Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]([CH3:19])([OH:18])[CH3:17])=[N:12][CH:13]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](OB(O)O)=[CH:23][CH:22]=1>O1CCOCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]([CH3:19])([OH:18])[CH3:17])=[N:12][CH:13]=2)=[CH:23][CH:22]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: CC(C)(O)C#Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(O)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
Under an argon atmosphere 3 mL 2 M Na2CO3 solution and 173 mg (0.15 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 720 mg (3.0 mmol) 4-(5-bromo-pyridin-2-yl)-2-methyl-but-3-yn-2-ol and 593 mg (3.6 mmol) 4-chlorophenyl-boric acid in 60 mL 1,4-dioxane and the reaction mixture is stirred for 18 h at 85° C. The mixture is evaporated down i. vac., the residue is combined with water, extracted exhaustively with EtOAc, the organic phase is washed with water and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, PE/EtOAc 1:1).
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH:15]=2)[C:6]=1[C:23]([OH:25])=[O:24])([OH:3])=[O:2].OS(O)(=O)=O.[CH2:31](O)[CH3:32]>O>[C:20]([C:16]1[CH:15]=[C:14]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([CH2:4][C:1]([O:3][CH2:31][CH3:32])=[O:2])=[C:6]2[C:23]([OH:25])=[O:24])[CH:19]=[CH:18][CH:17]=1)([OH:22])=[O:21]
Reactant: CCO
Reactant: O=C(O)Cc1c(C(=O)O)n(-c2cccc(C(=O)O)c2)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)Cc1c(C(=O)O)n(-c2cccc(C(=O)O)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
To a solution of solution of 3-carboxymethyl-1-(3-carboxy-phenyl)-1H-indole-2-carboxylic acid (0.743 g, 2.2 mmol) in ethanol (5 mL) was added a drop of conc. H2SO4 and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL). The extract was washed with brine, dried over MgSO4 and concentrated to give 0.94 g of 1-(3-carboxy-phenyl)-3-ethoxycarbonylmethyl-1H-indole-2-carboxylic acid as a yellow oil (94% yield): 1H NMR (CDCl3, 300 MHz) δ 1.17 (t, J=7.25 Hz, 3H), 4.09 (q, J=7.05 Hz, 2H), 4.18 (s, 2H), 7.04 (d, J=8.39 Hz, 1H), 7.20 (t, J=7.25 Hz, 1H), 7.30 (t, J=7.25 Hz, 1H), 7.71–7.60 (m, 2H), 7.76–7.80 (m, 2H), 8.02 (d, J=7.06 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][C:50]1([CH3:67])[C:54]2[C:55]([O:59][C:60]3[N:65]=[CH:64][C:63]([NH2:66])=[CH:62][CH:61]=3)=[CH:56][CH:57]=[CH:58][C:53]=2[O:52][CH2:51]1>CN(C=O)C>[CH3:49][C:50]1([CH3:67])[C:54]2[C:55]([O:59][C:60]3[N:65]=[CH:64][C:63]([NH:66][C:13]([C:9]4([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:10][CH2:11][CH2:12]4)=[O:15])=[CH:62][CH:61]=3)=[CH:56][CH:57]=[CH:58][C:53]=2[O:52][CH2:51]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Reactant: