Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[NH2:17][C:18]1[N:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[N:19]=1>O1CCOCC1>[F:16][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:17][C:18]1[N:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[N:19]=1)=[O:15])(=[O:12])=[O:11]
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(F)F
Solvent: C1COCCO1
Product: Cc1cc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)n1
Temperature: 20 °C

Procedure:
34.2 g of 2-difluoromethoxyphenylsulfonyl isocyanate and 19.7 g of 2-amino-4-chloro-6-methyl-pyrimidine are stirred in 40 ml of dioxane for 3 hours at 90°-100° C. The solution is then cooled to 20° C., filtered, and concentrated to about 1/4 of its volume. After addition of ether, 32.9 g of N-(2-difluoromethoxyphenylsulfonyl)-N'-(4-chloro-6-methyl-pyrimidin-2-yl)urea crystallise from the residue.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:12][C@H:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1)[CH2:7]2.[O-:20][Mn](=O)(=O)=O.[K+].C1OCCOCCOCCOCCOCCOC1>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:12][C@H:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1)[C:7]2=[O:20]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC1(C)OC[C@H](CN2CCc3c(Br)cccc3C2)O1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: ClCCl
Product: CC1(C)OC[C@H](CN2CCc3c(Br)cccc3C2=O)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture containing (S)-5-bromo-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline (303 mg, 0.93 mmol), KMnO4 (176 mg, 1.12 mmol), 18-crown-6 (2-(5 mg, 0.93 mmol) in dichloromethane (4 ml) is stirred at room temperature for 18 hours. The reaction mixture is filtered through a celite pad and the filtrate is concentrated to dryness by rotary evaporation to give (S)-5-Bromo-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (LC-MS m/z: 341.2 (M+1)), which is used without further purification in the next step.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:56]([OH:58])=O)[CH2:19][S:20][CH2:21][C@H:22]([O:40][C:41](=[O:55])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:23][O:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])C3C(=CC=CC=3)C=2C=CC=1.[NH2:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][P:72](=[O:79])([O:76]CC)[O:73]CC>>[NH2:17][C@@H:18]([CH2:19][S:20][CH2:21][C@H:22]([O:40][C:41](=[O:55])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:23][O:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:56](=[O:58])[NH:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][CH2:70][CH2:71][P:72](=[O:73])([OH:79])[OH:76]
Reactant: CCCCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCCCC
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Product: CCCCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(O)O)OC(=O)CCCCCCCCCCCCC

Procedure:
The title product was prepared from (5R,9R)-1-(9H-fluoren-9-yl)-3,12-dioxo-9-(tetradecanoyloxy)-2,11-dioxa-7-thia-4-azapentacosane-5-carboxylic acid (1 eq) and diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.3 eq, from example 18, step 4) by following the procedure described for example 20, step 6-8. 1H NMR (CDCl3): δ 7.30 (br s, 1H), 5.13-5.23 (m, 2H), 4.30-4.43 (m, 2H), 4.07-4.20 (m, 2H), 3.44-3.87 (m, 11H), 2.92-3.13 (m, 3H), 2.68-2.92 (m, 4H), 2.22-2.38 (m, 4H), 1.69-2.17 (m, 8H), 1.52-1.67 (m, 4H), 1.10-1.36 (m, 32H), 0.88 (t, 6H). LRMS [M+H]=855.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:25][CH2:26][CH3:27]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:25][CH2:26][CH3:27])[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(C(F)(F)F)c21
Yield: 34.7 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (0.146 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopropane (0.098 mL, 1.0 mmol) to give the title compound (0.058 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[N:5]2.[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2](/[CH:30]=[CH:29]/[C:28]([O:32][CH3:33])=[O:31])[CH:3]=3)[N:8]=2)=[CH:17][CH:16]=1
Reactant: C=CC(=O)OC
Reactant: COc1ccc(-c2nc3ccc(Br)cc3nc2-c2ccc(OC)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
A solution of 6-bromo-2,3-bis(4-methoxyphenyl)quinoxaline (100 mg, 0.24 mmol, 1.00 equiv), methyl acrylate (40.8 mg, 0.47 mmol, 2.00 equiv), Pd(OAc)2 (5.3 mg, 0.02 mmol, 0.10 equiv), PPh3 (24.8 mg, 0.09 mmol, 0.40 equiv) in DMF/Et3N (4/2 mL). The resulting solution was stirred overnight at 100° C. under an inert atmosphere. The mixture was concentrated under vacuum and purified via silica gel column (ethyl acetate/petroleum ether (1:30)), yielding 80 mg (79%) of (E)-methyl 3-(2,3-bis(4-methoxyphenyl)quinoxalin-6-yl)acrylate as a yellow solid.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:35])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13](=[O:34])[CH:12]=1.CO>C1COCC1>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:35])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13](=[O:34])[CH:12]=1
Reactant: CCOC(=O)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCC(=O)O
Reaction time: 24 h

