Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:34])[CH2:32][C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:31])[C:26]([O:28]CC)=[O:27])[CH:21]=[CH:22][CH:23]=3)=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:11][C:7]=2[C:6](=[O:33])[CH2:5]1>C1COCC1.O>[CH3:3][C:4]1([CH3:34])[CH2:32][C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:31])[C:26]([OH:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:11][C:7]=2[C:6](=[O:33])[CH2:5]1
Reactant: CCOC(=O)C(=O)Nc1cccc(-c2c(N3CCOCC3)sc3c2CC(C)(C)CC3=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3cccc(NC(=O)C(=O)O)c3)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
Sodium hydroxide (53 mg, 1.32 mmol) was added to a mixture of Example 256 (300 mg, 0.66 mmol) in THF (10 mL) and water (10 mL) and the reaction mixture was stirred at room temperature for 3 h. The THF was removed in vacuo and the aqueous phase was diluted with water (10 mL), washed with EtOAc (20 mL) and acidified to pH 2 with 2M aqueous HCl. The aqueous phase was extracted with EtOAc (50 mL) and the organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo to give the title compound (204 mg, 72%) as a yellow solid. δH (CDCl3) 9.04 (1H, br s), 7.77-7.74 (1H, m), 7.59-7.47 (2H, m), 7.28-7.25 (1H, m), 3.72-3.66 (4H, m), 3.04-2.98 (4H, m), 2.51 (2H, s), 2.47 (2H, s), 1.06 (6H, s). LCMS (ES+) 429.0 (M+H)+.
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:16][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]([CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:26][CH2:25]2)[CH2:13]1)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][CH:12]1[CH2:16][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]([CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][CH2:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:28][CH2:29]2)[CH2:13]1
Reactant: O=C(NC1CC(CN2CCC(CCCc3ccccc3)CC2)C(c2ccccc2)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1CC(CN2CCC(CCCc3ccccc3)CC2)C(c2ccccc2)C1
Reaction time: 2 h

Procedure:
To a solution of 1-(SR)-(benzyloxycarbonylamino)-3-(SR)-((4-(3-phenylprop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane (from Step G, derived from the Higher Rf isomer from Step E) (500 mg, 1.0 mmol) in methanol (10 mL) was added 10% Pd/C (100 mg). The mixture was hydrogenated on a Parr shaker at 40 psi for 2 h and was then filtered and concentrated to afford the crude title compound (350 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]3[CH2:19][CH2:18][CH2:17][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:29]#[CH:30])[CH:26]=[CH:27][CH:28]=1>C(NCC)C.CN(C)C=O.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.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]3[CH2:19][CH2:18][CH2:17][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:30]#[C:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(I)c2[C@@H]2CCCN12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1cccc(C#Cc2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)c1

