Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[N:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1n[nH]c2ncccc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nn(C(=O)OC(C)(C)C)c2ncccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 692 mg (5.20 mmol) of 3-methyl-1H-pyrazolo[3,4-b]pyridine in 25 mL of acetonitrile under nitrogen was cooled to 0° C. in an ice bath, and was treated with 635 mg (5.20 mmol) of DMAP and 761 μL (5.46 mmol) of triethylamine. A solution of 1.36 g (6.24 mmol) of (BOC)2O in 5 mL acetonitrile was then added dropwise using an addition funnel. Upon completion of addition, the ice bath was removed and the mixture was stirred for an additional 18 hours at room temperature. Solvent was removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to an orange oil. This crude material was purified by flash chromatography over silica gel with 1:1 ethyl acetate/hexanes to give the title product as a clear oil. 1H NMR (CDCl3): δ 1.74 (s, 9H), 2.60 (s, 3H), 7.29 (m, 1H), 8.02 (dd, 1H), 8.74 (dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15])[CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-aminopyridine (9.41 g, 100 mmol) and triethylamine (16.7 mL, 120 mmol) in CH2Cl2 (300 mL) at 0° C. was added trimethylacetyl chloride (14.8 mL, 120 mmol) dropwise over 15 min. The reaction was warmed to rt and stirred overnight. The mixture was concentrated in vacuo, the residue partitioned between EtOAc and H2O, and the layers separated. The aqueous layer was made basic with saturated NaHCO3 and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo to give N-(pyridin-3-yl)-2,2-dimethylpropanamide as a tan solid. 1H NMR (CDCl3, 300 MHz) δ 8.57 (d, 1H), 8.33 (dd, 1H), 8.17 (ddd, 1H), 7.69 (br s, 1H), 7.27 (dd, 1H), 1.33 (s, 9H).
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:12]=[C:11]([Br:13])[C:10]2[C:5](=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl-:20].[Al+3].[Cl-:22].[Cl-:23]>C(=S)=S>[Cl:20][C:2]([Cl:23])([Cl:22])[C:3]1[CH:12]=[C:11]([Br:13])[C:10]2[C:5](=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: [Cl-]
Reactant: FC(F)(F)c1cc(Br)c2cccc(C(F)(F)F)c2n1
Agent: [Al+3]
Solvent: S=C=S
Product: FC(F)(F)c1cccc2c(Br)cc(C(Cl)(Cl)Cl)nc12