CC1(C)COc2cccc(Oc3ccc(N)cn3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)Nc2ccc(Oc3cccc4c3C(C)(C)CO4)nc2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclobutanecarboxylic acid (Intermediate 68, 20.16 mg) in dry N,Ndimethylformamide (3 ml), DIPEA (20.44 μl, 0.117 mmol) and then HATU (35.6 mg, 0.094 mmol) were added and the reaction mixture was stirred for 15 minutes at room temperature under argon. Then 6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinamine Intermediate 59, 20 mg) was added and the reaction mixture was stirred at 60° C. under argon during 12 hours. The reaction mixture was cooled down and a prestirred (15 min) solution of HATU (1 equiv), 1-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclobutanecarboxylic acid (1 equiv) and DIPEA (1 equiv) in 1 mL of dry DMF was added. The reaction mixture was heated under argon an additional 12 hours at 60° C. The reaction mixture was evaporated. The residue obtained was purified on silica gel (Companion instrument) with cyclohexane/ethylacetate as eluents from 100/0 to 70/30. This afforded the title compound (14 mg)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18]/[N:19]=[C:20](/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)\[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1.C(O)C.[OH-].[Na+].Cl>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18]/[N:19]=[C:20](/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)\[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(CO/N=C(\CCC(=O)O)c2ccccc2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of methyl E-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxyimino]-4-phenylbutyrate (1.55 g, ethanol (10 ml) and 1N aqueous sodium hydroxide (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water and acidified with 1N hydrochloric acid to give E-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxyimino]-4-phenylbutyric acid as crystals (1.40 g, yield 93%). Recrystallization from ethanol-isopropyl ether gave colorless prisms. m.p. 131-132 ° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[C:21]4[C:16](=[CH:17][C:18]([O:23][CH3:24])=[C:19]([OH:22])[CH:20]=4)[N:15]=[CH:14][CH:13]=3)=[CH:10][C:2]1=2.[CH3:25][C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=O)[O:33]C2C=CC([N+]([O-])=O)=CC=2)[CH:27]=1.C(N(CC)CC)C>C1COCC1>[OH:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:23][CH3:24])[N:15]=[CH:14][CH:13]=[C:12]2[O:11][C:9]1[CH:8]=[CH:7][C:3]2[N:4]([C:32]([NH:31][C:28]3[CH:27]=[C:26]([CH3:25])[O:30][N:29]=3)=[O:33])[CH2:5][CH2:6][O:1][C:2]=2[CH:10]=1
Reactant: COc1cc2nccc(Oc3ccc4c(c3)OCCN4)c2cc1O
Reactant: Cc1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)no1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc4c(c3)OCCN4C(=O)Nc3cc(C)on3)c2cc1O
Temperature: 50 °C
Reaction time: 15 h
Yield: 37.6 %

