Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)([O-:5])=[O:4].[CH3:15][O:16][C:17](Cl)=[O:18].O>CN(C=O)C>[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][N:10]2[C:17]([O:16][CH3:15])=[O:18])([O-:5])=[O:4]
Reactant: COC(=O)Cl
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)n1ncc2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.3 g, 12.5 mmol) suspended in DMF (5 mL) at 0° C. was treated with 4-nitro-1H-indazole (1.33 g, 10 mmol). After stirring at room temperature for 1 hour, the mixture was treated with methylchloroformate (0.9 mL). After stirring at room temperature for 3 hours, the mixture was carefully treated with water and filtered to provide the title compound (1.2 g). 1H NMR (300 MHz, DMSO-d6) δ 4.1 9 (s, 3H), 7.9 (t, 1H), 8.38 (d, 1H), 8.62 (d, 1H), 8.85 (s, 1H).
Reaction SMILES: [OH-].[K+].[CH2:3]([S:10][CH2:11][CH2:12][CH:13]([N:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:14]([O:16]C)=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCOCC1.O>[CH2:3]([S:10][CH2:11][CH2:12][CH:13]([N:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[C:14]([OH:16])=[O:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(CCSCc1ccccc1)N(CC(C)C)S(=O)(=O)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(S(=O)(=O)N(CC(C)C)C(CCSCc2ccccc2)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
1.77 mmol of potassium hydroxide are added to 0.95 mmol of the compound obtained in Step C in a 3/1 mixture of dioxane/water. After stirring for 3 hours at 50° C., the dioxane is evaporated off, the residual aqueous phase is diluted with water, acidified to pH 2 by the addition of a 5% hydrochloric acid solution, and then extracted with ethyl acetate. The combined organic phases are washed, dried and filtered and then evaporated under reduced pressure. Chromatography on silica gel (dichloromethane/methanol: 93/7) allows the expected product to be isolated in the form of syrup.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:12]=3[S:11]2)=[CH:6][CH:5]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(O)(=O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[C@@H:16]([O:17][C:30](=[O:32])[CH3:31])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:12]=3[S:11]2)=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3ccc(OC)cc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc([C@@H]2Sc3ccc(OC)cc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
A mixture of 1 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, 1.5 ml of acetic anhydride and 1.5 ml of acetic acid is stirred at 110° C. for 4 hours. After the reaction is completed, the mixture is evaporated under reduced pressure to remove acetic anhydride and acetic acid. Benzene is added to the residue, and the mixture is evaporated under reduced pressure to remove acetic anhydride and acetic acid. The residue thus obtained is recrystallized from a mixture of ethanol and ether. 0.87 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-7-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride 1/2 hydrate is obtained. Yield: 78%
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([CH3:14])[NH:11]2)=[CH:6][CH:5]=1.[Br:17]C1C=C2C(=NC=1C(OC)OC)NCCC2>>[Br:17][C:5]1[CH:6]=[C:7]2[C:12](=[N:13][C:4]=1[CH:3]([O:2][CH3:1])[O:15][CH3:16])[NH:11][CH:10]([CH3:14])[CH2:9][CH2:8]2
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Reactant: COC(OC)c1ccc2c(n1)NC(C)CC2
Product: COC(OC)c1nc2c(cc1Br)CCC(C)N2

Procedure:
From (racemic) 7-(dimethoxymethyl)-2-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 260), synthesized in an analogous manner to intermediate 12, the title compound was obtained as a light brown oil. (UPLC-MS 6) tR 0.90; ESI-MS 301.1/303.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[C:23]([F:37])=[CH:24][C:25]([O:35][CH3:36])=[C:26]([N:28]2[C:32](=[O:33])[N:31]([CH3:34])[N:30]=[N:29]2)[CH:27]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(O)(C)C>[CH3:18][C:11]1([CH3:19])[CH2:10][C@H:9]([NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:21][C:22]3[C:23]([F:37])=[CH:24][C:25]([O:35][CH3:36])=[C:26]([N:28]4[C:32](=[O:33])[N:31]([CH3:34])[N:30]=[N:29]4)[CH:27]=3)[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Reactant: COc1cc(F)c(N)cc1-n1nnn(C)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1cc(F)c(Nc2ncc(F)c(N[C@@H]3C[C@@H]4CCCN4C(C)(C)C3)n2)cc1-n1nnn(C)c1=O
Temperature: 100 °C

