Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][C:14]([OH:16])=O)[C:9]2=O)=[CH:4][CH:3]=1.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH:8]3[C:9]([C:10]=2[CH:11]=1)=[N:24][N:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](=[O:16])[CH2:13]3
Reactant: NNc1ccccc1
Reactant: O=C(O)CC1CCc2ccc(Cl)cc2C1=O
Solvent: CCO
Product: O=C1CC2CCc3ccc(Cl)cc3C2=NN1c1ccccc1
Yield: 71 %

Procedure:
A mixture of 12 g of 7-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid and 8.1 g of phenylhydrazine in 150 ml of ethanol is refluxed under heating for 14 hours. Then the ethanol is distilled off under reduced pressure, 100 ml of acetic acid is added to the residue and the mixture is refluxed under heating for 7 hours. After the acetic acid is distilled off, the residue is extracted with chloroform. The extract is washed with water, dried over magnesium sulfate anhydride and then the chloroform is distilled off to give crystals. The precipitated crystals are collected by filtration and recrystallized from alcohol to give 11.1 g of 9-chloro-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one as colorless prisms, melting at 120°-122° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1)#[N:2].I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=[C:13]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=3)[C:21]=12
Reactant: N#Cc1ccc(B(O)O)cn1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc(C#N)nc2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 12.8 %

Procedure:
A solution of 2-cyanopyridine 5-boronic acid pinocol ester (18 mg, 0.08 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 mL). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA21 (2.5 mg, 14% yield). ESI-MS (M+H)+ m/z calcd 280.1, found 280.1.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:42]=[CH:41][CH:40]=[CH:39][C:26]=2[O:27][CH2:28][CH:29]=[C:30]2[CH2:35][CH2:34][CH:33]([C:36]([NH2:38])=[O:37])[CH2:32][CH2:31]2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[Cl:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH2:49]Br>CN(C=O)C.O>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:42]=[CH:41][CH:40]=[CH:39][C:26]=2[O:27][CH2:28][CH:29]=[C:30]2[CH2:35][CH2:34][CH:33]([C:36]([NH:38][CH2:49][C:48]3[CH:51]=[CH:52][CH:53]=[C:46]([Cl:45])[CH:47]=3)=[O:37])[CH2:32][CH2:31]2)[N:22]=[CH:21]1
Reactant: Clc1cccc(CBr)c1
Reactant: NC(=O)C1CCC(=CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(Cl)c1)C1CCC(=CCOc2ccccc2-c2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 33.8 %

Procedure:
To a stirred solution of 4-(2-(2-(1-trityl-1H-imidazol-4-yl)phenoxy)ethylidene)cyclohexanecarboxamide (177 mg, 0.320 mmol) in anhydrous DMF (3 mL) at 0° C. was added NaH (9.0 mg, 0.384 mmol). The resulting suspension was allowed to stir at room temperature for 45 min. To the resulting solution was added 3-chlorobenzyl bromide (79 mg, 0.384 mmol). After stirring overnight, the reaction mixture was carefully diluted with water and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water, brine and dried (Na2SO4). The solvent was removed under reduced pressure and the crude product was taken to next step without further purification. To a solution of the crude ether was added acetic acid (1.0 mL) and MeOH (4.0 mL). The solution was stirred at 80° C. for 2 h. The solution was allowed to cool to room temperature and the pH was adjusted to ˜10 with 10% NaOH (aq). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layer were washed with water, brine, and dried. The solvent was removed in vacuo to afford the crude residue, which was purified by flash column chromatography on silica gel to afford the desired product (47 mg, 0.108 mmol, 34%). 1H NMR (DMSO-d6): 1.44-1.52 (m, 4H), 1.69-1.79 (m, 4H), 2.19-2.23 (m, 1H), 3.85 (s, 2H), 4.05-4.11 (m, 2H), 6.63 (d, 1H, J=10.5 Hz), 6.88-6.93 (m, 2H), 6.99 (t, 1H, J=6.8 Hz), 7.09-7.11 (m, 2H), 7.18 (d, 1H, J=7.6 Hz), 7.25 (t, 1H, J=7.6 Hz), 7.41-7.48 (m, 2H), 7.65 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][CH2:6][C:7](O)=[O:8]>O=S(Cl)Cl>[ClH:1].[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][CH2:6][C:7]([Cl:1])=[O:8]
Reactant: CN(C)CCCC(=O)O
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CN(C)CCCC(=O)Cl

