Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:3]([CH3:19])([CH3:18])[O:4][C:5]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:6]=2[C:7]=1[C:8]([NH2:10])=O.C([BH3-])#N.[Na+].O1CCCC1.C(O)(=O)C>CO>[C:8]([C:7]1[C:6]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:5]=2[O:4][C:3]([CH3:19])([CH3:18])[CH:2]=1)#[N:10]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(C(N)=O)=C1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)C=C(C#N)c2cc([N+](=O)[O-])ccc2O1
Reaction time: 18 h
Yield: 88.6 %

Procedure:
To a mixture of 23.2 g of 3-hydroxy-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamide, 16.6 g of sodium cyanoborohydride, and 200 ml of tetrahydrofuran was added 100 ml of acetic acid with stirring and ice-cooling, followed by stirring for 3 hours under ice-cooling and then at room temperature for 18 hours. To the reaction mixture were further added 5.6 g of sodium cyanoborohydride and 50 ml of methanol, followed by stirring at room temperature for 40 hours. The reaction mixture was distilled under reduced pressure, water was added to the residue, and the mixture was extracted with a mixed solvent of ethyl acetate and diethyl ether. The organic layer was washed with water and dried, and the solvent was removed by distillation to recover 24 g of 3,4-dihydro-3-hydroxy-2,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamide. To the resulting compound were added 51.5 g of p-toluenesulfonyl chloride and 400 ml of pyridine, followed by refluxing for 3 hours. The solvent was removed from the reaction mixture by distillation. Ice-water was added to the residue, and the mixture was made acidic with hydrochloric acid. The thus precipitated crystal was collected by filtration, washed with water, and dried. The crystal was further purified by silica gel column chromatography (developing solution: CH2Cl2 :hexane=7:3) to give 17.9 g of 4-cyano-2,2-dimethyl-6-nitro-2H-1-benzopyran represented by formula shown below.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:47]CC2C=CC=CC=2)[C@@H:15]([N:32](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([O:24]CC3C=CC=CC=3)[CH:18]=2)[CH2:12][O:11][CH:10]([OH:55])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:56][CH2:57][C:58](OS(C(F)(F)F)(=O)=O)([CH2:60][F:61])[CH3:59]>>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:47])[C@@H:15]([NH2:32])[CH2:16][C:17]2[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@H:10]([O:55][C:58]([CH2:60][F:61])([CH3:59])[CH2:57][F:56])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)OC[C@@H]1[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(OCc2ccccc2)c1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CC(CF)(CF)OS(=O)(=O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1C[C@@H](OC(C)(CF)CF)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(O)cc(F)c1

Procedure:
Beginning with (5R)-5-[(1S,2S)-1-Benzyloxy-3-(3-benzyloxy-5-fluoro-phenyl)-2-dibenzylamino-propyl]-2-hydroxy-morpholine-4-carboxylic acid tert-butyl ester and trifluoromethanesulfonic acid 2-fluoro-1-fluoromethyl-1-methyl-ethyl ester, the desired compound may be prepared essentially as described in Preparation 306.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[NH:12][C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.Cl>[OH-].[Na+].C(O)C>[F:24][C:21]([F:22])([F:23])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]1[NH:12][C:8]2[CH:9]=[N:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=2[N:14]=1
Reactant: CCOC(=O)c1cncc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cncc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Yield: 82.3 %

Procedure:
2-(2-Trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine-7-carboxylic acid ethyl ester (80; 2.35 g, 7 mmol) was taken up in 10% aqueous NaOH (40 mL) and ethanol (20 mL). The reaction mixture was stirred under reflux for 30 min. Upon cooling to room temperature, the reaction mixture was acidified with 5N HCl. The resulting yellow solids were collected by filtration, washed with water, and dried to afford 2-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine-7-carboxylic acid 81 (1.77 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][CH:9]=[CH:10][C:6]=2[C:5]([C:11]([OH:13])=O)=[CH:4][N:3]=1.Cl.[CH:15]1([CH2:19][NH2:20])[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:19][NH:20][C:11]([C:5]2[C:6]3[CH:10]=[CH:9][NH:8][C:7]=3[C:2]([Cl:1])=[N:3][CH:4]=2)=[O:13])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)c1cnc(Cl)c2[nH]ccc12
Reactant: NCC1CCC1
Agent: Cl
Product: O=C(NCC1CCC1)c1cnc(Cl)c2[nH]ccc12

