Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[N:7]([CH3:24])[N:6]=1)=[O:4].[NH2:25][C@H:26]([CH2:28][OH:29])[CH3:27].N12CCCNC1=NCCC2>C1(C)C=CC=CC=1>[OH:29][CH2:28][C@@H:26]([NH:25][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[N:7]([CH3:24])[N:6]=1)=[O:4])[CH3:27]
Reactant: C[C@H](N)CO
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)n(C)n1
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)N[C@@H](C)CO)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 1-methyl-5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-1H-pyrazole-3-carboxylic acid methyl ester (80 mg, 0.24 mmol) and L-alaninol (24 mg, 0.32 mmol) in toluene (1 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (14 mg, 0.1 mmol) and the reaction was stirred at room temperature under argon overnight. The mixture was evaporated and purification by chromatography (silica, dichloromethane:methanol=100:0 to 9:1) afforded the title compound (87 mg, 96%) which was obtained as a colorless oil. MS: m/e=372.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7](Cl)=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.C(Cl)CCl.[CH:16]1[CH:17]=C[C:19]2[N:24](O)N=[N:22][C:20]=2[CH:21]=1.CN(C=[O:30])C>>[N:9]1[CH:10]=[CH:11][C:3]2[C:4]=1[NH:5][CH:6]=[CH:7][C:2]=2[C:16]1[CH:21]=[C:20]([C:19]([NH2:24])=[O:30])[NH:22][CH:17]=1
Reactant: CN(C)C=O
Reactant: Clc1cnc2[nH]ccc2c1Br
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Product: NC(=O)c1cc(-c2cc[nH]c3nccc2-3)c[nH]1
Temperature: 25 °C

Procedure:
To a vial with Compound D′ (0.1 mmol) in DMF (1 mL), EDC (2 equivalent, 0.2 mmol) and HOBt (0.5 equivalent, 0.05 mmol) were added and the reaction mixture was stirred at room temperature for half an hour, amine (1.2 equivalent, 0.12 mmol) was added and the reaction mixture was stirred at room temperature for 2-3 hour. Reverse phase HPLC was used to purify the final compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14]CC)=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(Cl)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1OB(O)c2cc(O)cc(Cl)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
To a solution of ethyl 2-(4-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (150 mg, 0.55 mmol) in THF (2 mL) was added an aqueous solution of lithium hydroxide (116 mg, 2.77 mmol) in water (1 mL) at 0° C. The resulting mixture was stirred at ambient temperature for 3 h and acidified with diluted hydrochloric acid at 0° C. to pH=1˜2. The mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (78 mg. Yield: 69%). 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.40 (s, 1H), 8.15 (s, 1H), 7.06 (d, J=1.6 Hz, 1H), 6.91 (d, J=1.6 Hz, 1H), 5.38-5.41 (m, 1H), 3.14-3.19 (m, 1H), 2.15-2.22 (m, 1H). MS (ESI) m/z=243 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH3:27])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]=2[CH3:21])[NH:12][C:11]1=[O:28].[CH2:29]([N:31]([CH2:36][CH3:37])[C:32](=[O:35])[CH2:33]Cl)[CH3:30]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH3:27])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]=2[CH3:21])[N:12]([CH2:33][C:32]([N:31]([CH2:36][CH3:37])[CH2:29][CH3:30])=[O:35])[C:11]1=[O:28]
Reactant: CCOC(=O)c1c(C)cc2[nH]c(=O)n(-c3ccccc3Cl)c(=O)c2c1C
Reactant: CCN(CC)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc2c(c1C)c(=O)n(-c1ccccc1Cl)c(=O)n2CC(=O)N(CC)CC
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
