Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:47])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:32]([Br:47])=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(-c5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Br)c(-c5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of compound 9-1 (104 mg, 0.2 mmol) in CHCl3 (5 mL) was added NBS (40 mg 0.22 mmol.) and the mixture was stirred at room temperature overnight. The mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 83 mg of 9-3.
Reaction SMILES: [CH:1]1([CH2:5][NH:6][C@H:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:4][CH2:3][CH2:2]1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]1([CH2:5][N:6]([C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[C:20]([F:19])([F:30])[F:31])[C@H:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NCC2CCC2)C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](N(CC2CCC2)C(=O)c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.2 %

Procedure:
tert-butyl (3S)-3-[(cyclobutylmethyl)amino]pyrrolidine-1-carboxylate (0.80 g, 3.15 mmol) in toluene (10 ml) was treated with 2-(trifluoromethyl)benzoyl chloride (0.55 ml, 3.78 mmol) and triethylamine (0.88 ml, 6.3 mmol). The solution was stirred for 18 hours at room temperature and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient of pentane:ethylacetate (4:1 by volume) changing to pentane:ethylacetate (1:1 by volume) to afford the title compound as a colorless oil (1.40 g, crude) which is used directly in the next step.
Reaction SMILES: [C:1]1([O:11][C:12]2[S:18][CH:17]3[N:14]([C:15](=[O:19])[CH2:16]3)[C:13]=2[C:20]([O:22]CC2C=CC([N+]([O-])=O)=CC=2)=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+:37]>O1CCOCC1.O.[Pd]>[C:1]1([O:11][C:12]2[S:18][CH:17]3[N:14]([C:15](=[O:19])[CH2:16]3)[C:13]=2[C:20]([O-:22])=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Na+:37]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(Oc2cccc3ccccc23)SC2CC(=O)N12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C([O-])C1=C(Oc2cccc3ccccc23)SC2CC(=O)N12

Procedure:
A mixture of a solution of 800 mg of 4-nitrobenzyl 3-(1-naphthyloxy)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 150 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>N1CCCCC1.C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:31]=[C:30]3[C:26]([C:27](=[CH:12][C:9]4[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=4[CH3:11])[C:28](=[O:32])[NH:29]3)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(CCC(=O)O)c2C)cc1
Yield: 56.5 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (98 mg), 120 mg 6-(4-methoxyphenyl)-2-oxindole and 3 drops piperidine in 2 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 118 mg (57%) of the title compound as a brown solid.
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][C:8]2([CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]2)[CH2:7]1.[CH3:19][Si:20]([CH3:27])([CH3:26])N1C=CN=C1>C1COCC1>[CH3:17][C:2]([O:1][Si:20]([CH3:27])([CH3:26])[CH3:19])([CH3:18])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][C:8]2([CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]2)[CH2:7]1
Reactant: CC(C)(O)CCCC1CCC2(CCCC(=O)C2)C1
Reactant: C[Si](C)(C)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(CCCC1CCC2(CCCC(=O)C2)C1)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of a 2-(4-hydroxy-4-methylpentyl)-spiro[4.5]decan-7-one (19a) (50 mg, 0.198 mmol) in dry THF (1 mL) was added 1-(trimethylsilyl)-imidazole (0.146 mL, 0.99 mmol). The reaction mixture was stirred at room temperature for 4 hours and the solvent was then removed in vacuo. The resulting residue was purified over silica (petroleum ether/EtOAc, 95:5) to afford the desired product which was used directly for the next reaction step.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[CH2:16][C:17]([NH:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[O:18]>>[CH3:1][CH:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH2:16][C:17]([NH:19][C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])=[O:18])[CH2:3]1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: Cc1ccc(N2CCNCC2C)cc1
Product: Cc1ccc(N2CCN(CC(=O)Nc3c(C)cccc3C)CC2C)cc1

Procedure:
The title compound was prepared from (±)-3-methyl-4-(4-methylphenyl)piperazine (0.1 g) and 2-chloro-N-(2,6-dimethylphenyl)acetamide (0.1 g) by the method of Example 1 step (iii) as a white solid. Yield 0.056 g.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[NH:21]1[CH2:25][CH2:24][CH:23]([CH2:26][NH2:27])[CH2:22]1>C(#N)C>[NH2:27][CH2:26][CH:23]1[CH2:24][CH2:25][N:21]([C:3]2[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:5]=34)[CH2:22]1
Reactant: NCC1CCNC1
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CC#N
Product: CC1COc2c(N3CCC(CN)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 922.4 %