Procedure:
A resealable tube was charged with 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yloxy)-7-methoxyquinolin-6-ol (0.200 g, 0.617 mmol), 4-nitrophenyl 5-methylisoxazol-3-ylcarbamate (0.243 g, 0.925 mmol), and THF (5.0 mL). Triethylamine (0.258 mL, 1.85 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture stirred at 50° C. for 15 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow-orange oil. This material was purified via column chromatography on silica gel (RediSep 40 g column, eluting with 5% methanol-dichloromethane) to afford a yellow oil. This material was triturated with dichloromethane and filtered to afford 7-(6-hydroxy-7-methoxyquinolin-4-yloxy)-N-(5-methylisoxazol-3-yl)-2,3-dihydrobenzo[b][1,4]oxazine-4-carboxamide (0.104 g, 38% yield) as an off-white solid.
Reaction SMILES: Br[C:2]1[C:3]([Cl:13])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.COCCOC>ClCCl.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:13][C:3]1[C:2]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:12])[N:7]2[CH3:11]
Reactant: OB(O)c1cccnc1
Reactant: CN1C(=O)Cc2c1ccc(Br)c2Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1C(=O)Cc2c1ccc(-c1cccnc1)c2Cl
Temperature: 100 °C

Procedure:
To 5-bromo-4-chloro-1-methyl-1,3-dihydro-indol-2-one (78 mg, 0.3 mmol) was added 3-pyridine boronic acid (CAS#1692-25-7, 50.2 mg, 0.41 mmol), 1,2-dimethoxyethane (2.5 mL) and 2 M aqueous sodium carbonate (0.410 mL, 0.82 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.09 mmol/g loading, (167 mg, 0.015 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 75 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane and saturated aqueous sodium carbonate, and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 40 to 100%) to afford 4-chloro-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 259.0636 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.27 (s, 3H), 3.62 (s, 2H), 6.85 (d, J=8.1 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.38-7.48 (m, 1H), 7.85 (d, J=7.8 Hz, 1H), 8.64 (dd, J=4.9, 1.6 Hz, 1H), 8.69 (d, J=2.3 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.I[CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C>[CH:19]1([CH2:18][N:13]2[C:10]3[CH:11]=[CH:12][C:7]4[N:8]([C:4]([CH3:3])=[N:5][N:6]=4)[C:9]=3[CH:15]=[C:14]2[CH3:16])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: ICC1CCCC1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnc(C)n32)n1CC1CCCC1
Reaction time: 0.25 h

Procedure:
Sodium hydride (13 mg, 0.32 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (20 mg, 0.1 mmol, from Example 2, Step 5) in DMF (3.0 mL). After stirring for 15 minutes, (iodomethyl)cyclopentane (0.022 g, 0.11 mmol, Acros) was added. After stirring for 45 minutes at room temperature, excess NaH (13 mg, 0.32 mmol, 60% in mineral oil) and (iodomethyl)cyclopentane (0.022 g, 0.11 mmol) were added and the reaction was continued for 20 minutes and then was quenched by the addition of water and diluted to 5 mL volume with MeCN. The resulting solution was filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (4 mg, 10%).
Reaction SMILES: C(OC([N:6]1[CH2:9][C:8]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][CH:24]3[CH2:26][CH2:25]3)(=[O:22])=[O:21])[CH:11]=2)[CH2:7]1)=O)C.[OH-].[Na+].CCO>[Cl-].[Na+].O>[CH2:27]([C:8]1([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][CH:24]2[CH2:25][CH2:26]2)(=[O:22])=[O:21])[CH2:7][NH:6][CH2:9]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)N1CC(Cc2ccccc2)(c2cccc(OCCNS(=O)(=O)CC3CC3)c2)C1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=S(=O)(CC1CC1)NCCOc1cccc(C2(Cc3ccccc3)CNC2)c1

Procedure:
To 3-benzyl-3-[3-(2-cyclopropylmethanesulfonylamino-ethoxy)-phenyl]-azetidine-1-carboxylic acid ethyl ester (50 mg, 0.11 mmol) was added 4 ml 2N NaOH/EtOH. The mixture was heated for 1 hour in a microwave. After cooling to room temperature 50% brine was added and the mixture extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium bicarbonate, filtered and the solvent evaporated. The residue was purified on 4 g SiO2 using 10% methanol in dichloromethane affording the desired product as a clear oil. m=15.5 mg
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)NCc1ccc(CO)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc(CCl)cc1