A portion (30 mg) of sodium hydride suspension (50%) in mineral oil was added to a stirred solution of 3-(2-chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-2,4-(1H, 3H)-quinazolinedione (187 mg) in dimethylformamide (10 ml). After addition of N,N-diethyl-chloroacetamide (80 mg), the mixture was stirred at 80° C. for 3 hours. The solvent was evaporated off at reduced pressure, and the residue was extracted with CHCl3. The CHCl3 extract was washed with water, dried over NaSO4 and concentrated. The residue was recrystallized from methanol to give 3-(2-chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-1-(N,N-diethyl)aminocarbonylmethyl-2,4(1H, 3H)-quinazolinedione (138 mg, 57%) melting at 228°-229° C. MS: M/e, 485(M+), 450. NMR: δ (ppm, CDCl3), 1.38 (9H, m), 2.39 (3H, s), 2.72 (3H, s), 3.45 (4H, q), 4.40 (2H, q), 4.95 (2H, d), 6.75 (1H, s), 7.40 (4H, m).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([OH:20])[CH:14]=1.[N+:21]([O-])([OH:23])=[O:22].S(=O)(=O)(O)O>>[OH:19][C:17]1[CH:16]=[C:15]([CH:14]=[CH:13][C:18]=1[N+:21]([O-:23])=[O:22])[O:20][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cccc(O)c1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1O

Procedure:
2,3-Dichloro-5-trifluoromethyl pyridine was condensed with resorcine and the product was nitrated with a mixed acid of nitric acid and sulfuric acid to obtain 2-(3-hydroxy-4-nitrophenoxy)-3-chloro-5-trifluoromethyl pyridine. In 10 ml of methyl ethyl ketone, 1.67 g of the resulting product and 1.09 g of ethyl 2-bromopropionate were dissolved and then, 1.38 g of anhydrous potassium carbonate was admixed. The mixture was refluxed with stirring for 4 hours. After the reaction, a small amount of water was added to the reaction mixture. The solvent was distilled off and the product was extracted with methylene chloride. The extracted phase was washed with water and dried over anhydrous sodium sulfate. Methylene chloride was distilled off. The resulting oily product was adsorbed in a silica gel column and developed and eluted with toluene to obtain 0.8 g of the object compound (nD15 1.5337).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Na].C1(C)C=CC=CC=1[Na:16].C([Na])C1C=CC=CC=1.[C:26](=[O:28])=[O:27].[C]=O>>[C:3]1([CH2:8][C:26]([O-:28])=[O:27])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1.[Na+:16]
Reactant: Cc1ccccc1[Na]
Reactant: Cc1ccccc1Cl
Reactant: O=C=O
Agent: [C]=O
Agent: [Na]
Agent: [Na]Cc1ccccc1
Product: O=C([O-])Cc1ccccc1
Product: [Na+]

Procedure:
In the preferred embodiments of the present invention, chlorotoluene is contacted with sodium which is dispersed in an inert organic solvent at 0° C to 50° C, preferably 10° C to 40° C for 5 minutes to 2 hours preferably about 30 minutes to 1 hour. Thereafter, rearrangement of the tolylsodium to benzylsodium is accomplished by heating the reaction mixture to 40° C to 150° C, preferably 50° C to 120° C for 1 hour to 10 hours preferably 3 hours to 7 hours. After the rearrangement reacting, carbon dioxide gas is introduced into the reaction mixture at room temperature or solid carbon oxide is added to the reaction mixture at room temperature and then the reaction is conducted to produce sodium phenylacetate. Thereafter, a mineral acid is added to the reaction mixture to produce phenylacetic acid; as shown in the first embodiment.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[C:13]3[CH:14]=[N:15][C:16]([NH2:18])=[CH:17][C:12]=3[N:11]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.C1N=CN([C:54](N2C=NC=C2)=[O:55])C=1.N1C=CN=C1.CCN(C(C)C)C(C)C.[CH3:75][O:76][C:77](=[O:86])[C@@H:78]([NH2:85])[C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[C:9]2[C:13]3[CH:14]=[N:15][C:16]([NH:18][C:54](=[O:55])[NH:85][C@@H:78]([C:79]4[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=4)[C:77]([O:76][CH3:75])=[O:86])=[CH:17][C:12]=3[N:11]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:10]=2)=[CH:47][CH:48]=1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(N)ncc23)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)[C@@H](NC(=O)Nc1cc2c(cn1)c(N(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-N,N-bis(4-methoxybenzyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine-3,6-diamine (0.1 g, 0.16 mmol) in anhydrous 1,4-dioxane (3 mL) was added CDI (0.13 g, 0.79 mmol) followed by the addition of imidazole (0.05 g, 0.78 mmol) and the contents were stirred at ambient temperature. After 16 h, DIPEA (0.12 mL, 0.64 mmol) and (S)-methyl-2-amino-2-phenylacetate (0.064 g, 0.32 mmol) were added and stirred. After 2 h, the reaction mixture was quenched with H2O and the organic contents were extracted with EtOAc (2×20 mL), dried over anhydrous Na2SO4 and concentrated. The residue thus obtained was purified by preparative HPLC to afford the title compound MS ES calc'd. for C51H46N6O5 [M+H]+ 823. Found 823.