Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.[C:22]1([CH3:53])[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([Sn](CCCC)(CCCC)CCCC)[CH:37]=3)[CH2:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:12][C:11]1[C:2]([C:35]2[CH:34]=[C:33]3[C:38](=[CH:37][CH:36]=2)[CH2:39][N:31]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:53])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:32]3)=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CN(S(=O)(=O)c1ccc(C)cc1)C2
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(Br)ccc2c1=O
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(-c3ccc4c(c3)CN(S(=O)(=O)c3ccc(C)cc3)C4)ccc2c1=O
Yield: 79 %

Procedure:
In the same manner as in Example 1, 0.45 g of ethyl 7-bromo-8-chloro-1-cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylate was reacted with 1.02 g of 2-(p-toluenesulfonyl)-5-tributylstannylisoindoline to obtain 0.54 g of ethyl 8-chloro-1-cyclopropyl-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([S:14][CH3:15])[CH:13]=1.CO.[O:21]1CCCC1>O.C(OCC)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N+:16]([O-:18])=[O:17])=[C:12]([S:14]([CH3:15])=[O:21])[CH:13]=1
Reactant: CSc1cc(Br)ccc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CS(=O)c1cc(Br)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Sodium periodate (4.2 g, 16.34 mmol) in water (8 mL) was added to the solution of the product of Example 14A (4.01 g, 16.34 mmol) in 2/1 methanol/tetrahydrofuran (60 mL) and the mixture stirred for 1 hour. The mixture was diluted with ethyl ether, washed with water and saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 3/1 ether/ethyl acetate to provide the title compound.
Reaction SMILES: O=S(Cl)Cl.[CH2:5]([N:12]1[CH2:16][CH2:15][C:14]2([CH2:21][CH2:20][C:19]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)(O)[CH2:18][CH2:17]2)[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH2:5]([N:12]1[CH2:16][CH2:15][C:14]2([CH2:21][CH2:20][C:19]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:18][CH2:17]2)[CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: OC1(c2cccnc2)CCC2(CCN(Cc3ccccc3)C2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C1=C(c2cccnc2)CCC2(C1)CCN(Cc1ccccc1)C2
Reaction time: 0.25 h
Yield: 71 %

Procedure:
SOCl2(1 ml) was added dropwise to a solution of 2-benzyl-8-(pyridin-3-yl)-2-azaspiro[4.5]decan-8-ol (450 mg, 1.39 mmol, 1.0 eq.) in pyridine (5 ml) at −10° C. and the reaction mixture was stirred at the same temperature for 15 min. After completion of the reaction (monitored by TLC), the reaction mixture was poured onto crushed ice and the mixture was then neutralized with sat. NaHCO3 solution (15 ml). It was extracted with methylene chloride (2×30 ml) and the combined organic layers were washed with water (20 ml) and brine (20 ml), and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 10% MeOH/DCM) to yield the desired compound as a reddish sticky solid. Yield: 71% (300 mg, 0.99 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[N+:21]([O-])=O)=[CH:7][CH:6]=1)[CH3:2].[Cl-].[NH4+].N.[S-2].[Na+].[Na+]>O.C(O)C>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[NH2:21])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(Nc2ccc([N+](=O)[O-])cc2N)cc1
Reaction time: 1 h
Yield: 104.5 %

