Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([OH:14])[C@@H:10]([NH2:13])[CH2:11][OH:12])=[CH:5][CH:4]=1.[C:15]1(C)[CH:20]=CC=C[CH:16]=1.O>CC(C)=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[O:14][C:15]([CH3:20])([CH3:16])[NH:13][C@H:10]2[CH2:11][OH:12])=[CH:7][CH:8]=1
Reactant: CSc1ccc([C@H](O)[C@@H](N)CO)cc1
Reactant: Cc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: CSc1ccc([C@@H]2OC(C)(C)N[C@H]2CO)cc1

Procedure:
A stirred mixture of enantiomerically pure (+)-thiomicamine (100 g; 0.469 mol), toluene (920 ml) and acetone (100 ml) was heated at reflux for 18 hours beneath a Dean Stark trap: a mixture of toluene, water and acetone (11 g) was collected. The solvent (200 ml) was distilled at ambient pressure and then under vacuum (internal temperature 80° C.) to give compound 7 (118.6 g) as residue.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2O.FC1C([O:17][C:18](=O)[O:19]C2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.[C:36]1([C@H:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:45][CH2:44][NH:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:52]([OH:59])(=[O:58])[CH2:53][CH2:54][C:55]([OH:57])=[O:56]>C1(C)C=CC=CC=1.CC(C)=O>[CH:39]1[CH:40]=[CH:41][C:36]([C@@H:42]2[N:43]([C:18]([O:19][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:17])[CH2:44][CH2:45][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:51]2=3)=[CH:37][CH:38]=1.[CH2:53]([C:52]([OH:59])=[O:58])[CH2:54][C:55]([OH:57])=[O:56]
Reactant: O[C@@H]1CC2CCN1CC2
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Agent: O=C(O)CCC(=O)O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270 mL of toluene and then stirred at 25˜30° C. for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g (1.2 mol) of bis(pentafluorophenyl)carbonate was added to the reaction solution to form a suspended reaction solution, and then the suspended reaction solution was stirred at 25˜30° C. for 3˜4 hours. After confirming the completion of a reaction using thin layer chromatography (TLC), 209.3 g (1.0 mol) of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added to the reaction solution, and then stirred at 25˜30° C. for 4˜5 hours. After confirming the completion of a reaction using high performance liquid chromatography (HPLC), the reaction solution was concentrated under reduced pressure. Subsequently, 1270 mL water was added to the reaction solution, and concentrated hydrochloric acid was added dropwise into the reaction solution to adjust the pH of the reaction solution to 1˜2. Then, the reaction solution was washed with 1270 mL of toluene to remove pentafluorophenol (a by-product formed during the reaction) from the reaction product. Then, an aqueous layer was extracted from the reaction solution using 1270 mL of dichloromethane, and then the reaction solution was concentrated under reduced pressure. Then, 1270 mL of water was added to the reaction solution, the pH of the reaction solution was adjusted to 9˜10 using ammonium hydroxide, and then an aqueous layer was further extracted from the reaction solution using 1270 mL of toluene. Subsequently, 1270 mL of acetone and 118.1 g (1.0 mol) of succinic acid were added to the reaction solution, stirred at 55˜60° C. for 30 minutes, further stirred at 10˜15° C. for 2 hours, and then filtered to obtain a reaction product. Finally, the reaction product was washed with 640 mL of toluene and 640 mL of acetone, and then dried in vacuum at 40° C. to obtain 390.2 g (81.2%) of solifenacin succinate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:16]([C:22]([NH:24][NH2:25])=O)=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:26](OC)(OC)(OC)[CH3:27].[CH2:34]([NH2:36])[CH3:35].CC(O)=O>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:16]([C:22]3[N:36]([CH2:34][CH3:35])[C:26]([CH3:27])=[N:25][N:24]=3)=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)nc2C(=O)NN)cc1
Reactant: COC(C)(OC)OC
Reactant: CCN
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCn1c(C)nnc1-c1nc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A 25 mL scintillation vial was charged with 4-tert-butyl-N-(6-chloro-2-hydrazinocarbonyl-pyridin-3-yl)-benzenesulfonamide (691 mg, 1.8 mmol), trimethyl orthoacetate (0.35 mL, 2.8 mmol), ethylamine (5 mL, 2.0 M), AcOH (3.0 mL), and dioxane (10 mL). The vial was sealed, heated to 130° C., and stirred for three hours. The volatiles were then evacuated in vacuo and the residue was purified via automated silica gel chromatography and then preparative HPLC to afford 4-tert-butyl-N-[6-chloro-2-(4-ethyl-5-methyl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-benzenesulfonamide as a white powder: MS (ES) M+H expected 434.1. found 434.1.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].P(Cl)(Cl)(Cl)=O.[Cl:20][C:21]([Cl:26])(Cl)[C:22](Cl)=[O:23]>CCOCC.[Cu].[Zn]>[Cl:20][C:21]1([Cl:26])[C:22](=[O:23])[CH2:3][CH:2]1[CH2:1][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(CC1CC(=O)C1(Cl)Cl)C(=O)OCC
