Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]=[C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH2:12])[CH2:5][CH2:4]1.[O-:13][C:14]#[N:15].[K+]>O>[O:2]=[C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH:12][C:14]([NH2:15])=[O:13])[CH2:5][CH2:4]1
Reactant: NC1CCC(=O)c2sccc21
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC1CCC(=O)c2sccc21

Procedure:
An aqueous solution of 4,5,6,7-tetrahydro-7-oxobenzo[b]thiophen-4-amine hydrochloride (1.01 g/5 ml water) is treated with 0.81 g of potassium cyanate in 2 ml of water at pH 6-7 to afford the title compound, which is collected and washed with water to afford 0.93 g, m.p. 241° C. to 242° C. dec.
Reaction SMILES: [C:1]12([NH:12][C:13](=[O:17])[CH:14]([Cl:16])[CH3:15])[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH:5]1[CH2:11][CH:2]2[CH2:3][CH2:4]1.C1(=O)[NH:22]C(=O)C2=CC=CC=C12.O.NN.Cl>>[ClH:16].[C:1]12([NH:12][C:13](=[O:17])[CH:14]([NH2:22])[CH3:15])[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH:5]1[CH2:11][CH:2]2[CH2:3][CH2:4]1
Reactant: CC(Cl)C(=O)NC12CCCC(C1)C1CCC2C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Agent: NN
Solvent: O
Product: CC(N)C(=O)NC12CCCC(C1)C1CCC2C1
Yield: 32 %

Procedure:
Under the same conditions as described in sections (D) and (E) of Example 8, N-(1-tricyclo[4.3.1.12,5 ]undecyl)-2-chloropropionamide was converted to the phthalimide derivative, the derivative was converted to an amine by 80% hydrazine hydrate and the amine was neutralized by hydrogen chloride gas to obtain viscous N-(1-tricyclo[4.3.1.12,5 ]undecyl)-2-aminopropionamide hydrochloride in a yield of 32%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[NH:13][C:12]2=[O:21])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C1COCC1>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:21])[C:11]2=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH:10]=2)[CH2:6][O:7]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Reaction time: 16 h
Yield: 80.4 %

Procedure:
A mixture of 3-(6-amino-3H-isobenzofuran-1-ylidene)-5-chloro-1,3-dihydro-indol-2-one (100 mg, 0.33 mmol), pyridine (1 ml) and methanesulfonyl chloride (76 mg, 0.66 mmol) in THF (3.5 ml) was stirred for 16 hours, and was then poured into water (100 ml). The solid was filtered, washed with water and dried under vacuum to give a crude product. The crude product was triturated with MeOH/water to provide N-[3-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-yl]-methanesulfonamide as a yellow solid (100 mg, 81%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:24])=[CH:6][C:7]([Cl:23])=[C:8]([CH:22]=1)[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:13]1)=[O:10])([O-])=O>[Ni]>[NH2:24][C:5]1[C:4]([NH2:1])=[CH:22][C:8]([C:9]([NH:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([F:19])([F:20])[F:21])[CH2:16][CH2:17]2)=[O:10])=[C:7]([Cl:23])[CH:6]=1
Reactant: Nc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Product: Nc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N

Procedure:
5-Nitro-2-chloro-4-amino-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-benzamide was hydrogenated with Ra—Ni in analogy to example 66g. The crude material was directly used without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH2:8].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]([CH2:26][N:27]([CH3:37])[C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)([OH:25])[CH2:21][CH2:20]2)=[CH:13][CH:12]=1)#[N:10].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][C:22]([CH2:26][N:27]([CH3:37])[C:28]3[CH:36]=[CH:35][C:31]([C:32]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:33])=[CH:30][CH:29]=3)([OH:25])[CH2:23][CH2:24]2)=[CH:15][CH:16]=1)#[N:10]
Reactant: NOC1CCCCO1
Reactant: CN(CC1(O)CCN(CCc2ccc(C#N)cc2)CC1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC1(O)CCN(CCc2ccc(C#N)cc2)CC1)c1ccc(C(=O)NOC2CCCCO2)cc1
Temperature: 0 °C
Yield: 61.9 %