Procedure:
2.0 g (5 mmol) (S)-8-chloro-11,12,13,13a-tetrahydro-1-iodo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one was heated to boiling under reflux for 9 hours with 0.73 g (5.6 mmol) of 3-methoxyphenylacetylene, 65 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 65 mg of copper(I) iodide in 20 ml of diethylamine and 20 ml of N,N-dimethylformamide. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with methylene chloride/methanol (99:1). By crystallization from methylene chloride and ethyl acetate there was obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-[(m-methoxyphenyl)ethynyl]-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 204°-205°.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)([O-:5])=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23]>C(C#N)(C)=O.CC(=O)OCC.O>[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[CH:10]=1)([O-:5])=[O:4]
Reactant: CC(=O)CCCCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: CC(=O)C#N
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)CCCCn1cc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 4-nitro-1H-pyrazole (8.29 g, 64.99 mmol) and Cs2CO3 (31.87 g, 71.49 mmol) in AcCN (75.0 mL) was treated with a solution of 6-bromo-hexan-2-one (12.80 g, 71.49 mmol) in AcCN (58.0 mL). The reaction mixture was stirred at 80° C. for 2 h. Water (270 mL) and EA (400 mL) were added to the cooled reaction mixture. The aq. layer was extracted with EA (400 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound. TLC: rf (50:50 hept-EA)=0.29. LC-MS-conditions 02: tR=0.82 min; [M+H]+=212.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]([CH2:17][CH3:18])([CH3:16])[CH2:14][CH3:15])=S)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][C:13]([CH2:17][CH3:18])([CH3:16])[CH2:14][CH3:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCC(C)(CC)NC(=S)Nc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C)(CC)N=C=Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 4.5 g of N-(3,5-dichlorophenyl)-N'-(1-ethyl-1-methylpropyl)thiourea produced in Example A-5 and 5.8 g of triphenylphosphine in 60 ml of dichloromethane were added 2.2 g of triethylamine and 3.4 g of carbon tetrachloride. The mixture was refluxed for 4 hours, cooled to room temperature and evaporated in vacuo. The residue was stirred with n-hexane and the resulting solid matter was removed by filtration. The filtrate was evaporated to give N-(3,5-dichlorophenyl)-N'-(1-ethyl-1-methylpropyl)carbodiimide as an oil. To a solution of this oil in 20 ml of DMF were added 3.4 g of cyanamide and 0.1 ml of diisopropylethylamine. The mixture was stirred at 100° C. for 40 minutes, cooled to room temperature and poured into water. The resulting crystals were filtered off and recrystallized from benzene to give 3.5 g of the title compound as colorless flakes melting at 148.0°-150.0° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:19][CH2:18][CH2:17][C:11]3([C:15](=[O:16])[NH:14][CH2:13][CH2:12]3)[CH2:10]2)=[N:7][CH:8]=1.O1CCOCC1.CN[C@H]1[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]1[NH:36][CH3:37].BrC1C=CN=CC=1C.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[CH3:35][C:34]1[CH:37]=[N:36][CH:31]=[CH:32][C:33]=1[N:14]1[CH2:13][CH2:12][C:11]2([CH2:17][CH2:18][CH2:19][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][N:7]=3)[CH2:10]2)[C:15]1=[O:16]
Reactant: CN[C@H]1CCCC[C@@H]1NC
Reactant: O=C1NCCC12CCCN(c1ccc(C(F)(F)F)cn1)C2
Agent: [Cu]I
Agent: Cc1cnccc1Br
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cnccc1N1CCC2(CCCN(c3ccc(C(F)(F)F)cn3)C2)C1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one (24.4 mg, 0.0000814 mol) in 1,4-dioxane (0.5 mL, 0.006 mol) were added (1S,2S)-N,N′-dimethylcyclohexane-1,2-diamine (2.3 mg, 0.000016 mol), copper(I) iodide (1.6 mg, 0.0000081 mol), 4-bromo-3-methylpyridine (28 mg, 0.00016 mol) and potassium carbonate (23.6 mg, 0.000171 mol); and the mixture was stirred at 100° C. overnight. The product was purified by prep-HPLC. LC-MS: 391.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][C@H:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:10](=[O:20])[N:11]([CH2:13][C:14]3[S:15][C:16](Cl)=[CH:17][CH:18]=3)[N:12]=2)=[CH:4][CH:3]=1.[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][C@H:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:10](=[O:20])[N:11]([CH2:13][C:14]3[S:15][C:16]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([F:28])[C:34]=4[F:35])=[CH:17][CH:18]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1n(Cc2ccc(Cl)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: OB(O)c1cccc(F)c1F
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1n(Cc2ccc(-c3cccc(F)c3F)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 110 °C

Procedure:
Under an atmosphere of argon, 84 mg (0.19 mmol) of the compound from Example 30A and 45 mg (0.29 mmol) of 2,3-difluorophenylboronic acid were dissolved in 2 ml of toluene. 9 mg (0.01 mmol) of tris(dibenzylideneacetone)dipalladium, 8 mg (0.02 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl and 81 mg (0.38 mmol) of potassium phosphate were then added, and under argon the mixture was heated at 110° C. for 14 h. For work-up, the mixture was diluted at RT with 10 ml of ethyl acetate and 10 ml of water, the organic phase was separated off and the aqueous phase was extracted two more times with in each case 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 25 mg (24% of theory) of the target compound.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:7]=1)([CH3:5])[CH3:4].[NH2:27][CH2:28][C:29]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:30]=1[O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH2:41][CH2:42][OH:43])[N:36]=[CH:35]2>CC(N(C)C)=O>[F:48][C:46]1[CH:45]=[CH:44][C:30]([O:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[N:37]([CH2:41][CH2:42][OH:43])[N:36]=[CH:35]3)=[C:29]([CH2:28][NH:27][C:12]([NH:11][C:9]2[N:8]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[N:7]=[C:6]([C:3]([CH3:5])([CH3:4])[CH2:2][OH:1])[CH:10]=2)=[O:19])[CH:47]=1
Reactant: NCc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Reactant: Cc1ccc(-n2nc(C(C)(C)CO)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-n2nc(C(C)(C)CO)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCO)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
2,2,2-Trichloroethyl 3-(1-hydroxy-2-methylpropan-2-yl)-1-p-tolyl-1H-pyrazol-5-ylcarbamate (0.010 g, 0.024 mmol) was added to a minimal amount of DMA, 2-(5-(2-(Aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethanol (prepared in steps E1-E6; 0.0079 g, 0.026 mmol) and DEA (0.0084 mmol, 0.048 mmol) were added, and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated to remove the majority of DMA. The residue was purified by silica gel chromatography using 5% MeOH in ethyl acetate to provide 7 mg of the title compound. MS M+1 (573).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH2:13][CH2:14][CH:15]1[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.C(N(C(C)C)C(C)C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9](=[O:11])(=[O:10])[NH2:12])[CH:5]=[CH:6][C:7]=1[NH:13][CH2:14][CH:15]1[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCOC(CNc2ccc(S(N)(=O)=O)cc2Cl)C1

