Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].CO>C(OCC)(=O)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:25][CH2:26][CH:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 80% overall yield. FDMS m/e=351 (M+ of free base). α[D]589 =-15.49 (c=0.86, methanol).
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]([CH3:18])[C:4]=2[N:3]=1.[CH2:19](Br)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:19][C:20](=[O:21])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6](=[O:17])[N:5]([CH3:18])[C:4]=2[N:3]=1
Reactant: CC(C)=CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(Br)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
30 g of 8-bromo-3-methyl-7-(3-methylbut-2-enyl)-3,7-dihydropurine-2,6-dione, 20.6 g of phenacyl bromide and 25.4 g of potassium carbonate are introduced into 400 ml of DMF and heated at an internal temperature of 80° C. for 3 hours. The solution is cooled to about 50° C., and 400 ml of water are slowly added. The mixture is then stirred overnight, and the precipitated solid is filtered off with suction. After washing with water, the pale brown solid is recrystallized from 300 ml of isopropanol.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([F:20])([F:19])[CH2:17]I.O>CS(C)=O>[F:15][C:16]([F:20])([F:19])[CH2:17][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: FC(F)(F)CI
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccccc1OCC(F)(F)F
Temperature: 120 °C
Reaction time: 6 h
Yield: 90.5 %

Procedure:
To a solution of catechol (5 g, 0.045 moles) in dimethylsulfoxide (25 ml) were added, potassium carbonate (12.55 g, 0.09 mole) and 2,2,2-trifluoroethyl iodide (4.77 g, 0.023 mole) under stirring. The reaction mixture was stirred vigorously at 120° C. for 6 hours. Water (150 ml) was added to the reaction mixture and the mixture was extracted in Toluene (250 ml). Organic layer was washed with 1 N Sodium hydroxide solution (150 ml), followed by brine wash. The extract was dried over sodium sulphate. The solvent was evaporated under reduced pressure to give 4.0 g of (XI) as oil. Purity (by GC)=96%
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:26])[NH:1][C:2]2[CH:16]=[CH:15][C:5]([C:6]([N:8]([CH2:10][CH2:11][N:12]([CH3:13])[CH3:14])[CH3:9])=[O:7])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN(C)CCN(C)C(=O)c1ccc(N)cc1
Solvent: ClCCl
Product: CN(C)CCN(C)C(=O)c1ccc(NC(=O)Nc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.9 %

Procedure:
To a solution of 4-amino-N-(2-dimethylamino-ethyl)-N-methyl-benzamide (4.0 g, 0.01809 mol) and TEA (2.01 g, 0.01809 mol) in DCM (50 mL) was added 4-bromophenyl isocyanate (4.3 g, 0.0217 mol). The reaction mixture was stirred at room temperature for 12 h. The white solid was obtained and was filtered and dried to afford the title compound [5.0 g, 67%]; LC-MS (ESI): Calculated mass: 418.1; Observed mass: 421.1 [M+H]+ (RT: 1.23 min).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[C:22]([CH3:25])[C:23]=1[CH3:24].C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:17][C:18]1[N:19]=[N:20][C:21]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=3)[CH2:14][CH2:13]2)=[C:22]([CH3:25])[C:23]=1[CH3:24]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)nnc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Temperature: 180 °C
Yield: 82 %

Procedure:
1-(5-Trifluoromethyl-pyridin-2-yl)-piperazine (10 g, 43.3 mmol) is combined with 3,6-dichloro-4,5-dimethyl-pyridazine (14.4 g, 84.3 mmol), triethylamine (8.25 mL), and NMP (40 mL). The reaction mixture is heated to a temperature of 180° C. for 25 min, and then concentrated in vacuo. The residue is purified by flash chromatography on silica gel (0-8% MeOH/CH2Cl2) to afford the title compound (13.2 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH:16][C:17](=[N:20][C:21]([O:23][CH3:24])=[O:22])[S:18][CH3:19])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N+:25]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([O-:27])=[O:26]>C1C=CC=CC=1>[NH:1]=[C:2]1[C:15]([NH:16][C:17](=[N:20][C:21]([O:23][CH3:24])=[O:22])[S:18][CH3:19])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:32][C:31]1[CH:34]=[CH:35][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=1
Reactant: COC(=O)N=C(Nc1ccc(C(=O)c2ccccc2)cc1N)SC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccc([N+](=O)[O-])cc2)C1=N)SC
Reaction time: 3 h

