Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:45])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:44])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:43])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:42])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:41])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:40])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:39])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:38])=[CH:35]/[CH2:36][OH:37].[C:47](O)(=[O:65])[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][CH2:63][CH3:64].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[C:47]([O:37][CH2:36][CH:35]=[C:34]([CH3:38])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:39])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:40])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:41])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:42])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:43])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:44])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:45])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:46])[CH3:1])(=[O:65])[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][CH2:63][CH3:64]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
16 Grams of solanesol, 7.5 g of stearic acid and 10 g of polyphosphoric acid ethyl ester were dissolved in 40 ml of chloroform and the solution was refluxed under stirring for 4 hours. After completion of the reaction, the reaction product was poured in water and added with about 10 g of sodium hydrogencarbonate to decompose the polyphosphoric acid ester. After extraction with ether, the ether layer was washed with water and subjected to distillation under reduced pressure. The residual oily substance was purified by column chromatography with 100 g of silica gel to obtain 12.5 g (54.8%) of a white solid (m.p. 36°-37° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[C:25][Si](C)(C)C)[CH:22]=2)[CH2:17][CH2:16]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO.C1COCC1>[C:24]([C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][CH2:16][N:15]2[C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:19][CH:20]=1)#[CH:25]
Reactant: COc1cc2ncnc(N3CCc4ccc(C#C[Si](C)(C)C)cc43)c2cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc2c(c1)N(c1ncnc3cc(OC)c(OC)cc13)CC2

Procedure:
To 6,7-dimethoxy-4-(6-trimethylsilanylethynyl-2,3-dihydro-indol-1-yl)-quinazoline (1 eq.; 50 mg; 0.124 mmol) in MeOH (2 mL)/THF (2 mL) was treated with 1M tetrabutylammonium fluoride (2 eq.; 0.248 mL) in THF at 20° C. for 16 hours. Solvents were removed in vacuo and the residue was dissolved in 1:1 EtOAc/Et2O washed with saturated aqueous NaHCO3, dried over Na2SO4(s), filtered and concentrated in vacuo. The product was converted to the HCl salt using a procedure analogous to that described for Example 2. (M.P. 241°-243° C.; LC-MS: 332 (MH+); RP18-HPLC RT: 4.48 min)
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)C.C(=O)=O.C([N-]C(C)C)(C)C.[Li+].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:30]#[N:31]>O1CCCC1.O>[CH3:38][O:37][C:33]1[CH:32]=[C:29]([C:30]2[N:31]=[C:4]([OH:6])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[CH:1]=2)[CH:28]=[C:27]([O:26][CH3:25])[C:34]=1[O:35][CH3:36]
Reactant: COc1cc(C#N)cc(OC)c1OC
Reactant: Cc1ncccc1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(-c2cc3ncccc3c(O)n2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7 g 2-Methyl-nicotinic acid was suspended in 150 mL of tetrahydrofuran, and cooled to −70° C. with a bath of ethanol/dry ice. 80 mL lithium diisopropylamide (2.0 M in tetrahydrofuran/n-heptane/ethylbenzene) was added dropwise over 10 min and the mixture was stirred for 2 h at 0° C. Then it was cooled to −73° C. and a solution of 10 g 3,4,5-trimethoxy-benzonitrile (4.24) in 50 mL tetrahydrofuran was added. Then the reaction mixture was warmed overnight to ambient temperature. 30 mL Water was added and the solvent was distilled off before 200 mL ethyl acetate was added and the precipitate that formed was collected.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=O.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CN(C1C=CN=CC=1)C.O>[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:1][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][CH:7]=[CH:6]3)[CH2:32][CH2:31]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: OCCN1CCN(Cc2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2.7 h
Yield: 132.2 %