Temperature: 25 °C

Procedure:
To a stirred suspension of Cu.Zn (1.771 g, 13.73 mmol) and diethyl 2-allylmalonate (1.084 mL, 5.49 mmol) in anhydrous Et2O (20 mL) at reflux was added a solution of phosphorus oxychloride (1.127 mL, 12.09 mmol) and 2,2,2-trichloroacetyl chloride (1.357 mL, 12.09 mmol) in Et2O (10 mL) dropwise through an addition funnel over 2 h. The resulting mixture was then heated at reflux overnight. After cooling to room temperature, the mixture was filtered through CELITE® and washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel column chromatography (80 g, EtOAc/hexane=0-50%) to afford Intermediate S-1A (1.59 g, 93%). 1H NMR (400 MHz, chloroform-d) δ 4.32-4.23 (m, 4H), 3.58 (dd, J=8.9, 6.1 Hz, 1H), 3.47-3.32 (m, 1H), 3.16-2.92 (m, 2H), 2.51 (ddd, J=14.3, 7.2, 6.1 Hz, 1H), 2.40-2.25 (m, 1H), 1.36-1.30 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][NH2:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH:23]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29])=O.C(O)(=O)C>CCO>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19]/[N:20]=[CH:23]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reactant: N#Cc1cccc(C=O)c1
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1cccc(/C=N/OC2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)c1

Procedure:
A solution of O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl)hydroxylamine (130 mg, 0.38 mmol), 3-formylbenzonitrile (45 mg, 0.38 mmol) and acetic acid (0.022 ml, 0.38 mmol) in EtOH (4 ml) was stirred for 1 hour and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (EtOAc/Hexanes 20/80-50/50) and recrystallized from EtOAc/Hexanes to give (E)-3-((1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxyimino)methyl)benzonitrile (96 mg, 56%, colorless solid, LC: 98%, retention time: 7.94 min (Method A), M/Z: 453.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)=[O:4].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C>[Cl:12][C:10]1[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1
Reactant: C1CCNCC1
Reactant: O=C(CBr)Nc1cc(Cl)nc(-c2ccccc2)n1
Solvent: CC#N
Product: O=C(CN1CCCCC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Reaction time: 1.5 h

Procedure:
2-Bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide (28 mg) was dissolved in acetonitrile (2 ml) and piperidine added (23 μl in 500 ul acetonitrile). The mixture was left to stir for 1.5 hr after which time the solvent was removed in vacuo. Purification using a short silica plug, eluting with a mixture of ethyl acetate and petroleum ether (1:1 v/v) furnished the title compound (25 mg).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)([CH3:15])[CH2:11][CH2:12][CH:13]=[CH2:14])=[CH:2]1.C([Li])CCC.CCCCCC.O1CCCC1.O1CCCC1.O1CCCC1.[Cl-:48].[Cl-].[Cl-].[Cr+3:51]>O1CCCC1>[Cl-:48].[Cl-:48].[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]([Cr+2:51])[CH:2]=1)([CH3:15])[CH2:11][CH2:12][CH:13]=[CH2:14]
Reactant: [Cr+3]
Reactant: C=CCCC(C)(C1=CCc2ccccc21)c1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCCC(C)(C1=CC([Cr+2])c2ccccc21)c1ccccn1
Temperature: -100 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
A solution of 4.81 g (0.01747 mol) of 2-[1-(1H-inden-3-yl)-1-methyl-4-pentenyl]pyridine in 60 ml of tetrahydrofuran was cooled to −100° C. 11.5 ml of a 15% strength n-butyllithium solution in hexane (0.01834 mol) were slowly added dropwise. After the addition was complete, the reaction mixture was stirred at −100° C. for a further 1 hour. The mixture was subsequently allowed to warm to room temperature. After stirring for a further 2 hour, the solution was cooled to −60° C. and 7.07 g (0.0189 mol) of chromium trichloride tris(tetrahydrofuran) were added while stirring. The mixture was allowed to warm slowly to room temperature and was subsequently stirred at room temperature for a further 10 hours. The solid which had precipitated was filtered off, washed with diethyl ether and dried under reduced pressure. Recrystallization from a mixture of dichloromethane and diethyle ether gave 2.5 g of (3-(2-pyridyl-1-methyl-4-pentenyl)indenyl)chromium dichloride (36%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](=[O:29])[NH:12][C:13](=[O:28])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][C:20]([N+:24]([O-:26])=[O:25])=[CH:21][CH:22]=3)[N:17]([CH3:27])[CH:16]=2)=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:40](Cl)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57].C1C[O:62]CC1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](=[O:29])[N:12]([C:40](=[O:62])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[C:13](=[O:28])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][C:20]([N+:24]([O-:26])=[O:25])=[CH:21][CH:22]=3)[N:17]([CH3:27])[CH:16]=2)=[CH:2]1