Procedure:
To a mixture of 3-amino-4-(3-carbomethoxy-S-methylisothioureido)benzophenone (3.43 g.; 0.01 mol) in benzene (100 ml.) there is added 4-nitrobenzaldehyde (1.5 g.; 0.01 mol). The mixture is refluxed and stirred for 3 hours. Water of the reaction is removed by a Dean-Stark distillation receiver. The mixture is poured into an excess of hexane and the suspension formed is vacuum filtered. The filter cake is dried to afford 3-imino-(4-nitrophenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone.
Reaction SMILES: CC(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH2:17])[C:14]([OH:16])=[O:15])=O)(C)C.C(O)(C(F)(F)F)=O>>[NH2:17][C@H:13]([C:14]([OH:16])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][NH2:8]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: NCCCC[C@H](N)C(=O)O

Procedure:
A portion of 40.0 mg (18.9 μmol, 1.00 eq) of PMB-protected (Trimer-lys(Boc))2-TEGDA OMe was treated with hot TFA according to general procedure E to yield (Trimer-Lys)2-TEGDA as a colorless solid. Yield: 26.0 mg (18.3 μmol, 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: BrCCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 64.4 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with (4-bromobutoxy)benzene (1.37 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 3:1) and crystallized from dichloromethane-hexane to provide 0.85 g of alpha-oxo-4-[[(4phenoxy)butyl]oxy]benzeneacetic acid methyl ester, mp 57°-59°C.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)#[N:15]>N1C=CC=CC=1>[O:6]=[C:4]1[C:3]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:2]=2[S:1][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:15]1
Reactant: O=C(O)c1ccc(C(=O)O)c(S)c1
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: O=C(O)c1ccc2c(=O)nc(-c3ccccn3)sc2c1
Yield: 42.9 %

Procedure:
A mixture of 2-mercaptoterephthalic acid (2.0 g, 10 mmol), 2-cyanopyridine (1.3 g, 11 mmol) and pyridine (10 ml) was refluxed for 8 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from methanol-diisopropylether to give the titled compound (1.22 g, 42%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.[S:18](Cl)([C:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:26]([N:27]([CH3:29])[CH3:28])[C:25]=2[CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C(Cl)Cl>[C:1]([O:5][CH2:6][CH2:7][O:8][S:18]([C:21]1[C:33]2[C:25](=[C:26]([N:27]([CH3:29])[CH3:28])[CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCO
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)OCCOS(=O)(=O)c1cccc2c(N(C)C)cccc12
Yield: 56.5 %

Procedure:
To a solution of 2-hydroxyethyl acrylate (25.8 mg, 0.2 mmol) in 2 ml of freshly distilled CH2Cl2 was added diisopropylethylamine (DIPEA, 0.35 ml, 0.2 mmol) dropwise at 0° C. Dansyl chloride (50.0 mg, 0.19 mmol) was then added dropwise, and the resultant mixture was stirred at room temperature until TLC indicated the disappearance of starting material. The reaction was quenched with a 5% solution of NH4Cl and extracted (3×20 ml) with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and purified with column chromatography on silica gel (1:4, EtOAc:hexanes) to give 37.5 mg (56%) of 2-(5-dimethylamino-naphthalene-1-sulfonyloxy)-ethyl acrylate as a yellow semi solid. 1H NMR (250 MHz) δ 8.61 (d, J=8.6 Hz, 1H), 8.26 (t, J=6.3 Hz, 2H), 7.56 (m, 2H), 7.20 (d, J=7.7 Hz, 1H), 6.19 (dd, J=16.5, 2.5 Hz, 1H), 5.80 (dd, J=16.5, 10.3 Hz, 1H), 5.71 (dd, J=16.5, 10.3 Hz, 1H), 4.25 (m, 4H), 2.88 (s, 6H). 13C NMR (63 MHz) δ 158.0, 151.7, 131.8, 131.5, 130.9, 130.6, 129.8, 128.8, 127.3, 123.0, 119.4, 115.6, 67.8, 61.5, 45.4.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:11]1[CH:15]2[CH2:16][NH:17][CH2:18][CH:14]2[CH2:13][O:12]1.C(N(CC)CC)C>C1C=CC=CC=1>[C:2]([N:17]1[CH2:18][CH:14]2[CH2:13][O:12][CH2:11][CH:15]2[CH2:16]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: C1NCC2COCC12
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(c1cccnc1)N1CC2COCC2C1
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
Nicotinoyl chloride hydrochloride, represented by formula (XII), (0.1 mole, 17.81 grams) was slowly added to a mixture of hexahydro-1H-furo(3,4-c)pyrrole, represented by formula (X), (0.1 mole, 11.3 grams), and triethylamine (0.2 mole, 20.24 grams) in 160 ml of benzene at 15°C. The reaction mixture was stirred for 1.5 hours at 15°C. and then left overnight at room temperature. The HCl salt of triethylamine was filtered and the salt was washed with benzene. The washings were combined with the filtrate and benzene was stripped under vacuum. The product, 5-nicotinoyl-hexahydro-1H-furo(3,4-c)pyrrole, represented by formula (XIII), light yellow viscous liquid, was purified by column chromatography (Alumina-eluted with methyl acetate).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(F)c(Cl)c4)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3ccc(F)c(Cl)c3)c2O1

