Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[C:1]([NH:8][C@H:9]([C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)N1CCOCC1
Yield: 96 %

Procedure:
In substantially the same manner as in Example 5, morpholine (290 μl) was condensed with Boc-p-nitro-L-phenylalanine (996 mg, Bachem Fein Chemikalien AG, Switzerland) to give N-(Boc-p-nitro-L-phenylalanyl)morpholine (1.22 g) as a white powder (yield 96%). After Boc group elimination with 4N HCl/ethyl acetate, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate as obtained in Reference Example 8 (465 mg) to yield the title compound (compound 71; 878 mg) as a white powder (yield 81%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH:29](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[OH:49])[CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[CH:23][CH:22]=1)#[N:20]>C(#N)C>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH:29](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[O:49][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Reactant: BrCCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCCCCCc2ccccc2)CCc2ccc(C#N)cc2)cc1
Yield: 99.5 %

Procedure:
464.2 mg (2.04 mmol) of (5-bromopentyl)benzene and 353.05 mg (2.55 mmol) of potassium carbonate are added to a solution of 700.8 mg (1.7 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 65 ml of acetonitrile, and the mixture is stirred under reflux for 12 hours. After cooling, the potassium carbonate is filtered off and the filtrate is evaporated. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3). 945 mg (1.7 mmol, 99.5% yield) are obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][CH2:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20].C(O)=[O:28]>>[CH2:22]([O:21][P:19]([CH2:18][CH2:17][CH2:16][CH2:15][O:14][N:6]1[CH:5]=[N:4][C:3]2[C:2](=[O:28])[NH:10][C:9]([NH2:11])=[N:8][C:7]1=2)([O:24][CH2:25][CH3:26])=[O:20])[CH3:23]
Reactant: CCOP(=O)(CCCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Reactant: O=CO
Product: CCOP(=O)(CCCCOn1cnc2c(=O)[nH]c(N)nc21)OCC
Yield: 76 %

Procedure:
A solution of 6-chloro-9-[4-(diethoxyphosphoryl)butoxy]-2-formamidopurine (0.220 g, 0.54 mmol) in 80% formic acid (5 ml) was stirred at 80° C. for 5 hr. The solvent was evaporated under vacuum and the residue coevaporated with toluene (2×10 ml). The residue was chromatographed on silica gel (eluted with chloroform-ethanol 9:1) to give the title compound (0.148 g, 76%). 1H NMR: δH ((CD3)2SO) 1.22 (6H, t, J=7 Hz, (OCH2CH3)2), 1.64 (2H, m, CH2P), 1.79 (4H, m, CH2CH2), 3.9 (4H, m, (OCH2CH3)2), 4.26 (2H, t, NOCH2), 6.67 (2H, br.s, D2O exchangeable, NH2), 7.96 (1H, s, H-8), 10.75 (1H, br.s, D2O exchangeable, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[NH2:26]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1OC

