Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:4]=1.[OH-].[Na+]>>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:28])[NH2:29])=[CH:25][CH:26]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:4]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3cccnc3)ccc21
Yield: 85 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-dihydrochloride and sodium hydroxide solution. Yield: 85% of theory, C25H25N7O3 (471.5) ##EQU51##
Reaction SMILES: [CH3:1][N:2]([CH3:24])[N:3]=[C:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]12[CH3:6])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3.[CH2:25]([Li])CCC.CI.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:24][N:2]([CH3:1])[N:3]=[C:4]1[C@H:9]([CH3:25])[CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]12[CH3:6])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NN(C)C)CC[C@@H]12
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NN(C)C)[C@H](C)C[C@@H]12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5 g of 3-methoxy-1,3,5(10)-estratrien-17-one N,N-dimethylhydrazone in 50 ml of absolute tetrahydrofuran (THF) is combined dropwise at 0° C. with 13 ml of a 15% solution of n-butyllithium in hexane. After this addition the mixture is stirred for 60 minutes under argon at 0° C., then 1.3 ml of methyl iodide is added dropwise thereto at 0° C., and the mixture is stirred for another 30 minutes at room temperature. To work up the mixture, it is poured into saturated ammonium chloride solution and extracted with ethyl acetate. Crystallization from acetonitrile yields 5 g of 3-methoxy-16α-methyl-1,3,5(10)-estratrien-17-one N,N-dimethylhydrazone, m.p. 122°-124° C.
Reaction SMILES: COC1C=CC([C@@H]([NH:11][C@H:12]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:13][C:14]([O:16][CH3:17])=[O:15])C)=CC=1.C([SiH](CC)CC)C.[ClH:31]>C(O)=O.C(OCC)(=O)C.CO>[ClH:31].[ClH:31].[NH2:11][C@H:12]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C[C@H](N[C@@H](C)c1ccc(OC)cc1)c1cccnc1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O=CO
Product: COC(=O)C[C@H](N)c1cccnc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
A mixture of methyl N-[(S)-1-(4-methoxyphenyl)ethyl)-(S)-3-amino-3-(3-pyridyl)propanoate (57.35 g, 0.148 mol) and triethylsilane (25.81 g, 0.222 mol) in formic acid (120 mL) was heated to 90° C. (oil-bath) while stirring. The initial suspension became a clear solution after 5 minutes at 90° C. Heating and stirring was continued for 2 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure at 50° C. to give a residual oil. The residual oil was dissolved in ethyl acetate (300 mL) and methanol (100 mL). The solution was filtered. The filtrate was treated slowly with 9.8 M HCl in methanol (30.2 mL, 0.296 mol) with stirring. The resulting solution was diluted with ethyl acetate (200 mL) and heated on a steam-bath to remove excess methanol until the solution became cloudy. The mixture was then stirred at room temperature overnight and the solid product crystallized from the solution. Ethyl acetate (150 mL) was added to the suspension and the mixture was stirred for another 2 h. The solid was collected by filtration and washed with 200 mL of ethyl acetate, then dried in vacu for 1 h. The desired product was obtained as a white powder (27.05 g, 72% yield).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH:13]=[CH:14][CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:8][C:7]=1[C:18](=[O:20])[CH3:19])([OH:3])=[O:2].[CH:21]([C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1)=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[OH-].[K+]>C(O)C>[C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]=[C:15]([CH3:16])[CH3:17])[CH:9]=[CH:8][C:7]=1[C:18](=[O:20])[CH:19]=[CH:33][C:32]1[CH:35]=[CH:36][C:29](/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:30][CH:31]=1)([OH:3])=[O:2]
Reactant: CC(=O)c1ccc(OC=CC(C)C)cc1OCC(=O)O
Reactant: CCCCCCC=Cc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC/C=C/c1ccc(C=CC(=O)c2ccc(OCC=C(C)C)cc2OCC(=O)O)cc1
Reaction time: 0.75 h
Yield: 57.5 %

