Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([C@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)[C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][Cl:8])[CH:2]=[CH2:3].I[C:22]1[CH:23]=[C:24]2[CH2:39][C@@:29]3([C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:28][C:25]2=[N:26][CH:27]=1.C1(CNCC2CCCCC2)CCCCC1>CN(C=O)C.[Pd].C(P(CCCC)CCCC)CCC.C(P(CCCC)CCCC)CCC>[Cl:8][CH2:7][C:6]([CH3:10])([CH3:9])[C:5]([N:4]([C@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)[CH2:1]/[CH:2]=[CH:3]/[C:22]1[CH:23]=[C:24]2[CH2:39][C@@:29]3([C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:28][C:25]2=[N:26][CH:27]=1)=[O:11]
Reactant: C=CCN(C(=O)C(C)(C)CCl)[C@@H]1CCc2ccccc21
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc(I)cnc1C2
Agent: [Pd]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CCCCP(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(C)(CCl)C(=O)N(C/C=C/c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21)[C@@H]1CCc2ccccc21
Temperature: 120 °C

Procedure:
To a degassed solution of N-allyl-3-chloro-N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2,2-dimethylpropanamide (110. mg, 0.377 mmol, prepared in Step B), (6S)-3-iodo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (137 mg, 0.377 mmol, Intermediate 7) and N,N-dicyclohexylmethylamine (81.0 mg, 0.415 mmol) in DMF (3.77 mL) was added bis-(tri-1-butylphosphine) palladium(0) (57.8 mg, 0.113 mmol). This solution was once again degassed, before being sealed and heated in a microwave at 120° C. for 20 minutes. The reaction mixture was then diluted with DCM and washed twice with half-saturated brine. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a residue. The residue was then applied to a silica gel column for purification, eluting with a gradient of 1-7% MeOH in DCM to provide the title compound. MS: m/z=527 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:28]=1[NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:31]3[CH:30]=[CH:29][C:28]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[C:27]([O:26][CH3:25])[CH:32]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C

Procedure:
trans-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.0 g, 9.06 mmol), tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (3.48 g, 9.97 mmol), palladium tetrakistriphenyphosphine (0.63 g, 0.64 mmol) and sodium carbonate (2.30 g, 21.75 mmol) were mixed with ethylene glycol dimethyl ether (100 mL) and water (50 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (80:20) as mobile phase to give trans-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate (4.75 g, 98%). 1H NMR (DMSO-d6) δ 1.48 (m, 11H), 2.02 (m, 6H), 2.15 (s, 3H), 2.35 (m, 5H), 2.53 (m, 4H), 3.87 (s, 3H), 4.64 (m, 1H), 7.20 (m, 2H), 7.90 (d, J=8.15, 1H), 8.03 (s, 1H), 8.22 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH3:11])[CH3:4].CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.O>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[C:2]([C@@H:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH3:11])[CH3:4])([OH:25])=[O:1]
Reactant: C[C@@H](CO)[C@@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Product: C[C@@H](OC(=O)OCc1ccccc1)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)O

