Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.[Si:25]([O:42][CH2:43][C@H:44](I)[CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:1]([S:3][C@H:44]([CH2:43][O:42][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: COC(=O)CC[C@@H](I)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)SC(C)=O
Reaction time: 18 h

Procedure:
Thioacetic acid (1 mL, 13.2 mmol) was added to 20 mL of toluene under a nitrogen atmosphere. A 1 M solution of tetrabutylammonium hydroxide in methanol (11 mL, 11 mmol) with a washing of 1 mL methanol was added to the thioacetic acid solution. The methanol was removed azeotropically with toluene and residual salt redissolved in 30 mL toluene. The salt solution with a washing of 20 mL toluene was added to a solution of 8 (4.75 g, 9.6 mmol) in 50 mL toluene and stirred under nitrogen for 18 hours. After removal of solvent and precipitated salts, the crude product was purified by flash chromatography with 6:1 hexane/ethyl acetate. Yield 3.47 g (81%) of a viscous oil [α]D25 -16.0° (C=0.7, CDCl3); FAB MS 445 (M+H)+, 387 (M-t-butyl)+ ; 1H NMR (CDCl3) δ 7.65 (m, 4, ArH), 7.4 (m, 6, ArH), 3.8 (m, 1, H-4), 3.7 (s, 3, OCH3), 3.7 (m, 2, CH2), 2.35 (m, 2, CH2), 2.3 (s, 3, acetyl CH3), 2.2 (m, 1, H-2), 1.9 (m, 1, H-2), 1.05 (s, 9, t-butyl).
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[CH:12][N:13]([C@@H:15]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:21]([O:22][C:23](=[O:26])[CH2:24][CH3:25])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[N:14]=[C:9]3[C:10]2=[C:4]([C:5](=O)[NH:6][N:7]=[CH:8]3)[CH:3]=1.N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42]>O1CCOCC1>[NH2:1][C:2]1[C:11]2=[CH:12][N:13]([C@@H:15]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:21]([O:22][C:23](=[O:26])[CH2:24][CH3:25])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[N:14]=[C:9]3[C:10]2=[C:4]([C:5](=[S:42])[NH:6][N:7]=[CH:8]3)[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc3c(N)cc4c(=O)[nH]ncc(n2)c34)O[C@@H]1COC(C)=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc3c(N)cc4c(=S)[nH]ncc(n2)c34)O[C@@H]1COC(C)=O

Procedure:
To a solution of the compound from Step 1 (75 mg, 0.16 mmol) in dioxane (2 mL) is added pyridine (2.5 mL) followed by phosphorus pentasulfide (2 equiv). The reaction mixture is heated at reflux for 24 h. The solvent is evaporated then and the residue washed with pyridine. The combined washings are evaporated and the residue is dissolved in CHCl3 and washed with 10% aq. NaHCO3 and water and dried (Na2SO4). The evaporated residue is used as such for the next step.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH:13]=[O:14])[O:11][C:10]([CH3:16])([CH3:15])[N:9]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:24]1(Br)[CH2:26][CH2:25]1.[Mg].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([C@H:13]([CH:24]3[CH2:26][CH2:25]3)[OH:14])[O:11][C:10]([CH3:16])([CH3:15])[N:9]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: BrC1CC1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C=O)OC1(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)C2CC2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
A solution of 3.21 g (9.8 mmol) of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-formyl-2,2-dimethyl-3-oxazolidinecarboxylate (WO 87/05302) in 25 ml of tetrahydrofuran is added dropwise at about 15° to a solution of the Grignard compound prepared from 3.94 ml (49 mmol) of cyclopropyl bromide and 1.2 g (0.049 gram atom) of magnesium shavings in 22 ml of tetrahydrofuran and the reaction mixture is subsequently stirred at room temperature under argon for 16 hours. Thereafter, the reaction mixture is poured into 40 ml of an ice-cold, saturated ammonium chloride solution and extracted twice with 50 ml of ethyl acetate each time. The ethyl acetate extracts are washed with 40 ml of ice-cold, saturated ammonium chloride solution, combined, dried over sodium sulphate and evaporated under reduced pressure. For purification, the residue (4.33 g) is chromatographed over a column of 110 g of silica gel, prepared with toluene and 1% triethylamine, using a 95:5 mixture of toluene and ethyl acetate as the eluent. There are obtained 1.9 g of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-cyclopropylhydroxymethyl]-2,2-dimethyl-3-oxazolidinecarboxylate, MS: 368 (M+H)+, and 0.5 g of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(R)-cyclopropylhydroxymethyl]-2,2-dimethyl-3-oxazolidinecarboxylate, MS: 368 (M+H)+, each as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[Br-:15].[Na+].[CH3:17][C:18]1[C:26]([CH3:28])([CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:29]([OH:32])(=[O:31])=[O:30])[CH:24]=2)[N:19]=1.[K]>S1(CCCC1)(=O)=O.CC(C)=O>[Br-:15].[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][N+:19]1[C:20]2[C:25](=[CH:24][C:23]([S:29]([OH:32])(=[O:30])=[O:31])=[CH:22][CH:21]=2)[C:26]([CH3:28])([CH3:27])[C:18]=1[CH3:17])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Reactant: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)C
Agent: [Br-]
Agent: [K]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=S1(=O)CCCC1
Product: CC1=[N+](Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)c2ccc(S(=O)(=O)O)cc2C1(C)C
Temperature: 100 °C
Reaction time: 5 h

