Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@@:10]1([CH3:23])[C:15]([O:16][CH3:17])=N[C@H](C(C)C)C(OC)=[N:11]1.O.FC(F)(F)C(O)=[O:28].[Cl-].[NH4+]>C(#N)C>[CH3:17][O:16][C:15](=[O:28])[C@:10]([NH2:11])([CH3:23])[CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C(O)C(F)(F)F
Reactant: COC1=N[C@@](C)(CCc2ccccc2Cl)C(OC)=N[C@@H]1C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@@](C)(N)CCc1ccccc1Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-2-[2-(2-chloro-phenyl)-ethyl]-5-isopropyl-3,6-dimethoxy-2-methyl-2,5-dihydro-pyrazine (1.22 g, 3.62 mmol) in acetonitrile (12 ml) were added water (4 ml) and trifluoroacetic acid (2 ml). The mixture was stirred overnight at 40° C. Saturated ammonium chloride solution was added and the mixture was extracted with dichloromethane three times. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/MeOH=95:5 to yield a colorless oil, (0.46 g, 52%); MS (ISP): 242.1; 244.1 ((M+H)+.).
Reaction SMILES: [NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:2]([C:11]([N:13]1[CH2:25][CH2:24][CH2:23][C@H:14]1[C:15]([NH:17][C@@H:18]([C:20]([NH2:22])=[O:21])[CH3:19])=[O:16])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH:8]([CH3:10])[CH3:9].[C:33](Cl)([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34]>C1COCC1.CCOC(C)=O>[NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:2]([C:11]([N:13]1[CH2:25][CH2:24][CH2:23][C@H:14]1[C:15]([NH:17][C@@H:18]([C:20]([NH2:22])=[O:21])[CH3:19])=[O:16])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:33]([O:35][CH2:36][CH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:34])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(N)=O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)N(CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(N)=O)C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 79.3 %

Procedure:
A solution of Boc-Lys(iPr)-Pro-D-Ala-NH2 (9.11 gm) in 10% Na2 CO3 (25 mL) and THF (30 mL) was cooled to 0° C. and treated with a solution of Fmoc-Cl (6.46 gm) in THF. After 1 hour at 0° C. the mixture was partitioned between EtOAc (200 mL) and water (100 mL) and the layers were separated. The organic layer was washed with water (100 mL), 10% citric acid (2×100 mL) and water (100 mL), then dried over Na2SO4 and evaporated to dryness to yield an oil. The residue was dissolved in EtOAc and precipitated from heptane to yield 11.66 gm of crude product. This material was dissolved in a small in EtOAc and loaded onto a silica gel (200 gm) column which was eluted with an EtOAc/heptane mixture (2/1), followed by EtOAc and finally by ethanol. The product-containing fractions were combined and evaporated in vacuo to dryness to yield an oil. The residue was dissolved in a small amount of EtOAc and precipitated from heptane to yield 10.75 gm of Boc-Lys(iPr,Fmoc)-Pro-D-Ala-NH2. HPLC: 98.1%, MS: (M+H)+ =678, (M+NH4)+ =695, [a]D=-12.2 (c=1, HOAc)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[C:7](OC(=O)C)(=[O:9])[CH3:8].C(Cl)(=O)C>>[C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][Cl:1])(=[O:9])[CH3:8]
Reactant: NC(=O)CCCl
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Product: CC(=O)NC(=O)CCCl

Procedure:
A mixture of 0.2 mole 3-chloropropionamide, 35 ml. of acetic anhydride and 1 ml. acetylchloride is refluxed under nitrogen for 1 hour and then concentrated in vacuo to give crude N-acetyl-3-chloropropionamide as an oil which is used in the next step without purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23]>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH:22]([CH3:23])[CH3:21])[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC(C)NCC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: CC(C)NCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 88.5 %

Procedure:
A suspension of 1.1 g (3.9 mmole) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.4 g (10 mmole) of N-(2-propyl)-3-pyrrolidinemethanamine and 50 ml of acetonitrile was refluxed for 2 hours. The precipitate was removed by filtration, washed with acetonitrile, ether, and dried in vaco to give 1.4 g of the title compound, mp 218°-221° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=O.O>C(O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[CH:14]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cn3ccccc3n2)cc1

