentrated to remove most of the methanol, and acidified with 6M aqueous hydrochloric acid until a pH=1 was obtained (pH paper). The product formed a gummy solid. The mixture was then concentrated to dryness. A light yellow gummy residue was obtained, which was used in the amide formation step as is. 5-bromo-3-(1,1-dioxido-4-thiepanyl)-1H-indole-7-carboxylic acid (prepared above) was diluted in N,N-dimethylformamide (1 mL) in a 20 mL microwave vial. EDCl hydrochloride (275 mg, 275 mg, 1.43 mmol, 2.7 eq), HOBt hydrate (81 mg, 0.6 mmol, 1.1 eq), and NH3 (0.5 M in dioxane, Aldrich, 8 mL) were added. The mixture was heated in a Biotage microwave oven at 10° C. for 20 minutes under regular absorption. The crude reaction mixture was diluted in ethyl acetate and washed with water. The aqueous layer was washed three times with ethyl acetate (30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuum oven. The crude brown oil was purified by Isco Combiflash, 40 gram column, eluting with 0-20% methanol in dichloromethane. The title compound was obtained as a yellow tarry residue (198 mg, 97% combined yield for both steps).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([O:13]CC)(=[O:12])[CH:10]=[CH2:11].[OH-].[K+]>C(O)C>[C:1]1(=[N:7][O:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(=O)OCC
Reactant: ON=C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCON=C1CCCCC1
Temperature: 60 °C
Reaction time: 96 h
Yield: 24503 %

Procedure:
A mixture of 32.8 g (0.29 mol) of cyclohexanone oxime, 26 g (0.26 mmol) of ethyl acrylate, 26 ml (0.052 mol) of a 2N solution of KOH in ethanol and 150 ml of ethanol is stirred for 96 hours at 60° C. and afterwards concentrated on a vacuum rotary evaporator. The residue (an orange oil) is dissolved in 175 g (0.31 tool) of a 10% solution of KOH in ethanol and the solution is heated for 1 hour to 60° C. The solvent is distilled off and the solid residue is taken up in water. After acidification with c. 15 ml of conc. hydrochloric acid and extraction with ethyl acetate, the organic phase is washed with water, dried over Na2SO4 and concentrated on a vacuum rotary evaporator. Distillation of the residue yields 11.8 g (25%) of the desired acid as an orange liquid. The boiling point is 135° C./0.05 mbar.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:14](O)=[O:15].CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:11]([CH3:10])[CH:12]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NC(=O)c1ccc([N+](=O)[O-])c(C)c1
Yield: 87.8 %

Procedure:
The same operation as in Example (102a) was performed using serine methyl ester hydrochloride (5.24 g, 33.7 mmol), 3-methyl-4-nitrobenzoic acid (6.1 g, 33.7 mmol), WSC hydrochloride (6.71 g, 35 mmol), DMAP (0.18 g, 1.5 mmol), N,N-diisopropylethylamine (4.52 g, 35 mmol) and dichloromethane (100 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 2/1, 1/0) to obtain 8.35 g of the title compound as a light yellow solid (88%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)=[N+:12]=[N-:13]
Reactant: O=Cc1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc(C=O)cc1
Temperature: 60 °C
Yield: 92.2 %

