Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](Cl)=[O:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)=[O:23])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)c1ccccn1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Cl)cc21)c1ccccn1

Procedure:
N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-pyridinecarboxamide was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and picolinoyl chloride in a similar manner as described in Example 14 to give an off-white solid (62% yield). 1H-NMR (DMSO-d6): δ 10.93 (s, 1H), 8.78 (d, 1H), 8.61 (m, 1H), 8.12 (m, 1H), 8.02 (m, 1H), 7.61 (m, 1H), 7.43 (m, 1H), 7.26 (d, 1H), 7.01 (dd, 1H), 5.34 (m, 1H), 2.64 (m, 2H), 2.00 (m, 3H), 1.82 (m, 1H); MS m/z 348 (M+Na).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1.CCN(CC)CC.[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][BH:33][O:32]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:30][C:31]1([CH3:38])[C:35]([CH3:37])([CH3:36])[O:34][B:33]([C:2]2[C:3]3[C:4]4[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:5]=4[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[O:32]1
Reactant: CC1(C)OBOC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cccc(Br)c3c2CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3cccc(B4OC(C)(C)C(C)(C)O4)c3c2CC1
Yield: 92.4 %

Procedure:
tert-Butyl 10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.51 g, 4.12 mmol) and dioxane (26 mL) were combined at rt under N2. Et3N (3.43 mL, 2.49 g, 24.6 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.28 mL, 1.05 g, 8.21 mmol) were added to the mixture by syringe. trans-Dichlorobis(triphenylphosphine)palladium(II) (0.147 g, 0.209 mmol) was added and Ar was bubbled through the reaction mixture for 15 min. The reaction mixture was refluxed under N2 for 16 h. The cooled reaction mixture was concentrated and the residue was combined with toluene (50 mL), brine (20 mL) and H2O (100 mL). The layers were separated and the aqueous layer was extracted with toluene (2 ×50 mL). The combined organic extracts were washed with brine (40 mL), dried over MgSO4, filtered and concentrated. The crude product (1.90 g) was chromatographed (SiO2 60 g, eluted with 2:2:1 heptane:CH2Cl2:Et2O) to give tert-butyl 10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.57 g) in 93% yield. MS (ESI+) for C23H33BN2O4 m/z 413.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:5][NH:6][C:7](=[O:36])[CH:8]([CH3:35])[C:9]([NH:11][CH:12]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=[O:14])=[O:10].F[C:42]1C=C(C=C(F)C=1)CNC(=O)C(C)(C)C(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:5][NH:6][C:7](=[O:36])[C:8]([CH3:42])([CH3:35])[C:9]([NH:11][CH:12]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[C:13]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)=[O:14])=[O:10]
Reactant: CC(C)(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1
Product: CC(C)(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1

Procedure:
N-(3,5-Difluoro-benzyl)-N′-[2-(3,4-dihydro-1H-isoguinolin-2-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2,2-dimethyl-malonamide. MS: m/e=559.3 (M+H+), was prepared in analogy to N-(3,5-difluoro-benzyl)-N′-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-2-methyl-malonamide (example 16) from N-(3,5-difluoro-benzyl)-2,2-dimethyl-malonamic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH3:9])=[N:6][C:5]([Br:10])=[CH:4][N:3]=1.Cl[CH2:12][C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=O>CN(C)C=O>[Br:10][C:5]1[N:6]=[C:7]([NH:8][CH3:9])[C:2]2[N:3]([CH:12]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:1]=2)[CH:4]=1
Reactant: CNc1nc(Br)cnc1N
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn2cc(Br)nc(NC)c2n1
Yield: 12.8 %