Procedure:
To a solution of 9.35 g of 2'-carboxymethoxy-4'-(3-methyl-butenyloxy)acetophenone and 7.37 g of 4-(1-octenyl)benzaldehyde in 170 ml of ethanol was added 11.5 g of potassium hydroxide and the mixture was stirred for 45 minutes. After neutralization with dilute hydrochloric acid, the precipitated solid was collected by filtration and recrystallized from 90% ethanol to give 9.2 g of 2'-carboxymethoxy-4'-(3-methyl-2-butenyloxy)-4-(1-(E)-octenyl)chalcone of the title compound as a plae yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33].CCOCC>CO.C1COCC1>[ClH:33].[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: NCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
{4-[4-(2-tert-Butoxycarbonylaminoethoxy)phenyl]butyl}carbamic acid benzyl ester 1 (11.0 g, 24.9 mmol) was dissolved in methanol (110 mL) and THF (20 mL). 12N Hydrochloric acid (40 mL) was added dropwise, and the reaction was allowed to stir. After 1.5 h, ether (200 mL) was added, and the reaction was suction filtered to collect a white solid. The solid was washed with ether, air dried, and dried under vacuum. This afforded 7.6 g, (82%) of 7 as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.39 (br s, 11H), 1.52 (m, 2H).
Reaction SMILES: C([N:4]([C:6]([C:8]1[C:16]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)=[N:14][CH:13]=[N:12][C:11]=2[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1)=O)[NH2:5])(=O)C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:35].CO[CH2:50][CH2:51]OC>>[CH3:50][C:51]1[S:35][C:6]([C:8]2[C:16]3[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=4)=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=2)=[N:4][N:5]=1
Reactant: CC(=O)N(N)C(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc([N+](=O)[O-])c3)c12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COCCOC
Product: Cc1nnc(-c2cn(COCC[Si](C)(C)C)c3ncnc(-c4cccc([N+](=O)[O-])c4)c23)s1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of N-acetyl-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbohydrazide (0.40 g, 0.85 mmol) in ethylene glycol dimethyl ether (10 mL), was added P2S5 (378 mg, 1.70 mmol). The resulting solution was stirred for 1 hour at 50° C., then concentrated in vacuo and extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was purified by chromatography using silica gel, eluting with 1-100% ethyl acetate/petroleum ether. The product was collected and concentrated in vacuo to afford 2-methyl-5-(4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1,3,4-thiadiazole as a yellow oil. LRMS (ESI) calc'd for C21H25N6O3SSi [M+H]+: 469, found 469.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[C:26]([F:39])[CH:25]=3)[N:20]=2)[CH:15]=[N:16][C:17]=1Cl>CC(C)CO.C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([F:39])[CH:25]=3)[N:20]=2)[CH:15]=[N:16][C:17]=1[O:23][CH2:19][CH:14]([CH3:15])[CH3:13]
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2noc(-c3cnc(Cl)c(Cl)c3)n2)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(C)CO
Solvent: C1CCOC1
Product: CC(C)COc1ncc(-c2nc(-c3ccc(OCC(=O)O)c(F)c3)no2)cc1Cl
Temperature: 130 °C