Procedure:
10 g (60 mmol) of 4-dimethylaminobutyric acid hydrochloride (Janssen; Bruggen/Germany) are heated for approximately 3 h at 65° C. in 30 ml of SOCl2. SOCl2 is evaporated off and the residue is stirred to yield the title compound: TLC of a sample dissolved in methanol, Rf (U)=0.67; TLC of 4-dimethylaminobutyric acid hydrochloride, Rf (U)=0.50.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[C:14]([O:47][CH3:48])=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=4)[CH2:27][CH:26]3[CH2:44]O)=[O:24])=[CH:18][C:17]=2[CH:46]=1.[CH2:49]([N:51](CC)[CH2:52][CH3:53])[CH3:50]>C(Cl)Cl>[CH2:49]([N:51]([CH2:44][CH:26]1[CH2:27][N:28]([CH2:31][C:32]2[CH:33]=[C:34]([O:42][CH3:43])[C:35]([O:40][CH3:41])=[C:36]([O:38][CH3:39])[CH:37]=2)[CH2:29][CH2:30][N:25]1[C:23]([C:19]1[CH2:20][CH2:21][CH2:22][C:16]2[CH:15]=[C:14]([O:47][CH3:48])[C:13]([O:12][CH3:11])=[CH:46][C:17]=2[CH:18]=1)=[O:24])[CH2:52][CH3:53])[CH3:50]
Reactant: CCN(CC)CC
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CO)=C2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCN(CC)CC1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.8 %

Procedure:
To a solution of oxalyl chloride (360 mg) in methylene chloride (5 ml) is added dropwise at -78° C. a (340 mg) solution of dimethyl sulfoxide (340 mg) in methylene chloride (2 ml), and the mixture is stirred for 10 minutes. To the resulting reaction mixture is added dropwise a solution of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine-2-methanol (750 mg) in methylene chloride (2 ml), then the mixture is stirred for 15 minutes. To the reaction mixture is added triethylamine (1 g), then the reaction temperature is raised up to room temperature. The reaction mixture is poured into ice-water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is dissolved in methanol (10 ml). To the solution is added diethylamine hydrochloride (1.4 g), and the mixture is stirred for 3 hours at 50° C. To the reaction mixture is added, after cooling, sodium cyanoborohydride (90 mg), followed by stirring for one hour at room temperature. The reaction mixture is poured into ice-water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:ethyl acetate-methanol=9:1) to give 2-diethylaminomethyl-1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine (230 mg). This product is converted to its hydrochloride, followed by recrystallization from ethanol to give colorless crystals, m.p. 157-160° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH3:13][N:14]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:14]([CH3:15])[CH3:13])=[CH:22][CH:21]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CNc1ccc(Br)cc1
Reactant: CN(C)Cc1ccc(N)cc1
Product: CN(C)Cc1ccc(NC(=O)CNc2ccc(Br)cc2)cc1

Procedure:
The product was prepared according to general working method I from (4-bromo-phenylamino)-acetic acid and 4-dimethylaminomethyl-phenylamine.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH2:11]([O:13][C:14](=[O:25])[C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:12]>>[CH2:11]([O:13][C:14](=[O:25])[C:15](=[CH:21][NH:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:9]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:12]
Reactant: CCCc1cccc(N)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCCc1cccc(NC=C(C(=O)OCC)C(=O)OCC)n1

Procedure:
The product from Example 2c (223 mg, 1.52 mmol) was reacted with 2-ethoxymethylene-malonic acid diethyl ester 0.350 mL, 1.75 mmol) following the procedure in Example 1a to give the title compound after silica gel column chromatography eluting with EtOAc/hexane (386 mg, 80%).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([NH2:13])(=[O:12])=[O:11])[C:4]=2[CH2:3][S:2]1.C(N=[C:19]=[O:20])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([N:13]=[C:19]=[O:20])(=[O:11])=[O:12])[C:4]=2[CH2:3][S:2]1
Reactant: CCCCN=C=O
Reactant: NS(=O)(=O)c1cccc2c1CSC2
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1cccc2c1CSC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 5.5 g of 1,3-dihydrobenzo[c]thiophene-4-sulfonamide, 2.5 g of butyl isocyanate and 0.05 g of DABCO® in 50 ml of xylene was heated to 135° and 2.2 ml of liquid phosgene was added in small portions at approximately 135°. When the addition of phosgene was complete, heating was continued for 5 minutes before the dark brown suspension was cooled to ambient temperature under a slow stream of nitrogen. The reaction mixture was filtered under nitrogen and the filtrate was concentrated in vacuo to give 1,3-dihydrobenzo[c]thiophene-4-sulfonyl isocyanate as a dark red-brown oil. The crude sulfonyl isocyanates was dissolved in methylene chloride (total volume=26 ml) for reaction with aminoheterocycles.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[C:14]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:13]=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C:10]1[N:15]=[C:14]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(CO)n1
Reaction time: 1 h