Procedure:
2.03 g (10 mmol) of 2-amino-5-bromo-3-methylaminopyrazine are dissolved in 5 ml of dimethylformamide (DMF). A solution of 1.645 g(10 mmol) of ethyl (chloroacetyl)acetate in 5 ml of DMF is added dropwise with stirring. The mixture is maintained with stirring and under gentle reflux for 3 hours. The DMF is then evaporated off under reduced pressure and the residue, dissolved in 50 ml of anhydrous ethanol, is brought to reflux for one hour. After removal of the solvent, the residue is taken up with water, alkalinized and extracted with dichloromethane. After dehydration over anhydrous calcium chloride, the solvent is evaporated off under reduced pressure. The crude product is purified by chromatography on a silica column (eluant=dichloromethane to which 5% of methanol has been added). 0.4 g (Yld=30%) of ethyl 6-bromo-8-methylaminoimidazo[1,2-a]pyrazine-2-acetate (m.p. 104° C.) is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[C:9]1([CH2:15][N:16]2[CH2:20][CH:19]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F-].[Cs+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([C:18]2[CH2:17][N:16]([CH2:15][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:20][CH:19]=2)=[CH:7][N:6]=1
Reactant: Cc1ncc(Br)cn1
Reactant: CC1(C)OB(C2=CCN(Cc3ccccc3)C2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ncc(C2=CCN(Cc3ccccc3)C2)cn1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
The title compound can be prepared through a coupling palladium mediated reaction, e.g. starting from 5-bromo-2-methylpyrimidine and 1-(phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole. For example, to a solution of 5-bromo-2-methylpyrimidine (1.3 eq.) in THF, 1-(phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole (1 eq.), tetrakis(triphenylphosphine)palladium(0) (5% mol) and cesium fluoride (4 eq.) may be added at room temperature. The resulting mixture should be stirred at 80° C. for 1.5 hours. After cooling the solvent should be evaporated under reduced pressure and the residue partitioned between dichloromethane and sodium hydroxyde (1M). The organic phase should be evaporated under reduced pressure and the crude product purified by flash chromatography to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21](F)[C:18]=1[C:19]#[N:20]>CN(C=O)C>[C:6]([O:5][C:3]([N:10]1[CH2:11][CH2:12][N:13]([C:21]2[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[C:18]=2[C:19]#[N:20])[CH2:14][CH2:15]1)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(F)c2C#N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
In a round bottom flask, sodium hydride (60%) (2.40 g; 60 mmol) was suspended in DMF (25 mL) and cooled in an ice water bath under nitrogen. 1-Boc-piperazine (9.53 g; 50.6 mmol) was added in small portions to the reaction mixture at 0° C. over 30 minutes. The mixture was allowed to stir at room temperature for 3 hours and the recooled to 0° C. 2,6-Difluorobenzonitrile (8.57 g; 60 mmol) was added to the reaction mixture in DMF (10 mL) over 45 minutes. The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured in ice water (250 mL) and stirred. The solid was collected by vacuum filtration and washed with water. And then dried under vacuum to yield the title compound (11.65 g; 75% yield).
Reaction SMILES: [F:1][CH:2]([C:8](=O)[CH2:9][F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+:16].C(=O)(O)[O-].[Na+]>CO>[F:1][C:2](=[C:8]([NH2:16])[CH2:9][F:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)C(=O)CF
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(F)=C(N)CF
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.4 %

Procedure:
A mixture of ethyl 2,4-difluoro-3-oxobutanoate (24.6 g, 0.148 mol), ammonium acetate (200 g, 2.6 mol) and anhydrous methanol (400 mL) is stirred at room temperature for 3 days. The solution is poured into a saturated aqueous solution of sodium bicarbonate (1L) and extracted four times with ether. The combined organic phases are washed with brine and dried over magnesium sulfate. The solvent is evaporated to yield ethyl 2,4-difluoro-3-amino-2-butenoate (11.1 g, 45%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[CH2:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[CH2:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([NH:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=2)[N:8]=1
Reactant: COc1cc(Br)cc(CNc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CCCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Br)cc(CNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Temperature: 70 °C
Yield: 98.9 %