Procedure:
Lithium bis(trimethylsilyl)amide (225 μl; 1 M; 0.22 mmol) was added to a solution of tert-butyl {4-[5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl]-2-fluorophenoxy}acetate (66.04 mg; 0.15 mmol) in 2-methyl-1-propanol (1.50 mL) and THF (2 mL). The resulting mixture was heated at 130° C. for 10 min in the microwave. A mixture of the desired product and the isopropyl ester was isolated. NaOH (5N solution; 5 eq; 0.15 mL) was added and the mixture was stirred at RT for 2 hours. The reaction mixture was diluted with EtOAc and washed with HCl 1N, brine and dried over MgSO4. After evaporation of the solvents, the title product was isolated as white solid (51 mg; 81%). 1H NMR (DMSO-d6, 300 MHz) δ 13.25 (br s, 1H), 8.91 (d, J=2 Hz, 1H), 8.57 (d, J=2 Hz, 1H), 7.90-7.86 (m, 2H), 7.32 (t, J=9 Hz, 1H), 4.91 (s, 2H), 4.27 (d, J=6 Hz, 2H), 2.12 (m, 1H), 1.02 (d, J=6 Hz, 6H). LC/MS (Method B): 420.3 (M−H)−. HPLC (Method A) Rt 5.29 min (Purity: 100%).
Reaction SMILES: [F:1][C:2]1[C:7](F)=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Na].CC[O:16]CC>CO>[F:9][C:6]1[CH:5]=[C:4]([OH:16])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([F:1])[CH:7]=1
Reactant: CCOCC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [Na]
Solvent: CO
Product: O=[N+]([O-])c1c(O)cc(F)cc1F

Procedure:
To a stirred solution of 2,3,4-trifluoronitrobenzene (5 g, 28.23 mmol) in dry methanol (70 ml) was added a solution of sodium (0.68, 29.46) in dry methanol (30 ml). The solution was stirred until all starting material was consumed (˜2 h). After concentration water was added and the solution was extracted with ether, dried over Na2SO4, filtered and concentrated to a yellow residue (4.65 g). To the solution of the yellow residue in dichloromethane (140 ml) was added boron tribromide (1M in dichloromethane, 40 ml) and stirred at room temperature overnight. Water was then added and the solution stirred for further 30 min. The organic phase was separated and the water phase was extracted with ether. The combined organic phase were dried over Na2SO4, filtered and concentrated in vacuo to give a brownish residue. The residue was taken up into ether and washed with 2M sodium hydroxide and water. The water and sodium hydroxide washings were combined and neutralized with 6M HCl and extracted with ether, dried over Na2SO4 and evaporated to give a yellow residue which was purified by flash chromatography on silica gel with EtOAc:Heptan; 1:2 as eluent to give the desired product 2 g, 11.42 mmol.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:18])C=1.O>COCCOC>[NH:1]1[C:5]2=[N+:6]([O-:18])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: O
Solvent: COCCOC
Product: [O-][n+]1cccc2cc[nH]c21
Reaction time: 1 h
Yield: 41 %