Procedure:
3.4 g of 2,8-bis-(trifluoromethyl)-4-bromo-quinoline, 1.5 g of freshly sublimated aluminum-chloride are allowed to stand in 30 ml of abs. carbon disulfide for a night at room temperature. The organic phase is washed with 50 ml of 10 percent icy hydrochloric acid, 2×50 ml of water, dried and evaporated. The residue is recrystallized from aqueous methanol.
Reaction SMILES: CS(C)=O.[OH-].[K+].[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)([O-:9])=[O:8].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([N:15]1[C:16]2[C:12](=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:18][CH:17]=2)[CH:13]=[CH:14]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(ccn2Cc2ccccc2)c1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
Dry dimethylsulphoxide (20 ml) was added to potassium hydroxide (4.2 g, 0.074 mol) (crushed pellets) and the mixture was stirred under nitrogen for 5 mins. 5-Nitroindole (commercially available) (3.0 g, 0.019 mol) was then added and the red mixture stirred for 30 min at room temperature. The mixture was then cooled to −10° C., benzyl bromide (4.4 ml, 0.037 mol) was slowly added and the mixture stirred and allowed to warm to room temperature over a period of 40 mins. Water (50 ml) was then added and the mixture was extracted with diethyl ether (2×200 ml). The extracts were washed with water (4×50 ml), dried over sodium sulphate and evaporated to leave an oily solid. The excess benzyl bromide was removed by dissolving the whole in diethyl ether (50 ml), diluting this solution with 40-60 petrol (50 ml) and then gradually removing the diethyl ether in vacuo to leave a yellow solid suspended in the petrol. The solid was filtered, washed with copious amounts of 40-60 petrol and dried to give 1-benzyl-5-nitroindole (2.4 g, 51%) as a yellow solid, m.p. 102-104° C.; δH [2H6]-DMSO 8.53 (1H, s, 4-H), 8.00 (1H, d, J 9. 6-H), 7.78 (1H, s, 2-H), 7.68 (1H, d, J 9, 7-H), 7.36-7.20 (5H, m, 2′-H, 3′-H, 4′-H, 5′-H, 6′-H), 6.81 (1H, s, 3-H), 5.52 (2H, s, CH2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]([CH3:18])[N:10]=1.[N+:19]([O-])([OH:21])=[O:20]>>[F:1][C:2]1[CH:7]=[C:6]([N+:19]([O-:21])=[O:20])[C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[N:11]([CH3:18])[N:10]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1nc(-c2cc(F)ccc2F)cc1C(F)(F)F
Product: Cn1nc(-c2cc(F)c([N+](=O)[O-])cc2F)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
To an ice cooled solution of 50 ml of fuming nitric acid (90%) was added slowly 8.29 g of 3-(2,5-difluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole. After addition, the mixture was allowed to warm to room temperature and then gently heated to 52° C. Heated for 2.5 hours, then cooled and poured onto ice. The resulting mixture was extracted with ether and the ether then washed twice with water, dried with anhydrous magnesium sulfate, filtered and the solvent removed by concentration in vacuo. The residue was purified utilizing a combination of chromatography and crystallization to give 5.62 g of 3-(2,5-difluoro-4-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole, mp 80°-81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[SH:8].[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][C:19]=1[CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[S:8][C:17]1[N:16]=[N:15][C:14]([Cl:13])=[C:19]([CH:20]([CH3:22])[CH3:21])[CH:18]=1
Reactant: OCCc1cc(Cl)c(S)c(Cl)c1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1cc(Sc2c(Cl)cc(CCO)cc2Cl)nnc1Cl
Temperature: 90 °C
Yield: 52.4 %

Procedure:
A solution of 2-(3,5-dichloro-4-mercapto-phenyl)-ethanol (73) (620 mg, 2.78 mmol) in dimethyl sulfoxide (25 mL) was treated with 3,6-dichloro-4-isopropyl-pyridazine (7) (530 mg, 2.78 mmol) and potassium carbonate (1.54 g, 11.12). The resulting mixture was heated to 90° C. for 18 h. At this time, the reaction was cooled to 25° C., poured into a solution of water (200 mL) and a 1N aqueous hydrochloric acid solution (25 mL). The mixture was extracted with ethyl acetate (2×200 mL). The organics were then washed with water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried with magnesium sulfate, filtered, and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70:30 petroleum ether/ethyl acetate) afforded 2-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-ylsulfanyl)-phenyl]-ethanol (74) (550 mg, 52%) as a pale yellow oil; EI(+)-HRMS m/e calcd for C15H15Cl3N2OS (M+H)+ 377.0044, found 377.0043. Exact Mass=375.9971; Molecular weight=377.72
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:15])[CH2:10][CH2:9]2)=O)=[CH:4][CH:3]=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][OH:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl.C1COCC1>[Cl:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[C:41]([O:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)=[O:42]
Reactant: OCc1cccc(Cl)c1
Reactant: O=C(Oc1cccnc1)N1CCN(C(=O)c2ccc(O)cc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Oc1ccc(CN2CCN(C(=O)Oc3cccnc3)CC2)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.8 %

Procedure:
A THF (5 ml) solution containing 3-pyridyl 4-(4-hydroxybenzoyl)-1-piperazinecarboxylate (300 mg) and diethyl azodicarboxylate (0.62 ml, 40% Tol solution) was dropwise added to a THF (5 ml) solution containing 3-chlorobenzyl alcohol (200 mg) and triphenylphosphine (360 mg), at 0° C., followed by stirring at room temperature for 3 days. The reaction solution was diluted with chloroform, washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=95:5 (v/v)), and the resulting solid was recrystallized from 2-propanol to obtain 3-pyridyl 4-{4-[(3-chlorobenzoyl)oxy]benzyl}-1-piperazinecarboxylate (260 mg).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[C:5]1[C:15]([F:18])([F:17])[F:16])[C:2]#[CH:3].[C:19](Br)#[CH:20].[Mg].[Mg].P(O)(O)([O-])=O.[Na+].C(OC(C)C)(C)C>O1CCCC1>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]([OH:14])[C:19]#[CH:20])=[C:5]1[C:15]([F:18])([F:16])[F:17])[C:2]#[CH:3]
Reactant: C#CBr
Reactant: C#CCn1c(C(F)(F)F)c(C=O)c2ccccc21
Agent: O=P([O-])(O)O
Agent: [Mg]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: C#CCn1c(C(F)(F)F)c(C(O)C#C)c2ccccc21
Temperature: -5 °C
Reaction time: 1 h

