Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:29]([OH:49])[C:30]2[N:34](COCC[Si](C)(C)C)[C:33]3[CH:43]=[CH:44][C:45]([C:47]#[N:48])=[CH:46][C:32]=3[N:31]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[C:6]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2].C(C1C(C(O)C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2C1C=CC=CC=1)C>Cl.CO.CCOC(C)=O>[CH2:1]([C:3]1[C:4]([CH:29]([OH:49])[C:30]2[NH:34][C:33]3[CH:43]=[CH:44][C:45]([C:47]#[N:48])=[CH:46][C:32]=3[N:31]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[C:6]2[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:2]
Reactant: CCc1cc(C)c2c(c(-c3ccccc3)cn2S(=O)(=O)c2ccc(C)cc2)c1C(O)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCc1cc(C)c2c(c(-c3ccccc3)cn2S(=O)(=O)c2ccc(C)cc2)c1C(O)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cc(C)c2c(c(-c3ccccc3)cn2S(=O)(=O)c2ccc(C)cc2)c1C(O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of a mixture of (±)-2-((5-ethyl-7-methyl-3-phenyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5-ethyl-7-methyl-3-phenyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (25 mg, 0.036 mmol) in 1M HCl in MeOH (2 mL) was stirred at 60° C. for 17 h. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with EtOAc. The mixture was successively washed by 5% aq. NaHCO3, H2O and brine, dried over Na2SO4, and filtered. Concentration of the filtrate gave the title compound, which was used in the next reaction without any further purification. MS (ESI+) m/z 561.2 (M+H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([CH3:16])=[C:12]([CH2:13][CH2:14]Cl)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C([O-])(=O)C([O-])=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([CH3:16])=[C:12]([CH2:13][CH2:14][N:29]3[CH2:28][CH2:27][CH:26]([C:23]4[C:22]5[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=5[O:25][N:24]=4)[CH2:31][CH2:30]3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2sc(C)c(CCCl)c2C1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Product: CC(=O)N1CCc2sc(C)c(CCN3CCC(c4noc5cc(F)ccc45)CC3)c2C1
Yield: 14.5 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.0 g of 5-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.25 g of 5-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine as an oil, m.p. 198°-200° C. (decomposition) as an oxalate thereof.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)([Cl:23])=O>C(Cl)Cl.CN(C)C=O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:20]=[CH:19][CH:18]=1)[CH2:2][Cl:23]
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
25.6g (93.5 mmoles) of 2-(3-hydroxymethylphenoxy)methylquinoline is dissolved in 30 ml of methylene chloride and 3 drops of dimethylformamide is added. 60.7 ml of a 2.0M solution of thionyl chloride in methylene chloride is then added dropwise at 0° C. The mixture is allowed to warm to room temperature and stirred for 5 hours. The solution is washed with sodium bicarbonate solution, dried, concentrated in vacuo and the crude product purified by silica gel HPLC to yield 12.1 g 3-(2-quinolinylmethyloxy)benzylchloride as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.I[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([NH2:28])=[N:25][N:24]=2)=[C:19]([O:29][CH3:30])[CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:30][O:29][C:19]1[CH:18]=[C:17]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[S:27][C:26]([NH2:28])=[N:25][N:24]=1
Reactant: COc1cc(I)ccc1-c1nnc(N)s1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: O
Solvent: C1COCCO1
Product: COc1cc(-c2cnn(C)c2)ccc1-c1nnc(N)s1
Temperature: 80 °C
Yield: 62.1 %

Procedure:
To a stirred suspension of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (137 mg, 0.660 mmol) and 5-(4-iodo-2-methoxyphenyl)-1,3,4-thiadiazol-2-amine (200 mg, 0.6 mmol) in dioxane (4 mL) was added Pd(PPh3)4 (35 mg, 0.03 mmol) followed by a solution of Na2CO3 (191 mg, 1.801 mmol) in water (1 mL). The reaction was purged with nitrogen then heated at 80° C. for 18 hours. The reaction mixture was diluted with MeOH (20 mL), filtered through celite, and rinsed with DCM (20 mL). The filtrate was concentrated in vacuo to afford the crude product as an orange oily residue. The crude product was pre-absorbed onto silica gel and purified by flash chromatography using a 24 g silica cartridge, running a MeOH/DCM gradient to afford the title compound as a pale yellow solid (107 mg, 62% yield). LC-MS: Rt 0.81 min; MS m/z 288.1 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 8.05 (d, J=8.08 Hz, 1H), 7.98 (s, 1H), 7.36 (d, J=1.52 Hz, 1H), 7.28 (dd, J=8.08, 1.52 Hz, 1H), 7.13 (s, 2H), 3.99 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27]([OH:29])=O)[CH:24]=[CH:23][S:22]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:30][C:31]([F:39])([F:38])[C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH:1]1([O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27]([NH:37][C:34]2[S:35][CH:36]=[C:32]([C:31]([F:39])([F:38])[F:30])[N:33]=2)=[O:29])[CH:24]=[CH:23][S:22]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1c(/C=C/c2cccc(OC(F)F)c2OC2CCCC2)nc2sccn12
Reactant: Nc1nc(C(F)(F)F)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1nc(C(F)(F)F)cs1)c1c(/C=C/c2cccc(OC(F)F)c2OC2CCCC2)nc2sccn12

