Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Br:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1>>[Br:44][C:45]1[CH:46]=[CH:47][C:48]([OH:51])=[C:49]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])[CH:50]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 4-bromophenol, the title compound was obtained (41%): 1H NMR (300 MHz, CDCl3) δ 9.46-9.25 (br, 1H), 7.51-6.80 (m, 7H), 4.73-4.51(br, 1H), 3.79-3.56 (m, 2H), 1.76-1.60 (m, 2H), 1.41-1.22 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 377 (M−17), 379 (M−17), 412 (M+23), 414 (M+23).
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10](=[O:13])[CH2:11][OH:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[C:15]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[C:34]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])=[C:33](Cl)[N:32]=[C:31]([N:45]3[CH2:50][CH2:49][N:48]([CH:51]=[O:52])[CH2:47][CH2:46]3)[N:30]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].Cl>CS(C)=O.O>[C:1]1([CH:7]([NH:9][C:10](=[O:13])[CH2:11][O:12][C:33]2[C:34]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])=[C:29]([NH:28][S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[N:30]=[C:31]([N:45]3[CH2:50][CH2:49][N:48]([CH:51]=[O:52])[CH2:47][CH2:46]3)[N:32]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCN(C=O)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: CC(NC(=O)CO)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(C=O)CC2)nc1OCC(=O)NC(C)c1ccccc1
Yield: 33.9 %

Procedure:
N-(1-Phenylethyl)-hydroxyacetamide (50 mg, 0.3 mmol) was dissolved in dimethyl sulfoxide (0.56 ml). Sodium (11.5 mg; 0.5 mmol) was added to the solution, and the resultant mixture was stirred at room temperature for two hours. 4-t-Butyl-N-[6-chloro-2-(4-formylpiperazinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide (56 mg; 0.1 mmol) was added thereto, and the resultant mixture was stirred for 1 hour at 120° C., then poured into water, made acidic with hydrochloric acid, and extracted with ethyl acetate. The extracted was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1), to thereby obtain 23.8 mg (yield: 34%) of the title compound as a pale yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[CH:10]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:11]([C:17](O)=[O:18])=[C:12]([CH3:16])[NH:13][C:14]=1[CH3:15])=[O:8]>ClCCl>[Cl:3][C:17]([C:11]1[C@H:10]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:9]([C:7]([O:6][CH3:5])=[O:8])=[C:14]([CH3:15])[NH:13][C:12]=1[CH3:16])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)Cl)[C@@H]1c1cccc([N+](=O)[O-])c1

