Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:11])[C:7](=[O:8])[O:6][C:4](=[O:5])[C:3]1([F:10])[F:9].[Cl:12][C:13]1[CH:32]=[CH:31][C:16]2[O:17][C:18]3[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=3[C@@H:20]3[C@H:25]([NH2:26])[CH2:24][CH2:23][CH2:22][N:21]3[C:15]=2[CH:14]=1>O1CCOCC1>[Cl:12][C:13]1[CH:32]=[CH:31][C:16]2[O:17][C:18]3[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=3[C@@H:20]3[C@H:25]([NH:26][C:7](=[O:8])[C:2]([F:11])([F:1])[C:3]([F:10])([F:9])[C:4]([OH:6])=[O:5])[CH2:24][CH2:23][CH2:22][N:21]3[C:15]=2[CH:14]=1
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reactant: O=C1OC(=O)C(F)(F)C1(F)F
Solvent: C1COCCO1
Product: O=C(O)C(F)(F)C(F)(F)C(=O)N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
Tetrafluorosuccinic anhydride (5.35 μL, 0.05 mmol) was added to trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) in 1 mL of dioxane. The resulting mixture was stirred at room temperature for 30 minutes. Dioxane was removed by evaporation under reduced pressure and ethyl acetate and 2% citric acid were added. The organic layer was washed with brine, dried (Na2SO4) and evaporated to give trans-4-[(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)amino]-2,2,3,3-tetrafluoro-4-oxobutanoic acid (10.6 mg, 51%). Data: (m/z)=472 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17])=[NH:10].Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22]N>CO>[CH3:19][O:20][C:21](=[O:24])[CH2:22]/[N:10]=[C:9](/[C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH2:1])\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17]
Reactant: N=C(c1cc(F)ccc1N)c1ccccc1Br
Reactant: COC(=O)CN
Agent: Cl
Solvent: CO
Product: COC(=O)C/N=C(/c1cc(F)ccc1N)c1ccccc1Br

Procedure:
A solution of 139.5 g (0.446 moles) of (2-amino-5-fluorophenyl)(2-bromophenyl)methanimine, 69.9 g (0.557 moles) of glycine methyl ester hydrochloride and 1.68 L of methanol was stirred at reflux for 5 hours under nitrogen. The solvent was then removed by evaporation under vacuum and the yellow, residual solid was partitioned between 1.4 L of methylene chloride and 1.4 L of saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with 0.5 L of methylene chloride. The combined organic extracts were dried with Na2SO4, filtered, and concentrated under vacuum. The residue was redissolved in 0.5L of methylene chloride and concentrated to a dark yellow semi-solid (156.6 g). This solid was recrystallized from 400 mL of 1:3 EtOAc/Hexane to give 72.8 of (Z)-N-[(2-Amino-5-fluorophenyl)(2-bromophenyl)methylene]glycine methyl ester).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][N:6]([C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=3[O:34][CH3:35])=[CH:22][CH:21]=2)[CH:13]=1)[C:7]([CH3:10])([CH3:9])[CH3:8])C.[Li+].[OH-]>C1COCC1.O>[C:7]([N:6]([CH2:5][C:4]([OH:37])=[O:3])[C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=3[O:34][CH3:35])=[CH:22][CH:21]=2)[CH:13]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CCOC(=O)CN(C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(C(=O)N(CC(=O)O)C(C)(C)C)c2)cc1

Procedure:
A solution of {[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoyl]-tert-butyl-amino}-acetic acid ethyl ester (11.6 g, 23.3 mmol) in THF (500 mL) was treated with a solution LiOH (2.8 g, 116.7 mmol) in water (500 mL) at room temperature for 12 h. THF was then removed by evaporation. The mixture was then poured into ice and carefully acidified with dilute HCl to pH-1. The precipitate was collected by filtration, washed with water, and dried in vacuum to afford {tert-butyl-[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoyl]-amino}-acetic acid as a white solid, 10.6 g (94%). LC-MS (ES) calculated for C27H27F2NO5, 483; found m/z 484 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[N:12]=[CH:11][C:10]([CH:13]([OH:15])[CH3:14])=[C:9]([I:16])[CH:8]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[F:6][C:7]1[N:12]=[CH:11][C:10]([CH:13]([O:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:14])=[C:9]([I:16])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1cnc(F)cc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(OS(C)(=O)=O)c1cnc(F)cc1I
Reaction time: 4 h
Yield: 64.2 %

