Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:18](OCC(C)C)=[O:19].[N+](=C)=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[OH-].[K+].C(OCCOCCO)C>O1CCCC1.C(OCC)C.O.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:18][OH:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1CCO
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (3.0 g in a mixture of 26 mL dry tetrahydrofuran and 26 mL dry diethyl ether) at -10° C. was added 1.91 mL of triethylamine followed by the dropwise addition of 1.78 mL isobutyl chloroformate. The reaction was stirred at -10° C. for 30 minutes then warmed to 0° C. Over the next hour, 26 mL of a solution of diazomethane in diethyl ether was added (prepared from: 8.0 g Diazald® in 70 mL diethyl ether; 4 g potassium hydroxide; 20 mL 2-(2-ethoxyethoxy)ethanol; 6 mL water and 12 mL diethyl ether using a mini Diazald Kit) and the mixture allowed to stir at room temperature for an additional 2 hours. At this time the reaction was quenched by the addition of 3 mL acetic acid at 0° C. This was then diluted with 100 mL water and 100 mL diethyl ether, the layers separated and the aqueous portion extracted with (2×75 mL) diethyl ether. The combined organics were washed with water (75 mL), saturated sodium bicarbonate (2×75 mL) and brine (75 mL) then dried over magnesium sulfate. Removal of the solvent in vacuo and purification of the residue by flash chromatography on silica gel (hexane:ethyl acetate, 8:2) gave the title compound (2.99 g).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[N:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=1O)=[O:5].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:27]=[N:26][CH:25]=[CH:24][C:3]=1[C:4]1[O:5][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:22])([C:18]([F:20])([F:19])[F:21])[C:14]([F:17])([F:16])[F:15])=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O)c1ccncc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: FC(F)(F)C(F)(c1ccc2oc(-c3ccncc3Cl)nc2c1)C(F)(F)F
Reaction time: 1.2 h
Yield: 67.4 %

Procedure:
To a mixture of 0.90 g of 3-chloro-N-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide, 10 ml of tetrahydrofuran and 0.68 g of triphenylphosphine, 1.13 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred for 1.2 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.58 g of 2-(3-chloropyridin-4-yl)-5-(heptafluoroisopropyl)benzoxazole (hereinafter, referred to as “active compound 68”).
Reaction SMILES: C(OC([N:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH:29]4[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]4)[CH2:25]3)=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[NH2:9])=O)(C)(C)C.[ClH:32]>CCOC(C)=O>[ClH:32].[ClH:32].[N:26]12[CH2:31][CH2:30][CH:29]([CH2:28][CH2:27]1)[CH:24]([O:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]([NH:8][NH2:9])=[CH:11][CH:12]=3)=[CH:22][CH:21]=1)[CH2:25]2
Reactant: CC(C)(C)OC(=O)N(N)c1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NNc1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1
Yield: 79.3 %

Procedure:
The product of Example 39A (80 mg, 0.19 mmol) was treated with HCl (Aldrich, 4 M in dioxane, 0.5 mL, 2.0 mmol) in EtOAc (5 mL) at room temperature for 10 h to give the title compound as yellow solid (60 mg, yield, 79%). 1H NMR (MeOH-d4, 300 MHz) δ 1.76–2.20 (m, 3H), 2.21–2.40 (m, 1H), 2.40–2.59 (m, 1H), 3.20–3.48 (m, 6H), 3.70–3.85 (m, 1H), 6.83–7.19 (m, 8H) ppm. MS (DCl/NH3) m/z 426(M+H)+. Anal. Calculated for C19H23N3O2.2.40HCl.0.20H2O.0.50EtOAc: C, 54.76; H, 6.52; N, 9.12. Found: C, 54.50; H, 6.13; N, 8.84.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2.[CH3:19][O:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O.C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]3)=[CH:26][CH:25]=1)=[O:22]
Reactant: COC(=O)Nc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(Br)cccc2C1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc(-c2cccc3c2CCN(C(=O)OC(C)(C)C)C3)cc1
Temperature: 100 °C
Yield: 30.6 %

