Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][C:4](=[O:7])[CH:3]=1.[CH2:8](Cl)[CH:9]=[C:10]([CH3:12])[CH3:11].C1(C)C=CC=CC=1.[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11]
Reactant: CC1=CC(=O)CC1
Reactant: CC(C)=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)=CCC1=C(C)CCC1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
A mixture of 3-methyl-2-cyclopentenone 24.5 g (0.25 mole) and prenyl chloride 54 g (0.51 mole) was fed into a reaction flask containing 30 ml of toluene, sodium hydroxide 21.3 g, water 21.3 g and Aliquat 3361 g maintaining 100° C. The reaction mass was aged for 4 hours, cooled to 25° C. and neutralized with acetic acid. The organic layer was removed and distilled to give 20.5 g of 3-methyl-2-(3-methyl-2-butenyl)-2-cyclopenten-1-one. The 3-methyl-2-(3-methyl-2-butenyl)-2-cyclopenten-1-one had a Bp of 115° C. at 5 mmHg.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[NH2:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[CH3:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][N:17]=[C:7]2[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(N)c(C(=O)c2ccccc2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a solution of 2-amino-5-methylphenyl phenyl ketone (2.0 g, 9.5 mmol) in HCl (45 mL of a 6M solution) at 0° C. was added sodium nitrite (NaNO2) (719 mg, 10.4 mmol) in water (2 mL). The reaction was stirred for 30 min when the homogeneous solution was added dropwise to a solution of SnCl2 (5.88, 26 mmol) in concentrated HCl (15 mL) at room temperature. The reaction was stirred for 30 min when it was filtered. The solid was then taken up in ethyl acetate (80 mL) and saturated sodium bicarbonate (80 mL). The suspension was then filtered and the ethyl acetate layer dried (Na2SO4) and concentrated to give the product (1.59 g, 80% yield). (1H NMR (DMSO-d6) δ 7.96 (d, 2H), 7.85 (br s, 1H), 7.54-7.46 (m, 3H), 7.39 (t, 1H), 7.24 (d, 1H), 2.45 (s, 3H); ES-MS (m/z) 209 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([Cl:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([Cl:23])[CH:29]=[C:28]([Cl:30])[CH:27]=3)[CH2:36][CH2:35]2)=[S:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Product: COc1nc2ccccc2cc1NC(=S)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 62 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:15]2)[C:11]([NH2:23])=[CH:10][C:9]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[CH:32]=[N:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][C:35]=23)[CH:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([NH:24][C:25]2[N:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][C:35]=34)[CH:28]=[CH:27][N:26]=2)=[CH:10][C:11]([NH:23][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([N:14]2[CH2:15][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:17]2)[CH:13]=1
Reactant: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4c3CCCC4)n2)c(OC)cc1N1CC2(CCCN2C)C1
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A solution of acryloyl chloride (42 μL, 0.52 mmol) in CH2Cl2 (1 mL) was added dropwise to 4-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 141, 240 mg, 0.52 mmol) and DIPEA (0.099 mL, 0.57 mmol) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 1 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (135 mg, 50%) as a yellow solid after trituration with CH3CN; 1H NMR: 1.61-1.74 (2H, m), 1.73-1.85 (2H, m), 1.87-1.99 (2H, m), 2.03 (2H, t), 2.35 (3H, s), 2.61 (2H, t), 3.01 (2H, t), 3.60 (2H, d), 3.84 (3H, s), 3.89 (2H, d), 4.09 (2H, t), 5.70 (1H, d), 6.14-6.30 (2H, m), 6.47 (1H, dd), 6.95 (1H, d), 7.73 (1H, s), 7.83 (1H, s), 8.05 (1H, s), 8.26 (1H, d), 9.26 (1H, s); m/z: ES+ MH+ 515.7.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([CH:36]3[CH2:38][CH2:37]3)=[CH:28][CH:27]=2)[C:6]([S:9][CH2:10][C:11]([NH:13][CH:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([O:17]C)=[O:16])=[O:12])=[N:7][N:8]=1>C1COCC1.O>[Br:3][C:4]1[N:5]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([CH:36]3[CH2:38][CH2:37]3)=[CH:28][CH:27]=2)[C:6]([S:9][CH2:10][C:11]([NH:13][CH:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([OH:17])=[O:16])=[O:12])=[N:7][N:8]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)NC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aqueous lithium hydroxide solution (1M, 0.8 mL, 0.8 mmol) is added to a solution of methyl 2-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio) acetamido)-3-phenylpropanoate (0.4 mmol) in 3:1, THF/H2O (1.6 mL) and the mixture stirred for 18 h at room temperature. The crude reaction mixture is concentrated and acidified with aqueous HCL (1M, 1.2 mL) and then is extracted with ethyl acetate (3×3 mL). The combined organic extracts are dried (sodium sulfate), filtered and concentrated to provide the desired product.