Procedure:
Add methanesulfonyl chloride (1.93 g, 16.8 mmol) to a solution of 1-(6-fluoro-4-iodo-pyridin-3-yl)-ethanol (1.5 g, 5.6 mmol) and diisopropylethylamine (2.2 g, 16.8 mmol) in DCM (50 mL) at 0° C. Continue to stir the mixture at 0° C. to RT for 4 h. Dilute the reaction mixture with diluted sodium carbonate. Extract the product into chloroform. Dry the organic phase over sodium sulfate. Concentrate the solution in vacuo. Purify the crude by column chromatography (20% ethyl acetate in hexane) to afford the title compound as a white solid (1.24 g, 64%). MS (ES) m/z 346 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.[NH2:21]O.[OH-].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[O:18][N:21]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(CC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Brc1ccc(-c2cc(-c3ccc(Br)cc3)on2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a 250 ml round bottom flask, 4 g (10.4 mmol) of [2] was dissolved in 100 ml dry dioxane and heated to reflux, then 3.0 g (43.2 mmol) hydroxylamine hydrogen chloride in 10 ml water and 5 ml (25 mmol) 5 N NaOH was then dropped into the refluxing mixture. After 12 hours, the reaction mixture was cooled down to room temperature, and the solvent was removed in vacuo. The product was recrystallized from ethanol. Characterization. Yield: 3.41 g (85%). M.P. 218.5-219.5° C. 1H NMR (300 MHz, CDCl3, 20° C., δ): 7.78 (d, 2H, ArH), 7.74 (d, 2H, Ar′H), 7.66 (d, 2H, ArH), 7.62 (d, 2H, Ar′H), 6.82 (s, 1H, isoxazole proton). EI-MS: 379 (M+), 224, 183, 155.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][C:15]4[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:23]([OH:28])(=O)[C:24](O)=[O:25]>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([NH:22][C:23](=[O:28])[C:24]([NH:22][C:20]5[CH:19]=[CH:18][C:16]6[NH:17][C:13]([C:10]7[CH:11]=[CH:12][C:7]([N:4]8[CH2:3][CH2:2][O:1][CH2:6][CH2:5]8)=[CH:8][CH:9]=7)=[N:14][C:15]=6[CH:21]=5)=[O:25])=[CH:21][C:15]=4[N:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C(=O)O
Reactant: Nc1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1)C(=O)Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1

Procedure:
Compound 434 was prepared according to the procedure similar to that described in Scheme V from 2-(4-morpholinophenyl)-5-aminobenzimidazole and oxalic acid. [M+H]+ calcd for C36H34N8O4: 643.27; found: 643.09.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[N+:11]([O-])([OH:13])=[O:12].O>C(Cl)Cl>[OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1ccc(O)cc1C#N
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c(O)cc1C#N
Yield: 29.2 %

Procedure:
5-Hydroxy-2-methylbenzonitrile (D36, 475 mg, 3.57 mmol) was dissolved in DCM (5 mL) and 70% nitric acid (1 mL, 22 mmol) was added dropwise to the reaction. The mixture was stirred for 45 min before the addition of H2O (15 mL). The two phases were separated and the aqueous phase was extracted with DCM (2×). The combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a yellow solid. The crude residues were purified by flash column chromatography (silica, 10% EtOAc/90% iso-hexane to 50% EtOAc/50% iso-hexane) to give 5-hydroxy-2-methyl-4-nitrobenzonitrile (D37, 186 mg, 26%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@H:27]([F:28])[CH2:26][NH:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH:36](=O)[CH3:37]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@H:27]([F:28])[CH2:26][N:25]([CH2:36][CH3:37])[CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:34])([F:35])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CNC[C@H]1F
Reactant: CC=O
Product: CCN1C[C@@H](F)[C@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-1-ethyl-4-fluoropyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-4-fluoropyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione (Example 317) and acetaldehyde (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[S:12]1(=[O:18])(=[O:17])[CH:16]=[CH:15][CH2:14][CH2:13]1>C(O)C>[OH:4][CH2:3][CH2:2][NH:1][CH:14]1[CH2:15][CH2:16][S:12](=[O:18])(=[O:17])[CH2:13]1
Reactant: O=S1(=O)C=CCC1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=S1(=O)CCC(NCCO)C1
Temperature: 78 °C

