Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1ccc(-c2ccc(F)cn2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(-c2ccc(CBr)cc2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
A solution of alcohol 111 (305 mg, 1.50 mmol) and triphenylphosphine (474 mg, 1.81 mmol) in anhydrous CH2Cl2 (12 mL) was carefully treated with recrystallized N-bromosuccinimide (322 mg, 1.81 mmol) (water bath cooling), and the mixture was stirred at room temperature for 3 h. The resulting solution was concentrated, and then added to excess pentane at the top of a silica gel column (20 g in pentane), rinsing on with minimal extra CH2Cl2. Elution with pentane firstly gave foreruns, and then further elution with 20-50% Et2O/pentane gave 2-[4-(bromomethyl)phenyl]-5-fluoropyridine (112) (348 mg, 87%) as a white solid that was used directly in the next step; 1H NMR (CDCl3) δ 8.54 (d, J=2.9 Hz, 1H), 7.92 (dt, J=8.4, 1.9 Hz, 2H), 7.72 (ddd, J=8.7, 4.3, 0.4 Hz, 1H), 7.52-7.43 (m, 3H), 4.54 (s, 2H); HRESIMS calcd for C12H10BrFN m/z [M+H]+ 267.9955, 265.9975, found 267.9959, 265.9979.
Reaction SMILES: [Cl:1][CH2:2]C(CCl)=O.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:26]([OH:28])=O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Na]>CO.O1CCCC1>[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:26]([OH:28])[CH2:2][Cl:1])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 60 °C
Yield: 42.8 %

Procedure:
To a solution of 75.0 g (0.226 mol) of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of 807 mL of methanol and 807 mL of tetrahydrofuran at -2° C., was added 13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borehydride over one hundred minutes. The solvents were removed under reduced pressure at 40° C. and the residue dissolved in ethyl acetate (approx. 1L). The solution was washed sequentially with 1M potassium hydrogen sulfate, saturated sodium bicarbonate and then saturated sodium chloride solutions. After drying over anhydrous magnesium sulfate and filtering, the solution was removed under reduced pressure. To the resulting oil was added hexane (approx. 1L) and the mixture warmed to 60° C. with swirling. After cooling to room temperature, the solids were collected and washed with 2L of hexane. The resulting solid was recrystallized from hot ethyl acetate and hexane to afford 32.3 g (43% yield) of N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp 150°-151° C. and M+Li+ =340.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:31])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([Cl:27])([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:28])[CH:17]=[CH:18]2)[C@@H:13]([Cl:29])[CH2:12]3)[CH2:9][C@H:8]1[CH3:30])(=O)C.Cl(O)(=O)(=O)=O>CO>[Cl:29][C@@H:13]1[C:14]2[C@:19]([CH3:20])([CH:18]=[CH:17][C:16](=[O:28])[CH:15]=2)[C@:21]2([Cl:27])[C@H:11]([C@H:10]3[C@:24]([CH3:25])([CH2:23][C@@H:22]2[OH:26])[C@@H:7]([C:6](=[O:31])[CH2:5][OH:4])[C@H:8]([CH3:30])[CH2:9]3)[CH2:12]1
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)C=C[C@]4(C)[C@@]3(Cl)[C@@H](O)C[C@@]21C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: C[C@@H]1C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)C=C[C@]4(C)[C@@]3(Cl)[C@@H](O)C[C@]2(C)[C@H]1C(=O)CO
Temperature: 0 °C
Reaction time: 20 h
Yield: 46.7 %