Procedure:
5-Formylindole (2.00 g, 13.8 mmol) was dissolved in acetonitrile (40 mL), and the solution was added with di-tert-butyldicarbonate (3.31 g, 15.2 mmol) and DMAP (16.8 mg, 0.138 mmol), followed by stirring at room temperature for 2.7 hours. The solution was added with a solution of N-(2-hydroxyethyl)piperazine (6.46 g, 49.6 mmol) in acetonitrile (15 mL), and acetic acid (14.2 mL, 248 mmol), then sodium triacetoxyborohydride (13.1 g, 62.0 mmol) was added thereto little by little, followed by stirring at room temperature for 2.5 hours. The reaction mixture was added with water and sodium carbonate to adjust the pH to 9, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (chloroform/methanol=9/1, 4/1) to obtain 5-[4-(2-hydroxyethyl)piperazin-1-ylmethyl]indole (4.73 g, yield 95%).
Reaction SMILES: [C:1]([C:9]1[C:10]([Cl:16])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:16][C:10]1[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([N+:17]([O-:19])=[O:18])[CH:7]=2)=[CH:14][CH:13]=[C:12]([CH3:15])[N:11]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(=O)c2ccccc2)c(Cl)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)c(Cl)n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
3-Benzoyl-2-chloro-6-methylpyridine (3.00 g, 12.9 mmol) dissolved in 40 ml of concentrated sulfuric acid was cooled to 5° C. or lower, 1.0 ml of fuming nitric acid was slowly added dropwise thereto, followed by stirring for 30 minutes. The reaction solution was poured into ice water, neutralized with sodium hydroxide aqueous solution and then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the solvent was evaporated under a reduced pressure and the resulting residue was recrystallized from ethyl aretate-diisopropyl ether to give 1.81 g (51%) of 2-chloro-6-methyl-3-(3-nitrobenzoyl)pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]2([CH3:21])[CH3:20].I[CH:23]([CH3:25])[CH3:24].CC([O-])(C)C.[K+].C(Cl)Cl.CO>CN(C)C=O>[CH:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6](=[O:19])[C:5]2([CH3:20])[CH3:21])([CH3:25])[CH3:24]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Reactant: CC(C)I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CCCCCN1C(=O)C(C)(C)c2cc(NC(C)C)c([N+](=O)[O-])cc21
Yield: 35 %

Procedure:
A8 (0.5 g) is alkylated using 2-iodopropane (0.5 ml; 5 mmol) and KOtBu (561 mg; 5 mmol) in N,N-dimethylformamide (7 ml) for 20 h at RT. After aqueous work-up and flash chromatography on silica gel eluting with CH2Cl2/MeOH (98:2) the compound (200 mg) is obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]([C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)=O)C1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([CH3:35])[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1>ClCCl>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:20]1[CH:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:33][C:30]1[CH:31]=[CH:32][C:27]([CH3:35])=[CH:28][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: O=C1c2ccc(Cl)cc2N(C(=O)C2CCCN2)CN1Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(CN2CCCC2c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 23.7 %

Procedure:
Formula I where U—V is —N(R6)—CReRf—; R1, R2, R4, and Ra to Rf are H; R3 is chloro; R5 is benzyl: and R6 is p-methyl-benzyl: Crude 3-benzyl-7-chloro-1-(pyrrolidine-2-carbonyl)-2,3-dihydro-1H-quinazoline-4-one (170 mg, 0.50 mmol) dissolved in dichloromethane (5 mL) was treated with p-tolualdehyde (80 μL, 0.7 mmol) and NaHB(OAc)3 (350 mg, 1.65 mmol), and the mixture was stirred for 40 minutes at room temperature. The reaction was quenched with saturated NaHCO3 (2.2 mL) and the aqueous phase extracted with dichloromethane (25 mL). The organic layers were combined and dried over Na2SO3, filtered and concentrated under vacuum. The crude residue was purified by silica gel chromatography using a stepwise gradient of 20% ethyl acetate/hexanes to 50% methanol/ethyl acetate as eluent to give 52.5 mg (24% yield) of desired product of Formula I, 3-benzyl-7-chloro-2-[1-(4-methyl-benzyl)-pyrrolidin-2-yl]-3Hquinazolin4-one. LRMS (MH+) m/z 445.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([I:11])=[N:6]1
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: ClCCCCBr
Product: Fc1ccc2c(c1)c(I)nn2CCCCBr
Yield: 74 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and 1-bromo-4-chlorobutane in 74% yield according to the general procedure for Preparation 11A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 1.76-1.80 (2H, m), 2.07-2.11 (2H, m), 3.55 (2H, t, J=6.4 Hz), 4.42 (2H, t, J=6.8 Hz), 7.11 (1H, dd, J=2.0, 8.4 Hz), 7.22 (1H, td, J=2.4, 8.8 Hz), 7.33 (1H, dd, J=4.0, 9.2 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[Cl:20][C:21]1[CH:22]=[C:23]([SH:28])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)Nc2c(OCCCCCl)cccc21
Product: CC1(C)OC(=O)Nc2c(OCCCCSc3ccc(Cl)c(Cl)c3)cccc21