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 3,4-dimethoxyaniline (78.3 mg, 0.51 mmol). The title compound was obtained as a yellow solid (25.0 mg, 12% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.54 (1H, m), 9.00 (2H, m), 8.67 (1H, m), 7.30 (1H, m), 7.22 (1H, m), 6.94 (1H, m), 3.72 (6H, s). MS m/z: 484.24, 486.25 [M+H]+.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[C:6](Cl)(=[O:8])[CH3:7].[S:10]1[C:14]([NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[CH:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2.O>ClCCl>[C:6]([C:13]1[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[S:10][C:14]=1[NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])(=[O:8])[CH3:7]
Reactant: CC(=O)Cl
Reactant: CCS(=O)(=O)Nc1cc2ccccc2s1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCS(=O)(=O)Nc1sc2ccccc2c1C(C)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Tin (IV) chloride (173 μL, 1.48 mmol) was added to a solution of acetyl chloride (124 μL, 1.75 mmol) in dichloromethane (10 mL), at 0° C., and the resulting solution was stirred for 5 min. To the resulting mixture was then added a solution of ethanesulfonic acid benzo[b]thiophen-2-ylamide (325 mg, 1.35 mmol) in dichloromethane (2 mL) at 0° C. The resulting solution was allowed to warm to ambient temperature and then stirred overnight. The resulting solution was treated with water (10 mL), the organic layer separated, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo to yield N-(3-acetyl-benzo[b]thiophen-2-yl)-ethanesulfonamide as a colorless solid. 1H-NMR (DMSO-d6): δ 1.25 (t, 3H), 2.71 (s, 3H), 3.39 (q, 2H), 7.34-7.48 (m, 2H), 7.94 (d, 1H), 8.10 (d, 1H); MS: m/z 284.1 (MH+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[CH2:42]([OH:46])[CH2:43][C:44]#[CH:45].C(N(CC)CC)C.O>C(#N)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.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.[Cu](I)I>[OH:46][CH2:42][CH2:43][C:44]#[C:45][C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: C#CCCO
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(C#CCCO)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 40.7 h
Yield: 51.2 %

Procedure:
4-Trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in acetonitrile (4.8 mL), and the solution was added with tetrakis(triphenylphosphine)palladium (23.4 mg, 0.0203 mmol), copper iodide (10 mg, 0.054 mmol), tetrabutylammonium chloride (150 mg, 0.405 mmol), 3-butyn-1-ol (0.051 mL, 0.68 mmol) and triethylamine (0.96 mL, 0.70 mmol), followed by stirring at room temperature for 40.7 hours under argon atmosphere. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=5/1) to obtain 4-(4-hydroxy-1-butynyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidino methyl)indol-2-yl]isoindolinone (35.5 mg, yield 51%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[N:16]=O.[H][H]>C(O)C.[Pd]>[ClH:1].[ClH:1].[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:7]2[C:3]([NH2:2])=[C:4]([NH2:16])[CH:5]=[N:6]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(-n2ncc(N=O)c2N)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(-n2ncc(N)c2N)cc1

Procedure:
8.0 g (31 mmol) of 5-amino-1-(4-methoxyphenyl)4-nitrosopyrazole hydrochloride from Step 1.2 in 200 mL of ethanol was hydrogenated for 6 hours on 0.8 g of Pd/C (10%) at 8 bar of hydrogen pressure. The catalyst was filtered off, and the reaction mixture was concentrated to a total volume of about 30 mL. After the addition of 40 mL of 3-molar ethanolic hydrochloric acid and agitation in an ice bath, the product crystallized. Suction filtration and washing with 50 mL of ethyl acetate gave 7.4 g (27 mmol), 86% of the theoretical) of 1-(4-methoxyphenyl)-4,5-diamino-1H-pyrazole dihydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=2)[NH:14][C:15](=[O:28])[NH:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[Li+].[OH-].Cl>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][N:30]=2)[NH:14][C:15](=[O:28])[NH:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:10])([F:11])[F:12]
Reactant: CCOC(=O)c1ccc(NC(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)O)cc1)N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Temperature: 25 °C

Procedure:
To a solution of (S)-ethyl 4-(3-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)ureido)benzoate (109 mg, 0.220 mmol) in THF (3 mL) and MeOH (1 mL) was added 1 M aqueous LiOH (4 mL, 4.00 mmol). The resulting mixture was then stirred at rt. After stirring for 24 h, the reaction was acidified with 1 N HCl to ˜pH 7. The aqueous solution was extracted with DCM (3×10 mL). The combined DCM layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound as an off-white solid. 1H-NMR (300 MHz, MeOH-d4): δ ppm 8.48 (d, J=4.7 Hz, 1H), 7.83-7.98 (m, 2H), 7.62 (ddd, J=9.8, 8.5, 1.3 Hz, 1H), 7.27-7.51 (m, 6H), 6.40 (d, J=1.5 Hz, 1H). MS (ESI pos. ion) m/z: 445.9 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([C:26]([OH:28])=O)=[CH:23]2)=[CH:18][CH:17]=1.CCN(CC)CC.[Cl:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1>CN(C=O)C.C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([C:26]([NH:41][C:40]3[CH:42]=[CH:43][C:37]([Cl:36])=[CH:38][CH:39]=3)=[O:28])=[CH:23]2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc4ccc(C(=O)O)cc4c3)c2cc1OC
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc4ccc(C(=O)Nc5ccc(Cl)cc5)cc4c3)c2cc1OC
Reaction time: 2 h