Reaction SMILES: [CH3:1][C:2]([OH:10])([C:5]([CH3:9])([CH3:8])[CH2:6][CH3:7])[C:3]#[CH:4].[H][H]>>[CH3:1][C:2]([OH:10])([C:5]([CH3:9])([CH3:8])[CH2:6][CH3:7])[CH:3]=[CH2:4]
Reactant: C#CC(C)(O)C(C)(C)CC
Reactant: [H][H]
Product: C=CC(C)(O)C(C)(C)CC

Procedure:
3,4,4-Trimethylhex-l-yn-3-ol can be hydrogenated at from 0° to 50° C., preferably 5° to 20° C., and from 0.01 to 50 bar, preferably 0.1 to 10 bar, particularly preferably 0.5 to 5 bar, in a hydrogen atmosphere, in the presence or absence of an inert solvent on partial hydrogenation catalysts, such as e.g. according to Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Volume 4/lc, pages 107 to 109. After hydrogen absorption is complete, the catalyst is as a rule filtered off and the solvent is removed by distillation. The crude product can be directly processed or distilled again.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:17]([F:18])=[C:16](F)[C:15]([Cl:20])=[C:14]2[C:9]=1[C:10](=[O:33])[C:11]([C:30]([OH:32])=[O:31])=[CH:12][N:13]2[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([NH2:29])[N:22]=1.C(O)(=O)C.C(O)(=O)C.[CH3:42][NH:43][CH:44]1[CH2:47][NH:46][CH2:45]1.CN1CCCC1>C(OCC)C>[NH2:7][C:8]1[C:17]([F:18])=[C:16]([N:46]2[CH2:47][CH:44]([NH:43][CH3:42])[CH2:45]2)[C:15]([Cl:20])=[C:14]2[C:9]=1[C:10](=[O:33])[C:11]([C:30]([OH:32])=[O:31])=[CH:12][N:13]2[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([NH2:29])[N:22]=1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CNC1CNC1
Agent: CN1CCCC1
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CNC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
To 300 mg of pyridine were added 120 mg of 5-amino-1-(6-amino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-methylaminoazetidine diacetate, and 250 mg of N-methylpyrrolidine, and the mixture was stirred at 100° C. for 10 minutes. After adding 5 ml of diethylether, the mixture was stirred and allowed to cool for 1 hour, and decanted. 2 ml of ethanol was added and the mixture was stirred. The precipitate was collected by filtration and washed with ethanol and diethylether successively to obtain 72 mg of the title compound as a yellow powder.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O>[CH:8](=[C:2]1/[C:1](=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3]/1)\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCCC1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CCCC/C1=C\c1ccccc1
Temperature: 98 °C
Yield: 32.8 %

Procedure:
Into an inert 100 gallon reactor, there is drawn 29.3 kg of cyclohexanone from a grounded drum on a weight scale. The reactor is vented with nitrogen and then 28.5 kg of benzaldehyde is added. Then 125 liters of deionized water is metered into the above mixture. The vessel is closed and `reinserted` with nitrogen. To the resulting reactor contents there is added, from a grounded drum on a weight scale, a 50 percent (w/v) solution of sodium hydroxide in water solution, (10.6 kg), while stirring the mixture. The resulting mixture is stirred and heated to reflux (about 98° C.) under an atmosphere of nitrogen. The mixture is held at reflux temperature for about three hours and then stirred and cooled overnight. The resulting cooled reaction mixture is extracted once with a 198 liter batch of methylene chloride, separating the aqueous layer, and then again with 132 liters of methylene chloride, neutralizing and discarding the aqueous layer. The combined methylene chloride liquid layers are washed with 284 liters of water and then with 284 liters of water containing 50 ml of acetic acid. After aqueous layer separation, the methylene chloride liquid layer is dried over sodium