Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1.C(N(CC)CC)C.Cl[C:31](=[O:42])[CH:32]([P:34](=[O:41])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[F:33]>CN(C=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([NH:1][C:31](=[O:42])[CH:32]([P:34](=[O:41])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[F:33])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: CCOP(=O)(OCC)C(F)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C(F)C(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-amino-4-(3-chloro-4-fluorophenylamino)-7-methoxy-quinazoline (1.0 eq.) and triethylamine (1.5 eq.) were dissolved in DMF (10 ml), and the mixture was stirred at 0° C. for 30 min. A solution of diethyl (2-chloro-1-fluoro-2-oxoethyl)phosphonate (1.5 eq.) in DMF (5 ml) was added dropwise slowly into the mixture mentioned above, and stirred overnight at room temperature. After the reaction finished, the mixture was quenched with saturated NaHCO3, extracted with EtOAc, and the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, then the crude product was purified by column chromatography (mobile phase 40:1 DCM/MeOH) and a light yellow solid of diethyl (2-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxy-quinazolin-6-yl)amino)-1-fluoro-2-oxoethyl)phosphonate was given. (50% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][N:4]([CH3:30])[C:5]1[N:10]=[C:9](S(C)(=O)=O)[N:8]=[C:7]([NH:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:19]([NH:21][CH3:22])=[O:20])[C:6]=1[N+:27]([O-:29])=[O:28].[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38]>C(#N)C>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH:38][C:9]1[N:8]=[C:7]([NH:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:19]([NH:21][CH3:22])=[O:20])[C:6]([N+:27]([O-:29])=[O:28])=[C:5]([N:4]([CH2:3][C:2]([CH3:32])([CH3:31])[CH3:1])[CH3:30])[N:10]=1
Reactant: CNC(=O)c1ccc(C)c(Nc2nc(S(C)(=O)=O)nc(N(C)CC(C)(C)C)c2[N+](=O)[O-])c1
Reactant: CN(C)CCCN
Solvent: CC#N
Product: CNC(=O)c1ccc(C)c(Nc2nc(NCCCN(C)C)nc(N(C)CC(C)(C)C)c2[N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of 3-{6-[(2,2-Dimethyl-propyl)-methyl-amino]-2-methanesulfonyl-5-nitro-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (4.2 mg, 0.01 mmol) and 3-(Dimethylamino)propylamine (0.2 mL) in 2 mL of acetonitrile was heated with stirring at 80° C. for 16 h. The solvent was then evaporated under vacuum and the crude product was purified by flash chromatography to afford 2.8 mg of the product (Yield: 64%). MS (m/z) calcd for C24H38N8O3 (MH+), 487.3, found, 487.3.
Reaction SMILES: [C:1]([NH:18][C@H:19]1[CH2:23][CH2:22][C@@H:21]([C:24](O)=[O:25])[CH2:20]1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]1[CH:41]=[CH:40][C:39]([NH:42][CH3:43])=[CH:38][CH:37]=1.N1C(C)=CC(C)=CC=1C>C(Cl)Cl>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1](=[O:2])[NH:18][CH:19]3[CH2:23][CH2:22][CH:21]([C:24](=[O:25])[N:42]([C:39]4[CH:40]=[CH:41][C:36]([C:28]5[O:27][C:31]6[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=6[N:29]=5)=[CH:37][CH:38]=4)[CH3:43])[CH2:20]3)[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CNc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O=C(N[C@H]1CC[C@@H](C(=O)O)C1)OCC1c2ccccc2-c2ccccc21
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CN(C(=O)C1CCC(NC(=O)OCC2c3ccccc3-c3ccccc32)C1)c1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 2 h

Procedure:
250 mg (0.71 mmol) (−)-(1S,3R)—N-Fmoc-1-Aminocyclopentane-3-carboxylic acid and 0.14 mL (1.07 mmol) 1-chloro-N,N,2-trimethylpropenyldiamine are dissolved in 5 mL DCM and stirred for 2 hours. The resulting product is added to a mixture of 159.6 mg (0.71 mmol) (4-Benzooxazol-2-yl-phenyl)-methyl-amine and 0.14 mL (1.07 mmol) 2,4,6-collidine in 5 mL DCM. The reaction mixture is stirred overnight at RT. The mixture is concentrated under reduced pressure. The residue is taken up in water and extracted with DCM. The organic layer is dried, filtered off and concentrated under reduced pressure. The product is purified by RP-HPLC (water+5-95% acetonitrile (with addition of 0.1% TFA)). The solvent is evaporated.
Reaction SMILES: Cl.[C:2]([CH:4]([C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH3:22])[CH2:17][CH2:16]1)[CH2:5][CH2:6][CH:7]([OH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])#N.[O:23]1CCCOC1>O>[CH3:22][O:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([CH:4]2[CH2:5][CH2:6][CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:14][C:2]2=[O:23])[CH2:16][CH2:17]1
Reactant: CCCCCCC(O)CCC(C#N)[C@H]1CC[C@H](OC)CC1
Reactant: C1COCOC1
Agent: Cl
Solvent: O
Product: CCCCCCC1CCC([C@H]2CC[C@H](OC)CC2)C(=O)O1
Temperature: 25 °C