Procedure:
Thionyl chloride (0.4 g, 3.4 mmol) was slowly added to a solution of 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (1.0 g, 3 mmol) in dichloromethane dropwisely at −25° C. After the completion of the dropwise addition, the reaction was continued under cooling in an ice bath until the solution became clear. After the completion of reaction, the reaction solution was rotary evaporated to dryness. The product was directly used in the next step.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C@H:25]3[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]3)[C:16]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]3)=[O:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[N:32]([C@@H:35]([CH:40]([CH3:42])[CH3:41])[C:36]([O:38][CH3:39])=[O:37])=[C:33]=[O:34].O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C@H:25]3[CH2:26][CH2:27][C@H:28]([O:31][C:33](=[O:34])[NH:32][CH:35]([C:36]([O:38][CH3:39])=[O:37])[CH:40]([CH3:42])[CH3:41])[CH2:29][CH2:30]3)[C:16]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]3)=[O:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(NC(=O)O[C@H]1CC[C@H](N(c2cc(C3=CCCCC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1)C(C)C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 5-cyclohex-1-enyl-3-{(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexane-carbonyl)-amino}-thiophene-2-carboxylic acid (20 mg, 0.045 mmol) and methyl (S)-(−)-2-isocyanato −3-methylbutyrate (10 μl, 0.07 mmol) in toluene (1 mL) was stirred at 70° C. for 2 h. It was cooled and water (1 mL) was added. The mixture was stirred at room temperature for one h. It was extracted with EtOAc (50 mL), washed with brine, dried (MgSO4) and evaporated. Pure 5-cyclohex-1-enyl-3-[{trans-4-(1-methoxycarbonyl-2-methyl-propylcarbamoyloxy)-cyclohexyl}-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid was obtained by chromatography over silica gel (hexane-EtOAc mixtures, pure EtOAc and 5% acetone in DCM as eluent) (12.4 mg, 45%).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:41]=[CH:42][CH:43]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[C:24](=[O:32])[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:9])([CH3:6])([CH3:5])[CH3:4].O.Cl>O1CCCC1.C(O)C>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:41]=[CH:42][CH:43]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=1)[C:24](=[O:32])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CCC(=O)N(Cc1ccc(O)cc1)c1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N(Cc2ccc(O)cc2)C(=O)CCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
Aqueous 1 N sodium hydroxide solution (8 ml, 8 mmols) was added to a solution of ethyl N-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-(4-hydroxybenzyl)succinamate (2.57 g, 4 mmols) in tetrahydrofuran (10 ml) and ethanol (10 ml). The resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was then acidified with 1 N hydrochloric acid added thereto. Then, this was extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure to give an amorphous solid of N-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-(4-hydroxybenzyl) succinamic acid (1.47 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][Cl:17]>C1(C)C(C)=CC=CC=1>[Cl-:17].[NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[CH2:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Br:8]
Reactant: Nc1ncccn1
Reactant: ClCOc1ccccc1Br
Solvent: Cc1ccccc1C
Product: Nc1nccc[n+]1COc1ccccc1Br
Product: [Cl-]
Temperature: 25 °C
Reaction time: 40 h
Yield: 100.8 %

Procedure:
To a solution of 7.1 g of 2-aminopyrimidine in 35 ml of xylene is added, dropwise,, a solution of 11.1 g of o-bromo-α-chloroanisole in 45 ml of xylene. The mixture is warmed at 50° for 5 minutes and allowed to stir for 40 hours at room temperature. The solid is filtered and dried to give about 16.0 g of the product. This is recrystallized from 2-propanol to give about 14.0 g of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1B(O)O.Br[C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[CH3:28])=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[CH3:28])=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1
Reactant: COc1cccc(OC)c1B(O)O
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2c(OC)cccc2OC)cc1
Yield: 71 %

Procedure:
(E)-Ethyl 3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-enoate (1.02 g, 73% yield) was prepared from 2,6-dimethoxyphenylboronic acid (1.20 g, 6.60 mmol) and (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (1.0 g, 4.40 mmol) by a procedure analogous to that described in example 52 a.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27]Br)[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[CH3:30][O:31][P:32]([O:35]C)[O:33][CH3:34]>>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:32]([O:33][CH3:34])([O:31][CH3:30])=[O:35])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21]
Reactant: COC(=O)C(CC=CCBr)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: COP(OC)OC
Product: COC(=O)C(CC=CCP(=O)(OC)OC)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
Under a N2 atmosphere, a solution of 2-(4-bromo-but-2-enyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester (490 mg, 1.05 mmol) in trimethylphosphite (2.5 mL, 21.1 mmol) was heated at 120° C. for 1 hour. The reaction was allowed to cool to room temperature. The reaction mixture was worked up by removal of the solvent in vacuo followed by chromatography using EtOAc-hexanes to provide 460 mg (88%) of the product as an oil. 1H NMR (300 MHz, CDCl3) δ 1.77 (s, 3H), 2.081-2.31 (m, 4H), 2.15 (s, 3H), 2.52 (d, 1H, J=22 Hz), 2.54 (d, 1H, J=22 Hz), 2.55-2.63 (m, 1H), 3.36 (d, 2H, J=7 Hz), 3.57 (s, 3H), 3.72 (d, 6H, J=11 Hz), 3.76 (s, 3H), 5.20 (s, 2H), 5.20-5.26 (m, 1H), 5.36-5.56 (m, 2H), 7.69 (s, 1H) ppm; 31p (121.4 MHz, CDCl3) δ 30.1 ppm; MS (m/z) 497.2 [M+H]+, 519.2 [M+Na]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[CH2:8](Br)[CH2:9][CH3:10].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:8]([NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])[CH2:9][CH3:10]
Reactant: CCCBr
Reactant: COC(=O)CN
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCNCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
A suspension of glycine methyl ester HCl (5.0 g, 39.8 mmol) in acetonitrile (100 mL) was treated with propyl bromide (3.7 mL, 39.8 mmol), and diisopropylethylamine (13.9 mL, 79.6 mmol). After stirring at room temperature for 1 hour, the mixture was heated at reflux overnight. Solution occurred at reflux temperature. The solvent was removed under reduced pressure and the residue triturated with Et2O/EtOAc. Filtering and removal of the solvent under pressure left 1.13 g of the crude product. Chromatography on silica gel, eluting with CHCl3/MeOH (98:2) gave 0.53 g (10.2% yield) of the product as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=O)N2)C.Br[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:20][CH:19]=1.C(=O)([O-])[O-:38].[K+].[K+]>COCCOC>[CH2:13]([C:11]1[CH:10]=[C:9]([O:38][CH2:17][C:18]2[CH:36]=[CH:35][C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:20][CH:19]=2)[C:4]2[CH2:5][CH2:6][CH2:7][CH2:1][C:3]=2[N:12]=1)[CH3:14]
Reactant: CCc1cc2[nH]c(=O)ccc2c(CC)n1
Reactant: CCOC(=O)Cc1ccccc1Oc1ccc(CBr)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)Cc1ccccc1Oc1ccc(COc2cc(CC)nc3c2CCCC3)cc1
Yield: 43.8 %