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:27][O:28][NH2:29]>N1C=CC=CC=1>[CH3:27][O:28]/[N:29]=[C:12](\[C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:8][CH:9]=1)/[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1
Reactant: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CO/N=C(/c1cc(OC)c(OC)c(OC)c1)c1csc(-c2ccccc2)n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of 1h (110 mg, 0.59 mmol) in 10 mL pyridine was added O-methylhydroxylamine hydrochloride (52 mg, 0.63 mmol) and the mixture was stirred at 60° C. for overnight. The reaction was quenched with 1 N HCl solution, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to give pure compounds 2f-cis (41 mg) and 2f-trans (33 mg). 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.96-7.94 (m, 2H), 7.45-7.44 (m, 3H), 6.94 (s, 2H), 4.13 (s, 3H), 3.91 (s, 6H), 3.88 (s, 3H). MS (ESI) m/z 407.2 (M+Na)+.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:28]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[CH:27][C:26]=1[C:42]([F:45])([F:44])[F:43]>>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:25]3[C:26]([C:42]([F:44])([F:45])[F:43])=[CH:27][C:28]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:29][C:30]=3[C:31]([F:32])([F:33])[F:34])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCOC(=O)CCc1cc(C(F)(F)F)c(O)c(C(F)(F)F)c1
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2c(C(F)(F)F)cc(CCC(=O)O)cc2C(F)(F)F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(4-ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-3,5-bis(trifluoromethyl)phenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H-NMR (300 Hz, CD3OD): δ 7.75 (s, 1H), 7.69 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 5.36 (s, 2H), 2.67-2.74 (m, 4H), 2.45 (t, J=7.2 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C24H18F9NO3S, 572.1 (M+H). found 572.1.
Reaction SMILES: [C:1]([C:4](C)([CH3:15])[CH2:5]OB(C1C=CC=CC=1)O)([OH:3])=[O:2].Cl[C:18]1[C:23]([S:24]([N:27]([C:37]([O:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[O:38])[C:28]2[C:33]([O:34][CH3:35])=[N:32][C:31]([CH3:36])=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:50]1([CH3:56])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O>[C:1]([C:4]([CH3:15])([CH3:5])[CH2:56][C:50]1[CH:55]=[CH:54][C:53]([C:18]2[C:23]([S:24]([N:27]([C:37]([O:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[O:38])[C:28]3[C:33]([O:34][CH3:35])=[N:32][C:31]([CH3:36])=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:52][CH:51]=1)([OH:3])=[O:2]
Reactant: Cc1ccccc1
Reactant: CC(C)(COB(O)c1ccccc1)C(=O)O
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CC(C)(C)C(=O)O)cc1
Temperature: 85 °C

Procedure:
(2-Carboxy-2-methylpropyl)phenylboronic acid (608 mg), 2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (1.03 g) and sodium carbonate (583 mg) were added to a mixture of toluene (25 ml) ethanol (25 ml) and water (10 ml). The mixture was deoxygenated by alternatively bubbling argon through and evacuating (3 cycles) and tetrakis(triphenylphosphine)palladium(0) (100 mgs) was added. The reaction mixture was heated to 85° C. for 18 hours, cooled to ambient temperature and partitioned between water (15 ml) and ethyl acetate (25 ml). The organic phase was extracted with saturated aqueous sodium carbonate solution (15 ml) and the combined aqueous phases were washed with ethyl acetate (15 ml). The aqueous phase was acidified with 2M hydrochloric acid to pH 1 and extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried (MgSO4) and evaporated to give 2-[4-(2-carboxy-2-methylpropyl)phenyl]-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (495 mg); 1H NMR (d6-DMSO): 0.6 (d, 6H), 1.10 (s, 6H), 1.51-1.69 (m, 1H), 2.52 (s-partly obscured by DMSO), 2.87 (s, 2H), 3.82 (d, 2H), 3.95 (s, 3H), 7.20 (d, 2H), 7.43 (d, 2H), 7.79 (dd, 1H), 8.16 (s, 1H), 8.84-8.97 (m, 2H); mass spectum (+ve ESP) 557.