Procedure:
A slurry of 7-(6,7-dimethoxyquinolin-4-yloxy)-2-naphthoic acid (0.54 g, 1.44 mmol) in 10 mL of C2O2Cl2 and 2 drops of DMF was stirred at RT. After 2 h, the solution was concentrated to dryness and placed under high vacuum overnight. A portion of the crude residue (0.075 g, 0.191 mmol) was dissolved in 1 mL of CH2Cl2. To the resulting solution was added Et3N (0.106 mL, 0.76 mmol), 4-chloroaniline (0.036 g, 0.286 mmol) and a catalytic amount of DMAP. The reaction was stirred under a nitrogen atmosphere for 16 h. The reaction was diluted with CH2Cl2, washed with saturated aqueous NaHCO3, and brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was passed through a medium-pressure silica gel column (solvent gradient: 95:5 CH2Cl2:MeOH; 90:10 CH2Cl2:MeOH) to afford the desired crude compound. The fractions were concentrated to dryness to afford a solid residue. The residue was triturated with Et2O/Hexanes to afford the desired compound as a pale yellow solid. MS (ESI, pos. ion) m/z: 485.0 (M+1). Mass Calc'd for C28H21ClN2O4: 484.937.
Reaction SMILES: [H-].[Na+].FC(F)(F)C(O)=O.Cl[C:11]1[CH:12]=[C:13]([CH3:21])[C:14]2[N:15]([C:17]([NH2:20])=[N:18][N:19]=2)[N:16]=1.[CH3:22][CH2:23][CH:24]([OH:27])[CH2:25][CH3:26]>CN(C=O)C>[CH2:23]([CH:24]([O:27][C:11]1[CH:12]=[C:13]([CH3:21])[C:14]2[N:15]([C:17]([NH2:20])=[N:18][N:19]=2)[N:16]=1)[CH2:25][CH3:26])[CH3:22]
Reactant: CCC(O)CC
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)Oc1cc(C)c2nnc(N)n2n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Pentanol (10.2 ml) was initially charged at RT with stirring and cooled almost to 0° C. with an ice bath. Subsequently, the mixture was admixed with portions of sodium hydride (511 mg). The suspension formed was heated to 55° C. for 30 min and admixed with portions of 6-chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine trifluoroacetate (W2.002b; 500 mg), suspended in 3-pentanol (5 ml) and DMF (10 ml). After stirring at 55° C. for 1.5 h, the mixture was left to stand at RT overnight, the DMF was removed under reduced pressure, and the residue was then admixed with water and extracted four times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The residue was purified by means of preparative HPLC (met. A), and the clean product fractions were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated potassium carbonate solution and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 198 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:22]=[C:21]3[C:15]([N:16]([CH3:29])[C:17](=[O:28])[CH2:18][CH2:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:14][N:13]=2)[C:8]([O:30][CH3:31])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.Cl.[CH3:34][N:35]1[CH2:39][CH2:38][C@@H:37]([NH2:40])[CH2:36]1.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>CN(C=O)C.CO>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:22]=[C:21]3[C:15]([N:16]([CH3:29])[C:17](=[O:28])[CH2:18][CH2:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:14][N:13]=2)[C:8]([O:30][CH3:31])=[CH:7][C:3]=1[C:4]([NH:40][C@@H:37]1[CH2:38][CH2:39][N:35]([CH3:34])[CH2:36]1)=[O:6]
Reactant: CN1CC[C@@H](N)C1
Reactant: COc1cc(C(=O)O)c(Cl)cc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
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
Solvent: CO
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)c(Cl)cc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
2-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-5-methoxy-benzoic acid (Intermediate 231; 100 mg, 0.224 mmol), (3R)-1-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 40 mg, 0.235 mmol), HATU (94 mg, 0.246 mmol) and DIPEA (195 μL, 1.12 mmol) were combined in DMF (3 mL) and stirred at room temperature overnight. The reaction mixture was added to an SCX-2 column (5 g) pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (76 mg, 64%).
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([CH3:16])([S:7]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)(=[O:9])=[O:8])[CH3:6])C.[OH-].[Na+]>O1CCOCC1.O>[CH3:16][C:5]([S:7]([CH:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)(=[O:8])=[O:9])([CH3:6])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C(=O)O)S(=O)(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 82.6 %

