Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19](O)=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:32][C@H:33]([C:42]([CH2:44][Cl:45])=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.Cl.N(C(OCC1C=CC=CC=1)=O)[C@H](C(NCC(N[C@H](C(N[C@H](C(CCl)=O)CC(C)C)=O)CC(C)C)=O)=O)CC1C=CC=CC=1>>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:32][C@H:33]([C:42]([CH2:44][Cl:45])=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)CCl
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl
Agent: Cl
Product: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)CCl

Procedure:
Z-Phe-Gly-Ala-OH (0.77 g, 1.80 mmol) was coupled to H-TyrCH2Cl.HCl by a mixed anhydride coupling procedure substantially similar to that described for preparation of Z-Phe-Gly-Leu-LeuCH2Cl in Procedure E, above. Product was crystallized from ethyl acetate to yield 0.73 g of Z-Phe-Gly-Ala-TyrCH2Cl. Product slowly decomposed at 140°-160° and melted with complete decomposition at 160°-160.5°.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[C@H:13](O)[CH2:12][N:11]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:29]([O:32][NH:33][S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44])(=[O:36])=[O:35])[CH:30]=[CH2:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:29]([O:32][N:33]([C@H:13]1[CH2:12][N:11]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH:15]=[C:14]1[C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N+:43]([O-:45])=[O:44])(=[O:36])=[O:35])[CH:30]=[CH2:31]
Reactant: CN(C)C(=O)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(=O)N(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A stirred suspension of (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-(dimethylcarbamoyl)-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 137, 3.09 g, 7.45 mmol), N-(allyloxy)-2-nitrobenzenesulfonamide (2.348 g, 9.09 mmol) and triphenylphosphine (2.150 g, 8.20 mmol) in toluene (65 mL) was cooled in a salt-ice-bath and then (E)-diisopropyl diazene-1,2-dicarboxylate (1.588 mL, 8.20 mmol) was added dropwise. The reaction was let warm up to rt and was stirred for an additional 2 h. The solvent was removed and the crude product was loaded onto silica gel, purified via flash chromatography (25-75% EA/Hex) to obtain the desired product (4.0 g, 82%) as an off-white solid.
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[N:31]=1>CN(C)C=O>[F:36][C:32]1[N:31]=[C:30]([CH2:29][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: Fc1cccc(CCl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3cccc(F)n3)cc2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
Tetrahydrofuran (3 mL) and a 5 N aqueous sodium hydroxide solution (36.0 μL, 0.18 mmol) were added to 4-(5-(2-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (48.2 mg, 0.18 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction mixture was then concentrated under a reduced pressure to obtain a white solid. This solid and 2-chloromethyl-6-fluoro-pyridine (63.2 mg, 0.43 mmol) described in Manufacturing Example 45-1-1 were added to N,N-dimethylformamide (3 mL), which was stirred for 3 hours at room temperature. This mixture was partitioned into water and ethyl acetate. This organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (47.9 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[Cl:14].[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([O:30][CH3:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:14][C:3]1[CH:4]=[C:5]2[CH:6]=[N:7][NH:8][C:9]2=[C:10]2[C:2]=1[N:1]=[C:27]([C:26]1[N:22]([C:17]3[C:16]([Cl:15])=[CH:21][CH:20]=[CH:19][N:18]=3)[N:23]=[C:24]([O:30][CH3:31])[CH:25]=1)[O:12][C:11]2=[O:13]
Reactant: COc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Reactant: Nc1c(Cl)cc2cn[nH]c2c1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(-c2nc3c(Cl)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 400 mg (1.89 mmol) of 6-amino-5-chloro-1H-indazole-7-carboxylic acid in 16 mL of anhydrous tetrahydrofuran is added 479 mg (1.89 mmol) of 2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carboxylic acid followed by 684 μL (8.50 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 516 μL (6.66 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature for 5 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated and washed with cold water. The pale yellowish product obtained (870 mg) is engaged in the next step; LC/MS:530/532 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20](F)=[N:21][CH:22]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N+](C1C=C(B(O)O)C=CC=1)([O-])=[O:25].N12[CH2:46][CH2:45][CH2:44][N:43]=[C:42]1CCCCC2>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:43]4[CH2:42][CH2:46][CH:45]([OH:25])[CH2:44]4)=[N:21][CH:22]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COc1ccc(Cc2ccc(F)nc2)cc1-c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(Cc2ccc(N3CCC(O)C3)nc2)cc1-c1cccc(Cl)c1
Temperature: 100 °C

