Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=O)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:21][CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: COc1ccc(C(=O)O)cc1
Product: COc1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)cc1
Yield: 63 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 4-methoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 192 mg, 63%) which was obtained as a white foam. MS: m/e=334.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[O:7][S:6](=[O:8])[N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.I([O-])(=O)(=O)=[O:17].[Na+].Cl>C(#N)C.O>[CH3:1][CH:2]1[O:7][S:6](=[O:17])(=[O:8])[N:5]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:4][CH2:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC1CCN(C(=O)OC(C)(C)C)S(=O)O1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1CCN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reaction time: 0.08 h
Yield: 60.6 %

Procedure:
The crude tert-butyl 6-methyl-1,2,3-oxathiazinane-3-carboxylate 2-oxide (2.52 g, 10.7 mmol) is dissolved in acetonitrile (25 mL) and H2O (15 mL) is added. The solution is cooled in an ice bath and sodium periodate (3.4 g, 16.1 mmol) is added in one portion. After 5 min, the pH is adjusted to 7-8 by addition of saturated Na2HPO4 solution. Then RuCl3 (22 mg, 0.11 mmol) in H2O (0.5 mL) is added. The pH is kept between 6 and 9 by addition of Na2HPO4 solution. After 2 h, H2O (100 mL) is added and pH is adjusted to 6 by addition of 2M HCl solution. The reaction mixture is extracted with EtOAc and the organic layer is washed with NaHCO3 and brine and the washes are back extracted once with EtOAc. The combined organic layers are dried (MgSO4), filtered and concentrated. The crude product is purified via by flash column chromatography using a gradient elution of 5-80% ethyl acetate/hexanes which affords the title compound (1.63 g, 61%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[CH3:9][C:4]1[C:3]([CH2:2][S:17][C:15]2[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=2)=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1noc(C)c1CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2c(C)noc2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-dimethyl-1,2-oxazole (6.3 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (611 mg, 4.3 mmol), and triethylamine (5 mL, 36.0 mmol) in absolute ethanol (25 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was recovered, evaporated, and co-evaporated with EtOAc (20 mL). The solid residue was treated with water (200 mL). The solid product was recovered by filtration, washed with water (2×20 mL), diethyl ether (2×20 mL), and hexanes (2×20 mL), and then dried in vacuo, affording the title compound (783 mg, 72% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (m, 6H), 2.40 (s, 3H), 4.16 (s, 2H), 5.99 (s (br), 1H); M+ 252.
Reaction SMILES: [C:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)=[CH:8][CH:7]=1)(O)=[O:2].S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][C:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)=[CH:8][CH:7]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccc(OC(=O)c2ccc(F)c(F)c2)cc1
Solvent: ClCCl
Product: O=C(Cl)C=Cc1ccc(OC(=O)c2ccc(F)c(F)c2)cc1
Temperature: 35 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
About 10 g (about 21.68 mmol) of 3,4-difluoro-benzoic acid 4-(2-carboxy-vinyl)-phenyl ester was dissolved in about 200 ml of methylene chloride, and about 2.84 g (23.848 mmol) of thionyl chloride (SOCl2) was added thereto. Thereafter, the reaction mixture was stirred at about 35° C. for about 6 hours, followed by removing the solvent. Subsequently, a vacuum drying process was conducted, thus obtaining the desired compound (Yield about 90%).
Reaction SMILES: [C:1](=[O:38])([O:3][C:4]([CH3:37])([CH3:36])[CH2:5][C@@H:6]([CH2:17][C:18]([N:21]1[CH2:25][CH2:24][C@H:23]2[CH2:26][N:27]([C:29]([C:31]3([C:34]#[N:35])[CH2:33][CH2:32]3)=[O:30])[CH2:28][C@@H:22]12)=[C:19]=[O:20])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[NH2:2].OO.C(=O)([O-])[O-:42].[K+].[K+].O>CS(C)=O>[C:1](=[O:38])([O:3][C:4]([CH3:36])([CH3:37])[CH2:5][C@@H:6]([CH2:17][C:18]([N:21]1[CH2:25][CH2:24][C@H:23]2[CH2:26][N:27]([C:29]([C:31]3([C:34]([NH2:35])=[O:42])[CH2:32][CH2:33]3)=[O:30])[CH2:28][C@@H:22]12)=[C:19]=[O:20])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[NH2:2]
Reactant: CC(C)(C[C@@H](CC(=C=O)N1CC[C@H]2CN(C(=O)C3(C#N)CC3)C[C@H]21)Cc1cc(F)c(F)cc1F)OC(N)=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C[C@@H](CC(=C=O)N1CC[C@H]2CN(C(=O)C3(C(N)=O)CC3)C[C@H]21)Cc1cc(F)c(F)cc1F)OC(N)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
(R)-4-((3aS,6aS)-5-(1-cyanocyclopropylcarbonyl)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4-carbonyl-1-(2,4,5-trifluorophenyl)butan-2-yltertbutyl carbamate 17a (300 mg, 0.58 mmol) was dissolved in DMSO (5 mL), added 30% of hydrogen peroxide (0.5 mL) and potassium carbonate (160 mg, 1.16 mmol) at 0° C., the temperature of reaction solution was raised to room temperature and stirred for 5 minutes, added water (20 mL), extracted by dichloromethane, dried by anhydrous sodium sulfate, concentrated, residues was purified by column chromatography to give (R)-4-((3aS,6aS)-5-(1-aminocarbonylcyclopropylcarbonyl)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-4-carbonyl-1-(2,4,5-trifluorophenyl)butan-2-yltertbutyl carbamate 28a (265 mg, 85%) as white foamy solid. MS m/z (ESI): 539.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:52]=[C:53]([F:55])[CH:54]=1)[CH2:5][C@H:6]([C:37](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:38])[C@@H:7]([CH:9]1[CH2:18][C:17]2[C:12](=[C:13]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:14]=[CH:15][CH:16]=2)[CH2:11][N:10]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[OH:8].[Li+].[OH-:57].OO>C1COCC1.O>[F:55][C:53]1[CH:52]=[C:4]([CH:3]=[C:2]([F:1])[CH:54]=1)[CH2:5][C@@H:6]([C@@H:7]([CH:9]1[CH2:18][C:17]2[C:12](=[C:13]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:25])[CH3:26])[CH:21]([CH3:23])[CH3:22])[CH:14]=[CH:15][CH:16]=2)[CH2:11][N:10]1[C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[OH:8])[C:37]([OH:57])=[O:38]
Reactant: [OH-]
Reactant: CC(C)[Si](Oc1cccc2c1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C2)(C(C)C)C(C)C
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1cccc2c1CN(C(=O)OC(C)(C)C)C([C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)O)C2)(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-((1S,2S)-2-(3,5-difluorobenzyl)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-3-oxopropyl)-8-(triisopropylsilyloxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step F (9), 2.0 g, 2.57 mmol) in THF (50 mL) was added a solution of LiOH (123 mg, 5.13 mmol) in H2O (8 mL), then 30% H2O2 (3.0 g, 25.7 mmol) was added at −5° C. This reaction mixture was stirred from −5° C. to 0° C. over 1 h and stirred at rt for 3 h. Solvent was removed and ethyl acetate (500 mL) was added. The mixture was washed with 1N HCl, and H2O, dried (Na2SO4), and concentrated in vacuo to give the crude product which was ready for next step without purification. MS (ESI) (M−H)− 618.22.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([C:24](O)=[O:25])[NH:10][S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.O.[ClH:35].[N:36]1C=CC=CC=1>>[ClH:35].[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([NH:10][CH:9]([CH2:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:24]([NH2:36])=[O:25])(=[O:12])=[O:13]
Reactant: Nc1ccc(C[C@@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)O)cc1
Reactant: c1ccncc1
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: NC(=O)C(Cc1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 20 h