Procedure:
A mixture of (7R,8aS)-N-(2-choro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (49 mg, 0.16 mmol, 1 equiv), 1-(5-amino-4-fluoro-2-methoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (59 mg, 0.25 mmol, 1.5 equiv) and pTsOH.H2O (25 mg, 0.13 mmol, 0.8 equiv) in isopropanol (1.5 ml) was heated at 100° C. overnight in a sealed vial. After allowing to cool to room temperature, the solvent was removed and the residue was purified by HPLC to give the product as a solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([N:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[CH3:25])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:26]([O:28]C)=[O:27])[CH:16]=2)[N:11]=1.[OH-].[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:19]([N:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[CH3:25])=[N:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:26]([OH:28])=[O:27])[CH:16]=2)[N:11]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of (S)-methyl 2-(benzofuran-2-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (100.0 mg, 0.39 mmol) in MeOH (20 mL) was added sodium hydroxide (49.2 mg, 1.23 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (20 mL) and adjusted to pH 6 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)-2-(benzofuran-2-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (50.9 mg, 53%).
Reaction SMILES: [CH:1]12[C:9](=[C:10]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)[C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[CH:1]12[C:9](=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:18]3[CH:23]=[CH:22][C:21](/[CH:27]=[CH:26]/[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:20][CH:19]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2
Reactant: Oc1ccc(C(=C2C3CCCC2CCC3)c2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2C3CCCC2CCC3)c2ccc(O)cc2)cc1
Temperature: 85 °C
Yield: 91.9 %

Procedure:
Compound 43 (0.32 g, 0.834 mmol), t-butyl acrylate (0.734 mL, 5.01 mmol), P(o-tolyl)3 (0.11 g, 0.359 mmol), Pd(OAc)2 (0.0394 g, 0.175 mmol) and Et3N (0.7 mL, 5.01 mmol) were added to a flask containing CH3CN (13 mL) and the stirred reaction mixture was heated at 85° C. for 24 h under a nitrogen atmosphere. The reaction mixture was allowed to cool at RT and then partitioned between water and EtOAc. The layers were separated, and the organic phase was washed with brine, dried (MgSO4), filtered, and the filtrate was concentrated to give an oily residue. The crude oil was adsorbed onto silica and purified by flash column chromatography on silica gel with a hexanes:EtOAc gradient (100:0 to 50:50) to give compound 44 as a yellow foam (0.33 g, 92%). 1H NMR (400 MHz, DMSO-d6): δ 1.45-1.53 (m, 10H), 1.72-1.73 (m, 7H), 1.96-2.01 (m, 2H), 2.53-2.64 (m, 4H), 6.42 (d, J=16.1 Hz, 1H), 6.66 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.48 (d, J=16.1 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 9.30 (s, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:9]=12)#[N:13]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(F)c2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(Cc3cccc(F)c3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-1-(3-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 369 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH3:46])[C:24]([N:26]([CH2:36][C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)[C@@H:27]([CH3:35])[CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])=[O:25]>>[S:40]1[CH:41]=[C:37]([CH2:36][N:26]([C@@H:27]([CH3:35])[CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])[C:24](=[O:25])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[O:17])[CH3:46])[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]1=2
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 118 mg (0.41 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-12) 100 mg (0.27 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[N:12]([CH:17]1[CH2:21][CH2:20][O:19][C:18]1=[O:22])[C:13](=[O:16])[CH2:14]Cl.[C:23]([O-:26])(=[O:25])[CH3:24].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[N:12]([CH:17]1[CH2:21][CH2:20][O:19][C:18]1=[O:22])[C:13](=[O:16])[CH2:14][O:26][C:23](=[O:25])[CH3:24]
Reactant: CC(=O)[O-]
Reactant: Cc1ccc2ccccc2c1N(C(=O)CCl)C1CCOC1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC(=O)N(c1c(C)ccc2ccccc12)C1CCOC1=O
Temperature: 25 °C