Procedure:
A solution of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.36 g) in anhydrous dimethylformamide (5 mL) was added dropwise to a solution of the compound (0.80 g) obtained in Example 1, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.47 g) and 1-hydroxybenzotriazole monohydrate (0.39 g) in anhydrous dimethylformamide (20 mL) under cooling with ice-water under nitrogen atmosphere, followed by stirring at the same temperature for twenty minutes and further stirring at room temperature for two days. After adding water, the mixture was treated with saturated aqueous sodium hydrogen carbonate solution to be adjusted to pH 8 and was extracted with ethyl acetate. The combined organic layer was sequentially washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=4:1), was crystallized from ether to yield the titled compound (620 mg) as crystals.
Reaction SMILES: B1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:2]1CC[CH2:5]2.[C:10]1([CH3:37])[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH2:21][C@@H:20]2[CH:35]=[CH2:36])(=[O:18])=[O:17])=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.IC1C=CC=CC=1.[OH-].[Na+]>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:35]([CH:20]1[CH2:21][N:22]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:23][CH2:24][N:19]1[S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:37])=[CH:11][CH:12]=1)(=[O:17])=[O:18])[CH2:36][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=1
Reactant: B1C2CCCC1CCC2
Reactant: C=C[C@H]1CN(S(=O)(=O)c2ccc(C)cc2)CCN1S(=O)(=O)c1ccc(C)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Ic1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)C(CCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Add 9-BBN (0.5 M THF solution, 13.7 mL, 6.85 mmol) to a 100 mL schlenk flask containing (S)-1,4-bis(toluene-4-sulfonyl)-2-vinyl-piperazine(0.96 g, 2.3 mmol) in THF (5 mL), at room temperature under nitrogen and stir. After 18 hours, treat the reaction with tetrakis(triphenylphosphine) palladium (53 mg, 0.046 mmol), triphenyl phosphine (94.6 mg, 0.36 mmol), iodiobenzene (0.703 g, 3.4 mmol) and 3N NaOH (2.8 mL, 8.4 mmol) and heat to reflux. After 24 hours, cool the reaction to room temperature, remove in vacuo the THF solvent, dilute the residue with CH2Cl2, wash with 1N HCl, brine, and dry over Na2SO4. Purification by flash chromatography twice (Gradient: Hexanes/CH2Cl2=50/50, to Hexanes/CH2Cl2/EtOAc=40/40/10), and recrystallization in MeOH gives 860 mg (75%) of the title compound: mass spectrum (electrospray): (m/z)=499.2 (M+1); 1H NMR (CDCl3): δ7.58–7.54 (m, 4H), 7.33–7.20 (m, 7H), 7.19–7.07 (m, 2H), 3.99 (m, 1H), 3.81–3.78 (m, 1H), 3.64–3.60 (m, 2H), 3.22 (dt, 1H, J=3.2 Hz, J=12.4 Hz), 2.57–2.41 (m, 2H), 2.41 (s, 3H), 2.33 (s, 3H), 2.33–2.20 (m, 2H), 2.03–1.98 (m, 1H), 1.75–1.63 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][OH:29])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH3:31])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2

Procedure:
The title compound was prepared by the method of Preparation 2b using (R)-1-(4-fluorophenyl)-4a-hydroxymethyl-1,4,4a,5,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester and iodomethane. LCMS (Method D): 414 (M+H)+, Retention time 4.3 minutes.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH2:8](O)[CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[O:10]1[C:4]2([CH2:5][CH2:6][S:1][CH2:2][CH2:3]2)[O:7][CH2:8][CH2:9]1
Reactant: OCCO
Reactant: O=C1CCSCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C1COC2(CCSCC2)O1

Procedure:
A mixture of 5.0 g of tetrahydrothiopyran-4-one, 2.5 ml of ethylene glycol, 0.230 g of p-toluenesulfonic acid and 125 ml of benzene is stirred at reflux temperature for 2.5 hours. The water formed is removed using a Dean-Stark trap. The reaction is treated with saturated sodium bicarbonate, water, saturated sodium chloride, dried and concentrated in vacuo to give 6.52 g of the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([O:13]CC)=O)[N:7]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.[OH-].[Na+].O.CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH:33][C:11]([C:8]1[N:7]=[C:6]([CH2:5][C:4]2[CH:16]=[CH:17][C:18]([F:19])=[C:2]([F:1])[CH:3]=2)[O:10][N:9]=1)=[O:13]
Reactant: CCOC(=O)c1noc(Cc2ccc(F)c(F)c2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccc(F)c(F)c2)n1
Yield: 44.7 %