Procedure:
Prepared analogously to Example 1 from 8-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16](/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:28]([O:38][CH3:39])[CH:27]=3)[N:17]3[CH2:22][CH2:21][O:20][C:19](=[O:23])[C:18]=23)=[CH:10][CH:9]=1.C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>C1COCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]=[C:16](/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]4)=[C:28]([O:38][CH3:39])[CH:27]=3)[N:17]([CH2:22][CH2:21][OH:20])[C:18]=2[CH2:19][OH:23])=[CH:12][CH:13]=1
Reactant: COc1cc(/C=C/c2nc(-c3ccc(F)cc3)c3n2CCOC3=O)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/c2nc(-c3ccc(F)cc3)c(CO)n2CCO)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 104.4 %

Procedure:
LAH (10 mg) was added to a solution of 1-(4-fluorophenyl)-3-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6-dihydroimidazo[5,1-c][1,4]oxazin-8-one (56 mg) in THF (3 mL), and the reaction solution was stirred at room temperature for 40 minutes. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 59 mg of the title crude product. The property value of the compound is as follows.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][NH:3][C:2]=1/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9].[O-]P(OP([O-])([O-])=O)(=O)[O-].[NH2:20][C@@H](CCC(N[C@H](C(NCC(O)=O)=O)CS)=O)C(O)=O>N[C@H](C(O)=O)CC1N=CNC=1>[NH3:3].[NH2:20][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][C:2]1[N:3]=[CH:4][NH:5][CH:1]=1
Reactant: O=C(O)/C=C/c1cnc[nH]1
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: O=P([O-])([O-])OP(=O)([O-])[O-]
Product: N
Reaction time: 0.08 h

Procedure:
HAL enzyme activity can be determined as described in Baedeker & Schulz (Eur. J. Biochem 2002, 269, 1790-1797), wherein enzyme activity was determined as the rate of urocanate formation, measured spectrophotometrically at 277 nm. For a standard assay, the enzyme was preincubated at 25° C. for 5 min in 2.5 mL buffer containing 0.1 M pyrophosphate (pH 9.3), 10 μM ZnC12 and 2 mM glutathione. The reaction was started by adding 200 μL of 0.5 M histidine solution and then monitored for approximately 5 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>>[NH:20]([C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)[NH2:21]
Reactant: CS(=O)(=O)Nc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: NN
Solvent: O
Product: CS(=O)(=O)Nc1ccc(-c2ccc(NN)nn2)cc1

Procedure:
A suspension of N-(4-(6-chloropyridazin-3-yl)phenyl)methanesulfonamide (2.82 mmole) in hydrazine monohydrate (6 mL) was heated at 120 C for 1 hour and evaporated in vacuo. The residue was dissolved in dichloromethane, washed with water, dried over Na2SO4, and evaporated in vacuo to afford N-(4-(6-hydrazinylpyridazin-3-yl)phenyl)methanesulfonamide.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:13]([OH:15])=[O:14].O>CCCCCC>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[C:4]2[C:5]([O:15][C:13](=[O:14])[C:3]=12)=[O:7]
Reactant: O=C(O)c1c(F)cc(F)c(F)c1C(=O)O
Solvent: O
Solvent: CCCCCC
Product: O=C1OC(=O)c2c(F)c(F)cc(F)c21
Temperature: 25 °C