Procedure:
A mixture of 2-aminoethanol (310 mg, 5.08 mmol), triethylamine (514 mg, 5.08 mmol) and 2,3-dihydrothiophene 1,1-dioxide (200 mg, 1.693 mmol) in ethanol (3 mL) was heated up at 78° C. for 16 hours. TLC indicated the starting material was consumed and desired product was formed (30% methanol/ethyl acetate). The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography with 0-35% methanol/ethyl acetate to provide the title compound as a colorless oil (260 mg, 86%). 1H NMR (400 MHz, CHLOROFORM-d) δ 3.78-3.56 (m, 3H), 3.38-3.21 (m, 2H), 3.14-3.00 (m, 1H), 2.94 (dd, J=13.3, 6.0 Hz, 1H), 2.85-2.68 (m, 2H), 2.53-2.34 (m, 1H), 2.22-2.03 (m, 1H).
Reaction SMILES: C([N:5]1[C:9](=O)[N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[S:6]1)CCC.C([C:16]([O:18][CH3:19])=[O:17])#N>ClCCl>[CH3:19][O:18][C:16]([C:9]1[N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[S:6][N:5]=1)=[O:17]
Reactant: COC(=O)C#N
Reactant: CCCCn1sc2nccn2c1=O
Solvent: ClCCl
Product: COC(=O)c1nsc2nccn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a cooled solution of 2-butylimidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-one (2.95 g, 15.0 mmole) in 25 mL dichloromethane, methyl cyanoformate (2.54 g, 30 mmole) was added dropwise and the mixture was stirred for 16 h at room temperature. The precipitate was filtered and subsequently washed with dichloromethane to give 2.18 g (80%) of 3-(methoxycarbonyl)imidazo[1,2-d]-1,2,4-thiadiazole as colourless crystals: mp 164.5-165° C.; 1H NMR (CDCl3) δ 8.13 (s, 1H), 7.51 (s, 1H), 4.11 (s, 3H) ppm; IR (KBr) ν 3440, 1737, 1527, 1253, 1071 cm-1. Anal. Calcd for C6H5N3O2S: C, 39.34; H, 2.75; N, 22.94. Found: C, 39.41; H, 2.51; N, 22.94.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[N:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=1)N.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[OH:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([N:16]2[C:4](=[O:15])[C:5]([N:10]3[CH:14]=[CH:13][N:12]=[N:11]3)=[CH:6][NH:7]2)=[N:23][CH:22]=1
Reactant: NNc1ccc(CO)cn1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: O=c1c(-n2ccnn2)c[nH]n1-c1ccc(CO)cn1
Temperature: 25 °C

Procedure:
15.1 g (71.9 mmol) of the compound from Example 3A and 10.0 g (71.9 mmol) of the compound from Example 4A are dissolved in 375 ml ethanol and 1.7 g (7.2 mmol) camphor-10-sulfonic acid are added. The mixture is heated under reflux for 16 h. After cooling to RT, the reaction mixture is concentrated and the residue is purified by column chromatography over silica gel (mobile phase: methylene chloride/methanol 9:1, then 1:1). The product fraction is concentrated in vacuo and the residue is stirred in diisopropyl ether, filtered off and dried in vacuo.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:6]([CH2:17][OH:18])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[C:24]([O:18][CH2:17][C:6]1[C:7]([CH2:13][CH:14]2[CH2:15][CH2:16]2)=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:3]([CH:2]([F:1])[F:23])=[N:4][C:5]=1[C:19]([F:22])([F:20])[F:21])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CO)c1CC1CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(COC(=O)c2ccccc2)c1CC1CC1

