Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]2[CH2:17]C[CH2:15]2)[C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[Li+].[OH-]>C(O)C.O>[Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH:14]([CH3:17])[CH3:15])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC1CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Nc1cc(Cl)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 6-chloro-4-(cyclobutylamino)nicotinate (2) (3 g, 12.3 mmol) in ethanol (20 mL) and water (10 mL) was stirred at rt. LiOH (61.7 mmol, 5 equiv.) was added and the reaction mixture was stirred at room temperature for 4 h. The solvent was concentrated under reduced pressure. Diluted with EtOAc and added water. The aqueous layer was collected and acidified to pH 3-4 using solid citric acid. Solid material precipitated out. Filtered the solid material and dried under vacuum to furnish the title compound (3). 1H NMR: 400 MHz, DMSO-d6: δ1.20 (d, J=6.40 Hz, 6H), 3.80-3.88 (m, 1H), 6.80 (s, 1H), 8.20 (d, J=7.60 Hz, 1H), 8.51 (s, 1H), 13.33 (bs, 1H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:26])=[O:27])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CS(=O)(=O)c2ccccc2)no1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(CS(=O)(=O)c2ccccc2)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl (3R)-6-cyclohexyl-3-{3-[(phenylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 54) (78 mg, 0.16 mmol) was treated with trifluoroacetic acid (2 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene then dichloromethane to afford the title compound as an oil which crystallised on standing (60 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([Cl:16])=[O:6]
Reactant: COc1ccc(OC)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: COc1ccc(OC)c(C(=O)Cl)c1
Yield: 96.3 %

Procedure:
A mixture of 2,5-dimethoxybenzoic acid (25 g, 137.2 mmol) and thionyl chloride (35 mL, 470.6 mmol) was heated at reflux under Ar for 4 h. The reaction solution was evaporated to dryness and the residue was purified by high vacuum distillation at 127° C./2 mm Hg to give compound 45 as a pale yellow oil (26.5 g, 96.7%). When standing at room temperature, this oil changed to yellow crystals, m.p. 36°-38° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]2[C:11]([CH2:21][C:22](O)=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:13]=[C:3]12.[CH3:25][NH2:26]>O1CCCC1>[CH3:25][NH:26][C:22](=[O:23])[CH2:21][C:11]1[N:4]2[C:3]([N:2]([CH3:1])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=32)=[N:13][C:12]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1
Reactant: Cc1ccc(-c2nc3n(C)c4ccccc4n3c2CC(=O)O)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Cc1c(-c2ccc(C)cc2)nc2n(C)c3ccccc3n12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1.9 g (0.006 mol) of 9-methyl-2-(4-methylphenyl)-9H-imidazo[1,2-a]benzimidazole-3-acetic acid is prepared in 50 ml of dry tetrahydrofuran, 1.45 g (0.009 mol) of N,N'-carbonyldiimidazole are added, in small portions, under an inert atmosphere and the mixture is stirred at room temperature for 2 h. The mixture is cooled in an ice-cold water bath, and treated with an excess of dry methylamine. Stirring is maintained for 16 h at room temperature. The solvent is evaporated under reduced pressure, and the residue is taken up in water, separated by filtration, washed with water, dried under vacuum and purified by recrystallization from methanol. 1 g of compound is obtained. Melting point: 251°-252° C.
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.F[B-](F)(F)F.[F:13][S:14]([F:26])([F:25])([F:24])([F:23])[C:15]1[CH:20]=[CH:19][C:18]([N+]#N)=[CH:17][CH:16]=1>>[F:13][S:14]([F:23])([F:24])([F:25])([F:26])[C:15]1[CH:16]=[CH:17][C:18]([N:5]=[N+:6]=[N-:7])=[CH:19][CH:20]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: F[B-](F)(F)F
Product: [N-]=[N+]=Nc1ccc(S(F)(F)(F)(F)F)cc1
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
(Sheppard, J. Am. Chem. Soc. 1962, 84, 3064-3072) Trimethylsilyl azide (6.5 mg, 0.056 mmol) was added to a solution of 1 (10.2 mg, 0.0321 mmol) in [BMIM][BF4] (65.0 mg). After stirring for 5 min, the mixture was extracted with hexane (0.5 mL×3) and the combined extracts was evaporated to give pure 25a as a colorless oil (6.8 mg, 86%): IR (ATR): {tilde over (v)}=2124, 2099, 1586, 1501, 1287, 843 cm−1. MS (GC, EI): m/z=245 [M+], 219 [M+-CN], 200 [M+-CFN], 111. 1H NMR (500 MHz, CDCl3): δ=7.74 (d, J=9.0 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ=150.3 (C), 143.3 (C), 127.7 (2CH), 118.9 (2CH) ppm. 19F NMR (470 MHz, CDCl3): δ=84.4 (quint, J=150 Hz, 1 F), 63.5 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21]([C:25]([OH:27])=[O:26])=[CH:20][CH:19]=[C:18]2[N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO>ClCCl.CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21]([C:25]([O:27][CH3:1])=[O:26])=[CH:20][CH:19]=[C:18]2[N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)c2cc(OCc3ccccc3)ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (2.60 g, 1.79 mL, 20.5 mmol) was added dropwise to a solution of 6-(benzyloxy)-4-(dibenzylamino)-1-naphthoic acid (3.236 g, 6.834 mmol) in dichloromethane (70 mL) and DMF (1 drop). The mixture stirred at RT for 1 h and was concentrated to afford a yellow solid. CH2Cl2 (60 mL) was added followed by the dropwise addition of MeOH(10 mL), and the mixture stirred at RT for 45 min. The mixture was concentrated to afford methyl 6-(benzyloxy)-4-(dibenzylamino)-1-naphthoate as a light brown solid. MS (ESI, pos. ion) m/z: 488.2 (M+H). Mass Calc'd for C33H29NO3: 487.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[C:12](=O)([O-:14])[O-:13].[Na+].[Na+].[C]=O>[Pd](Cl)Cl.C1(P(C(C(P(C2C=CC=CC=2)C2C=CC=CC=2)C)C)C2C=CC=CC=2)C=CC=CC=1.O>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:12]([OH:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: CC(C(C)P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: O
Product: O=C(O)c1ccccc1C(F)(F)F
Temperature: 210 °C
Reaction time: 5 h
Yield: 14.8 %

