Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[NH:23][C:15]3=[N:16][CH:17]=[C:18]([N+:20]([O-])=O)[CH:19]=[C:14]3[CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Cl.O>C(O)C.[Fe]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[NH:23][C:15]3=[N:16][CH:17]=[C:18]([NH2:20])[CH:19]=[C:14]3[CH:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COCCOc1cccc(-c2cc3cc([N+](=O)[O-])cnc3[nH]2)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COCCOc1cccc(-c2cc3cc(N)cnc3[nH]2)c1
Temperature: 70 °C
Yield: 59.7 %

Procedure:
To a mixture of 2-[3-(2-methoxy-ethoxy)-phenyl]-5-nitro-1H-pyrrolo[2,3-b]pyridine (7.1 mmol, 2.2 g) and iron powder (6.7 g) in ethanol (50 mL) was added HCl (conc) (0.7 mL) and water (5 mL). The mixture was heated at 70° C. for 3 hours then cooled and filtered through Celite®. The solvent was removed in vacuo and the residue resolvated in ethyl acetate (30 mL), washed with saturated sodium bicarbonate (15 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, ethyl acetate) to afford 2-[3-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-5-ylamine (1.2 g, 60%).
Reaction SMILES: [H-].[Na+].[CH:3](OCC)=[O:4].[CH:8]1([CH:13]2[C:18]([O:19][CH3:20])=[CH:17][CH2:16][CH2:15][C:14]2=[O:21])[CH2:12][CH2:11][CH2:10][CH2:9]1.P([O-])([O-])(O)=O.[Na+].[Na+]>C1C=CC=CC=1>[CH:8]1([C:13]2[C:14](=[O:21])[C:15](=[CH:3][OH:4])[CH2:16][CH2:17][C:18]=2[O:19][CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCOC=O
Reactant: COC1=CCCC(=O)C1C1CCCC1
Agent: O=P([O-])([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC1=C(C2CCCC2)C(=O)C(=CO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.9 %

Procedure:
To a suspension of sodium hydride (2.04 g, 60% suspension, 51 mmol) in benzene (100 mL), a mixture of ethyl formate (6.7 g) and 2-cyclopentyl-3-methoxycyclohex-3-en-1-one (2.82 g, 17 mmol) in benzene was added dropwise at 5° C. The reaction mixture was stirred at ice temperature for 1 hour and 18 hours at room temperature. The reaction mixture was cooled in ice bath, and 200 mL of 10% sodium hydrogen phosphate solution was added dropwise. The organic layer was separated, and aqueous layer was extracted with ethyl acetate (2×50 mL). Combined organic extract was washed with brine and dried over anhydrous sodium sulfate. Solvent was removed in vacuo and the resulting product was purified on a column of silica gel (Hex:EtOAc) to give the title compound as a viscous liquid (2 g, 60%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.S(Cl)(Cl)=O.[CH3:18]O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:18])=[O:12])=[CH:2]1
Reactant: CO
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of carboxylic acid 73 (10 g, 57.1 mmol) in MeOH (500 mL) was added dropwise thionyl chloride (21 mL, 285 mmol) at 0° C. The mixture was stirred at room temperature for 2 h and concentrated in vacuo to remove solvent. The residue was diluted with EtOAc and washed with aq. saturated NH4Cl solution, aq. saturated NaHCO3 solution and brine successively. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude titled compound 74 (10.9 g, quantitative) was used without further purification. MH+190.
Reaction SMILES: [Cl:1]Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[CH2:24][C:25]2[O:33][C:32]3[C:27](=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[O:17])=[CH:6][CH:5]=1>ClCCl>[Cl:1][C:26]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:32]2[O:33][C:25]=1[CH2:24][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:18]1[C:16]([C:11]1[N:12]=[C:13]([CH3:15])[S:14][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=1)=[O:17]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2cc3ncccc3o2)c(-c2ccc(F)cc2)s1
Reactant: ClCl
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCCCC2Cc2oc3cccnc3c2Cl)c(-c2ccc(F)cc2)s1
Temperature: -12 °C
Reaction time: 0.5 h

