Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:9](=[O:31])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[C:13]([O:29][CH3:30])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([N:8]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:9](=[O:31])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[C:13]([O:29][CH3:30])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)O)c(OC)c1
Reaction time: 0.12 h
Yield: 45 %

Procedure:
Methyl 2-[(4-{2-[benzyl(hexyl)amino]-2-oxoethyl}-2-methoxyphenoxy)methyl]benzoate (98 mg, 0.195 mmol) was dissolved in THF (2 ml). Lithium hydroxide (9.3 mg, 0.389 mmol) solved in water (1 ml) was added. The mixture was put in a microwave oven (Smith Synthesizer) at 150° C. for 7 minutes. It was then acidified with 1% hydrochloric acid, pH˜3, and extracted with ethyl acetate. The organic extract was washed with brine and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE®) SI, 2 g/6 ml) using DCM and then MeOH/DCM (0.5:99.5, then 1:99) as eluant gave 43 mg the desired product, yield 45%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[CH2:10][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:28]([Si:32](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O.O>[CH2:1]([O:8][C:9](=[O:22])[CH2:10][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:12][O:13][Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (S)-3-tert-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (1.34 g, 4.37 mmol) (prepared using the method of Rodriguez, Marc; Linares, Muriel; Doulut, Sylvie; Heitz, Annie; Martinez, Jean; Tetrahedron Lett. (1991), 32(7), 923-6) and imidazole (0.88 g, 13.01 mmol in dimethylformamide (7 ml) is treated with tertbutyldiphenylsilyl chloride (1.69 ml, 6.5 mmol). The reaction mixture is stirred together at room temperature for 1 hour, then diluted with water and extracted into ethylacetate. The ethylacetate phase is dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 1:1 ethylacetate/hexane) to afford (S)-3-tert-butoxycarbonylamino-4-(tert-butyl-diphenyl-silanyloxy)-butyric acid benzyl ester. [M-BOC] 448.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[C:8]([CH3:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:11][C:8]1[CH:9]=[CH:10][N:6]2[C:7]=1[C:2]([Cl:1])=[N:3][CH:4]=[N:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccn2ncnc(Cl)c12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncnn2ccc(CBr)c12
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
A mixture of 4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (2.0 g, 11.93 mmol, WO 03/042172) and AIBN (195 mg, 1.19 mmol) in CCl4 (80 mL) under N2 was heated to 100° C. for 5 min, NBS (2.55 g, 14.3 mmol) was added. The reaction mixture was stirred for 10 min, then cooled to rt, filtered. The CCl4 layer was washed with dilute NaHCO3 aqueous solution, dried (MgSO4), filtered and concentrated to give the desired product (2.70 g, 92%).
Reaction SMILES: C([NH:9][C:10](=[S:23])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[C:18]([O:17][C:16](=[O:22])[NH:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]([NH2:9])=[S:23])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCCNC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCNC(N)=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 145.2 %