Procedure:
A solution of (3S,4S)-4-(1-(R)-hydroxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone (6.1 g) in acetone (60 ml) was treated with the Jones reagent, prepared from chromium trioxide (2.78 g), 98% sulfuric acid (4.4 g) and water (8.1 ml), at 10°-20° C. for 1 hour. The reaction mixture was quenched with isopropanol (0.5 ml) at 10°-20° C. for 15 minutes, diluted with ethyl acetate (122 ml) and washed with water (135 ml). The aqueous layer was separated from the organic layer and extracted with ethyl acetate (61 ml). The ethyl acetate extracts and the organic layer were combined together and extracted with 5% aqueous sodium bicarbonate solution (30 ml). The extract was washed with dichloromethane (60 ml) and acidified with 10% hydrochloric acid solution (20 ml) with ice-cooling. The acidic solution was extracted twice with dichloromethane (60 ml). The extracts were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give (3S,4S)-4-(1-(R)-carboxyethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone.
Reaction SMILES: CCN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[NH2:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:22].[N+:40]([C:43]1[CH:44]=[C:45]([C:52]([F:55])([F:54])[F:53])[CH:46]=[C:47]([CH:51]=1)[C:48](O)=[O:49])([O-:42])=[O:41]>>[N+:40]([C:43]1[CH:51]=[C:47]([CH:46]=[C:45]([C:52]([F:53])([F:54])[F:55])[CH:44]=1)[C:48]([NH:19][CH2:20][C:21](=[O:22])[NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:49])([O-:42])=[O:41]
Reactant: NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from the EDCI coupling of 2-amino-N-[1-(4-phenyl-cyclohexyl)-azetidin-3-yl]-acetamide TFA salt (as prepared in Step D of Example 66) and 5-nitro-3-trifluoromethyl-benzoic acid (Aldrich) using the procedure described in Step F of Example 1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([O:14]C(=O)C)(=[O:13])[CH3:12].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:11]([O:14][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])(=[O:13])[CH3:12]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 2-bromoacetophenone (199 g, 1.0M), acetic acid (200 mL) and acetic anhydride (30 mL) was stirred and heated to about 60° C. Anhydrous sodium acetate (100 g, 1.2M) was added and the reaction mixture was heated and stirred at about 130° C. for 6.0 hrs and then allowed to cool. To remove most of the salt, the reaction mixture was filtered through a sintered glass funnel. The acetic acid and acetic anhydride were removed from the filtrate using a rotary evaporator. A white solid was obtained upon cooling (yield--97.0 g). Mass spectroscopy supported the proposed structure.
Reaction SMILES: [CH2:1]([N:4]([CH2:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[C:16]1(C)[CH:21]=[CH:20][C:19]([C:22]([C:33]2[CH:38]=[CH:37][C:36](C)=[CH:35][CH:34]=2)=[CH:23][CH2:24]P([O-])(OCC)OCC)=[CH:18][CH:17]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[C:19]1([C:22]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:23][CH:24]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([N:4]([CH2:13][CH2:14][CH3:15])[CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=2)[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: CCCN(CCC)c1ccc(C=O)cc1
Reactant: CCO[PH]([O-])(CC=C(c1ccc(C)cc1)c1ccc(C)cc1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(CCC)c1ccc(C=CC=C(c2ccccc2)c2ccccc2)cc1
Yield: 61.6 %

Procedure:
Using 2.05 g (10.0 mmol) of p-di-n-propylaminobenzaldehyde, 3.6 g (10.9 mmol) of diethyl 3,3-diphenylallylphosphite ((5), R1 =R2 =H, R=Et), 1.3 g (11.6 mmol) of potassium tert-butoxide, and 15 ml of DMF, the same treatments as in step (5) in Example 1 were performed. Thus, 2.35 g of 1,1-diphenyl-4-(p-di-n-propylaminophenyl)-1,3-butadiene was obtained.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:17]([O:19][CH3:20])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:21][C:22]([S:25]([NH2:27])=[O:26])([CH3:24])[CH3:23]>ClC(Cl)C.S([O-])([O-])(=O)=O.[Cu+2]>[C:22]([S:25](/[N:27]=[CH:2]/[CH2:3][C:4]1([C:17]([O:19][CH3:20])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:26])([CH3:24])([CH3:23])[CH3:21]
Reactant: COC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(Cl)Cl
Product: COC(=O)C1(C/C=N/S(=O)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Yield: 80.4 %

Procedure:
A solution of 1-tert-butyl 4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate (822 mg, 2.88 mmol), copper(II) sulfate (1.38 g, 8.64 mmol) and 2-methyl-2-propanesulfinamide (354 mg, 3.17 mmol) in dichloroethane (15 mL) was heated at 65° C. for 24 h. The reaction was cooled, filtered and concentrated. The residue was partitioned between saturated aqueous NaHCO3 and dichloromethane, separated, the organic layer dried over MgSO4, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 0 to 7% methanol:dichloromethane to give the title compound (0.9 g). MS: m/z=389.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[F:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=2)[CH:31]=[CH:30][N:29]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccnc(F)c3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 68.5 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.12 g) and 2-fluoropyridine-4-boronic acid (0.072 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.065 g) to obtain the title compound (0.085 g) as a colorless foam. MS (ISN): 483.4 (M−H)−
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[N:5][N:4]=[N:3]1.C(N(CC)CC)C.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].CCOC(C)=O>C1COCC1>[C:25]1([O:24][C:22](=[O:23])[NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)=[CH:8][CH:9]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cn1nnnc1-c1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1nnnc1-c1ccc(NC(=O)Oc2ccccc2)cc1
Reaction time: 16 h
Yield: 29.2 %

