Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:6][C:5]=1[O:21]C.B(Br)(Br)Br.CO>C(Cl)Cl>[CH3:10][C:9]1[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[NH:6][C:5](=[O:21])[C:4]=1[C:3]([OH:23])=[O:2]
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)[nH]c(=O)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.325 g (1.0 mmol) of 2-methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid methyl ester (intermediate 12C) in 10 ml of CH2Cl2 was cooled down to 0° C., 2.0 ml (2.0 mmol) of a solution of boron tribromide (1 molar in CH2Cl2) was added drop by drop and the reaction mixture was subsequently warmed up to RT. After two hours, 1.0 ml of MeOH was added and 90 min later, the reaction mixture was evaporated. The crude intermediate formed was used without purification in the next step.
Reaction SMILES: [CH:1]1([N:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8](=[O:24])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([CH:22]=[O:23])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=[O:32])C.S(=O)(O)[O-].[Na+].ClCCl>N1C=CC=CC=1>[CH:1]1([N:7]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8](=[O:24])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([C:22]([OH:32])=[O:23])[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(C)=O
Reactant: COC(=O)CN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1)C1CCCCC1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CN(C(=O)CCCOc1ccc([N+](=O)[O-])c(C(=O)O)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(N-cyclohexyl-4-(3-formyl-4-nitrophenyl)oxybutyramidyl)acetate (3.5 g) in dry pyridine (20 ml) under a blanket of nitrogen was added solid tetra-N-butylammonium permanganate portionwise over 1 hour. The reaction was stirred at room temperature for 1 hour and was then poured into ethyl acetate/6M hydrogen chloride (100 ml each). Solid sodium bisulfite was added to decolorize the solution and the layers were separated. The aqueous layer was washed with ethyl acetate (2×50 ml). The combined organic layers were washed with 1M HCl (3×50 ml) and brine (2×50 ml), dried, filtered and evaporated to give a syrup which foamed at high vacuum from dichloromethane to yield methyl 2-(N-cyclohexyl-4-(3-carboxy-4-nitrophenyl)oxybutyramidyl)acetate.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[O:4]=[C:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].N1C=CC=CC=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>O1CCCC1>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([CH:6]([C:5](=[O:4])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)Cc1ccccc1)C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a suspension of magnesium chloride (1.46 g) in tetrahydrofuran (10 ml) was added a solution of ethyl 3-oxo-4-phenylbutanoate (2.0 g) in tetrahydrofuran (10 ml) and the mixture was cooled to 0° C., then pyridine (25 ml) was added. The mixture was stirred at 20° C. for 30 minutes, then a solution of 4-fluorobenzoyl chloride (2.44 g) in tetrahydrofuran (10 ml) was added at 0° C. After stirring at 20° C. for 2 hours, the mixture was partitioned between 0.5N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate (2.15 g) as an oil.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:12]([C:13]([CH:15]([NH2:17])[CH3:16])=[O:14])=[C:11]2[N:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)[N:5]=1)[CH3:3].[CH3:18][CH:19]([C:21]1[C:22]([C:30](C(C)C)=[O:31])=[C:23]2[N:28]([N:29]=1)[CH:27]=[CH:26][CH:25]=[CH:24]2)[CH3:20].C(C1C=C2C=CC=CN2N=1)(C)C.CC(C)C=[O:50]>>[CH3:3][CH:2]([C:4]1[C:12]([C:13]([CH:15]([NH2:17])[CH3:16])=[O:14])=[C:11]2[N:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)[N:5]=1)[CH3:1].[CH:19]([C:21]1[CH:22]=[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:28]2[N:29]=1)([CH3:20])[CH3:18].[CH:19]([C:21]1[C:22]([C:30]([OH:31])=[O:50])=[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:28]2[N:29]=1)([CH3:18])[CH3:20]
Reactant: CC(C)C=O