Procedure:
3,5-Dinitrobenzyl chloride (22.1g, 102 mmol) and sodium bromide (10.5 g, 102 mmol) were added to 2,3,3-trimethyl-5-sulpho-indole, potassium salt (5.0 g, 20.4 mmol) in sulpholane (25 ml). The reaction mixture was stirred at 100° C. for 5 hours. The solution was then cooled to room temperature and acetone (300 ml) was added to the reaction flask. A brown precipitate was formed which was collected by filtration and then purified by reverse phase HPLC. This gave a beige solid which was dried in vacuo. UV (water/acetonitrile): λmax=283 nm. MS: m/z=420 (C18H18N3O7S=420.4).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:23])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:23])[CH3:2]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CC[C@@H]2O
Yield: 96.5 %

Procedure:
Dissolve dl-13-ethyl-3-methoxy-6-methylgona-1,3,5(10)-trien-17-one (7.0 g) in methanol (300 ml) and treat with sodium borohydride (3.0 g). After spontaneous reflux ceases, acidify the reaction mixture with 50% acetic acid (20 ml). Work up by the usual procedures to obtain dl-13-ethyl-3-methoxy-6-methylgona-1,3,5(10)-trien-17β-ol (6.8 g), m.p. 158°-160°; infrared absorption peaks (potassium bromide) at 3.05 μ, 6.45 μ.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[CH2:12]([O:14][C:15](=[O:22])[CH2:16][C@@H:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[CH3:13].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:12]([O:14][C:15](=[O:22])[CH2:16][C@@H:17]([NH:21][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1)[CH2:18][CH2:19][CH3:20])[CH3:13]
Reactant: CCC[C@H](N)CC(=O)OCC
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC[C@@H](CC(=O)OCC)Nc1nc(C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.5 %

Procedure:
To a solution of 2-chloro-3-nitro-6-picoline (500 mg, 2.99 mmol) in DMF (3 mL) were added the (S)-3-amino-hexanoic acid ethyl ester (554 mg, 3.48 mmol) and diisopropylethyl amine (DIPEA) (1.0 mL, 5.80 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was then dried over Na2SO4 and concentrated. The resulting residue was purified by preparative TLC using hexane and ethyl acetate (4:1) as an eluent to afford 358 mg (42%) of the title compound as orange oil. LCMS, M++1, m/z: 296.65.
Reaction SMILES: ClC(Cl)C.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:18]2[CH:19]=[C:20]([N:23]=[C:24]=[O:25])[CH:21]=[CH:22][C:17]=2[N:16]([CH3:26])[C:15](=[O:27])[CH2:14][N:13]=1.[NH2:28]C1C=CC2N(C)C(=O)CN=C(C3C=CC=CC=3F)C=2C=1.[NH2:49][CH2:50][CH:51]([OH:53])[CH3:52]>ClCCCl>[NH2:28][C:24]([NH2:23])=[O:25].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:18]2[CH:19]=[C:20]([NH:23][C:24]([NH:49][CH2:50][CH:51]([OH:53])[CH3:52])=[O:25])[CH:21]=[CH:22][C:17]=2[N:16]([CH3:26])[C:15](=[O:27])[CH2:14][N:13]=1
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Reactant: CC(O)CN
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N=C=O)ccc21
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: CC(O)CNC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Product: NC(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A dichloroethane solution of [5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate, prepared as described in paragraph (a) of Example 1 from 12.5 g (0.044 M) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one, is added to a solution of 8 g of 1-amino-2-propanol in 100 ml of 1,2-dichloroethane, the mixture is stirred at room temperature for 15 minutes and then concentrated. The residue is purified on a 300 g silica gel column using methylene chloride and then acetone as the eluting agent. This operation is repeated once using ethyl acetate as the eluting agent. After crystallisation from ethyl acetate, there is obtained rac-1-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxypropyl)urea urea which melts at 149°-151° C. with decomposition.
Reaction SMILES: [OH-].[Na+].[N+]([CH:6]([CH:8]1[CH:15]2[CH:11]([O:12][C:13](=[O:16])[CH2:14]2)[CH2:10][CH:9]1[CH3:17])[CH3:7])([O-])=O.S(=O)(=O)(O)[OH:19].[N+](=C)([O-])[O-]>CO.O.C(O)(=O)C>[C:6]([CH:8]1[CH:15]2[CH:11]([O:12][C:13](=[O:16])[CH2:14]2)[CH2:10][CH:9]1[CH3:17])(=[O:19])[CH3:7]
Reactant: O=S(=O)(O)O
Reactant: CC1CC2OC(=O)CC2C1C(C)[N+](=O)[O-]
Agent: C=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C1C(C)CC2OC(=O)CC21