Procedure:
This compound was prepared according to method F with ethyl 5-(3,4-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.116 g; 0.433 mmol) in methanol (2 mL) and sodium hydroxide in water (2M, 2 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol) in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.0806 g (45%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3,4-difluorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Clc1nc2ccccc2o1
Product: Fc1cc(Br)ccc1Nc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.6 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline 1.00 g, 5.26 mmol) in toluence (25 mL) was added 2-chlorobenzoxazole (0.66 mL, 5.79 mmol, 1.1 equiv). The purple solution was heated at reflux for 30 min. and then at 100° C. for 17 hours. The resulting white suspension/purple solution was cooled to room temperature and the precipitate was filtered. The filter cake was washed with five 2-mL portion of heptane to afford N2-(4-bromo-2-fluorophenyl)-1,3-benzoxazol-2-amine (1.480 g, 92%) as a light purple powder. RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 minutes at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=12.87 min., 97%; and m/z 306.7(MH+).
Reaction SMILES: [Si:1]([O:18][C@H:19]([CH2:31][C@H:32]([O:35][Si:36]([C:49]([CH3:52])([CH3:51])[CH3:50])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:33]=[CH2:34])[CH2:20][C:21]#[C:22][CH2:23][O:24]C1CCCCO1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[C:14]([Si:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:18][C@H:19]([CH2:31][C@H:32]([O:35][Si:36]([C:49]([CH3:50])([CH3:51])[CH3:52])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH:33]=[CH2:34])[CH2:20][C:21]#[C:22][CH2:23][OH:24])([CH3:15])([CH3:16])[CH3:17]
Reactant: C=C[C@H](C[C@H](CC#CCOC1CCCCO1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: C=C[C@H](C[C@H](CC#CCO)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 86.1 %

Procedure:
25.16 g (34.4 mmol) of (5S,7S)-2-[5,7-bis-(tert-butyl-diphenylsilanyloxy)-non-8-en-2-ynyloxy]-tetrahydro-pyran was deprotected by treatment at ambient temperature with 1.30 g (15 mol %) of pyridinium p-toluenesulfonate in 290 ml of abs. MeOH. The solution gradually became homogeneous. After 18 h the reaction mixture was quenched by pouring onto crushed ice/Na2CO3, extracted with ether, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=82/18) yielded 19.17 g of (5S,7S)-5,7-bis-(tert-butyl-diphenyl-silanyloxy)-non-8-en-2-yn-1-ol as yellowish crystals of mp. 114-116°.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C([Cl:35])=O.CN(C)C=O>ClCCl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([Cl:35])=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Cc1ccc(C(Cc2ccc(C(=O)O)cc2)c2ccc(CC(C)C)cc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(C(Cc2ccc(C(=O)Cl)cc2)c2ccc(CC(C)C)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2,2-bis(4-isobutylphenyl)ethyl]benzoic acid (400 mg) in dichloromethane (10 ml) were added oxalyl chloride (0.1 ml) and a drop of N,N-dimethylformamide at 0° C. After stirred at 20° C. for 1 hour, the,mixture was evaporated to give 4-[2,2-bis(4-isobutylphenyl)ethyl]benzoyl chloride (450 mg) as pale yellow oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([Cl:17])[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[O:18]=[C:19]1[C@@H:24]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][CH2:22][CH2:21][NH:20]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I>[Cl:17][C:14]1[N:13]=[CH:12][C:11]2[CH:10]=[N:9][N:8]([C:6]3[N:7]=[C:2]([N:20]4[CH2:21][CH2:22][CH2:23][C@H:24]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[C:19]4=[O:18])[CH:3]=[CH:4][CH:5]=3)[C:16]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1=O
Reactant: Clc1cc2c(cn1)cnn2-c1cccc(Br)n1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)C1=O
Temperature: 110 °C
Yield: 47.2 %

Procedure:
A solution containing 1-(6-bromo-2-pyridyl)-6-chloro-pyrazolo[4,3-c]pyridine (200 mg, 0.646 mmol), tert-butyl N-[(3S)-2-oxo-3-piperidyl]carbamate (166 mg, 0.775 mmol), Copper(I) iodide (123 mg, 0.646 mmol), Potassium carbonate (107 mg, 0.775 mmol) and N,N′-Dimethylethylenediamine (114 mg, 1.29 mmol) was stirred at 110° C. 4 h. The reaction was filtered through celite and concentrated. The crude product purified by isco column (EtOAc/Hep eluted at 70% EtOAc) to give the desired product 135 mg 47% yield. MS (ESI) m/z: 443.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:11][C:12](=[O:15])[CH2:13][CH2:14][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: C=CC(=O)NC(C)(C)c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: CC(C)(NC(=O)CCn1ccnc1)c1ccc(Cl)cc1