Procedure:
At an internal temperature of 78° C. (90° C. bath temperature), 566 mg (1.7 mmol) of 4-(2,4-dinitrophenylamino)benzoic acid ethyl ester, 761 mg (12.2 mmol) of ammonium chloride, 0.68 ml of concentrated ammonia, 15 ml of ethanol and 6 ml of distilled water are combined. To this mixture is added 1.27 g (5.68 mmol) of sodium sulfide (35% strength) in 3 portions, and the mixture is stirred for one hour. The batch is vacuum-filtered at room temperature and first washed with water and then under ether, thus obtaining 535 mg of 4-(2-amino-4-nitrophenylamino)benzoic acid ethyl ester as the crude product (processed without further purification).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:6][C@H:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][N:16]([CH2:19][CH2:20][C@@:21]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])[C:15](=[O:37])[CH:14]=3)=[CH:9][CH:8]=2)[CH2:4]1>O1CCOCC1>[OH:25][NH:24][C:22](=[O:23])[C@:21]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:20][CH2:19][N:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([C@H:5]3[CH2:4][C@H:3]([OH:2])[CH2:6]3)=[CH:8][CH:9]=2)=[CH:14][C:15]1=[O:37]
Reactant: C[C@@](CCn1ccc(-c2ccc([C@H]3C[C@H](O)C3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@](CCn1ccc(-c2ccc([C@H]3C[C@H](O)C3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 1 h
Yield: 59.5 %

Procedure:
HCl (1.0 N in water, 2.17 mL) was added to a solution of (2R)-4-{4-[4-(trans-3-hydroxycyclobutyl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (375 mg, 0.723 mmol) in 1,4-dioxane (5 mL). After 1 hour, the reaction was concentrated to give a brown solid. The solid was triturated with 2-propanol at 50° C., for 30 minutes. After cooling, filtration afforded the title compound as a white solid (187 mg, 60%). LCMS m/z 435.6 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3H) 2.11-2.23 (m, 1H) 2.26-2.38 (m, 4H) 2.38-2.48 (m, 1H) 3.11 (s, 3H) 3.42-3.60 (m, 1H) 3.74 (td, J=12.00, 4.68 Hz, 1H) 4.00-4.21 (m, 1H) 4.25-4.42 (m, 1H) 6.58-6.72 (m, 2H) 7.36 (d, J=8.20 Hz, 2H) 7.61-7.71 (m, 2H) 7.74 (d, J=7.22 Hz, 1H) 11.17 (br. s., 1H)
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]3[NH:15][C:16]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)=[CH:17][N:18]=3)=[C:7]2[N:6]=[N:5]1)[C:2]#[CH:3].[H-].[Na+].[CH3:26]I>CN(C=O)C>[CH3:26][N:18]1[CH:17]=[C:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[N:15]=[C:14]1[C:13]1[N:12]=[CH:11][N:8]2[C:9](=[O:10])[N:4]([CH2:1][C:2]#[CH:3])[N:5]=[N:6][C:7]=12
Reactant: CI
Reactant: C#CCn1nnc2c(-c3ncc(-c4cccs4)[nH]3)ncn2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCn1nnc2c(-c3nc(-c4cccs4)cn3C)ncn2c1=O
Reaction time: 0.17 h
Yield: 90 %

Procedure:
3-(Prop-2-ynyl)-8-(5-(thiophen-2-yl)-1H-imidazol-2-yl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (0.15 mmol) was dissolved in dry DMF (1 mL) and cooled in ice under a nitrogen atmosphere. A 60% suspension of sodium hydride in mineral oil (0.17 mmol) was added in one portion and the reaction stirred on ice for 10 minutes. Methyl iodide (0.30 mmol) was then added dropwise to the reaction and the mixture stirred at room temperature for 24 hours. Solvent was then removed under vacuum and product isolated by preparative thin layer chromatography eluting with 2.5% MeOH/DCM. Yield 90%. δH (DMSO-d6) 8.97 (1H, s), 7.78 (1H, s), 7.40 (1H, dd, J=5.2, 1.2), 7.33 (1H, dd, J=3.6, 1.2), 7.08 (1H, m), 5.13 (2H, d, J=2.4), 3.96 (3H, s), 3.52 (1H, t, J=2.4).
Reaction SMILES: O[CH:2]([CH3:24])[CH:3]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:70]=[N+:71]=[N-:72])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:70]([CH:2]([CH3:24])[CH:3]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:4][C:5]1[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:6]=1)=[N+:71]=[N-:72]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)O)o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)N=[N+]=[N-])o1
Yield: 82.3 %