Procedure:
Into a reaction flask were added N-(3-bromo-5-methoxybenzyl)-2,5-dichloropyrimidin-4-amine (2.0 g, 5.5 mmol), 1,4-dioxane (30 mL), 3-(3-aminophenyl)propan-1-ol (1.2 g, 8.3 mmol, prepared according to Example 12, Step B), and p-toluenesulfonic acid monohydrate (0.12 g, 0.63 mmol). The mixture was heated at 70° C. over two days and NaHCO3 (saturated aqueous solution) was added. After removal of the organic solvent, the aqueous layer was extracted with methylene chloride twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated to give the desired product as a white powder (2.6 g, 99%). LCMS for C21H22BrClN4O2 (M+H)+: m/z=477.0, 479.0.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:22])[CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:17]([O:22][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=1)[C:11]([O:13][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O)c1ccccc1
Product: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)OCc1ccccc1)c1ccccc1
Yield: 196.1 %

Procedure:
The procedure of Example 1 part (3) was repeated, except that (2S)-2-benzoylamino-3-(3,4-dihydroxyphenyl)propanoic acid (1.53 g, 5.1 mmol) was used instead of methyl (2S)-2-benzoylamino-3-(3,4-dihydroxyphenyl)propanoate, and benzyl bromide (3.59 g, 21.0 mmol) was used instead of methyl iodide, and 2.85 g (5.0 mmol, yield: 98%) of benzyl (2S)-2-benzoylamino-3-(3,4-dibenzyloxyphenyl)propanoate was obtained.
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:44]1[O:46][CH:45]1[CH2:47][OH:48]>C(O)CC>[CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH2:44][CH:45]([OH:46])[CH2:47][OH:48])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCC1CO1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Solvent: CCCO
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(CC(O)CO)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Yield: 27 %

Procedure:
Compound 1 (100 mg, 0.167 mmol) obtained in Example 1 was dissolved in 1-propanol (1 mL), and irradiated with microwave (300 W, 100° C., 2 hours) after adding glycidol (0.111 mL, 1.67 mmol). The reaction solution was concentrated under reduced pressure after adding water. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 87/13) to give compound 24 (30.4 mg, 27.1%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:15]1[N:19]=[N:18][C:17]([C:20]([F:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([O:23]CC)=[O:22])=[N:16]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CO.O>[CH2:3]([N:15]1[N:19]=[N:18][C:17]([C:20]([F:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([OH:23])=[O:22])=[N:16]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCn1nnc(C(F)(C(=O)OCC)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCn1nnc(C(F)(C(=O)O)c2ccccc2)n1
Reaction time: 3 h
Yield: 0.1 %

Procedure:
NaOH (0.12 g, 3 mole) was added in one portion to a stirred solution of 2-dodecyl-α-fluoro-α-phenyl-2H-tetrazole-5-acetic acid, ethyl ester (0.59 g, 1.4 mole) dissolved in 6 mL of 5:1 CH3OH-H2O at room temperature. After stirring for 3 hours, the mixture was concentrated, diluted with H2O, acidified with 6N HCl (pH 1) and extracted with ethyl acetate (2×150 mL). The combined ethyl acetate extracts were washed with brine (50 mL) and dried. Filtration and concentration afforded 0.5 g (91%) of the title compound as an oil.
Reaction SMILES: O[CH:2]([C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)[CH2:3][N+:4]([O-:6])=[O:5].[CH2:14]1OCCOCCOCCOCCOCC[O:16][CH2:15]1.[F-].[K+].C(OC(=O)C)(=O)C>>[N+:4]([CH:3]=[CH:2][C:7]1[CH:8]=[C:9]([O:13][C:15](=[O:16])[CH3:14])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5]
Reactant: O=[N+]([O-])CC(O)c1cccc(O)c1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cccc(C=C[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 987 %

