Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[C:8]([Cl:24])=[CH:9][C:10]([F:23])=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]3)[CH:12]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:28].N([O-])=O.[Na+].C1(C)C(C)=CC=CC=1>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:24][C:8]1[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([OH:28])=[CH:26][CH:25]=2)=[CH:12][C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:20])[F:21])[C:15]([CH3:22])=[N:14]2)=[C:10]([F:23])[CH:9]=1
Reactant: Cc1nn(-c2cc(Oc3ccc(N)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: O=S(=O)(O)O
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1nn(-c2cc(Oc3ccc(O)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 20 °C

Procedure:
While maintaining a temperature of 20° to 25° C., 4.4 g (0.011 mole) of 1-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-difluoromethyl-4,5-dihydro -3-methyl-1,2,4-triazol-5(1H)-one was added to 4.0 mL of stirred, concentrated sulfuric acid. To this was added a solution of 0.89 g (0.13 mole) of sodium nitrite dissolved in 6.0 mL of water, while continuing to maintain a temperature of about 20° C. After complete addition, the mixture was stirred at 20° C. for 30 minutes. This mixture was added through a glass tube to the bottom of a stirred, refluxing mixture of 32.0 g (0.13 mole) of copper (II) sulfate pentahydrate, 80 mL of water and 30 mL of xylene. After complete addition the mixture was refluxed for one hour. The mixture was cooled, and the organic phase was separated from the aqueous phase. The organic phase was extracted with an aqueous, sodium hydroxide solution (6.0 g of sodium hydroxide pellets dissolved in 250 mL of water). The basic extract was neutralized with concentrated hydrochloric acid, causing a precipitate to form. The solid was collected by filtration to yield 2.3 g of 1-[4-chloro-2-fluoro-5-(4-hydroxyphenoxy)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5-(1H)-one, m.p. 162°-162° C., Compound 2 of Table 1.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH:25]=O)[C:22]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[N:21]2)=[CH:17][CH:16]=1.[C:34]([O:42][CH2:43][CH3:44])(=[O:41])[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].N1CCCCC1.C(O)(=O)C1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:34]([O:42][CH2:43][CH3:44])=[O:41])[C:22]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[N:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)c(-c3cccs3)n2)cc1
Agent: Cl
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1cccs1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A mixture of 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (5.02 g), diethyl malonate (2.12 g), piperidine (0.35 ml), benzoic acid (0.27 g), and toluene (50 ml) was subjected to azeotropic dehydration for 1 hour. The reaction mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel-chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). Sodium borohydride (170 mg) was added to a mixture of the obtained colorless oily substance, ethanol (20 ml), and tetrahydrofuran (20 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel chromatography to obtain diethyl [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]methylmalonate (6.08 g, yield: 92%) as a pale yellow oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [H-].[Na+].[I-].[K+].[CH3:5][C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].Cl[CH2:12][C:13]1[CH:24]=[CH:23][C:16]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>CN(C)C=O.O1CCCC1>[CH3:5][C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[CH:23][CH:24]=1
Reactant: CON(C)C(=O)c1ccc(CCl)cc1
Reactant: CC(C)(C)CO
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(COCC(C)(C)C)cc1
Temperature: 25 °C
Yield: 24.5 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 286 mg) in N,N-dimethylformamide (23.4 mL), a solution of potassium iodide (70.2 mg) and 2,2-dimethyl-1-propanol (618 mg) in N,N-dimethylformamide (5.00 mL) were added. After stirring the mixture at room temperature for an hour, a solution in tetrahydrofuran (5.00 mL) of the compound (1.00 g) obtained in step (1) above was added. After stirring the mixture at room temperature for 3 hours, a saturated aqueous solution of ammonium chloride was added. Two extractions were conducted with a liquid mixture of n-hexane/ethyl acetate (1:1) and the combined organic layers were washed with saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-65:35) to give 4-[(2,2-dimethylpropoxy)methyl]-N-methoxy-N-methylbenzamide as a colorless oil (304 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[Cl:32][CH2:33][C:34](=N)OCC.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>ClCCCl>[Cl:32][CH2:33][C:34]1[N:12]([C@H:13]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNS(C)(=O)=O)Nc1c(N)cnc2ccccc12