Procedure:
3.66 g of ethyl 5-{(2RS,3SR)-3-hydroxy-2-(4-nitrophenyl)butyl}-2-furancarboxylate was dissolved in 40 ml of tetrahydrofuran, and 4.32 g of triphenylphosphine, 2.60 ml of diethyl azodicarboxylate and 4.53 g of diphenylphosphoryl azide were added under cooling with ice with stirring, followed by stirring at room temperature for 18 hours. The reaction solution was evaporated to dryness under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/1) to obtain 3.24 g of the above-identified compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([NH:20][C:21]([C:23]3[N:24]=[CH:25][O:26][C:27]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:22])[CH:17]=[N:16]1)[CH2:7][CH2:6]2>CC(C)=O.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([NH:20][C:21]([C:23]3[N:24]=[CH:25][O:26][C:27]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:22])[CH:17]=[N:16]1)[CH:7]=[CH:6]2
Reactant: COc1ccc2c(c1)CCN2CCCn1cc(NC(=O)c2ncoc2-c2cccc(C)c2)cn1
Agent: O=[Mn]=O
Solvent: CC(C)=O
Product: COc1ccc2c(ccn2CCCn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)c1
Yield: 7.3 %

Procedure:
A solution of N-(1-(3-(5-methoxyindolin-1-yl)propyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (69 mg, 0.15 mmol) in acetone (1.0 mL) was added dropwise to a suspension of MnO2 (50 mg, 0.575 mmol) in acetone (0.5 mL). After stirring the dark reaction mixture for 18 h, the mixture was filtered over celite, rinsed with acetone and the solvent was removed under reduced pressure. Purification by prep. HPLC yielded the title compound (5 mg) as a brown oil. LC-MS conditions D: tR=1.12 min, [M+H]+=456.3.
Reaction SMILES: CS([O:5][CH:6]1CN(C(C2OC(C3C=CC=CC=3)=NN=2)=O)C1)(=O)=O.C[C:24]1[CH:31]=[C:30]([O:32][CH:33]2[CH2:36][N:35]([C:37]([C:39]3[O:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[N:42][N:43]=3)=[O:38])[CH2:34]2)[CH:29]=[CH:28][C:25]=1[CH:26]=[O:27].COC1C=CC(C2OC(C(OCC)=O)=NN=2)=CC=1>>[CH3:6][O:5][C:47]1[CH:48]=[CH:49][C:44]([C:41]2[O:40][C:39]([C:37]([N:35]3[CH2:34][CH:33]([O:32][C:30]4[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:31]=4)[CH2:36]3)=[O:38])=[N:43][N:42]=2)=[CH:45][CH:46]=1
Reactant: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1C=O
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Agent: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Yield: 32 %

Procedure:
Using similar protocols as described in Example 53A, 53B and 53C employing ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate as starting material afforded 0.47 g (32%) of 55A as a solid. 1H NMR (500 MHz, CDCl3): δ 3.89 (s, 3H), 4.36 (d, 1H), 4.70 (dd, 1H), 4.79 (m, 1H), 5.18 (m, 2H), 6.91 (d, 2H), 7.03 (d, 2H), 7.88 (d, 2H), 8.10 (d, 2H), 9.93 (s, 1H), MS (APCI+) m/z 380 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Na].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Clc1nccc(Sc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a stirred solution of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol) in absolute ethanol (10 mL), was added sodium salt of benzenethiol (0.89 g, 6.73 mmol)in small portions. The mixture was stirred at room temperature for 2 hours, then at 40° C. for 16 hours. It was diluted with ethyl acetate (20 mL), and filtered. The filtrate was concentrated in vacuo, and the residue was flash chromatographed on silica gel using ethyl acetate:petroleum ether (1:99→25:75) as eluant to give the desired product (498 mg, 36%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13](C(OCC)=O)[CH2:12][CH2:11]2)=[N:2]1.[BrH:21]>O>[BrH:21].[BrH:21].[N:10]1([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][N:2]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)N1CCN(c2nsc3ccccc23)CC1
Agent: Br
Solvent: O
Product: c1ccc2c(N3CCNCC3)nsc2c1
Reaction time: 1.5 h
Yield: 73 %