Procedure:
Reaction of methyl 2-(difluoromethyl)-5-(hydroxymethyl)-4-(cyclopropylmethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (U.S. Pat. No. 5,169,432 example A compound A4) with. Benzoyl chloride and triethylamine according to the procedure in example 99 of U.S. Pat. No. 5,169,432 gave the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[S:13][CH:14]=[C:15]([CH2:17]Cl)[N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]1([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH:23]=[N:22][N:21]=[N:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[S:13][CH:14]=[C:15]([CH2:17][O:30][C:27]3[CH:28]=[CH:29][C:24]([N:19]4[CH:23]=[N:22][N:21]=[N:20]4)=[CH:25][CH:26]=3)[N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(c2nc(CCl)cs2)C1
Reactant: Oc1ccc(-n2cnnn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)C1

Procedure:
A mixture of 3-(4-chloromethyl-thiazol-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (From Step 1) (386 mg, 1.34 mmol), 4-tetrazol-1-yl-phenol (217 mg, 1.34 mmol), Cs2CO3 (655 mg, 2.01 mmol) and KI (22 mg, 0.13 mmol) in acetonitrile (5 mL) was heated under reflux for 4 hours. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 8.92 (1H, s), 7.61 (2H, d), 7.32 (1H, s), 7.19 (2H, d), 5.25 (2H, s), 4.39 (2H, m), 4.18 (2H, m), 4.14 (1H, m), 1.46 (9H, s).
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:13][C:12]1[C:11]2[C:14]([O:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:16]=[CH:17][C:10]=2[O:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OCc3cccnc3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)O)oc2cccc(OCc3cccnc3)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 3-methyl-4-(pyridin-3-ylmethoxy)-benzofuran-2-carboxylic acid t-butyl ester was dissolved into a 40% TFA/methylene chloride solution, and stirred at room temperature for 4 hours. Evaporation of the solvent gave 3-methyl-4-(pyridin-3-ylmethoxy)-benzofuran-2-carboxylic acid in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[C:10]1=[O:19].I[CH:21]([CH3:23])[CH3:22]>C1COCC1>[CH:21]([C:9]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[C:10]1=[O:19])([CH3:23])[CH3:22]
Reactant: CC(C)I
Reactant: COc1ccccc1C1C(=O)N(C)c2ccccc21
Solvent: C1CCOC1
Product: COc1ccccc1C1(C(C)C)C(=O)N(C)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
35.4 g (0.14 mol) of 3-(2-methoxyphenyl)-1-methylindolin- -2-one in 350 ml of dry THF are stirred with 16.1 g (0.14 mol) of potassium tertiary-butylate at room temperature for 15 minutes. Then at 10° C., a solution of 14.3 ml of 2-iodopropane in 70 ml of dry THF are added dropwise, and the mixture is then stirred at room temperature for 4 hours. The reaction mixture is left to stand overnight and then partitioned between water and ethyl acetate. After the organic phase has been evaporated, 4.8 g of product of melting point 113°-115° C. are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>ClCCl>[CH3:24][S:21]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Temperature: 23 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
A solution of tert-butyl 2-hydroxyethylcarbamate (25 mL, 161.6 mmol) in dichloromethane (60 mL) was cooled to 0° C. and stirred while first diisopropylethylamine (33.8 mL, 193.9 mmol) was added and then mesyl chloride (13.7 mL, 177.8 mmol) then was added dropwise. The mixture was allowed to warm to 23° C., stirred for 18 hours, poured into dichloromethane (200 mL) and washed with aqueous hydrochloric acid (3M, 3×25 mL) and saturated aqueous sodium hydrogencarbonate (2×25 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo to provide tert-butyl 2-methylsulfonyloxyethylcarbamate (37.39 g, 97% yield) as a brown oil; MS (PB-PCI) C8H17NO5S m/e calc 239.08; found 240 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[NH2:19][CH2:20][CH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:8][C:6]1[N:7]=[C:2]([NH:19][CH2:20][CH2:21][OH:22])[N:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:5]=1
Reactant: NCCO
Reactant: COc1ccc(CNc2nc(Cl)nc(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(CNc2nc(Cl)nc(NCCO)n2)cc1
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A 1.43 g (5.01 mmol) portion of 2,4-dichloro-6-(4-methoxybenzylamino)-1,3,5-triazine was suspended in 100 ml of ethanol, mixed with 303 μl (5.01 mmol) of 2-aminoethanol and 693 mg of potassium carbonate and stirred at 45° C. for 1 day. After evaporation of the solvent under a reduced pressure, water was added to the residue and the resulting precipitate was collected by filtration to obtain 1.56 g (quantitative) of the title compound as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:17].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:17])=[O:15])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: Cc1cccnc1-c1ccc(CO)cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccnc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 23.4 %