Procedure:
Bromide 3 (180 mg, 0.90 mmol) was dissolved in DMF (10 ml). Sodium azide (88 mg, 1.35 mmol) was added. The reaction mixture was then heated at 60° C. for an hour. The reaction mixture was allowed to cool and was dissolve in ethyl acetate (150 ml) and H2O (150 ml). The phases were separated and the organic phase was washed again with water (2×150 ml). The organic phase was dried over sodium sulphate, and evaporated under reduced pressure to yield 4 as an oil (134 mg, 0.83 mmol, 92%). Rf=0.70 (DCM); νmax=2094, 1694, 1607, 1207, 1167, 812, 773 cm−1; 1H NMR (300 MHz, CDCl3) δ=10.02 (s, 1H, CHO), 7.90 (d, 3J(H,H)=7.9 Hz, 2H, ArCH α to CHO), 7.48 (d, 3J(H,H)=7.9 Hz, 2H, ArCH α to CH2N3), 4.45 (s, 2H, CH2N3); 13C NMR (75 MHz, CDCl3) δ=191.6 (CHO), 142.1 (ArCCH2N3), 136.2 (ArCCHO), 130.2 (ArCH α to ArCCHO), 128.4 (ArCH α to ArCCH2N3), 54.2 (CH2N3); HRMS (ESI+): m/z calculated for C8H7N3ONa [M+Na]+: 184.0481, found 184.0497.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([CH2:12]Cl)[NH:9][C:10](=[O:11])[C:5]=2[S:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]1>CO>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([CH2:12][N:20]3[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]3)[NH:9][C:10](=[O:11])[C:5]=2[S:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]c(CCl)nc2c(Br)c(-c3ccccc3)sc12
Reactant: O[C@@H]1CCNC1
Solvent: CO
Product: O=c1[nH]c(CN2CC[C@@H](O)C2)nc2c(Br)c(-c3ccccc3)sc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of EXAMPLE 10A (90 mg, 0.25 mmol) in methanol (5 mL) was added (R)-pyrrolidin-3-ol (87 mg, 1 mmol) and the mixture stirred at ambient temperature for 2 days. The solvent was removed and residue purified by flash chromatography on silica gel using 1:10:0.5 methanol/ethyl acetate/concentrated ammonium hydroxide to give the title compound. 1H NMR (DMSO-d6) δ 7.75-7.77 (m, 2H), 7.54-7.59 (m, 3H), 4.85 (br, 1H), 4.20 (t, J=6.3 Hz, 1H), 3.69-3.75 (m, 2H), 2.81-2.86 (m, 2H), 2.57-2.58 (m, 2H), 2.01-2.08 (m, 1H), 1.59-1.65 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=O)[CH2:17]Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[C:26]([Br:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:20]=[C:21]2[C:26]([Br:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]2[CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnc(N)c(Br)c1
Reactant: O=C(CBr)[C@@H]1CCCN1C(=O)OCc1ccccc1
Product: Cc1cc(Br)c2nc([C@@H]3CCCN3C(=O)OCc3ccccc3)cn2c1
Yield: 44.4 %

Procedure:
Following the procedures of example 14, (S)-benzyl-2-(2-bromoacetyl)pyrrolidine-1-carboxylate (0.295 g, 0.90 mmol) and 2-amino-3-bromo-5-methylpyridine (0.1765 g, 0.94 mmol), produced the crude material which was adsorbed onto silica gel and purified by flash chromatography (12 g SiO2, 0-50% ethyl acetate in hexanes) to give (S)-benzyl-2-(8-bromo-6-methylimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.165 g, 0.40 mmol, 44%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:35][CH2:34][C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)[N:21]=[CH:22][C:17]=2[CH2:16]1)=O)(C)(C)C.C(N(CC)CC)C.[S:43]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44]1>C(Cl)Cl>[CH2:31]([C:28]1[CH:27]=[CH:26][C:25]([C:24]([NH:23][C:20]2[N:21]=[CH:22][C:17]3[CH2:16][N:15]([S:48]([C:45]4[CH:46]=[CH:47][S:43][CH:44]=4)(=[O:50])=[O:49])[CH2:35][CH2:34][C:18]=3[N:19]=2)=[O:33])=[CH:30][CH:29]=1)[CH3:32]
Reactant: CCc1ccc(C(=O)Nc2ncc3c(n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: O=S(=O)(Cl)c1ccsc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCc1ccc(C(=O)Nc2ncc3c(n2)CCN(S(=O)(=O)c2ccsc2)C3)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66.9 %

Procedure:
Trifluoroacetic acid 7.3 ml (96 mmol) was added to a solution of 2-(4-ethyl-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 567 mg (1.48 mmol) in CH2Cl2 (10 ml) under nitrogen as inert gas and stirring was performed for 1.5 h at RT. After removal of the solvent, the intermediate (4-ethyl-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamide trifluoroacetate) was dissolved in CH2Cl2 (10 ml). After the addition of triethylamine 1150 μl (8.20 mmol), the solution was cooled to 0° C. and 3-thiophene sulfonyl chloride 253 mg (1.39 mmol) was added. The reaction mixture was stirred for 1 h at 0° C. and then overnight at RT. After removal of the solvent, purification was performed by means of column chromatography and the product 4-ethyl-N-[6-(thiophene-3-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide 400 mg (0.93 mmol, 63% of theoretical) was obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]([CH3:17])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([N:3]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]([CH3:17])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCCCCCCN(CC)C(C)CCCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCN(CC)C(C)CCCc1ccc(N)cc1
Yield: 94.2 %