Procedure:
4.5 g of 1-(2-propynyl)-2-trifluoromethyl-3-formyl-(1H)-indole in 30 ml of tetrahydrofuran were cooled at -15° C. and over 15 minutes, 26 ml of a solution of magnesium ethynyl bromide in tetrahydrofuran (0.8M ) were added. After stirring for one hour at -5° C., another 5 ml of magnesium solution were added, and the mixture was allowed to return to ambient temperature. After stirring for 30 minutes and then pouring into a saturated aqueous solution of monosodium phosphate, extraction was carried out with isopropyl ether. The solvent was eliminated under reduced pressure to obtain 5.89 g of crude product which was purified by chromatography over silica (eluent: hexane-ethyl acetate 9-1) to obtain 1.91 g of 1(RS) [1-(2-propynyl)-2-trifluoromethyl-(1H)-indol-3-yl]-prop-2-ynyl alcohol melting at 98° C.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[NH:24][N:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[CH3:21])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: Cc1n[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]nc(C)c4c3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 4 h
Yield: 35.8 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (180 mg, 0.61 mmol) in 1,4-dioxane (1 mL) was added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (440 mg, crude), K3PO4 (360 mg, 1.71 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol) under nitrogen atmosphere. After stirring 4 h at 95° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.5% methanol in dichloromethane to afford methyl 3-(isopropyl(methyl)amino)-2-(3-methyl-1H-indazol-5-yl)quinoxaline-6-carboxylate as a light yellow solid (85 mg, 35%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9](N)=[O:10])=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([CH3:17])[S:15][CH:16]=1.[OH-:18].[Na+]>O>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]([OH:18])=[O:10])=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([CH3:17])[S:15][CH:16]=1
Reactant: Cc1nc(-c2cc(C(N)=O)c(=O)[nH]c2C)cs1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(-c2cc(C(=O)O)c(=O)[nH]c2C)cs1

Procedure:
C-4. 1,2-Dihydro-6-methyl-5-(2-methyl-4-thiazolyl)2-oxo-3-pyridinecarboxylic acid--A mixture containing 32 g of 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarboxamide, 50 ml of 35% aqueous sodium hydroxide solution and 300 ml of water was heated on a steam bath for 15 hours and cooled. The reaction mixture was filtered to remove a small quantity of insoluble material and the filtrate was acidified with concentrated hydrochloric acid. The resulting precipitate was collected, washed with water and dried in an oven at 80° C. to produce 30.2 g of 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarboxylic acid, m.p. 297°-299° C. with decomposition.
Reaction SMILES: [SiH:1]([Cl:4])([CH3:3])[CH3:2].[CH2:5]([Cl:9])[C:6](=[CH2:8])[CH3:7]>>[Si:1]([CH2:7][CH:6]([CH2:5][Cl:9])[CH3:8])([CH3:3])([CH3:2])[Cl:4]
Reactant: C=C(C)CCl
Reactant: C[SiH](C)Cl
Product: CC(CCl)C[Si](C)(C)Cl
Temperature: 80 °C
Yield: 83.3 %

Procedure:
In a 100 ml apparatus, there were combined 14.2 g (0.15 mol) of Me2SiHCl and 13.6 g (0.15 mol) of methallyl chloride, followed by 0.05 ml Pt catalyst solution at 21° C. Gentle heating caused a smooth exothermic reaction to 90° C. in 16 in. Reaction was heated at 80° C. until completed (50 min). Vacuum distillation yielded 23.14 g (83.4%) of Me2SiClCH2CHMeCH2Cl.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Cl:11][C:4]1[CH:3]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: C1CCNC1
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Product: Clc1cc(N2CCCC2)nc2c1CCC2
Yield: 38.7 %