Procedure:
A solution of chlorine (28 mg) in dichloromethane (3 ml) was added to a cooled (−12° C.) solution (RS)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-(2-furo[3,2-b]-pyridin-2-ylmethyl-piperidin-1-yl)methanone, E79 (170 mg) in dichloromethane (4 ml). After stirring at −12° C. for 0.5 h the reaction mixture was stirred at room temperature for 16 h then the solution was washed with saturated aqueous NaHCO3, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-100% ethyl acetate-hexane then 0-10% methanol-ethyl acetate) afforded the title compound (24 mg).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH:13]([C:19](=O)[CH3:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=O)=[CH:7][CH:6]=1.O>C(O)C>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[C:19]([CH3:20])=[N:2][NH:3][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COC(=O)Cc1c(C)n[nH]c1-c1ccc(Cl)cc1

Procedure:
2.236 g (45 mmol) of hydrazine hydrate were added to a solution of 10 g (37 mmol) of methyl 3-[(4-chlorophenyl)carbonyl]-4-oxopentanoate in ethanol (100 ml). The mixture was heated under reflux for 6 hours and then added to water and extracted with dichloromethane. The combined organic phases were dried with magnesium sulfate, filtered and concentrated. This gave 6.9 g of product (63% of theory); NMR (CDCl3, 400 MHz): 2.28 (s, 3H); 3.5 (s, 2H); 3.7 (s, 3H); 7.39 (d, 2H); 7.5 (d, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:10][CH2:11][S:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1.[OH:21][CH:22]([C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([O:45][CH3:46])[CH:43]=2)[N:38]=[CH:37][CH:36]=1)[CH2:23][CH2:24][C@@H:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]1[C:31]([O:33][CH3:34])=[O:32]>C(#N)C.CO>[F:20][C:15]1[CH:14]=[C:13]([S:12][CH2:11][CH2:10][N:28]2[CH2:29][CH2:30][C@@H:25]([CH2:24][CH2:23][CH:22]([OH:21])[C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[C:42]([O:45][CH3:46])[CH:43]=4)[N:38]=[CH:37][CH:36]=3)[C@@H:26]([C:31]([O:33][CH3:34])=[O:32])[CH2:27]2)[CH:18]=[C:17]([F:19])[CH:16]=1
Reactant: Fc1cc(F)cc(SCCBr)c1
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)[C@H]1CN(CCSc2cc(F)cc(F)c2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 80 °C
Yield: 44.3 %

Procedure:
0.332 g of potassium carbonate, then 0.4 g of potassium iodide and, finally, 0.675 g of 1-[(2-bromoethyl)thio]-3,5-difluorobenzene, dissolved beforehand in 5 cm3 of acetonitrile, were added at a temperature in the region of 20° C., with stirring and under an inert atmosphere, to a solution of 0.717 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 15 cm3 of acetonitrile and 1 cm3 of methanol. The mixture was heated for 3 hours at a temperature in the region of 80° C. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and the cake was washed with 2 times 5 cm3 of acetonitrile. The filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 40-63 μm; diameter 3.5 cm; height 35 cm), elution was carried out with a dichloromethane/methanol (95/5 by volume) mixture, and 35-cm3 fractions were collected. Fractions 18 to 21 were combined and then evaporated as above. 0.47 g of methyl (3R,4R)-1-[2-(3,5-difluorophenylthio)ethyl]-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate was obtained in the form of a viscous oil with an orange-yellow color.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>C(#N)C>[NH:30]1[C:29]([NH:28][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:8])=[N:33][N:32]=[N:31]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccco1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1nnn[nH]1)c1ccco1
Yield: 61.5 %