Procedure:
tert-Butyl 5-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.20 g, 0.64 mmol), 4-(methoxycarbonylamino)phenylboronic acid (0.125 g, 0.641 mmol), potassium phosphate tribasic (0.476 g, 2.24 mmol) and tricyclohexylphosphine (0.018 g, 0.064 mmol) were placed in a pressure vial containing toluene (10 mL) and H2O (1.0 mL) which had been degassed with argon for 15 minutes. Pd(OAc)2 (7.19 mg, 0.032 mmol) was added, the vial was sealed, and heated at 100° C. for 12 h. After cooling to rt, the reaction mixture was diluted with EtOAc (50 mL), and filtered through a plug of celite. The filtrate was washed with H2O (50 mL). The aqueous phase was extracted with EtOAc (3×25 mL). Combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated. Purification by silica gel chromatography gave tert-butyl 5-(4-(methoxycarbonylamino)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate as a colorless oil (75 mg, 31%). This material was treated with 50% TFA/DCM for 48 h and then concentrated. The resulting oil was dissolved in EtOAc and neutralized with saturated NaHCO3. The organic layer was washed with H2O, brine, dried over Na2SO4, filtered, and concentrated. The residue was oxidized as in Example 8B and then carried onto an Ugi reaction with Intermediate 2 and Intermediate 6 in a similar manner as Example 8 followed by TFA deprotection. Purification by reverse phase HPLC and freeze-drying afforded Example 39 (8 mg, 1.75%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 12.70 (1H, br.s.), 10.81 (1H, s), 9.86 (1H, s), 9.76 (1H, s), 8.38 (1H, d, J=2.21 Hz), 7.88 (2H, d, J=8.83 Hz), 7.68-7.79 (4H, m), 7.63 (1H, d, J=7.57 Hz), 7.49-7.58 (3H, m), 7.33 (1H, t, J=7.72 Hz), 7.26-7.31 (2H, m), 7.22 (1H, d, J=7.57 Hz), 6.96 (1H, d, J=15.45 Hz), 5.88 (1H, s), 4.22-4.30 (1H, m), 3.72-3.80 (1H, m), 3.03-3.12 (1H, m), 2.86-2.94 (1H, m) ppm. MS (ESI) m/z: 678.0 (M+H)+. Analytical HPLC: RT=6.76 min.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22]CC4C=CC([N+]([O-])=O)=CC=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C(O)(=O)C.O.[H][H]>[C].[Pd].O1CCCC1.CO>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Yield: 79.7 %

Procedure:
A suspension of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (anti isomer, 4.2 g.), 10% palladium carbon (1.7 g.), acetic acid (0.63 ml.), water (6.3 ml), methanol (42 ml.), and tetrahydrofuran (84 ml.) was subjected to catalytic reduction in a hydrogen atmosphere at room temperature for 2 hours. After removing the catalyst by filtration, the filtrate was concentrated to a volume of about 15 ml. under reduced pressure. Water (30 ml.) and ethyl acetate (50 ml.) were added to the concentrated solution, and the solution was adjusted to pH 8.0 with sodium bicarbonate under stirring. The insoluble substance was removed by filtration, and the aqueous layer was separated and washed with ethyl acetate (50 ml.). The solution was treated with activated charcoal, and adjusted to pH 2.2 with 10% hydrochloric acid under ice cooling. The precipitates were collected by filtration and washed with water to give 7-[2-(2 -formamidothiazol-4-yl)-2-methoxyiminoactamido]-3-cephem-4-carboxylic acid (anti isomer, 2.52 g.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[CH:7]([O:10][Si](C)(C)C)[C:8]#[N:9])([O-:3])=[O:2].CC[O:23]C(C)=O>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[CH:7]([OH:10])[C:8]([NH2:9])=[O:23])([O-:3])=[O:2]
Reactant: CCOC(C)=O
Reactant: C[Si](C)(C)OC(C#N)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: O
Product: NC(=O)C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 115 °C
Reaction time: 0.17 h
Yield: 54 %