Procedure:
In an autoclave made of metal were placed 18 g of ortho-chlorobenzotrifluoride, 3.5 mg of palladium chloride, 170 mg of bisdiphenylphosphinobutane and 23 g of sodium carbonate. The air in the autoclave was replaced with carbon monoxide introduced thereinto in several times, after which carbon monoxide was further introduced to adjust its pressure therein to 30 kg/cm2. The reaction was carried out with stirring for 5 hours on a salt bath at a bath temperature of 210° C. After completion of the reaction, the reaction mixture was cooled to room temperature and water was added. The aqueous layer was separated and then acid was added thereto, followed by extraction from the aqueous layer with ether. The ether layer was dried and then concentrated to obtain 2.8 g of ortho-trifluoromethylbenzoic acid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[N:5][C:6]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:7]([Cl:18])[N:8]=2)[N:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:18][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:3]=[C:2]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: Clc1nc(N2CCSCC2)c2nc(Cl)c(NCc3ccccc3)nc2n1
Reactant: C1CNCCN1
Product: Clc1nc2c(N3CCSCC3)nc(N3CCNCC3)nc2nc1NCc1ccccc1

Procedure:
This compound was prepared analogous to Example 1 from 2,6-dichloro-4-thiomorpholino-7-benzylamino-pteridine and piperazine.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([NH:19][C:20]2[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:21]=2[C:22]([OH:24])=O)=[CH:17][CH:16]=1.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:20]2[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:21]=2[C:22]([NH:42][O:41][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:24])=[CH:31][CH:32]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(Nc2cc(F)c(F)cc2C(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2cc(F)c(F)cc2C(=O)NOCc2ccccc2)cc1
Yield: 102 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (3.6 g, 22.4 mmol), 2-(4methoxy-anilino)-4,5-difluorobenzoic acid (Example O, 5.72 g, 20.4 mmol), O-benzylhydroxylamine hydrochloride (3.26 g, 20.4 mmol), and triethylamine (3.1 mL, 22.4 mmol) provided 8.0 g of the crude title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:13]3[O:14][CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:28]>CO>[NH2:28][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([OH:17])[C@H:13]3[O:14][CH3:15])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: CO[C@@H]1[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1n1cc(I)c2c(Cl)ncnc21
Solvent: CO
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c2c(N)ncnc21
Temperature: -55 °C