Procedure:
A mixture of 25.2 g. of sodium bicarbonate, 12.3 g. of 2-aminopyridine and 30 g. of α-bromo-p-methoxyacetophenone in 100 ml. of water and 550 ml. of absolute ethanol is heated at reflux temperatures for 1.5 hrs. The reaction mixture is concentrated under reduced pressure to a yellow solid, which is partitioned between chloroform and water. The organic layer is separated, dried over sodium sulfate. Removal of the chloroform in vacuo leaves the crude intermediate as a yellow solid. Recrystallization from ethanolwater give 15.2 g. of the desired material, m.p. 131-134° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]2[CH:12]3[CH2:16][S:15](=[O:18])(=[O:17])[CH2:14][CH:13]3[CH:8]2[C:7]1=[O:19].Cl.[Cl:21][C:22]1[N:27]=[C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[N:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O>[ClH:21].[Cl:21][C:22]1[N:27]=[C:26]([N:28]2[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH:9]4[CH:12]5[CH2:16][S:15](=[O:18])(=[O:17])[CH2:14][CH:13]5[CH:8]4[C:7]3=[O:19])[CH2:32][CH2:33]2)[CH:25]=[N:24][CH:23]=1
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: O=C1C2C3CS(=O)(=O)CC3C2C(=O)N1CCCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1C2C3CS(=O)(=O)CC3C2C(=O)N1CCCCN1CCN(c2cncc(Cl)n2)CC1
Reaction time: 8 h

Procedure:
A solution of 2.0 g of 5-(4-bromobutyl)tetrahydro-1H-thieno-[3',4':3,4]cyclobuta[1,2-c]pyrrole-4,6(3H,5H)dione 2,2-dioxide in 50 ml of dimethylformamide is added to a stirred solution 2.0 g (0.007 mol) of 1-(6-chloro-2-pyrazinyl)-piperazine hydrochloride and 4 ml of triethylamine. The reaction mixture is stirred overnight and the solvent is removed under vacuum. The residue is partitioned between water and methlene chloride. The methylene chloride extracts are combined, washed with brine and dried over anhydrous sodium sulfate. Filtration and roto-evaporation gives the crude free base. Preparative HPLC [silica gel; ethyl acetate:methylene chloride (9:1)] followed by evaporation of the appropriate fractions (TLC Rf=0.4), treatment with ethanolic hydrogen chloride and recrystallization from ethanol gives the title compound: m.p. 154°-157° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:28]=[C:27]([CH2:29]Cl)[CH:26]=[CH:25][C:24]=1[O:31][CH:32]([CH2:35][F:36])[CH2:33][F:34]>>[Cl:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][C:24]=1[O:31][CH:32]([CH2:35][F:36])[CH2:33][F:34])[CH2:29][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([OH:17])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: FCC(CF)Oc1ccc(CCl)cc1Cl
Product: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(OC(CF)CF)c(Cl)c3)ccc12