Procedure:
A solution of 3-chloro-4-fluorobenzenesulfonamide (1.0 g), tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (1.135 g) and N-ethyl-N-isopropylpropan-2-amine (1.246 mL) in dimethylsulfoxide (15 mL) was stirred at 115° C. for 72 hours. The mixture was concentrated, and the residue was purified on a silica gel column eluting with 60% ethyl acetate to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([CH2:10][NH:11][C@@H:12]([CH3:31])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23]CC4C=CC=CC=4)[CH:21]=3)[NH:16][CH:15]=2)[OH:9])=[CH:4][CH:3]=1.C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([CH2:10][NH:11][C@@H:12]([CH3:31])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=3)[NH:16][CH:15]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](Cc1c[nH]c2ccc(OCc3ccccc3)cc12)NC[C@H](O)c1ccc(N)nc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: C[C@@H](Cc1c[nH]c2ccc(O)cc12)NC[C@H](O)c1ccc(N)nc1
Yield: 46.2 %

Procedure:
A solution of (R)-6-Amino-α-[[(1(S)-methyl-2-(5-benzyloxy-1H-indol-3-yl)ethyl)amino]methyl]-3-pyridinemethanol (619 mg) in 47 ml of absolute ethanol containing 7.9 g of cyclohexene and 198 mg of 10% Pd/C was heated at reflux under nitrogen for 3 hours. The reaction mixture was filtered and concentrated to dryness (510 mg). This residue was purified twice by preparative TLC (85:15:0.5 CH2Cl2 :MeOH:NH4OH) to give 224 mg of (R)-6-Amino-α-[[(1(S)-methyl-2-(5-hydroxy-1H-indol-3-yl)ethyl)amino]methyl]-3-pyridinemethanol.
Reaction SMILES: C(O)(=O)C.[Si]([O:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(C(C)(C)C)(C)C.CCOC(C)=O.CCCCCC>O.C1COCC1>[OH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21]
Reactant: CN(CCCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CN(CCCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.1 %

Procedure:
482.5 ml (5 eq) acetic acid dissolved in 386 ml water were added dropwise over a period of 45 min to a solution of 95.6 g (1 eq) tert-butyl 3-(tert-butyldimethylsilyloxy)propyl(methyl)-carbamate dissolved in 386 ml THF at 0° C. and the reaction mixture was then stirred for 20 h at room temperature. As the starting product had not yet been completely converted, the mixture was cooled to 0° C., 50 ml dilute acetic acid were added over a period of 20 min and the mixture was stirred for a further 1 h at 0° C. The reaction course was monitored by thin-layer chromatography (10% EtOAc/hexane). Once the conversion was almost complete, the reaction mixture was concentrated under reduced pressure, adjusted to a pH of ˜9 with Na2CO3 solution and extracted with 10% IPA/CH3Cl. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, the residue was purified by column chromatography (silica gel; 10% EtOAc/hexane). 40 g (66%) of product were obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[CH2:15][C@H:14]([C@H:16]([O:18][C:19]3[C:20]4[N:21]([N:34]=[CH:35][CH:36]=4)[CH:22]=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH3:17])[CH2:13][C:12]2=[O:37])[CH3:10])=[CH:5][CH:4]=1.Br[C:39]1[N:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]2)=[CH:41][CH:40]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[C:12](=[O:37])[CH2:13][C@@H:14]([C@H:16]([O:18][C:19]3[C:20]4[N:21]([N:34]=[CH:35][CH:36]=4)[CH:22]=[C:23]([C:39]4[N:44]=[CH:43][C:42]([N:45]5[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]5)=[CH:41][CH:40]=4)[CH:24]=3)[CH3:17])[CH2:15]2)[CH3:10])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)nc2)CC1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(B4OC(C)(C)C(C)(C)O4)cn4nccc34)CC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)cn4nccc34)CC2=O)cc1
Temperature: 90 °C