Reactant: CCOC(=N)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNS(C)(=O)=O)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 65 °C
Yield: 99.9 %

Procedure:
tert-Butyl (4S)-4-[(3-aminoquinolin-4-yl)amino]-5-[(methylsulfonyl)amino]pentylcarbamate (7.13 g, 16.3 mmol) was dissolved in 100 mL of anhydrous 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (7.73 g, 48.9 mmol) was then added and the reaction mixture was heated to 65° C. After stirring overnight, the reaction mixture was cooled and treated with 100 mL of saturated NaHCO3 solution and 200 mL of CHCl3. The layers were separated and the organic portion was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (4S)-4-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-5-[(methylsulfonyl)amino]pentylcarbamate (8.08 g) as an orange foam. The crude material was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH2:7][CH2:6]2.[CH3:15][CH2:16][OH:17].[CH2:18]([C@@H:22]1[CH2:39][N:26]2[CH2:27][CH2:28][C:29]3[C:34]([C@H:25]2[CH2:24][C:23]1=[O:40])=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[CH:19]([CH3:21])[CH3:20]>O>[CH3:21][CH:19]([CH2:18][C@H:22]1[C:23](=[O:40])[CH2:24][C@H:25]2[N:26]([CH2:27][CH2:28][C:29]3[C:34]2=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[CH2:39]1)[CH3:20].[CH3:20][CH:19]([CH2:18][C@@H:22]1[C:16](=[O:17])[CH2:15][C@@H:9]2[N:8]([CH2:7][CH2:6][C:5]3[C:10]2=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:23]1)[CH3:21]
Reactant: CCO
Reactant: COc1cc2c(cc1OC)CCN=C2
Agent: COc1cc2c(cc1OC)[C@H]1CC(=O)[C@H](CC(C)C)CN1CC2
Solvent: O
Product: COc1cc2c(cc1OC)[C@@H]1CC(=O)[C@@H](CC(C)C)CN1CC2
Temperature: 80 °C

Procedure:
To a round bottom flask was added 6,7-dimethoxy-3,4-dihydroisoquinoline (13 g, 67.8 mmol), 3-dimethylaminomethyl-5-methyl-hexan-2-one methiodide 1b (26 g, 81.4 mmol) and EtOH (130 mL). The suspension was heated to 80° C. overnight. The reaction mixture was allowed to cool to room temperature and H2O (200 mL) was added forming a precipitate. The EtOH was removed in vacuo and CH2Cl2 (400 mL) was added. A 10% NaOH solution was added to the mixture until basic. The aqueous layer was then extracted 3× with CH2Cl2 (250 mL). The organic layers were combined, dried over MgSO4 and concentrated. The crude reaction mixture was purified via flash column chromatography (0.5:9.5 Acetone:CH2Cl2) and further recrystallized from EtOAc and Hexanes to give 16.1 g (51 mmol) of a racemic mix of (3S,11bS) and (3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one 1c (tetrabenazine, TBZ) in a 75% yield. The enantiomers of tetrabenazine were separated by SFC utilizing a Chiralpak AD-H column with 15% CAN/MeOH plus 0.5% DMEA at 2.5 mL/min at 100 bar and 35° C. to yield 4.3 g of (3R,11bR)-tetrabenazine 1c.1 and 4.3 g of (3S,11bS)-tetrabenazine 1c.2. (3R,11bR)-tetrabenazine 1c.1: MS calcd: (317); Found 318.7 (M+H). (3S,11bS)-tetrabenazine 1c.2: MS calcd: (317); Found 318.7 (M+H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH2:11][NH:12][C@H:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15].C1(C)C=CC=CC=1.[BH4-].[Na+]>CO>[CH2:1]([NH:9][CH2:10][CH2:11][NH:12][C@H:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](NCCN)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)[C@@H](NCCNCc1ccccc1)C(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A solution of benzaldehyde (23 g, 217 mmol) and the product of Example 111-3 (50 g, 217 mmol, 1 equivalent) in 50:50 mixture of toluene and methanol (total volume=1400 mL), stirred at 50° C. overnight, cooled to −3° C., treated with NaBH4 (16.6 g, 434 mmol, 2equivalents) slowly over 5 hours, and stirred at room temperature for 16 hours. The reaction mixture was quenched with a saturated NaHCO3 solution (1400 mL) and extracted with ethyl acetate (1.3 L). The layers were separated and the aqueous layer was extracted with ethyl acetate (850 mL). The organic layers were combined, washed with brine (900 mL), and concentrated. The residue was dissolved in heptanes (700 mL), decanted inorganic salt, distilled to oil and chased to yield 69.4 g of crude material. 1H NMR (CDCl3): δ 7.05-7.3(m, 7H), 3.75(d, 2H), 2.4-2.8(m, 5H), 1.4(s, 9H), 0.87(s, 9H).