Procedure:
To a solution of 166 g (0.63 mol) of 2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid ethyl ester in THF/water (4/1, 1.66 L) are added 50.5 g (1.26 mol) of NaOH pellets in portions over 20 min. The reaction is stirred at room temperature for 2.5 d. The organic solvent is removed under reduced pressure and the aqueous residue is diluted with water (2 L) and washed with DCM (2 L). The aqueous layer is acidified to pH 1-2 with concentrated HCl and then extracted with DCM (3×2 L). The acidic aqueous is further saturated with NaCl and extracted again with DCM (6×2 L). The combined organic extracts are concentrated under reduced pressure to give 123 g of 2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid as a white solid. Yield: 83%, ES-MS: m/z 235 [M−H]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2.[Li+].CC([N-]C(C)C)C.Br[CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24](=[O:25])[CH2:23][CH2:28][CH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[CH2:8][CH2:9][C:10]1=[O:13]
Reactant: COc1cccc2c1CC(=O)CC2
Reactant: COC(=O)C(C)Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CCC1C(=O)CCc2cccc(OC)c21
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
A three-neck, round-bottomed flask, equipped with a dropping funnel and septum, was charged with 1.76 g (10 mmol) of 8-methoxy-2-tetralone and 20 mL of THF under a nitrogen atmosphere. The solution was cooled to -30° C. and 7.5 mL (11 mmol) of LDA (1.5M in cyclohexane) was added dropwise. The solution was stirred for 30 minutes and warmed to 0° C. To this solution, 1.3 mL (12 mmol) of methyl bromopropionate was added. The solution was stirred at room temperature for two hours. The reaction was quenched with 3 N HCl until pH of the mixture was <3. THF was removed in vacuo and the concentrate was extracted with methylene chloride (2×500 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. This oil was purified by liquid chromatography on 400 g silica gel 60 (230-400 m), eluting with hexane-acetone (4:1), and collecting 40 mL fractions. Fractions homogeneous by TLC were combined and concentrated in vacuo to give 1.63 g (63%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:9][C:10]([OH:12])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH2:14](O)[CH3:15]>>[NH2:1][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:9][C:10]([O:12][CH2:14][CH3:15])=[O:11]
Reactant: N[C@H](CC(=O)O)c1ccccc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CC(N)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
β-Phenylalanine from II.2a (93) was suspended in ethanol (1.5 l) and the solution was saturated with gaseous HCl at room temperature. It was then heated under reflux for 4 h and stirred overnight at room temperature. The solution was cooled to 5° C. and filtered with suction. The filtrate was concentrated in vacuo, and the residue was washed with ether and dried. A white solid was obtained (yield: 52 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9](=[O:10])[CH2:8][S:7][C:6]=2[CH:11]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]([OH:10])[CH2:8][S:7][C:6]=2[CH:11]=1
Reactant: O=C1CSc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CSc2cc(Br)ccc21