Procedure:
Treatment of (±)-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.68 g, 1.57 mmol) with sodium azide (0.25 g, 3.92 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.035 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.186 g (38%) of (±)-1-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >210° C.; Anal. calcd. for C15H13ClFNOHCl: C, 57.34; H, 4.49; N, 4.46. Found: C, 57.38; H, 4.32; N, 4.55.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][Si](C(C)(C)C)(C)C.[OH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C@H:24]([C:28]([O:30][CH3:31])=[O:29])[N:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:22][CH2:21]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:6][C:5]1[CH:4]=[C:3]([CH:16]=[CH:15][CH:14]=1)[CH2:2][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C@H:24]([C:28]([O:30][CH3:31])=[O:29])[N:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:22][CH2:21]2
Reactant: COC(=O)[C@H]1c2ccc(O)cc2CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COC(=O)[C@H]1c2ccc(OCc3cccc(O)c3)cc2CCN1C(=O)OC(C)(C)C

Procedure:
Example 4 was synthesized from (3-(bromomethyl)phenoxy)(tert-butyl)dimethylsilane and (R)-2-tert-butyl 1-methyl 6-hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate using a similar procedure as described in procedure 2, followed by tetrabutylammonium fluoride deprotection. HPLC retention time (Method c)=3.75 min. LC/MS (ESI) (M+H)+=436.20. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 4H), 1.49 (s, 5H), 2.73-2.99 (m, 2H), 3.62-3.83 (m, 2H), 3.69 (s, 3H), 5.00 (s, 2H), 5.12 (brs, 1H), 5.35 (d, J=14.65 Hz, 0.5H), 5.52 (d, J=7.07 Hz, 0.5H), 6.74-6.97 (m, 3H), 6.89-6.93 (m, 1H), 6.96 (d, J=8.08 Hz, 1H), 7.23 (d, J=7.83 Hz, 1H), 7.37 (dd, J=8.59, 4.29 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][C:10]1([CH3:19])[CH2:15][CH:14]([OH:16])[CH2:13][C:12]([CH3:18])([CH3:17])[NH:11]1.C(O[K])(C)(C)C>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:16][CH:14]2[CH2:15][C:10]([CH3:19])([CH3:9])[NH:11][C:12]([CH3:18])([CH3:17])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: CC1(C)CC(Oc2ccc(Cl)nn2)CC(C)(C)N1
Temperature: 0 °C
Yield: 71.6 %

Procedure:
To a 30-L reactor was charged 3,6-dichloropyridazine (1 kg, 6.7 mol), 2,2,6,6-tetramethylpiperidin-4-ol (1.05 kg, 6.7 mol) and THF (5 L). The mixture was stirred and cooled to −5° C. tBuOK (1.13 kg, 10.1 mol) dissolved in THF (10 L) was added slowly to the reactor while keeping the temperature at −5-0° C. The reaction mixture became deep brown during addition. After the addition was complete, the mixture was stirred for 1 hour at −5-0° C., after which time HPLC analysis showed that the reaction was complete. Ice water (1:1, 10 kg) was added slowly to quench the reaction. The mixture was concentrated under reduced pressure to remove most of the THF. The residue was extracted with EtOAc twice (10 L+5 L). The combined organic layer was washed with water (10 L×3), then concentrated under reduced pressure to give a black residue. Petroleum ether (25 L) was added to this residue while stirring. The dark solid that formed was removed by filtration. The pale yellow filtrate was concentrated under reduced pressure to give a yellow solid, which was dried at 50° C. in vacuo to give 3-chloro-6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazine (1.3 kg, 4.8 mol), and was used in the next step without further purification. MS m/z 270.1 [M+H]; 1H-NMR: (CDCl3, 400 MHz) δ 7.36 (d, J=9.2 Hz, 1H), 6.90 (d, J=9.2 Hz, 1H), 5.74 (m, 1H), 2.20 (dd, Ja=4 Hz, Jb=12.4 Hz, 2H), 1.30 (m, 14H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:23])[C:10](=[O:22])[CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[F:25][C:26]([F:34])([F:33])[C:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1>>[NH2:7][C:8]1[N:9]([CH3:23])[C:10](=[O:22])[CH2:11][C@:12]([C:15]2[CH:16]=[C:17]([NH:21][C:30]([C:27]3([C:26]([F:34])([F:33])[F:25])[CH2:29][CH2:28]3)=[O:31])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CN1C(=O)C[C@@](C)(c2cccc(N)c2)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)C1(C(F)(F)F)CC1
Product: CN1C(=O)C[C@@](C)(c2cccc(NC(=O)C3(C(F)(F)F)CC3)c2)N=C1N