Procedure:
0.75 g (0.27 mmole) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, 40 ml acetonitrile, and 0.80 g (8.0 mmole) of 3-pyrrolidinemethanamine were refluxed overnight. The solvent was removed at reduced pressure and the residue titurated with 40 ml of ethanol/ether (1:1), to give 0.90 g of 10-[3-(aminomethyl)-1-pyrrolidinyl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, mp 213°-216° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([OH:12])=[CH:5]2.[CH3:13]N(C)C=O.CI>CO.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([O:12][CH3:13])=[CH:5]2
Reactant: Oc1cc2cc(Br)ccc2cn1
Reactant: CN(C)C=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CI
Solvent: CO
Product: COc1cc2cc(Br)ccc2cn1
Temperature: 25 °C
Reaction time: 0.27 h
Yield: 14 %

Procedure:
A mixture of 6-bromoisoquinolin-3-ol (606 mg, 2.70 mmol), silver carbonate (1.5 g, 5.3 mmol), and N,N-dimethylformamide (12 mL) was stirred at room temperature for 16 minutes. Methyl iodide (186 μL, 2.97 mmol) was added and the reaction was left stirring for 18 hours. The reaction was diluted with methanol and filtered through Celite. The filtrate was concentrated and purified by flash column chromatography to give the title compound (90 mg, 14%). +ESI (M+H+1) 240.0; 1H NMR (400 MHz, CDCl3, δ): 8.91 (s, 1H), 7.86 (d, J=1.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.43 (dd, J=8.8, 1.8 Hz, 1H), 6.90 (s, 1H), 4.02 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@@H:4]([CH3:36])[NH:5][C:6](=[O:35])[C@H:7]([CH2:19][CH2:20]/[CH:21]=[C:22](/[C:31]([O:33][CH3:34])=[O:32])\[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[H][H]>C(O)(=O)C.C1COCC1.Cl([O-])(=O)(=O)=O.[Rh+]>[CH3:1][O:2][C:3](=[O:37])[C@@H:4]([CH3:36])[NH:5][C:6](=[O:35])[C@@H:7]([CH2:19][CH2:20][CH2:21][CH:22]([C:31]([O:33][CH3:34])=[O:32])[NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: COC(=O)/C(=C/CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OC)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Rh+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C(CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C)C(=O)OC)NC(=O)OC(C)(C)C
Yield: 92.6 %

Procedure:
A solution of 8.5 g of 47c in 25 mL of acetic acid and 250 mL of THF is hydrogenated at 48 psi of hydrogen over 0.5 g of (bicyclo(2.2.1.)hepta-2,5-diene[2S, 3S]bis(diphenylphosphino)butane)rhodium(I) perchlorate for 18 h. The reaction is filtered and evaporated to a residue. The residue is chromatographed using variable gradient hexane-ethyl acetate to give 7.9 g of reduced product as a residue. Multiple crystallizations give 2.6 g of diastereomerically pure 40c. NMR(CDCl3) δ 1.40(d,J=6 Hz,3H); 1.43(s,9H); 1.60-1.97(m,6H); 3.73(s,3H); 3.74(s,3H); 4.12-4.37(m,2H); 4.52-4.61(m,1H); 5.12(bs,3H); 5.44-5.55(b s,1H); 6.73(b s,1H); 7.36(b s,5H); 13C-NMR: δ 18.02(CH--CH3); 21.12(CH2 --CH2 --CH2); 28.23(--OC(CH3)3); 31.87 (--CH2 --CH2 --); 32.29 (--CH2CH2 --); 47.99 (--CHCH3); 52.23(--OCH3); 52.38(--OCH3); 52.75(OCCCHN); 54.41(OCCHN); 67.01(--OCH2Ar); 79.97(--OC(CH3)3); 127.99 (phenyl ring carbon); 128.09 (phenyl ring carbon); 128.44 (ArCH); 136.13 (ArCC); 155.48 (OCONH); 156.23 (OCONH); 171.10 (--CONH--); 173.03 (--CO2 --2X); IR(KBr) (cm-1): 3340(s); 1760(s); 1740(s); 1680(s); 1660 (s); 1660 (s); 1520 (s); MS (FAB) m/z 546 (M+Na)+ ; 524 (MH)+ ; 424 (MH--C4H8CO2)+ ; Anal. Calcd: C, 57.35; H, 7.12; N, 8.03; Found: C, 57.23; H, 7.27; N, 8.03; rotation [α]D25 -9±1; m.p. 120°-121° C.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][C:22]1[C:27]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:10][C@H:11]([N:13]5[CH2:18][CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:12]4)[S:8][C:4]=3[CH:3]=2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@H](N5CCCCC5)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 44A for the product of Example 1E and substituting the product of Example 2A for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.02 (d, J=8.24 Hz, 1H) 7.76 (s, 1H) 7.47 (d, J=7.63 Hz, 1H) 7.40 (dd, J=8.54, 1.53 Hz, 1H) 7.08 (d, J=7.63 Hz, 1H) 3.83-3.92 (m, 1H) 3.42-3.53 (m, 1H) 2.92-3.04 (m, 1H) 2.62-2.74 (m, 3H) 2.60 (s, 3H) 2.50 (s, 3H) 2.08 (s, 4H) 1.71-1.83 (m, 4H) 1.50-1.61 (m, 2H). MS: (M+H)+=378.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl[CH2:11][C:12]([O:14][CH3:15])=[O:13].O.O.O.C([O-])(=O)C.[Na+].CO>O>[CH3:15][O:14][C:12](=[O:13])[CH2:11][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COC(=O)CCl
Reactant: COc1cccc(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CNc1cccc(OC)c1