sulfate with stirring. The resulting dried methylene chloride layer is concentrated to an oil using 35° C. jacket water temperature and jet vacuum procedures. The (E)-2-(benzylidene)cyclohexanone is crystallized by dissolving the oily residue in 60 liters of Skellysolve® B and seeding with authentic material and cooling the vessel overnight by circulating a cooled water/methanol mixture through the reactor jacket. The pale yellow crystals are collected on a 24-inch filter, washed with Skellysolve® B, and recrystallized from 75 gallons of Skellysolve® B by heating to 50° C. to effect dissolution and then cooling the tank contents to 0° C. Alternatively, we have used isopropanol in this crystallization step with approximately equal effectiveness in terms of quality of the crystalline intermediate (E)-2-(benzylidene)cyclohexanone. The crystalline intermediate is dried in a vacuum oven at room temperature to give about 16.4 kg (33 percent yield) of the (E)-2-(benzylidene)cyclohexanone, m.p. 47°-54° C. (Lit. m.p. 54° C.). TLC analysis (silica gel GF; 5 percent ethyl acetate in Skellysolve® B developer) indicates the presence of a small amount of a less polar impurity, identified as ##STR10## on the basis of isolation and melting point.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:11]([OH:13])[CH3:12])[CH2:10][O:9][CH2:8][CH2:7][O:6]1)=[O:4].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1([CH:11]([O:13][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH3:12])[CH2:10][O:9][CH2:8][CH2:7][O:6]1)=[O:4]
Reactant: COC(=O)C1(C(C)O)COCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)C1(C(C)OS(=O)(=O)c2ccc(C)cc2)COCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
A solution of 2-(1-hydroxy-ethyl)-[1,4]dioxane-2-carboxylic acid methyl ester (1.49 g, 7.8 mmol) in pyridine (8 mL) was stirred at room temperature. 4-Toluenesulfonyl chloride (1.50 g, 7.8 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The majority of the pyridine was evaporated, 1 M hydrochloric acid was added to acidify the mixture to pH 2 and the mixture was extracted with ethyl acetate. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 3:1 to 0:1 to afford the title compound (1.70 g, 63%) as a yellow gum and as a 3:1 mixture of diastereoisomers. LCMS (m/z) 367.0 [M+Na], Tr=2.44 min.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:11](OC(=O)C)(=[O:13])[CH3:12].O>N1C=CC=CC=1>[C:11]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)(=[O:13])[CH3:12]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
2-aminoindan (6.0 g, 45 mmol) was dissolved in dry pyridine (7 ml), to which acetic anhydride (4.5 ml, 47.3 mmol) was added dropwise while cooling in ice water. After the reaction mixture was returned to room temperature and stirred for 20 minutes, water was added. The precipitate that deposited was filtered to obtain 2-acetamidoindan (5.6 g, 32 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:23]1([CH2:22][CH2:21][CH2:20][NH:19][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:18])[NH:11][C:12]=2[CH3:17])=[O:16])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Reactant: NCCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCCCN2CCOCC2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