Procedure:
To 5-(3′-chloro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (I-140, 0.22 g, 0.67 mmol) and 3-pyrrolidinol (2) (0.12 g, 1.34 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.51 g, 3.36 mmol). The reaction mixture was stirred and heated at 100° C. for 1.5 h, cooled to room temperature, diluted with dichloromethane (8 mL), washed with 0.5 N HCl (2×4 mL), dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane to afford 0.13 g (49%) of P-602 as white solid. 1H NMR (DMSO-d6, 400 MHz): 7.9 (d, J=2.4 Hz, 1H), 7.3-7.49 (m, 5H), 7.12-7.2 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.34 (d, J=8.8 Hz, 1H), 4.89 (d, J=3.6 Hz, 1H), 4.35 (br s, 1H), 3.76 (s, 2H), 3.73 (s, 3H), 3.2-3.45 (m, 4H), 1.8-2.05 (m, 2H) ppm; MS (APCI+): 395.1 (M+1), LC-MS: 99.1%.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:28]1([C:34]2[CH:39]=[CH:38][C:37]([P:40](Cl)(Cl)=[O:41])=[CH:36][CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCCCCC.C(OCC)C.C1CCCCC1>[C:28]1([C:34]2[CH:39]=[CH:38][C:37]([P:40]3(=[O:41])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:21]3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:36][CH:35]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=P(Cl)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: O=P1(c2ccc(-c3ccccc3)cc2)c2ccccc2CN1c1ccccc1
Temperature: 26 °C
Reaction time: 2 h
Yield: 4.8 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (3.94 g, 0.0615 mol) in hexane was added to a solution of tetramethylethylenediamine (1.86 g, 0.016 mol) in 30 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-benzylaniline (5.5 g, 0.03 mol) in 30 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound which was stirred for an additional 2 hours at 26° C. 4-Phenylphenylphosphonic dichloride (8.7 g, 0.032 mol) was directly added to this suspension followed by 60 ml. of cyclohexane. The resulting mixture was stirred for 16 hours at 26° C. The reaction was quenched with the rapid addition of a solution of acetic acid (6 g, mol) in 30 ml. of anhydrous cyclohexane. After stirring for 30 minutes, the cyclohexane layer was removed under vacuum and the resulting residue was partitioned in methylene chloride and water. The layers were separated and the methylene chloride layer was washed with water, dried over sodium sulfate and concentrated in vacuo to yield an oily residue. The oily residue was chromatographically separated on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was slurried in anhydrous diethyl ether to yield 1-(4-phenylphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.55 g, 5% yield) as a white solid having a melting point of 259°-261° C. and the following analysis:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1(C=O)[CH2:12][CH:11]=C[S:9]1.C(O[BH-](O[C:25](=O)[CH3:26])OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:7][C:8]1[S:9][C:25]([CH2:26][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1
Reactant: C1COCCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=CC1(Br)CC=CS1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCOCC2)s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 148.8 %

Procedure:
Morpholine (0.96 g) was added portionwise to a solution of 2-bromothiophene carboxaldehyde (1.195 g) in tetrahydrofuran (50 ml). After stirring at room temperature for 5 minutes, sodium triacetoxyborohydride (3.18 g) was added and the mixture stirred at room temperature for a further 3 h. The mixture was added to saturated aqueous sodium bicarbonate (100 ml) and extracted twice with ethyl acetate. The combined extracts were evapourated to dryness. The product was purified by column chromatography elutinig with ethyl acetate in hexane mixtures to give a yellow oil (2.414 g).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][C:30](=[O:33])[CH2:31]Br.O>CN(C)C=O>[CH3:28][O:29][C:30](=[O:33])[CH2:31][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:3]2[C:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[S:6][C:5]=3[CH:13]=[CH:14][C:2]=2[Br:1])=[CH:16][CH:17]=1
Reactant: Oc1ccc(-c2c(Br)ccc3sc4ccccc4c23)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(-c2c(Br)ccc3sc4ccccc4c23)cc1
Reaction time: 24 h
Yield: 88.2 %