Procedure:
20 mL of concentrated hydrochloric acid was added to a solution of 1-cyano-1-(trans-4-methoxycyclohexyl)-4-decanol (49) (5.1 g, 17.4 mmol) obtained in the third step dissolved in 200 mL of 1,3-dioxane, and refluxed under heating for 20 hours. The reaction mixture was cooled to room temperature and then put in 100 mL of water, and then extracted with 100 mL of ethyl acetate. The resulting organic layer was washed with water (100 mL×2) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (developing solvent: heptane/ethyl acetate=20/1, column packing: silica gel) and then recrystallized from heptane to obtain 3-(trans-4-methoxycyclohexyl)-6-hexyl-tetrahydro-2-pyranone (Compound No. 25) (2.1 g, 6.9 mmol). The resulting compound was in the form of a colorless liquid, and the yield based on the compound (49) was 40%.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N([CH2:25][CH3:26])CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[C:10]1([S:16]([N:6]([S:16]([C:26]2[CH:25]=[CH:12][CH:11]=[CH:10][CH:15]=2)(=[O:18])=[O:17])[C:5]2[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=2[I:9])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCN(CC)CC
Reactant: Nc1ccc(Br)cc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)N(c1ccc(Br)cc1I)S(=O)(=O)c1ccccc1
Reaction time: 96 h
Yield: 34.8 %

Procedure:
A solution of 4-bromo-2-iodoaniline (8.5 g, 28.5 mmol) in 200 mL of dichloromethane was sequentially treated with benzenesulfonyl chloride (15 mL, 117.5 mmol) and triethylamine (25 mL, 179.6 mmol). After 4 days, the mixture was diluted with 100 mL of saturated aqueous sodium bicarbonate solution and extracted with three 100 mL portions of ethyl acetate. The combined organic layers were washed with 50 mL of brine, three 60 mL portions of saturated aqueous ammonium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with diethyl ether to afford 5.74 g (35% yield) of N,N-bisbenzenesulfonyl-(4-bromo-2-iodoaniline).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:14]C1C=CC=CC=1OC>>[F:14][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[CH:2]=[CH:3][C:4]=1[CH2:10][C:11]([OH:13])=[O:12].[F:14][C:5]1[CH:6]=[C:7]([OH:8])[CH:2]=[CH:3][C:4]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COc1ccc(CC(=O)O)cc1F
Reactant: COc1ccccc1F
Product: COc1ccc(CC(=O)O)c(F)c1
Product: O=C(O)Cc1ccc(O)cc1F

Procedure:
The synthesis of 3-fluoro-4-methoxyphenylacetic acid 15 starting from 2-fluoroanisole has been described by M. Kucha{hacek over (r)} et al. (Collect. Czech. Chem. Commun. 1990, 55, 296-306). 2-Fluoro-4-methoxyphenylacetic acid 16 is obtained from 2-fluoro-4-hydroxyphenylacetic acid [S.-I. Sugita, S. Toda, T. Yoshiyasu, T. Teraji, Mol. Cryst. Liq. Cryst. 1993, 237, 399-406; E. J. Corey, J. P. Dittami, J. Am. Chem. Soc. 1985, 107, 256-257; H. H. Wassermann, J. Wang, J. Org. Chem. 1998, 63, 5581-5586] by dimethylation and ester saponification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1cccc(OC2CCCC2)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A mixture of 3-bromophenol (commercially available) (1.72 g, 10 mmol), bromocyclopentane (commercially available) (2.96 g, 20 mmol), and K2CO3 (2.56 g, 20 mmol) in acetone (30 mL) was stirred at 80° C. for 18 h. The solvent was removed under reduced pressure and the mixture was extracted with EtOAc (100 mL×2). The combined organic layers was washed with sat NaCl (50 mL), dried over Na2SO4, concentrated, and purified by column to give the title product (1.8 g, yield 75%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:21]>ClCCl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]2[CH:11]([O:21]2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCC2OC2C1
Temperature: 25 °C
Reaction time: 19 h
Yield: 166.1 %