Procedure:
A 25 mL round-bottom flask equipped with a Barrett trap and a condenser was charged with 1.00 g of 3,4,6-trifluorophthalic acid and 15 mL of mixed xylenes under a dry nitrogen atmosphere. The reaction mixture was then heated under reflux with azeotropic removal of water for 5 hr. and was then cooled to room temperature. After the addition of 20 mL of hexane the mixture was cooled in an ice bath. The solvent was then removed on a rotary evaporator to afford 3,4,6-trifluorophthalic anhydride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH2:8][CH2:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[CH2:19][O:18][CH2:17][CH2:16][C:14]=2[N:15]=1.C([BH3-])#N.C(O)(=O)C>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:8][CH2:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[CH2:19][O:18][CH2:17][CH2:16][C:14]=2[N:15]=1
Reactant: O=Cc1cccs1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: [BH3-]C#N
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]c(CNCc2cccs2)nc2c1COCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.2 %

Procedure:
A mixture of thiophene-2-carbaldehyde (0.021 mL, 0.22 mmol), 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (40 mg, 0.22 mmol), and siliabond cyanoborohydride (240 mg, 0.24 mmol, 1 mmol/g) in ethanol (1 mL) was stirred at ambient temperature for 10 minutes. Acetic acid (0.013 mL, 0.22 mmol) was then added, and the mixture was stirred at ambient temperature for another 5 minutes. The reaction mixture was concentrated in vacuo and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0, methanol: dichloromethane, 1:99 to 10:90) to provide the title compound (30 mg, 49% yield). m/z 278.1 (M+1), retention time=0.89 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=[CH:5][CH:4]=1.C(Cl)(=O)C(C)(C)C.FC(F)(F)C(O)=O.[CH3:46][N:47]([CH3:53])[C@H:48]1[CH2:52][CH2:51][NH:50][CH2:49]1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(#N)C.C(N(CC)CC)C>[CH3:46][N:47]([CH3:53])[C@H:48]1[CH2:52][CH2:51][N:50]([C:27]([C@@H:11]2[CH2:10][C@H:9]([S:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=3)[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])=[O:29])[CH2:49]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CN(C)[C@H]1CCNC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](N(C)C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 78.7 %

Procedure:
924 mg of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid were dissolved in 10 ml of dry tetrahydrofuran, and the resulting solution was cooled to -20° C. 209 mg of triethylamine, followed by 250 mg of pivaloyl chloride, were then added to the solution, after which the mixture was stirred at the same temperature for 5 minutes. At the end of this time, a mixture of 651 mg of (3S)-3-dimethylaminopyrrolidine trifluoroacetate, 560 mg of diisopropylethylamine and 7 ml of dry acetonitrile was added to the mixture, and the mixture was gradually heated and then stirred at 0° C. for 1 hour. After this, the reaction mixture was filtered, and the solvent was removed by evaporation under reduced pressure. The resulting residue was diluted with ethyl acetate, and the diluted solution was washed with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a 3:1 by volume mixture of acetonitrile and methanol as the eluent, to obtain 884 mg of the title compound as a powder.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:25])([F:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)[N:3]=1.[CH3:26][C:27]1[NH:31][N:30]=[C:29]([NH2:32])[CH:28]=1>O1CCOCC1>[F:24][C:16]([F:25])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:4]1[N:3]=[C:2]([NH:32][C:29]2[CH:28]=[C:27]([CH3:26])[NH:31][N:30]=2)[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: COC(=O)c1cccc2c(Br)nc(C(F)(F)c3ccc(F)cn3)nc12
Solvent: C1COCCO1
Product: COC(=O)c1cccc2c(Nc3cc(C)[nH]n3)nc(C(F)(F)c3ccc(F)cn3)nc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline-8-carboxylate (27 g, 65.5 mmol) in dioxane (300 mL) was added 5-methyl-1H-pyrazol-3-amine (12.7 g, 131 mmol) and the mixture was stirred at 50° C. overnight. The mixture was concentrated and the residue was triturated with water (1 L). The solid was collected by filtration, washed with water, and dried in air to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazoline-8-carboxylate as a solid. (26.7 g, 95%). LC-MS (ESI) m/z 429.6 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 12.23 (1H, s), 10.86 (1H, s), 8.82 (1H, d, J=8.2 Hz), 8.67 (1H, d, J=2.6 Hz), 7.99 (3H, m), 7.68 (1H, t, J=8.0 Hz), 6.05 (1H, s), 3.83 (3H, s), 2.19 (3H, s).
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]2[CH2:15][C@H:14]3[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=2[N:19]=1.Cl.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.[OH-].[Na+]>O>[N:21]1([C:3]2[CH:4]=[CH:5][C:6]3[CH2:15][C@H:14]4[C@@H:9]([CH2:10][CH2:11][CH2:12][N:13]4[CH2:16][CH2:17][CH3:18])[CH2:8][C:7]=3[N:19]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCCN1CCC[C@H]2Cc3nc(Cl)ccc3C[C@@H]21
Reactant: C1CCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN1CCC[C@H]2Cc3nc(N4CCCC4)ccc3C[C@@H]21
Temperature: 210 °C
Yield: 53.1 %