Procedure:
To a solution of tert-butyl (3-(3-benzoylthioureido)propyl)carbamate (0.83 g, 2.45 mmol) in MeOH (15 mL) was added sodium hydroxide aqueous solution (1.96 mL, 2.45 mmol). After stirring at rt for 2 h, the reaction mixture was concentrated in vacuo and azeotropped with toluene. The crude residue was purified via silica gel chromatography (MeOH-DCM, 9% with 1% NH4OH), affording the title compound (0.83 g, 43%). LCMS: Rt=0.47 min, m/z=234.2 (M+1) Method 2m_acidic.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]#[C:8][NH2:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:21])=[C:15]2/[CH:22]=[C:23]1/[C:24](=[O:30])[N:25]=[C:26](SC)[S:27]/1.O>C(O)(C)(C)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH3:21])=[C:15]2/[CH:22]=[C:23]1/[C:24](=[O:30])[N:25]=[C:26]([NH:9][C:8]#[N:7])[S:27]/1
Reactant: N#CN
Reactant: COc1ccc2[nH]c(C)c(/C=C3\SC(SC)=NC3=O)c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc2[nH]c(C)c(/C=C3\SC(NC#N)=NC3=O)c2c1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
To a room temperature suspension of potassium t-butoxide (73 mg, .65 mmols) and cyanamide (96 mg, 2.27 mmols) in 10 mL of t-butanol is added (Z)-5-[(5-methoxy-2-methyl-1H-indol-3-yl)methylene]-2-(methylthio)- 4(5H)-thiazolone (146 mg, 0.46 mmols). The mixture is heated at reflux for 5 minutes, then cooled to room temperature. The mixture is poured into 50 mL of water and the orange solution is washed with diethyl ether. The layers are separated and the aqueous layer is acidified with 10% aqueous hydrochloric acid. The orange solid is collected by filtration, washing with water to give 106 mg (74%) of (Z)- [4,5-dihydro-5-[(5-methoxy-2-methyl-1H-indol-3-yl)methylene]-4-oxo-2-thiazolyl]cyanamide; mp >300.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:19]([CH3:28])[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([N:19]([CH3:28])[CH2:20][C:21]([OH:23])=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1)#[N:2]
Reactant: CN(CC(=O)OC(C)(C)C)c1ccc(Oc2ccc([N+](=O)[O-])cn2)c(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CC(=O)O)c1ccc(Oc2ccc([N+](=O)[O-])cn2)c(C#N)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of t-butyl 2-((3-cyano-4-(5-nitropyridin-2-yloxy)phenyl)(methyl)amino)acetate (1.2 g, 3.1 mmol) in dichloromethane (12 mL) was added trifluoroacetic acid (12 mL), and the resulting reaction solution was stirred at room temperature for 5 hours. The solvent was evaporated, and water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield crude 2-((3-cyano-4-(5-nitropyridin-2-yloxy)phenyl)(methyl)amino)-acetic acid. To a solution of this compound in DMF (24 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (659 mg, 3.4 mmol), 1-hydroxybenzotriazole monohydrate (526 mg, 3.4 mmol) and 1-piperonylpiperazine (757 mg, 3.4 mmol), and the resulting reaction solution was stirred for 8 hours at room temperature. Water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was then washed with, in order, saturated aqueous sodium bicarbonate solution, water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate), to thereby yield 412 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:20][CH2:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]=3[CH:9]2[C:21]2[CH:22]=[CH:23][C:24]3[O:28][CH2:27][CH2:26][C:25]=3[CH:29]=2)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:20][CH2:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]=3[CH:9]2[C:21]2[CH:22]=[CH:23][C:24]3[O:28][CH2:27][CH2:26][C:25]=3[CH:29]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)CCO3)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: c1ccc(-c2ccc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)CCO4)nc2)nc1

Procedure:
The product from step A above (0.4 g, 0.896 mmol), 2-tributylstannanyl-pyridine (0.8 g, 2.17 mmol) and Pd(PPh3)4 (0.12 g, 0.104 mmol) were stirred in 1,4-dioxane (5 mL) at 88° C. for 24 h. The reaction mixture was filtered through a plug of Celite with CH2Cl2 and then concentrated to a small volume. Preparative TLC (3:7 ethyl acetate/heaxne; then 5% CH3OH/CH2Cl2) yielded the product as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].O>CO>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na]
Solvent: CO
Solvent: O
Product: OCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 98.4 %

Procedure:
2,4-Dibenzyloxybenzaldehyde [V] (20 g) was dissolved in methanol (700 ml) and then, thereto was added sodium boronhydride (3.6 g) and this was left to stand at room temperature (20° C.) for 1.5 hours. To the reaction mixture was added water (1.5 liter) and the resulting precipitate was collected by filtration and recrystallized from ethanol to obtain 2,4-dibenzyloxybenzyl alcohol [VI] (19.8 g, yield 98%). Melting point: 84°-85° C.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([C:17](=[O:19])[CH3:18])[CH:9]=[CH:8]2.CO>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([C:17](=[O:19])[CH2:18][Br:1])[CH:9]=[CH:8]2
Reactant: BrBr
Reactant: COc1cc2ccc(C(C)=O)cc2cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2ccc(C(=O)CBr)cc2cc1OC
Yield: 66.9 %