Procedure:
A solution of sodium hydroxide (22 g, 0.55 mole) in methanol (275 mL) was cooled to 0° and added all at once to a cold (0°) solution of crude, racemic (3aR,4S,5R,6aS)-4-(1-nitroethyl)hexahydro-5-methyl-2H-cyclopenta[b]furan-2-one (91.5 g, 0.43 mole) in methanol (350 mL). The resulting solution was stirred without further cooling for 11/2 hours during which time a solution of concentrated sulfuric acid (65 mL, 1.22 mole) in methanol (350 mL) was prepared by slow addition of the acid to the methanol while stirring and cooling in a dry ice/acetone bath. Both solutions were chilled to (-35°) and the nitronate anion solution as added all at once to the acid solution. This mixture was kept for 11/2 hours during which the color changed from yellow to a pale blue-green. Approximately 500 mL of methanol was stripped off under reduced pressure using a 35° bath and a solution of acetic acid (50 mL) in water (300 mL) was added. Stripping was continued for 11/4 hours (40° bath) during which the remaining solvent was removed. The product was extracted with ethyl acetate. The extract was washed with NaHCO3 solution and with brine, dried over sodium sulfate, and stripped of solvent. The racemic (3aR,4S,5R,6aS)-4-acetylhexahydro-5-methyl-2H-cyclopenta[b]furan-2-one thus obtained was 70.8 g (90.5%) of amber-colored oil. The yield based on racemic 3-methyl-5-oxo-1-cyclopentene-1-acetic acid ethyl ester was 77.8%. A sample for analysis was vacuum distilled giving a colorless liquid. Anal. Found: C, 65.78; H, 7.91.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]([F:12])([F:11])[C:8]([OH:10])=[O:9].[F:13][C:14]([F:19])([F:18])[C:15]([OH:17])=[O:16].[NH:20]1[CH2:23][CH:22]([C:24]2[C:25]([O:44][CH3:45])=[C:26]([CH:32]([NH:34][C:35]3[N:43]=[CH:42][N:41]=[C:40]4[C:36]=3[N:37]=[CH:38][NH:39]4)[CH3:33])[CH:27]=[C:28]([Cl:31])[C:29]=2[CH3:30])[CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:6][C:7]([F:12])([F:11])[C:8]([OH:10])=[O:9].[Cl:31][C:28]1[C:29]([CH3:30])=[C:24]([CH:22]2[CH2:21][N:20]([C:2]([O:4][CH3:5])=[O:3])[CH2:23]2)[C:25]([O:44][CH3:45])=[C:26]([CH:32]([NH:34][C:35]2[N:43]=[CH:42][N:41]=[C:40]3[C:36]=2[N:37]=[CH:38][NH:39]3)[CH3:33])[CH:27]=1.[C:15]([OH:17])([C:14]([F:19])([F:18])[F:13])=[O:16]
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CNC1
Reactant: COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CC(c2c(C)c(Cl)cc(C(C)Nc3ncnc4[nH]cnc34)c2OC)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (1.6 pt, 0.021 mmol) was added to a solution of N-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine bis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA (0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0° C. and then the reaction was stirred at room temperature for 30 minutes. The crude mixture was purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C20H24ClN6O3 (M+H)+: m/z=431.2. found: 431.1. 1H NMR (300 MHz, DMSO-d6) δ 8.30 (1H, br s), 8.18 (2H, m), 7.46 (1H, s), 5.68 (1H, m), 4.31 (3H, m), 4.14 (1H, m), 4.02 (1H, m), 3.75 (3H, s), 3.55 (3H, s), 2.16 (3H, s), 1.44 (3H, d, J=6.9 Hz) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1.[C:17]([NH:21][NH2:22])([CH3:20])([CH3:19])[CH3:18].Cl.C(N(CC)CC)C>CO>[C:17]([N:21]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][C:10]([CH2:11][CH2:12][CH2:13][OH:14])=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(CCCO)CC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)n1nc(CCCO)cc1-c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 14 h