Procedure:
A mixture of (±)-trans-2-chloro-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinoline hydrochloride (2.50 g, 8.3 mmol) and pyrrolidine hydrochloride (10 g) was heated to 210° C. to form a homogeneous molten semi-solid. After 45 minutes the molten semi-solid was poured into water, made basic with dilute NaOH solution, and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give the crude product as a brown solid. Purification by flash chromatography (10% methanol in methylene chloride, NH4OH) provided (±)-trans-2-pyrrolidino-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinoline (Rf =0.45, 1.32 g, 53% yield) as a brown oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:11]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17]([C@H:21]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](Cl)=[O:40])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si](C(C)(C)C)(C)C)[CH:23]=2)[C@@H:16]([CH3:45])[CH2:15]1)[CH:12]=[CH2:13]>>[CH2:11]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17]([C@H:21]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:40])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[C@@H:16]([CH3:45])[CH2:15]1)[CH:12]=[CH2:13]
Reactant: CC(C)Nc1ccccc1
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(c3ccccc3)C(C)C)c2)C[C@H]1C

Procedure:
N-Isopropylaniline was then coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)-benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-isopropyl-N-phenylbenzamide as an off-white solid. NMR (200 MHz, DMSO-d6): δ 0.92 (d, J=6.1 Hz, 3H); 0.99 (d, J=5.9 Hz, 3H); 1.11 (d, J=6.9 Hz, 6H); 1.70 (dd, J1 =7.2 Hz, J2 =11.1 Hz, 1H); 2.07 (dd, J1 =7.6 Hz, J2 =10.6 Hz, 1H); 2.33 (br d, J=9.9 Hz, 1H); 2.42-2.54 (m, 2H); 2.68 (br d, J=10.4 Hz, 1H); 2.85 (dd, J1 =6.5 Hz, J2 =13.9 Hz, 1H); 3.16 (dd, J1 =4.9 Hz, J2 =14.1 Hz, 1H); 4.75 (s, 1H); 4.85 (m, 1H); 5.10 (d, J=10.2 Hz, 1H); 5.18 (d, J=16.8 Hz, 1H); 5.70-5.84 (m, 1H); 6.50 (d, J=7.1 Hz, 1H); 6.59 (s, 1H); 6.65 (d, J=8.2 Hz, 1H); 7.03-7.32 (m, 10H); 9.33 (s, 1H). Mass spectrum (CI--CH4) m/e: 498 (M+1, 100%), 344 (43%), 153 (76%). [α]D20 =+6.4° (abs. ethanol, c=1.4). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 4.0 followed by precipitation with diethyl ether from dichloromethane to give the monohydrochloride salt as a hygroscopic off-white powder. Calc. for C32H39N3O2HCl 0.5 H2O: C, 70.76; H, 7.61; N, 7.74; Cl, 6.53. Found: C, 71.01; H, 7.83; N, 7.49; Cl, 6.41.