Procedure:
A solution. of.0.7 g of 3-(p-aminophenyl)-N-(2-naphthylsulfonyl)-D-alanine (Example 35a) in 5 ml of pyridine is treated with 1 ml of acetic anhydride and left to stand at room temperature for 20 hours. After the addition of water and conc. HCl (ice-cooling) the separated product is filtered off under suction, dissolved in ethyl acetate, washed with water, dried and evaporated. The product is dissolved in 20 ml of methanolic 1N NaOH and left to stand. The solution is evaporated, the residue is dissolved in water, acidified with conc. HCl, the precipitated product is filtered off under suction, dissolved in ethyl acetate and washed with water. After evaporation the residue is reacted analogously to Example 5 and gives 146 mg of (R)-p-acetamido-N-[(RS)-1-amidino-3-piperidinyl]methyl]-α-(2-naphthylsulfonamido)hydrocinnamamide hydrochloride, FAB-MS: 551 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([I:25])=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(I)cc2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(C)Sc1nc(CCOc2ccc(I)cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
2-({4-[2-(4-Iodophenoxy)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (6.0 g) obtained in Example 144-1 was dissolved in dichloromethane (25 mL), trifluoroacetic acid (20 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (60 mL). Thionyl chloride (5.63 g) was added under ice-cooling and the mixture was refluxed for 4 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=6:1 to 4:1) to give the title compound (5.2 g) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:2]1=2.[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:25](Cl)=[N:24][CH:23]=[N:22][C:21]=2[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[CH2:12]([N:19]1[CH2:28][CH2:27][C:26]2[C:25]([NH:11][C:8]3[CH:9]=[CH:10][C:2]4[O:1][CH2:6][CH2:5][O:4][C:3]=4[CH:7]=3)=[N:24][CH:23]=[N:22][C:21]=2[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: CC#N
Product: c1ccc(CN2CCc3c(ncnc3Nc3ccc4c(c3)OCCO4)C2)cc1