Procedure:
To a solution of [4-(3-methyl-2-pyridinyl)phenyl]methanol (12 g, 0.06 mol) in dry DMF (150 mL) was added pyridiniumdichromate (91 g, 0.24 mol) and stirred at RT for 3 days. The reaction mixture was poured into water and extracted with ethyl acetate (250 mL). The organic layer was washed with water, brine, dried and concentrated. The crude was purified by column chromatography over silica gel to give 4-(3-methyl-2-pyridinyl)benzoic acid (3 g, 25%) as white solid.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[C:9]([NH:11]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:8]([F:31])=[CH:7][N:6]=1)C.OS(O)(=O)=O.CC#N>O>[NH2:11][C:9]1[C:8]([F:31])=[CH:7][N:6]=[C:5]([CH:4]=[O:3])[CH:10]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)cn1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: Nc1cc(C=O)ncc1F
Yield: 89.9 %

Procedure:
Following the procedure for Example 12, 2-(diethoxymethyl)-5-fluoro-N-tritylpyridin-4-amine (457 mg, 1 mmol), conc H2SO4 (0.2 mL), CH3CN (5 mL) and H2O (5 mL) gave 4-amino-5-fluoropicolinaldehyde (126 mg, 87%) as a white solid: mp 133-135° C.; 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 8.34 (d, J=2.7 Hz, 1H), 7.36 (d, J=7.5 Hz, 1H), 4.47 (br s, 2H); 19F NMR (376 MHz, CDCl3) δ −144.44; HRMS-ESI (P/z) [M+H]+ calcd for C6H5FN2O, 140.0386. found, 140.0384.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:28]=[CH:27][C:8]([CH:9]=[C:10]2[C:22]3[N:21]4[CH:23]=[CH:24][N:25]=[C:20]4[C:19](=[O:26])[NH:18][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C)C=O>[Pd].CO>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[C:22]3[N:21]4[CH:23]=[CH:24][N:25]=[C:20]4[C:19](=[O:26])[NH:18][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)=[CH:27][CH:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=c2c3ccccc3c3[nH]c(=O)c4nccn4c23)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)Nc1ccc(CC2c3ccccc3-c3[nH]c(=O)c4nccn4c32)cc1
Yield: 25.4 %

Procedure:
The process is performed as in Example 3 but starting with 4.7 g of 10-(4-acetylaminobenzylidene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 250 ml of dimethylformamide, 50 ml of methanol and 0.6 g of 10% palladium-on-charcoal for 26 hours. 1.2 g of 10-(4-acetylaminobenzyl)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one are obtained in the form of a cream-white solid melting above 260° C. (Analysis, % calculated C: 71.34, H: 4.90, N: 15.13, O: 8.64, % found C: 71.3, H: 4.7, N: 15.3, O: 8.3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(O)Cc1cccc(F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)CC(=O)Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
102 mg of 1-(3-fluorophenyl)-4-methyl-2-pentanol, 122 mg of PCC, and 100 mg of MS-4A were dissolved in 1 mL of dichloromethane, followed by stirring at room temperature overnight. After completion of the reaction, the reaction liquid was filtered, water was added to the filtrate, followed by extraction with chloroform, and the organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PLC (chloroform alone) to obtain 36 mg (yield 36%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[N:7]=1)[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=3)[C:14]=2[CH3:24])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)n1
Reactant: CCCn1cc(Br)cn1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)OCC)n3)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: [6-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-pyridin-2-yl]-acetic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.