Procedure:
Prepared in a similar manner to Example 19 (e) from 7-chloro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid using cyclobutylmethylamine hydrochloride (46 mg) instead of tetrahydro-pyran-4-ylmethylamine to give the title compound (39 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.Br[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](=[O:19])[CH3:18]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH3:18])=[O:19])=[CH:4][CH:3]=1
Reactant: CC(=O)C(Br)c1ccccc1
Reactant: Sc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)C(Sc1ccc(Cl)cc1)c1ccccc1
Reaction time: 8 h

Procedure:
In a 100 ml round-bottomed flask, 1 eq. of 4-chlorothiophenol is dissolved in 4 eq. of pyridine and 50 ml of anhydrous ether, with magnetic stirring. 1.2 eq. of bromophenylacetone are then added dropwise and stirring is then carried out overnight at ambient temperature. The reaction mixture is then poured onto ice-cold water and is extracted with ethyl acetate. The organic phase is washed with 1M HCl solution and then with water, is dried over MgSO4 and is evaporated under reduced pressure. The residue obtained is purified by chromatography on a silica gel column.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[C:28]([O:32][C:33](=[O:44])[NH:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[NH2:43])([CH3:31])([CH3:30])[CH3:29]>CCCCCCC.C(OCC)(=O)C>[C:28]([O:32][C:33](=[O:44])[NH:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[NH:43][C:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[O:4][C:3]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=1[Cl:1])=[O:12])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1N
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (WO2008000643A1) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light yellow solid (73%). MS (ESI): m/z=510.080 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH:4]([CH2:8][OH:9])[C:5](=[O:7])[CH3:6])=[CH2:3].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[CH3:3][C:2]([CH:4]([CH2:8][O:9][C:10](=[O:12])[CH3:11])[C:5](=[O:7])[CH3:6])=[CH2:1]
Reactant: C=C(C)C(CO)C(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=C(C)C(COC(C)=O)C(C)=O

Procedure:
256 g (2 mols) of 2-methyl-3-hydroxymethyl-pent-1-en-4-one were boiled for three hours under reflux with 1,000 ml of acetic anhydride. The acetic acid produced, and the excess acetic anhydride, were than distilled off in a waterpump vacuum. The residue was distilled in a high vacuum. 249 g of 2-methyl-3-acetoxymethyl-pent-1-en-4-one of boiling point 52° - 55° C/0.05 mm Hg were obtained.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[S:14][CH:15]=3)=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][NH:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:32][C:33]2([CH3:37])[CH2:36][O:35][CH2:34]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:32][C:33]1([CH2:37][N:10]2[C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=3[C:8]([C:11]3[CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[S:14][CH:15]=3)=[N:9]2)[CH2:36][O:35][CH2:34]1
Reactant: NC(=O)c1cc(-c2n[nH]c3cc[nH]c(=O)c23)cs1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(Cn2nc(-c3csc(C(N)=O)c3)c3c(=O)[nH]ccc32)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
To a solution of 4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (60.0 mg) in DMF (3 mL) was added sodium hydride (60% dispersion in mineral oil, 23.0 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (148 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (2.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:29])[C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[C:20]([CH3:28])[CH:19]=3)=[O:16])[C:10](=[O:30])[CH:9]=2)[CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:29])[C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[C:20]([CH3:28])[CH:19]=3)=[O:16])[C:10](=[O:30])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(NC(=O)C(C)n2ccc(-c3cc(Cl)ccc3C#N)cc2=O)cc1C
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(NC(=O)C(C)n2ccc(-c3cc(Cl)ccc3C#N)cc2=O)ccc1C(=O)O

Procedure:
120 mg (0.27 mmol) of methyl 4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)-2-methylbenzoate (racemate) (Example 2.6A) were hydrolysed with lithium hydroxide according to General Method 3. Yield: 39 mg (purity 93%, 33% of theory)
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)CCCBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CC(C)CCCN1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 41.9 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 1-bromo-4-methyl pentane (103 mg, 0.690 mmol) gave 7-cyclopentyl-2-{5-[4-(4-methyl-pentyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 42%). MS (ESI) m/z 519.4 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([CH3:25])([CH2:23]O)[CH2:21][OH:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][C:20]([CH3:25])([CH3:23])[CH2:21][OH:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(CO)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)CO
Reaction time: 23 h
Yield: 88.6 %

