Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:8])=[C:5]([O:20][CH3:21])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].BrCCCC[C:33]1[CH:43]=[CH:42][CH:41]=[C:35]2[C:36]([NH:38][C:39](=[O:40])[C:34]=12)=[O:37].[C:44]1(C)[CH:49]=CC=[CH:46][CH:45]=1>CN(C)C=O>[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:49][CH2:44][CH2:45][CH2:46][N:38]3[C:39](=[O:40])[C:34]4[C:35](=[CH:41][CH:42]=[CH:43][CH:33]=4)[C:36]3=[O:37])[CH2:15][CH2:16]2)=[O:8])=[C:5]([O:20][CH3:21])[CH:4]=1
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Reactant: Cc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide hydrochloride (15.0 g) was dissolved in dimethylformamide (100 ml) and toluene (150 ml). Potassium carbonate (18.6 g) and 4-bromobutylphthalimide (12.7 g) were added, and the mixture was stirred at 70 ° C. for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 13.6 g of 4-amino-5-chloro-N-(1-(4-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)butyl)-piperidin-4-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]2[C:10]([C:11]=1[C:12](Cl)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:17][C@H:18]([C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1)[CH3:19]>>[OH:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]2[C:10]([C:11]=1[C:12]([NH:17][C@H:18]([C:20]1[CH:21]=[C:22]([N:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:30][CH2:31]3)[CH:23]=[CH:24][CH:25]=1)[CH3:19])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cn1c(=O)c(O)c(C(=O)Cl)c2ccccc21
Reactant: C[C@H](N)c1cccc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Product: C[C@H](NC(=O)c1c(O)c(=O)n(C)c2ccccc12)c1cccc(N2CCN(C(=O)OCc3ccccc3)CC2)c1

Procedure:
Following the same procedure as described for Example 3, Example 205 was prepared as an off-white powder by using 3-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-4-carbonyl chloride and (S)-benzyl 4-(3-(1-aminoethyl)phenyl)piperazine-1-carboxylate (Intermediate 34). LC-MS (ESI) m/z 541 (M+H), RT=2.00 min (Method B). Orthogonal HPLC (150×4.6 mm 3.5 μm, 254 nm): Sunfire {RT=8.9 min, 93%}; Xbridge {RT=8.5 min, 92%}.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cccc(CN)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COc1cccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (200 mg, 0.57 mmol) and 3-methoxy benzylamine (104 mg, 0.68 mmol). The title compound was obtained as a yellow solid (35 mg, 14% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.37 (1H, m), 8.98 (2H, m), 8.47 (1H, s), 7.23 (1H, m), 6.83 (3H, m) 4.37 (2H, m), 3.72 (3H, s). MS m/z: 468.26, 470.28 [M+H]+.
Reaction SMILES: C([C:6]1[C:7](=O)[NH:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:11][CH:10]=2)(=O)CCC.NC1C(C)=CC=CC=1>O1CCOCC1>[C:19]([O:18][CH2:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:15]2)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCC(=O)c1c(Cl)c2cc(COC(=O)c3ccccc3)ccc2[nH]c1=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1N
Product: O=C(OCc1ccc2ncccc2c1)c1ccccc1
Yield: 108.9 %

Procedure:
3-butyryl-4-chloro-6-benzoyloxymethylquinolone (10 g, 30 mmol) and o-toluidine (3.7 ml, 35 mmol) were heated together under reflux in 1,4-dioxan (150 ml) for 1.5 hours. The solvent was evaporated and the residue dissolved in chloroform, washed with 2 M HCl, sodium hydrogen carbonate solution (x2) and brine, dried, filtered and evaporated to an oil which immediately crystallized to give 3-butyryl-4-2-methylphenylamino)-6-benzoyloxymethyl quinoline (8.6 g, 66%), m.p. 142° C.-4° C.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]([CH:8]([CH2:37][CH2:38][C:39]([OH:42])([CH3:41])[CH3:40])[CH2:9][CH:10]([O:33][C:34](=[O:36])[CH3:35])[CH:11]([NH:20][C:21]([C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)=O.C([O-])(=O)C.[NH4+:49].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[F:19][C:15]1[CH:14]=[C:13]([CH2:12][CH:11]([CH:10]([O:33][C:34](=[O:36])[CH3:35])[CH2:9][CH:8]([C:6]2[NH:5][CH:4]=[CH:3][N:49]=2)[CH2:37][CH2:38][C:39]([OH:42])([CH3:40])[CH3:41])[NH:20][C:21]([C:23]2[CH:32]=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH:18]=[CH:17][CH:16]=1
Reactant: [NH4+]
Reactant: COC(CNC(=O)C(CCC(C)(C)O)CC(OC(C)=O)C(Cc1cccc(F)c1)NC(=O)c1cnc2ccccc2n1)OC
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC(CC(CCC(C)(C)O)c1ncc[nH]1)C(Cc1cccc(F)c1)NC(=O)c1cnc2ccccc2n1
Temperature: 115 °C
Yield: 16.8 %