240 mg (0.900 mmol) of 4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 156 mg (1.08 mmol) of N-(3-aminopropyl)morpholine were dissolved in 10 ml of DMF. 259 mg (1.35 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1 to 10/1) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH2:16][C:17]2([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:20][CH2:19][CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[S:28]1[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][N:30]=[CH:29]1.CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:11]([O:10][C:9]([N:8]([CH2:16][C:17]1([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:20][CH2:19][CH2:18]1)[C:5]1[N:6]=[N:7][C:2]([C:29]2[S:28][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][N:30]=2)=[CH:3][CH:4]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1cncs1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(Cl)nn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(-c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)s1
Temperature: 145 °C
Yield: 24.8 %

Procedure:
tert-butyl 6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (500 mg, 1.27 mmol), ethyl thiazole-5-carboxylate (300 mg, 1.91 mmol), Pd(OAc)2 (86 mg, 0.13 mmol), JohnPhos (92 mg, 0.26 mmol) and Cs2CO3 (827 mg, 2.54 mmol) in toluene (10 mL) were combined and heated in a microwave reactor for 30 min at 145° C. The reaction mixture was filtered through a celite plug and the filtrate was concentrated. The resulting residue was purified on silica gel using a mixture of ethyl acetate and hexanes to provide the title compound as yellow oil (162 mg, 82% pure, 21%), LRMS (M+H+) m/z 514.3.
Reaction SMILES: [Na].[CH3:2][CH:3]([C:6](=O)[CH3:7])[CH:4]=O.[C:9]([CH2:11][C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])#[N:10].N1CCCCC1.C(O)(=O)C>CN(C)C=O>[CH:15]([N:14]1[C:6]([CH3:7])=[C:3]([CH3:4])[CH:2]=[C:11]([C:9]#[N:10])[C:12]1=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)NC(=O)CC#N
Reactant: CC(=O)C(C)C=O
Agent: [Na]
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc(C#N)c(=O)n(C(C)C)c1C
Temperature: 135 °C
Reaction time: 7 h
Yield: 25.7 %

Procedure:
To a stirred solution of 2-methyl-3-oxobutanal sodium salt (2.73 g, 22.4 mmol, prepared according to Paine, John B et al., J. Heterocycl. Chem., 1987, 24, 351), 2-cyano-N-isopropylacetamide (2.17 g, 17.2 mmol, prepared according to Wuerthner, Frank et al., J. Amer, Chem. Soc., 2002, 32, 9431) in N,N-dimethylformamide (17.2 mL) were added piperidine (292 mg, 3.43 mmol) and acetic acid (1.34 g, 22.4 mmol) successively at room temperature, and the mixture was stirred at 135° C. for 7 h. After cooling, the mixture was quenched with water (100 mL), extracted with dichloromethane (50 mL×4). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (v/v=2/1˜1/1) to give 840 mg (26%) of the title compound as an orange colored solid.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[N:23][C:5]2[N:6](COCC[Si](C)(C)C)[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.Br.[OH-].[Na+].Cl>O1CCOCC1>[OH:1][C:2]1[CH:24]=[N:23][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(O)cnc21
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cc2c(cn1)[nH]c1ncc(O)cc12
Temperature: 75 °C
Yield: 33.9 %

Procedure:
A solution of 3-hydroxy-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (90.9 mg, 0.267 mmol) in 1,4-dioxane (500 μL) was treated with 48% aqueous hydrobromic acid (500 μL) and heated at 75° C. for 10 min. The cooled reaction mixture was basified to pH 12 with 6N aqueous sodium hydroxide solution and then adjusted to pH 7-9 with dropwise addition of 1N hydrochloric acid. The solid was collected via centrifugation, the aqueous supernate discarded, and the solid dissolved in 1-2 mL of DMSO and purified by preparative HPLC (0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min) to afford the title compound as an off-white solid (19 mg, 33%). 1H NMR (DMSO-D6, 400 MHz): 12.51 (s, 1H), 9.94 (s, 1H), 8.94 (s, 1H), 8.87 (s, 1H), 8.32 (d, J=2.7 Hz, 1H), 8.08 (d, J=2.7 Hz, 1H). LCMS (Method E): RT=2.90 min, M+H+=211.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:15])([CH3:14])[CH:12]=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F-].[K+].[CH3:18][N+:19]([O-:21])=[O:20]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:15])([CH3:14])[CH:12]([OH:13])[CH2:18][N+:19]([O-:21])=[O:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C(C)(C)C=O)cc1OC