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[N+:30]([C:33]1[CH:55]=[CH:54][C:36]([CH2:37][O:38][C:39]([NH:41][CH2:42][CH2:43][CH2:44][S:45][C:46]2[N:47]=[CH:48][N:49]3[CH:53]=[CH:52][S:51][C:50]=23)=[O:40])=[CH:35][CH:34]=1)([O-:32])=[O:31].[Cl-].[NH4+]>C1COCC1>[N+:30]([C:33]1[CH:34]=[CH:35][C:36]([CH2:37][O:38][C:39]([NH:41][CH2:42][CH2:43][CH2:44][S:45][C:46]2[N:47]=[CH:48][N:49]3[CH:53]=[C:52]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])[S:51][C:50]=23)=[O:40])=[CH:54][CH:55]=1)([O-:32])=[O:31]
Reactant: O=C(NCCCSc1ncn2ccsc12)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Reaction time: 1 h

Procedure:
Tri-n-butylstannyl chloride (1.21 ml) and 9.47 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were added to a solution of 1.11 g of 7-[3-(4-nitrobenzyloxycarbonyl)aminopropyl]thioimidazo[5,1-b]thiazole in 28 ml of THF at −45° C. under an argon atmosphere, and the mixture was stirred for one hr. An aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing with brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to prepare 1.24 g of the title compound.
Reaction SMILES: [CH:1]1([CH:4]=[C:5]2[C:14](=O)[C:13]3[C:8](=[CH:9][C:10]([C:16]([O:18]C)=[O:17])=[CH:11][CH:12]=3)[O:7][CH2:6]2)[CH2:3][CH2:2]1.Cl.[Cl:21][C:22]1[CH:29]=[C:28]([NH:30][NH2:31])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>>[Cl:21][C:22]1[CH:29]=[C:28]([N:30]2[CH:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]3[CH2:6][O:7][C:8]4[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[CH:11]=[CH:12][C:13]=4[C:14]3=[N:31]2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: N#Cc1ccc(NN)cc1Cl
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC1CC1)C2=O
Agent: Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2CC2)cc1Cl

Procedure:
The title compound was prepared from methyl 3-(cyclopropylmethylene)-4-oxochroman-7-carboxylate; Preparation 33 and 2-chloro-4-hydrazinylbenzonitrile hydrochloride; Preparation 1 according to Method B and Method C. The crude product was purified by reverse-phase HPLC (65 to 85% acetonitrile/water/0.05% trifluoroacetic acid) to give 2-(3-chloro-4-cyanophenyl)-3-cyclopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid (yellow solid, 14 mg). The title compound was largely present as (±)-(3RS,3aSR)-2-(3-chloro-4-cyanophenyl)-3-cyclopropyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br. s., 1H), 7.97 (d, J=8.2 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.59 (dd, J=8.2, 1.6 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.23 (dd, J=8.6, 1.6 Hz, 1H), 4.84 (dd, J=10.5, 5.9 Hz, 1H), 4.46 (dd, J=12.9, 10.5 Hz, 1H), 4.39 (t, J=10.0 Hz, 1H), 3.93 (ddd, J=13.1, 10.2, 5.7 Hz, 1H), 0.74-0.85 (m, 1H), 0.63-0.71 (m, 1H), 0.52-0.61 (m, 1H), 0.37-0.45 (m, 1H), 0.18-0.26 (m, 1H).
