Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19])[CH2:6]2)=[O:4].C(N(CC)CC)C.[CH3:38][CH:39]([O:42][C:43]([S:45]Cl)=[O:44])[CH2:40][CH3:41]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([N:20]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[S:45][C:43]([O:42][CH:39]([CH3:38])[CH2:40][CH3:41])=[O:44])=[O:19])[CH2:6]2)=[O:4]
Reactant: COC(=O)C12CCc3ccccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Reactant: CCC(C)OC(=O)SCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)OC(=O)SN(C(=O)N1CC2(C(=O)OC)CCc3ccccc3C2=N1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Step B (Example 1) 0.4 g, 0.96 mmol)in 5 ml methylene chloride was added triethylamine (0.12 g) and cooled to 0° C. To this solution was added (1-methylpropoxycarbonyl)sulfenyl chloride (Step A) (0.2 g, 0.0012 mol). The mixture was stirred at room temperature for one hour. At this stage thin layer chromatography indicated only partial conversion, therefor, additional amounts of (1-methylpropoxycarbonyl)sulfenyl chloride (0.2 g) and triethylamine (0.12g) was added and the mixture was let stand over night. The reaction mixturewas subjected to silica gel column chromatography using hexane-ether (7:1) as eluent. The title compound was obtained (0 g) in high purity; m.p.: 125°-126° C.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)([CH3:9])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:50]([CH2:51][C:52](O)=[O:53])[C:49]2[N:55]=[CH:56][CH:57]=[CH:58][C:48]=2[C:47](=[O:59])[N:46]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:50]([CH2:51][C:52]([N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:33])([F:32])[F:34])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[CH:13]2[CH2:14][CH2:15][N:10]([C:2]([CH3:1])([CH3:9])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4])[CH2:11][CH2:12]2)=[O:53])[C:49]2[N:55]=[CH:56][CH:57]=[CH:58][C:48]=2[C:47](=[O:59])[N:46]=1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
Reactant: CC(C)OC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
A mixture of 1-methylethyl 2-methyl-2-{4-[({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)-amino]-1-piperidinyl}propanoate (Int. B5) (80 mg, 1 equiv), [2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (67 mg, 1 equiv), HATU (400 mg, 5 equiv), DIPEA (0.22 ml, 1.5 equiv) and DMF (2.0 ml) was stirred at room temperature for 30 min. The crude reaction mixture was applied directly to reverse-phase HPLC (Preparative Method A) to obtain 1-methylethyl 2-{4-[{[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}-2-methylpropanoate (25 mg).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC>CN(C=O)C>[CH:13]1([O:12][C:3]2[C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COC(=O)c1cnc(OC2CCCC2)c(Br)c1
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC2CCCC2)c(-c2ccccn2)c1
Yield: 42.1 %

Procedure:
A solution of methyl 5-bromo-6-(cyclopentyloxy)nicotinate (4.53 g, 15.1 mmol) and 2-(tributylstannyl)pyridine (5.00 g, 13.6 mmol) was stirred in 100 mL of DMF at 120° C. for 6 h. The resulting solution was cooled and concentrated in vacuo. The crude reaction mixture was then partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted 1×EtOAc. The organic phases were combined, washed 3× brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was taken up in CH2Cl2 and loaded on to a 40 g pre-packed silica gel column. Elution with 0-30% EtOAc:hexanes provided the title compound as an off-white powder (1.71 g, 38%). MS m/z: 299 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[NH:28]1[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[C:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:28]4[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[CH2:30][CH2:29]4)=[O:27])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S1(=O)CCNCC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCS(=O)(=O)CC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), thiomorpholine-1,1-dioxide (44.8 mg, 331 μmol), diisopropylethylamine (145 μl, 828 μmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7.00 ml) is stirred for 4 hours at 70° C. and then for 60 hours at 25° C. under nitrogen atmosphere. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording 4-(1,1-dioxo-thiomorpholine-4-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (112 mg, 84.7%) as a white solid. mp.: >250° C. MS: m/z=480.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:20]([O:38][CH:39]1[CH:44]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH:43]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])[CH2:42][CH:41]([C:83](O)=[O:84])[CH2:40]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.O>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:83]([CH:41]2[CH2:42][CH:43]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])[CH:44]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH:39]([O:38][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:40]2)=[O:84])=[CH:3][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)O)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: Nc1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC1CC(C(=O)Nc2ccc(CO)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
4-Aminobenzyl alcohol (282 mg, 2.29 mmol) was dissolved in chloroform (40 ml), and HOBt (32 mg, 0.23 mmol) and 3,4,5-tris(octadecyloxy)cyclohexylcarboxylic acid (1.11 g, 1.19 mmol) were added. EDC.HCl (356 mg, 1.86 mmol) and pure water (120 μl) were added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated, and the residue was precipitated with acetonitrile (10 ml), and isolated by silica gel column chromatography (chloroform/ethyl acetate=10:1) to give N-(4-hydroxymethylphenyl) 3,4,5-tris(octadecyloxy)cyclohexylcarboxamide (556 mg, 0.54 mmol, yield 45%).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].Br[CH2:6][CH:7]([CH2:11]Br)[C:8]([OH:10])=[O:9].Cl>[OH-].[K+]>[C:1]([S:3][CH2:6][CH:7]([CH2:11][S:3][C:1](=[O:4])[CH3:2])[C:8]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: O=C(O)C(CBr)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(=O)SCC(CSC(C)=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.36 g (40 mmoles) of thioacetic acid in 40 ml of N-potassium hydroxide is added dropwise to a solution of 2-bromomethyl-3-bromopropanoic acid in 1.0N potassium hydroxide (20 ml). The mixture is stirred at room temperature overnight, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated in vacuo. The residue is converted into a dicyclohexylammonium salt (m.p. 116°-118°) and the salt converted back into the free acid, 2-(acetylthiomethyl)-3-(acetylthio)propanoic acid, by distribution between ethyl acetate and 10% potassium bisulfate.
Reaction SMILES: Cl[CH:2]([N:7]=[C:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:3]([F:6])([F:5])[F:4].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[NH:7][C:2]([C:3]([F:6])([F:5])[F:4])=[CH:19][C:18]=2[C:17]([O:21][CH3:22])=[O:20])=[CH:10][CH:11]=1
Reactant: FC(F)(F)C(Cl)N=C(Cl)c1ccc(Cl)cc1
Reactant: C=CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 26.1 %