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C(C)(C)C(O)C[N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a solution of 2-(3,4-dimethoxyphenyl)-2-methylpropanal (1.0 g, 4.8 mmol) in EtOH (30 mL) were added KF (335 mg, 5.8 mmol) and CH3NO2 (1.56 mL, 28.8 mmol). The resulting mixture was stirred overnight at room temperature. The solution was concentrated, diluted with EtOAc, and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated to give 3-(3,4-dimethoxyphenyl)-3-methyl-1-nitrobutan-2-ol (1.25 g, 97%). 1H NMR (400 MHz, CDCl3) δ 6.91-6.84 (m, 3H), 4.44 (m, 1H), 4.24 (d, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 2.38 (d, 1H), 1.40 (s, 3H), 1.38 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:24][Si](C)(C)C)=[N-].C(O)(=O)C>ClCCl.CO>[C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:24])=[O:18])=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)O)cc2)CCC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1
Yield: 93 %

Procedure:
To a solution of 4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)benzoic acid (15 g, 52 mmol) in dichloromethane (200 mL) and methanol (50 mL), cooled at 0° C., was added in a dropwise manner a 2 M solution of diazomethyl trimethylsilane in hexanes (28 mL, 57 mmol). The reaction mixture was stirred at room temperature for one hour before the addition, at 0° C., of acetic acid (10 mL). The mixture was washed with saturated aqueous sodium bicarbonate solution until the aqueous phase remained basic. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo, yielding the methyl 4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)benzoate as a white crystalline solid (14.8 g, 93%). M.p.=90° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.91 (d, J=7.6 Hz, 2H), 7.74 (s, 1H), 7.50 (d, J=8.0 Hz, 2H), 3.84 (s, 3H), 2.38 (br.s, 4H), 2.1-1.9 (m, 1H), 1.85-1.7 (m, 1H), 1.32 (br.s, 9H); LCMS [M-tBu+H]: 250.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CC(O)CN1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C

Procedure:
To a solution of 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5 g, 20.4 mmol) in DCM (100 mL), Dess-Martin periodinane (12.97 g, 30.6 mmol) is added. After completion of the reaction as judged by TLC the reaction is quenched with sat NaHCO3, washed with sat sodium thiosulfate and extracted with DCM. The organics are dried and evaporated and used crude in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:3]=1[F:20].[CH3:21]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[C:5]([C:6]([OH:8])=[O:7])=[CH:9][C:10]2[O:11][CH:21]=[N:1][C:2]=2[C:3]=1[F:20]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1c(O)cc(C(=O)O)c(Nc2ccccc2Cl)c1F
Solvent: O
Solvent: COC(OC)OC
Product: O=C(O)c1cc2ocnc2c(F)c1Nc1ccccc1Cl
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 4-amino-2-((2-chlorophenyl)amino)-3-fluoro-5-hydroxybenzoic acid in trimethyl orthoformate (100 mL) was added p-TsOH (0.42 g, 1.35 mmol). The reaction mixture was stirred for 1 h and treated with water (300 mL). The precipitate was filtered off and the filter cake was washed with water to afford a yellow solid (12.31 g, 87.9% yield for two steps). 1H NMR (400 MHz, DMSO-d6): δ 13.9 (s, 1H), 9.05 (s, 1H), 8.8 (s, 1H), 8.23 (s, 1H), 7.43 (m, 1H), 7.15 (m, 1H), 6.98 (m, 1H), 6.74 (m, 1H).