Reactant: CC(C)C(=O)c1c(C(C)C)nn2ccccc12
Agent: CC(C)c1cc2ccccn2n1
Agent: CC(N)C(=O)c1c(C(C)C)nn2ccccc12
Product: CC(C)c1nn2ccccc2c1C(=O)O

Procedure:
According to one approach, therefore, the desired S-enantiomer of AV1013 is prepared by chiral resolution of the corresponding racemic mixture. As shown in FIG. 6, and described in the Example 1 below, synthesis of AV1013 involves several steps. The first step involves the synthesis of 2-chloro-nor-methylibudilast using either ibudilast (2-methyl-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one) or the corresponding 3-carboxylic acid (2-isopropyl-pyrazolo[1,5-a]pyridin-3-carboxylic acid, ibudilast acid) as the starting material. Thus, reacting ibudilast with an aqueous solution of a strong inorganic acid, for example, 50% aqueous sulfuric gave isopropylpyrazolo[1,5-a]pyridine (IPPP) following a loss of its 3-ring substituent (2-methyl-propan-1-one). Alternatively IPPP is obtained via the decarboxylation of 2-isopropyl-pyrazolo[1,5-a]pyridin-3-carboxylic acid under acidic conditions. See, Example 1, method 2, step 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[C:10]([CH3:24])([CH3:23])[N:9]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:25])[C:11](=[O:22])[C:10]([CH3:24])([CH3:23])[N:9]=1
Reactant: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
18.2 g (0.056 mol) of 5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 150 ml of dry acetone, treated with 18 g of powdered potassium carbonate and 9 ml of methyl iodide and stirred at room temperature for 21/2 hours. Subsequently, the reaction mixture is evaporated and the residue is partitioned between methylene chloride and water. After separating the organic phase, it is extracted several times more with methylene chloride. The combined organic extracts are then dried and evaporated. The residue is recrystallized from benzene/hexane/petroleum ether and gives 5-(o-fluorphenyl)-1,3-dihydro-1,3,3-trimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 128°-129°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([O:9]CC)=[O:8])=[C:2]1[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.[OH-].[Na+]>CO>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=[O:8])=[C:2]1[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)Cc1ccsc1-c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1ccsc1-c1cccs1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
In a 500 ml flask, 5.5 g (22 mmol) of ethyl (2,2′-bithiophene)-3-acetate dissolved in 50 ml of methanol was added, followed by 200 ml of 15% aqueous sodium hydroxide solution. The solution was refluxed for 3 hours. After cooling down the mixture to room temperature, the solution was concentrated via methanol removal using rotary evaporation. The aqueous solution was washed with diethyl ether, and then acidified with HCl to pH 1 upon which precipitation occurs. The white precipitate was dissolved in CH2Cl2 (150 ml×3) and the organic portion was collected. Chloroform was removed using a rotary evaporator after drying over magnesium sulfate to yield 4.7 g of white solid 96% yield. 1H-NMR (CDCl3): 7.34 (dd, 1H), 7.25 (d, 1H), 7.18 (dd, 1H), 7.08 (dd, 1H), 7.06 (d, 1H), 3.80 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[S:32](Cl)(=[O:34])=[O:33])[CH:25]=[CH:24][CH:23]=1.C(Cl)Cl>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[N:17]([S:32]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]5[C:31]=4[N:22]=[CH:23][CH:24]=[CH:25]5)(=[O:33])=[O:34])[CH:18]=[CH:19][C:12]=23)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: COc1ccc(-c2ccnc3[nH]ccc23)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2ccnc3c2ccn3S(=O)(=O)c2cccc3cccnc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a Round bottom flask was added 4-(3,4-Dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (0.222 g, 0.000873 mol), 50 and Tetra-N-butylammonium bromide (0.0282 g, 0.0000874 mol), and 5.000 M of Sodium hydroxide in Water (2.25 mL). 