Procedure:
A mixture of 18.2 g of N-(2-methylnaphthyl)-N-(2-oxo-tetrahydrofuran-3-yl)-N-chloroacetyl-amine, 11.5 g of anhydrous sodium acetate and 0.1 g of KJ in 70 ml of dimethylformamide (DMF) is heated at 110° for 16 hours. The reaction mixture is afterwards cooled to room temperature, poured into 200 ml of water and extracted three times with 50 ml of ethyl acetate each time. The combined extracts are washed with 50 ml of water, dried over sodium sulfate, filtered and then concentrated by evaporation. The dark-brown oil remaining is purified through silica gel 60 (particle size 0.06-0.2 mm) using chloroform/diethyl ether (1:1) as the eluant. The last 10 of 12 fractions are combined and the eluant is evaporated off. The diastereoisomeric mixture of the compound No. 19 which remains solidifies on cooling, m.p. 50°-70°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[F:34][CH:35]1[CH2:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][NH2:43])[CH2:36]1>>[F:34][CH:35]1[CH2:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][NH:43][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:36]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: NCCN1CCCC(F)C1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCCC(F)C1

Procedure:
5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was coupled with 2-(3-fluoro-piperidin-1-yl)-ethylamine to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[C:17]1(=[O:27])[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:17]([C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20]([OH:22])=[O:21])=[O:27])=[CH:7][C:6]=3[C:5]2([CH3:16])[CH3:15])=[CH:13][CH:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC1(C)c2ccccc2-c2ccc(Br)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)c2cc(Br)ccc2-c2ccc(C(=O)c3ccccc3C(=O)O)cc21
Temperature: 25 °C
Yield: 59.9 %

Procedure:
2-bromo-9,9-dimethyl-9H-fluorene (25.0 g, 0.092 mol) and phthalic anhydride (17.68 g, 0.119 mol) were placed in a reaction vessel, and added with dichloromethane (700 ml). At 0° C., aluminum chloride (18.5 g, 0.138 mol) was gradually added thereto, and the temperature was raised up to room temperature. Then, the resultant mixture was stirred for 12 hours. After the reaction was completed, the resultant product was gradually added with distilled water. The resultant product was extracted with an excess of dichloromethane, and washed several times with distilled water. After solvent removal, the produced solid was placed in a Hexane 2 l-containing vessel, washed, filtered, and dried, 2-(7-bromo-9,9-dimethyl-9H-fluorene-2-carbonyl)benzoic acid (23.2 g, yield 60%) was obtained.
Reaction SMILES: Cl.[CH:2]1([N:8]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:39]1([CH2:45][S:46](Cl)(=[O:48])=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH:24]1([N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([S:46]([CH2:45][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)(=[O:48])=[O:47])[CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Nc1ncc(CN2CCNCC2)s1)N(C1CCCCC1)C1CCCCC1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncc(CN2CCN(S(=O)(=O)Cc3ccccc3)CC2)s1)N(C1CCCCC1)C1CCCCC1
Yield: 28.6 %