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([C:9](=[O:11])[CH3:10])[C:5]([CH:12]=[CH2:13])=[CH:4][N:3]=1.[CH2:14]([Mg]Br)[CH3:15]>O1CCCC1>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([C:9]([OH:11])([CH2:14][CH3:15])[CH3:10])[C:5]([CH:12]=[CH2:13])=[CH:4][N:3]=1
Reactant: C=Cc1cnc(C)c(O)c1C(C)=O
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: C=Cc1cnc(C)c(O)c1C(C)(O)CC
Reaction time: 48 h

Procedure:
A solution of 3.93 g. of the product from Step A in 200 ml. of tetrahydrofuran was treated dropwise with 110% excess of ethyl magnesium bromide in tetrahydrofuran. After aging 2 days at ambient temperature the reaction was quenched on ice-water (100 ml.) containing 10 g. of ammonium chloride. The aqueous layer was separated and extracted with ether. The combined organic layers were dried over magnesium sulfate and evaporated to dryness to give 2-methyl-3hydroxy-4-(2-hydroxybut-2-yl)-5-vinylpyridine, which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:4].[CH2:14]([Li])CCC.[C:19]([O:26]CC)(=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>O1CCCC1.CCCCCC.O>[CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[CH2:14][C:19](=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:4]
Reactant: [Li]CCCC
Reactant: CC(C)(C)C(=O)Nc1ccncc1
Reactant: CCOC(=O)C(=O)OCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)C(=O)Cc1cnccc1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 10 g of 4-trimethylacetamido pyridine in 150 mL of dry tetrahydrofuran is cooled to −78° C. and 88 mL of 1.6M n-butyllithium in hexane is added in a dropwise fashion. The mixture is then stirred at 0° C. for 3 hours, cooled again to −78° C. and 21.3 g of diethyl oxalate dissolved in 190 mL of tetrahydrofuran is added in a dropwise fashion, the reaction mixture was then gradually allowed to come to room temperature. The reaction mixture is diluted with water and the product is extracted with ether. After drying over magnesium sulfate the solvent is removed in vacuo. The residue is chromatagraphed on silica gel with hexane/ether 2:1 as the eluent to afford ethyl 4-trimethylacetamido-3-pyridylpyruvate as an orange oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22]C(=O)OC(C)(C)C)[CH2:17]2)=[C:4]2[C:10]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:38]>>[ClH:38].[NH2:22][C@@H:18]1[CH2:19][CH2:20][CH2:21][N:16]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=23)[CH2:17]1
Reactant: CCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
(R)-tert-butyl 1-(5-bromo-3-propionamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.150 g, 0.322 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added. The reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase HPLC (0-50% ACN in water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)propionamide hydrochloride (0.110 g, 77.9% yield). 1H NMR (400 MHz, D2O) δ 8.24 (s, 1H), 7.27 (s, 1H), 3.74-3.71 (m, 1H), 3.56-3.52 (m, 1H), 3.33-3.30 (m, 1H), 3.20-3.15 (m, 2H), 2.42-2.37 (q, 2H), 2.08-2.06 (m, 1H), 1.80-1.76 (m, 1H), 1.67-1.54 (m, 2H), 1.10-1.06 (t, 3H). LCMS (APCI+) m/z 366, 368 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7](=O)[CH2:6]2.[NH:14]1C[CH2:17][CH2:16][CH2:15]1.FC(F)(F)C(O)=[O:22]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][C:7]3[NH:14][C:15](=[O:22])[CH2:16][CH2:17][C:6]=3[C:5]=2[CH:4]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc2c(c1)CC(=O)CO2