Reactant: CCCCCCCC/C=C\CCCCCCCCCl
Reactant: C1CCOC1
Reactant: Cn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCCCCCCCC=CCCCCCCCC(=O)N1C(=O)C(c2c[nH]c3ccccc23)=C(c2cn(C)c3cc([N+](=O)[O-])ccc23)C1=O
Temperature: -60 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 3-(1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (250 mg, 0.65 mmol), prepared as described in U.S. Ser. No. 09/268,887, was dissolved in THF (15 ml) and cooled to −60° C. To this solution was added lithium bis(trimethylsilyl)amide (0.7 mmol, 0.7 ml, 1.0 M in THF), followed by oleyl chloride (Aldrich) (0.300 g, 1.0 mmol) in THF (5 ml). The resulting mixture was stirred at 0° C. for 1 hr. All solvent was evaporated and the crude material was pre-purified by silica gel chromatography. The resulting products were separated using silica gel chromatography using a gradient of ethyl acetate and hexane. This gave 310 mg of 3-(1H-Indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-1-octadec-9-enoyl-pyrrole-2,5-dione. (Yield 70 %)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:33]=1[O:40][CH3:41])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[C:33]=2[O:40][CH3:41])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(OC)c1OC
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC)c2OC)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.5 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (600 mg, 0.003 mol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (1.80 g, 0.014 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,3-dimethoxy-phenoxy)-but-2-enoic acid ethyl ester (1.00 g, 0.003 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,3-dimethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (430 mg, 33%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:48])[NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.[CH3:49][N:50]([CH3:56])[C@H:51]1[CH2:55][CH2:54][NH:53][CH2:52]1>CN(C)C=O>[CH3:49][N:50]([CH3:56])[C@H:51]1[CH2:55][CH2:54][N:53]([C:13]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[O:48])[CH2:39][CH2:38]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:14])[CH2:52]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccccc4)CC3)c(F)c2)ccn1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)c(F)c3)ccn2)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85.4 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) was added (3S)-(−)-3-dimethylaminopyrrolidine (44 mg), followed by stirring at room temperature for 3.5 hr. The reaction mixture was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated. A solid was precipitated by addition of diethyl ether:hexane=1:2 to the residue. The solvent was removed, and the residue was dried under reduced pressure to provide the titled compound as white powder (36.1 mg, 85%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=1)[C:5]2=[O:28].C(N(C(C)C)CC)(C)C.[F:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46]#[CH:47])=[CH:41][CH:40]=1.O>CN(C=O)C.[Cu]I>[F:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46]#[C:47][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[C:5]3=[O:28])=[CH:41][CH:40]=1
Reactant: Cn1c(=O)n(Cc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)c2cc(I)ccc21
Reactant: C#CCc1ccc(F)cc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n(Cc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)c2cc(C#CCc3ccc(F)cc3)ccc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 1.0 g (2.0 mmol) 3-(3,4-Difluoro-benzyl)-6-iodo-1-methyl-1H-quinazoline-2,4-dione from Example 14 Step 1 and 1.0 g (8.4 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by CuI (catalytic). 0.44 g (3.3 mmol) 1-fluoro-4-prop-2-ynyl-benzene is added and the mixture is heated to 70° C. for 6 hrs. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filtered and dry under reduced pressure.