Procedure:
Following the procedure described in Example 120, 2-furancarboxylic acid (5.00 g, 44.46 mmol) is treated with 1,1'-carbonyl diimidazole (8.31 g, 51.25 mmol, 1.15 equiv), triethylamine (10.9 g, 107.6 mmol, 2.4 equiv) and 5-aminotetrazole (4.51 g, 53.02 mmol, 1.19 equiv) in refluxing (17 hours) acetonitrile (250 mL) to give the crude carbamoyl product. Recrystallization from N,N-dimethyl formamide/water afforded 4.90 g (7.96 g theo., 62%) of N-1H-tetrazol-5-yl-2-furancarboxamide as a white solid; mp 280°-283° C. (dec).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[C:27]([CH3:38])[C:26]=1[CH3:39]>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:38])[C:26]=3[CH3:39])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: COc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (5-(trifluoromethyl)-3-(4-methoxyphenyl) isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ: 7.65 (d, J=6.9 Hz, 2H), 6.96-7.02 (m, 3H), 6.72 (d, J=8.4 Hz, 1H), 5.13 (s, 2H), 3.55 (s, 3H), 2.92 (t, J=8.4 Hz, 2H), 2.51 (t, J=8.1 Hz, 2H), 2.28 (s, 3H), 2.07 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H22F3NO4S, 466.1 (M+H). found 466.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:29])[C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[CH:18]=1.[CH2:30](OC[C@@H]1[C@@H](C=O)[C@@]1(C)C1C=C(C(C)C)C=C(C(C)C)C=1)C>>[CH2:1]([O:2][CH2:3][C@@H:4]1[C@@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@:5]1([CH3:29])[C:17]1[CH:18]=[C:19]([CH:26]([CH3:28])[CH3:27])[CH:20]=[C:21]([CH:23]([CH3:24])[CH3:25])[CH:22]=1)[CH3:30]
Reactant: CCOC[C@@H]1[C@@H](C=O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: CCOC[C@@H]1[C@@H](/C=C/C(C)=C/C(=O)OCC)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 73 %

Procedure:
Following a procedure similar to that for the preparation of Compound 24 but using Intermediate 48b as the starting material afforded the title compound (36 mg, 73% yield) as a white solid:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([CH:15]=[N:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[N:20][NH:21]2)([OH:14])[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].C(=O)(O)[O-].[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[NH:21]1[C:22]2[C:18](=[C:17]([NH:16][CH:15]3[C:9]4[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:5]([CH3:7])([CH3:6])[CH2:4][C:3]3([C:2]([F:1])([F:26])[F:27])[OH:14])[CH:25]=[CH:24][CH:23]=2)[CH:19]=[N:20]1
Reactant: CC(C)(CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]ncc23)c2ccccc21
Temperature: -70 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
190 mg (0.51 mmol) of 1,1,1-trifluoro-4-phenyl-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol is dissolved in 100 ml of dichloromethane and cooled to −70° C. The solution is mixed over 10 minutes with 9 ml of titanium tetrachloride solution (1 mol in dichloromethane), and it is stirred for 1 hour at −70° C. Then, the cold solution is poured into 200 ml of saturated sodium bicarbonate solution and stirred for 15 minutes. For working-up, the mixture is extracted with dichloromethane, the organic phase is washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum: 208 mg. Column chromatography with dichloromethane-methanol yields 53 mg (28%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12]>>[CH3:9][C:10]([CH3:15])([CH3:14])[C:11]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1)=[O:12]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(Cl)ccn1
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccn1

Procedure:
The synthetic strategy used in the preparation of compounds 4, 5, 6, 7, and 8 is illustrated in FIG. 2. Polychlorinated pyridines were synthesized from the 2-amino-4-chloro-pyridine (compound 3). For example, compound 3 was dissolved in concentrated hydrochloric acid (HCl), reacted at 0° C. with hydrogen peroxide (H2O2), and allowed to warm to room temperature yielding a mixture of 2-amnino-4,5-dichloro-pyridine (compound 4), 2-amino-3,4-dichloro-pyridine (compound 5), and 2-amino-3,4,5-trichloro-pyridine (compound 6). In another method, compound 3 was dissolved in concentrated hydrochloric acid (HCl) and heated at reflux temperature to yield 2-amino-4,5-dichloro-pyridine (compound 4) in 97% yield. In another method, compound 3 was dissolved in concentrated hydrochloric acid (HCl), reacted at 0° C. with hydrogen peroxide (H2O2), and allowed to warm to room temperature yielding 2-amino-3,4,5-dichloro-pyridine (compound 6) in 80% yield. In still another method, compound 3 was reacted with trimethylacetyl chloride ((CH3)3COCl) to yield 2-trimethylacetamido-4-chloro-pyridine (compound 7). Compound 7 was then reacted with N-chlorosuccinimide (NCS) to yield 2-trimethylacetamido-4,5-chloro-pyridine (compound 8). Compound 8 was then reacted with hydrochloric acid (HCl) to yield 2-amino-4,5-chloro-pyridine (compound 4).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:11][OH:12]>N1C=CC=CC=1>[C:1](=[N:11][OH:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: NO
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 95 %