Procedure:
Following general procedure B1, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol) was reacted with pyrrolidine (0.085 g, 1.2 mmol) to afford the title compound (0.069 g, 38%) as a light yellow solid. MW=222.71. 1H NMR (CDCl3, 300 MHz) δ 6.13 (s, 1H), 3.46-3.36 (m, 4H), 2.97-2.81 (m, 4H), 2.13-1.94 (6H); APCI MS m/z 223 [M+H]+.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:15](=[O:21])[CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]>CCOCC>[Br:1][CH:16]([CH2:17][CH2:18][O:19][CH3:20])[C:15]([C:11]1([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:12][CH2:13][CH2:14]1)=[O:21]
Reactant: BrBr
Reactant: COCCCC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: CCOCC
Product: COCCC(Br)C(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (0.35 ml) was added dropwise over 20 minutes at ambient temperature to a stirred solution of 1-[1-(3,4-dichlorophenyl)cyclobutyl]-4-methoxybutan-1-one (2 g) in ether (40 ml). After the addition was complete and the bromine colour had dissipated, the mixture was stirred at ambient temperature for a further 1 hour then it was washed with water (30 ml), saturated aqueous sodium hydrogen carbonate solution (2×30 ml) and water (30 ml), dried (MgSO4), and the solvent removed in vacuo to give 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-4-methoxybutan-1-one as an oil which was used without purification.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:26]2[C:25](=[O:27])[N:24]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:23](=[O:36])[C:22]=2[C:21]([OH:37])=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:45]N(C=O)C.C([O-])([O-])=O.[K+].[K+].CI>O>[CH:1]([O:14][C:15]1[C:26]2[C:25](=[O:27])[N:24]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[C:23](=[O:36])[C:22]=2[C:21]([O:37][CH3:45])=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C1c2c(c(O)c3c(ncn3Cc3ccccc3)c2OC(c2ccccc2)c2ccccc2)C(=O)N1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncn(Cc4ccccc4)c13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reaction time: 16 h
Yield: 73 %

Procedure:
Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-1H-1,3,6-triaza-s-indacene-5,7-dione 258 (103 mg, 0.177 mmol, 1 equiv.) was added to a flask containing DMF (4 mL) followed by K2CO3 (122 mg, 0.88 mmol, 5 equiv.). To this was added methyl iodide (MeI, 109 μL, 1.76 mmol, 10 equiv.) under a nitrogen atmosphere and stirred for 16 hours. To the reaction was added water (50 mL) and extracted with ethyl acetate (2×40 mL). The organic layer was washed several times with water (3×30 mL), saturated NaHCO3 (40 mL), brine solution (30 mL). It was dried over Na2SO4, filtered and concentrated in vacuo and purified by silica gel chromatography using 7/3 Hexanes/Ethyl acetate to obtain 4-benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-methoxy-1H-1,3,6-triaza-s-indacene-5,7-dione 259 (73%, 75 mg, 0.125 mmol). 1H NMR (300 MHz) CDCl3 δ 8.09 (s, 1 H), 7.94 (s, 1 H), 7.88 (s, 1 H), 7.64-7.43 (m, 4 H), 7.41-7.46 (m, 2 H), 7.17-7.43 (m, 10 H), 6.98-7.04 (m, 3 H), 5.56 (s, 2 H), 4.80 (s, 2 H), 3.84 (s, 3 H). MS: 620.1 (M+23). TLC Rf: 0.6 Hexanes/Ethyl acetate (1/1).
Reaction SMILES: [CH3:1][C@@H:2]([O:5][C:6]1[CH:7]=[C:8]([CH2:12]O)[CH:9]=[CH:10][CH:11]=1)[CH2:3][CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[Cl:34][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][C@H:2]([CH3:1])[CH2:3][CH3:4])[CH:7]=1
Reactant: CC[C@@H](C)Oc1cccc(CO)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC[C@@H](C)Oc1cccc(CCl)c1