Procedure:
In analogy to the procedures described for the preparation of intermediate A-8 [A], intermediates A-2 [B] and A-2 [C], 6-bromo-benzo[b]thiophen-3-one was reacted with sodium borohydride in ethanol to give (rac)-6-bromo-2,3-dihydro-benzo[b]thiophen-3-ol, which was subsequently reacted with diphenylphosphoryl azide, DBU in toluene to give (rac)-3-azido-6-bromo-2,3-dihydro-benzo[b]thiophene, which was then reduced with triphenylphosphine in THF/water to yield the title compound as light yellow oil. MS: 229 (M+, 1Br).
Reaction SMILES: [CH2:1]1[CH2:13][N:12]2[C:4]3[C:5]([CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:2]1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.CN(C)[CH:30]=[O:31]>>[CH2:10]1[CH2:11][N:12]2[CH2:13][CH2:1][CH2:2][C:3]3=[C:4]2[C:5](=[CH:6][C:7]([CH:30]=[O:31])=[CH:8]3)[CH2:9]1
Reactant: CN(C)C=O
Reactant: c1cc2c3c(c1)CCCN3CCC2
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2c3c(c1)CCCN3CCC2
Reaction time: 0.17 h

Procedure:
9-JA is synthesized by the formulation julolidine with phosphorus oxychloride in N,N-dimethyl formamide by a procedure similar to that described for the formulation of N,N-dimethylaniline (Organic Synthesis, Coll. Vol. 4, Wiley, New York, 1963, pp 331-333). N,N-Dimethyl formamide (45 mL) is added to a round bottom flask fitted with a magnetic stirrer, pressure equalizing dropping funnel, and a Claisen head whose sidearm was fitted with a drying tube. The flask is flushed with dry nitrogen and then cooled in a dry ice/isopropyl alcohol bath. Phosphorus oxychloride (16 mL, about 26.3 g) is added. After 10 min, 19 g of julolidine is added dropwise with stirring. The reaction mixture is stirred for 15 min after addition of the julolidine is complete, heated on a steam bath for 2 hr, and poured into a slurry of about 400 mL of crushed ice and water. The resulting solution is carefully neutralized by the addition of 150 g of sodium acetate in 250 mL of water. The precipitated aldehyde is collected by filtration, and the filtrate is kept at 0° C. overnight. The additional precipitate thus formed is collected and combined with the first crop. The combined precipitates are treated with activated charcoal (Darco® G-60) and recrystallized from ethanol/water to give 21.2 g (96%) of 9-JA as light yellow needles, mp 81° C.-82° C. [lit. 83° C., J. Org. Chem., 17, 1281 (1952)].
Reaction SMILES: [S:1]1[C:5]2[C:6]([CH:10]=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:12][O:13][C:14](=[O:18])[CH2:15][C:16]#[N:17].C([O-])(=O)C.[NH4+].[Na+].[Cl-]>C(OCC)(=O)C.C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:12][O:13][C:14](=[O:18])[C:15]([C:16]#[N:17])=[CH:10][C:6]1[C:5]2[S:1][CH:2]=[CH:3][C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1cccc2ccsc12
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C#N)=Cc1cccc2ccsc12
Yield: 99.4 %

Procedure:
A mixture of 1.0 g (6.2 mmoles) of 7-benzothiophene-carbaldehyde, 0.4 g (6.8 mmoles) of cyanoacetic acid methyl ester, 0.07 g of ammonium acetate, 0.2 g of acetic acid, 1 g of molecular sieve (3 Å) and 10 ml of toluene are boiled under reflux for 4 hours, and then the reaction mixture is cooled and mixed with 20 ml of ethyl acetate and with 20 ml of 10% NaCl solution. The separated organic phase is dried with MgSO4, filtered and the solvent is evaporated in vacuo. 1.5 g of 2-cyano-3-(benzothiophen-7-yl)-acrylic acid methyl ester in the form of a crude product is obtained as residue.