Procedure:
(R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-((R)-1-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 6.19 (55.0 mg, 0.109 mmol), tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate 7.13 (65.2 mg, 0.190 mmol) and Cs2CO3 (106 mg, 0.326 mmol) were dissolved in 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL). The mixture was degassed for 5 minutes. PEPPSI-IPr catalyst (7.42 mg, 0.0109 mmol) was added and the mixture was heated for 1 h at 90° C. The reaction was cooled and diluted with EtOAc and water. The layers were separated and the organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (50 to 100% EtOAc in hexanes) to provide tert-butyl 4-(6-(4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)pyridin-3-yl)piperazine-1-carboxylate 6.20.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl>ClC1C=CC=CC=1>[ClH:9].[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([N:1]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:3]=[CH:4][CH:5]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1c(Cl)cccc1N1CCNCC1
Yield: 176.4 %

Procedure:
A mixture of 6-amino-2-chlorotoluene (158.66 g) and bis-(2-chloroethyl)amine hydrochloride (200.0 g) in chlorobenzene (800 mL) was allowed to reflux for 3 days. After cooling, the reaction mixture was filtered and then washed with ether to give the titled compound (244.3 g) as a white powder: 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.06 (m, 4H), 3.22 (m, 4H), 7.05 (dd, J=2.0, 6.8 Hz, 1H), 7.17-7.23 (m, 2H), and 9.40 (br s, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:12]([C:13]2[N:14]([CH2:38][CH3:39])[C:15]3[C:20]([S:21]([N:24]4[CH2:28][CH2:27][C@H:26]([NH:29]C(OC(C)(C)C)=O)[CH2:25]4)(=[O:23])=[O:22])=[CH:19][N:18]=[CH:17][C:16]=3[N:37]=2)=[N:11][O:10][N:9]=1)(C)(C)C.C(OC(=O)NC1C(C2N(CC)C3C(Br)=CN=CC=3N=2)=NON=1)(C)(C)C.[H-].[Na+].C([Li])CCC>O1CCCC1.N1C=CC=CC=1>[NH2:29][C@H:26]1[CH2:27][CH2:28][N:24]([S:21]([C:20]2[C:15]3[N:14]([CH2:38][CH3:39])[C:13]([C:12]4[C:8]([NH2:7])=[N:9][O:10][N:11]=4)=[N:37][C:16]=3[CH:17]=[N:18][CH:19]=2)(=[O:22])=[O:23])[CH2:25]1
Reactant: CCn1c(-c2nonc2NC(=O)OC(C)(C)C)nc2cncc(S(=O)(=O)N3CC[C@H](NC(=O)OC(C)(C)C)C3)c21
Agent: CCn1c(-c2nonc2NC(=O)OC(C)(C)C)nc2cncc(Br)c21
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCn1c(-c2nonc2N)nc2cncc(S(=O)(=O)N3CC[C@H](N)C3)c21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
{4-[7-((S)-3-tert-Butoxycarbonylamino-pyrrolidine-1-sulfonyl)-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-yl)-carbamic acid tert-butyl ester A solution of the product from Example 279 (0.150 g, 0.367 mmol) in tetrahydrofuran (2 ml) at ambient temperature was treated with NaH (60%) under Argon. After 10 minutes, the mixture was cooled to −78° C., and was treated with n-butyllithium. After 10 minutes, the mixture was treated with a SO2 solution (2 mL), formed from bubbling SO2 gas into THF (2 mL). After 10 minutes of stirring, the mixture was treated with SO2Cl2, and was allowed to warm to ambient temperature. The reaction mixture was then concentrtated, in-vacuo, to dryness. The solid was dissolved in dichloromethane (2.5 mL) and pyridine (2.5 mL) under Argon, and was treated with the amine (0.085 g, 0.46 mmol), and was stirred at ambient temperature overnight. The completed reaction was concentrated down to afford the title compound; MS (ES+) m/e 580 [M+H]+. Step 2. 4-[7-((S)-3-Amino-pyrrolidine-1-sulfonyl)-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl]-furazan-3-ylamine
Reaction SMILES: [O:1]=[C:2]1[CH2:25][O:24][C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([N:11]([CH2:13][CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[N:10]=[CH:9]3)=[C:4]2[NH:3]1.[H-].[Na+].IC.[CH3:30]N(C)C=O>O1CCCC1>[CH3:30][N:3]1[C:4]2[C:5](=[CH:6][CH:7]=[C:8]3[C:12]=2[N:11]([CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH3:15])[N:10]=[CH:9]3)[O:24][CH2:25][C:2]1=[O:1]
Reactant: CN(C)C=O
Reactant: CC(Cn1ncc2ccc3c(c21)NC(=O)CO3)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc3c(c21)N(C)C(=O)CO3)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a solution of the product from Example 2, Step F (0.22 g, 0.64 mmol) in anhydrous tetrahydrofuran (30 mL) was added sodium hydride (60% dispersion, 28 mg, 0.70 mmol) and this mixture was stirred under a nitrogen atmosphere for 10 min. Iodomethane (99 mg, 44 uL, 0.70 mmol) was added and the mixture was stirred for 1 h followed by the addition of anhydrous dimethylformamide (20 mL); this mixture was stirred for 4 h, poured into ice water, and the solution was extracted with ethyl acetate (3×50 mL). The combined extracts were evaporated to a residue that was purified by chromatography (gradient, 20% to 50% ethyl acetate in hexane to give an oil (0.14 g, 57%): LC/MS (+APCI) m/z 361 (M+H).
Reaction SMILES: [CH:1]12[CH2:11][CH:7]([C:8](=[O:10])[CH2:9]1)[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1.[CH3:12][Mg]Cl.O>O1CCCC1>[CH3:12][C:8]1([OH:10])[CH2:9][CH:1]2[CH2:11][CH:7]1[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1
Reactant: C[Mg]Cl
Reactant: O=C1CC2CC1C1CCCC21
Solvent: C1CCOC1
Solvent: O
Product: CC1(O)CC2CC1C1CCCC21