Procedure:
A mixture of compound H (404 mg), ethyl 2-(4-bromomethylphenoxy)phenylacetate (700 mg) and potassium carbonate (552 mg) in 1,2-dimethoxyethane (10 ml) was heated under reflux for 1 hour. Insoluble material was removed by filtration and the filtrate was concentrated. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (7:3 v/v), to give ethyl 2-[4-((5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl)methyl)phenoxy]phenylacetate (A) (390 mg), as a gum; NMR (CDCl3): 1.2(t, 3H), 1.25(t, 3H), 1.35(t, 3H), 2.8(q, 2H), 3.1(q, 2H), 4.1-4.25(m, 2H), 5.4(s, 2H), 5.55(s, 1H), 6.7(d, 1H), 6.85(s, 1H), 6.9(d, 2H), 7.15(d, 2H), 7.3-7.4(m, 3H), 7.5-7.6(m, 2H), 7.95(d, 1H).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:31])=[C:19]([C@:21]2([CH3:30])[CH2:26][S:25](=[O:28])(=[O:27])[CH2:24][C:23]([NH2:29])=[N:22]2)[CH:20]=1>>[NH2:29][C:23]1[CH2:24][S:25](=[O:27])(=[O:28])[CH2:26][C@:21]([C:19]2[CH:20]=[C:15]([NH:14][C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:1])[F:13])=[CH:9][N:8]=3)=[O:12])[CH:16]=[CH:17][C:18]=2[F:31])([CH3:30])[N:22]=1
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)CC(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(OC(F)F)cn3)ccc2F)CS(=O)(=O)CC(N)=N1
Yield: 52 %