Procedure:
Add 3-(1-hydroxy-2-nitroethyl)-phenol (22.3 g, 121.8 mmol), 18-Crown-6 (3.3 g, 12.5 mmol), potassium fluoride (spray-dried) (7.1 g, 141 mmol) to acetic anhydride (115 mL, 1.218 mol). Stir for 1 hour. Cool in an ice bath and pour into ice water (400 mL) and stir for 15 minutes. Decant and extract the aqueous with ethyl acetate (twice). Combine extracts with the solid, wash with water (twice), saturated aqueous sodium chloride (twice), dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 25:75 hexanes:dichloromethane to 100% dichloromethane) to give the desired compound as an orange oil (25.56 g, 91%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1([CH2:19][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([N:16]2[CH2:15][CH2:14][N:13]([CH2:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])[CH2:18][CH2:17]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(CC(=O)N3CCCC3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 2-(piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone (0.108 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.55 mmol). The reaction mixture was heated at 45° C. for 22 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 70% ethyl acetate in dichloromethane and then 90% ethyl acetate in dichloromethane. The title compound was obtained as a yellow solid (0.162 g, 78%); 1H-NMR (500 MHz, DMSO-d6) 1.74 (m, 2H) and 1.85 (m, 2H) (pyrrolidine 3-CH2 and 4-CH2), 2.60 (br s, 4H, piperazine N(CH2)2), 3.04 (br s, 4H, piperazine N(CH2)2), 3.16 (s, 2H, NCH2CO), 3.27 (t, J=6.90 Hz, 2H) and 3.45 (t, J=6.70 Hz, 2H) (pyrrolidine 2-CH2 and 5-CH2), 7.02 (s, 2H, NH2), 8.16 (s, 1H, 6-H);
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Cl)[O:17][CH3:18]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([O:9][CH2:16][O:17][CH3:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1F
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(Cl)nc1F
Temperature: 60 °C
Yield: 82.3 %

Procedure:
A solution of 6-chloro-2-fluoropyridin-3-ol (1.4 Kg, 9.49 mol) was dissolved in acetone (13 L), and treated with K2CO3 (1574 g, 11.39 mol, 1.2 eq) and MOMCl (840 g, 10.44 mol, 1.1 eq). The mixture was heated at 60° C. for 2 hrs. After cooling to RT, the reaction mixture was filtered to remove inorganic salts. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (0-10% EtOAc/hexanes), affording 6-chloro-2-fluoro-3-(methoxymethoxy)pyridine (1496 g) as a colorless oil in 80% yield over two steps.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH3:8][Si:9](Cl)([CH3:11])[CH3:10]>C[Si](N[Si](C)(C)C)(C)C>[Si:9]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][Si:9]([CH3:11])([CH3:10])[CH3:8])([CH3:11])([CH3:10])[CH3:8]
Reactant: OCCCCCO
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)OCCCCCO[Si](C)(C)C
Temperature: 50 °C

Procedure:
1,5-Pentanediol (65 g, 0.62 mol) was placed in a 500 mL 3-necked RB flask and treated with 0.4 mL trimethylsilyl chloride. A portion of HMDS (ca. 20 mL) was added, and an exothermic reaction took place as the mixture became homogeneous. The remainder of the HMDS (130 mL, 0.71 mol total) was added at a controlled rate (ca. 3-5 mL/min), maintaining the reaction temperature at ca. 50° C. Heating was continued at 100° C. (1 h), and 150° C. (2.5 h). GC analysis (method 1) revealed excess HMDS and one product. Distillation provided 139 g of colorless oil, bp 47°-49° C./0.1 mm. 1H NMR (CDCl3): 3.60 (t, J=7Hz, 4H), 1.57 (m, 4H), 1.40 (m, 2H), 0.12 (s, 18H), consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([OH:17])=O)[CH:3]=1.C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C=O)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([Cl:21])=[O:17])[CH:3]=1
Reactant: Cc1ccc(Cn2nc(C(=O)O)cc2C)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(C(=O)Cl)cc2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylic acid (Intermediate B, 390 mg, 1.69 mmol), was dissolved in dichloromethane (26 mL) and cooled to 0° C. Oxalyl chloride was added (0.79 mL, 8.47 mmol) along with 1 drop of DMF. The ice bath was removed and the mixture was stirred at rt for 30 min before the solvent was evaporated. The residue was used in the next step with no further purification or characterization.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[CH:17](O)=O>C=O>[ClH:1].[ClH:1].[CH3:17][N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1cncc(OCC[C@@H]2CCCN2)c1
Reactant: O=CO
Agent: C=O
Agent: Cl
Product: CN1CCC[C@H]1CCOc1cccnc1