Procedure:
A mixture of N-[1-(4-chlorophenyl)-1-methylethyl]acrylamide (200 g), imidazole (60.9 g), Triton B (20 ml) and 1,4-dioxane (1600 ml) was stirred and boiled under reflux for 20 hours. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane (2000 ml). The mixture was extracted with 2M hydrochloric acid. The combined aqueous extracts were basified with 2M sodium hydroxide solution and extracted with dichloromethane to give N-[1-(4-chlorophenyl)-1-methylethyl]-3-(imidazol-1-yl)propionamide, m.p. 154°-155° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10](O)=[O:11])=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:59][C@@H:60]([CH2:75][C:76]1[CH:81]=[C:80]([F:82])[CH:79]=[C:78]([F:83])[CH:77]=1)[C@H:61]([OH:74])[CH2:62][NH:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([CH:71]([CH3:73])[CH3:72])[CH:66]=1>CN(C=O)C>[F:82][C:80]1[CH:81]=[C:76]([CH:77]=[C:78]([F:83])[CH:79]=1)[CH2:75][C@H:60]([NH:59][C:10](=[O:11])[C:9]1[CH:13]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=1)[C@H:61]([OH:74])[CH2:62][NH:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([CH:71]([CH3:73])[CH3:72])[CH:66]=1
Reactant: CC(C)c1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nccs2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(C(C)C)c2)cc(-c2nccs2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[(Dipropylamino)carbonyl]-5-(1,3-thiazol-2-yl)benzoic acid is dissolved in DMF (8 mL), and diisopropylethylamine (456 μL, 2.6 mmol), HATU (342 mg, 0.9 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-isopropylbenzyl)amino]butan-2-ol dihydrochloride (350 mg, 0.83 mmol) are added. The reaction stirred at room temperature 1 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) provides the title compound as the free base. The residue is dissolved in diethyl ether (5 mL) and 1N hydrochloric acid in diethyl ether (2 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 663.3 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([NH:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:14]
Reactant: CC1=C(C(=O)O)SCCO1
Reactant: CCOC(=O)c1ccc(C)c(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(C)c(NC(=O)C2=C(C)OCCS2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
Thionyl chloride (4.5 g, 0.038 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (6.0 g, 0.037 mole) and methylene chloride (100 ml . The mixture was warmed to 30°-35° C. for 3 hours, then evaporated under reduced pressure. The residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (100 ml), and the ice-chilled solution treated dropwise with a solution of ethyl 3-amino-4-methylbenzoate (6.7 g, 0.037 mole) and triethylamine (4.0 g, 0.040 mole) in methylene chloride (100 ml). The reaction mixture was stirred overnight at room temperature and then worked up by washing in sequence with water, dilute hydrochloric acid, water, 2% sodium hydroxide and water. Evaporation of the solvent gave an oil, which solidified. After recrystallization from ethanol (30 ml), the product (7.1 g, 59% yield) melted at 105°-107° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([CH2:25][OH:26])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[CH3:29]>CN(C)C=O.[Ag]=O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:10]([CH2:25][O:26][CH3:29])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Reactant: CI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: COC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1R,3R,4S)-(4-benzyloxycarbonylamino-3-hydroxymethyl-cyclohexyl)carbamic acid tert-butyl ester (1.8 g) was dissolved in N,N-dimethylformamide (15 mL). Iodomethane (50 mL) was added, followed by silver oxide (5.52 g), and the mixture was stirred at room temperature overnight. The mixture was filtered through Celite and the solids were washed with ethyl acetate. The filtrate was washed sequentially with water and brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography to provide (1R,3R,4S)-(4-benzyloxycarbonylamino-3-methoxymethylcyclohexyl)carbamic acid tert-butyl ester as a colorless gum (1.78 g). MS found: (M+H)+=393.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[F:6][C:7]1[CH:8]=[C:9]([NH2:16])[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=[O:12].C(N(CC)CC)C>O1CCOCC1>[F:6][C:7]1[CH:8]=[C:9]([NH:16][C:1](=[O:4])[CH2:2][CH3:3])[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=[O:12]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: CCC(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cc(F)ccc1C(=O)O

Procedure:
Propionyl chloride (1.7 ml) was added to a solution of 4-fluoroanthranilic acid (1 g) and triethylamine (2.8 ml) in 1,4-dioxane (30 ml). The mixture was heated under reflux for 4 hours, cooled and concentrated under reduced pressure. The residue was suspended in ethyl acetate and extracted with water. The organic phase was dried and evaporated and the residue purified by silica gel chromatography to give 4-fluoro-N-propionylanthranilic acid, mp 170°-171°. (Compound 9).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.4 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (42.8 mg, 36%).