Procedure:
The coupling of [(S)-4-(3-amino-phenyl)-1,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F3) and 1-trifluoromethyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=369.2 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)=[O:12])[CH2:6][CH2:7][C:8](=[O:10])[OH:9].[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36](O)=[O:37])=[CH:30]2>>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36]([NH:4][C@@H:5]([C:11]([N:13]1[CH2:14][CH2:15][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:17][CH2:18]1)=[O:12])[CH2:6][CH2:7][C:8](=[O:9])[OH:10])=[O:37])=[CH:30]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)CCC(=O)O)CC2)CC1
Agent: Cl
Product: CN1CCC(N2CCN(C(=O)[C@@H](CCC(=O)O)NC(=O)c3cc4cc(Cl)ccc4[nH]3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-(D-glutamyl)-4-(1-methylpiperidin-4-yl)piperazine trihydrochloride and 5-chloroindole-2-carboxylic acid (43%).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:36])=[C:5]([C:27]([O:34]C)=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])=[C:9]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:8]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:31][O:30][C:29]1[C:3](=[O:2])[C:4]([CH3:36])=[C:5]([CH2:6][C:7]2[CH:20]=[CH:19][C:10]([C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[O:12])=[C:9]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:8]=2)[C:27](=[O:34])[C:28]=1[O:32][CH3:33]
Reactant: COc1c(C)c(Cc2ccc(C(=O)N3CCOCC3)c(-c3cccnc3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)N3CCOCC3)c(-c3cccnc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
N-[4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoyl]morpholine (8 mg, 0.0162 mmol) was dissolved in a mixed solvent of acetonitrile (3 ml) and water (1 ml), then CAN (26 mg, 0.0483 mmol) was added thereto at room temperature and the mixture was stirred for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (4.5 mg, 0.0097 mmol, 60%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][Cl:15])[CH:6]=1)=O.[NH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>C(O)C>[Cl:15][CH2:14][CH2:13][CH2:12][O:11][C:7]1[CH:6]=[C:5]([C:3]2[N:16]=[C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(OCCCCl)c1
Reactant: Cc1ccnc(N)c1
Solvent: CCO
Product: Cc1ccn2cc(-c3cccc(OCCCCl)c3)nc2c1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A solution of the product of Step B (2.6 g) and 2-amino-4-picoline (0.96 g) in ethanol (10 mL) was heated at 73° C. for 2 hours. The reaction mixture was cooled to ambient temperature and the solvent evaporated in vacuo. The residue was dissolved in dichloromethane (75 mL), washed with saturated sodium bicarbonate solution (2×75 mL), brine (75 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (ethyl acetate/hexane) to give the title compound (1.3 g).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([C:7]1[CH:12]=[C:11]([SH:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])[CH3:5].C([O:21][C:22](=[O:28])[CH:23](Br)[CH2:24][CH2:25][CH3:26])C>CC(C)=O>[CH3:6][C:4]([C:7]1[CH:12]=[C:11]([S:13][CH:23]([CH2:24][CH2:25][CH3:26])[C:22]([OH:28])=[O:21])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:3])[CH3:5]
Reactant: CCCC(Br)C(=O)OCC
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O

Procedure:
The title compound was prepared according to the method of Example 41 from potassium hydroxide flakes (3.36 g, 0.06 mole), 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (4.76 g, 0.02 mole) and ethyl-2-bromovalerate (4.18 g, 0.02 mole) in acetone (100 ml). The structure was confirmed by NMR.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[N:4]([NH2:19])[CH:3]=1.CN1CCCC1=O.Cl.Cl[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[F:35].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:35][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][C:29]=1[NH:19][N:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][CH:6]=2)[C:2]([CH3:1])=[CH:3]1
Reactant: Fc1cnccc1Cl
Reactant: Cc1cn(N)c2ccc(OCc3ccccc3)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cn(Nc2ccncc2F)c2ccc(OCc3ccccc3)cc12
Temperature: 80 °C
Yield: 60.5 %

Procedure:
To a solution consisting of 3-methyl-5-(phenylmethoxy)-1H-indol-1-amine (4.81 g) and 1-methyl-2-pyrrolidinone (83 ml) was added 4-chloro-3-fluoro pyridine hydrochloride (3.20 g). The resulting mixture was heated at 80° C. for 2 hours. Upon cooling to room temperature, dilute aqueous sodium bicarbonate and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted with EtOAc (3x). The combined organic layers were washed successively with water (2x) and brine (1x), and thereafter dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 50% ethyl acetate/dichloromethane) afforded 4.0 g of the desired product as a solid, m.p. 210°-213° C.