Procedure:
To a solution of N-(4-hydroxymethylphenylmethyl)acetamide (1.5 g) in chloroform (50 ml) was added thionyl chloride (0.73 ml) and the mixture was refluxed under heating for 1 hr. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give the title compound (1.8 g) as pale-yellow crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])=[O:9].C(N(CC)CC)C.[C:27](=[O:35])([O:32][CH2:33][CH3:34])[O:28][CH:29](Cl)[CH3:30].[I-].[Na+]>CC(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH:29]([O:28][C:27]([O:32][CH2:33][CH3:34])=[O:35])[CH3:30])=[O:14])=[O:9]
Reactant: CCOC(=O)OC(C)Cl
Reactant: O=C(C=Cc1cccs1)Nc1ccccc1C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=O)OC(C)OC(=O)c1ccccc1NC(=O)C=Cc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
A mixture of 2-[3-(2-thienyl)acrylamido]benzoic acid (273 mg, 1 mmol) and triethylamine (0.2 ml, 1.4 mmol) in dry acetone (10 ml) was stirred at room temperature for 30 minutes. To the solution, 1-chloroethyl ethyl carbonate (214 mg, 1.4 mmol) and sodium iodide (210 mg, 1.4 mmol) were added under ice cooling, and the mixture was heated under reflux for 19 hours. The reaction mixture was filtered by suction and the solvent was removed from the filtrate. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate, then with saturated aqueous sodium chloride, and dried over magnesium sulfate. After removing the solvent, the residue was purified by silica gel column chromatography (developing solvent:benzene:ether=49:1). The second eluate was collected. After removing the solvent, the resulted oily product was crystallized with isopropyl ether to give the desired compound (98 mg, yield, 25%). m.p., 154°-156° C. (white crystals, recrystallized from methanol/tetrahydrofuran/water).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](=[O:30])[C:7](=[N:10][NH:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([CH:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:20]#[N:21])=[C:14]([Cl:29])[CH:13]=1)[C:8]#[N:9])C.C([O-])(=O)C.[K+]>C(O)(=O)C>[Cl:29][C:14]1[CH:13]=[C:12]([N:11]2[C:4](=[O:3])[NH:5][C:6](=[O:30])[C:7]([C:8]#[N:9])=[N:10]2)[CH:17]=[C:16]([Cl:18])[C:15]=1[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:20]#[N:21]
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1cc(Cl)c(C(C#N)c2ccc(Cl)cc2)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: N#Cc1nn(-c2cc(Cl)c(C(C#N)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]c1=O

Procedure:
A mixture of 7.8 parts of ethyl[2-[[3,5-dichloro-4-[(4-chlorophenyl)cyanomethyl]phenyl]hydrazono]-2-cyanoacetyl]carbamate (intermediate 3), 1.98 parts of anhydrous potassium acetate and 120 parts of acetic acid is stirred and heated under reflux for 3 hours. The reaction mixture is concentrated to a volume of 30 parts. Water is added until the product is precipitated. It is sucked off, washed with water and dissolved in trichloromethane. The remaining water is separated and the organic phase is dried, filtered and evaporated, yielding 2-[3,5-dichloro-4-[(4-chlorophenyl)cyanomethyl]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carbonitrile (intermediate 4).
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].IC.[C:16]([O-])([O-])=O.[K+].[K+]>>[N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH3:16])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
A mixture of 2,3-dinitrophenol (5.43 mmol, 1 g), iodomethane (21.7 mmol, 1.35 mL) and K2CO3 (21.7 mmol, 2.99 g) was stirred at room temperature for 14 h. The reaction was then filtered through celite and the filter bed was washed with additional acetone. The filtrate was concentrated to provide 2,3-dinitroanisole (100%), which was dissolved in a mixture of EtOH/H2O (1:1, 20 mL) and Fe (19.4 mmol, 1.06 g) and concentrated HCl (8 drops) was added. The mixture was refluxed for 90 min., after which it was filtered through celite and the filter bed was washed with additional EtOH. The filtrate was concentrated and basified (pH>12) with 4 M NaOH and the aqueous layer was extracted with CH2Cl2. The organic phase was then separated and washed with brine, dried MgSO4 and concentrated to provide 2,3-diaminoanisole 36b (0.65 g).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[S:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.I[CH2:31][CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([S:22][CH2:31][CH2:32][CH3:33])=[N:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:28])([F:27])[F:29])[CH:3]=1
Reactant: O=C1NC(=S)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CCCI
Product: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one and iodopropane following General Procedure B.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:3])[CH3:2].Cl.[OH:21][C:22]1[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:16]=[C:15]([C:17]([N:26]2[CH2:25][CH2:24][C:23]3[C:28](=[CH:29][CH:30]=[C:31]([CH3:32])[C:22]=3[OH:21])[CH2:27]2)=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: CC(=O)NCCc1nc(C(=O)O)c2ccccc2n1
Agent: Cl
Product: CC(=O)NCCc1nc(C(=O)N2CCc3c(ccc(C)c3O)C2)c2ccccc2n1
Yield: 7 %