Procedure:
A solution of bromine (4.5 g, 0.029 mol) in chloroform (30 ml) is added dropwise to a solution of 6,7-dimethoxy-2-acetylnaphthalene (6.7 g, 0.029 mol) in a mixture chloroform (70 ml)/methanol (15 ml). Once the reaction mixture discoloures, it is concentrated to dryness and the residue is treated with a mixture ethyl ether/isopropyl ether. The thus obtained solid is triturated with methanol yielding 6,7-dimethoxy-2-(2-bromoacetyl)naphthalene (6 g). M.p. 120°-122° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]5)[CH:27]=4)[CH2:23][C:22](=[O:38])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cn(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)cn1

Procedure:
Prepared from (4′-fluoro-3-{3-[3-(4-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K47) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (196 mg).
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[C:18]([C:21]12[CH2:31][C:25]3([OH:32])[CH2:26][C:27]([OH:30])([CH2:29][C:23]([OH:33])([CH2:24]3)[CH2:22]1)[CH2:28]2)([OH:20])=[O:19]>>[C:18]([C:21]12[CH2:22][C:23]3([OH:33])[CH2:24][C:25]([O:32][C:1](=[O:4])[CH:2]=[CH2:3])([CH2:26][C:27]([OH:30])([CH2:29]3)[CH2:28]1)[CH2:31]2)([OH:20])=[O:19]
Reactant: O=C(O)C12CC3(O)CC(O)(CC(O)(C3)C1)C2
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3(O)CC(O)(C1)CC(C(=O)O)(C3)C2
Yield: 81 %

Procedure:
The reaction was conducted in the same manner as said (2) except that 1-carboxy-3,5,7-trihydroxyadamantane was used instead of the 1-carboxy-3,5-dihydroxyadamantane, and, as a result, a 1-carboxy-3,5-dihydroxy-7-acryloyloxyadamantane (yield: 81%, white solid) was produced.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([C:6]1[O:10][N:9]=[C:8]([CH3:11])[C:7]=1[C:12]([O:14]CC)=[O:13])=[O:5])[CH3:2].[OH-].[K+]>O.C(O)C>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[O:10][N:9]=[C:8]([CH3:11])[C:7]=1[C:12]([OH:14])=[O:13])=[O:5])[CH3:18]
Reactant: CCOC(=O)c1c(C)noc1C(=O)N(CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)c1onc(C)c1C(=O)O
Yield: 67.4 %