Procedure:
A mixture of 7.389 g (0.022 mol) of N-ethyl-N-heptyl-α-methyl-4-nitrobenzenebutanamine in 92 ml of ethanol was hydrogenated at room temperature overnight in the presence 0.74 g of 5% palladium-on-carbon. A total of 87% of theoretical hydrogen uptake was observed. The reaction mixture was filtered through Celite and the filtrate was evaporated to dryness under reduced pressure to provide 6.312 g of N-ethyl-N-heptyl-α-methyl-4-aminobenzenebutanamine as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[C:13]1([CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1O
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccccc1OCCc1ccccc1
Temperature: 80 °C
Reaction time: 7.5 h
Yield: 34.9 %

Procedure:
A solution of 2-hydroxybenzaldehyde (0.20 mL, 1.9 mmol) in DMF (2.0 mL) was added with (2-bromoethyl)benzene (0.39 mL, 2.8 mmol) and potassium carbonate (0.78 g, 5.6 mmol), stirred at room temperature for 3.0 hours and at 80° C. for 7.5 hours. The reaction mixture was added with water and ethyl acetate to separate the mixture into organic layer and aqueous layer and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain 2-(2-phenylethyloxy)benzaldehyde (0.15 g, 36%).
Reaction SMILES: B1C2CCCC1CCC2.[CH3:10][O:11][CH2:12][CH:13]=[CH2:14].Br[C:16]1[CH:17]=[CH:18][C:19]([S:26][CH3:27])=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CCOCC.O.CN(C=O)C.C1COCC1>[CH3:10][O:11][CH2:12][CH2:13][CH2:14][C:16]1[CH:17]=[CH:18][C:19]([S:26][CH3:27])=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: C=CCOC
Reactant: COC(=O)c1cc(Br)ccc1SC
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COCCCc1ccc(SC)c(C(=O)OC)c1
Temperature: 25 °C

Procedure:
To a THF (0.29 M) solution of 9-BBN (2 eq.) was added allyl methyl ether (2.1 eq.) dropwise and the resulting solution was stirred at RT until no more gaseous evolution was observed. The reaction mixture was then heated to 50° C. for 1 h. To this solution was subsequently added a DMF (0.34 M) solution of methyl 5-bromo-2-(methylthio)benzoate (1 eq.) from the previous step, potassium phosphate (2.5 eq.) and [1,1′-bis(diphenylphosphino)-ferrocene]dipalladium(II) dichloromethane complex (0.1 eq.). The resulting red suspension was heated at 80° C. for 16 h. After cooling to RT, the reaction was diluted with ether and water. The organic layer was separated and washed further with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→7:3 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH2:15])=[O:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>CO>[NH2:1][C:2]1[C:3]([C:13](=[O:14])[NH2:15])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(N)c(C(N)=O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(N)=O)c(N)cc1C(=O)O
Yield: 59.6 %

Procedure:
Methyl 5-amino-4-(aminocarbonyl)-2-methylbenzoate (108 mg, 0.52 mmol) was dissolved in methanol (1.5 mL) and was treated with 1 M sodium hydroxide (1.5 mL, 1.5 mmol) for 1 h. The reaction mixture was concentrated to afford an aqueous residue that was acidified with 1N hydrochloric acid to pH ˜3. The precipitate was collected by filtration, washed with water, and dried in vacuo to afford 5-amino-4-carbamoyl-2-methylbenzoic acid (60.8 mg, 0.31 mmol, 61% yield). 1H NMR (400 MHz, d6-DMSO): δ 12.95 (br s, 1H), 7.99 (br s, 1H), 7.52 (s, 1H), 7.42 (br s, 1H), 7.35 (s, 1H), 4.75 (br s, 2H), 2.33 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]2[C:20](=O)[NH:21][N:22]=[C:12]2[C:11]2[CH:24]=[CH:25][CH:26]=[N:27][C:10]1=2)=[O:8])[CH3:5].[CH3:28]I>CN(C)C=O>[CH3:28][N:21]1[CH2:20][N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:9]([C:7](=[O:8])[CH2:6][N:4]([CH3:5])[CH3:3])[C:10]3[N:27]=[CH:26][CH:25]=[CH:24][C:11]=3[C:12]2=[N:22]1
Reactant: CN(C)CC(=O)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1c2ccccc2N2CN(C)N=C2c2cccnc21
Temperature: 50 °C
Reaction time: 21 h