Procedure:
A mixture of N-benzyloxycarbonyl-L-valine (2.50 g, 10.0 mmol), 2,2-dimethyl-1,3-propanediol (5.30 g, 50.9 mmol), dicyclohexylcarbodiimide (2.60 g, 12.6 mmol), and 4-dimethylaminopyridine (125 mg, 1.0 mmol) in 100 mL dry CH2Cl2 was stirred for 23 h. The reaction mixture was filtered and washed successively with 50 mL each of water, saturated aqueous NH4Cl, saturated aqueous NaHCO3, and water. The organic phase was dried over anhydrous Na2SO4 and concentrated. The title compound (2.99 g, 87%) was isolated by flash column chromatography (silica, 2/1 petroleum ether-ethyl acetate) as a white waxy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([CH2:13][OH:14])[CH2:8]2.[C:15]1([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](=[O:23])[O:14][CH2:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[CH:12][C:3]=3[O:2][CH3:1])[CH2:8]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc2c1CCC(CO)C2
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: COc1cccc2c1CCC(COC(=O)N(c1ccccc1)c1ccccc1)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A mixture of (1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methanol (192 mg) and N,N-diphenylcarbamoyl chloride (348 mg) in pyridine (180 mg) was stirred at 100° C. for 2 hours, cooled to room temperature, and partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed successively with brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diethyl ether to afford (1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methyl N,N-diphenylcarbamate (218 mg) as a pale purple powder.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: Nc1cc([N+](=O)[O-])c(Br)cc1F
Temperature: 0 °C
Yield: 22.6 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (58.6 g) in conc. sulfuric acid (100 ml), there is dropwise added a mixture of conc. nitric acid (25.3 g) and conc. sulfuric acid (15 ml) at a temperature of 0° to -10° C. The resultant mixture is stirred at 0°-5° C. for 1 hour, poured into ice-water and extracted with toluene. The toluene layer is washed with water and an aqueous sodium hydrogen carbonate solution and concentrated. The residue is purified by silica gel chromatography to give 16.4 g of 4-bromo-2-fluoro-5-nitroaniline. M.P., 90°-92° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCCc1nc2cccc(Cl)c2o1
Reactant: Brc1ccccn1
Product: Clc1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 45000 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (32 mg, 0.20 mmol) and 2-(but-3-ynyl)-7-chlorobenzo[d]oxazole (42 mg, 0.20 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 25 mg (90 mmol, 44%) of 7-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oil.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>FC(F)(F)C(O)=O.ClCCl>[NH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][NH:18]2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)N1C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCNN1C1CCNCC1
Reaction time: 15 h
Yield: 108.5 %

Procedure:
tert-Butyl 2-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-3-oxotetrahydropyridazin-1(2H)-carboxylate (0.84 g) obtained in Example 29a} was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (1.5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was made alkaline with an aqueous sodium bicarbonate solution and then extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol (10 mL), and 10% palladium on carbon (0.1 g) was added,followed by stirring under a hydrogen atmosphere for 15 hours. After the catalyst was removed, the solvent was distilled off under reduced pressure to obtain the title compound (0.40 g, quantitative) as a yellow oil.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][C:16]=3[CH:25]=2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].CCOCC>C(O)C>[OH:5][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][C:16]=3[CH:25]=2)=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)=O)cc3)ccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc2cc(-c3ccc(C(C)O)cc3)ccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of sodium borohydride was added in one portion to a stirred mixture of 15.0 g of 6A, 200 ml of ether and 40 ml of ethanol. The mixture was stirred at room temperature for 2 hours. The solvents were evaporated under reduced pressure. 1.6 liters of water was added to the residue and the mixture was extracted with chloroform. The extract was dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in 150 ml of chloroform. The solution was filtered through charcoal. 400 ml of hexane was added. The solid which formed was collected, recrystallized from a 3/50 v/v mixture of chloroform and hexane and dried in a vacuum oven to give ethyl 5-(4-(1-hydroxyethyl)phenyl)-2-benzofurancarboxylate (6B), mp: 108°-109° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:24])[C@H:6]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[O:14])[NH2:12])[NH2:7])[CH:2]=[CH2:3].C([BH3-])#N.[Na+].[C:29]([CH:36]([NH2:39])[CH:37]=O)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].Cl>CO.CCOCC.C(O)(=O)C>[CH2:1]([O:4][C:5](=[O:24])[C@H:6]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[O:14])[NH2:12])[NH:7][CH2:37][CH:36]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[NH2:39])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@@H](N)CCCC(N)C(=O)OCc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)C(N)C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: C=CCOC(=O)[C@H](CCCC(N)C(=O)OCc1ccccc1Cl)NCC(N)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
ε-(2-chlorobenzyloxycarbonyl)-lysine allyl ester (from example 18) was dissolved in methanol (50 mL) and cooled to 0° C. To the resulting solution was added sodium cyanoborohydride (5.9 mmol) followed by acetic acid (0.75 mL). After 5 minutes BOC-amino-acetaldehyde (13.3 mmol) was added and the reaction mixture was stirred for an additional 1 h. The methanol was removed in vacuo and the oil was dissolved in ethyl acetate (40 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated to give a clear colorless oil. This oil was dissolved in dry ether (80 mL), cooled to −20° C., and a molar equivalent of HCl in ether was added slowly. The resulting white solid was collected by filtration and air dried Precipitation of tie air-dried white solid from dry ember gave analytically pure title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].C(=O)(O)[O-].[Na+].NN.Cl[O-].[Na+]>COCC(O)C.O>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:11])=[CH:2][N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCC(C)O
Product: Clc1cnc(Cl)c(Cl)c1
Temperature: 92 °C
Reaction time: 1.5 h