Procedure:
5.0 g of the ester from Example 9 and 1.4 g of potassium hydroxide in 10 ml of water and 20 ml of ethanol are stirred at room temperature. When the reaction is complete, the mixture is diluted with water and extracted with dichloromethane. Thereafter, the aqueous phase is acidified with hydrochloric acid and extracted with dichlormethane, and the organic phase is evaporated down. 3.0 g of 5-diethylaminocarbonyl-3-methylisoxazole-4-carboxylic acid are obtained as a pale oil (compound No. 4).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:21](Cl)(=O)C>CO>[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH:8]=1)[CH2:3][C:4]([O:6][CH3:21])=[O:5]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC1CCCC1
Solvent: CO
Product: COC(=O)CC(N)c1ccc(OC)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a stirred suspension of 3-amino-3-(3'-cyclopentyloxy-4'-methoxyphenyl)propionic acid (30 grams, 279 mmol) in methanol (150 mL) at 0° C., was added acetyl chloride (15.2 mL, 212 mmol) dropwise. After 15 minutes, the ice-water bath was removed. The resulting clear solution was stirred at room temperature for 2 h. The system was opened and the solvent was blown off with N2 overnight. To the solid was added methanol (50 mL) and ether (300 mL). The resulting suspension was stirred at room temperature for 1 h. The suspension was filtered and the solid was washed with ether (100 mL). The solid was dissolved in a mixture of aqueous sodium carbonate (200 mL, sat), water (200 mL), and methylene chloride (250 mL). The organic layer was separated. The aqueous layer was extracted with methylene chloride (3×250 mL). The combined organic layers were dried over magnesium sulfate. Removal of solvent gave methyl 3-amino-3-(3'-cyclopentoxy-4'-methoxyphenyl)propionate as an oil (28.41 grams, 90% yield): 1H NMR (CDCl3)δ1.56-1.97 (m, 10H, NH2, C5H8), 2.62 (d, J=7 Hz, 2H, CH2), 3.67 (s, 3H, CH3), 3.81 (s, 3H, CH3), 4.34 (t, J=6.8 Hz, 1H, CH), 4.74-4.79 (dd, J=5, 8.5 Hz, 1H, NCH), 6.78-6.90 (m, 3H, Ar); 13C NMR (CDCl3)δ23.97, 32.76, 44.17, 51.58, 52.25, 56.07, 80.37, 111.96, 113.08, 119.08, 137.25, 147.72, 149.27, 172.49.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:16]([O-])=O)=[C:4]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.CCO>[Pd].CCOC(C)=O>[NH2:16][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCNc1cccc(F)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCNc1cccc(F)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
A round bottomed flask was charged with palladium on carbon (0.306 g, 0.287 mmol) and a stirbar. Ethyl 3-(3-fluoro-2-nitrophenylamino)propionate (1.473 g, 5.75 mmol) in 1:1 EtOH:EtOAc (40 mL) was added, and the flask was evacuated and purged with hydrogen three times before being stirred at room temperature overnight. The mixture was filtered, concentrated with celite, and purified by silica gel chromatography (eluting with hexanes/ethyl acetate) to yield ethyl 3-(2-amino-3-fluorophenylamino)propanoate as a brown oil (1.074 g, 4.75 mmol, 83%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13]C1C=CC2CCN(C3CCC3)CCC=2C=1)[C:6]([NH:8][CH3:9])=[O:7])#[N:2].B(Br)(Br)Br.O.Cl>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([NH:8][CH3:9])=[O:7])#[N:2]
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(C#N)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1ccc(O)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
3-Cyano-N-methyl-4-(methyloxy)benzamide (E279, Step 2) (346 mg, 1.82 mmol), was dissolved in dry dichloromethane (10 ml), cooled to 0° C. and treated with boron tribromide (1 M solution in dichloromethane) (9.11 ml, 9.11 mmol). The mixture was stirred for 30 minutes, allowed to warm to room temperature and stirred for 18 hours. The mixture was cooled in an ice bath, treated with water added dropwise and then allowed to warm to room temperature. The mixture was poured onto 2M hydrochloric acid (10 ml) and extracted with ethyl acetate. The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate dichloromethane (1:1) to afford the title compound (86 mg); MS (ES+) m/e 177 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:20][C@H:19]([CH3:21])[N:18]2[C:5](=[C:6]([O:22][CH3:23])[C:7]3[C:12](=[O:13])[NH:11][N:10]=[C:9]([C:14]([NH:16]N)=[O:15])[C:8]=32)[C:4]1=[O:24])[CH3:2].[CH3:25]N.II.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:1]([N:3]1[CH2:20][C@H:19]([CH3:21])[N:18]2[C:5](=[C:6]([O:22][CH3:23])[C:7]3[C:12](=[O:13])[NH:11][N:10]=[C:9]([C:14]([NH:16][CH3:25])=[O:15])[C:8]=32)[C:4]1=[O:24])[CH3:2]
Reactant: CN
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]nc(C(=O)NN)c32)C1=O
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]nc(C(=O)NC)c32)C1=O
Reaction time: 0.17 h

