Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH2:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[C:22](N=C(N(C)C)N(C)C)([CH3:25])([CH3:24])[CH3:23].BrCC(C)C>C(#N)C>[CH2:23]([N:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=1)[S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[CH2:21])=[CH:18][CH:19]=1)(=[O:12])=[O:13])[CH:22]([CH3:25])[CH3:24]
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Solvent: CC(C)CBr
Product: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(5-isopropylpyridin-2-yl)-4-vinylbenzenesulfonamide (507 mg, 1.677 mmol) in acetonitrile (10 mL), was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.676 mL, 3.35 mmol). The mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.676 mL, 3.35 mmol) added. The reaction was then heated by microwaves to 150° C., for 30 minutes. After cooling, the solvent was removed under a stream of nitrogen and the crude purified by normal phase chromatography on silica (Si) (0-50% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the title product, 179 mg, as a yellow oil which solidified on standing. LCMS (2 min, High pH) Rt 1.49 min, m/z (ES+) 359 (M+H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10](=[O:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17].[OH-].[Li+].C(O)C.Cl>O>[O:1]=[C:2]1[NH:11][C:10](=[O:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)CCCn1c2c(c(=O)[nH]c1=O)CCCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCn1c2c(c(=O)[nH]c1=O)CCCC2
Yield: 79.1 %

Procedure:
A solution of 14.4 g (54.1 mmol) of ethyl 3-(2,4-dioxo-3,4,5,6,7,8-hexahydro-1(2H)-quinazolinyl)-propanecarboxylate and 6.47 g (270.4 mmol) of lithium hydroxide in 200 ml of a mixture of ethanol and water (4:1) are heated under reflux for one hour. The cooled solution is then mixed with 1 M hydrochloric acid until a pH of 1 is reached, and then concentrated to dryness. The resulting residue is dissolved in about 20 ml of water. On addition of ether, the product is obtained as a precipitate which is filtered off with suction and dried under reduced pressure. This gives 10.2 g (42.8 mmol, 79% yield) of a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.ClC(OCCCC)=O.Br.[NH2:27][CH2:28][C:29]([N:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1([CH3:38])[CH3:37])=[O:30]>ClCCl>[CH3:37][C:32]1([CH3:38])[NH:33][C:34](=[O:36])[CH2:35][N:31]1[C:29](=[O:30])[CH2:28][NH:27][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CC1(C)NC(=O)CN1C(=O)CN
Reactant: O=C(O)CN1CCCC1=O
Agent: Br
Agent: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)NC(=O)CN1C(=O)CNC(=O)CN1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
An ice cold solution of 2-oxo-1-pyrrolidineacetic acid (1.03 g) and triethylamine (1.01 ml) in dichloromethane (20 ml) was treated dropwise with butyl chloroformate (0.92 ml). After stirring at 0° C. for 30 minutes a suspension of 1-(2-aminoacetyl)-2,2-dimethyl-4-imidazolidinone hydrobromide (1.82 g) and triethylamine (1.01 ml) in dichloromethane (20 ml) was added, and the temperature was gradually raised to room temperature. After stirring at room temperature for 1 day the suspension was evaporated under reduced pressure. The residue was chromatographed on a silica/gel column eluting with methanol/dichloromethane 1:1. The selected fractions were collected and evaporated, the residue was washed with ethyl acetate and crystallized from ethanol to give the title compound as a white solid, m.p. 229°-231° C.
Reaction SMILES: Br[C:2]1[C:11]([Br:12])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[C:13]([Cu])#[N:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:12][C:11]1[C:2]([C:13]#[N:14])=[CH:3][C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[CH:10]=1
Reactant: N#C[Cu]
Reactant: Brc1cc2c(cc1Br)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc2c(cc1Br)OCCO2
Temperature: 150 °C
Reaction time: 144 h