Procedure:
The title compound was prepared using the general procedure set forth in Example 2, above, using 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (0.32 mL, 2.63 mmol) and 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, prepared as described in Example 1.B. (0.621 g, 2.39 mmol) in acetonitile (3 mL). The title compound was obtained as a brown solid (0.756 g, 84%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:12][CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NC1CCNC1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(NC2CCNC2)cc1
Temperature: 70 °C
Reaction time: 48 h
Yield: 102.6 %

Procedure:
To 500 mg (2.87 mmol) 4-fluorophenyl methyl sulfone dissolved in 4 mL DMF was added 247 mg (2.87 mmol) 3-aminopyrrolidine followed by 793 mg (5.74 mmol) potassium carbonate. The mixture was heated to 70° C. and stirred for 48 h. Upon cooling to room temperature, the mixture was partitioned between EtOAc and water, dried over MgSO4 and concentrated to provide 708 mg of 4-(pyrrolidin-3-ylamino)phenyl methyl sulfone, pure by 1H NMR.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[CH2:30][OH:31])(=[O:4])=[O:3].Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[C:37]([O:36][C:34](=[O:35])[CH2:33][O:31][CH2:30][C@@H:6]1[CH2:7][C@@H:8]([S:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][N:5]1[S:2]([CH3:1])(=[O:3])=[O:4])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Product: CC(C)(C)OC(=O)COC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(C)(=O)=O

Procedure:
Following Method A, (2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-yl)-methanol and tert-butyl bromoacetate gave (2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-ylmethoxy)-acetic acid tert-butyl ester, mp 98° C., slow dec., MS: 568 (MH+).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[O:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:30][C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:15]4[S:14][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=4)=[CH:29][CH:28]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Fc1ncccc1C1CCOCC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(C2CCOCC2)c1
Temperature: 180 °C

Procedure:
A glass microwave reaction vessel was charged with 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (0.3904 g, 2.154 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.783 g, 3.23 mmol), and cesium carbonate (2.106 g, 6.46 mmol) in N-Methyl-2-pyrrolidinone (7.18 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 180° C. for 30 min. Reaction was worked up via seperatory funnel. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Synergi column, 4 micron, MAX-RP, 80 Å, 150×30 mM, 0.1% TFA in ACN/H2O, gradient 15% to 100% over 15 min. Further purification was pursued by absorbing crude product onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (25M), eluting with a gradient of 5% to 60% EtOAc in hexane, to provide N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. MS (ESI, pos. ion) m/z: 404.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]#[N:12])[N:7]([CH3:13])[C:6](=[O:14])[CH2:5]2.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH3:13][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)=[C:10]([C:11]#[N:12])[CH:9]=2)[CH2:5][C:6]1=[O:14]
Reactant: CN1C(=O)Cc2cc(Br)c(C#N)cc21
Reactant: OB(O)c1cccnc1
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)Cc2cc(-c3cccnc3)c(C#N)cc21
Temperature: 100 °C

Procedure:
To 5-bromo-1-methyl-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile (58 mg, 0.23 mmol) was added 3-pyridine boronic acid (CAS#1692-25-7, 28 mg, 0.23 mmol), 1,2-dimethoxyethane (2.0 mL) and 2 M aqueous sodium carbonate (0.230 mL, 0.46 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, (105 mg, 0.009 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 1.75 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate 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 (ethanol-dichloromethane, 0 to 6%) to afford 1-methyl-2-oxo-5-pyridin-3-yl-2,3-dihydro-1H-indole-6-carbonitrile; HRMS: (ESI) m/z 248.0838 (M−H)−; 1H NMR (400 MHz, CDCl3) δ ppm 3.30 (s, 2H), 3.68 (s, 2H), 7.19 (s, 1H), 7.42 (s, 1H), 7.49-7.58 (m, 1H), 8.02 (d, J=7.6 Hz, 1H), 8.72 (dd, J=4.8, 1.1 Hz, 1H), 8.77 (d, J=1.8 Hz, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:9]=1[O:10][CH3:11])=[O:4].[OH-].[K+]>O.CO>[CH3:11][O:10][C:9]1[CH:8]=[C:7]([C:12]([F:14])([F:15])[F:13])[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(C(F)(F)F)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(F)(F)F)sc1C(=O)O
Yield: 88.4 %