Procedure:
To a solution of acetic acid 3-(2,2-dimethoxy-ethylcarbamoyl)-1-{2-(3-fluoro-phenyl)-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-6-hydroxy-6-methyl-heptyl ester (150 mg, 0.245 mmol) in acetic acid (2 mL) was added ammonium acetate (1.5 g 19.5 mmol). The resulting mixture was heated to 115° C. for 3 hours, cooled to ambient temperature and diluted with ethyl acetate. The solution was then neutralized with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated. Chromatography on silica gel gave the title compound (22.5 mg, 17%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:38][CH3:39])=[C:6]([CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18][N:19]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[C:23]=2[Cl:32])=[O:21])[CH:7]=1.[N:40]1[CH:45]=[CH:44][CH:43]=[C:42](B(O)O)[CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:32][C:23]1[C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[C:20]([N:19]([CH2:18][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[CH2:8][C:6]1[CH:7]=[C:2]([C:42]2[CH:41]=[N:40][CH:45]=[CH:44][CH:43]=2)[CH:3]=[CH:4][C:5]=1[O:38][CH3:39])[CH2:33][CH2:34][CH:35]([CH3:36])[CH3:37])=[O:21]
Reactant: OB(O)c1cccnc1
Reactant: COc1ccc(Br)cc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OC)c2Cl)nc2ccccn12
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: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(-c2cccnc2)cc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OC)c2Cl)nc2ccccn12
Temperature: 85 °C
Yield: 89.7 %

Procedure:
A solution of 61 mg (0.1 mmol) N-({3-[(5-bromo-2-methoxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide in 2 mL toluene is treated with 4 mg (0.003 mmol) tetrakis(triphenylphosphine)palladium(0), 15 mg (0.12 mmol) pyridine-3-boronic acid and 0.2 mL 2M potassium carbonate. The solution is heated to 85° C. for 18 hr and cooled to room temperature. The solution is diluted with 10 mL dichloromethane, washed with 10 mL brine, dried over anhydrous MgSO4 and the solvent removed in vacuo to give the crude residue. The residue is prep-plate chromatographed (9% MeOH/CH2Cl2/0.5% NH4OH) to afford 55 mg (89%) (2-chloro-3,4-dimethoxyphenyl)-N-({3-[(2-methoxy-5-(3-pyridyl)phenyl)methyl](imidazol[1,2-a]pyridin-2-yl)}methyl)-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 613.
Reaction SMILES: F[C:2]1[CH:10]=[C:9](F)[CH:8]=[CH:7]C=1C([Cl:6])=O.FC1C=CC(F)=CC=1OC.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30]([C:32]1[CH:37]=[C:36]([F:38])[C:35]([O:39][CH3:40])=[CH:34][C:33]=1[F:41])=[O:31].Br.BrCCCCCCBr.[CH2:51]([NH:54][CH3:55])[CH:52]=[CH2:53]>>[ClH:6].[CH2:51]([N:54]([CH3:55])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:2][CH2:40][O:39][C:35]1[C:36]([F:38])=[CH:37][C:32]([C:30]([C:24]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=2[F:22])=[O:31])=[C:33]([F:41])[CH:34]=1)[CH:52]=[CH2:53]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: COc1cc(F)c(C(=O)c2ccc(F)cc2F)cc1F
Reactant: C=CCNC
Agent: Br
Agent: BrCCCCCCBr
Agent: COc1cc(F)ccc1F
Product: C=CCN(C)CCCCCCOc1cc(F)c(C(=O)c2ccc(F)cc2F)cc1F
Product: Cl