Procedure:
A mixture of 20.0 g (62.6 mmol) of 6,7-dibromo-2,3-dihydrobenzo[1,4]dioxine, 8.50 g (93.9 mmol) CuCN and 13.0 (93.9 mmol) K2CO3 in 300 mL DMF is stirred at 150° C. for 6 d. The reaction is quenched by the addition of water and extracted with EtOAc. The org. layers are combined and washed with water (3×) and sat. aq. NaCl solution. After drying over Na2SO4, the mixture is filtered and the solvent is removed in vacuo. The resulting residue is purified by column chromatography (silica gel, PE/EtOAc 20/1→10/1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13]C(=O)C)=[N:10][C:9]=2[CH3:17])=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[C:23]([CH3:29])=[N:24][N:25]([CH3:28])[C:26]=1[Cl:27])(=[O:21])=[O:20].Cl>C(O)C>[NH2:13][C:11]1[S:12][C:8]([C:5]2[CH:4]=[C:3]([NH:18][S:19]([C:22]3[C:23]([CH3:29])=[N:24][N:25]([CH3:28])[C:26]=3[Cl:27])(=[O:20])=[O:21])[C:2]([Cl:1])=[N:7][CH:6]=2)=[C:9]([CH3:17])[N:10]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NS(=O)(=O)c3c(C)nn(C)c3Cl)c2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1cnc(Cl)c(NS(=O)(=O)c2c(C)nn(C)c2Cl)c1
Temperature: 80 °C
Yield: 36.6 %

Procedure:
A mixture of N-{5-[6-chloro-5-(5-chloro-1,3-dimethyl-1H-pyrazol-4-ylsulfonamido)pyridin-3-yl]-4-methyl-1,3-thiazol-2-yl}acetamide (300 mg), a 6N aqueous hydrochloric acid solution (5 mL) and ethanol (5 mL) was stirred and heated to 80° C. for 5 hours. The mixture was cooled to room temperature and concentrated by evaporation. The residue was purified by preparative HPLC. There was thus obtained the title compound as a white solid (100 mg); 1H NMR Spectrum: (DMSOd6) 2.19 (s, 6H), 3.73 (s, 3H), 7.39 (br s, 2H), 7.66 (s, 1H), 8.25 (s, 1H); Mass Spectrum: M+H+ 433.
Reaction SMILES: I[C:2]1[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:22]2[S:26][C:25]3[CH:27]=[CH:28][C:29]([NH2:31])=[CH:30][C:24]=3[CH:23]=2)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[NH2:31][C:29]1[CH:28]=[CH:27][C:25]2[S:26][C:22]([C:2]3[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([C:8]4[N:9]=[N:10][NH:11][N:12]=4)[CH:7]=3)=[CH:23][C:24]=2[CH:30]=1
Reactant: Nc1ncc(-c2nn[nH]n2)cc1I
Reactant: CC1(C)OB(c2cc3cc(N)ccc3s2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Nc1ccc2sc(-c3cc(-c4nn[nH]n4)cnc3N)cc2c1
Temperature: 40 °C

Procedure:
The reaction mixture of 3-iodo-5-(2H-tetrazol-5-yl)pyridin-2-amine (288 mg, 1.0 mmol, 1 eq), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-amine (330 mg, 1.2 eq), triphenylphosphine (53 mg, 0.2 eq), and palladium diacetate (22 mg, 0.1 eq) in dioxane (3 mL) and aqueous sodium carbonate (2 M, 2 mL, 4 eq) under nitrogen atmosphere was vigorously stirred and heated at 40° C. for 30 minutes. The mixture was then partitioned between aqueous ammonium chloride and THF-EtOAc (1:10). The organic layer was isolated and dried with anhydrous sodium sulfate. The upper solution was concentrated down with silica gel. Upon a gradient column chromatography (EtOAc to MeOH-EtOAc 1:10) 3-(5-amino-1-benzothien-2-yl)-5-(2H-tetrazol-5-yl)pyridin-2-amine was obtained in the amount of 5 mg.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[C:25]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][N:17]=1.O.[OH-].[Na+]>C(OCC)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[N:17]=[CH:18][C:19]([CH2:20][OH:21])=[CH:24][C:25]=1[O:26][CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OCC(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(F)c(-c2ncc(CO)cc2OCC(C)C)c1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a suspension of lithium aluminum hydride (622 mg) in diethyl ether (20 mL) was added a solution of methyl 6-(2-fluoro-5-methoxyphenyl)-5-isobutoxynicotinate (1.82 g) in diethyl ether (5.0 mL) at 0° C., and the mixture was stirred for 30 min. Water and aqueous sodium hydroxide solution were added to the reaction mixture, and the resulting precipitate was filtered off. The solvent in the filtrate was concentrated, and the residue was recrystallized (ethyl acetate/hexane) to give the title compound (1.30 g) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][NH2:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[C:7]1([CH2:13][CH2:14][NH:15][CH2:29][CH2:28][CH2:27][O:26][C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CCNCCCOc2ccc3ccccc3c2)cc1
Temperature: 145 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 2-phenylethylamine (0.51 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 145° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(2-phenylethyl)-(3-(naphthalen-2-yloxy)propyl)amine, solid, m.p. 270° C., (yield 0.65 gm, 93.7%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[N+](C1C=C(S(O[CH2:26][C@@H:27]2[O:29][CH2:28]2)(=O)=O)C=CC=1)([O-])=O>CN(C)C=O.C(OCC)(=O)C.CCCCCCC>[O:29]1[CH2:28][CH:27]1[CH2:26][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: Oc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: c1cc(OCC2CO2)c2cc[nH]c2c1