8-quinoline-sulfonyl chloride (0.238 g, 0.00105 mol) dissolved in Methylene chloride (0.616 mL, 0.00960 mol) was added dropwise at 0 Celsius. The reaction was stirred at ambient temperature for 3 h and the reaction mixture was diliuted with an addional 25 mL of methylene chloride. The organic layer was washed with 1 M sodium bicarbonate (aq.) (30 ml×2) and then with brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to yield the titled compound as a white solid. MS(ESI) [M+H+]+=446.20.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].O.[OH-].[NH4+].[C:20](O)(=O)[CH2:21][CH3:22]>>[CH2:21]([C:22]1[N:4]([CH2:3][CH:2]([CH3:16])[CH3:1])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:20]
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Reactant: CCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCc1nc2cnc3ccccc3c2n1CC(C)C
Temperature: 120 °C

Procedure:
A 16.55 g (0.077 mol) portion of N4 -(2-methylpropyl)-3,4-quinolinediamine (U.S. Pat. No. 4,689,338 example 16) was suspended in 100 mL of propionic acid and then heated at 120° C. for about 20 hours. After cooling to room temperature, the reaction mixture was poured into 300 mL of water, made basic with concentrated ammonium hydroxide, cooled in an ice bath and then extracted with diethyl ether. The volume of the ether extract was reduced under vacuum. The resulting precipitate was collected, rinsed with ether and dried to provide 11 g of crystalline solid, m.p. 72-73.5° C. Analysis: Calculated for C16H19N3 : %C, 75.8; %H, 7.6; %N, 16.6; Found: %C, 75.6; %H, 7.7; %N, 16.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([N:18]1[C:22]([C:23](O)=[O:24])=[CH:21][C:20]([CH3:26])=[N:19]1)[CH3:17]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH:15][C:23]([C:22]1[N:18]([CH2:16][CH3:17])[N:19]=[C:20]([CH3:26])[CH:21]=1)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Product: CCn1nc(C)cc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)OC(C)(C)C

Procedure:
prepared by reaction of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. 1H-NMR (CDCl3): δ=0.19 (q, J=4.3 Hz, 1H); 0.73 (dt, J=7.7 Hz, J=5.5 Hz, 1H); 1.30-1.36 (m, 1H); 1.38-1.43 (m, 3H); 1.45 (s, 9H); 1.46-1.53 (m, 1H); 2.24 (s, 3H); 3.34-3.42 (m, 2H); 3.55-3.64 (m, 2H); 4.18 (dd, J=10.8 Hz, J=3.0 Hz, 1H); 4.47-4.62 (m, 2H); 6.36 (s, 1H); 7.76 (bs, 1H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.C([O:16][C:17]([C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][N:24]=[C:25]([CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:26]=2)[N:21]([CH3:37])[CH:20]=1)=O)C>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:11][C:17]([C:19]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][N:24]=[C:25]([CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:26]=3)[N:21]([CH3:37])[CH:20]=2)=[O:16])=[CH:8][CH:7]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C)c2cnc(CN3CCOCC3)cc2c1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ncc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
At 0° C., a solution of 2.0M AlCl3 in toluene (0.14 mL) is added to a solution of 4-chlorobenzylamine (0.044 mL) in CH2Cl2 (5 mL). The compound from ethyl-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxylate (Preparation 46, 0.058 g) is added and the mixture allowed to stir at room temperature for 3 hours at which time the mixture is partitioned between CH2Cl2 (30 mL) and water (30 mL). The organics are dried with Na2SO4, filtered and the solvent evaporated. The remaining solid is chromatographed with MeOH/CH2Cl2 (1-4%) to obtain 0.049 g (67%) of the title compound as an off-white solid. Physical characteristics: MS (ESI+) m/z 427 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S@:27]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41]C)=[O:40])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:43])=[N:3]1.[OH-].[Na+].Cl>C1COCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S@:27]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:43])=[N:3]1