Procedure:
Prepared as described in general procedure (Q) using 1,1-dicyclohexyl-3-(5-piperazin-1-ylmethyl-thiazol-2-yl)-urea hydrochloride (26 mg, 0.05 mmol), DIEA (26 μL, 0.15 mmol) and alpha-toluenesulfonyl chloride (20 mg, 0.10 mmol) to afford 8 mg (29%) of the desired product after purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:15]([OH:17])=O)[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1)([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:15]([Cl:21])=[O:17])[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc2c(c(C(=O)O)c1)CCCC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1cc2c(c(C(=O)Cl)c1)CCCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(isopropoxy)-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.318 g, 1.36 mmol) in DCM (5 mL) was added oxalyl chloride (0.15 mL, 1.70 mmol) and 2 drops of DMF. The mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo and the 3-(isopropoxy)-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([O:13][CH3:14])=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9].[H-].[Na+].I[CH3:18]>O1CCCC1>[CH3:12][O:11][C:6]1[CH:5]=[C:4]([O:13][CH3:14])[C:3]([CH2:2][O:1][CH3:18])=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: CI
Reactant: COc1cc(OC)c(CO)cc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cc(C#N)c(OC)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
To a solution of 5-hydroxymethyl-2,4-dimethoxy-benzonitrile (218 mg, 1.128 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. were sequentially added sodium hydride (34.2 mg, 1.354 mmol) and iodomethane (140 μL, 2.256 mmol). The icebath was removed after 5 min and the reaction mixture was stirred at room temperature under argon for 12 h. Water was added and the product was extracted with methylene chloride (2×15 mL). The organic layers were washed with brine (1×2 mL) and dried over anhydrous sodium sulfate. The solid was filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 40% ethyl acetate in hexanes yielded 2,4-dimethoxy-5-methoxymethyl-benzonitrile as a white solid (221 mg, 95%).
Reaction SMILES: [C:1]([N:8](C)[C@H:9]([C:14]([NH:16][C@H:17]([C:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])[CH3:18])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[NH:8]([CH3:1])[C@H:9]([C:14]([NH:16][C@H:17]([C:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])[CH3:18])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
46.8 g (115 mMol) BOC-MeLeu-Ala-Bzl are dissolved in 100 ml trifluoroacetic acid pre-cooled to 0° C. and allowed to stand for 1 hr. at 0° C. and 1/2 hr. at room temperature. The obtained solution is concentrated under vacuum, diluted with 500 ml methylene chloride, poured onto ice and washed with 300 ml saturated potassium carbonate solution. The aqueous phase is extracted with 200 ml methylene chloride, the combined organic phases dried over potassium carbonate, filtered and concentrated. The residue is chromatographed on 2 kg silica gel 60 (0.063-0.24 mm) using 5% methanol in methylene chloride as eluant to yield the title compound: rotation, [α]D25 =-44.5° (c=1.0 in chloroform).
Reaction SMILES: [CH2:1]([CH:3]([C:6](=O)[CH3:7])[CH:4]=O)[CH3:2].[Na].[N+:10]([CH2:13][C:14]([NH2:16])=[O:15])([O-:12])=[O:11].C([O-])(=O)C.[NH2+]1CCCCC1>O>[CH2:6]([C:3]1[CH:4]=[C:13]([N+:10]([O-:12])=[O:11])[C:14](=[O:15])[NH:16][C:1]=1[CH3:2])[CH3:7]
Reactant: CCC(C=O)C(C)=O
Reactant: NC(=O)C[N+](=O)[O-]
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: O
Product: CCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-ethyl-3-oxobutanal, sodium salt (7.5 g, 55 mmol), nitroacetamide (6.6 g, 63 mmol), aqueous piperidinium acetate (4.4 mL) [prepared from glacial acetic acid (42 mL), water (100 mL) and piperidine (72 mL)] in water (45 mL) was stirred at room temperature for 22 hours. The yellow precipitate was collected by filtration and air dried to yield 5-ethyl-6-methyl-3-nitro-2-(1H)-pyidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH:26]=[O:27])[N:9]=2)=[CH:4][CH:3]=1.CC(=CC)C.Cl([O-])=[O:34].[Na+]>CC(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[C:26]([OH:34])=[O:27])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C=O)c1nnc(C)n1-2
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C(=O)O)c1nnc(C)n1-2
Reaction time: 3.5 h

Procedure:
To a solution of crude (1S,2R)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]-2-carbaldehyde (298 mg, 0.752 mmol) in t-BuOH (5 mL) was added 2-methylbut-2-ene (1055 mg, 15.04 mmol) and a pH 7 buffer solution (5 mL). Then sodium chlorite was added at rt, and the biphasic reaction was vigorously stirred for 3.5 h. When the starting material was entirely consumed, sat. aq. NH4Cl was added, and the product was extracted with DCM/MeOH (19:1) (repeated 3 times). The organic layers were combined, dried over Na2SO4, filtered and concentrated to dryness. The residue was used in the next step without purification. LRMS (M+H)+: 413 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:27]([O:29]CC)=[O:28])[O:26][CH2:25][C:11]3([C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:18][C:17]4[C:12]3=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:27]([OH:29])=[O:28])[O:9][CH2:10][C:11]3([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[O:18][C:19]4[C:24]3=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:25][O:26]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(c2ccc(Cl)cc2)OCC2(CO1)c1ccccc1Oc1ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1(c2ccc(Cl)cc2)OCC2(CO1)c1ccccc1Oc1ccccc12
Yield: 73.4 %

Procedure:
A mixture of 0.09 g (0.2 mmol) of the ester prepared in Example 77, Example [sic], 0.5 g (9 mmol) of KOH, 20 ml of ethanol and 10 ml of water is stirred at reflux for 3 h. After cooling, the reaction medium is acidified with concentrated HCl solution to pH=5 and extracted with ethyl acetate. The combined organic phases are dried over Na2SO4 and then evaporated. The residual oil is crystallized from a suitable solvent. 0.06 g of white solid is isolated (yield=64%). m.p.=244-246° C.