Procedure:
A solution of compound 5.6 (28.8 mg, 0.057 mmol) in MeOH (3 mL) was transferred to a steel bomb, cooled to −50 to −60° C., and treated with a saturated solution of ammonia in MeOH (10 mL). The reactor was sealed and heated at 118° C. overnight. The reaction vessel was cooled (0-5° C.), opened carefully and the reaction mixture was evaporated to dryness. The crude product was dissolved in MeOH, adsorbed onto silica gel and purified by flash column chromatography on silica gel using pure CH2Cl2 to 4% MeOH in CH2Cl2 as eluents to give the desired compound 5.7 (20.7 mg) as an off white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25][CH2:24]1)=[O:22]
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC3(CCc4ccccc43)CC2)cnc2c(C(=O)O)cnn12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Yield: 98.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.06 g, 0.13 mmol) obtained in step 4 and ethanesulfonamide (0.066 g, 0.62 mmol), the title compound (0.073 g, 100%) was obtained. ESI-MS m/z: 573 (M+H)+; 1H-NMR (CDCl3,δ):1.46 (t, J=7.3 Hz, 3H), 1.46-1.53 (m, 2H), 1.57-1.70 (m, 2H), 1.98 (t, J=7.3 Hz, 2H), 2.43 (s, 3H), 2.92 (t, J=7.1 Hz, 2H), 3.61 (q, J=7.5 Hz, 2H), 3.70-4.06 (m, 4H), 7.09-7.23 (m, 4H), 7.29-7.42 (m, 4H), 8.35 (s, 1H), 8.35 (s, 1H), 8.63 (s, 1H), 10.54 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:11][C:10](=[O:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([CH:14]([CH3:16])[CH3:15])[O:5][C:4]=2[CH:3]=1.[F-].[Cs+].CC(O)(C)C.Cl>C(OC)(C)(C)C>[OH:5][C:4]1[CH:3]=[C:2]([CH3:1])[O:11][C:10](=[O:12])[C:9]=1[C:8](=[O:13])[CH:7]=[CH:6][CH:14]([CH3:15])[CH3:16]
Reactant: Cc1cc2c(c(=O)o1)C(=O)CC(C(C)C)O2
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: CC(C)(C)O
Product: Cc1cc(O)c(C(=O)C=CC(C)C)c(=O)o1
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A mixture of 108 mg of 2,3-dihydro-7-methyl-2-(1-methylethyl)-4H, 5H-pyrano[4,3-b]pyran-4,5-dione, 200 mg of cesium fluoride and 5m1 of 2-methyl-2-propanol was stirred for 2 hours under reflux-heating. After that, methyl t-butyl ether and 3% hydrochloric acid were added to the reaction mixture. The separated organic layer was washed with saturated brine once, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 86 mg of 4-hydroxy-6-methyl-3-(4-methyl-2-pentenoyl)-2-pyrone.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.Cl.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[CH2:35][NH:34][CH2:33][CH2:32]2>>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:34]2[CH2:33][CH2:32][C:31]3[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=3)[CH2:35]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1ccc(C(CCCCCBr)Sc2ccc(C)cc2)cc1OC
Agent: Cl
Product: COc1ccc(C(CCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 59.6 %

Procedure:
The procedure of Example 39 is repeated using 2.12 g of 4-[6-Bromo-1-[(4-methylphenyl)thio]hexyl]-1,2-dimethoxybenzene and 2.3 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 1.6 g of the desired product as a light yellow oil. MS(Hi res): m/z Calcd for C32H41NO4S 535.2756 Found 536.2834(M+H). Calcd for C32H41NO4S: C=70.13, H=7.83, N=3.07, S=5.62 Found C=70.15, H=7.51, N=2.79, S=5.25
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[SH:13].[CH2:14](OC(OCC)OCC)C>S(=O)(=O)(O)O.C(O)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[CH:5][C:4]2[S:13][CH:14]=[N:2][C:3]=2[CH:8]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: CCOC(OCC)OCC
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: FC(F)(F)c1ccc2scnc2c1
Temperature: 180 °C
Yield: 84.2 %

Procedure:
A mixture of 5.1 g (22.2 mmol) of 2-amino-4-(trifluoromethyl) benzenethiol hydrochloride, 5.5 mL (33.3 mmol) of triethylorthoformate, and 2 drops of sulfuric acid was slowly heated to 180° C. over 1 h. The ethanol formed was allowed to escape via a short path distillation still. The reaction mixture was cooled to room temperature and the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate:hexane (1:9) to afford 3.8 g (86%) of 5-(trifluoromethyl)-1,3-benzothiazole as a solid. 1H-NMR (400 MHz, DMSO-d6): δ 9.58 (s, 1H), 8.44–8.42 (m, 2H), 7.80 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH3:16][S:17]([N:20]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)(=[O:19])=[O:18]>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:31]2[CH2:32][CH2:33][C:28]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][N:20]3[S:17]([CH3:16])(=[O:18])=[O:19])[CH2:29][CH2:30]2)=[O:14])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1Cc2ccccc2C12CCNCC2
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC3(CC2)c2ccccc2CN3S(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 2-(methylsulfonyl)-2,3-dihydrospiro[isoindole-1,4′-piperidine] (13.2 mg, 0.050 mmol, 1.1 eq), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C24H25N3O4S: 451.1566, found 451.1567.
Reaction SMILES: [SH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8])=[O:4].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[SH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][S:8][C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:4]
Reactant: CC(C)(S)C(=O)N[C@@H](CS)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(S)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a stirred solution of N-(2-mercapto-2-methylpropionyl)-L-cysteine (11.2 g) in dimethylformamide(50 ml), trityl chloride(16.7 g) was added slowly. The reaction mixture was stirred for 2 hours at room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 14.2 g(60%) of the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(OC(=O)C)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[O:17][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)Nc1ccccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=c1oc(Cc2ccc([N+](=O)[O-])cc2)nc2ccccc12
Yield: 80.8 %