Procedure:
3,5-dinitro-O-trimethylsilylmandelonitrile (5.0 g, 16.9 mmol) and BF3-acetic acid complex (30 ml) were dissolved in H2O (5 ml) at room temperature. The reaction temperature was raised to 115° C. immediately and stirred for 10 minutes. The reaction solution was then cooled to 0° C. H2O (100 ml) and EtOAc (200 ml) were added. The organic phase was washed with sat NaHCO3 (100 ml) and brine (100 ml). Drying over MgSO4 was followed by removal of solvents at reduced pressure. The residue was crystallized from isopropylacetate. The crystalline residue was left for preparative HPLC, which gave 2.2 g (54%) of 3,5-dinitromandeloamide.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1([O:28][C:29](=O)[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:32]=2)C=CC=CC=1.O>CS(C)=O.C(OCC)(=O)C.CCCCCC>[CH3:40][S:37]([C:33]1[CH:32]=[C:31]([NH:30][C:29]([NH:1][C:2]2[CH:21]=[CH:20][C:5]([O:6][C:7]3[CH:8]=[C:9]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:10]=[CH:11][N:12]=3)=[CH:4][CH:3]=2)=[O:28])[CH:36]=[CH:35][CH:34]=1)(=[O:38])=[O:39]
Reactant: Nc1ccc(Oc2cc(Nc3ccccc3)ncn2)cc1
Reactant: CS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1cccc(NC(=O)Nc2ccc(Oc3cc(Nc4ccccc4)ncn3)cc2)c1
Yield: 81 %

Procedure:
N-(6-(4-Aminophenoxy)pyrimidin-4-yl)phenylamine (55.6 mg, 0.200 mmol) and (3-methylsulfonylphenyl)carbamic acid phenyl ester (63.8 mg, 0.220 mmol) were heated and stirred in dimethylsulfoxide (1 ml) at 85° C. for 2 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with 1N aqueous sodium hydroxide, water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (77.0 mg, 0.162 mmol, 81%) as colorless crystals.
Reaction SMILES: [N:1]([C@H:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[N+]=[N-].O.O.Cl[Sn]Cl>CO>[Br:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C@H:4]([NH2:1])[CH2:5][CH2:6]2
Reactant: [N-]=[N+]=N[C@@H]1CCc2cc(Br)ccc21
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: N[C@@H]1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A solution of (R)-1-azido-5-bromo-indane (154 g, 0.645 mol) was dissolved in methanol (2.4 L) and SnCl2.2H2O (265 g, 1.18 mol) was added. The mixture was stirred at room temperature overnight (TLC indicated no starting material) and was concentrated to dryness. The resulting residue was treated with 2N aqueous NaOH (2.5 L) and EtOAc (1.5 L). The mixture was stirred for 1 hour and filtered through Celite® with the aid of EtOAc (3×250 ml). The organic solution was separated and the aqueous layer was extracted with EtOAc (3×2 L). The combined organic extracts were washed with 1 N HCl (2×2 L) followed by water (2 L). The pH of the combined aqueous layers was adjusted to 11 with cold saturated NaOH solution and the mixture was extracted with EtOAc (3×2 L). The combined organic extracts were dried over MgSO4, filtered and concentrated to give (87.5 g, 64.0%) (R)-5-bromo-2,3-dihydro-1H-inden-1-amine as a dark yellow oil which solidified upon refrigeration. MS (ES+) 213.9 (M+H)+. 1H NMR (CDCl3) δ 1.70-1.75 (m, 1H), 2.40-2.45 (m, 1H), 2.77-2.82 (m, 1H), 2.93-2.97 (m, 1H), 4.28-4.33 (m, 1H), 7.18-7.23 (m, 1H), 7.36-7.41 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:3]=12.[CH3:16][C:17]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:18]=1[CH2:19][NH:20][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)CCC>[CH3:16][C:17]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:18]=1[CH2:19][N:20]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:3]=12
Reactant: Clc1ncnc2c1cnn2C1CCCO1
Reactant: Cc1ccc(C)c(CNC2CCCC2)c1
Solvent: CCCCO
Product: Cc1ccc(C)c(CN(c2ncnc3c2cnn3C2CCCO2)C2CCCC2)c1