Procedure:
4-hydroxy indole (0.08 g, mmol) was dissolved in dimethylformamide (1.5 mL). Sodium hydride (0.02 g, 0.51 mmol) was slowly added to the reaction mixture followed by addition of (R)-glycidyl 3-nitrobenzene sulfonate (0.132, 0.51 mmol). A red color appeared. After 3 hour the reaction mixture was poured into a separatory funnel and ethyl acetate (100 mL) was added. The organic layer was washed 3 times with a 10% solution of sodium carbonate in water. The aqueous layers were discarded, the organic layer was dried with sodium sulfate and the solvent was removed by reduced pressure to yield crude product. The crude product was dissolved in ethyl acetate, Celite® (approximately 3 grams) was added, followed by removal of the solvent under reduced pressure. The Celite®/reaction mixture was loaded into an Isco solid phase loading cartridge. Flash chromatography was carried out using an Isco Companion automated chromatography system, silica column (4 g), initially holding at 5% ethyl acetate in heptane for 3 column volumes, increasing the ethyl acetate concentration to 60% over 40 column volumes, holding at 60% ethyl acetate for 10 more column volumes to yield the title compound as a residue.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH2:26][CH:27]=[CH2:28])[C@@:10]2([N:22]=[N+]=[N-])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].P(C)(C)C>C1COCC1.O.CCOCC>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH2:26][CH:27]=[CH2:28])[C@@:10]2([NH2:22])[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:5])[CH3:2]
Reactant: C=CCO[C@@H]1C[C@H]2[C@H](C(=O)OCC)[C@H]2[C@]1(N=[N+]=[N-])C(=O)OCc1ccccc1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C=CCO[C@@H]1C[C@H]2[C@H](C(=O)OCC)[C@H]2[C@]1(N)C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 49.9 %

Procedure:
To a solution of (1S,2R,3R,5R,6S)-3-allyloxy-2-azido-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIII-2) (101 mg, 0.262 mmol) in THF (3.9 mL) and H2O (0.4 mL) was added Me3P (0.29 mL, 0.29 mmol, 1 M sol. in THF) and stirring was continued at 23° C. for 3 h. The reaction mixture was diluted with ether, washed with sat. NaHCO3 -sol., brine and dried over Na2SO4. The crude product was purified by silica gel column chromatography with hexane/EtOAc 1:1 (+small amount of Et3N) to give (1S,2R,3R,5R,6S)-3-allyloxy-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIV-2) (47 mg, 50%) as a light brown oil. 1H-NMR (250 MHz, CDCl3) □1.24 (3H, t, J=7.1 Hz), 1.76 (1H, t, J=3.5 Hz), 1.93 (2H, bs), 1.99 (1H, m), 2.07-2.18 (2H, m), 2.31 (1H, dd, J=12.5, 7 Hz), 3.45 (1H, bt, J=8 Hz), 3.93 (2H, bd,J=6 Hz), 4.12 (2H, q, J=7.1 Hz), 5.10-5.35 (4H, m), 5.78 (1H, m), 7.28-7.38 (5H, m); MS[ISP] 360 [(M+H)+ ]; □D20 -10.67° (c=1.00, CHCl3).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH3:6][C:7]1[CH:8]=[C:9]2[C:14](=O)[O:13][C:11](=[O:12])[C:10]2=[CH:16][CH:17]=1>O>[CH3:6][C:7]1[CH:8]=[C:9]2[C:14](=[O:13])[N:2]([OH:3])[C:11](=[O:12])[C:10]2=[CH:16][CH:17]=1
Reactant: NO
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)C(=O)N(O)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride in an amount of 21.4 g was dissolved in 80 ml of distilled water. To this solution, 12.3 g of NaOH dissolved in 50 ml of distilled water was added over a period of 30 minutes as the solution was cooled in an ice bath. Thereto, 50.0 g of 4-methylphthalic anhydride was further added, and stirred for 1 hour at room temperature, followed by 4-hour reflux. The reaction solution was cooled in an ice bath, and the powdery matter thus precipitated was filtered off and washed with water. The resultant crude crystals were recrystallized from an acetone/water mixture to give 27.0 g of 4-methyl-N-hydroxyphthalimide.
Reaction SMILES: O[CH2:2][C:3]([O:5]C)=[O:4].ClC([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(Cl)=O>C1COCC1.O>[C:12]1([CH2:2][C:3]([OH:5])=[O:4])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CO
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccccc1
Yield: 166.9 %