Procedure:
To a solution of 4-(2-bromo-dibenzothiophen-1-yl)-phenol (0.480 g, 1.35 mmol) and potassium carbonate (0.385 g, 2.79 mmol, 2.06 eq) in anhydrous N,N-dimethylformamide (3 mL) was added methylbromoacetate (0.255 mL, 2.07 mmol, 2 eq) dropwise at room temperature under a dry nitrogen atmosphere. After stirring 24 hours the reaction mixture was poured into water (100 mL) and the organics were extracted into ether (100 mL) The ether was washed with water (100 mL) and brine (100 mL). Silica gel was added and the solvents removed. The adsorbate was flash chromatographed (55/45 petroleum ether/methylene chloride) and dried in vacuo at 58° C. to provide the title compound as a white solid (0.509 g, 88%); mp 122-122.5° C. NMR (DMSO-d6), δ 8.02 (d, J=8 Hz, 1H), 8.00 (d, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 7.26-7.20 (m, 2H), 7.19 -7.16 (m, 2H), 7.13-7.09 (ddd, J=8,7,1, 1H), 6.53 (d, J=8 Hz 1H), 4.94 (s, 2H), 3.75 (s, 3H), MS [PBEI] M*+ m/z=426(100%), 428(98%), 1 bromine isotope pattern detected, Anal. Calc. for C21H15O3SBr: C, 59.03, H, 3.54, N, 0.00. Found: C, 58.91, H, 3,27, N, -0.02.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:67][C:68]1[O:69][C:70]2[C:71]([N:76]=1)=[N:72][CH:73]=[CH:74][CH:75]=2>>[O:69]1[C:70]2[C:71](=[N:72][CH:73]=[CH:74][CH:75]=2)[N:76]=[C:68]1[S:67][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[O:36])[CH2:32][CH2:33]1
Reactant: Sc1nc2ncccc2o1
Reactant: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCOCC2)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCSc3nc4ncccc4o3)CC2)c(N2CCOCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptooxazolo[4,5-b]pyridine, to thereby yield the title compound as a colorless foamed substance.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH3:30][C:31]1[CH:35]=[CH:34][NH:33][N:32]=1>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:33]2[CH:34]=[CH:35][C:31]([CH3:30])=[N:32]2)=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: Cc1cc[nH]n1
Product: Cc1ccn(-c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)n1

Procedure:
The title compound was prepared according to the procedure described for example 294 from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK) and 3-Methyl-1H-pyrazole (15%yield, white solid, MS (m/e): 493.5 (M+H, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:5][CH:4]=1.[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:12]([CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH2:7][CH2:8]2)=[O:14])[CH:19]=[N:18]1)[CH3:16]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: COc1ccc2c(c1)C(C(=O)O)CC2
Product: CCn1cc(CN(C(=O)C2CCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 55.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6-methoxyindan-1-carboxylic acid (0.29 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6-methoxyindan-1-carboxamide (0.35 g) was obtained.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].S(OC)(O[CH3:31])(=O)=O.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][C:9]=3[N:10]([CH3:31])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3)c(C3CCCCC3)c2s1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2)c(C2CCCCC2)c2sc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A solution (0.1 M) of methyl 6-cyclohexyl-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in THF at 0° C. was treated with NaH (4 eq., 60% dispersion in mineral oil), and the suspension was stirred at RT for 30 min then it was treated dimethyl sulfate (3 eq.). The mixture was stirred at RT for 2 h then it was quenched with water and extracted with AcOEt. The combined organic phase was washed with aqueous NaHCO3 (saturated solution) then dried. Evaporation of the solvent gave a residue that was dissolved in MeOH. The resulting solution (0.13 M) was treated with aqueous NaOH (2 N solution, 8 eq.) then the mixture was heated to reflux for 2 h. After cooling down, the mixture was concentrated and the residue was purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 5 micron, 19×150 mm; flow: 18 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 95% A linear to 90% A in 2 min, linear to 60% A in 2 min, linear to 40% in 2 min, linear to 30% A in 2 min, linear to 0% A in 2 min) to afford the title compound (42%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]([C:52]1[CH:53]=[C:54](B(O)O)[CH:55]=[CH:56][CH:57]=1)(=[O:51])[NH2:50]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:56]3[CH:55]=[CH:54][CH:53]=[C:52]([C:49](=[O:51])[NH2:50])[CH:57]=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(Br)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: NC(=O)c1cccc(B(O)O)c1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3cccc(C(N)=O)c3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1