Procedure:
1.90 g of 21-acetoxy-6α,9-dichloro-11β-hydroxy-16α-methyl-1,4-pregnadiene-3,20-dione is dissolved in 53 ml of methanol. The mixture is conbined with 1.7 ml of 70% perchloric acid and allowed to stand for 20 hours at room temperature. The reaction mixture is poured into ice water; the precipitated product is isolated and chromatographed on silica gel. With 37-52% ethyl acetate-dichloromethane, after recrystallization from acetone-diisopropyl ether, 807 mg of 6α,9-dichloro-11β,21-dihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione is obtained, m.p. 230° C. [α]D25 =+99° (chloroform).
Reaction SMILES: [Li+].[O:2]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([O-])=[O:24])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:60]([C:63]1[CH:75]=[CH:74][C:66]([O:67][CH:68]2[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]2)=[CH:65][C:64]=1[C:76]([F:79])([F:78])[F:77])([O-:62])=[O:61]>CN(C)C=O.ClCCl.O1CCCC1>[N+:60]([C:63]1[CH:75]=[CH:74][C:66]([O:67][CH:68]2[CH2:73][CH2:72][N:71]([C:23](=[O:24])[CH2:22][CH2:21][N:18]3[CH2:19][CH2:20][CH:15]([C:12]4[CH:11]=[CH:10][C:9]([O:2][C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=5)=[CH:14][CH:13]=4)[CH2:16][CH2:17]3)[CH2:70][CH2:69]2)=[CH:65][C:64]=1[C:76]([F:79])([F:77])[F:78])([O-:62])=[O:61]
Reactant: O=C([O-])CCN1CCC(c2ccc(Oc3ccccc3)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCN1CCC(c2ccc(Oc3ccccc3)cc2)CC1)N1CCC(Oc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 0.08 h

Procedure:
3-[4-(4-Phenoxy-phenyl)-piperidin-1-yl]-propionic acid lithium salt (115 mg; 0.36 mmol, prepared in accordance with Example 43), diisopropylethyl amine (124 μL; 0.71 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (117 mg; 0.36 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution 4-(4-nitro-3-trifluoromethyl-phenoxy)-piperidine hydrochloride (103 mg; 0.32 mmol, prepared in accordance with Example 44) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 3 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (2×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (56 mg; 0.09 mmol). The structure was confirmed using Protocol I-B. Calculated mass=598; observed mass=598; HPLC retention time=5.22 min.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:16]C1C=CC(C(C2C=CC(Cl)=CC=2)=O)=CC=1.OC1C=CC(C(C2C=CC(F)=CC=2)=O)=CC=1.OC1C=CC(C(C2C=CC=CC=2O)=O)=CC=1.OC1C(C)=CC(C(C2C=CC(O)=CC=2O)=O)=CC=1C.OC1C=CC(C(C2C=CC(O)=CC=2O)=O)=CC=1.OC1C=C(O)C=CC=1C(C1C=CC=CC=1)=O.OC1C=CC(C(C2C=CC(OC)=CC=2)=O)=CC=1.OC1C=C(C)C(C(C2C=CC(O)=CC=2)=O)=C(C)C=1.OC1C=CC(C(C2C=CC(C(=O)C3C=CC(O)=CC=3)=CC=2)=O)=CC=1.OC1C=CC(C(C2C=CC=C(C(=O)C3C=CC(O)=CC=3)C=2)=O)=CC=1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:16])=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: COc1ccc(C(=O)c2ccc(O)cc2)cc1
Agent: Cc1cc(C(=O)c2ccc(O)cc2O)cc(C)c1O
Agent: Cc1cc(O)cc(C)c1C(=O)c1ccc(O)cc1
Product: O=C(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
4-hydroxy-benzophenone; 4-hydroxy-4'-chloro-benzophenone, 4-hydroxy-4'-fluorobenzophenone; 4,2'-dihydroxy-benzophenone; 4,2',4'-trihydroxy-3,5-dimethyl-benzophenone; 4,2',4'-trihydroxy-benzophenone; 2,4-dihydroxybenzophenone; 4-hydroxy-4'-methoxy-benzophenone; 4,4'-dihydroxy-2,6-dimethyl-benzophenone; 4-hydroxy-4'-(4-hydroxybenzoyl)-diphenyl; 1,4-bis(4-hydroxybenzoyl)-benzene; and 1,3-bis(4-hydroxybenzoyl)-benzene.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]2=O)=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]=1[O:25][CH3:26])([CH3:4])([CH3:3])[CH3:2].CO.[BH4-].[Na+].Cl>C1COCC1>[C:1]([C:5]1[CH:13]=[C:12]2[C:8](=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=1[O:25][CH3:26])[CH2:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(CC(C)C)C2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(CC(C)C)=C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
To a solution of 9.0 g (25.7 mmol) of 6-tert-butyl-2-isobutyl-5-methoxy-4-phenylindan-1-one in 100 ml of THF and 50 ml of methanol 10.0 g (0.265 mol) of NaBH4 was added by small portions by vigorous stirring for ca. 1.5 h at room temperature. This mixture was additionally stirred overnight and then acidified by 2 M HCl to pH 1. The product was extracted with 3×150 ml of dichloromethane. The organic extract was evaporated to dryness, and a mixture of the residue with 150 ml of toluene and 0.5 g of TsOH was refluxed for 15 min using Dean-Stark head. The obtained solution was washed by 10% aqueous K2CO3. The organic layer was separated, and the aqueous layer was extracted with 2×50 ml of dichloromethane. The combined organic extract was dried over K2CO3, evaporated to dryness, and then passed through short layer of silica gel 60 (40-63 um). The silica gel layer was additionally washed by hexanes-dichloromethane (1:1, vol.). The elute was evaporated to dryness, and the residue was dried in vacuum. This procedure gave 8.52 g (99%) of yellowish oil of the title product which was further used without an additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([C:21]2[C:25]([NH2:26])=[CH:24][N:23]([CH3:27])[N:22]=2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:26][C:25]3[C:21]([C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=4)=[N:22][N:23]([CH3:27])[CH:24]=3)=[O:12])=[C:4]2[N:3]=1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Reactant: Cn1cc(N)c(-c2cccc(Cl)c2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(NC(=O)c2cnn3ccc(Cl)nc23)c(-c2cccc(Cl)c2)n1
Reaction time: 1 h