Procedure:
A stirred solution of 2-{[(4-nitrophenyl)acetyl]amino}benzoic acid (7.5 g, 25 mmol) in acetic anhydride (50 mL) was refluxed for 3 hours. The solvent was removed in vacuum and the residue was taken up in diethyl ether, to provide after filtration and drying the title compound (5.7 g, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6]3=[C:7]([C:12]([O:14][C:15](=[O:16])[C:5]3=[CH:4][CH:3]=1)=O)[CH:8]=[CH:9][CH:10]=2.[CH:17]([C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:21]=1[NH2:22])([CH3:19])[CH3:18]>CN1CCCC1=O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[Cl:1][C:2]1[C:11]2[C:6]3=[C:7]([C:12](=[O:14])[N:22]([C:21]4[C:23]([CH:27]([CH3:28])[CH3:29])=[CH:24][CH:25]=[CH:26][C:20]=4[CH:17]([CH3:19])[CH3:18])[C:15](=[O:16])[C:5]3=[CH:4][CH:3]=1)[CH:8]=[CH:9][CH:10]=2
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C1OC(=O)c2ccc(Cl)c3cccc1c23
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CN1CCCC1=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cccc3c(Cl)ccc(c23)C1=O
Temperature: 200 °C

Procedure:
A mixture of 23.3 g of 4-chloronaphthalene-1,8-dicarboxylic anhydride, 19.0 g of 2,6-diisopropylaniline and 9.2 g of anhydrous zinc acetate in 65 ml of N-methylpyrrolidone was heated at 200° C. for 3 hours. After cooling, the precipitate formed was filtered off, washed and dried. This gave 22.4 g of 4-chloro-N-(2,6-diisopropylphenyl)naphthalene-1,8-dicarboximide having a melting point of 289° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([CH:16]([CH3:18])[CH3:17])[C:5]=1[NH2:19])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH:26]1([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.C(OCC)(=O)C>[CH:26]1([CH2:31][C:32]([NH:19][C:5]2[C:6]([CH:16]([CH3:18])[CH3:17])=[CH:7][C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: CC(C)c1cc(N2CCOCC2)cc(C(C)C)c1N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1cc(N2CCOCC2)cc(C(C)C)c1NC(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of 2,6-diisopropyl-4-morpholin-4-yl-phenylamine (279 mg) and pyridine (245 μL) in tetrahydrofuran (2 mL) was added cyclopentylacetyl chloride (210 μL) and the mixture was stirred for 1 hour at 25° C. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with 10% aqueous sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography. Recrystallisation of the crude brown material from hot ethyl acetate/heptane furnished 122 mg (33%) of the title compound as a white solid. LC-MS (m/z) 373 (MH+); tR=2.58, (UV, ELSD) 98%, 99%. 1H NMR (500 MHz, CDCl3): 1.19 (d, 12H), 1.27 (m, 2H), 1.60 (m, 2H), 1.68 (m, 2H), 1.93 (m, 2H), 2.40 (m, 1H), 2.41 (m, 2H), 3.05 (m, 2H), 3.17 (m, 4H), 3.87 (m, 4H), 6.49 (s, 1H), 6.70 (s, 2H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:78]1[C:86]2[CH:85]=[CH:84][N:83]=[CH:82][C:81]=2[C:80](=[O:87])[NH:79]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:79]4[CH2:78][C:86]5[CH:85]=[CH:84][N:83]=[CH:82][C:81]=5[C:80]4=[O:87])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1NCc2ccncc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4Cc5ccncc5C4=O)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (28 mg, 0.053 mmol) in anhydrous THF (1.2 mL, degassed) was added Pd2(dba)3 (3 mg, 0.05 eq.), XantPhos (5 mg, 0.15 eq.), 1H-pyrrolo[3,4-c]pyridin-3(2H)-one (14 mg, 2 eq.) and Cs2CO3 (35 mg, 2 eq.). The reaction mixture was heated at 100° C. for 2 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C34H32ClN4O4S: 627.2 (M+H+); Found: 627.3 (M+H+).