Procedure:
Lithium hydroxide (2.0 mL, 1M, 2.0 mmol) was added to a solution of ethyl 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoate (100 mg, 0.20 mmol), MeOH (2 mL), and THF (8 mL). The mixture was stirred for 24 h, quenched with 1N HCl (30 mL), and extracted with EtOAc (40 mL×2). The organic extracts were dried, filtered, and concentrated to give 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoic acid: 1H NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 8.88 (s, 1H), 8.77 (s, 2H), 7.89 (d, 1H), 7.06 (d, 1H), 4.80 (s, 1H), 3.95 (t, 2H), 3.90 (s, 3H), 2.22 (t, 2H), 1.76 (m, 2H), 1.55 (m, 2H), 1.39 (m, 2H); MS (ESI): 465.8.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:15]([CH3:16])=[N:14][N:13]=[N:12]1)(=[O:4])=[O:3].[CH3:17][O:18][C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[N:20]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[CH3:17][O:18][C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][C:27]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]2[C:15]([CH3:16])=[N:14][N:13]=[N:12]2)(=[O:4])=[O:3])=[O:28])[N:20]=1
Reactant: Cc1nnnn1-c1ccccc1S(N)(=O)=O
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2-n2nnnc2C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
To 0.48 g of 1-(2-aminosulfonylphenyl)-5-methyl-1H-tetrazole and 0.52 g of phenyl N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate in 25 mL of acetonitrile at ambient temperature and pressure was added 0.3 mL of DBU. The mixture was stirred for three hours and then added to 25 g of ice and acidified with hydrochloric acid. The precipitate thus obtained was filtered, washed with water and dried in vacuo to yield 0.65 g of the desired product melting at 207°-209° C. Infrared absorption spectra showed absorption at 1700, 1600 and 1550 cm-1, consistent for the desired structure.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[CH3:10][O:11][C:12]1[C:13](=[O:40])[C:14]([CH3:39])=[C:15]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:26]([CH:30]=2)[C:27](O)=[O:28])[C:16](=[O:20])[C:17]=1[O:18][CH3:19].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C1COCC1>[CH3:10][O:11][C:12]1[C:13](=[O:40])[C:14]([CH3:39])=[C:15]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[C:26]([CH:30]=2)[C:27]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:28])[C:16](=[O:20])[C:17]=1[O:18][CH3:19]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccccc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
Oxalyl chloride (0.150 g, 1.18 mmol) was added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (0.050 g, 0.118 mmol) and the resulting solution was stirred at room temperature for 1 hour. The reaction solution was concentrated and after adding a THF solution of morpholine (0.036 g, 0.414 mmol) to the obtained residue, the solution was stirred at room temperature for 30 minutes. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) to obtain the titled compound (0.058 g, 0.117 mmol, 99%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:15]3[S:16][C:17]([C:19]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[Cl:30])[CH:22]=[N:21][N:20]=4)=[CH:18][C:14]=3[CH2:13][CH2:12][O:11][C:10]=2[CH:31]=1)=[O:4].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:23]1[CH:22]=[N:21][N:20]=[C:19]1[C:17]1[S:16][C:15]2[C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:31][C:10]=3[O:11][CH2:12][CH2:13][C:14]=2[CH:18]=1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Product: O=C(CN1CCOCC1)Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedure in Example 147 for 237, 2-chloro-N-(2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)acetamide was reacted with morpholine to give 236. MS: (ESI+) 522.3
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([I:11])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[I:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([O:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH3:12])[CH:3]=1
Reactant: COc1ccccc1O
Reactant: O=[N+]([O-])c1cc(F)cc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccccc1Oc1cc(I)cc([N+](=O)[O-])c1
Temperature: 110 °C
Yield: 70.4 %