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C1=C(CO2)NC(=O)CC1

Procedure:
The starting material is prepared as follows: A solution of 17.8 g of 6-methoxy-3-chromanone, 7.5 g of pyrrolidine and 0.1 ml of trifluoroacetic acid in 200 ml of toluene is refluxed for 8 hours in a Dean Stark apparatus. After removal of solvent in vacuo 14.0 g of acrylamide is added and the mixture is heated for 3 hours at 80°. Water is added, the organic layer is separated and evaporated to dryness to afford 9-methoxy-1,2,3,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridin-3-one.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[CH2:8][C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[NH:5]1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>>[CH3:1][N:2]([CH2:3][CH:4]1[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[CH2:8][C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[NH:5]1)[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: CNCC1Nc2ccccc2Cn2cccc21
Reactant: C=CC(=O)OC
Product: COC(=O)CCN(C)CC1Nc2ccccc2Cn2cccc21

Procedure:
The solution of 1.5 g of 11-(N-methylaminomethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (Example 1) in 7.5 ml of methyl acrylate is stirred at room temperature for 24 hours and the excess reagent is evaporated to yield the 11-(N-methyl-N-methoxycarbonylethylamino-methyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine as an oil, which is chromatographed on silica gel and eluted with 2% methanol-methylene chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26](C)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:30])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Product: CC(C)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(4-fluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 376) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.024 g, 6%). mp 132–136° C. 1H NMR (300 MHz, DMSO d6) δ 0.79 (d, J=6 Hz, 6H), 1.83 (m, 1H), 4.19 (d, J=6 Hz, 2H), 7.36 (m, 2H), 7.50 (m, 2H), 7.66 (m, 2H), 7.84 (m, 2H), 7.95 (m, 2H), 8.18 (s, 1H). MS (DCI/NH3) m/z 418 (M+H)+, 435 (M+NH)+. Anal. calc. for C20H20FN3O4S: C, 57.54; H, 4.83; N, 10.07. Found C, 57.26; H, 5.00; N, 9.78.
Reaction SMILES: CS(C)=O.[CH2:5]([O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH-].[K+]>O.C1COCC1>[CH2:18]([O:17][CH2:16][CH:13]([CH2:14][O:15][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCBr
Reactant: OCC(CO)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCCCCCOCC(COCCCCCCCC)OCc1ccccc1
Yield: 76.5 %

Procedure:
In a mixed solution consisting of 50 ml of DMSO and 30 ml of THF were dissolved 3.64 g (20 mmole) of 2-benzylglycerin and 9.26 g (48 mmole) of octyl bromide, and 8.96 g (160 mmole) of powdered potassium hydroxide was added to the solution, followed by vigorous stirring. Two hours later, the reaction solution was poured in cold water, and the mixture was extracted with n-hexane. The extract was washed with water, dried and concentrated, followed by purification by silica-gel chromatography (eluent: n-hexane-ethyl acetate, 20:1) to give 6.22 g (77%) of the desired compound as colorless liquid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]O.[C:12]([Cl:15])(Cl)=[O:13].C1(C)C=CC=CC=1.CC[O:25]CC>>[Cl:15][C:12]([O:13][CH2:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH3:10])=[O:25]
Reactant: CCOCC
Reactant: O=C(Cl)Cl
Reactant: COCCOCCOCCO
Solvent: Cc1ccccc1
Product: CCOCCOCCOCOC(=O)Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
A solution of triethylene glycol monomethyl ether (2 g, 12.2 mmol) in ether (15 mL) was added dropwise to a stirred, ice-cold solution of 20% phosgene in toluene (11.36 mL, 21.92 mmol) over 20 min. The reaction mixture was allowed to warm to rt and stirring was continued for 15 h. Evaporation of the solvent give 2.63 g (95%) of the title compound. 1H NMR (CDCl3): δ4.44 (m, 2H), 3.37 (m, 2H), 3.68-3.63 (m, 6H), 3.55 (m, 2H), 3.38 (s, 3H).