Procedure:
tert-Butyl (2R)-2-({[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]oxy}methyl)pyrrolidine-1-carboxylate (604 mg, 1.4 mmol) was dissolved in THF (5 mL) and tetrabutylammonium fluoride (2.1 mL, 1.0M in THF, 2.1 mmol) was added. The reaction mixture was stirred 1 h. The organic solvent was evaporated and the residue purified by flash chromatography using a gradient of EtOAc/heptane to give the title compound as a clear oil. Yield: 430 mg (97%). MS (ESI+) 309.3 (M+1H+).
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[CH2:11][CH2:10][N:9]([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=4)[C:20]([O:22]CC)=[O:21])=[O:15])[CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[NH:3][N:2]=1.[OH-].[Na+]>CO>[CH:1]1[C:13]2[C:12]3[CH2:11][CH2:10][N:9]([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=4)[C:20]([OH:22])=[O:21])=[O:15])[CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[NH:3][N:2]=1
Reactant: CCOC(=O)c1cccc(NC(=O)N2CCc3c(cnc4[nH]ncc34)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(NC(=O)N2CCc3c(cnc4[nH]ncc34)C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a solution of ethyl 3-(6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoate (0.593 g, 1.62 mmol) in methanol (10 mL) was added aqueous NaOH (0.64 g in 6 mL of H2O, 16.2 mmol). The reaction was stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure the resulting aqueous solution acidified to pH<2 using 2N HCl. A white precipitate crashed out, which was filtered, washed with water and dried to give the pure desired product, 3-(6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoic acid (0.539 g, 98%) as a white solid; M.p.=237-241° C.; 400 MHz 1H NMR (DMSO-d6) δ: 9.0 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.14-8.1 (m, 1H), 7.82-7.78 (m, 1H), 7.56-7.51 (m, 1H), 7.4-7.34 (m, 1H), 4.81 (s, 2H), 3.86 (t, J=6 hz, 2H), 3.18 (t, J=6 Hz, 2H); LCMS [M+H]: 338.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:42])([CH3:41])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][C:32]1=[O:40].FC(F)(F)C([O-])=O>>[CH3:42][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:41])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][C:32]1=[O:40]
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CC(C)(N)CCn1c(=O)oc2ccccc21
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(CCn1c(=O)oc2ccccc21)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
This is prepared according to General Method 1 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 220 mg (1 mmol) 3-(3-amino-3-methyl-butyl)-3H-benzoxazol-2-one. Yield: 227 mg (42%, trifluoroacetate); mass spectroscopy: [M+H]+=428.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH:29]2[CH2:31][O:30]2)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH:29]([OH:30])[CH2:31][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Fc1ccc(OCC2CO2)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)COc3ccc(F)cc3)CC1)O2

Procedure:
Compound 164 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(4-fluorophenoxy)methyl]oxirane and conditions outlined in procedure X. M.p.=163-167° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 6.95 (t, 2H), 6.85 (m, 2H), 4.15 (m, 1H), 3.95 (d, 2H), 3.0-2.9 (m, 3H), 2.8 (d, 2H), 2.7-2.6 (m, 2H), 2.55 (t, 2H), 2.15 (d, 2H), 1.95-1.85 (m, 2H); LCMS: 470 [M+H].
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[Cl:31][C:32]1[CH:33]=C(C=[CH:38][CH:39]=1)CN>>[Cl:31][C:32]1[CH:33]=[C:11]([CH:12]=[CH:38][CH:39]=1)[CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCc1cccc(Cl)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 3-chlorobenzylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 383 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.27 (1H, s) 8.72 (1H, t, J=5.95 Hz) 8.03 (1H, d, J=5.47 Hz) 7.82 (1H, d, J=5.47 Hz) 7.50 (1H, d, J=5.47 Hz) 7.21-7.41 (5H, m) 6.84 (1H, d, J=5.47 Hz) 6.41 (1H, dd, J=3.51, 1.95 Hz) 4.46 (2H, d, J=5.86 Hz)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C@H:24]([CH3:25])[CH2:23][CH2:22][C@H:21]3[CH3:26])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[CH3:26][C@@H:21]1[CH2:22][CH2:23][C@@H:24]([CH3:25])[N:20]1[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1)=[O:19]
Reactant: C[C@@H]1CC[C@@H](C)N1C(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Reactant: CCNCC
Product: CCN(CC)CCCOc1ccc(-c2ccc(C(=O)N3[C@H](C)CC[C@H]3C)cc2)cc1