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=1)=O.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C.O>[I:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:6]([NH2:5])[CH3:15])=[CH:13][CH:12]=1
Reactant: C[C@H](Cc1ccc(I)cc1)NC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](N)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2,2-trifluoro-N-[(1R)-2-(4-iodophenyl)-1-methylethyl]acetamide in dioxane (10 ml) was added 1N sodium hydroxide (12 ml) and the mixture was stirred for 1 hour at room temperature. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated to give [(1R)-2-(4-iodophenyl)-1-methylethyl]amine (2.34 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][CH2:17][CH2:16][CH:15]=[C:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1cccc(C23CCCC=C2C(=O)NC(=O)C3)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cccc([C@@]23CCCC[C@H]2C(=O)NC(=O)C3)c1

Procedure:
A solution of 4a-(m-methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (6.0 g) in 250 ml of glacial acetic acid was treated with 1 g of 5% palladium on carbon and the mixture hydrogenated under 40 psi of hydrogen for 24 hours in a Parr shaker. The catalyst was then filtered off and the filtrate evaporated. The residual 4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline was recrystallized from ethanol, m.p. 189-190.
Reaction SMILES: NC1C(C(NC2C=NC=CC=2N2CC[C@@H](O[Si](C(C)(C)C)(C)C)[C@H](NC(=O)OC(C)(C)C)C2)=O)=NC(Br)=CC=1.FC1C=CC=C(F)C=1B(O)O.[NH2:51][C:52]1[C:53]([C:66]([NH:68][C:69]2[CH:70]=[N:71][CH:72]=[CH:73][C:74]=2[N:75]2[CH2:80][CH2:79][C@@H:78]([O:81][Si](C(C)(C)C)(C)C)[C@H:77]([NH:89]C(=O)OC(C)(C)C)[CH2:76]2)=[O:67])=[N:54][C:55]([C:58]2[C:63]([F:64])=[CH:62][CH:61]=[CH:60][C:59]=2[F:65])=[CH:56][CH:57]=1.Cl>CO.C1COCC1>[NH2:51][C:52]1[C:53]([C:66]([NH:68][C:69]2[CH:70]=[N:71][CH:72]=[CH:73][C:74]=2[N:75]2[CH2:80][CH2:79][C@@H:78]([OH:81])[C@H:77]([NH2:89])[CH2:76]2)=[O:67])=[N:54][C:55]([C:58]2[C:63]([F:64])=[CH:62][CH:61]=[CH:60][C:59]=2[F:65])=[CH:56][CH:57]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2NC(=O)c2nc(-c3c(F)cccc3F)ccc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2NC(=O)c2nc(Br)ccc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: OB(O)c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(-c2c(F)cccc2F)nc1C(=O)Nc1cnccc1N1CC[C@@H](O)[C@H](N)C1
Reaction time: 2 h

Procedure:
3-amino-6-(2,6-difluorophenyl)picolinic acid and tert-butyl (3R,4R)-1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate were coupled following method 11 (example 249), to yield tert-butyl (3R,4R)-1-(3-(3-amino-6-(2,6-difluorophenyl)picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate after HPLC purification. Alternatively, tert-butyl (3R,4R)-1-(3-(3-amino-6-(2,6-difluorophenyl)picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)-piperidin-3-ylcarbamate could be obtained starting with tert-butyl (3R,4R)-1-(3-(3-amino-6-bromo-picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-yl-carbamate and 2,6 difluorophenylboronic acid following the Suzuki procedure outlined in method 14. The TBDMS deprotection of tert-butyl (3R,4R)-1-(3-(3-amino-6-(2,6-difluorophenyl)picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-yl-carbamate was performed with 6N HCl, THF, methanol (1:2:1) at room temperature for 2 h. After volatile materials were removed, the crude material was stirred in 30% TFA in dichloromethane for 2 hours. After volatile materials were removed in vacuo, purification and lyophilization yielded 3-amino-N-(4-((3R,4R)-3-amino-4-hydroxy-piperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)picolinamide. HPLC. LCMS (m/z): 441.2 (MH+); LC Rt=2.03 min.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:21](OC)([O:24]C)[O:22]C>O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:21]([OH:24])[OH:22])=[CH:3][CH:4]=1)#[N:7]