Procedure:
To a solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (0.166 g, 0.768 mmol) in dichloromethane (8 mL) was added 3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-amine (73.6 mg, 0.354 mmol) and triethylamine (0.20 mL, 1.4 mmol) at room temperature. After 1 hour, the reaction mixture was partitioned between dichloromethane and half-saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated to yield 5-chloro-N-(3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which is carried forward without purification. LCMS (ESI) m+H=387.1.
Reaction SMILES: C(O)(=O)CCCCC(O)=O.C(#N)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17].[C:19]([O:29][CH3:30])(=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[C:16]([CH:15]([CH2:14][CH2:13][CH3:12])[C:24]([O:26][CH3:27])=[O:25])#[N:17].[C:24]([O:26][CH3:27])(=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][C:19]([O:29][CH3:30])=[O:28]
Reactant: N#CCCCCC#N
Agent: O=C(O)CCCCC(=O)O
Solvent: COC(=O)CCCCC(=O)OC
Product: CCCC(C#N)C(=O)OC

Procedure:
Then, 59.1 g (0.405 mole) of adipic acid, 43.7 g (0.405 mole) of adiponitrile and 26.8 g (0.154 mole) of dimethyl adipate were added to the liquid distillation residue and the resulting mixture was introduced into the autoclave mentioned above. Thereafter, reaction was carried out in the same manner as above. As a result of distillation, there were obtained 120.0 g (0.851 mole) of methyl cyanovalerate and 25.6 g (0.147 mole) of dimethyl adipate (Repeated Experiment 1). Subsequently, by the same procedure as above, the same amount of adipic acid as used in Repeated Experiment 1 and adiponitrile in an amount as shown in Table 3 were added to the liquid distillation residue obtained by distilling off methyl cyanovalerate and dimethyl adipate, and the reaction and distillation were repeated (Repeated Experiments 2-5). The results are shown in Table 3.
Reaction SMILES: [O:1]1CCC[O:3][CH:2]1[C:7]1[CH:8]=[C:9]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[OH:18])[CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14].[Na+].[Cl-]>C1COCC1.OS(O)(=O)=O>[CH3:14][O:13][C:12]1[C:11]([O:15][CH3:16])=[CH:10][C:9]([C:17](=[O:18])[C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[CH:8][C:7]=1[C:2]([OH:3])=[O:1]
Reactant: COc1cc(C(O)c2ccc(C)cc2)cc(C2OCCCO2)c1OC
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ccc(C)cc2)cc(C(=O)O)c1OC
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of (3-[1,3]Dioxan-2-yl-4,5-dimethoxy-phenyl)-p-tolyl-methanol (2.13 g, 6.18 mmol) in 75 mL THF, 56 mL 8N H2SO4 was added and the resulting solution was stirred 2 h at 50° C. After addition of 50 mL saturated NaCl-solution the mixture was extracted with EtOAc (3×50 mL). The pooled organic fractions were washed with saturated NaHCO3-solution (50 mL), then saturated NaCl-solution (50 mL) before being dried over MgSO4 and evaporated under reduced pressure to yield the desired product as a colorless oil. This crude product (2 g) was added to a mixture of 45 mL t-BuOH, 24 mL of a 1.25M K2HPO4-solution and 37 mL of a IM KMnO4-solution and stirred 45 min. at 60° C. The mixture was partitioned between 100 mL saturated NaCl-solution and 100 mL CHCl3 and the aqueous phase was extracted with CHCl3 (3×100 mL). The pooled organic fractions were extracted with 2N NaOH-solution (3×100 mL), then the combined aqueous fractions were acidified with conc. HCl and extracted with CHCl3 (4×100 mL). The organic fractions were pooled, dried over MgSO4 and evaporated in vacuo to yield the title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:27][CH2:26][N:25]4[C:18](=[CH:19][C:20]5[CH2:21][C:22]([CH3:29])([CH3:28])[CH2:23][C:24]=54)[C:17]3=[O:30])[C:11]=2[CH2:31][OH:32])[CH:3]=1.