Procedure:
Aryl halide 9 was coupled to 3-carbamoylphenylboronic acid to give 30 on a 0.1 mmol scale via General Procedure H (57 mg, 52%): δH (400 MHz, CDCl3) 2.38 (s, 3H, CH3), 2.81 (s, 3H, CH3), 3.68 (s, 2H, CH2), 4.83 (s, 2H, CH2), 5.02 (s, 2H, CH2), 5.34 (s, 2H, CH2), 5.93 (s, 1H, NH2), 6.33 (s, 2H, NH2), 6.64 (s, 1H, CH), 6.67 (dd, J=6.0 and 1.2 Hz, 1H, CH), 7.18 (d, J=6.0 Hz, 2H, CH), 7.31-7.39 (m, 13H, CH), 7.50 (d, J=6.0 Hz, 2H, CH), 7.60 (d, J=6.3 Hz, 2H, CH), 7.70 (d, J=5.7 Hz, 1H, CH), 7.77 (d, J=5.7 Hz, 1H, CH), 7.83 (d, J=6.0 Hz, 1H, CH), 8.03 (s, 1H, CH); δC (100 MHz, CDCl3) 21.3, 35.9, 51.3, 52.7, 66.9, 70.6, 113.9, 119.2, 119.9, 126.0, 126.9, 127.0, 127.2, 127.3, 127.9, 128.1, 128.1, 128.4, 128.4, 128.7, 128.9, 129.2, 129.4, 130.3, 132.3, 133.0, 133.8, 135.1, 135.5, 135.6, 136.0, 139.4, 140.8, 143.3, 144.8, 158.7, 165.2, 167.0, 169.1; LRMS (ES+) calcd for [C45H41N3O7S+H]768.27 found 768.27.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.C1(C)C=CC=CC=1.[CH3:18][O:19][C:20]([C:22]1[N:23]=[N:24][C:25]([C:32](OC)=[O:33])=[CH:26][C:27]=1[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:21]>C(Cl)Cl>[CH3:18][O:19][C:20]([C:22]1[N:23]=[N:24][C:25]([C:32]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:33])=[CH:26][C:27]=1[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:21]
Reactant: COC(=O)c1cc(CC(C)C)c(C(=O)OC)nn1
Reactant: C1CCNCC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1nnc(C(=O)N2CCCCC2)cc1CC(C)C
Temperature: 25 °C
Yield: 54.5 %

Procedure:
An oven dried, nitrogen cooled two-necked 25 mL round bottom flask was charged with a solution of 78 μL piperidine (0.793 mmol, 68 mg) in 4.0 mL anhydrous DCM. Trimethyl aluminum was added slowly (2.0M/toluene, 436 μL, 0.872 mmol). The resulting mixture was stirred for twenty minutes at room temperature. To this solution was added 200 mg of the diester 3 (0.793 mmol) dissolved in 2.0 mL anhydrous DCM. The flask was sealed and heated to 41° C. for 15 hours. The reaction was allowed to cool to room temperature and quenched with slow addition of 1M HCl. The product was extracted three times with DCM, the organic fractions collected, washed with brine, dried over magnesium sulfate and evaporated to give a brownish/yellow oil. The crude mixture was applied to a column of silica gel and eluted with a 2:1 hexane-ethyl acetate solution (Rf=0.16) to give 132 mg of product (54% yield) as a yellow oil. MS: (ESI-TOF) MH+ expected: 306.1812, found: 306.1807.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3[CH:25]=[CH:24]S[CH:22]=3)=[O:20])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.NC(C1N=NC(NC2C=CC([O:42]C)=CC=2)=NC=1)C.O1C=CC(C(O)=O)=C1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3[CH:25]=[CH:24][O:42][CH:22]=3)=[O:20])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccsc3)nn2)cc1
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Agent: O=C(O)c1ccoc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccoc3)nn2)cc1

Procedure:
In a similar manner as described for Intermediate 57, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 3-furoic acid (50 mg, 0.45 mmol). Except, that during the saturated sodium bicarbonate solution wash, a solid was formed which was collected by filtration and dried to give N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-3-furancarboxamide (110 mg) as a yellow solid. MS m/z 340 (M+1).