Procedure:
In a 50 ml round-bottom flask, a mixture of acetophenone, hydroxylamine hydrochloride in pyridine was stirred, at room temperature under nitrogen blanket, for five days. The reaction mixture was then concentrated under vacuum to remove most of pyridine. The oil was then distilled at 55° C. under 0.1 mbar. The product was obtained in 95% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:20]([NH:27][C:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NCc2ccccc2)CCN(C(=O)OC(C)(C)C)C1

Procedure:
A solution of 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperidin-4-one (prepared from 3-ethoxycarbonylpiperidin-4-one and di-tert-butyl-dicarbonate in dichloromethane and triethylamine) (25 g) and benzylamine (10.85 g) in toluene was heated under reflux in a Dean and Stark apparatus for 18 hours and then evaporated to dryness to give an oil.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:26][NH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([O:36][C:37](=[O:51])[NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:32][CH2:31]1>C(Cl)Cl>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([CH2:26][NH:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([O:36][C:37](=[O:51])[NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:32][CH2:31]2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=Cc1ccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.6 %

Procedure:
To a three-necked 1-L flask was added 4-carboxybenzaldehyde (4.77 g, 31.8 mmol), EDC (6.64 g, 34.7 mmol), HOBT (1.91 g, 31.8 mmol), and DCM (200 mL). When the mixture was homogenous, a solution of biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester (10 g, 31.8 mmol; prepared as described in Preparation 9) in DCM (100 mL) was added slowly. The reaction mixture was stirred at room temperature for 16 hours and then washed with water (1×100 mL), 1N HCl (5×60 mL), 1N NaOH (1×100 mL) brine (1×50 mL), dried over sodium sulfate, filtered and concentrated to afford 12.6 g of the title compound (92% yield; 85% purity based on HPLC). MS m/z: [M+H+] calcd for C29H31N3O4, 486.2; found, 486.4. Rf=3.12 min (10-70 ACN:H2O, reverse phase HPLC).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:16]([CH3:17])=[CH:15][C:13]([NH2:14])=[C:12]([O:18][CH3:19])[CH:11]=1>C(#N)C>[Br:1][C:15]1[C:16]([CH3:17])=[C:10]([Cl:9])[CH:11]=[C:12]([O:18][CH3:19])[C:13]=1[NH2:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(Cl)c(C)cc1N
Solvent: CC#N
Product: COc1cc(Cl)c(C)c(Br)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
N-Bromosuccinimid (3.9 g, 22 mmol) was added to 4-chloro-2-methoxy-5-methylanilin (4.04 g, 20 mmol) dissolved in acetonitril (200 ml). The reaction was stirred at r.t. overnight, and the solvent was evaporated. The residue was purified by column chromatography (silica gel, methylene chloride) to yield the title compound (3.1 g, 62%) as an orange solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C(Cl)Cl.[F:9][C:10]1[C:15]([F:16])=[CH:14][C:13]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[N:21][CH:22]=2)=[C:12](CO)[CH:11]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(OCC)C>[Br:5][CH2:1][C:12]1[CH:11]=[C:10]([F:9])[C:15]([F:16])=[CH:14][C:13]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[N:21][CH:22]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CO)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CBr)cn1
Temperature: 25 °C

Procedure:
Neat CBr4 (4.6 g, 13.7 mmol) was added to a 0° C., DCM solution (66 mL) of ethyl 3-(5-(4,5-difluoro-2-(hydroxymethyl)phenyl)picolinamido)propanoate (4.2 g, 11.4 mmol) and PPh3 (3.6 g, 13.7 mmol), the cold bath was removed, and the resulting mixture was allowed to warm to room temperature. After 2 h the resulting mixture was diluted with diethyl ether, filtered through a pad of CELITE, concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.[CH3:32][S:33]SC>O1CCCC1.C(O)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:33][CH3:32])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CSSC
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CSc1ccc2c(c1)CC[C@H]1N(C)C(=O)CC[C@]21C
Temperature: -75 °C
Reaction time: 1.5 h