Procedure:
To a solution of cyclohex-3-enylmethyl-carbamic acid tert-butyl ester (1.5 g, 7.10 mmol) in ml of anhydrous dichloromethane was added 3-chloroperoxybenzoic acid (2.45 g, 14.2 mmol) under cooling. The resulting mixture was stirred for 19 hours at room temperature and washed with saturated sodium bicarbonate and 0.5M aqueous solution of sodium thiosulphate. The aqueous phase was extracted three times with dichloromethane and the combined organic phases were washed with brine. The resulting organic phase was dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield 1.48 g of crude product. Column chromatography of 3.17 g of crude product (silica, petrol ether/ethyl acetate=3/1) resulted in (7-oxa-bicyclo[4.1.0]hept-3-ylmethyl)-carbamic acid tert-butyl ester (Rf=0.19, 2.68 g, 81% yield) as colorless solid.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][OH:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([S:24](Cl)(=[O:26])=[O:25])=[C:19]([CH3:28])[CH:18]=1>ClCCl>[CH:1]1([N:4]([CH2:5][CH2:6][OH:7])[S:24]([C:20]2[C:21]([CH3:23])=[CH:22][C:17]([O:16][CH3:15])=[CH:18][C:19]=2[CH3:28])(=[O:26])=[O:25])[CH2:3][CH2:2]1
Reactant: OCCNC1CC1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(CCO)C2CC2)c(C)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 20 %

Procedure:
To a cold (0° C.) solution of 2-cyclopropylamino-ethanol (8 mmol) in dichloromethane (24 ml) and triethylamine (2.5 equiv.) a solution of 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (7 mmol) in dichloromethane (12 ml) was added dropwise maintaining the temperature at 0° C. After complete addition the reaction mixture was stirred at 25° C. for 90 min by which time the reaction was complete (TLC). The reaction mixture was diluted with dichloromethane (200 ml) and washed with water and finally with brine. The organic layer was dried over sodium sulfate and evaporated to dryness to obtain the pure product. Yield: 20%
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)Cl.[CH2:17]([O:19][C:20]([C:22]1([NH2:31])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])[CH3:18].CCN(C(C)C)C(C)C>CC(O)C.C(Cl)Cl>[CH2:17]([O:19][C:20]([C:22]1([NH:31][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][CH:1]([CH3:2])[CH3:3])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: CC(C)Sc1ccccc1C(=O)O
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)C1(NC(=O)c2ccccc2SC(C)C)Cc2ccccc2C1
Reaction time: 0.08 h

Procedure:
A 30 mL reaction vial is charged with 2-isopropylsulfanylbenzoic acid (430 mg, 2.19 mmol) and dry DCM (7 mL). A stirring bar is added. Stirring is initiated. After dissolution is complete, the HTBU (831 mg, 2.19 mmol) is added. After 5 min, 2-amino-indane-2-carboxylic acid ethyl ester. (450 mg, 2.19 mmol) is added followed by DIPEA (0.96 mL, 5.48 mmol). The reaction is allowed to stir for 3 days. Analysis by tlc of the reaction mixture (silica, 5% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (50 mL). This is washed consecutively with dilute aqueous HCl (3%, 25 mL), saturated aqueous NaHCO3 (25 mL) and brine (25 mL), and then dried over MgSO4, filtered and evaporated in vacuo to provide 0.87 g of light yellow solid. This material is dissolved in 10 mL of DCM. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 50% EtOAc in heptanes over 10 column volumes. 17 mL fractions of eluent are collected. Fractions 32 through 40 are combined and evaporated in vacuo. This provides white solid material (0.69 g, 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([C:32]([O:34]CC)=[O:33])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:18]([Cl:37])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl.C(OCC)(=O)C>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:31])[C:32]([OH:34])=[O:33])=[C:18]([Cl:37])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)C(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
The compound of Example 194 (2.74 g) was dissolved in ethanol (10 mL). To this solution, potassium hydroxide (330 mg) was added and the mixture was stirred overnight at 50° C. Subsequently, the reaction mixture was diluted with water, followed by addition of 2 mol/L hydrochloric acid and extraction with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, was dried over anhydrous magnesium sulfate, and was then concentrated. The resulting residue was purified on a silica gel chromatography (hexane:ethyl acetate=10:1 to 2:1) to give the desired product as a yellow oil (2.38 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=O)O[C:6](=[O:7])[C:5]2=[CH:12][C:13]=1[I:14].C(O)(=O)C.C(N)=[NH:20]>CN(C)C=O>[OH:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([F:1])=[C:13]([I:14])[CH:12]=2)[N:10]=[CH:9][N:20]=1
Reactant: O=c1[nH]c2cc(F)c(I)cc2c(=O)o1
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Oc1ncnc2cc(F)c(I)cc12
Temperature: 110 °C
Yield: 91.2 %