Procedure:
4-(1-Methyl-1H-tetrazol-5-yl)-phenylamine (190 mg, 1.08 mmol, 1 eq.), triethylamine (0.14 ml, 1.08 mmol, 1 eq.), in 10 ml of THF under nitrogen were cooled to 0° C. A 5 ml solution of phenyl chloroformate (0.14 ml, 1.08 mmol, 1 eq.), was added dropwise via an addition funnel. Worked up after 16 hours by adding EtOAc then rinsing 3× with H2O. The organic layer was dried over MgSO4, then stripped to obtain yellow solids which were purified over silica gel in 3:1 hexanes/EtOAc to 100% EtOAc. Obtained 93 mg of white solids as product. Mass Spec, 296 (M+H). NMR (300 MHz, DMSO-d6) δ 10.65 (s, 2H), 7.86 (d, 2H, J=7 Hz), 7.76 (d, 2H, J=7 Hz), 7.44 (t, 2H, J=7 Hz), 7.28 (t, 2H, J=7 Hz), 4.18 s, 3H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].[CH3:10][NH2:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)Cl>[CH3:10][NH:11][CH:6]1[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]1
Reactant: CN
Reactant: N#CC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
To a solution of 4-cyanocyclohexanone (200 mg, 1.626 mmol) and CH3NH2 (2M in THF) (0.8 mL, 1.626 mmol) in THF:CH2Cl2 (1:1) (4.0 mL) at 0° C. was added NaBH(OAc)3 (689 mg, 3.252 mmol) and the resulting mixture was stirred at rt for 48 h. Subsequently, the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate, washed with water, brine, dried over Na2SO4 and concentrated to afford 200 mg (89%) of 4-(methylamino)cyclohexanecarbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) 2.91 & 2.61 (two signals, 1H) 2.23-2.24 (m, 3H) 1.02-1.99 (m, 9H); ELSD/MS (Method 3) (m/z): [M+H]+ 139.06.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18]1(I)[CH2:20][CH2:19]1>CS(C)=O>[CH:18]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[Cl:11])[CH2:20][CH2:19]1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: IC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Clc1nc(Cl)c2ncn(C3CC3)c2n1
Yield: 35 %

Procedure:
2,6-Dichloropurine (1 mmol), powdered potassium carbonate (4 mmol) and cyclopropyliodide were vigorously stirred in 5 mL DMSO overnight. After evaporation of the solvent the product was extracted (water/diethylether) and purified by column chromatography (silicagel/1% MeOH in CHCl3). Crystallization from diethylether gave product in 35% yield, mp 121-124° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][C:14]([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23]3)=[CH:18][CH:17]=2)=[O:15])[C:10]2=[N:33][C:34]([C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)=[CH:35][C:36](=[O:37])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][C:14]([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][NH:22][CH2:23]3)=[CH:18][CH:17]=2)=[O:15])[C:10]2=[N:33][C:34]([C:38]3[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=3)=[CH:35][C:36](=[O:37])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncc3)cc2=O)C(NC(=O)c2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)C1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCn2c(nc(-c3ccncc3)cc2=O)C(NC(=O)c2ccc3c(c2)CNCC3)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 1186.7 %

Procedure:
To a solution of 0.0265 g (0. mmol) of (+/−)-9-[(2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-isoquinoline-7-carbonyl)-amino]-4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester (example 5) dissolved in 1 mL of dichloromethane was added 1.13 mL (4.50 mmol) of hydrochloric acid (4M in dioxane). The resulting mixture was stirred at room temperature for 16 hours. The resulting residue was filtered, washed with dichloromethane and isopropylether to afford 0.261 g (100%) of the pure product as a white powder.
Reaction SMILES: [CH3:1][C:2]1([C:11]#[C:12][Si](C)(C)C)[CH2:7][CH2:6][C:5](=[O:8])[C:4]([C:9]#[N:10])=[CH:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(Cl)Cl.CCOCC>[C:11]([C:2]1([CH3:1])[CH2:7][CH2:6][C:5](=[O:8])[C:4]([C:9]#[N:10])=[CH:3]1)#[CH:12]
Reactant: CC1(C#C[Si](C)(C)C)C=C(C#N)C(=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#CC1(C)C=C(C#N)C(=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
A solution of 10 (20 mg, 0.086 mmol) in THF (0.6 mL) was degassed by gentle argon stream for 5 min. To the solution was added tetra-(n-butyl)ammonium fluoride (TBAF, 70 mg). The mixture was stirred at room temperature for 20 min. The mixture was diluted with methylene chloride/ether (1:2, 20 mL). The mixture was extracted with saturated aqueous sodium bicarbonate solution (10 mL ×3). The basic extract was acidified with 5% aqueous HCl solution. The acidic mixture was extracted with methylene chloride/ether (1:2, 10 mL ×4). The extract was washed with water (10 mL ×2), dried over MgSO4, and filtered. The filtrate was evaporated in vacuo to give a crystalline solid. The solid was purified by preparative TLC [hexanes-ethyl acetate (2.5:1)] to give MCE-3 as a crystalline solid (6.9 mg, 50%): 1H NMR (CDCl3) δ 7.39 (1H, d, J=1.8 Hz), 2.84 (1H, m), 2.62 (1H, m), 2.38 (1H, s), 2.32 (1H, m), 2.05 (1H, m), 1.55 (3H, s).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5](O)=[O:6])=[CH2:3].[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14]>CO>[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13][N:14]1[C:5](=[O:6])[CH2:4][CH:2]([C:1]([OH:9])=[O:8])[CH2:3]1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: CN(C)CCN
Solvent: CO
Product: CN(C)CCN1CC(C(=O)O)CC1=O
Temperature: 160 °C
Yield: 56 %