Procedure:
Prepared from 5-(difluoromethoxy)picolinic acid (69.7 mg, 369 μmol, Eq: 1.00) and (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (100 mg, 369 μmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (85 mg, 192 μmol, 52.1% yield) as a white foam. MS (ISP): m/z=443.4 [(M+H)].
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:4]=[C:5]([C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(O)(=[O:20])C.C([O-])(=O)C.[K+].Cl>O>[CH:2]([C:3]1[CH:4]=[C:5]([C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)=[O:20]
Reactant: CCOC(=O)C(C)(C)c1cccc(C(Br)Br)c1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCOC(=O)C(C)(C)c1cccc(C=O)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixed liquid of 2.95 g of ethyl 2-[3-(dibromomethyl)phenyl]-2-methylpropionate and 30 ml of acetic acid was added 4.77 g of potassium acetate, followed by stirring at 100° C. for 6 hours. After cooling the reaction solution, 10 ml of 6 M hydrochloric acid was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was poured into water, followed by extraction with hexane, and the organic layer was washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated to obtain 1.74 g of ethyl 2-(3-formylphenyl)-2-methylpropionate as a colorless oily substance.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[C:29]([C:30]([O:32]CC)=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1.[OH-].[Li+].O1CCCC1.O>CO>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CCOC(=O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A 250 mL round-bottom flask was charged with ethyl 2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylate (2.3 g, 5.0 mmol), lithium hydroxide (0.48 g, 20.0 mmol), tetrahydrofuran (30.mL), water (50.mL) and methanol (30 mL). The reaction mixture was stirred under nitrogen at reflux for 5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was taken up in water (100 mL) and acidified to pH 1 by the addition of 10 M hydrochloric acid, causing a precipitate to be deposited. The solid was collected by filtration, washed with water and recrystallized from ethanol (50 mL) to afford 2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-carboxylic acid (1.96 g, 91%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.57-8.45 (m, 1H), 8.33-8.26 (m, 1H), 7.42 (dd, J=7.82, 4.77 Hz, 1H), 7.21-6.83 (m, 4H), 6.49-6.44 (m, 2H), 5.39 (ABq, 2H), 4.72 (ABq, 2H), 4.24-4.00 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C(=O)(O)[O-].[Na+].[N:27]#[C:28]Br>O1CCOCC1.O.C(OCC)(=O)C>[NH2:27][C:28]1[O:19][C:18]([CH2:17][CH2:16][C:7]2[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH:8]=2)=[N:20][N:21]=1
Reactant: N#CBr
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(CCc2nnc(N)o2)cc(C(C)(C)C)c1O
Reaction time: 5 h
Yield: 59 %

Procedure:
A solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid hydrazide (0.50 g, 1.71 mmol) in dioxane (15 mL) is added to a solution of sodium bicarbonate (0.16 g, 1.88 mmol) in water (4 mL). Cyanogen bromide (0.20 g, 1.88 mmol) is then added in 4 equal portions at 1-minute intervals, and stirring is continued for 5 hours. The reaction mixture is diluted with ethyl acetate and sequentially washed with aqueous sodium bicarbonate, water, and brine. Drying the organic phase over magnesium sulfate and evaporation provides a solid which is crystallized from ethyl acetate/hexane followed by methanol/water to give 0.32 g (59%) of 4-[2-(5-amino-1,3,4-oxadiazol-2-yl)ethyl]-2,6-bis(1,1-dimethylethyl)phenol, mp 220.0°-221.0° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][N:6]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]([CH2:9][C@@H:10]([C:12]([O-:14])=[O:13])[NH2:11])=[CH:7]1.[CH3:21]O>>[ClH:3].[CH3:5][N:6]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]([CH2:9][C@@H:10]([C:12]([O:14][CH3:21])=[O:13])[NH2:11])=[CH:7]1
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: Cn1cc(C[C@H](N)C(=O)[O-])c2ccccc21
Product: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Product: Cl
Reaction time: 20 h
Yield: 87 %

