Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[C:24]1[N:25]=[N:26][C:27]([NH:30][NH2:31])=[CH:28][CH:29]=1)[CH:21]=[CH:20][O:19]2.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[C:24]1[CH:29]=[CH:28][C:27]3[N:26]([C:4]([CH2:3][C:2]([CH3:7])([OH:1])[CH3:6])=[N:31][N:30]=3)[N:25]=1)[CH:21]=[CH:20][O:19]2
Reactant: CC(C)(O)CC=O
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3occn23)nn1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: Ic1ccccc1
Product: CC(C)(O)Cc1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To round bottom flask, 3-hydroxy-3-methylbutanal (0.178 g, 1.185 mmol) and 6-(2,4-difluorophenyl)-5-(6-hydrazinylpyridazin-3-yl)imidazo[2,1-b]oxazole (0.3 g, 0.859 mmol) and DCM 5 mL were added. The reaction mixture was stirred at about ambient temperature for about 1 h. Iodobenzene diacetate (0.38 g, 1.18 mmol) was added and was stirred at ambient temperature for overnight. The reaction mixture was quenched with water. The aqueous phase was extracted with DCM and the organic layer was concentrated under reduced pressure. The crude material was purified by silica gel chromatography using DCM/MeOH (90:10). After concentration of the fractions with product, the resulting solid was triturated with ether. The solid was collected by filtration then dried under vacuum at about 60° C. for about 2 days to give the title compound (0.118 g, 33.5%): LC/MS (Table 1, Method g) Rt=1.78 min; MS m/z: 411.2 (M+H)+. 1H NMR (DMSO-d6) δ 8.52 (d, 1H), 8.27 (d, 1H), 8.21 (d, 1H), 7.75 (m, 1H), 7.50-7.40 (m, 1H), 7.34-7.25 (m, 1H), 6.90 (m, 1H), 4.71 (s, 1H), 3.33 (s, 2H), 1.27 (s, 6H)
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.[CH3:11][O:12][C:13]1[C:21]2[CH:20]=[C:19]([C:22](OC)=O)[O:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C1COCC1>[CH3:11][O:12][C:13]1[C:21]2[CH:20]=[C:19]([C:22]3[O:5][N:4]=[C:2]([CH3:3])[CH:1]=3)[O:18][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)=NO
Reactant: COC(=O)c1cc2c(OC)cccc2o1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2oc(-c3cc(C)no3)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a solution (160 ml) of acetone oxime (5.0 g) in THF was added dropwise n-butyllithium (1.6 M hexane solution) over 15 min under ice-cooling and the mixture was stirred for 1 hr. Thereto was added dropwise a solution (60 ml) of methyl 4-methoxybenzo(b)furan-2-carboxylate (6.7 g) in THF and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into ice water, and conc. sulfuric acid (4 ml) was added carefully. The mixture was stirred for 20 min more. The aqueous layer was neutralized with sodium hydrogencarbonate and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give the title compound (3.0 g) as yellow crystals.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[OH-].[Na+]>O.C(O)C>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:9]2[CH2:10][CH2:11][CH2:12][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]2=[O:13])=[CH:17][CH:16]=1
Reactant: O=C1CCCCC1c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1C(=Cc2ccc(Cl)cc2)CCCC1c1ccccc1
Yield: 95.3 %

Procedure:
Fifty grams of 2-phenylcyclohexanone, 54.0 g of 4-chlorobenzaldehyde and a solution of 20 g of sodium hydroxide in 125 ml of water are reacted in 300 ml of ethanol according to the procedure described in part A of Example 1 to yield 81.2 g of material, melting point 103°-109° C. After crystallization from 100 ml of acetonitrile, the crystalline product weighs 61.6 g, melting point 118°-120° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[O:35]C)[CH:19]=[C:20]([NH:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:37])[CH2:3][CH2:2]1.C[S-].[Na+].CN(C)C=O.[Cl-].[NH4+]>O>[CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[OH:35])[CH:19]=[C:20]([NH:21][CH2:22][CH2:23][C:24]([F:27])([F:25])[F:26])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:37])[CH2:2][CH2:3]1
Reactant: COc1ccccc1Oc1cc(NCCC(F)(F)F)c2ncc(-c3ccc(C(=O)NC4CC4)c(C)c3)n2n1
Agent: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(Oc4ccccc4O)nn23)ccc1C(=O)NC1CC1