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH2:14]O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O.O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH2:14][Cl:18])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1nccc2c(CO)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)c1nccc2c(CCl)cccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-iso-Propyl-5-hydroxymethylisoquinoline (6.5 g) was dissolved in 50 ml of chloroform and 6.5 ml of phosphorus oxychloride was added dropwise under ice cooling. The mixture was stirred at room temperature for 1 hour. Water (50 ml) was added to the reaction mixture, and it was made weakly alkaline with potassium carbonate. The chloroform layer was washed in water, and dried. The solvent was distilled off under reduced pressure to afford 7.1 g of 1-isopropyl-5-chloromethylisoquinoline as a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][C:9]2=[O:19])=[CH:5][C:4]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@:38]1([CH3:45])[C:42](O)=[O:43])=[O:36])([CH3:33])([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(#N)C>[O:19]=[C:9]1[NH:10][C:11](=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]1[CH2:7][C:6]1[CH:20]=[CH:21][C:3]([F:2])=[C:4]([CH:5]=1)[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:42]([C@@:38]2([CH3:45])[CH2:39][CH2:40][CH2:41][N:37]2[C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])=[O:43])[CH2:26][CH2:25]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)O
Reactant: O=C(c1cc(Cn2c(=O)[nH]c(=O)c3ccccc32)ccc1F)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@]1(C)C(=O)N1CCN(C(=O)c2cc(Cn3c(=O)[nH]c(=O)c4ccccc43)ccc2F)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
1-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione hydrochloric acid (30b, 37 mg) was suspended in acetonitrile (1.5 mL), treated with (R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (40a, 30 mg), HATU (47 mg), and Et3N (0.5 mL) sequentially. The reaction mixture was stirred at ambient temperature (25° C.) for 19 hrs. The reaction mixture was directly purified by flash chromatography with MeOH—CH2Cl2 (0-20% gradient elution) to afford the desired product, (R)-tert-butyl 2-(4-(5-((2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)-2-fluorobenzoyl)piperazine-1-carbonyl)-2-methylpyrrolidine-1-carboxylate (40b) as the major fraction (colorless oil, 50 mg). MS (ESI): m/z=594 (M+H+)
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][C:24]=2[N:25]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:30][C:27]2[CH:28]=[CH:29][C:23]3[S:22][C:21]([CH3:20])=[N:25][C:24]=3[CH:26]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: Cc1nc2cc(C=O)ccc2s1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2sc(C)nc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 2-methylbenzo[d]thiazole-5-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.78 min.; [M+H]+: 397.01 g/mol.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.Cl.Cl.Cl.[NH:21]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.COCCO>CCOCC>[N:21]1([C:2]2[C:3]3[CH2:13][CH2:12][CH2:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=4[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCNCCN1
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1CCC2
Agent: Cl
Solvent: CCOCC
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(c(N3CCNCCNCC3)n1)CCCc1ccccc1-2
Temperature: 110 °C
Reaction time: 19 h

Procedure:
The product from Example 68A (52 mg, 0.212 mmol) was treated with 1,4,7-triazonane trihydrochloride (202 mg, 0.847 mmol), treated with Hunig's base (554 μl, 3.17 mmol), treated with 2-methoxyethanol (2116 μl), stirred at 110° C. for 19 hours, cooled, diluted with Et2O (25 mL), washed with 0.1 M NaOH (2×10 mL), washed with brine, dried (MgSO4), filtered, concentrated and purified by chromatography on silica gel (eluting with 2, 10 and 50% (9:1 MeOH:concentrated NH4OH) in CH2Cl2) to provide the title compound. 1H NMR (CD3OD) δ 2.08-2.24 (m, 2H), 2.40 (t, J=6.94 Hz, 2H), 2.67 (t, J=6.74 Hz, 2H), 2.94 (s, 4H), 3.10-3.16 (m, 4H), 3.71-3.77 (m, 4H), 7.24-7.29 (m, 1H), 7.32-7.41 (m, 2H), 7.63-7.68 (m, 1H); MS (M+H)+ m/z 339.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([OH:23])=O.[CH3:24][C:25]1([CH3:32])[NH:30][CH2:29][CH2:28][NH:27][C:26]1=[O:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:24][C:25]1([CH3:32])[N:30]([C:21](=[O:23])[CH2:20][N:3]2[CH2:4][CH2:5][CH2:6][C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]2=[O:1])[CH2:29][CH2:28][NH:27][C:26]1=[O:31]
Reactant: CC1(C)NCCNC1=O
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
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: ClCCl
Product: CC1(C)C(=O)NCCN1C(=O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.15 g, 0.485 mmol) and 3,3-dimethylpiperazin-2-one (CAS 22476-74-0) (0.062 g, 0.485 mmol) in dichloromethane (3 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.184, 0.485 mmol) and diisopropylethylamine (0.53 mL, 2.91 mmol). The reaction mixture was stirred at ambient temperature overnight and then concentrated followed by chromatographic purification on an Analogix silica gel column eluting with 5% methanol/dichloromethane to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.05-8.11 (m, 1H), 7.16-7.32 (m, 10H), 4.20 (s, 2H), 3.46-3.52 (m, 2H), 3.33-3.41 (m, 2H), 3.16-3.22 (m, 2H), 2.51-2.57 (m, 2H), 1.63-1.75 (m, 2H), 1.60 (s, 6H); MS (DCI+) m/z 420 (M+H)+.