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 5 (365 mg, 0.868 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (157 mg, 0.965 mmol) in the presence of EDCI hydrochloride (333 mg, 1.737 mmol) and DMAP (98 mg, 0.868 mmol) in a mixture of THF and DMF (1:1, 6 mL) to give 34 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.75-1.85 (m, 8H), 4.70-4.78 (m, 1H), 7.18 (t, J=74.7 Hz, 1H), 7.20-7.5 (m, 2H), 7.40-7.46 (m, 1H), 7.53 (d, J=15.9 Hz, 1H), 7.60-7.70 (m, 1H), 7.79 (d, J=15.0 Hz, 1H), 8.05-8.12 (m, 2H), 13.03 (br s, 1H); APCI-MS (m/z) 571.07 (MH)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-ethyl 3-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinate (1.00 g, 285 mmol, EXAMPLE 33 Step 1) in dichloromethane (10 mL) was added trifluoroacetic acid (3 mL) at room temperature. After being stirred at room temperature for 8 h, the volatile was evaporated to afford 1.36 g (quant.) of the title compound that was used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[N:6][CH:7]=1.C([Li])CCC.[CH3:27][S:28]SC>C1COCC1>[CH3:15][C:14]1[O:13][N:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]=1[CH2:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([S:28][CH3:27])=[CH:7][N:6]=1
Reactant: CSSC
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 5-bromo-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine (300 mg, 0.87 mmol) in THF (3 mL) was added n-butyllithium (1.6 M, 543.1 μL, 0.87 mmol) and the resulting mixture stirred at −78° C. for 30 min. Then methyl disulfide (78.7 μL, 0.87 mmol) was added and the resulting mixture stirred overnight. The mixture was then evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate 8:2 to 1:3) afforded the title compound (136 mg, 50%) as a light yellow oil. MS: m/e=313.1 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:15]([C:16](O)=[O:17])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:15]([C:16]([Cl:3])=[O:17])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)O)c1Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)Cl)c1Cl
Yield: 94.9 %

Procedure:
2 drops of dimethylformamide and 11.9 g (0.1 mol) of thionyl chloride were added to a solution of 6.0 g (0.021 mol) of methyl 2-chloro-3-hydroxycarbonyl-4-methylsulfonylbenzoate and 50 ml of dry toluene. The solution was heated under reflux for 4 hours. Removal of the solvent under reduced pressure gave 6.2 g of methyl 2-chloro-3-chlorocarbonyl-4-methylsulfonylbenzoate.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[CH2:40]([O:42][C:43]([CH:45]1[CH2:50][CH2:49][CH2:48][NH:47][CH2:46]1)=[O:44])[CH3:41]>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:47]3[CH2:48][CH2:49][CH2:50][CH:45]([C:43]([O:42][CH2:40][CH3:41])=[O:44])[CH2:46]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: CCOC(=O)C1CCCNC1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Product: CCOC(=O)C1CCCN(c2nc3c(c(-c4ccccc4C)n2)C(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCN3)C1
Yield: 78 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 3-(ethoxycarbonyl)piperidine (28.3 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-2-[3-(ethoxycarbonyl)piperidine-1-yl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine (76.0 mg, 78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>ClCCl>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([NH:15][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=2)=[O:27])[N:12]=[CH:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCn1cnc(N)c1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCn1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)c1
Reaction time: 0.1 h
Yield: 75 %