Procedure:
Reaction of 2-(2-(acetamido)ethyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 78 (7% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.74 and 1.76 (2s, 3H), 2.12 and 2.16 (2s, 3H), 2.62 and 2.88 (2t, 2H), 3.12-3.20 (m, 2H), 3.48 and 4.00 (2t, 2H), 3.54-3.64 (m, 2H), 4.35 and 4.88 (2s, 2H), 6.31 and 6.72 (2d, 1H), 6.80 and 6.98 (2d, 1H), 7.72-7.92 (m, 3H), 8.01-8.06 (m, 2H), 8.34 and 8.42 (2s, 1H); MS (ESI) m/z 405 ([M+H]+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.CN(C)C=O.F[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]>O>[N+:26]([C:17]1[CH:18]=[C:19]([C:22]([F:23])([F:24])[F:25])[CH:20]=[CH:21][C:16]=1[N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: c1ccc2c(c1)CNC2
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isoindoline (679 μl, 5.98 mmol, commercially available product) was added at 0° C. to an N,N-dimethylformamide (DMF; 2 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (508 mg, 2.43 mmol, commercially available product). The resulting mixture was warmed to room temperature and stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=15/1). Thus, 2-[2-nitro-4-(trifluoromethyl)phenyl]isoindoline (749 mg, quant.) was yielded as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][C@H:8]3[CH2:13][NH:14][CH2:15][CH2:16][N:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:17]=O>>[CH3:17][N:14]1[CH2:15][CH2:16][N:7]2[C@@H:8]([CH2:9][CH2:10][O:11][C:12]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=32)[CH2:13]1
Reactant: C=O
Reactant: Cc1cccc2c1OCC[C@H]1CNCCN21
Product: Cc1cccc2c1OCC[C@H]1CN(C)CCN21

Procedure:
To a solution of Example 226 (50 mg, 0.229 mmol) in a pH 4 buffer solution (10 mL, made from 48 g acetic acid and 30.5 g sodium acetate in 1 L methanol) was added formaldehyde (36% solution, 13.8 mg, 0.46 mmol) and macroporous-cyanoborohydride resin (0.32 g, 0.69 mmol). The reaction was allowed to stir for 2 hours before the macroporous-cyanoborohydride resin was removed by filtration, and the solution concentrated. The concentrate was basified to pH=10 with NaOH (1 M aqueous), and the product was extracted with ethyl acetate. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.69-6.86 (m, 3H), 4.24-4.37 (m, 1H), 4.06-4.16 (m, 1H), 2.99-3.18 (m, 3H), 2.56-2.68 (m, 1H), 2.46-2.55 (m, 1H), 2.18-2.29 (m, 1H), 2.21 (s, 3H), 2.02-2.16 (m, 1H), 2.09 (s, 3H), 1.79-1.99 (m, 2H); MS (DCI+) m/z 233 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([CH2:9][F:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[CH3:18].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:35]([F:39])([F:38])([F:37])[F:36]>C(OCC)C>[F:36][B-:35]([F:39])([F:38])[F:37].[CH3:11][C:12]1[CH:13]=[C:14]([S+:7]([CH2:9][F:10])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: O=S(CF)c1ccccc1
Reactant: Cc1ccccc1C
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1ccc([S+](CF)c2ccccc2)cc1C

Procedure:
Monofluoromethyl phenyl sulfoxide (645 mg, 4.08 mmol) of example 2 was dissolved in dry diethyl ether (15 ml) under argon atmosphere. O-xylene (0.54 ml, 1.1 eq) was added to the previous solution and then the mixture was cooled to a temperature below −50° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.68 mL, 1.0 eq) was added slowly maintaining the same temperature. The mixture was stirred until the reaction was complete. HBF4 solution (54%, 1.12 mL, 2 eq) was added and the resulting suspension was stirred for 30 minutes. The precipitate tetrafluoroborate salt was isolated by filtration, washed with diethyl ether at 0° C. and dried. The desired product was obtained as a slightly yellow oily solid (1.729 g).