Procedure:
A mixture of 7.8 g. (35 mmole) 4-chloro-1-(tetrahydrofuran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine, 20.3 g. (100 mmole) N-(2,5-dimethylbenzyl)-cyclopentylamine and 100 ml. n-butanol is heated under reflux for 16 hours. The reaction mixture is evaporated, the residue is taken up in water and extracted with dichloromethane and the extract is washed with dilute acetic acid and dilute aqueous sodium hydrogen carbonate solution, dried, evaporated and chromatographed on silica gel. 5.0 g. (37% of theory) of the title compound are eluted with dichloromethane/methanol (98:2 v/v) which, after trituration with diethyl ether, melts at 173°-174° C.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][C@H:14]([O:16]CC2C=CC=CC=2)[CH2:13][CH2:12][C@@H:11]1[C:24]1[N:28]([CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[N:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@@H]1CC[C@H](OCC2C=CC=CC=2)C[C@@H]1C1N(COCCOC)N=CC=1)(=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[C:1]([O:9][C@H:10]1[CH2:15][C@H:14]([OH:16])[CH2:13][CH2:12][C@@H:11]1[C:24]1[N:28]([CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[N:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCn1nccc1[C@H]1CC[C@@H](OCc2ccccc2)C[C@@H]1OC(=O)c1ccccc1
Agent: [Pd]
Agent: COCCOCn1nccc1[C@H]1C[C@@H](OCc2ccccc2)CC[C@H]1OC(=O)c1ccccc1
Solvent: CCO
Product: COCCOCn1nccc1[C@H]1CC[C@@H](O)C[C@@H]1OC(=O)c1ccccc1
Yield: 48.5 %

Procedure:
A solution of the mixture (2.72 g, 5.84 mmol) of (1S*,2R*,5R*)-5-(benzyloxy)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl benzoate and (1R*,2R*,4S*)-4-(benzyloxy)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl benzoate prepared in Example 155c and palladium carbon (5%; 3.00 g) in ethanol (20 mL) was stirred at 50° C. for 11 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified with silica gel chromatography (ethyl acetate) to yield the title compound (1.06 g, 48%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:10]1([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:2]1=[O:1])[CH3:32]
Reactant: O=C1C(Cc2ccncn2)c2ccccc2N1c1ccccc1
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCC1(Cc2ccncn2)C(=O)N(c2ccccc2)c2ccccc21
Yield: 55 %

Procedure:
By substituting 2,3-dihydro-2-oxo-1-phenyl-3-(4-pyrimidinylmethyl)-1H-indole and ethyl 4-bromobutyrate in Example 1, the desired product was obtained in 55% yield as an oil; NMR(CDCl3TMS) δ1.22 (t, 3H, J=7 Hz); 1.42 (m, 1H); 1.53 (m, 1H); 2.06 (m, 1H); 2.25 (m, 3H); 3.25 (d, 1H, J=14 Hz); 3.55 (d, 1H, J=14 Hz); 4.09 (q, 2H, J=7 Hz); 6.63 (d, 1H, J=8 Hz); 6.98 (m, 1H); 7.07 (m, 2H); 7.26 (m, 3H); 7.40 (m, 1H); 7.50 (m, 2H); 8.42 (d, 1H, J=5 Hz); 8.90 (s, 1H). IR(KBr): 1728, 1583, 1501, 1481, 1466, 1376, 1326, 1182, 1157, 758, 700 cm-1 ; mass spec m/e 416 (M+1); high resolution mass spec m/e calcd 416.197417, m/e found 416.196591 (M+H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]2[O:19][CH2:18]2)=[N:5][N:6]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:23][CH:20]2[CH2:22][CH2:21]2)=[N:5][N:6]=1
Reactant: NC1CC1
Reactant: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Solvent: Cc1ccccc1
Product: Cc1nnc(C=Cc2ccccc2OCC(O)CNC2CC2)s1