[NH2:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([N:40]2[CH2:44][CH2:43][CH:42]([C:45]([OH:47])=[O:46])[CH2:41]2)[N:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH3:28][C:22]1([CH3:29])[CH2:21][C:20]2[CH:19]=[C:18]3[N:25]([CH2:26][CH2:27][N:16]([C:12]4[C:11]([CH2:31][OH:32])=[C:10]([C:4]5[CH:3]=[C:2]([NH:33][C:34]6[CH:39]=[CH:38][N:37]=[C:36]([N:40]7[CH2:44][CH2:43][CH:42]([C:45]([OH:47])=[O:46])[CH2:41]7)[N:35]=6)[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=5)[CH:15]=[CH:14][N:13]=4)[C:17]3=[O:30])[C:24]=2[CH2:23]1
Reactant: Nc1ccnc(N2CCC(C(=O)O)C2)n1
Reactant: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(Nc2ccnc(N3CCC(C(=O)O)C3)n2)c1=O
Temperature: 80 °C
Yield: 13.1 %

Procedure:
A 100 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 10-[4-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(hydroxymethyl)pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one 102b (497 mg, 1.0 mmol), 102a (312 mg, 1.5 mmol), Pd2(dba)3 (92 mg, 0.10 mmol), XantPhos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, CAS Reg. No. 161265-03-8, 116 mg, 0.20 mmol), Cs2CO3 (652 mg, 2.0 mmol), and DMF (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 80° C. for 4 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 102c (82 mg, 13%) as a white solid. MS: [M+H]+ 625.4
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4]>CO.O.[Fe]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([CH:10]2[C:9]([CH3:24])([CH3:25])[CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[NH:11]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc([N+](=O)[O-])cc1)N2
Agent: [Fe]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Yield: 95.6 %

Procedure:
To a solution of methyl 4-hydroxy-3,3-dimethyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (61 mg 0.18 mmol) and triethylsilane (0.06 mL, 0.34 mmol) in dichloromethane (10 mL) was added dropwise a solution of trifluoroacetic acid (0.04 mL, 0.51 mol) in dichloromethane (5 mL) below 0° C. Upon completion of addition, the resultant mixture was stirred at room temperature for 24 h, then was quenched with sodium bicarbonate solution and separated. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to afford 50 mg of methyl 3,3-dimethyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid Yield: 78%. Methyl-3,3-dimethyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (110 mg, 0.32 mmol) was dissolved in methanol/water Solution, iron powder (25 mg, 3.2 mmol) was added. The reaction mixture was heated to reflux for 2 hrs The mixture was filtered, the filtration was concentrated and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=4:1) to afford 95 mg of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid. (yield: 96%). MS (ESI+APCI) M+1=311.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([C:9]2[CH2:10][CH2:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[C:14]([O:25][CH3:26])[CH:13]=3)=[O:8])=[CH:5][CH:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[C:19]1([C:18]2[C:17]3[C:12](=[CH:13][C:14]([O:25][CH3:26])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)C2=C(c3ccccc3)c3ccc(OC)cc3CC2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COc1ccc(C(=O)c2ccc3cc(OC)ccc3c2-c2ccccc2)cc1