Procedure:
A mixture of 1-fluoro-3-iodo-5-nitrobenzene (5.0 g, 18.0 mmol), 2-methoxyphenol (2.3 g, 18.0 mmol) in dry DMSO (10.0 mL) and anhydrous K2CO3 (3.8 g, 27.5 mmol) was heated at 110° C. for 16 h. The mixture was poured into ice water and extracted with EtOAc (3×50 mL). The organic layer was sequentially washed with brine (2×75 mL), dried over anhydrous Na2SO4, concentrated by rotary evaporation, and purified by column chromatography to give 1-iodo-3-(2-methoxyphenoxy)-5-nitrobenzene (7) (4.7g, 70%). 1H NMR (400 MHz, CDCl3) δ 8.23-8.13 (m, 1H), 7.69-7.48 (m, 2H), 7.30-7.25 (m, 1H), 7.12-6.93 (m, 3H), 3.80 (d, J=1.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][NH:36][CH2:37][CH:38]([OH:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:36]([CH2:37][CH:38]([OH:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH3:35])[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Reactant: CNCC(O)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc2c(c1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.8 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.06 gm) from Preparation No. 35 in dry NMP (2 mL) containing diisopropylethylarnine (0.04 mL) is treated with α-(methylaminomethyl)-benzyl alcohol (0.04 gm). The reaction mixture is shaken at room temperature for 3 days then concentrated under reduced pressure. The residue is partioned between dichloromethane and water. The separated organic layer is washed with two additional portions of water, brine, dried (Na2SO4) and concentrated under reduced pressure. The residue is adsorbed onto silica and purified by flash column chromatography eluting with 2% to 6% methanol in dichloromethane and then by recrystallization from ethyl acetate-hexanes to afford 0.05 gm of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:23])([CH3:22])[C:11]=2[CH:10]=1.CC(C)([O-])C.[Na+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl.O1CCOCC1>[CH3:22][C:12]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:8][C:7]4[C:6]([C:21]3=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][N:4]=[CH:3][CH:2]=4
Reactant: CC1(C)c2ccccc2-c2ccc(Nc3ccncc3Cl)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccncc13
Temperature: 105 °C
Reaction time: 24 h

Procedure:
500 ml of dioxane are added to 42 g of (3-chloropyridin-4-yl)-(9,9-dimethyl-9H-fluoren-2-yl)amine (130 mmol), 1.46 g of palladium(II)acetate (6.5 mmol) and 75 g of sodium tert-butoxide (780 mmol), 7.8 ml of a 1 M solution of P(t-Bu)3 in toluene (7.8 mmol), and the mixture is stirred at 105° C. under nitrogen for 24 h. 200 ml of dichloromethane and 0.1 M Na2CO3 solution are then added. The mixture is partitioned between water and dichloromethane, the aqueous phase is extracted three times with dichloromethane, the combined organic phases are dried over Na2SO4 and evaporated in a rotary evaporator. The residue is recrystallised from toluene/heptane. The yield is 18.5 g (65.1 mmol, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH2:23][CH3:24])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>ClCCl>[CH:18]1([C:17]2[N:10]3[C:11]([C:12](=[O:14])[NH:13][C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])[CH:7]=[CH:6][CH:5]=4)=[N:9]3)=[C:15]([CH2:23][CH3:24])[N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1nc(C2CCCC2)n2nc(-c3cccc(N)c3)[nH]c(=O)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc(C2CCCC2)n2nc(-c3cccc(NC(=O)C(C)(C)C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50 mg (0.16 mmol) 2-(3-aminophenyl)-7-cyclopentyl-5-ethylimidazo[5,1-f][1,2,4]-triazin-4(3H)-one (Example 29) and 78 mg (0.77 mmol) triethylamine are dissolved in 4 ml dichloromethane. 37 mg (0.31 mmol) 2,2-dimethylpropanoyl chloride are added dropwise. The mixture is stirred for 2 hours at room temperature and then washed with 1 N potassium hydrogensulfate solution and with saturated sodium hydrogencarbonate solution. The organic layers are dried and evaporated to dryness in vacuo. The product is purified by chromatography (flash or column chromatography).
Reaction SMILES: O[CH2:2][CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1.C1(C)C=C[C:42]([S:45](Cl)(=O)=O)=CC=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:42][S:45][CH2:2][CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCO)CC2)c2ncnn12
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCSC)CC2)c2ncnn12
Reaction time: 4 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.2 g), p-toluenesulfonyl chloride (0.089 g), triethylamine (0.066 mL), 4-dimethylaminopyridine (0.005 g) and acetonitrile (10 mL) was stirred for 4 hr. The reaction mixture was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetonitrile (15 mL), sodium thiomethylate (15% aqueous solution, 1.8 g) was added, and the mixture was stirred at 50° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.2 g, 94%).
Reaction SMILES: [C:1]([CH2:3][N:4]([CH2:11][CH2:12][OH:13])[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])#[N:2].[C:14](OCCN(C#N)CC(C)C(OC)=O)(=[O:16])[CH3:15]>>[C:14]([O:13][CH2:12][CH2:11][N:4]([CH2:3][C:1]#[N:2])[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:16])[CH3:15]
Reactant: COC(=O)CCN(CC#N)CCO
Reactant: COC(=O)C(C)CN(C#N)CCOC(C)=O
Product: COC(=O)CCN(CC#N)CCOC(C)=O