Procedure:
A mixture of 12.5 parts of ethyl 4-(1,2-benzisothiazol-3-yl)-1-piperazinecarboxylate and 187.5 parts of a hydrobromic acid solution 48% in water was stirred for 1.5 hours at reflux temperature. After evaporation, the residue was taken up in 2-propanol and the solvent was evaporated again. The residue was dissolved in methanol, evaporated again and stirred in 2-propanone. The product was filtered off and dried, yielding 11.5 parts (73%) of 3-(1-piperazinyl)-1,2-benzisothiazole dihydrobromide (int. 4).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[C:14]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[C:13]([CH3:25])[NH:12][N:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>CO>[CH3:8][C:2]([O:9][C:10]1[C:14]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[C:13]([CH3:25])[NH:12][N:11]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1n[nH]c(C)c1-c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]nc(OC(C)(C)C(=O)O)c1-c1cccc2ccccc12
Yield: 71.6 %

Procedure:
A mixture of ethyl 2-methyl-2-(5-methyl-4-(naphthalen-1-yl)-1H-pyrazol-3-yloxy)propanoate (60 mg, 0.18 mmol), aqueous sodium hydroxide solution (10%, 5 mL) and methanol (5 mL) was stirred at reflux for 2 hours. The reaction was then cooled to room and the methanol removed. Water was added, neutralized with aqueous HCl solution (1N) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (95% dichloromethane/5% methanol) afforded compound 2-methyl-2-(5-methyl-4-(naphthalen-1-yl)-1H-pyrazol-3-yloxy)propanoic acid as a solid (40 mg, 71%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22](I)[CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>C1COCC1.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:23]=[C:22]([C:27]#[C:26][CH2:25][OH:28])[CH:21]=[CH:20][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: C#CCO
Reactant: Cn1cc(C(=O)NCCCO)c(Nc2ccc(I)cc2F)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCCCO)c(Nc2ccc(C#CCO)cc2F)cc1=O
Yield: 89 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with propargyl alcohol in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a cream solid (89%). 1H NMR [(CD3)2SO, 400 MHz] δ 10.27 (s, 1H), 8.40 (t, J=5.4 Hz, 1H), 8.25 (s, 1H), 7.48 (t, J=8.5 Hz, 1H), 7.39 (dd, J=11.6, 1.8 Hz, 1H), 7.27 (dd, J=8.3, 1.4 Hz, 1H), 5.70 (s, 1H), 5.34 (t, J=6.1 Hz, 1H), 4.47 (t, J=5.1 Hz, 1H), 4.30 (d, J=6.0 Hz, 2H), 3.46 (q, J=5.9 Hz, 2H), 3.38 (s, 3H), 3.27 (q, J=6.5 Hz, 2H), 1.66 (pentet, J=6.7 Hz, 2H). LCMS (APCI+) calcd for C19H21FN3O4 374 (MH+), found 374.
Reaction SMILES: C(N[C@H](C(O)=O)CC(C)C)(=O)C.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([C@H:24]([NH2:30])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH3:14].[C:31]([NH:34][C:35]1[CH:45]=[CH:44][CH:43]=[C:37]2[C:38]([O:40][C:41](=O)[C:36]=12)=[O:39])(=[O:33])[CH3:32].C(O)(=O)C.C=CCl>CCO>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:24]([N:30]2[C:41](=[O:40])[C:36]3[C:37](=[CH:43][CH:44]=[CH:45][C:35]=3[NH:34][C:31](=[O:33])[CH3:32])[C:38]2=[O:39])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH3:14]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Agent: C=CCl
Agent: CC(=O)N[C@@H](CC(C)C)C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 75 %