Procedure:
To 11.1 g. (0.03 mole) of the product from Example 4 dissolved in benzene were added 9.0 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The mixture was refluxed for two hours and then was filtered while hot through silica, and the silica was washed three times with ethyl acetate. The ethyl acetate washings were combined with the benzene reaction mixture, and the total was concentrated to dryness. The residue was dissolved in hot methanol, and the solution was allowed to cool to obtain 4.5 g. of product. The product was recrystallized again from methanol to obtain the title compound, m.p. 122°-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[CH2:33]OS(C)(=O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][N:27]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: CS(=O)(=O)OCc1cnccn1
Product: O=C(c1cn(Cc2cnccn2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69 above) with methanesulfonic acid pyrazin-2-ylmethyl ester (preparation described in WO 2002064574) gave the title compound. ES-MS m/e (%): 459.3 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[CH3:16])[CH:5]=[CH:6][CH:7]=1)=O.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18]C([O-])=O.[K+].CC(O)=O.N1CCCCC1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:4]2[CH:5]=[CH:6][CH:7]=[C:3]2[CH:1]=[CH:18][C:17]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([CH3:16])[CH:10]=1)#[N:13]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: Cc1cc(C#N)ccc1-n1cccc1C=O
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cccn1-c1ccc(C#N)cc1C
Reaction time: 48 h
Yield: 66.6 %

Procedure:
To a mixture of 4-(2-formyl-1H-pyrrol-1-yl)-3-methylbenzonitrile (24.5 g, 116.7 mmol), DMAP (2.9 g, 23.3 mmol) and potassium monoethyl malonate (99.2 g, 583.3 mmol) in DMF (600 mL) was added AcOH (35.0 g, 583.3 mmol) and piperidine (29.8 g, 350 mmol). The resultant mixture was heated to 80° C. and stirred for 48 h. The reaction mixture was poured into cooled water and extracted with ethyl acetate (800 mL×3). The combined organic layers were washed with sat. NaHCO3 and brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE:EA=5:1) to afford ethyl 3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)acrylate as a yellow oil (21.8 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[N:13][C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C[O:58][C:59](=[O:65])[C@H:60]([CH:62]([CH3:64])[CH3:63])[NH2:61].[Li+].[OH-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[N:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:61][CH:60]([CH:62]([CH3:64])[CH3:63])[C:59]([OH:65])=[O:58])=[O:21])=[CH:22][CH:23]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1ccc(-c2ccc(Nc3cccc(Cl)c3)nn2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(NC(=O)c1ccc(-c2ccc(Nc3cccc(Cl)c3)nn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[6-(3-Chloro-phenylamino)-pyridazin-3-yl]-benzoic acid (0.10 g, 0.31 mmol, 1.0 equiv) in 2 Ml DMF was added HATU (0.23 g, 0.62 mmol, 2.0 equiv) and N,N-diisopropylethylamine (0.27 Ml, 1.5 mmol, 5.0 equiv). Valine methyl ester (0.062 g, 0.37 mmol, 1.0 equiv) was added as a solid, and the homogeneous solution was allowed to stir at room temperature overnight. To the solution was then added 1 Ml 10% aqueous LiOH, and the mixture was then heated to 55° C. The reactions were then filtered and the purified by reverse-phase HPLC to afford the title compound: 1H NMR (400 MHz, MeOD) 0.96 (dd, J=9.35, 6.82 Hz, 6 H) 2.21 (dq, J=12.13, 6.82 Hz, 1 H) 4.41 (d, J=5.05 Hz, 1 H) 6.91 (ddd, J=1.26 Hz, 2.02, 1.01 Hz, 1 H) 7.21 (t, J=8.08 Hz, 1 H) 7.17 (d, J=9.35 Hz, 1 H) 7.48 (dd, J=9.22, 1.14 Hz, 1 H) 7.88-8.02 (m, 7 H); (M+H)+ 425.1.