Procedure:
A mixture of methyl 2-hydroxyacetate (0.2 mol) in THF (100 ml) was stirred on an ice bath. 2-Chloro-2-phenylacetyl chloride (0.132 mol) was added dropwise. The mixture was stirred overnight, poured out in water and then stirred for 20 minutes. The mixture was extracted with DEPE. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 30 g of benzeneacetic acid, α-chloro-, 2-methoxy-2-oxoethyl ester (intermediate 43).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH3:5][Li].[F:7][C:8]1[CH:37]=[CH:36][C:11]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][N:17]([C:20]3[CH:21]=[CH:22][C:23]4[N:27]=[C:26]([CH:28]5[CH2:31][C:30](=[O:32])[CH2:29]5)[N:25]([CH3:33])[C:24]=4[CH:34]=3)[C:16](=[O:35])[CH:15]=2)=[CH:10][CH:9]=1>C1COCC1>[F:7][C:8]1[CH:37]=[CH:36][C:11]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][N:17]([C:20]3[CH:21]=[CH:22][C:23]4[N:27]=[C:26]([CH:28]5[CH2:31][C:30]([OH:32])([CH3:5])[CH2:29]5)[N:25]([CH3:33])[C:24]=4[CH:34]=3)[C:16](=[O:35])[CH:15]=2)=[CH:10][CH:9]=1
Reactant: Cn1c(C2CC(=O)C2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Reactant: [Li]C
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cn1c(C2CC(C)(O)C2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of cerium chloride (532 mg) in THF (30 ml) was added methyllithium (3 M in diethoxymethane, 719 μl) at −78° C. A cold solution of 4-((4-fluorobenzyl)oxy)-1-(1-methyl-2-(3-oxocyclobutyl)-1H-benzimidazol-6-yl)pyridin-2(1H)-one (150 mg) in dry THF (3 ml) was slowly added to the reaction mixture at −78° C. and stirred for 1 h at the same temperature. The reaction mixture was quenched with saturated NH4Cl at −78° C. and then warmed up to room temperature. The mixture was extracted with DCM, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) followed by purification by preparative HPLC to give the title compound (33 mg) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[F:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43](O)=[O:44])[CH:38]=[CH:39][C:40]=1[CH3:41].Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:43](=[O:44])[CH2:42][C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([F:34])[CH:36]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(CC(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(CC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1F
Reaction time: 0.17 h
Yield: 72.7 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotraiazole (0.4 g, 2.6 mmol) and 3-fluoro-4-methylphenylacetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(3-fluoro-4-methyl-phenyl)-acetamide (0.7 g, 70%) as a white solid: mp 148-150° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.06 min. (98%); 1H NMR (DMSO-d6) δ 2.04-2.07 (m, 1H), 2.20 (s, 3H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.52 (s, 2H), 4.70 (d, J=5.7 Hz, 2H), 5.12-5.18 (dd, J=5.1 and 12.7 Hz, 1H), 6.99-7.07 (dd, J=11.2 and 14.7 hz, 2H), 7.21 (t, J=8.0 Hz, 1H), 7.63-7.76 (dd, J=3.3 and 7.5 Hz, 1H), 7.77-7.83 (dd, J=7.6 and 11.9 Hz, 2H), 8.65 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 13.74 (13.78), 21.95, 30.90, 37.84, 41.41, 48.83, 115.31, 115.60, 121.89, 124.84 (124.87), 127.12, 131.02 (131.28), 131.51, 133.20, 134.66, 135.87 (135.97), 139.09, 158.77 (161.98), 166.90, 167.42, 169.78, 170.26, 172.73; Anal. Calcd. for C23H20N3O5F: C, 63.15; H, 4.61; N, 9.61; F, 4.34. Found: C, 62.78; H, 4.45; N, 9.32; F, 4.47.
Reaction SMILES: CC(C)(CO)CO.[CH3:8][C:9]1([CH3:18])[CH2:14][O:13][CH:12]([CH2:15][CH2:16][CH3:17])[O:11][CH2:10]1.P(=O)(O)(O)O>[Pd].O>[CH2:12]([O:11][CH2:10][C:9]([CH3:8])([CH3:18])[CH2:14][OH:13])[CH2:15][CH2:16][CH3:17]
Reactant: CCCC1OCC(C)(C)CO1
Agent: [Pd]
Agent: CC(C)(CO)CO
Agent: O=P(O)(O)O
Solvent: O
Product: CCCCOCC(C)(C)CO
Temperature: 200 °C
Reaction time: 2 h