Procedure:
A mixture of commercially available itaconic acid and N,N-dimethylethylenediamine was heated up to 160° C. for about 20-25 minutes. The mixture was allowed to cool to 100° C. and then diluted with MeOH to prevent solidification. The product was obtained in a 56% yield after crystallization from MeOH/EtOAc. 1H-NMR (300 MHz, D2O): δ 2.63 (dd, 1H), 2.80 (dd, 1H), 2.95 (s, 6H), 3.15-3.25 (m, 1H), 3.32-3.44 (m, 1H), 3.44-3.76 (m, 4H), 3.82-3.94 (m, 1H). Retention Time (LC, method: ammonium acetate standard): 0.13 min. MS (M+H+): 201.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=3)[C:21]([CH3:31])=[C:20]2[CH3:32])[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[C:33]1([CH:39]([NH2:42])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:32][C:20]1[N:19]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=2)[C:27]2[C:22]([C:21]=1[CH3:31])=[CH:23][C:24]([C:28](=[O:29])[NH:42][CH:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:40][CH3:41])=[CH:25][CH:26]=2
Reactant: CCOC(=O)c1cccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: CCC(N)c1ccccc1
Product: CCOC(=O)c1cccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)NC(CC)c4ccccc4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the 1-phenylpropan-1-amine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:15]1CCC[CH2:16]1.C([Mg]Br)C.[OH-].[Na+]>O.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1([NH2:12])[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1CCCC1
Reactant: N#CCCOCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Mg]Br
Solvent: O
Product: NC1(CCOCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the compound (24.7 g) obtained in step (1) above, tetraisopropyl orthotitanate (49.4 mL) and methoxycyclopentane (306 mL), ethyl magnesium bromide (about 3 mol/L, solution in diethyl ether, 102 mL) was added at 0° C. and thereafter the mixture was stirred at room temperature for 3 hours. After adding boron trifluoride/diethylether complex (38.8 mL) at 0° C., the mixture was stirred at room temperature for 1.5 hours. After adding water at 0° C., pH was adjusted to 12 by adding a solution of 10% sodium hydroxide in water. The reaction mixture was extracted with chloroform three times. The combined organic layers were washed with saturated brine and then passed through a phase separator and concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=100:0-5:95) and further purified by silica gel column chromatography (n-hexane:ethylacetate=90:10-5:95, then chloroform:methanol=100:0-90:10) to give 1-[2-(benzyloxy)ethyl]cyclopropaneamine as a pale yellow oil (12.5 g).
Reaction SMILES: [CH3:1][N:2]([CH:28]([CH3:30])[CH3:29])[C:3]1[C:4]([C:17]2[O:18][CH:19]=[C:20](C3C=CC=CC=3)[CH:21]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH:28]([CH3:29])[CH3:30])[C:3]1[C:4]([C:17]2[O:18][C:19]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:20][CH:21]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3cc(-c4ccccc4)co3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 172.1 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(4-phenylfuran-2-yl)quinoxaline-6-carboxylate (50 mg, 0.12 mmol) in methanol (30 mL) and water (2 mL) was added sodium hydroxide (19.9 mg, 0.50 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3 N). The solids were collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-(5-phenylfuran-2-yl)quinoxaline-6-carboxylic acid as a light yellow solid (40 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9](O)=[O:10])=[O:5].[CH3:29][N:30]([CH3:32])[NH2:31]>>[CH3:29][N:30]([CH3:32])[NH:31][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:6]([C:4](=[O:5])[C:3]2[CH:16]=[CH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])=[CH:19][C:2]=2[Cl:1])[CH:7]=1
Reactant: Cc1ccc(C(=O)O)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CN(C)N
Product: Cc1ccc(C(=O)NN(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
Compound 424 (50 mg, 0.12 mmol) and N,N-dimethyl-hydrazine (19 μL, 0.25 mmol) were treated as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: graduated from 67/33 to 80/20) provided the title compound. 13C NMR (DMSO-d6) δ 194.7, 163.2, 158.9 (dd), 155.9 (dd), 149.6, 139.6, 139.5, 133.9, 133.8, 131.3, 131.0, 129.1, 127.2, 126.7 (dd), 126.3, 124.2 (dd), 114.9, 112.0 (dd), 111.9, 105.1 (dd), 46.1, 19.6