Procedure:
A mixture was prepared containing 50.3 grams (0.2 mole) of pentachloropyridine, 20 grams (0.24 mole) of sodium bicarbonate and 6.9 grams (0.205 mole) of 95 percent hydrazine in 215 milliliters of propylene glycol methyl ether. The mixture was heated at 92° C., with stirring, for 1.5 hours. The mixture was cooled to 30° C. and 50 milliliters of propylene glycol methyl ether was added. To this mixture was added 350 milliliters of a 10 percent sodium hypochlorite solution, over a 20 minute period while the temperature of the solution was maintained at 45°-50° C. At the completion of the reaction, the solution was diluted with 100 milliliters of water and extracted with hexane. The hexane extract was washed with water and the hexane evaporated off. The oily product which remained was dissolved in 250 milliliters of propylene glycol methyl ether and 20 grams of sodium bicarbonate and 6.9 grams of 95 percent hydrazine were added thereto. The mixture was heated at 92° C. for 1.5 hours and 1.0 gram of 95 percent hydrazine was added. Heating was continued for 3 additional hours and the reaction mixture was cooled to 45° C. To this mixture was added 450 milliliters of a 10 percent sodium hypochlorite solution over a 20 minute period while maintaining the reaction temperature at 45°-50° C. The reaction mixture was extracted with hexane and the hexane extract was washed with water and the hexane was removed by evaporation. The crude 2,3,5-trichloropyridine product was obtained in a yield of 30.5 grams and found to be 94.6 percent pure.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:37]=[N:36][C:18]3[N:19](COCC[Si](C)(C)C)[C:20]4[CH:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=4[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:37]=[N:36][C:18]3[NH:19][C:20]4[CH:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=4[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCN1CCCCC1c1ccc(-c2cnc3c(c2)c2cc(C#N)ncc2n3COCC[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCN1CCCCC1c1ccc(-c2cnc3[nH]c4cnc(C#N)cc4c3c2)cc1
Yield: 19.6 %

Procedure:
A solution of 3-[4-(1-ethyl-piperidin-2-yl)-phenyl]-9-(2-trimethylsilanylethoxy methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (75 mg, 0.147 mmol) in TBAF (1M in THF, 1.5 mL, 1.47 mmol) was heated at 55° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to give a yellow solid. The resultant solid was purified by flash chromatography (silica, Biotage 50 g column, 0-100% (10% methanol in DCM)) to afford the title compound (11 mg, 20%). 1H NMR (DMSO-D6, 400 MHz): 12.89 (s, 1H), 9.08 (d, J=2.3 Hz, 1H), 9.04 (d, J=1.1 Hz, 1H), 9.02 (d, J=2.3 Hz, 1H), 8.93 (d, J=1.1 Hz, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 3.16-3.07 (m, 2H), 2.54-2.42 (m, 1H), 2.11-1.93 (m, 2H), 1.79-1.64 (m, 3H), 1.63-1.20 (m, 3H), 0.89 (t, J=7.1 Hz, 3H). LCMS (Method A): RT=6.23 min; M+H+=382
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][O:4][CH2:5][C:6]([O:8]C)=[O:7].[OH-].[Na+].S(=O)(=O)(O)O>CO.CCOCC>[F:1][C:2]([F:11])([F:10])[CH2:3][O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)COCC(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: O=C(O)COCC(F)(F)F
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
To a solution of methyl 2-(2,2,2-trifluoroethoxy)acetate (8.26 g, 47.98 mmol) and methanol (16 mL) was added sodium hydroxide (1.92 g, 47.98 mmol) in methanol (16 mL). After stirring for 18 hours, the reaction was concentrated and ether (170 mL) was added. The mixture was cooled to 0° C. and concentrated sulfuric acid (2.15 g, 43.9 mmol) in ether (7.5 mL) was slowly added. The resulting mixture was stirred for 18 hours, filtered and concentrated to give the title compound as a colorless oil (7.15 g, 94%), MS(CI): 159(M+H); H-NMR (300 MHz, DMSO-d6): 4.14(q, J=9.3 Hz, 2H), 4.21(s, 2H), 12.92(s, 1H).