Procedure:
The commercially available 1H-pyrrolo[2,3-b]pyridine x7 (6.0 g, 50.8 mmol) is dissolved in 1,2-dimethoxyethane (50 ml). A solution of 70-75% m-chloroperbenzoic acid (17 g, 1.4 eq, 71.1 mmol) in 1,2-dimethoxyethane (40 ml) is added under cooling with cold water at a temperature below 25° C. The obtained suspension of the salt is stirred additionally for 1 h, kept overnight at −20° C. and filtered. The solid on the filter is washed with ether (2×30 ml) and air-dried. The obtained product is dissolved in a minimum of water. The pH of the solution is adjusted to 9 by the addition of aqueous K2CO3 under stirring and cooling with cold water. The formed suspension of the free N-oxide x257 is kept at +3° C. overnight and filtered. The product is washed with ice-cold water (2×10 ml) and dried over P2O5 under 1 mmHg to yield 1H-pyrrolo[2,3-b]pyridine 7-oxide x257 (3.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12](Cl)Cl.[CH2:15]([NH2:20])[CH2:16][CH2:17][CH2:18][NH2:19]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12]1[NH:20][CH2:15][CH2:16][CH2:17][CH2:18][NH:19]1
Reactant: NCCCCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(N=C(Cl)Cl)c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)c(N=C2NCCCCN2)c1
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
(2-Chloro-5-nitrophenyl)carbonimidic dichloride (17.8 g, 70.0 mmol) was dissolved in tetrahydrofuran (68 mL). The solution was added dropwise within 30 min to a solution of 1,4-butanediamine (30.9 g, 350 mmol) in tetrahydrofuran (168 mL) which was kept at 5-10° C. The reaction mixture was stirred for 1 h at 5-10° C. another 2 hr at room temperature. The suspension was filtered, and washed with tetrahydrofuran. The filtrate was concentrated in vacuo. The residue was taken up in water, filtered, and washed with water and disopropyl ether. After drying at 50° C. under vacuum, the title compound (8.9 g, 33.4 mmol, 48%) was obtained as a yellow amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N+:18]([O-])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23](C)C(Cl)=O.C[Si](C#N)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([C:22]#[N:23])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1ccc(-c2ccnc(Nc3cccc(Cl)c3)n2)cc1
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: N#Cc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
500 mg (1.67 mmol) of N-(3-chloro-phenyl)-4-(N-oxido-4-pyridyl)-2-pyrimidineamine are suspended in 5 ml of acetonitrile, and 0.42 ml (4.5 mmol) of dimethylcarbamoyl chloride and 0.56 ml (4.5 mmol) of trimethylsilyl cyanide are added. After stirring for 14 hours at 60°, the reaction mixture is cooled to RT and the reaction product is isolated by filtration and washed with diethyl ether. Recrystallisation from tetrahydrofuran gives N-(3-chloro-phenyl)-4-(2-cyano-4-pyridyl)-2-pyrimidineamine in the form of yellow crystals; m.p. 221°-222°, Rf =0.6 (hexane:ethyl acetate=1:1).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:13]=[O:14])=[CH:7]2.[C:15](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[C:11]([O:12][CH3:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:13]=[O:14])=[CH:7]2
Reactant: O=Cc1ccc2c(Br)c(O)ccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc2cc(C=O)ccc2c1Br
Yield: 96 %

Procedure:
Step c) A mixture of 5-bromo-6-hydroxy-2-naphthaldehyde (34.0 g, 135.5 mmol), potassium carbonate (18.7 g, 135.5 mmol), dimethyl sulfate (12.8 mL, 135.5 mmol) and acetone (500 mL), was refluxed for 3 hours. The volatiles were removed in vacuo, and the residue was suspended in water. The precipitated solid was filtered and dried, to yield a yellow solid (34.5 g, 96 % yield, m.p. 133°-135° C.).
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:7]=[C:6]([NH:16][C:17]([CH:19]2[CH2:23][CH2:22][C:21](=[O:24])[N:20]2[CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([CH3:39])[CH:33]=3)[CH2:27][CH2:26]2)=[O:18])[CH:5]=1.[OH-].[Na+]>CO>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:28]2[CH2:27][CH2:26][CH:25]([N:20]3[C:21](=[O:24])[CH2:22][CH2:23][CH:19]3[C:17]([NH:16][C:6]3[CH:5]=[C:4]([CH:9]=[C:8]([C:10]4[N:14]([CH3:15])[N:13]=[N:12][N:11]=4)[CH:7]=3)[C:3]([OH:40])=[O:2])=[O:18])[CH2:30][CH2:29]2)=[CH:33][C:34]=1[CH3:39]
Reactant: COC(=O)c1cc(NC(=O)C2CCC(=O)N2C2CCN(Cc3ccc(Cl)c(C)c3)CC2)cc(-c2nnnn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CN2CCC(N3C(=O)CCC3C(=O)Nc3cc(C(=O)O)cc(-c4nnnn4C)c3)CC2)ccc1Cl
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 3-({1-[1-(4-Chloro-3-methyl-benzyl)-piperidin-4-yl]-5-oxo-pyrrolidine-2-carbonyl}-amino)-5-(1-methyl-1H-tetrazol-5-yl)-benzoic acid methyl ester (270 mg) in MeOH (10 ml) at room temperature was added 4M NaOH (aq) (10 ml) and the reaction stirred overnight. The organic and aqueous layers were separated and the organic layer concentrated in vacuum. The residue was triturated in toluene and diethyl ether successively leaving the title compound (220 mg). Rt=0.96 min (method E).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].I[CH3:14]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: CI
Product: CC(C(=O)O)c1ccc(Cl)cc1Cl