Procedure:
To a solution of (6S)-8-ethyl-10-methoxy-6-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-4-carbohydrazide (0.39 g, 1.2 mmol) and methylamine (5.9 mL, 11.8 mmol; 2 M in THF) in anhydrous dichloromethane (25 mL) in a water bath at room temperature, a solution of iodine (0.60 g, 2.4 mmol) in dichloromethane was added dropwise. After the addition was completed, an aqueous solution of sodium sulfite was added and the mixture was stirred vigorously for 10 minutes. The organic phase was separated, diluted with chloroform, and washed with brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated with a mixture of ethanol (7 mL) and diethyl ether (25 mL). The white solid precipitated was obtained by filtration and dried from its solution in toluene under vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[CH2:10][CH:11]1[CH2:16][CH2:15][CH:14](C(OCC)=O)[CH2:13][CH2:12]1.[Br:23]C1C=CC(CC(O)=O)=CC=1>>[Br:23][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[OH:1])=[O:22])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C1CCC(CC(=O)c2ccc(O)cc2O)CC1
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: O=C(Cc1ccc(Br)cc1)c1ccc(O)cc1O
Yield: 27.9 %

Procedure:
Followed Step 4 of Intermediate C, starting with 2-(4-bromophenyl)acetic acid to give product as an orange powder (20 g, 27.9%). MS (ESI): m/z 307.0, 309.0 [M+1]+, [M+3]+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C[Al](C)C.CO[C:15](=O)[CH:16]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=1)[S:17][C:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH:23]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Br:31][C:27]1[CH:26]=[C:25]([CH:16]([S:17][C:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH:19]=2)[C:15]2[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)C(SC1=CCN(C)CC1)c1cccc(Br)c1
Reactant: Nc1ccccc1N
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CC=C(SC(c2cccc(Br)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To a solution of 1,2-phenylenediamine (213 mg) in toluene (2 mL) is added dropwise a solution of 2M trimethylaluminium in toluene (1 ml). The reaction mixture is heated at 75° C. for 2 hours then a solution of (3-bromophenyl)(1-methyl-1,2,3,6-tetrahydropyridin-4-ylsulfanyl)acetic acid methyl ester (example 530B, 358 mg) in toluene (2 mL) is added, and the heating is continued at 75° C. for 3 hours. Water is added and the reaction mixture is made alkaline by adding 1N sodium hydroxide. The aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, brine, then dried over magnesium sulfate and concentrated. The residue is the dissolved in acetic acid (5 mL) and the reaction mixture is refluxed for 3 hours. The solvent is removed under reduced pressure. Water is added and the reaction mixture is made alkaline by adding 2N sodium hydroxide. The aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, brine, then dried over magnesium sulfate and concentrated. The residual solid is triturated with acetonitrile, filtered and the solid is washed with diethyl ether to give 2-[(3-bromophenyl)(1-methyl-1,2,3,6-tetrahydropyridin-4-ylsulfanyl)methyl]-1H-benzimidazole melting at 189° C.
Reaction SMILES: [CH2:1](OC(C1C(=O)N(CC2C=CC=CC=2)C2SC=C(C)C=2C=1O)=O)C.[CH2:25]([N:32]1[C:37](=[O:38])[C:36]([C:39]#[N:40])=[C:35]([Cl:41])[C:34]2[CH:42]=[CH:43][S:44][C:33]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:37](=[O:38])[C:36]([C:39]#[N:40])=[C:35]([Cl:41])[C:34]2[C:42]([CH3:1])=[CH:43][S:44][C:33]1=2)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N#Cc1c(Cl)c2ccsc2n(Cc2ccccc2)c1=O
Reactant: CCOC(=O)c1c(O)c2c(C)csc2n(Cc2ccccc2)c1=O
Product: Cc1csc2c1c(Cl)c(C#N)c(=O)n2Cc1ccccc1
Yield: 87 %

Procedure:
This compound was prepared from 7-benzyl-4-hydroxy-3-methyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyrdine-5-carboxylic acid ethyl ester (61) by applying a similar procedure as described for the preparation of 7-benzyl-4-chloro-6,7-dihydro-6-oxo-thieno[2,3-b]pyrdine-5-carbonitrile (64). Yield 87%. 1H-NMR (DMSO-d6): δ 2.48 (s, 3H), 5.36 (s, 2H), 7.14 (s, 1H), 7.32 (m, 5H) ppm; EIMS m/z 315 (M+1).