Procedure:
Sodium hydride (0.178 g., 4.21 mmoles of a 57% dispersion in mineral oil) is added to a solution of 2,9-dihydro-9-[(dimethylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one (4.21 mmoles) in 50 ml. of dimethylformamide and the mixture is heated at 95° C. for 35 minutes. The mixture is cooled to 50° C., a solution of methyliodide (4.21 mmole) is added and heating is continued at 95° C. for 21 hours. The mixture is evaporated and methylene chloride-water is added to the residue. The organic layer is separated and extracted three times with 10 ml. portions of 10% aqueous hydrochloric acid. The acid extract is cooled, made alkaline with 15% aqueous sodium hydroxide and the basic mixture is extracted with methylene chloride. The extract is washed with saturated salt solution, dried over anhydrous magnesium sulfate and evaporated. Crystallization of the residue from ether gives 2,9-dihydro-2-methyl-9-[(dimethylamino)acetyl]-3 H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepine.
Reaction SMILES: COC(=O)C[NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[Cl-].[NH4+].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:34][CH2:35]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH2:5])=[O:37]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a solution of 0.10 g (0.21 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) in 1 mL N,N-dimethylformamide were added 0.022 g (0.41 mmol) ammonium chloride, 0.028 g (0.21 mmol) 1-hydroxybenzotriazole, 0.07 mL N,N-diisopropylethylamine and 0.040 g (0.21 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride. The resulting mixture was stirred at room temperature overnight, filtered over a syringe micro filter and purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to afford 80 mg (80%) of the desired compound as a light brown solid. MS (ESI): m/z=483.098 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[F:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=1>C(Cl)(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][C:15]=1[C:5](=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C)=O)c(F)c1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Aluminum chloride (30.0 g, 0.6 mol) and chloroform (750 mL) were place in a 2 L three-necked round bottom flask fitted with a mechanical stirrer and cooled by means of an ice bath. To the stirred solution acetyl chloride (51.0 g, 0.65 mol) was added dropwise, maintaining the temperature between 5-10° C. The mixture was stirred for 10 minutes at 5° C. before the dropwise addition at 5-10° C. of 3-fluoroanisole (62.6 g 0.5 mol). The mixture was stirred at 0-10° C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2×250 mL). The combined organic layers were washed with water (2×150 ml), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 93-94° C.; 1H NMR (DMSO-d6) 7.8 (m, 2H), 7.3 (t, 1H), 3.9 (s, 3H), 3.5 (s,3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[C:11](=[O:24])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].CO.[Cl:29][C:30]1[CH:39]=[CH:38][C:33]([C:34](OC)=[O:35])=[CH:32][CH:31]=1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Cl:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([CH:10]2[CH2:9][C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=3)[C:11]2=[O:24])=[O:35])=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: O=C1CC[C@H](c2cccc(F)c2)N1c1ccc(OC(F)(F)F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(c1ccc(Cl)cc1)C1C[C@H](c2cccc(F)c2)N(c2ccc(OC(F)(F)F)cc2)C1=O
Temperature: 25 °C
Yield: 87.5 %

Procedure:
Add (R)-5-(3-fluoro-phenyl)-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-2-one (0.89 g, 2.63 mmol) to a suspension of sodium hydride (0.61 g, 15.36 mmol) in dry toluene (40 mL) and stir at room temperature under nitrogen. Add methanol (0.29 mL, approx. 16 mmol) followed by methyl p-chlorobenzoate (1.2 g, 7.0 mmol). Heat under reflux overnight. Cool, add aqueous NH4Cl solution, extract with ethyl acetate. Collect the organic phase, dry over anhydrous magnesium sulfate, evaporate and purify on a silica gel column (isohexane-ethyl acetate) to give the titled compound (1.1 g, 88% yield) MS (m/z): 478 (M+1).