Reactant: COB(OC)OC
Reactant: N#Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(B(O)O)cc1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
4-Bromobenzonitrile (20 g, 0.1099 m) was dissolved in tetrahydrofuran (240 mls) and hexane (80 mls) and the mixture treated with butyl-lithium (1.6M solution in hexane 80 mls, 0.1204m) at -100° C. The mixture was then stirred for five minutes before adding trimethyl borate (25 mls, 0.2178 m) at -100° C. The mixture was then allowed to warm to 20° C. before adding it to 100 mls of 10% HCL. The organic layer was then separated and the aqueous layer extracted twice with dichloromethane (100 mls). The organic layers were then combined and washed till acid free with water. The solution was then dried using magnesium sulphate and evaporated to give 4-cyanophenyl boronic acid as an off-white solid 93% yield) which was dried under vacuum.
Reaction SMILES: Br.[CH:2]1([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]3[CH:16]=2)[CH2:4][CH2:3]1.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>>[CH:2]1([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][C:10]([NH:13][C:31]([C:28]4[CH:27]=[CH:26][C:25]([C:22]5[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:34])[F:35])=[CH:20][CH:21]=5)=[CH:30][CH:29]=4)=[O:32])=[CH:9][N:8]3[CH:16]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc2nc(C3CC3)cn2c1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Br
Product: O=C(Nc1ccc2nc(C3CC3)cn2c1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-6-nitroimidazo[1,2-a]pyridine hydrobromide and 4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid, to provide N-(2-cyclopropylimidazo[1,2-a]pyridin-6-yl)-4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxamide as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:28][C:11]3=[N:12][C:13]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])=[C:14]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH:15]=[C:10]3[C:9]=2[C:29](=[O:32])[NH:30][CH3:31])=[CH:4][CH:3]=1.C[N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[NH4+]>CN(C=O)C>[NH2:34][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:14]1[CH:15]=[C:10]2[C:9]([C:29]([NH:30][CH3:31])=[O:32])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[O:28][C:11]2=[N:12][C:13]=1[N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(CCCC(=O)O)cc12
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(CCCC(N)=O)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido) furo[2,3-b]pyridin-5-yl)butanoic acid (2.0 mg) in DMF (0.25 ml) is added HATU (3.3 mg). Stirred at rt for 10 min. Ammonium hydroxide (28% in water, 0.018 ml) is added and the mixture is stirred at rt for 30 min and purified by preparative HPLC to afford the title compound (M+H)+=463.1; Retention time=1.10 min, Method A. 1H NMR (400 MHz, DMSO) δ ppm 8.54 (br s, 1H), 8.09 (m, 1H), 8.06-7.97 (m, 2H), 7.53-7.47 (m, 2H), 7.27 (br s, 1H), 6.76 (br s, 1H), 3.21 (s, 3H), 3.19 (s, 3H), 2.86 (s, 3H), 2.84-2.77 (m, 2H), 2.13-2.08 (m, 2H), 1.91-1.81 (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)n1

Procedure:
The tide compound was prepared from ethyl 2-amino-4-thiazolylacetate and 3,4-dichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (50.1 mg) with purity >90%. LCMS (pos) m/z 395.0, 397.0.