Procedure:
(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (20.0 grams, 64.9 mmole, in 150 mL of tetrahydrofuran) was added to a freshly prepared solution of lithium diisopropylamide in 500 mL of tetrahydrofuran at -20° C. After standing 90 minutes in an ice bath, the resulting amide-enolate solution was cooled to -70° C. and added via cannula over 10 minutes to a freshly mixed solution of n-butyllithium (60.0 mL=2.54 M in hexane, 152 mmole, 2.34 equivalents) at -72 to -75° C. in 300 mL of tetrahydrofuran. The homogeneous solution was allowed to stir at approximately -75° C. for 45 minutes and quenched with dimethyldisulfide (11.0 mL, 123 mmole, 1.9 equiv) at approximately -75° C. After 30 minutes at -75° C., the mixture was treated with acetic acid (18 mL) and all volatiles removed under vacuum. The resulting white solid was treated with 300 mL of heptane-water (1:1, v/v) and the pH adjusted to 3 with 1N hydrogen sulfate. The biphasic mixture was filtered and the wet cake was washed with 1% aqueous sodium bicarbonate (2×50 mL portion) and water (200 mL). The material was dried at 50° C. under vacuum affording (+)-(4aR)-(10bR)-4-methyl-8-methylthio-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (IR, NMR, MS). Calculated for C16H21NOS: C, 69.77; H, 7.69; N, 5.09. Found C, 69.70; H, 7.62; N, 5.06.
Reaction SMILES: CO[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][CH2:7][CH:8](O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1.S(=O)(=O)(O)O.F[C:30](F)(F)C(O)=O>>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([CH:8]2[C:3]3[C:4](=[C:20]([CH3:30])[CH:21]=[CH:22][CH:23]=3)[CH2:5][NH:6][CH2:7]2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccccc1CNCC(O)c1ccc(OC)c(OC)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: COc1ccc(C2CNCc3c(C)cccc32)cc1OC

Procedure:
900 mg of α-[[(2-methoxybenzylamino]methyl]-3,4-dimethoxybenzyl alcohol was dissolved in 7 ml of trifluoroacetic acid, and after adding thereto 0.21 ml of conc. sulfuric acid under ice cooling, the mixture was allowed to react for 60 minutes. The reaction solution was concentrated, and subjected to zzeotropic distillation 3 times, and after adding chloroform, the mixture was basified by addition of 28% aqueous ammonia. By a separating procedure, the chloroform layer was collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue obtained was recrystallized from ethyl acetate-n-hexane, giving 440 mg of 4-(3,4-dimethoxyphenyl)-8-methyl-1,2,3,4-tetrahydroisoquinoline, m.p. 86°-88° C.
Reaction SMILES: [Cl:1][C:2](=[CH2:5])[C:3]#[N:4].N.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Cl:1][CH:2]([CH2:5][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]#[N:4]
Reactant: C=C(Cl)C#N
Reactant: O=C(Cl)c1ccccc1
Agent: N
Product: N#CC(Cl)CC(=O)c1ccccc1

Procedure:
In the past, alpha-halogeno-betaaminopropionitriles have been isolated in the form of the hydrochloride or benzoyl compound of alpha-chloro-beta-aminopropionitrile. For example, the method described in Japanese Patent Publication No. 30152/64 comprises reacting alpha-chloroacrylonitrile with aqueous ammonia, and treating the product with benzoyl chloride to isolate alpha-chloro-beta-benzoylpropionitrile. L. Doub et al., J. Heterocyclic Chem., Vol. 7, pp. 527-535 (June 1970) disclose isolating alpha-chloro-beta-aminopropionitrile hydrochloride in a yield of about 55% by dissolving ammonia gas in methanol, reacting alpha-chloroacrylonitrile with the solution, distilling off the unreacted ammonia and methanol under reduced pressure, adding 25% methanolic hydrochloride to the residue at a temperature of as low as -45° C. to -35° C., and treating the product with ether. However, both of these methods are not entirely satisfactory for commercial practice because the reaction operation is complex and the yield of the final product is low.