Procedure:
To a solution of (3-{[(1R)-1-methylpropyl]oxy}phenyl)methanol (1.01 g, 5.60 mmol) in carbon tetrachloride (18.7 ml) was added triphenylphosphine (1.40 g, 5.32 mmol). The reaction was heated to reflux overnight. The reaction was filtered through a fritted funnel and washed with carbon tetrachloride. The filtrate was concentrated. The residue was purified on a silica gel cartridge (0% EtOAc/hexanes to 10% EtOAc/hexanes) to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23](O)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[CH3:27][O:28][C:29]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][NH:33][CH2:34]2>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([N:33]3[CH2:32][CH2:31][C:30]4[C:35](=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:29]=4[O:28][CH3:27])[CH2:34]3)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc2c(c(OC)c1)CCNC2
Reactant: COc1cc(-c2nc(C(=O)O)c3ccccc3n2)cc(OC)c1OC
Agent: Cl
Product: COc1cc2c(c(OC)c1)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccccc13)C2
Yield: 33.3 %

Procedure:
Reaction of 2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 92 (33.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.81 and 2.99 (2t, 2H), 3.45 (s, 1H), 3.49 and 4.04 (2t, 2H), 3.73-3.77 (m, 6H), 3.86 and 3.92 (m, 8H), 4.24 and 4.79 (2s, 2H), 6.33-6.50 (m, 2H), 7.72-8.17 (m, 6H); MS (ESI) m/z 516 ([M+H]+).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:9][NH:8]C(=O)[C@H:6]1[C:11]([OH:13])=[O:12])[CH:2]([CH3:4])[CH3:3].Cl.O>CC(O)=O>[CH3:4][CH:2]([CH2:1][C@H:5]([CH2:9][NH2:8])[CH2:6][C:11]([OH:13])=[O:12])[CH3:3]
Reactant: CC(C)CC1CNC(=O)[C@H]1C(=O)O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 110 °C
Yield: 80 %

Procedure:
A reactor vessel (60 L) was charged with (S)-4-isobutyl-2-oxo-pyrrolidine-3-carboxylic acid (Formula 10), HCl (36-38%, 30 L), and water (29 L). HOAc (1 L) was added to the solution and the resulting slurry was heated for 36-38 h at 80° C. and for an additional 6 h at 110° C. The extent of reaction was monitored by HPLC (C18 column, 4.6 mm×150 mm, detection at 200 nm). Water and excess HCl were evaporated to afford an oil, which was washed with MTBE (2×15 L). Water was added to the oil and the mixture was stirred until the solution cleared. The pH of the solution was adjusted to 5.2-5.5 using KOH (about 6 kg), which resulted in the precipitation of pregabalin. The mixture was heated to 80° C. and subsequently cooled to 4° C. After 10 h, crystalline pregabalin was filtered and washed with IPA (12 L). The filtrate was concentrated under vacuum to afford a residual oil. Water (7.5 L) and EtOH (5.0 L) were added to the residual oil and the resulting mixture was heated to 80° C. and then cooled to 4° C. After 10 h, a second crop of pregabalin crystals were filtered and washed with IPA (1 L). The combined pregabalin crystals were dried in a vacuum oven at 45° C. for 24 h. MS m/z [M+H]+160.1340. 1H NMR (300 MHz, D2O): δ 2.97 (dd, J=5.4, 12.9 Hz, 1H), 2.89 (dd, J=6.6, 12.9 Hz, 1H), 2.05-2.34 (m, 2H), 1.50-1.70 (sept, J=6.9 Hz, 1H), 1.17 (t, J=7.0 Hz, 2H), 0.85 (dd, J=2.2, 6.6 Hz, 6H). 13C NMR (75 ppm, D2O) δ 181.54, 44.32, 41.28, 32.20, 24.94, 22.55, 22.09. Yield 80-85%; ee>99.5%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([CH2:11][CH:12]2[O:16]C(=O)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([CH2:11][CH:12]2[OH:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC1CC2CC1CN(Cc1ccccc1)C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC1CC2CC1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of acetic acid 3-benzyl-3-aza-bicyclo[3.2.1]oct-6-yl ester (8 mmol) in methanol (50 mL) and water (20 mL) was added potassium hydroxide (32 mmol). Reaction was stirred 18 h at room temperature. The methanol was removed in vacuo and product was extracted with aqueous dichloromethane (4×50 mL). The organic extracts were dried over MgSO4, filtered and stripped to provide a quantitative yield of an oil. APCl MS m/z 218.2 (M+H)+.