Procedure:
1-(4-chlorophenyl)-6-hydroxyhexane-1,3-dione (2.0 g, 8.310 mmol) was dissolved in 15 mL of methanol. t-BuNHNH2.HCl (2.1 g, 16.620 mmol) was dissolved in 15 mL of methanol and then added with triethylamine (TEA; 2.3 mL, 16.620 mmol). After they were all dissolved, the mixture was added into a solution of 1-(4-chlorophenyl)-6-hydroxyhexane-1,3-dione, and then stirred for 14 hours at 40° C. The reaction progress and completion were confirmed by TLC. Upon completion of the reaction, while the temperature was kept at room temperature, the solvent was removed under reduced pressure. The reaction residue was diluted with EtOAc, and added with water. The aqueous layer was extracted with EtOAc and the organic layer was dried with anhydrous MgSO4 and filtered and concentrated under reduced pressure. The concentrate was separated by column chromatography (EtOAc:Hexane=2:3, v/v) to obtain 1.57 g (64%) of target compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-:26][Cr](Cl)(=O)=O>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:26])[CH2:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C=CC1(C)C
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
A solution of aniline (19 mL, 0.20 mol), 3-acetoxy-3-methyl-1-butyne (26 g, 0.20 mol), CuCl (1.0 g, 10 mmol) and Et3N (28 mL, 0.20 mol) in THF (120 mL) was heated at reflux for 5 h and was filtered through a pad of Celite™. Removal of solvent and chromatography of the crude mixture (silica gel, EtOAc/hexane, 3/7) afforded 21 g (67%) of 3-methyl-3-phenylamino-1-butyne. Treatment of the aminobutyne with CuCl (0.70 mg, 7.0 mmol) in THF (200 mL) at 70° C. for 16 h followed by chromatography (silica gel, EtOAc/hexane, 3/7) afforded 13 g (60%) of 1,2-dihydro-2,2-dimethylquinoline (structure 75A of Scheme LII, where R1 =H, R2-3 =methyl). Treatment of the quinoline with di-tert-butyl dicarbonate (22 g, 0.10 mol) and DMAP (12 g, 0.10 mol) in THF (100 mL) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) afforded 15 g (71%) of 1-tert-butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline. 1-tert-Butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline (3.0 g, 11 mmol) in THF (30 mL) was treated with 1.0 M BH3 -THF in THF (29 mL, 29 mmol) at rt for 3 h and was quenched with 3 M KOH (20 mL). To the above solution 30% H2O2 (5 mL) was added and the mixture was stirred for 60 min, then 5 mL of water was introduced. The mixture was extracted, washed with brine and concentrated. Chromatography of the crude mixture on a silica gel column using a 10-30% mixture of EtOAc/Hexane as eluents afforded a 2:1 mixture of two isomers (0.87 g, 3.1 mmol), which was oxidized with PCC (2.5 g, 11 mmol) in 60 mL of methylene chloride at rt for 60 min. Removal of solvent and chromatography of the black oil on a silica gel column using a 20% mixture of EtOAc and hexane as solvent afforded 0.58 g (68%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone as a white solid. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.93 (d, J=7.8, 1 H), 7.42 (t, J=7.8, 1 H), 7.31 (d, J=7.8, 1 H), 7.02 (t, J=7.8, 1 H), 2.73 (s, 2H), 1.56 (s, 9 H), 1.49 (s, 6 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[OH:21][CH:22]1[CH:31]([OH:32])[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:33](O)=[O:34])[CH:29]=2)[O:24][C:23]1([CH3:37])[CH3:36]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:33]([C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[O:24][C:23]([CH3:37])([CH3:36])[CH:22]([OH:21])[CH:31]2[OH:32])=[O:34]
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: CC1(C)Oc2ccc(C(=O)O)cc2C(O)C1O
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)C(O)C(O)C(C)(C)O2