Procedure:
A mixture of 3-methoxyaniline (61.6 g), methyl chloroacetate (44 ml), sodium acetate trihydrate (114 g) and methanol (70 ml) was heated under reflux for 18 h. The mixture was poured into water (500 ml) and extracted with dichloromethane (3×250 ml). The combined, dried organic extracts were evaporated and the residue was treated with 10% concentrated sulphuric acid in methanol (250 ml). After 3 h the solution was poured carefully into 8% sodium bicarbonate (1200 ml) and partitioned with ether (4×500 ml). The combined organic extracts were washed successively with 0.5M citric acid solution (5×200 ml) and brine (500 ml), dried and evaporated to give an oil. Purification by FCC eluting initially with ether:petroleum ether 60°-80° (2:3) and then with ether:petroleum ether 60°-80° (1:1) gave the title compound (52 g) as an oil, t.l.c. (System A, 1:1) Rf 0.31.
Reaction SMILES: CS([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[C-:30]#[N:31].[K+]>C1C=CC=CC=1.CCCCC[N+](CCCCC)(CCCCC)CCCCC.[Br-].O>[C:30]([CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:31]
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [C-]#N
Agent: CCCCC[N+](CCCCC)(CCCCC)CCCCC
Agent: [Br-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
In 2 ml of benzene are dissolved 0.5 mmol of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone and 0.1 mmol of tetra-n-amylammonium bromide, and a solution of 0.55 mmol of potassium cyanide in 0.55 ml of water is added at 15° C. The mixture is stirred vigorously for 15 minutes and treated in the same manner as Example 20 to give (3S,4RS)-4-cyano-3-tritylamino-2-azetidinone with the (3S,4R):(3S,4S) ratio of 1:4.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[N:39]=[C:40]=[O:41]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:33]4[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=4[F:31])=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=Nc1c(F)cccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1)Nc1c(F)cccc1F
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 33.2 mg (0.21 mmol) of 2,6-difluorophenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 40 mg (75.9% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([O:34]C)=[O:33])[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([OH:34])=[O:33])[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)(=[O:22])=[O:23])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl)sulfonyl]-4-piperidine carboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl)sulfonyl]-4-piperidinecarboxylate (545 mg, 1.04 mmol) in 8 ml of tetrahydrofuran:methanol (1:1), and 1N sodium hydroxide (2.09 ml, 2.09 mmol) to obtain 446 mg (85%) of the acid. HR-MS: m/z Calculated for C23H25NO8S2 508.1094; Found 508.1073.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])[C:5]#[N:6].S(Cl)([Cl:19])=O.O>N1C=CC=CC=1>[Cl:19][CH2:2][CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])[C:5]#[N:6]
Reactant: N#CC(CCO)c1ccccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: N#CC(CCCl)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h

Procedure:
4-Hydroxy-2-(2-trifluoromethylphenyl) butyronitrile (2.6 g) was dissolved in pyridine (10 mL). Thionyl chloride (2.1 mL) was carefully added and the mixture was heated with stirring at 60° C. for four hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (1.3 g). The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C[Al](C)C.CO[C:11](=O)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([N:22]3[CH:27]=[CH:26][C:25]4[O:28][C:29]([C:31]5[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=5)=[CH:30][C:24]=4[C:23]3=[O:38])=[CH:19][CH:20]=2)[CH:15]=[N:14]1>C1(C)C=CC=CC=1.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:29]2[O:28][C:25]3[CH:26]=[CH:27][N:22]([C:18]4[CH:17]=[C:16]5[C:21](=[CH:20][CH:19]=4)[N:13]([CH2:12][C:11]4[NH:3][CH2:2][CH2:1][N:4]=4)[N:14]=[CH:15]5)[C:23](=[O:38])[C:24]=3[CH:30]=2)=[CH:32][CH:33]=1
Reactant: NCCN
Reactant: COC(=O)Cn1ncc2cc(-n3ccc4oc(-c5ccc(Cl)cc5)cc4c3=O)ccc21
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1c2cc(-c3ccc(Cl)cc3)oc2ccn1-c1ccc2c(cnn2CC2=NCCN2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 21.4 %