Procedure:
From tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate and 2-chloro-4-(chloromethyl)-1-(1,3-difluoropropan-2-yloxy)benzene, the title compound was prepared using a similar method to the one described in Example 1.48, Step B. LCMS m/z=450.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.27-2.36 (m, 1H), 2.67 (dd, J=16.4, 8.4 Hz, 1H), 2.87-2.97 (m, 2H), 3.75 (quintet, J=7.4 Hz, 1H), 3.98-4.05 (m, 1H), 4.15 (ddd, J=9.9, 8.6, 4.1 Hz, 1H), 4.56-4.69 (m, 3H), 4.75-4.78 (m, 2H), 5.00 (s, 2H), 6.12 (s, 1H), 6.86 (dd, J=8.7, 2.4 Hz, 1H), 7.06-7.09 (m, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.31 (dd, J=8.4, 2.1 Hz, 1H), 7.51 (d, J=2.1 Hz, 1H).
Reaction SMILES: Cl.[CH2:2]([NH:5][C@@H:6]([CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[CH2:3][CH3:4].[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][CH2:35][CH:36]=O)[C:28](=[O:38])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][CH2:35][CH2:36][N:5]([C@@H:6]([CH3:18])[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4])[C:28](=[O:38])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCCN[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCCN(CCCC=O)C(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCCN(CCCCN1CCCN(C(=O)OC(C)(C)C)CC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
A mixture of propyl-[(S)-2-(4-methanesulfonylphenyl)-1-methylethyl]-amine hydrochoride (0.50 g, 1.7 mmole), 3-oxo-4-(4-oxobutyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.5 g, 1.76 mmole), triethylamine (0.24 mL, 1.7 mmole), and sodium triacetoxyborohydride (0.54 g, 2.6 mmole) in 1,2-dichloroethane (20 mL) was stirred at room temperature for 17 hours. The solvent was removed, and the residue was partitioned between ethyl acetate (30 mL) and 5% sodium carbonate (20 mL). The organic phase was dried (magnesium sulfate) and concentrated to give 4-(4-{[(S)-2-(4-methanesulfonyl-phenyl)-1-methylethyl]propylamino}butyl)-3-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester, (0.89 g), as a syrup. Nmr (chloroform-d) δ (ppm): 0.82, t, 3H; 0.94, d, 3H; 1.46, s, 9H; 3.05, s, 3H; 7.36, d, 2H; 7.83, d, 2H.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]3[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC4C=CC=CC=4)=[CH:20][CH:19]=1)[C:12]3=[CH:32][CH:33]=2)C1C=CC=CC=1>O1CCCC1.C(O)C.[Pd]>[OH:8][C:9]1[C:10]2[N:11]3[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)[C:12]3=[CH:32][CH:33]=2
Reactant: c1ccc(COc2ccc(-c3cc4ccc(OCc5ccccc5)c5ccc3n45)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc(-c2cc3ccc(O)c4ccc2n34)cc1
Yield: 98.5 %

Procedure:
A solution of 5-benzyloxy-2-(4-benzyloxyphenyl)pyrrolo[2,1,5-cd]indolizine (48 mg, 0.11 mmol) in 2 ml of tetrahydrofuran and 3 ml of ethanol was hydrogenated in the presence of 10% palladium on carbon (30 mg). When the theoretical amount of hydrogen had been consumed the catalyst was filtered off and the filtrate was evaporated to afford 27 mg (99%) of the title compound. M.p. 165° C. (dec.). 1H-NMR (DMSO-d6, 200 MHz) δ: 6.92 (d, 2H), 7.15 (d, 1H), 7.36 (d, 1H), 7.43 (s, 1H), 7.73 (d, 1H), 7.88 (d, 2H). (Compound 53).
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C@@H:13]([C:19]1[C:20]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[C:21]2[C:26](=[CH:27][C:28]=1[CH3:29])[N+:25]([O-])=[C:24]([CH3:31])[CH:23]=[CH:22]2)[C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:11])([CH3:10])[CH3:9].C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(C)C=C2)C(OCC)=O)(C)(C)C>>[C:1]([O:4][CH2:31][C:24]1[CH:23]=[CH:22][C:21]2[C:26](=[CH:27][C:28]([CH3:29])=[C:19]([C@H:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:20]=2[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1-c1ccc(Cl)cc1
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(COC(C)=O)ccc2c1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Acetic anhydride was added to a flask containing (S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide (compound of Example 14) (42 mg, 0.095 mmol). The mixture was stirred at 80° C. for 1 hour. Acetic anhydride was removed under vacuum. The residue was dissolved in ethyl acetate (50 mL). The organic layer was washed with NaHCO3 solution and water, dried and concentrated in vacuo. The obtained residue was used for next step reaction without purification. LCMS-ESI+ (m/z): 484.2, 486.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([O:11][CH2:12][CH3:13])=[N:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.[CH3:16][N:17]=[C:18]=[O:19]>>[CH3:16][NH:17][C:18]([NH:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([O:11][CH2:12][CH3:13])=[N:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1)=[O:19]
Reactant: CCOC1=NS(=O)(=O)c2cc(N)ccc21
Reactant: CN=C=O
Product: CCOC1=NS(=O)(=O)c2cc(NC(=O)NC)ccc21