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 3,4-Dihydroxy-2,2-dimethyl-chroman-6-carboxylic acid. MS: 494.6 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[CH:14]=[C:15]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]4[CH2:42][CH2:41][C:39](=[O:40])[NH:38][C:36]=4[CH:37]=3)[CH2:23][CH2:22]2)[C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=1.[CH:43]([O:46][C:47](Cl)=[O:48])([CH3:45])[CH3:44]>CC1CCCO1>[Cl:20][C:16]1[C:17]([Cl:19])=[CH:18][CH:13]=[CH:14][C:15]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[C:36]3[C:35]([CH2:42][CH2:41][C:39](=[O:40])[N:38]3[C:47]([O:46][CH:43]([CH3:45])[CH3:44])=[O:48])=[CH:34][CH:33]=2)[CH2:23][CH2:22]1
Reactant: CC(C)OC(=O)Cl
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CC1CCCO1
Product: CC(C)OC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (1.11 mL, 7.87 mmol) in 2-methyltetrahydrofuran (37 mL) at −5° C. was added n-BuLi (3.0 mL, 2.5 M in hexanes, 7.49 mmol) slowly. After 20 minutes, the reaction was cooled to −78° C. and Aripiprazole (1.68 g, 3.74 mmol) was added. After a further 10 minutes, isopropylchloroformate (9.37 mL, 1.0 mol in toluene, 9.37 mmol) was added. The reaction was held at −78° C. for 2 hours before allowing to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica eluting with 1:1 ethyl acetate to dichloromethane to 2% methanol in 1:1 ethyl acetate to dichloromethane to give the product. The product was recrystallized from isopropanol to remove aliphatic impurities. The product was not sufficiently pure so was purified by column chromatography eluting with 0 to 10% tetrahydrofuran in ethyl acetate. The product was triturated in heptane and filtered to afford Compound-75 (0.593 g) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(Br)c1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)/C=C/c1cccc(Br)c1
Reaction time: 48 h

Procedure:
A magnetically stirred solution of 3-bromobenzaldehyde (86.5 g, 0.468 mol) and malonic acid (107 g, 1.03 mol) in pyridine (200 ml) was treated with piperidine (4.0 ml, 40.45 mmol) and heated at ~90° C. for 90 min then under reflux for 30 min. The cooled mixture was poured onto ice (200 g) and water (300 ml) then acidified to pH=1 with conc. hydrochloric acid. Filtration afforded a white solid which was washed with water (4×200 ml), dried by suction and placed in an oven at 70° C. for 48 h until constant weight was obtained (96.02 g, 90%); νmax (nujol)/cm-1 3400-2000 (br. OH), 1684.5, 1631.5, 1587.0; δH (270 MHz) 6.45 (1H, d, 2-H, 3J2,3 =16,2 Hz); 7.28 (1H, t, 5'-H, Jo =7.8 Hz); 7.48 (1-H, dt, 4'-H, Jo =7.9, Jm =1.3 Hz); 7.54 (1-H, dt, 6'-H, Jo =7.9, Jm =1.0 Hz); 7.70 (1-H, t, 2'-H, Jm =1.8 Hz); 7.71 (1H, d, 3-H, 3J3,2 =15.8 Hz).
Reaction SMILES: [OH:1][B:2]([OH:11])[C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[CH3:12][O:9][C:8]([C:6]1[O:7][C:3]([B:2]([OH:1])[OH:11])=[CH:4][CH:5]=1)=[O:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(B(O)O)o1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(B(O)O)o1
Reaction time: 0.75 h

Procedure:
5-(Dihydroxyboryl)-2-furoic acid (200 mg, 1.283 mmol) was dissolved in CH2Cl2 (5 mL) and MeOH (0.556 mL). Trimethylsilyldiazomethane (1.283 mL, 2.57 mmol) was added dropwise. After 45 min, the reaction was quenched with AcOH dropwise until the yellow color disappeared. The reaction was concentrated in vacuo to give [5-(methoxycarbonyl)-2-furyl]boronic acid. 1H NMR (500 MHz, CD3OD): δ 7.20 (d, J=3.5 Hz, 1H); 7.05 (d, J=3.6 Hz, 1H); 3.87 (s, 3H).