Procedure:
A solution of N-[1-chloro-(2,2,2-trifluoroethyl)]-4-chlorobenzimidoyl chloride (3.40 g, 0.012 mol) and methyl acrylate (1.26 g, 0.015 mol) in N,N-dimethylformamide (10 mL) is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 5.0 g, 0.033 mol) over 1 hour. The reaction mixture is then held at 600° C. for 15 minutes, quenched with dilute HCl, and extracted with ethyl acetate. The organic extract is concentrated in vacuo to obtain a residue. Flash chromatography of the residue on silica gel, packed and eluted with 20% ethyl acetate in heptane, and crystallization from heptane gives the title product as a yellow solid (0.95 g, 26.0% yield) which is identified by 1H and 19F NMR spectral analyses.
Reaction SMILES: [ClH:1].[C:2]1([CH:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][OH:22])=[O:18])[CH2:13][CH2:14][CH2:15][NH2:16])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH:45][C:46](=[N:49]C(OCC1C=CC=CC=1)=O)SC)(OCC1C=CC=CC=1)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:1].[C:29]1([CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([NH:11][C@@H:12]([C:17]([NH:19][C@H:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:21][OH:22])=[O:18])[CH2:13][CH2:14][CH2:15][NH:16][C:46](=[NH:45])[NH2:49])=[O:10])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Yield: 59.8 %

Procedure:
Prepared according to the method described in Example 1(f) above from (R)-N2 -(diphenylacetyl)-(R)-N-(2-hydroxy-1-phenylethyl)ornithine amide hydrochloride (0.5 g; 1.12 mmol), N,N'-bis(Cbz)-S-methylisothiourea (0.603 g; 1.68 mmol), DiPEA (0.2 mL) and DMF (15 mL) yielding 0.351 g of sub-title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:54]6[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C)CC4)c3)c2C)c1

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) with 1-methylpiperazine (26.6 mg., 0.00024 mol) and sodium triacetoxyborohydride (68 mg, 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a pale brown colored solid [55.1 mg (49%). LC-MS m/z 743.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=4)[CH:20]=3)[CH2:14][CH2:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:49]2[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=2)[CH2:52][Cl:53])[CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:69].Cl>>[ClH:53].[ClH:69].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=4)[CH:20]=3)[CH2:16][CH2:17]2)[CH2:52][C:51]2[CH:54]=[CH:55][CH:56]=[C:49]([C:41]3[CH:42]=[C:43]([O:47][CH3:48])[C:44]([O:45][CH3:46])=[C:39]([O:38][CH3:37])[CH:40]=3)[CH:50]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: COc1cc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc(OC)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(OC)cc(N(Cc2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)c1

Procedure:
4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:33][CH:34]2[CH2:39][CH2:38][S:37](=[O:40])[CH2:36][CH2:35]2)=[O:32])=[CH:5][CH:4]=1)#[N:2].C1(C)C=C(C)C=C(C)C=1S(O[NH2:53])(=O)=O>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:33][CH:34]2[CH2:39][CH2:38][S:37](=[NH:53])(=[O:40])[CH2:36][CH2:35]2)=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCS(=O)CC2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCS(=N)(=O)CC2)cc1
Temperature: 25 °C