Temperature: 120 °C
Yield: 42.4 %

Procedure:
A mixture of 28.0 mg (53 μmol) N-cyclopropyl-4-{6-(2-methoxyphenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide which was prepared according to example 223, 44.8 mg sodium methanethiolate and 350 μL N,N-dimethylformamide was heated under microwave irradiation for 30 minutes at 120° C. The mixture was poured into water, the pH was adjusted between 7 and 8 by addition of ammonium chloride and extracted with a mixture of dichloromethane and methanol. The combined organic phases were dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 11.5 mg (40%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[Br:15][C:16]1[C:17](F)=[C:18]2[C:24]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[N:29][CH:28]=3)=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1>CCCCO>[Br:15][C:16]1[C:17]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[C:18]2[C:24]([NH:25][C:26](=[O:34])[C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[N:29][CH:28]=3)=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1
Reactant: Cc1cncc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: Cc1cncc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)c1
Temperature: 160 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (172 mg, 0.859 mmol) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylnicotinamide (100 mg, 0.286 mmol) in n-BuOH (3 mL), and the reaction was stirred at 160° C. for 24 hours in a sealed tube. The reaction was concentrated to dryness, and then the residue was purified by chromatography (SP4, 25M, water/ACN 90/10 to 10/90, 30 CV) to yield (R)-tert-butyl 1-(5-bromo-3-(5-methylnicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (47 mg, 31.0% yield) as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)[CH2:3][Cl:4].[Mg].[CH2:14]([Si:16]([CH2:20][CH3:21])([CH2:18][CH3:19])Cl)[CH3:15]>O1CCCC1>[CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Si:16]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:14][CH3:15])=[CH:8][CH:7]=1)[CH2:3][Cl:4]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC(CCl)Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1ccc(CC(C)CCl)cc1

Procedure:
A solution of 24.7 parts of 2-methyl-3-(4-bromophenyl)-propyl chloride in 20 parts of tetrahydrofuran (THF) were added dropwise to 2.4 parts of magnesium in 25 parts of THF. The reaction was maintained at from 50° to 52° C., and the mixture was then refluxed for a further 30 minutes. 16.5 parts of triethylchlorosilane were added dropwise at room temperature and the mixture was then refluxed again for 6 hours, cooled and filtered. The solution was concentrated and the residue was distilled to give, at a boiling point of 115°-120° C./0.01 mm Hg, 20.3 parts of 2-methyl-3-(4-triethylsilylphenyl)-propyl chloride of n24 1.5080.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([CH:17]([CH3:19])[CH3:18])[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([CH:17]([CH3:19])[CH3:18])[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([S:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2]
Reactant: CCOC(=O)[C@H](NS(=O)(=O)c1ccc(F)cc1)C(C)C
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](NS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(C)C
Temperature: 70 °C
Yield: 41.7 %

Procedure:
To a solution of 7.76 g (25.6 mmol) of N-[(4-fluorophenyl)sulfonyl]-D-valine ethyl ester from Example 7a in 50 mL of anhydrous dimethylformamide was added 7.8 mL (77 mmol) of thiophenol. After purging with nitrogen for 5 minutes, 10.6 g (77 mmol) of powdered potassium carbonate was added and the reaction heated to 70° C. for 21 hours. The solution was cooled, water and ethyl acetate added and separated. The ethyl acetate layer was washed with saturated sodium bicarbonate, three times with brine, dried with sodium sulfate, filtered and concentrated to afford crude product. This was chromatographed on silica gel using 20% ethyl acetate/hexane to yield 4.2 g of N-[[4-(phenylthio)phenyl]sulfonyl]-D-valine ethyl ester, m/e=400 (M+Li).