Procedure:
Thionyl chloride (16.7 mL) was added dropwise to methanol (150 mL) at 0° C., and thereafter 1-methyl-L-tryptophanate (10.0 g) was added at room temperature. The mixture was allowed to stir for 20 hours, and thereafter heated and refluxed for 6 hours. To the residue obtained by distilling off the solvent under a reduced pressure was added diethylether, and crystals precipitated were filtered, to give the captioned compound (10.7 g, 87%).
Reaction SMILES: [CH3:1][C:2]([S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:7])[CH2:3][C:4]([OH:6])=O.ClC(Cl)(Cl)C(C(Cl)(Cl)Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)CC)C>C(Cl)Cl>[OH:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][N:51]([C:4](=[O:6])[CH2:3][C:2]([CH3:1])([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:7])[CH2:50][CH2:49]1
Reactant: OCCN1CCNCC1
Reactant: CC(C)(CC(=O)O)SCc1ccccc1
Agent: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CC(=O)N1CCN(CCO)CC1)SCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-methyl-3-(phenylmethylthio)butanoic acid (1 g, 4.6 mmol) and hexachloroacetone were dissolved in CH2Cl2 (20 mL) and cooled to −78° C. Triphenyl phosphine was added and the mixture was stirred for 30 minutes. Hydroxyethyl piperazine (550 μL, 4.5 mmol) was added in CH2Cl2 (10 mL) dropwise. Triethylamine (630 μL, 4.5 mmol) was added in CH2Cl2 (10 mL) dropwise. The cold bath was removed and the solution was stirred for 24 hours. The solvent was evaporated. The crude mixture was poured into 1N HCl (100 mL) and washed with Et2O (2×50 mL). The aqueous layer was made basic with 10% K2CO3 in a brine solution. The product was extracted with EtOAc (3×100 mL), dried over Na2SO4, and concentrated. This gave the title compound which was used immediately in the next reaction. 1H NMR (300 MHz, CDCl3) δ 7.18-7.37 (mult, 5H), 3.8 (s, 2H), 3.6 (t, J=5 Hz, 4H), 3.4 (t, J=5 Hz, 2H), 2.45-2.65 (mult, 8H), 1.5 (s, 6H).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35](=[O:42])[NH:36][C:37]4[NH:38][CH2:39][CH2:40][N:41]=4)=[CH:27][CH:26]=3)[C:17]([O:19]C(C)(C)C)=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>FC(F)(F)C(O)=O.O>[C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35](=[O:42])[NH:36][C:37]4[NH:41][CH2:40][CH2:39][N:38]=4)=[CH:29][CH:30]=3)[C:17]([OH:19])=[O:18])=[O:14])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCN2)cc1)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CCCOc1ccc(C[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)O)cc1)NC1=NCCN1
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
188 mg (0.32 mmol) of (5.1) were dissolved in 10 ml of trifluoroacetic acid/H2O (95:5). After 30 min, the solvent was removed in vacuo and the residue was digested with diisopropyl ether. After freeze-drying, 168 mg of an amorphous powder of (5.2) were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][N:3]=1.[Br-].[CH:18]1([CH2:24][Zn+])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.CCOC(C)=O>[C:13]([O:12][C:10]([NH:9][CH2:8][C:5]1[CH:4]=[N:3][C:2]([CH2:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:7][CH:6]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: [Zn+]CC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)nc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(CC2CCCCC2)nc1
Temperature: 60 °C
Yield: 68 %

Procedure:
Dissolve 2-bromo-5-tert-butoxycarbonylaminomethyl-pyridine (500 mg, 1.74 mmol) in anhydrous THF (5 mL) in a sealed tube. Degas the solution, purge with nitrogen and add 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (127 mg, 0.174 mmol) and 0.5 M cyclohexylmethylzinc bromide in THF (10.4 mL, 5.22 mmol). Heat the mixture at 60° C. overnight. Cool to room temperature and dilute the reaction mixture with EtOAc. Add water and filter the precipitate over Celite®. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (4:1, 3:2) to give the desired intermediate as an oil (359 mg, 68%). MS (ES+) m/z: 305 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:10][C:11](=[O:13])[CH:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>C(O)(=O)C.CO>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:21]2[C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][C:11]2=[O:13])=[CH:18][CH:17]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CN2C(=O)C=C(c3ccccc3)C2=O)cc1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
Phenylmaleic anhydride (2.4 g, 13.8 mmol) and 4-methoxybenzylamine (1.8 mL, 13.8 mmol) in 10 mL glacial acetic acid were heated in a 95° C. oil bath for 2 h. The mixture was cooled to room temperature, diluted with methanol and filtered to provide the title compound as a solid (3.2 g, 79%).