Procedure:
To a solution of compound 39.3 in dichloromethane under nitrogen was added 3-trifluoromethylphenyl isocyanate dropwise. After about 0.1 hour, a white precipitate formed. The precipitate was filtered off, washed with dichloromethane and dried under high-vacuum to yield 485 mg (75%) of (2-{4-[3-(3-trifluoromethyl-phenyl)-ureido]-imidazol-1-yl}ethyl)-carbamic acid tert-butyl ester (compound 39.4) as a white solid, ES (+) MS m/e=414 (M+H+).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]4[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:39][CH2:38][CH2:37][C@@H:33]1[C:34](O)=[O:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([C:34](=[O:35])[C@H:33]4[CH2:37][CH2:38][CH2:39][N:32]4[CH3:31])[CH2:18][C:17]4[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNCc1cc(F)ccc1-3
Reactant: CN1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)[C@H]1CCCN1C)Cc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1 eq of methyl-14-cyclohexyl-3-fluoro-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocin-11-carboxylate (prepared as described in Example 18, Step 5) in DCM (0.06 M), 1.5 eq of 1-methyl-D-proline (prepared according to literature precedent J. Org. Chem. 2003, 68, 2652) in DCM (0.2 M), 1.5 eq of DIPEA and 1.5 eq of TBTU were added and the mixture stirred at RT overnight. Volatiles were removed in vacuo and the crude was used in the next step without further purification; MS (ES+) m/z 518 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][C:12]2=[O:15])=[CH:7][N:6]=1)[CH3:3].C1C(=O)N([Cl:23])C(=O)C1>CC(O)=O>[Cl:23][C:14]1[C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[N:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:15])[NH:11][CH2:10][CH2:9]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Oc1cc2c(cn1)CCNC2=O
Solvent: CC(=O)O
Product: CC(C)Oc1ncc2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Yield: 69.2 %

Procedure:
A solution of 7-(propan-2-yloxy)-3,4-dihydro-2,6-naphthyridin-1(2H)-one (112d, 75 mg, 0.36 mmol)) and NCS (498 mg, 3.64 mmol) in AcOH (3 mL) was heated at 100° C. for 4.5 hours. The reaction mixture was cooled to room temperature, AcOH was removed under vacuum and the residue was purified by column chromatography (0-80% ethyl acetate/heptanes) to give 8-chloro-7-(propan-2-yloxy)-3,4-dihydro-2,6-naphthyridin-1(2H)-one (112e, 60 mg, 68%) as a white solid.
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)(C)=O.[CH2:13]([C@@:15]12[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][C@H:16]1[CH2:17][CH2:18][CH2:19][C:20]1[C:21]2=[CH:22][C:23]2[CH:24]=[N:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:27]=2[CH:28]=1)[CH3:14]>C1COCC1>[CH2:13]([C@@:15]12[CH2:39][CH2:38][C@@:37]3([CH2:8][O:40]3)[CH2:36][C@H:16]1[CH2:17][CH2:18][CH2:19][C:20]1[C:21]2=[CH:22][C:23]2[CH:24]=[N:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:27]=2[CH:28]=1)[CH3:14]
Reactant: CC[C@@]12CCC(=O)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC[C@@]12CC[C@@]3(CO3)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 65 °C

Procedure:
Sodium hydride (60 wt % in oil, 0.023 g, 0.967 mmol) was added carefully to a flask containing about 3 mL DMSO then heated to about 65° C. for about 30 min. The reaction was cooled to rt then diluted with 2 mL THF. The reaction was further cooled in an ice water bath and trimethylsulfoxonium iodide (0.213 g, 0.967 mmol) was added in one portion and stirred about 15 min. (4aR,12bR)-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3 (2H)-one (9, R1=4-Fluorophenyl, R2=Ethyl) (0.182, 0.483 mmol) in 2 mL THF was introduced via syringe and allowed to warm to rt over about 18 hrs. THF was removed in vacuo and the residue was diluted with 15 mL water and extracted with EtOAc (15 mL×3). The combined organics were washed with sat. aq. NaCl. The organic layer was dried over MgSO4 filtered and concentrated to a crude viscous oil.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:15]([O:19]C)(=[O:18])[CH:16]=[CH2:17].[OH-].[K+]>CO.O>[CH:4]1[C:5]2[CH:6]3[CH2:17][CH:16]([C:15]([OH:19])=[O:18])[CH:13]([C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: c1ccc2cc3ccccc3cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CC2c3ccccc3C1c1ccccc12
Temperature: 162.5 °C
Reaction time: 72 h

Procedure:
Anthracene (40 gm) was combined with methyl acrylate (30 gm) in a Parr bomb and heated to 150-175° C. for 6 hours. The mixture was allowed to remain in the bomb at room temperature for 72 hours. The mixture was dissolved in methanol (225 ml), treated with a solution of potassium hydroxide (40 gm) in water (40 ml) and heated to reflux for 4 hours. The solution was cooled to room temperature and most of the solvent was removed on a rotary evaporator. The residue was dissolved in water (200 ml), filtered through charcoal and acidified with concentrated hydrochloric acid. The resulting mixture was allowed to stand overnight and the precipitate was filtered. The white solid was dried at 80° and recrystallized from benzene to provide the product (mp=188-189° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:69])/[CH:4]=[CH:5]/[C:6]1[CH:68]=[CH:67][C:9]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:66])[C:21]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-])=O)=[CH:59][CH:58]=2)([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N+:53]([O-])=O)=[CH:49][CH:48]=2)[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32](=[O:45])[C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43][CH3:44])=[O:42])=[CH:35][CH:34]=2)=[O:23])=[O:11])=[CH:8][CH:7]=1>CN(C)C=O.O.[Zn]>[CH3:1][O:2][C:3](=[O:69])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20](=[O:66])[C:21]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=2)([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32](=[O:45])[C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43][CH3:44])=[O:42])=[CH:35][CH:34]=2)=[O:23])=[O:11])=[CH:67][CH:68]=1
Reactant: COC(=O)/C=C/c1ccc(C(=O)OCCCCCCOC(=O)C(Cc2ccc([N+](=O)[O-])cc2)(Cc2ccc([N+](=O)[O-])cc2)C(=O)OCCCCCCOC(=O)c2ccc(/C=C/C(=O)OC)cc2)cc1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(C(=O)OCCCCCCOC(=O)C(Cc2ccc(N)cc2)(Cc2ccc(N)cc2)C(=O)OCCCCCCOC(=O)c2ccc(/C=C/C(=O)OC)cc2)cc1
Yield: 64.4 %