Procedure:
Following the procedures outlined in Description 4a, 6-amino-3-ethoxy-benzoisothiazole-1,1-dioxide (0.23 g) was reacted with methyl isocyanate for 3 days to give the title compound.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH3:8][C:9]1([CH3:36])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([CH3:35])([C:31](=[O:34])[NH:32][CH3:33])[CH3:30])[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:1][S:2]([NH:5][C:19]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:22]1[CH:23]=[C:24]([NH:28][C:29]([CH3:35])([CH3:30])[C:31]([NH:32][CH3:33])=[O:34])[CH:25]=[CH:26][CH:27]=1)[C:9]([CH3:36])([CH3:8])[CH2:18]2)=[O:20])(=[O:4])=[O:3]
Reactant: CNC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(=O)NS(C)(=O)=O)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a suspension of methanesulfonamide (85 mg, 0.89 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (36 mg, 0.89 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-[3-(1-methyl-1-methylcarbamoyl-ethylamino)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (50 mg, 0.127 mmol) and 1,1′-carbonyldiimidazole (41 mg, 0.253 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 70° C. for 1 h. Then the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-methanesulfonylaminocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2,N-dimethyl-propionamide (15 mg, 25%) as a white solid: LC/MS m/e calcd for C24H32N4O4S (M+H)+: 473.61, observed: 473.1.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[C:21]3[C:33]4[C:34]5[C:24](=[CH:25][C:26]([C:35]6[NH:39][C:38]([C@@H:40]7[CH2:44][CH2:43][CH2:42][N:41]7C(OC(C)(C)C)=O)=[N:37][CH:36]=6)=[CH:27][C:28]=5[CH2:29][CH2:30][C:31]=4[CH:32]=2)[CH2:23][CH2:22]3)=[CH:17][N:18]=1)=[O:8])=[O:4].Cl.[CH3:56][O:57][C:58]([NH:60][C@@H:61]([CH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1)[C:62]([OH:64])=O)=[O:59].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:32]=[C:31]3[C:33]4[C:34]5[C:28](=[CH:27][C:26]([C:35]6[NH:39][C:38]([C@@H:40]7[CH2:44][CH2:43][CH2:42][N:41]7[C:62](=[O:64])[C@@H:61]([NH:60][C:58](=[O:59])[O:57][CH3:56])[CH:65]7[CH2:70][CH2:69][O:68][CH2:67][CH2:66]7)=[N:37][CH:36]=6)=[CH:25][C:24]=5[CH2:23][CH2:22][C:21]=4[CH:20]=2)[CH2:29][CH2:30]3)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2cc3c4c(c2)CCc2cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc(c2-4)CC3)[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2cc3c4c(c2)CCc2cc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C6CCOCC6)[nH]5)cc(c2-4)CC3)[nH]1)C(C)C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
To (S)-tert-butyl 2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-4,5,9,10-tetrahydropyren-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (55 mg, 0.08 mmol) in DCM (3 mL) was added HCl (4M in dioxane, 0.25 mL). The solution stirred for 1 h, and the solvent was removed. The intermediate was dissolved in DMF (2 mL). (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (16 mg, 0.08 mmol), HATU (29 mg, 0.08 mmol), and DIPEA (0.06 mL, 0.37 mmol) were added sequentially. The solution was stirred o/n and the mixture was purified by HPLC to yield product (17.9 mg). LCMS-ESI+: calc'd for C46H56N8O7: 832.99 (M+); Found: 833.25 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=O)=O)=CC=1.[OH-].[K+]>N1C=CC=CC=1.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Sc1ccc(I)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC1CSc1ccc(I)cc1
Reaction time: 4 h
Yield: 52.6 %