Procedure:
prepared from 2,4-dichlorophenylacetic acid and iodomethane;
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH2:7][CH2:8][CH2:9][O:10]C2CCCCO2)[NH:5][C:4](=[O:17])[CH2:3]1>C(O)(=O)C.C1COCC1.O>[OH:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH:5][C:4](=[O:17])[CH2:3][CH:2]1[CH3:1]
Reactant: CC1CC(=O)NC1CCCOC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC1CC(=O)NC1CCCO

Procedure:
A mixture of the title compound of EXAMPLE 234 is treated with acetic acid:THF:water (4:2:1), and concentrated. The resulting material is purified by column chromatography to yield the title material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][CH:16]=[CH:15][CH2:14][N:13]2[C:19]([OH:21])=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl>O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16]([C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[CH:15][CH2:14][N:13]2[C:19]([OH:21])=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N2C=CC=CCN2C(=O)O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(S(=O)(=O)N2C=CC(C(=O)OCc3ccccc3)=CCN2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 1-[(4-methoxyphenyl)sulfonyl]-diazepine-2-carboxylic acid (0.570 g, 1.33 mmol) is dissolved in water (5 mL) and p-dioxane (10 mL). Triethyl amine (0.74 mL, 5.32 mmol) and benzyl chloroformate (0.228 mL, 1.59 mmol) are next added. The reaction mixture is stirred overnight at room temperature, and then the solution is acidified with 1N HCl to pH˜1 and poured into water and extracted with methylene chloride. The organic extracts are dried (Na2SO4) and concentrated down to an oil. The oil is purified by HPLC with a reverse phase column using 70% (95% water, 5% acetonitrile, 0.1% formic acid) and 30% (80% acetonitrile, 20% water) as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[NH2:35][N:36]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27]([NH:35][N:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:33])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NN1CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NN4CCCCCC4)cc3)c2cc1OC
Yield: 47.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-aminohomopiperidine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (35 mg, yield 47%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=O)[CH:13]([Cl:15])[CH3:14])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:17]OC1C=CC(N)=CC=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1>>[Cl:15][CH:13]([C:12]1[N:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][C:29]=2[CH3:17])[C:7](=[O:9])[C:6]2[C:5](=[CH:4][CH:3]=[CH:2][CH:10]=2)[N:11]=1)[CH3:14]
Reactant: Cc1ccc(N)cc1
Reactant: COc1ccc(N)cc1
Reactant: CC(Cl)C(=O)Nc1ccc(Br)cc1C(=O)O
Product: Cc1ccc(-n2c(C(C)Cl)nc3ccccc3c2=O)c(C)c1

Procedure:
In a similar manner as described above in Paragraph A, but replacing 2-(2-chloropropionylamino)benzoic acid with 5-bromo-2-(2-chloro-propionylamino)benzoic acid and p-anisidine with 4-methyl-phenylamine, the following compound was prepared:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1([CH3:25])[NH:23][CH2:22][CH2:21][NH:20][C:19]1=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:23]2[CH2:22][CH2:21][NH:20][C:19](=[O:24])[C:18]2([CH3:25])[CH3:17])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: CC1(C)NCCNC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCNC(=O)C2(C)C)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.7 %

Procedure:
A mixture of intermediate 100.2 (Step 100.2) (18.4 g, 64 mmol), 3,3-dimethyl-piperazin-2-one (Step 108.4) (9 g, 70 mmol, 1.1 equiv) and Cs2CO3 (27.1 g, 83.2 mmol, 1.3 equiv) in DMF (75 ml) was stirred for 12 h at rt, quenched by addition of H2O (500 mL) and filtered to afford 14.5 g of the title compound as an off-white solid. Title compound: ESI-MS: 335.2 [M+H]+; tR=2.22 min (System 1).