Procedure:
A solution of 2 g (14 mmole) of methyl-3-methoxy-5-trifluoromethyl-2-thiophenecarboxylate, 2 g (28 mmole) of KOH in a mixture of 15 mL water and 50 mL of methanol was refluxed for 2 hr. The reaction mixture was partitioned with ether and dilute aqueous HCl. The organic phase was separated, dried over MgSO4, filtered and concentrated to give 2.8 g (87%) of a colorless solid. mp 131-132° C. 1H NMR (300 MHz, CDCl3): δ 7.2 (s, 1H); 4.1 (s, 3H). Anal. Calc'd for C7H5F3O3S: C, 37.17; H, 2.23; S, 14.18. Found: C, 36.96; H, 2.19; S, 14.08.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].CN(C)C1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)c1ccccc1O
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)Oc1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
60 g (434 mmol) of salicylic acid and 111 ml of N,N-dimethylaniline are dissolved in 360 ml of toluene. The medium is cooled to 0° C. and then 41.5 ml (434 mmol) of ethyl chloroformate are added dropwise. After stirring for 2 hours at ambient temperature, the mixture is washed with a 1N aqueous hydrochloric acid solution and then with a saturated sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is taken up in dichloromethane and precipitated from heptane. The solid is filtered off and then dried. 38 g of 2-(ethoxycarbonyloxy)benzoic acid are obtained in the form of a white solid with a yield of 42%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]#[N:14].COC1C=CC(C[NH2:22])=CC=1>CN(C=O)C>[NH2:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]#[N:14]
Reactant: N#Cc1c(Cl)c2ccccc2[nH]c1=O
Reactant: COc1ccc(CN)cc1
Solvent: CN(C)C=O
Product: N#Cc1c(N)c2ccccc2[nH]c1=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
4-chloro-2-oxo-1,2-dihydroquinoline-3-carbonitrile (example 72) (0.66 g, 3.23 mmol) was suspended in DMF (7 mL), and 4-methoxybenzylamine (0.94 mL, 7.26 mmol) was added. The reaction was heated at 100° C. for 1 hour and the DMF was removed under vacuum. The residue was dissolved in TFA (6 mL) and stirred at room temperature for 30 minutes and dichloromethane (10 mL) was added. The solid product that formed was collected, suspended in water and the solution stirred overnight. The solid was collected by filtration to give 4-amino-2-oxo-1,2-dihydroquinoline-3-carbonitrile (0.150 g, 25%) as a white solid. M.p.: >250° C. 1H NMR (400 MHz, DMSO-d6) δ 7.19 (m, 2H), 7.57 (m, 1H), 7.88 (bs, 2H), 8.12 (d, J=7.6 Hz, 1H), 11.23 (s, 1H). MS 186 (MH+).
Reaction SMILES: Cl.O1CCOCC1.[OH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[CH:21]=1)[CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C>CO>[NH2:12][CH2:11][CH2:10][C@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[CH:21]=1)[OH:8]
Reactant: Cc1cccc(COc2cccc([C@H](O)CCNC(=O)OC(C)(C)C)c2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cccc(COc2cccc([C@H](O)CCN)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl/dioxane (4M, 2 mL) was added at 0° C. to a solution of (R)-tert-butyl (3-hydroxy-3-(3-((6-methylpyridin-2-yl)methoxy)phenyl)propyl)carbamate (200 mg, 0.54 mmol) in MeOH (3 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give after purification by triturating in diethyl ether Example 12 hydrochloride as a white solid. Yield (0.15 g, 52%); 1H NMR (400 MHz, DMSO-d6) δ 7.92 (bs, 1H), 7.74 (bs, 3H), 7.47 (bs, 1H), 7.40 (bs, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.95-6.90 (m, 2H), 5.20 (s, 2H), 4.68-4.65 (m, 1H), 2.84 (bs, 2H), 2.56 (s, 3H), 1.88-1.83 (m, 2H); MS: m/z 273.20 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:14])=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=[O:9])[N:6]=1.[C:15](OC(=O)C)(=[O:17])C>C(O)=O>[CH:15]([NH:1][C:2]1[S:3][C:4]([CH3:14])=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:17]
Reactant: CON=C(C(=O)O)c1nc(N)sc1C
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CON=C(C(=O)O)c1nc(NC=O)sc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-amino-5-methylthiazol-4yl)-2-methoxyiminoacetic acid (syn isomer, 2.6 g.), acetic anhydride (31 ml.) and formic acid (13 ml.) was stirred at room temperature for 2 hrs. and then evaporated in vacuo. The residue was dissolved in a mixture of water and ethyl acetate. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and then filtered. The filtrate was evaporated in vacuo. The oily residue was treated with n-hexane and diisopropyl ether, and the precipitates were collected by filtration to give 2-(2-formamido-5-methylthiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 2.8 g.).