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:16][C:17]([NH:19][NH2:20])=[O:18])([CH3:15])([CH3:14])[CH3:13]>CS(C)=O>[CH3:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[NH2:20]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1cccc([N+](=O)[O-])c1F
Solvent: CS(C)=O
Product: Cc1cccc([N+](=O)[O-])c1N(N)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
To 250 mg of 2-fluoro-3-methyl-nitrobenzene in 5 mL of DMSO are added 1.065 g of commercial tert-butoxycarbonylhydrazine (5 equivalents). The whole is brought to 100° C. for 10 min under microwave heating. The medium is hydrolyzed and then extracted with ethyl acetate several times. The organic phases are collected, dried on magnesium sulfate, filtered and evaporated under reduced pressure leading to a residue which is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 80/20). 342 mg of product corresponding to the expected product are obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].Cl.Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([N:26]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]4[CH:34]=[N:35][N:36]([CH3:39])[C:37]=4[CH3:38])[CH2:28][CH2:27]3)=[N:22][CH:23]=[CH:24][N:25]=2)=[CH:16][CH:15]=1>CN(C=O)C>[CH3:39][N:36]1[C:37]([CH3:38])=[C:33]([CH2:32][N:29]2[CH2:28][CH2:27][N:26]([C:21]3[C:20]([C:17]4[CH:16]=[CH:15][C:14]([CH2:13][N:3]5[CH2:8][CH2:7][CH2:6][CH2:5][C:4]5=[O:9])=[CH:19][CH:18]=4)=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:31][CH2:30]2)[CH:34]=[N:35]1
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CCl)cc3)CC2)cnn1C
Reactant: O=C1CCCCN1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(CN4CCCCC4=O)cc3)CC2)cnn1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Add sodium hydride (0.175 g of 60% weight suspension in mineral oil; 2.62 mmol) to a solution of piperidin-2-one (0.270 g; 2.73 mmol) in DMF (5 mL). Cool the mixture to 5° C., stir for 30 min., remove the cooling bath, warm to room temperature and stir for 30 min. Add 3′-(4-chloromethyl-phenyl)-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride (0.253 g; 0.540 mmol) in 6 mL of DMF and stir for 20 hr. at room temperature. Quench with a solution of 10% aq. acetic acid (9 mL), add methanol (minimal volume to achieve a homogeneous solution) and add to a 5 gm SCX column (Varian; pre-rinsed with MeOH). Elute the crude product with 2 M ammonia in methanol (18 mL) and concentrate. Purify via chromatography on silica gel eluting 0-10% methanol/DCM to give 1-{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzyl}-piperidin-2-one (0.180 g; 73%). MS (ES+) m/z: 460 (M+H)+. Purify by high pH reverse phase HPLC, and concentrate to give the free base. Dissolve the free base in acetonitrile and convert to the hydrochloride salt by adding 1 eq. 2 M aq. HCl solution. Add water and lyophilize to give the title compound as a brown powder (164 mg, 66%). MS (ES): m/z=460 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:15]1COC[CH2:16]1.[C-]#[C-].[Na+].[Na+].Cl>C1(C)C(C)=CC=CC=1>[C:15]([C:12]1([OH:14])[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)#[CH:16]
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: C1CCOC1
Agent: Cl
Agent: [C-]#[C-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C#CC1(O)c2ccccc2-c2ccccc21
Reaction time: 8 h

Procedure:
9 g (0.05 mol) of 9-fluorenone and 100 ml of anhydrous THF are charged into a dry flask of 250 ml. To the resulting solution a suspension of sodium acetylide [17.8 g (0.0525 mol) in mineral oil/xylene, 18% by weight based on the suspension; solid purity 95%] is added under nitrogen, by means of a syringe. The resulting suspension is kept overnight under nitrogen and with stirring before being poured into 75 ml of 10% HCl. The phases are separated and the aqueous phase is extracted twice with 100 ml of ethyl ether. The organic extracts are combined and thoroughly dried over sodium sulfate. By eliminating the solvent, 10.1 g of product is obtained, which is used without any further purification.