Procedure:
Dimethylformamide (0.5 liters), 4-fluoro-5-iodo-isatoic anhydride (45 grams, 147 mmoles), and formamidine acetate (45.92 grams, 441 mmoles), were combined in a one liter one-neck flask fitted with a magnetic stir bar. The mixture was placed under anhydrous nitrogen and heated at 110° C. for 6 hours. The mixture was allowed to cool, followed by concentrating the reaction mixture to one third its original volume on the rotary evaporator. The resulting mixture was poured onto 3 liters of ice water. The resulting precipitated solid was collected by suction filtration. The solid was washed with an additional one liter of distilled water. The resulting solid was dried under vacuum at 70° C. to yield 38.9 grams (91%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 12.43 (s, 1H), 8.46 (d, 1H), 8.12 (s, 1H), 7.49 (d, 1H). ESI-MS m/z 291 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1.[CH2:10]([Li])CCC.[CH2:15]([C:19]1[C:23]([CH2:24]Cl)=[C:22]([CH3:26])[O:21][N:20]=1)[CH2:16][CH2:17][CH3:18]>C1COCC1.CCCCCC>[CH3:10][O:8][C:7]([C:4]1[S:3][C:2]([CH2:1][CH2:24][C:23]2[C:19]([CH2:15][CH2:16][CH2:17][CH3:18])=[N:20][O:21][C:22]=2[CH3:26])=[N:6][CH:5]=1)=[O:9]
Reactant: [Li]CCCC
Reactant: Cc1ncc(C(=O)O)s1
Reactant: CCCCc1noc(C)c1CCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1CCc1ncc(C(=O)OC)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a stirred solution of 2-methyl-thiazole-5-carboxylic acid (286 mg, 2.0 mmol) in THF (14 mL) at −72° C. and under argon was added n-butyllithium (2.50 mL of a 1.6M solution in hexane, 4.0 mmol) dropwise. After 2 h, a solution of 3-butyl-4-chloromethyl-5-methyl-isoxazole (375 mg, 2.0 mmol) in THF (6 mL) was added dropwise. After 2.5 h the reaction mixture was quenched with 10% aqueous citric acid (10 mL) then warmed to room temperature. The reaction mixture was extracted with ethyl acetate then the combined extracts were dried, filtered and concentrated. The resultant oil was dissolved in methanol (15 mL) and ether (7 mL) then (trimethylsilyl)diazomethane (3 mL of a 2M solution in ether, 6.0 mmol) was added dropwise. After 30 min, further (trimethylsilyl)diazomethane (3 mL of a 2M solution in ether, 6.0 mmol) was added. After 15 h, the reaction mixture was quenched with acetic acid (3 drops) then was concentrated and purified by chromatography (silica, 0 to 75% ethyl acetate in heptane) to give the title compound (360 mg, 58%) was a light brown oil. MS: m/e=309.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:23])([CH3:22])[C:4]=2[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.CCN(C(C)C)C(C)C.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](Cl)=[O:41]>C(Cl)Cl>[CH3:23][C:12]1([CH3:22])[C:4]2[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[C:2]([NH:1][C:40](=[O:41])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)[C:3]=2[CH2:14][N:13]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CCOC(=O)n1nc(N)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc(NC(=O)c2ccccn2)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 5-tert-butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate, A1(I), (7.32 g, 22.56 mmol) and DIPEA (12 mL) in CH2Cl2 (60 mL), picolinoyl chloride hydrochloride, A1(II), (4.82 g, 27.07 mmol) was added slowly. The reaction was stirred at room temperature for 2 hrs. The reaction mixture was diluted with CH2Cl2 (50 mL), washed with water (2×30 mL), sat. NaCl (brine), and dried over MgSO4, filtered and concentrated to give A1(III) (9.12 g, 94% yield). 1H NMR (400 MHz, CDCl3-d) δ ppm 1.39-1.50 (m, 2H) 1.49-1.58 (m, 10H) 1.72 (s, 3H) 1.78 (s, 3H) 4.63 (q, J=7.07 Hz, 2H) 4.81 (d, J=19.45 Hz, 2H) 7.46-7.58 (m, 1H) 7.82-7.97 (m, 1H) 8.25 (dd, J=7.71, 3.41 Hz, 1H) 8.73 (dd, J=9.60, 4.55 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:12])[CH:7]([OH:11])[CH2:8][CH:9]=[CH2:10])[CH3:4].Br[CH2:14][C:15]([CH3:17])=[CH2:16]>C1COCC1>[CH2:3]([O:5][C:6](=[O:12])[CH:7]([O:11][CH2:16][C:15]([CH3:17])=[CH2:14])[CH2:8][CH:9]=[CH2:10])[CH3:4]