Reactant: COC(=O)CCCC[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=[S@](=O)(CCCCC(=O)O)c4ccccc4)c3)c2)n(C)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of (S)-Methyl 5-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]pentanoate (120 mg, 0.2 mmol) in THF (4 mL) at 0° C. was added dropwise a solution of aqueous NaOH (0.5 N, 2.0 mL). After the reaction mixture was stirred at 0° C. for 2 hours, 2 N HCl was carefully added to adjust the pH˜5 followed by a partition between aqueous NH4Cl and EtOAc. The EtOAc layer was further washed with brine once and dried with anhydrous sodium sulfate. The organic layer was decanted, concentrated and subject to a gradient column chromatography (from EtOAc to MeOH-EtOAc 1:5) yielding the title compound as white foam in amount of (85 mg, 73%).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]2=[CH:17][C:18]3[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][CH:14]2[C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:25][C:19]1[C:18]2[CH2:17][C:15]3[CH2:16][N:12]([C@@H:4]([CH2:5][CH:6]4[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]4)[C:3]([OH:27])=[O:2])[C:13](=[O:26])[C:14]=3[O:24][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC2=Cc3c(Cl)cccc3OC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 79.8 %

Procedure:
A solution of (S)-2-(8-chloro-3-oxo-3,3a-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid methyl ester (1.5 g, 4.0 mmol) and lithium hydroxide monohydrate (0.22 g, 5.22 mmol) was stirred at 25° C. for 2 hours in tetrahydrofuran-water (3:1) mixture (50 mL). The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was acidified with 2N hydrochloric acid, and diluted with water. The resulting solution was extracted with ethyl acetate (3×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (1.2 g, 83.3%).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:14][N:12]2[CH2:13][C@@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@@:28]56[C@@H:39]([N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[C@@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:33]3([CH2:51][CH3:52])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]53)[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH2:10][CH2:11]2)[CH:4]=1.[Na].[O:60]1CCCC1>>[CH3:1][CH2:2][C@@:3]12[O:60][C@@H:4]1[C@H:5]1[CH2:13][N:12]([CH2:11][CH2:10][C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[NH:21][C:8]=3[C@@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@:28]56[C@@H:32]7[C@:33]([CH2:51][CH3:52])([C@@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@@H:39]5[N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[CH:34]=[CH:35][CH2:36][N:31]7[CH2:30][CH2:29]6)[CH2:6]1)[CH2:14]2
Reactant: C1CCOC1
Reactant: CCC1=C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Agent: [Na]
Product: CC[C@]12CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(c4cc5c(cc4OC)N(C)[C@H]4[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]6(CC)C=CCN7CC[C@]54[C@@H]76)C[C@H](C3)[C@H]1O2

Procedure:
To a solution of 50 mg. of 3',4'-anhydro-vinblastine in 5 ml. of tetrahydrofuran 50 mg. of a 15% aqueous sodium hychlorite solution is added.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[C:7]([CH2:19][C@@H:20]2[O:22][C@:21]2([CH2:24][CH2:25][CH2:26][C:27]([O:30][CH3:31])([CH3:29])[CH3:28])[CH3:23])([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[C:8]([O:12][CH3:13])=[CH:9][CH2:10][CH:11]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>CCOC(C)=O.CCCCCC>[CH3:13][O:12][C:8]1[C@@:7]2([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:19][CH:20]3[O:22][C@@:6]2([O:5][CH3:4])[C@H:11]([CH2:10][CH:9]=1)[C@@:21]3([CH2:24][CH2:25][CH2:26][C:27]([O:30][CH3:31])([CH3:29])[CH3:28])[CH3:23]
Reactant: COC1=CCC=C(OC)C1(CC=C(C)C)C[C@@H]1O[C@@]1(C)CCCC(C)(C)OC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC1=CC[C@H]2[C@]3(OC)OC(C[C@]13CC=C(C)C)[C@@]2(C)CCCC(C)(C)OC