Reaction SMILES: COC1C=C(C=CC=1OC)C[N:7]1[C:16]([CH3:18])([CH3:17])[CH:15]([C:19]([OH:21])=[O:20])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:22].C1(N2C(C)(C)C(C(O)=O)C3C(=CC=CC=3)C2=O)CC1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:17][C:16]1([CH3:18])[CH:15]([C:19]([OH:21])=[O:20])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:22])[NH:7]1
Reactant: COc1ccc(CN2C(=O)c3ccccc3C(C(=O)O)C2(C)C)cc1OC
Agent: CC1(C)C(C(=O)O)c2ccccc2C(=O)N1C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CC1(C)NC(=O)c2ccccc2C1C(=O)O
Temperature: 70 °C

Procedure:
To 2-(3,4-dimethoxy-benzyl)-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid (9.6 g, 26 mmol), prepared in manner analogous to 2-cyclopropyl-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid, is added thioanisole (36 mL, 304 mmol) and trifluoroacetic acid (360 mL). The resulting solution is heated to 70° C. for 13 h. The reaction is then cooled to room temperature and concentrated in vacuo to near dryness. The resulting purple oil is purified via silica gel flash chromatography (dichloromethane-methanol, 1:0 to 9:1, with 0.5% acetic acid) to furnish 3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid as an off-white foam; MS (ESI) m/z 220.0 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:39](=[CH:40][CH:41]=2)[O:38][C:15]2([CH2:20][CH2:19][N:18]([C:21]([C:23]4[CH:32]=[C:31]5[C:26]([CH:27]=[CH:28][N:29]=[C:30]5[CH:33]5[CH2:35][CH2:34]5)=[C:25]([O:36][CH3:37])[CH:24]=4)=[O:22])[CH2:17][CH2:16]2)[CH2:14][C:13]3=[O:42])[CH:7]=[N:6][CH:5]=1.[OH-].[Na+:45].Cl>CO.C1COCC1>[Na+:45].[CH:33]1([C:30]2[C:31]3[C:26](=[C:25]([O:36][CH3:37])[CH:24]=[C:23]([C:21]([N:18]4[CH2:17][CH2:16][C:15]5([CH2:14][C:13](=[O:42])[C:12]6[C:39](=[CH:40][CH:41]=[C:10]([C:8]7[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=7)[C:3]([O-:43])=[O:2])[CH:11]=6)[O:38]5)[CH2:20][CH2:19]4)=[O:22])[CH:32]=3)[CH:27]=[CH:28][N:29]=2)[CH2:35][CH2:34]1
Reactant: COC(=O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(OC)c5ccnc(C6CC6)c5c4)CC2)O3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)[O-])c4)ccc2O3)cc2c(C3CC3)nccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-{1′-[(1-Cyclopropyl-5-methoxy-isoquinolin-7-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic acid methyl ester (1.80 g, 3.11 mmol) was suspended in MeOH (18 mL) and THF (9 mL), and 1N NaOH (9.34 mL) was added thereto. After stirred at room temperature for 5 h, 1N HCl aq. (6.23 mL) was added to the reaction mixture and the solvents was removed in vacuo. The residue was purified by ODS column chromatography (H2O/MeOH=100/0 to 60/40) to obtain the intended compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.92 (1H, d, J=1.7 Hz), 8.76 (1H, d, J=2.4 Hz), 8.36 (1H, d, J=5.6 Hz), 8.31-8.28 (1H, m), 8.08 (1H, s), 8.00-7.96 (2H, m), 7.74 (1H, d, J=5.6 Hz), 7.23 (1H, d, J=9.3 Hz), 7.19 (1H, s), 4.41-4.26 (1H, br m), 4.01 (3H, s), 3.60-3.46 (1H, br m), 3.39-3.27 (2H, br m), 2.97-2.87 (1H, m), 2.95 (2H, s), 2.19-2.02 (1H, br m), 2.02-1.72 (3H, m), 1.15-1.04 (4H, m). ESI-MS [M+Na]+=586.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:12]=1[C:13](Br)=[O:14]>COC(C)(C)C>[Br:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:12]=1[C:13]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: Cc1cccc(CBr)c1C(=O)Br
Reactant: OCc1ccccc1
Solvent: COC(C)(C)C
Product: Cc1cccc(CBr)c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
24.2 g (221 mmol) of benzyl alcohol are added with ice cooling to 136 g (233 mmol) of 2-bromomethyl-6-methylbenzoyl bromide solution (35% solution in heptane). Subsequently, the mixture is left to stir at RT for one hour. After addition of 500 ml of tert-butyl methyl ether, the organic solution is washed successively with 410 ml of sat. sodium hydrogencarbonate solution and four times with 300 ml each time of water. Subsequently, the solvent is removed fully under reduced pressure. 74 g of benzyl 2-bromomethyl-6-methylbenzoate are obtained as a colorless oil having a purity of 80%. The benzyl 2-bromomethyl-6-methylbenzoate prepared in this way has a molecular weight of 318.02 (C16H15BrO2); MS (ESI): 341.0 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[OH:12]
Reactant: Cc1cc(F)c(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)c(O)c(F)c1
Reaction time: 18 h
Yield: 33.6 %

Procedure:
2-Fluoro-4-methyl-6-nitrophenol (D51, 3.276 g, 19.14 mmol) was dissolved in ethanol (100 mL). 10% Pd/C (0.323 g, 0.304 mmol) was added and the reaction mixture hydrogenated for ˜18 hr. Catalyst was filtered off and the filtrate evaporated to dryness. TLC showed only a small amount of material had been reduced. Solid was redissolved in 350 mL ethanol, 150 mL of this solution was passed down the H-cube at 1 mL/min with full hydrogen. After ˜2 hr the cartridge had been exhausted. A new cartridge was used and the reaction mixture was left recycling through the instrument for ˜4 hr. ˜30% of nitro compound was still remaining. The reaction mixture was evaporated to dryness. Redissolved in EtOH and passed through the H-cube with a new cartridge to give fully reduced material 2-fluoro-4-methyl-6-aminophenol (907 mg, 6.43 mmol, 33.6% yield) as a brown solid. The remaining nitro compound was passed down the H-cube at 1 mL/min with full hydrogen—still only 58% conversion. Redissolved in EtOH and passed through the H-cube with a new cartridge. Evaporated to dryness redissolved in MeOH and loaded onto an SCX-2 cartridge (50 g) washed with MeOH and eluted with 1M NH3/MeOH, evaporated to dryness to give a brown solid batch 2 (1.319 g, 9.35 mmol, 48.8% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[O:5][CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].[CH2:17]([N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[C:22]([CH3:33])[CH:21]=[N:20]1)[CH3:18]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([N:19]1[C:23]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[O:5][CH:6]=2)=[C:22]([CH3:33])[CH:21]=[N:20]1)[CH3:18]
Reactant: COC(=O)c1cc(Br)co1
Reactant: CCn1ncc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCn1ncc(C)c1-c1coc(C(=O)OC)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of methyl 4-bromo-2-furancarboxylate (500 mg, 2.439 mmol) in THF (5 mL) was added aqueous Na2CO3 (2N, 3.6 mL, 7.2 mmol), PdCl2(dppf) (160 mg, 0.22 mmol), and 1-ethyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (700 mg, 2.96 mmol). The reaction mixture was heated to 70° C. in a sealed tube. After 2 h, the reaction mixture was concentrated under vacuum and purified on silica (EtOAc/Hex, 20-40%) to afford the title compound (460 mg, 76%) as a light yellow solid: LC-MS (ES) m/z 235 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[CH2:5][CH2:4][N:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[F:18][C:19]([Si](C)(C)C)([F:21])[F:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[OH:7][C@@:6]1([C:19]([F:21])([F:20])[F:18])[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:2]1[CH3:1]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1N(C(=O)OCc2ccccc2)CC[C@@]1(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution (10 mL) of benzyl (2S)-2-methyl-3-oxopyrrolidine-1-carboxylate (1.0 g) in THF were added trifluoromethyltrimethylsilane (0.95 mL) and 1 mol/L tetrabutylammonium fluoride—THF solution (0.43 mL) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. A 1 mol/L tetrabutylammonium fluoride—THF solution (8.56 mL) was added to the reaction mixture, and the mixture was stirred at 50° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as colorless oil (yield: 1.06 g, yield: 81%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([N:32]2[C:39]3[C@H:38]4[CH2:40][C@H:37]4[CH2:36][C:35]=3[C:34]([C:41]([OH:43])=O)=[N:33]2)[CH:27]=1.Cl.[NH2:45][CH:46]([C:51]([F:54])([CH3:53])[CH3:52])[C:47]([O:49][CH3:50])=[O:48]>>[CH3:50][O:49][C:47](=[O:48])[CH:46]([NH:45][C:41]([C:34]1[C:35]2[CH2:36][C@@H:37]3[CH2:40][C@@H:38]3[C:39]=2[N:32]([C:28]2[CH:27]=[C:26]([Cl:25])[CH:31]=[CH:30][N:29]=2)[N:33]=1)=[O:43])[C:51]([F:54])([CH3:53])[CH3:52]
Reactant: COC(=O)C(N)C(C)(C)F
Reactant: O=C(O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)C(NC(=O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@@H]1C[C@H]21)C(C)(C)F

Procedure:
The title compound was prepared by HATU coupling method using (1aS,5aS)-2-(4-chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and methyl 2-amino-3-fluoro-3-methylbutanoate hydrochloride. LCMS m/z=407.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.42-0.50 (m, 1H), 1.23-1.30 (m, 1H), 1.49 (d, J=21.6 Hz, 3H), 1.57 (d, J=21.0 Hz, 3H), 2.22-2.30 (m, 1H), 2.79-2.85 (m, 1H), 2.87-3.05 (m, 2H), 3.81 (s, 3H), 4.85-4.94 (m, 1H), 7.22 (dd, J=5.4 and 1.8 Hz, 1H), 7.56 (d, J=9.5 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 8.35 (d, J=5.4 Hz, 1H).