Procedure:
By following the same procedure as Synthesis Example 3 except that methyl N-cyanomethyl-N-(2-hydroxyethyl)-3-aminopropionate was used instead of N,N-bis(2-hydroxyethyl)-3-aminopropiononitrile, methyl N-(2-acetoxyethyl)-N-cyano-methyl-3-aminopropionate was synthesized.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]2)[C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[N:3]=1.[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]1[CH:28]=O>>[CH3:1][C:2]1[N:6]([C@@H:7]2[CH2:8][CH2:9][C@H:10]([NH:13][CH2:28][CH:20]3[CH2:19][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[CH2:11][CH2:12]2)[C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[N:3]=1
Reactant: O=CC1Cc2ccccc2C1
Reactant: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@@H](N)CC1
Product: Cc1ccc2c(c1)nc(C)n2[C@H]1CC[C@@H](NCC2Cc3ccccc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-4-(2,5-dimethyl-benzoimidazol-1-yl)-cyclohexylamine and indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C25H31N3 (m/e) calcd 373.2518, obsd 374.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:4][C:3]=1[NH:18][C:19](=O)[O:20]C(C)=C.[CH3:25][C:26]([CH3:31])([CH3:30])[CH2:27][CH2:28][NH2:29].CN1CCCC1>O1CCOCC1>[CH3:25][C:26]([CH3:31])([CH3:30])[CH2:27][CH2:28][NH:29][C:19]([NH:18][C:3]1[CH:4]=[C:5]([B:9]2[O:10][C:11]([CH3:16])([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13]2)[C:6]([CH3:8])=[CH:7][C:2]=1[F:1])=[O:20]
Reactant: C=C(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1F
Reactant: CC(C)(C)CCN
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: Cc1cc(F)c(NC(=O)NCCC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 75 °C
Yield: 87.9 %

Procedure:
Treat a solution of prop-1-en-2-yl 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (6.67 g, 19.90 mmol) in dioxane (60 mL) with 3,3-dimethylbutan-1-amine (2.42 g, 23.9 mmol) and 1-methylpyrrolidine (0.169 g, 1.99 mmol) and heat at 75° C. overnight. Cool the mixture to RT, collect the solid via filtration and wash with diethyl ether to obtain the title compound (6.62 g, 88% yield over two steps). MS (m/z): 379.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12](CC3C=CC(OC)=CC=3OC)[C:11](=[O:32])[C@@:10]([CH3:36])([CH2:33][S:34][CH3:35])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:32])[C@@:10]([CH3:36])([CH2:33][S:34][CH3:35])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)[C@@](C)(CSC)C[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: CSC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O

Procedure:
A solution of (3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methyl-3-(methylthiomethyl)piperidin-2-one (Example 88, Step D) (0.406 g, 0.746 mmol) in TFA (6.00 mL) was heated at 50° C. under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo to provide a purple oil. Purification using a 40 g SiO2 column and eluting with 35 to 60% EtOAc/hexanes provided the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1C1C=CC=CC=1O.O.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[O:9]1[C:5]2[CH:6]=[CH:7][CH:11]=[CH:12][C:4]=2[N:10]=[C:8]1[C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:20])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1-c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc3ccccc3o2)cc1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
A solution of (2-hydroxyphenyl)-terephthalamic acid methyl ester (0.35 g, 1.3 mmol) in polyphosphoric acid (5 mL) was heated to reflux for 3 h. The solution was cooled to 0° C., water added (100 mL) and solid K2CO3 introduced until pH 7-9 was attained. The residue was diluted with ethyl acetate (2×100 mL) and the organic extract dried (MgSO4), filtered and concentrated to give cyclized methyl 4-(benzoxazol-2-yl)-benzoate (0.15 g, 45%) as a beige powder. 1H NMR (CDCl3) δ3.98 (s, 3H), 7.40 (m, 2H), 7.61 (m, 1H), 7.81 (m, 1H), 8.20 (d, 2H, J=7.8 Hz), 8.34 (d, 2H, J=7.8 Hz).