Procedure:
Tricyclo[5.2.1.02, 6]decan-8-one (15.0 g) in tetrahydrofuran (THF, 50 ml) is slowly added into CH3MgCl (9.7 g) in THF and the reaction mixture is stirred completely. Tetrahydrofuran (THF, 100 ml) with 5% of water is added into the reaction mixture. Then 100 ml of water is added to the reaction mixture. The reaction mixture is extracted by ether. The organic extract is concentrated in vacuo to yield 8-methyl-tricyclo[5.2.1.02,6]decan-8-ol (formula (X)) as white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Ca+2].[N:25]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37])=[N+]=[N-]>C1C=CC=CC=1>[NH2:25][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37]
Reactant: [N-]=[N+]=NCCc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: NCCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Triphenylphosphine (31.1 g, 0.118 mol) and calcium carbonate (50 mg, 0.5 mmol) were added to a solution of 2-(2-azidoethyl)nitrobenzene (22.8 g, 0.118 mol) in benzene (500 mL). The reaction was stirred at room temperature until complete. The solvent was removed in vacuo, and the residue treated with acetic acid (100 mL) and 48% hydrogen bromide (100 mL) at 100° C. for 1 h. The reaction was cooled and concentrated. Water was added and the solution extracted with methylene chloride. The aqueous layer was made basic by the addition of 5% aqueous sodium hydroxide solution, then extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over sodium sulfate. The title compound was obtained as an oil (8.0 g). MS 167 (M+1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH:6]1[CH:7]=[CH:8][C:9]2[O:16][C:14](=[O:15])[CH2:13][CH2:12][C:10]=2[CH:11]=1>>[CH2:1]([N:3]([CH2:4][CH3:5])[C:14](=[O:15])[CH2:13][CH2:12][C:10]1[CH:11]=[CH:6][CH:7]=[CH:8][C:9]=1[OH:16])[CH3:2]
Reactant: CCNCC
Reactant: O=C1CCc2ccccc2O1
Product: CCN(CC)C(=O)CCc1ccccc1O
Yield: 113.8 %

Procedure:
Diethylamine (98.5 g) and dihydrocoumarin (20.0 g) were refluxed for 4 hours. Excess diethylamine was removed in vacuo to leave 34.0 g of N,N-diethyl-3-(2-hydroxyphenyl) propionamide. 1H NMR (CDCl3): 7.26-7.03 (m, 2H), 6.91 (dd, 1H), 6.81 (td, 1H), 3.37 (quartet, 2H), 3.26 (quartet, 2H), 2.95 (m, 2H), 2.71 (m, 2H), 1.10 (quartet, 6H).