Reactant: C=C(C)CBr
Reactant: C=CCC(O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(OCC(=C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a cold (00C) stirred suspension of NaH (55% disperson in oil, 227.9 mg, 5.2 mmol, 1.3 eq) in THF (20 mL) was added drop wise a solution of 2-hydroxy-pent-4-enoic acid ethyl ester (0.576 g, 4.0 mmol) in THF (20 mL) and stirred for 1 h. The reaction mixture was then treated with 3-bromo-2-methylpropene (0.81 g, 6.0 mmol, 0.61 mL), slowly warmed up to rt, and stirred for 1 h. It was carefully quenched with saturated NH4Cl solution. Reaction mixture was extracted with EtOAc (3×20 mL) organic solution was washed with brine, dried (Na2SO4), concentrated. Purification of the residue on silica gel column chromatography using 5% EtOAc-Hexane furnished 2-(2-methyl-allyloxy)-pent-4-enoic acid ethyl ester (0.521 g, 66%) as oil. NMR 1H (CDCl3, 400 MHz): 5.9-5.78 (m, 1H), 5.16-5.06 (m, 2H), 4.97 (s, 1H), 4.91 (s, 1H), 4.26-4.16 (m, 2H), 4.072 (d, J=12.3, 1H), 3.93 (t, J=6.5, 1H), 3.813 (d, J=12.4, 1H), 1.15 (s, 3H), 1.28 (t, J=7.2, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:6]=2[O:5]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:6]=2[O:5]1)(=[O:24])=[O:23]
Reactant: N#Cc1ccc(-c2ccc3c(c2)CC(CCO)O3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1Cc2cc(-c3ccc(C#N)cc3)ccc2O1
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a solution of Example 67C (0.23 g, 0.87 mmol) and methanesulfonyl chloride (0.075 mL, 0.96 mmol) in CH2Cl2 (5 mL) at 0° C. was added triethylamine (0.13 mL, 9.4 mmol). The mixture was stirred for 30 minutes, diluted with CH2Cl2 (75 mL), washed with water (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on silica using CH2Cl2 to provide the titled compound (0.278 g, 90%). 1HNMR (CDCl3): H NMR: 1.95 (m, 2H), 2.93 (m, 2H), 3.00 (s, 3H), 3.46 (m, 2H), 5.00 (m, 1H), 6.81 (d, J=7 Hz, 1H), 7.40 (m, 2H), 7.65 (m, 4H); MS (DCI) 343 (M+), 361 (M+NH4+).
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)=[CH:4][CH:3]=1.IC1C=CC(O)=CC=1.[H][H]>O1CCCC1.[Ni].O>[I:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(I)cc2)nc1
Reactant: [H][H]
Agent: [Ni]
Agent: Oc1ccc(I)cc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccc(I)cc2)nc1
Yield: 92.1 %

Procedure:
2-(4-Iodo-phenoxy)-5-nitro-pyridine (50 grams, 146.1 mmol) and 4-iodo-phenol (96.5 grams, 438.6 mmol) were dissolved in tetrahydrofuran (500 mL) and added to a Parr shaker flask which contained Raney nickel (30 grams of a 50% slurry in water). The above mixture was shaken under hydrogen gas (50 psi) for 2 hours, at which time uptake of hydrogen gas had ceased and thin liquid chromatography indicated complete consumption of starting material. The Raney nickel was then removed by filtration through a pad of celite under nitrogen. The pad was rinsed several times with methylene chloride. The filtrate was diluted with methylene chloride and the organic layer was washed with 1M sodium hydroxide (4×200 mL) and brine (1×200 mL). The organic layer was dried with magnesium sulfate, filtered and concentrated under vacuum to give 42 grams (92%) of the title compound which was used without further purification. MS m/z: ESI+ 313.0 (M+H)+.