Procedure:
4-(4-Cyanophenyl)-2,5-dioxo-N-(1-oxo-hexahydro-1λ4-thiopyran-4-yl)-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxamide (example 71, 67 mg, 0.12 mmol) is added to a solution of O-mesitylenesulfonylhydroxylamine (25 mg, 0.12 mmol) in dichloromethane (1.0 mL), and the mixture is stirred at room temperature over night. All volatiles are removed under reduced pressure, and the residue is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 18 mg; ESI mass spectrum [M+H]+=586; Retention time HPLC: 0.92 min (Z018_S04).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:8]([CH:11](Br)Br)=[CH:9][CH:10]=1)=[O:4].[OH2:24]>C(#N)C.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:8]([CH:11]=[O:24])=[CH:9][CH:10]=1)=[O:4]
Reactant: O
Reactant: COC(=O)c1ccc(C(Br)Br)c(-c2cccc(C(F)(F)F)c2)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1ccc(C=O)c(-c2cccc(C(F)(F)F)c2)c1
Reaction time: 1 h

Procedure:
The compound of step 2 (2.1 g, 4.65 mmol) was dissolved in acetonitrile (25 ml). Silver nitrate (1.97 g, 11.6 mmol) was dissolved in water (3 ml) and this solution was added to the acetonitrile solution. This mixture was stirred for 1 h in reflux. Acetonitrile was evaporated in vacuo, the remainder was partitioned between ethyl acetate and water, the combined organic extracts were dried over sodium chloride, filtered over a small plug of silica and evaporated to dryness. A crystalline crop was yielded on addition of methanol and filtration. The mother liquor was evaporated to dryness and purified by silica gel chromatography with a heptane/ethyl acetate gradient to yield a second crop. Both were combined to yield the title compound (1.0 g).
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:32]=[C:33]([S:36]([NH2:39])(=[O:38])=[O:37])[S:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[OH:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:31]2[CH:32]=[C:33]([S:36]([NH2:39])(=[O:38])=[O:37])[S:34][CH:35]=2)=[CH:16][CH:17]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: NS(=O)(=O)c1cc(Br)cs1
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
Product: C[C@H](Oc1ccc(-c2csc(S(N)(=O)=O)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 66.5 %

Procedure:
Prepared by the method outlined in Example 15g) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-yl-butoxy]benzeneboronic acid (0.200 g, example 15f)), 4-bromothiophene-2-sulfonic acid amide (0.145 g, Example 42a)), 2M aqueous sodium carbonate (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.025 g) in ethanol (3 ml). The mixture was heated at 90° C. for 4 hours and after cooling to room temperature the mixture was concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to afford the title compound as a solid (0.134 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]2[C:10]([CH3:29])=[N:11][C:12]3[C:17]([N:18]=2)=[C:16]([C:19]2[NH:23][C:22]4[C@@H:24]([CH3:28])[NH:25][C:26](=[O:27])[C:21]=4[CH:20]=2)[CH:15]=[CH:14][CH:13]=3)[CH2:3]1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:29][C:10]1[C:9]([NH:8][C@H:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:30](=[O:32])[CH3:31])[CH2:3]2)=[N:18][C:17]2[C:12]([N:11]=1)=[CH:13][CH:14]=[CH:15][C:16]=2[C:19]1[NH:23][C:22]2[C@@H:24]([CH3:28])[NH:25][C:26](=[O:27])[C:21]=2[CH:20]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1N[C@H]1CCC[C@@H](N)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1CCC[C@H](Nc2nc3c(-c4cc5c([nH]4)[C@@H](C)NC5=O)cccc3nc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A mixture of (R)-2-(3-(((1S,3R)-3-aminocyclohexyl)amino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (483) (29 mg, 0.074 mmol), acetic anhydride (35.0 μL, 0.37 mmol), and N-ethyl-N-isopropylpropan-2-amine (91 μL, 0.52 mmol) in DCM (743 μL) was stirred at RT for 30 min when mostly product was observed via LCMS. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aqueous sodium bicarbonate (2×75 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product in DCM was loaded onto the column and was purified via automated flash chromatography (silica gel) with 100% DCM to 8% 2 M ammonia in MeOH/DCM to give N-((1R,3S)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinoxalin-2-yl)amino)cyclohexyl)acetamide (486, 19 mg, 0.044 mmol, 59% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.20 (m, 1H) 1.20-1.32 (m, 1H) 1.42 (d, J=6.65 Hz, 3H) 1.44-1.52 (m, 2H) 1.78 (s, 3H) 1.80-1.90 (m, 2H) 2.11 (br. s., 2H) 2.53 (s, 3H) 3.58-3.71 (m, 1H) 4.04-4.17 (m, 1H) 4.54 (q, J=6.59 Hz, 1H) 6.87 (d, J=7.63 Hz, 1H) 6.95 (d, J=1.57 Hz, 1H) 7.33 (t, J=7.82 Hz, 1H) 7.59 (dd, J=8.02, 1.37 Hz, 1H) 7.62 (s, 1H) 7.81-7.88 (m, 2H) 11.99 (s, 1H). MS (ESI, pos. ion) m/z: 433.1 (M+1).