Procedure:
3.8 g (0.014 mole) of 2-methyl-5-[2-(2,3-epoxypropoxy)-styryl]-1,3,4-thiadiazole and 1.0 g (0.018 mole) of cyclopropylamine are reacted by the method described in Example 1. 2.2 g (48% of theory) of yellow crystals are obtained from toluene; melting point 144°-145° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[S:17][C:18]([CH:22]([N:30]5[CH2:34][CH2:33][C@H:32]([O:35][Si](C(C)(C)C)(C)C)[CH2:31]5)[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[Cl:29])=[C:19]([CH3:21])[N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[S:17][C:18]([CH:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[Cl:29])[N:30]5[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31]5)=[C:19]([CH3:21])[N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)sc1C(c1ccccc1Cl)N1CC[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)sc1C(c1ccccc1Cl)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(((S)-3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(2-chlorophenyl)methyl)-4-methylthiazol-2-yl)cyclopropanecarboxamide (Isomer A) (400 mg, 0.64 mmol) and TBAF (1M in THF, 3.84 mL, 3.84 mmol) was stirred at room temperature for 5 h. The reaction was partitioned between H2O and EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was adsorbed onto silica gel and purified by column chromatography (25-75% EtOAc/hexanes) to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((2-chlorophenyl)((S)-3-hydroxypyrrolidin-1-yl)methyl)-4-methylthiazol-2-yl)cyclopropanecarboxamide (Isomer A) as a pale yellow solid (245 mg, 75%, >99% de). 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.85 (dd, J=8.1, 1.7 Hz, 1H), 7.29-7.26 (m, 2H), 7.14 (m, 1H), 6.88-6.84 (m, 2H), 6.79 (d, J=7.9 Hz, 1H), 6.00 (s, 2H), 5.07 (s, 1H), 4.30 (m, 1H), 2.79 (td, J=8.6, 5.8 Hz, 1H), 2.63-2.56 (m, 2H), 2.36 (s, 3H), 2.29 (td, J=9.0, 5.9 Hz, 1H), 2.15 (m, 1H), 1.85 (d, J=7.9 Hz, 1H), 1.78-1.65 (m, 3H), 1.18 (m, 2H); HPLC ret. time 2.70 min, 10-99% CH3CN, 5 min run; ESI-MS 512.5 m/z (MH+).
Reaction SMILES: CC([N:5]([C:9]([CH3:32])([CH3:31])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[C:28]3[CH:27]([CH2:29][CH3:30])[O:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:29]([CH:27]1[C:28]2[C:20]([O:19][C:16]3[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C:9]([CH3:32])([CH3:31])[NH2:5])=[CH:18][CH:17]=3)=[CH:21][CH:22]=[CH:23][C:24]=2[CH2:25][O:26]1)[CH3:30]
Reactant: CCC1OCc2cccc(Oc3ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cn3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1OCc2cccc(Oc3ccc(NC(=O)C(C)(C)N)cn3)c21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl[2-({6-[(3-ethyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-3-pyridinyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 148, 36.5 mg, 0.066 mmol) was dissolved in Dichloromethane (3 mL) to give a colourless solution. The reaction mixture was cooled at 0° C. and TFA (1.5 mL, 19.47 mmol) was added at that temperature. The reaction mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was evaporated in vacuo affording and the residue was charged on a 2 g SCX cartridge. It was then flushed with 15 mL of MeOH followed by 15 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated in vacuo affording the title compound (17.2 mg) as colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][N:31]([C:36]([C:38]1[N:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=1)=[O:37])[CH2:32]2)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][N:31]([C:36]([C:38]1[N:39]=[N:40][C:41]([NH:44][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:42][CH:43]=1)=[O:37])[CH2:32]2)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nn1)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)nn3)nc2n1C1CCCC1
Yield: 58 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (98 mg, 0.336 mmol), was combined with 3-(6-amino-pyridazine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (112 mg, 0.336 mmol) which gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (115 mg, 0.195 mmol) in 58% yield. MS m/z 590.6 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([NH:16]C(=O)C(F)(F)F)[C:11]([C:23]#[N:24])=[C:10]([CH3:25])[C:9]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[NH2:16][C:12]1[C:13]([O:14][CH3:15])=[C:8]([Br:7])[C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:10]([CH3:25])[C:11]=1[C:23]#[N:24]
Reactant: COc1c(Br)c(-c2ccccc2)c(C)c(C#N)c1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1c(N)c(C#N)c(C)c(-c2ccccc2)c1Br
Temperature: 70 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Aqueous potassium carbonate solution (1.25 ml) [potassium carbonate (15 g) was dissolved in water (100 ml)] and methanol (1.25 ml) were added to N-(2-bromo-5-cyano-3-methoxy-6-methylbiphenyl-4-yl)2,2,2-trifluoroacetamide (I-38) (133 mg, 0.322 mmol), followed by stirring overnight at 70° C. After cooling, methanol was evaporated away under reduced pressure, followed by extraction with ethyl acetate, washing with saturated brine and drying on anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure to obtain a pale brown residue. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the entitled compound (95 mg, 94%) as a colorless solid.