Procedure:
A 400 mg sample of 3-(2-(2-(S)-pyrrolidinyl)ethoxy)pyridine dihydrochloride, from Example 102 above, was dissolved in 14 mL of 37% HCHO, 14 mL of HCOOH was added, and the reaction mixture was stirred at reflux for 2.5 hours. The solution was washed with ether, adjusted to basic pH with K2CO3 and extracted with methylene chloride. The extract was dried over MgSO4 and concentrated. The residue was purified on a column of-silica gel, eluting with 10% methanol in methylene chloride. The compound was converted to the salt by the HCl in ether according to Example 14c to afford the title compound. MS (DCI/NH3) m/e: 207 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 1.71-1.98 (m, 1H, 2.00-2.23 (m, 3H), 2.37-2.45 (m, 1H, 2.50-2.63 (m, 1H), 2.98 (s, 3H), 3.13-3.25 (m, 1H, 3.53-3.67 (m, 1H), 3.68-3.78 (m, 1H), 4.31-4.48 (m, 2H), 8.00 (dd, J=11.0, 7.0 Hz, 1H), 8.20 (dd, J=10.5, 5.0 Hz, 1H), 8.42 (d, J=6.5 Hz, 1H), 8.50 (d, J=5.0 Hz, 1H). Anal. Calc. for C12H18N2OF.1.9 HCl.1.1 H20. C, 48.49; H, 7.46; N, 9.42; Found C, 48.51; H, 7.69; N, 9.61. [α]25D +36.28° (c=0.5, H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([NH:29][NH2:30])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:32](=N)(OC)[CH3:33]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]3[O:28][C:32]([CH3:33])=[N:30][N:29]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: COC(C)=N
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nnc(C[C@H]2C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N(CC3CC3)C2=O)o1

Procedure:
To a solution of 40 mg (90 μmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetohydrazide (Example 51) in 0.2 mL of toluene was added methyl acetimidate hydrochloride (13 mg, 116 μmol). The reaction mixture was heated to reflux for 14 h and then the reaction was concentrated under reduced pressure. Separation by reversed phase HPLC (10 to 90% AcCN/H2O in 45 min) provided the title compound as a colorless film.
Reaction SMILES: [CH:1]([CH:3]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=[C:6]([CH3:14])[CH2:5][CH2:4]1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][CH:3]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=[C:6]([CH3:14])[CH2:5][CH2:4]1
Reactant: CCOC(=O)C1C=C(C)CCC1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C1C=C(C)CCC1CO
Reaction time: 2 h

Procedure:
To ethyl(1R/S,6R/S)-6-formyl-3-methylcyclohex-2-ene-1-carboxylate (516 mg, 2.6 mmol) in methanol (13 mL) at 0° C. was added NaBH4 (199 mg, 5.3 mmol) and the reaction mixture was stirred for 2 h. Water was added, the product extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the product was purified by flash chromatography over silica gel (ethyl acetate/hexanes, 20/80 to 40/60) to afford ethyl(1R/S,6R/S)-6-(hydroxymethyl)-3-methylcyclohex-2-ene-1-carboxylate.