Procedure:
To a 0° C. solution of ethylenediamine (68 mL, 1.0 mmol) in toluene (0.36 mL) was slowly added trimethyl aluminium (0.50 mL, 10 M in toluene) over ten minutes. The solution was allowed to stir at 0° C. for 5 minutes; then a suspension of methyl-2-(5-(2-(4-chlorophenyl)-4-oxofuro[3,2-c]pyridin-5(4H)-yl)-1H-indazol-1-yl)acetate (0.22 g, 0.50 mmol) in toluene (7.27 mL) was added and the reaction mixture was heated to reflux. The reaction mixture was stirred at reflux for 18 h; then the reaction mixture was diluted with H2O (2 mL) and the solids were removed by filtration. The filtrate was extracted with CH2Cl2 (3×20 mL) and the extracts were dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/9:1 EtOH with NH4OH, 100:0 to 90:10) yielded the title compound (47.6 mg, 21%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.64 (s, 1H), 7.57-7.55 (m, 2H), 7.42 (dd, J=9.0, 2.0 Hz, 2H), 6.89 (d, J=7.0 Hz, 1H), 5.21 (s, 2H) 3.51 (br s, 1H), 3.30 (s, 4H); ESI MS m/z 444 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=15.8 min.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[F:17][C:18]([F:35])([F:34])[C:19]1[CH:20]=[CH:21][C:22]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)=[N:23][CH:24]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([N:1]=[CH:30][C:29]3[CH:28]=[CH:27][C:26]([O:25][C:22]4[CH:21]=[CH:20][C:19]([C:18]([F:35])([F:17])[F:34])=[CH:24][N:23]=4)=[CH:33][CH:32]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Yield: 52 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (100 mg) was then suspended in EtOH (4 mL) and 4-[{5-(Trifluoromethyl)pyridin-2-yl}oxy]benzaldehyde (230 mg, 1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((3-chlorophenyl)amino)-5-((4-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)amino)-1H-pyrazole-4-carbonitrile as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (217 mg, 52% yield).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[N:8]([N:12]=[C:13]([NH2:15])[N:14]=3)[CH:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.Cl[C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH3:28])([CH3:27])[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1>>[CH3:27][C:21]1([CH3:28])[C:20]2[C:24](=[CH:25][C:17]([NH:15][C:13]3[N:14]=[C:7]4[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)=[N:11][CH:10]=[CH:9][N:8]4[N:12]=3)=[CH:18][CH:19]=2)[NH:23][C:22]1=[O:26]
Reactant: CC1(C)C(=O)Nc2cc(Cl)ccc21
Reactant: Nc1nc2c(-c3cn[nH]c3)nccn2n1
Product: CC1(C)C(=O)Nc2cc(Nc3nc4c(-c5cn[nH]c5)nccn4n3)ccc21

Procedure:
8-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine synthesized as descried earlier, is reacted with 6-chloro-3,3-dimethyl-1,3-dihydro-indol-2-one under Buchwald Hartwig conditions using general procedure 2.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[CH3:31][C:32]1([CH3:41])[O:36][C@H:35]([CH2:37][CH:38]=O)[C:34](=[O:40])[O:33]1>CCOCC.CCOCC.C1COCC1>[CH3:2][O:3][CH:4]=[CH:38][CH2:37][C@H:35]1[O:36][C:32]([CH3:41])([CH3:31])[O:33][C:34]1=[O:40]
Reactant: CC1(C)OC(=O)[C@@H](CC=O)O1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC=CC[C@H]1OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 60.1 %

Procedure:
(Conditions modified from Duttone, F. E., et. al., J. Med. Chem. 2003, 46, 2057) To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (1.19 g, 3.48 mmol) in anhydrous ether (50 mL) at −10° C. under nitrogen was added phenyllithium (1.93 mL, 3.48 mmol) 1.8 M solution in diethyl ether, over 1 minute using a syringe. The mixture was stirred at 0° C. for 30 minutes and then cooled to −78° C. A solution of (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (Preparation D, Step B; 0.500 g, 3.16 mmol) in ether/THF 1:1 (50 mL) was introduced via addition funnel, and the reaction mixture was stirred at −78° C. for 1 hour and then warmed to ambient temperature and stirred for 4 hours. The crude was filtered and the residue was purified over silica gel (5-50% EtOAc in hexanes) to afford (R)-5-(3-methoxyallyl)-2,2-dimethyl-1,3-dioxolan-4-one (0.355 g, 1.90 mmol, 60% yield) as a clear, colorless oil (mixture of (E)- and (Z)-isomers).