Procedure:
To a stirred mixture of p-iodothiophenol (1.75 g, 7.43 mmol) and N-(tert-butoxycarbonyl)-2-pyrrolidinylmethyl p-toluenesulfonate (2.39 g, 6.75 mmol) in pyridine (12.7 mL) was added 8 N KOH (1.27 mL) at room temp, and the resulting mixture was stirred for 4 hr at the same temp. The reaction mixture was diluted with EtOAc. The solution was washed with H2O, sat. NH4Cl, brine, and dried over Na2SO4. The organic layer was concentrated under a reduced pressure. The residue was chromatographed on silica-gel with n-hexane-EtOAc (5:1, v/v) as eluent to afford 1.49 g (530%) [N-(tert-butoxycarbonyl)-2-pyrrolidinyl]methyl 4-iodophenyl sulfide as a pale yellowish oil. 1H-NMR (400 MHz, CDCl3) δ (s, 9H), 1.78–2.01 (br m, 4H), 2.71 (dt, 1H), 3.32–3.49 (br m, 3H), 3.90–4.02 (br m, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1), 7.57 (dd, J=2.0,8.3 Hz, 2H);MS(FAB)m/z 420(M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][N:19]=3)[C:16](=O)[C:15]3[C:14]([C:25]([O:27]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:31][NH:32][C:25](=[O:27])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:22]([CH3:23])[CH:21]=[N:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nncn1C)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1cnnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg) in 85% hydrazine monohydrate (2 mL) and methanol (5 mL) was stirred at room temperature for 4 h. Then the solution was evaporated, the crude product was purified by prep-HPLC to obtain the title compound as a white solid (20 mg, yield 18%). LC-MS (ESI) m/z: 363 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.50 (s, 3H), 4.83-4.86 (d, J=11.6 Hz, 1H), 5.00-5.03 (d, J=11.6 Hz, 1H), 7.12-7.19 (m, 3H), 7.39-7.42 (m, 2H), 7.47-7.51 (m, 2H), 7.60-7.64 (t, J=8 Hz, 1H), 8.31 (s, 1H), 12.24 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:4]([CH3:14])[C:3]=1[C:15]#[N:16].[C:17]([N:25]=[C:26]=[O:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1.CCOC(C)=O>[C:17]([NH:25][C:26](=[O:27])[NH:1][C:2]1[S:6][C:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[C:4]([CH3:14])[C:3]=1[C:15]#[N:16])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1c(C(=O)OC(C)(C)C)sc(N)c1C#N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(C(=O)OC(C)(C)C)sc(NC(=O)NC(=O)c2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a solution of tert-butyl 5-amino-4-cyano-3-methylthiophene-2-carboxylate (example 64b) (16 g, 67.14 mmol) in dioxane (200 mL), was added benzoyl isocyanate (10 g, 67.14 mmol). The reaction mixture was stirred at rt overnight, and upon completion was diluted with EtOAc, washed with NaHCO3, water, brine, dried over MgSO4, filtered and concentrated to yield tert-butyl 5-(3-benzoylureido)-4-cyano-3-methylthiophene-2-carboxylate (21.78 g, 84%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 1.54 (s, 9H), 3.58 (s, 3H), 7.58 (t, J=7.5 Hz, 2H), 7.71 (t, J=7.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 8.05 (d, J=7.5 Hz, 2H), 12.25 (br s, 1H).
Reaction SMILES: F[C:2]1[N:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([C:6]1[N:7]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5].[OH-].[NH4+:35]>>[NH2:35][C:2]1[N:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([C:6]1[N:7]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc(C(=O)c3cccnc3F)cc3ccccc23)CC1
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCCN(c2nc(C(=O)c3cccnc3N)cc3ccccc23)CC1
Temperature: 110 °C
Yield: 24 %

Procedure:
A microwave vial was charged with tert-butyl 4-(3-(2-fluoronicotinoyl)isoquinolin-1-yl)-1,4-diazepane-1-carboxylate (78 mg, 0.17 mmol) and a saturated aqueous solution of ammonium hydroxide (2 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 25 minutes. The mixture was cooled down to room temperature, partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified on silica gel by flash column chromatography to afford the title compound as a yellow solid (18 mg, 24% yield). MS (ES+) 448.