Procedure:
1.30 g (1.36 mmol) bis[6-({4-[(1E)-3-methoxy-3-oxoprop-1-enyl]benzoyl}oxy)-hexyl]2,2 bis(4-nitrobenzyl)malonate were dissolved in a mixture of 25 ml N,N-dimethylformamide and 2.8 ml water. 2.21 g (8.18 mmol) ferric chloride hexahydrate and 0.716 g (10.95 mmol) Zinc powder were added, the temperature rise to 40° C. The mixture was allowed to react for 1 hours. The black reaction mixture was then partitioned between ethyl acetate and water and filtered. The organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. A first chromatography on 50 g silica gel using tert-butyl methyl ether as eluant and a second chromatography on 25 g silica gel using toluene: ethyl acetate (9:1) then (4:1) as eluant yielded 0.78 g (64%) of bis[6-({4-[(1E)-3-methoxy-3-oxoprop-1-enyl]benzoyl}oxy)hexyl]2,2 bis(4-aminobenzyl)malonate as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:26])([F:25])[C:9]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])([OH:16])[CH2:10][N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[N:6][CH:7]=1.BrC(F)([F:34])C(OCC)=O.BrC1C=CC(F)=CN=1>CS(C)=O.[Cu]>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:9]([OH:16])([CH2:10][N:11]1[CH:15]=[N:14][N:13]=[N:12]1)[C:8]([F:26])([F:25])[C:5]1[CH:4]=[CH:3][C:2]([F:34])=[CH:7][N:6]=1
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Br)cn1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Agent: Fc1ccc(Br)nc1
Solvent: CS(C)=O
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 10 was prepared in a similar manner to compound 1. To a stirred solution of ethyl 2-bromo-2,2-difluoroacetate (2.18 mL, 17.0 mmol) in DMSO (18 mL) was added copper powder (2.16 g, 34.0 mmol) at RT under N2 atmosphere. After being stirred for 2 h at RT, 2-bromo-5-fluoropyridine (1.50 g, 8.52 mmol) was then added, and stirring was continued for 3 h at RT. The progress of the reaction was monitored by TLC. The reaction was quenched with aqueous NH4Cl and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product mixture. Purification by column chromatography (eluting with EtOAc/hexane) afforded the ester (1.40 g, 6.3 mmol, 77%) as a pale yellow oil. 1H NMR (500 MHz, CDCl3): δ 8.50 (s, 1H), 7.78 (dd, J=9.0, 4.0 Hz, 1H), 7.60-7.51 (m, 1H), 4.42-4.32 (m, 2H), 1.39-1.31 (m, 3H). MS (ESI): m/z 220 [M++1].
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([CH:27]([OH:54])[CH:28]([NH:36][C:37](=[O:53])[C@H:38]([CH:50]([CH3:52])[CH3:51])[NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(C(C)C)C(C)C)C.[CH3:64][O:65][CH2:66]Cl>ClCCl>[C:40]([NH:39][C@H:38]([C:37]([NH:36][CH:28]([CH:27]([O:54][CH2:64][O:65][CH3:66])[CH:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:53])[CH:50]([CH3:52])[CH3:51])([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]
Reactant: COCCl
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC(C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 10 %

Procedure:
A solution of 22 mg of the resultant compound of Example 70 in 1 ml of dichloromethane was treated with 0.07 ml of ethyldiisopropylamine and 0.03 ml of chloromethyl methyl ether. The resulting solution was heated at reflux for 1 h. The cooled solution was concentrated in vacuo to give 26 mg of a crude solid which was recrystallized from ethyl acetate/chloroform to provide 15 mg of the desired compound (Rf 0.6, 10% methanol in chloroform) as a white solid, m.p. 197°-198° C. Mass spectrum: (M+H)+ =781.