Procedure:
The product from Example 4A and diethylamine were processed as described in Example 10F to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].Cl[CH2:14][C:15](=[O:17])[CH3:16].O>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH2:14][C:15](=[O:17])[CH3:16])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Cn1c(Cl)nc2ccccc21
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloro-1H-benzimidazole (1.53 g) in DMF (20 ml) was added sodium hydride (60% in oil, 0.480 g) at 0° C. by small portions. After stirring for 10 min, chloroacetone (1.19 mL) was added, and the obtained mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate to give the title compound (1.73 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]4)[N:2]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C[Si](C([Si](C)(C)C)(C(F)(F)F)C(N)=O)(C)C>O1CCOCC1.C(OCC)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]4)[N:2]=1
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cc4ccccc4cn3)ccc12
Agent: C[Si](C)(C)C(C(N)=O)(C(F)(F)F)[Si](C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cc4ccccc4cn3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a suspension of (+)-(4aR)-(10bR)-8-(3-isoquinolinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (80 mg, 0.230 mmol), in 1.0 mL of 1,4-dioxane was added DDQ (58 mg, 1.1 equiv.) followed by bistrimethylsilyltrifluoromethyl acetamide (270 mg, 4.5 equiv.), and the solution was stirred at room temperature for 2 h, then heated at 100° for 20 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 2M sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give, after trituration from ether/hexanes, 18 mg (24%) of the title compound as a white solid. mp 248° (decomp.) FDMS m/e=340.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:40]=[CH:41][CH:42]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:46]2[CH2:45][CH2:44][N:43]([C:39]3[CH:40]=[CH:41][CH:42]=[C:37]([C:36]([F:49])([F:50])[F:35])[CH:38]=3)[CH2:48][CH2:47]2)=[O:18])[N:8]([C:6]([C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:31][CH:30]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 1-[3-(trifluoromethyl)phenyl]piperazine, the title compound was obtained in 88% purity by HPLC. MS(ESI+): m/z=565.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28]Cl)[C:23]=1[CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>C(O)C>[CH2:11]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][S:1][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[C:23]=1[CH3:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(OCCOCc2ccccc2)ccnc1CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(OCCOCc2ccccc2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 60 °C
Yield: 74.1 %

Procedure:
A mixture comprising 1.0 g of 2-mercaptobenzimidazole, 2.0 g of 4-(2-benzyloxyethoxy)-2-chloromethyl-3-methylpyridine, 302 mg of sodium hydroxide and 40 ml of ethanol was stirred under heating at 60° C. for 1.5 hours and distilled under a reduced pressure to remove the ethanol. The obtained residue was subjected to silica gel column chromatography. The column was treated with 30 to 60% ethyl acetate in n-hexane to obtain 2.0 g of the title compound as a white crystal.
Reaction SMILES: C(OC(CO[CH2:8][C:9]1[N:13](CC2C=CC(OC)=CC=2)[C:12]([SH:23])=[N:11][N:10]=1)=O)C.C([O:26][C:27](COCC(NN)=O)=[O:28])C.[OH-].[Na+]>>[C:27]([CH2:8][C:9]1[N:13]=[C:12]([SH:23])[NH:11][N:10]=1)([OH:28])=[O:26]
Reactant: CCOC(=O)COCC(=O)NN
Reactant: CCOC(=O)COCc1nnc(S)n1Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1n[nH]c(S)n1

Procedure:
By employing a procedure similar to that described in Example XVI, Part A, 3-(ethoxycarbonylmethoxymethyl)-4-(p-methoxybenzyl)-1,2,4-triazole-5-thiol was prepared from ethoxycarbonylmethoxyacetohydrazide. The ethoxycarbonyl group was then hydrolyzed to the free acid using aqueous 2 N sodium hydroxide, and the p-methoxybenzyl blocking group was thereafter removed by using trifluoroacetic acid in a manner similar to that earlier described in Example XVI, Part B to finally give pure 3-(carboxymethoxymethyl)-1,2,4-triazole-5-thiol, m.p. 180°-182° C.