Procedure:
A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), 3-acetamidophthalic anhydride (12.1 g 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to <50° C. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL×2), saturated aqeous NaHCO3 (250 mL×2), brine (250 mL×2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL×2). The product was dried in vacuo at 60° C. to a constant weight, affording 19.4 g (75% yield) of (S)-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-inoisoindoline-1,3-dione with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2PO4 @pH 0.5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm×4.6 mm, 0.4 mL/min., @240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%). 1H-NMR (CDCl3) δ: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68–3.75 (dd, 1H), 3.85 (s, 3H), 4.07–4.15 (q, 2H), 4.51–4.61 (dd, 1H), 5.84–5.90 (dd, 1H), 6.82–8.77 (m, 6H), 9.46 (s, 1H). 13C-NMR (DMSO-d6) δ: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3].[I-].[Li+]>N1C=CC=CC=1>[CH2:23]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:24][CH3:25]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2noc(C)n2)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2noc(C)n2)c1
Temperature: 25 °C

Procedure:
A stirred solution of methyl 3-[(dipropylamino)carbonyl]-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate (629 mg, 1.8 mmol) and lithium iodide (2.4 g, 18 mmol) in pyridine (7 ml) is refluxed for 18 h. The reaction mixture is cooled to room temperature and the solvent is concentrated under reduced pressure. The residue is dissolved in water, washed with ethyl acetate, the aqueous layer is acidified to pH 3 with 1 N hydrochloric acid and extracted with chloroform (3×100 mL). The organic layer is dried (sodium sulfate), filtered, and concentrated to give the title compound. 1H NMR (500 MHz, CDCl3) δ 11.11 (br s, 1H), 8.85 (t, J=1 Hz, 1H), 8.31 (t, J=1 Hz, 1H), 8.23 (t, J=1 Hz, 1H), 3.51 (s, 2H), 3.19 (s, 2H), 2.72 (s, 3H), 1.73 (d, J=7 Hz, 2H), 1.56 (d, J=7 Hz, 2H), 1.01 (t, J=7 Hz, 3H), 0.76 (t, J=7 Hz, 3H).
Reaction SMILES: [CH:1]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:40]([OH:42])=O)[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:39])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:30]=1)[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:46])=O>>[Cl:46][C:40]([C@:7]12[CH2:6][CH2:5][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:39])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:27])([CH3:28])[C@@H:16]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:30]=2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)=[O:42]
Reactant: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)O)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Reactant: O=C(Cl)C(=O)Cl
Product: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)Cl)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask containing (1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-1-isopropyl-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.154 g, 0.267 mmol) was added oxalyl chloride (2M in dichloromethane) (5 mL, 10.00 mmol). The solution was stirred at rt for 3 h. The mixture was concentrated under reduced pressure and was dissolved in dichloromethane and concentrated two additional times. The crude product was used in the next step with no additional purification.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([CH2:22][O:23][CH2:24][CH3:25])[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].CN>>[NH2:3][CH:12]([CH2:22][O:23][CH2:24][CH3:25])[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18]
Reactant: CCOCC(CNC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Agent: CN
Product: CCOCC(N)CNC(=O)OC(C)(C)C

Procedure:
4.88 g of rac-tert-butyl [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-ethoxypropyl]carbamate (14.0 mmol, 1 equivalent) were initially charged in 12 ml of 40% strength aqueous methylamine solution and reacted in a microwave at 100° C. for 1.5 h. The reaction mixture was concentrated, the residue was taken up in 10 ml of toluene and concentrated again. This step was repeated several times. The residue was then chromatographed on silica gel (mobile phase: dichloromethane/methanol 10:1). This gave 470 mg (15% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][O:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:45]=1[S:51](Cl)(=[O:53])=[O:52]>C(#N)C>[CH3:42][O:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:45]=1[S:51]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:53]
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(C)ccc1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 50.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0324 g, 0.0702 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0590 mL, 0.421 mmol) and 2-methoxy-4-methylbenzenesulfonyl chloride (0.0460 g, 0.211 mmol) to obtain 4-(2-methoxy-4-methylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0227 g, yield 50%).