Procedure:
90 g of 2,2-dimethyl-1,3-propanediol, 10 g of water, and 20 g of 5,5-dimethyl-2-propyl-1,3-dioxane were combined in a 300 mL autoclave with 1.5 g of 5% (by weight) Pd on carbon catalyst and 100 mg of phosphoric acid. The autoclave was sealed and purged twice with N2 and once with H2. The reactor was charged with H2 and heated to 200° C. The reactor was then brought to an operating pressure of 10.3 MPa and stirring commenced at 750 rpm. Pressure was maintained through the duration of the experiment. After 2 h, the autoclave was cooled and remaining gas vented. The autoclave was opened, its contents filtered, and the filtrate analyzed by gas chromatography (GC). 94% conversion of the acetal and 99% selectivity to 3-butoxy-2,2-dimethyl-propanol were observed.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[C:7](/[NH:14][CH:15]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[CH3:16])=[C:8](\[C:12]#[N:13])/[C:9]([OH:11])=O.[CH:22]([NH2:25])([CH3:24])[CH3:23].OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:14][CH:15]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[CH3:16])=[C:8]([C:12]#[N:13])[C:9]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:11]
Reactant: CC(C)N
Reactant: CC(N/C(=C(/C#N)C(=O)O)c1sccc1Br)c1nccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NC(=O)C(C#N)=C(NC(C)c1nccs1)c1sccc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a solution of (2Z)-3-(3-bromo-2-thienyl)-2-cyano-3-{[1-(1,3-thiazol-2-yl)ethyl]amino}acrylic acid (0.18 g, 0.468 mmol, 1 eq.) in 5 ml of DCM (CH2Cl2) were added isopropylamine (0.083 g, 1.40 mmol, 3 eq.), hydroxybenzotriazole (HOBT) (0.066 g, 0.49 mmol, 1.05 eq.) and diisopropylethylamine (DIPEA) (0.090 g, 0.70 mmol, 1.5 eq.). The reaction was cooled to 0° C. and dicyclohexylcarbodiimide (DCC) (0.101 g, 0.49 mmol, 1.05 eq.) was added. Stirring was allowed overnight and the solid formed removed by filtration. The solvent was removed under reduced pressure and the residual oil submitted to chromatography on silica gel to give 2Z)-3-(3-bromo-2-thienyl)-2-cyano-N-isopropyl-3-{[1-(1,3-thiazol-2-yl)ethyl]amino}acrylamide (0.090 g, 43% yield) as a white solid and a mixture of atropoisomers.
Reaction SMILES: [CH:1]1([CH:11]2[CH2:13][CH2:12]2)[CH2:3][CH:2]1[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[NH2:10].C(=O)([O-])[O-].[K+].[K+].[F:20][CH:21]([F:32])[C:22]1[C:26]([C:27](Cl)=[O:28])=[C:25]([F:30])[N:24]([CH3:31])[N:23]=1>C(#N)C>[CH:1]1([CH:11]2[CH2:13][CH2:12]2)[CH2:3][CH:2]1[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[NH:10][C:27]([C:26]1[C:22]([CH:21]([F:32])[F:20])=[N:23][N:24]([CH3:31])[C:25]=1[F:30])=[O:28]
Reactant: NC1CCCCC1C1CC1C1CC1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1nc(C(F)F)c(C(=O)NC2CCCCC2C2CC2C2CC2)c1F
Temperature: 25 °C
Yield: 41.2 %

Procedure:
To a mixture of 0.489 g (2.73 mmol) 2-[1,1′-bi(cyclopropyl)-2-yl]cyclohexanamine and 0.565 g (4.09 mmol) potassiumcarbonate in 30 ml Acetonitrile was added 0.638 g (3.00 mmol) 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl chloride and stirred at ambient temperature over night. At the end of the reaction the reaction mixture was extracted with ethylacetate and water. The organic layer was dried with natriumsulfate and the solvent was removed by vacuum. The crude product was purified by column chromathography (Solvent: Cyclohexane/ethylacetate gradient). Finally 0.40 g (33%) of N-{2-[1,1′-bi(cyclopropyl)-2-yl]cyclohexyl}-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide with a purity of 87% LC-MS was isolated. logP (acid) of 4.02.