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 76.2 %

Procedure:
A DCM (63 mL) solution of 30 (4.91 g, 12.5 mmol, 1 equiv.) and 2,6-lutidine (3.0 mL, 37.5 mmol, 3 equiv.) was cooled to −78° C. in a 200-mL round-bottom flask, and trimethylsilyl trifluoromethanesulfonate (4.5 mL, 25.0 mmol, 2 equiv.) was added slowly. The resulting bright yellow solution was stirred at −78° C. for 45 min and subsequently quenched at −78° C. with saturated aqueous NaHCO3. After warming the mixture to room temperature, it was extracted thrice with DCM. The organic extracts were combined, washed successively with 1 N HCl, H2O, and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a faint yellow oil. Flash column chromatography (300 mL SiO2, 95:5 to 9:1 hexane:EtOAc) afforded 3.74 g (9.52 mmol, 77% yield) of 31 as a faint yellow oil. TLC Rf 0.49 (8:2 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 5.33 (t, J=7.1 Hz, 1H), 4.51 (dd, J=5.5, 2.1 Hz, 1H), 3.74 (d, J=4.6 Hz, 1H), 3.47 (s, 3H), 3.45 (s, 3H), 3.15 (s, 3H), 2.34 (dd, J=14.7, 6.9 Hz, 1H), 2.21 (dd, J=6.8, 1.8 Hz, 1H), 2.18 (dd, J=6.7, 2.3 Hz, 1H), 2.03 (m, 1H), 2.02-1.99 (m, 1H), 1.77 (dd, J=12.0, 4.6 Hz, 1H), 1.75 (d, J=12.0 Hz, 1H), 1.69 (s, 3H), 1.60 (s, 3H), 1.42-1.28 (m, 4H), 1.18 (td, J=12.6, 3.0 Hz, 1H), 1.12 (s, 3H), 1.11 (s, 3H), 1.11 (s, 3H), 1.03-0.95 (m, 1H). 13C NMR (126 MHz; CDCl3): δ 158.6, 131.2, 123.5, 112.6, 90.5, 79.0, 74.6, 54.5, 51.4, 49.3, 46.5, 44.5, 41.9, 41.2, 39.3, 34.0, 32.8, 28.2, 26.4, 25.22, 25.14, 20.1, 18.4, 18.0. FTIR (thin film) νmax: 2968, 2839, 1670, 1451, 1374, 1363, 1208, 1166, 1078, 1006, 843, 805, 785 cm−1. HRMS-ESI (m/z): [M+Na]+ calculated for C24H40O4, 415.2819. found, 415.2832.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[N:12]=[C:13]([C:29]#[N:30])[C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][CH:17]=[C:16]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:15]=2)=[O:10])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39].Cl>C(Cl)Cl.CCOC(C)=O.O>[C:29]([C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=2)[C:20]([OH:21])=[C:11]([C:9]([NH:8][CH2:7][CH2:6][C@@H:2]([NH:1][C:41]([NH:40][CH2:38][CH3:39])=[O:42])[C:3]([OH:5])=[O:4])=[O:10])[N:12]=1)#[N:30]
Reactant: CCN=C=O
Reactant: N#Cc1nc(C(=O)NCC[C@@H](N)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCNC(=O)N[C@H](CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
(R)-2-Amino-4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)butanoic acid (15 mg, 0.03 mmol) in CH2Cl2 (1 mL) was cooled to 0° C. To the solution were added triethylamine (0.03 mL, 0.21 mmol) and ethyl isocyanate (5 μL, 0.06 mmol). After stirring for 40 minutes at 0° C., H2O (10 mL) and EtOAc (10 mL) were added. To the stirred mixture was added 1 N hydrochloric acid (1 mL). The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% MeOH/CH2Cl2 with 0.5% formic acid) to give the title compound in 13 mg. MS: (−) m/z 476.25 (M−1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.C([O:11][CH:12]=[C:13]([C:19]([O-])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[CH2:17]([O:16][C:14]([C:13]1[C:12](=[O:11])[N:4]2[N:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]2=[N:8][CH:19]=1)=[O:15])[CH3:18]
Reactant: Nc1ccc(Cl)nn1
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1cnc2ccc(Cl)nn2c1=O

Procedure:
A mixture of 3-chloro-6-aminopyridazine [J. Druey et al., Helv. Chim. Acta., 37, 121 (1954)] (8.20 g, 63.56 m mol) and ethyl ethoxymethylenemalonate (15.0 g, 69.4 m mol) in diphenyl ether (70 ml) was heated to distil out ethanol produced. After cooling, the mixture was diluted with n-hexane (300 ml) to precipitate the crude title product, which was dissolved in chloroform (200 ml), treated with a small amount of carbon and evaporated under reduced pressure to 50 ml. The residual solution was diluted with n-hexane (200 ml) to precipitate pure title product. Yield, 7.73 g (56%), M.p. 149°-152° C.