Procedure:
from 2,4-difluorobenzoyl chloride and 2,5-difluoroanisole via (2,4-difluoro-phenyl)-(2,5-difluoro-4-methoxy-phenyl)-methanone, which is deprotected with hydrogen bromide and reacted with 1,6-dibromohexane and N-allyl-methyl-amine, there is obtained [4-[6-(allyl-methyl-amino)-hexyloxy]-2,5-difluoro-phenyl]-(2,4-difluoro-phenyl)-methanone-hydrochloride (1:1), MS: m/e 423 (M),
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:24]1([C:36](O)=[O:37])[C:25]([C:33](O)=[O:34])=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[N:1]1[C:33](=[O:34])[C:25]2[C:24](=[CH:29][CH:28]=[C:27]([C:30]([OH:32])=[O:31])[CH:26]=2)[C:36]1=[O:37]
Reactant: Nc1cc(-c2nc3cc(-c4ccccc4)ccc3o2)ccc1Cl
Reactant: O=C(O)c1ccc(C(=O)O)c(C(=O)O)c1
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cc(-c3nc4cc(-c5ccccc5)ccc4o3)ccc1Cl)C2=O

Procedure:
Prepared by the method of Example 15e), from 2-(3-amino-4-chlorophenyl)-5-phenylbenzoxazole (43 mg, 0.13 mmol) and 1,2,4-benzenetricarboxylic acid (26 mg, 0.13 mmol) the title compound was obtained (10 mg, 15%). 1H NMR (DMSO) δ 8.58(d, 1H), 8.48(dd, 1H), 8.38(m, 2H), 8.17(d, 1H), 8.08(d, 1H), 7.99(d, 1H), 7.88(d, 1H), 7.76(m, 3H), 7.50(m, 2H), 7.39(t, 1H). MS 492.8 m/z (M−H)−.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([O:13]CC)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:16][C@H:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22].Cl>>[NH2:1][C@H:2]([C:11]([NH:16][C@H:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@@H](N)CCCCN
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Product: CCOC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
Mal-Tyr-Lys-OEt was prepared with CT as the catalyst in a 100 ml beaker with Mal-Tyr-OEt employed as the electrophile and Lys-OEt.2 HCl employed as the nucleophile. After a short time, the product separated out as a white precipitate and was filtered off, washed with water and dried in a vacuum at 50° C. The conditions and results employed are compiled in the following table:
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=1[S:20](=[O:23])(=[O:22])[NH2:21])=O)C.Cl>[OH-].[Na+]>[CH3:19][S:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]2[NH:8][C:6]([CH2:5][C:4]([OH:3])=[O:24])=[N:21][S:20](=[O:23])(=[O:22])[C:10]=2[CH:11]=1)(=[O:18])=[O:17]
Reactant: CCOC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
N-(4-Methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid ethyl ester (prepared as described in Example 1e, 9.55 g, 26.16 mmol) was dissolved in 8% aqueous sodium hydroxide solution (262 mL) and heated at 100° C. for 1.5 h. The reaction mixture was cooled to 0° C. and the solution was acidified by slowly adding 12.0 M aqueous hydrochloric acid solution until pH 1-2 was reached. A precipitate started to form and the suspension was allowed to stir for 30 min at 0° C. The precipitate was collected by vacuum filtration, washed with cold water, and dried under high vacuum to afford the desired product, (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (7.20 g, 21.621 mmol, 82.6%), as a pinkish solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.03 (3H, s), 3.56 (2H, s), 7.33 (1H, d, J=9.1 Hz), 7.52-7.54 (2H, m), 10.09 (1H, s), 12.24 (1H, s), 13.02 (1H, bs). LC-MS (ESI) calcd for C10H11N3O6S2 333.01, found 334.1 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=1)(=[O:13])=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1>ClCCl>[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)(=[O:12])=[O:13]
Reactant: O=Cc1ccc(O)cc1
Reactant: CS(=O)(=O)c1ccc(CCO)cc1
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CCOc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
1.83 g (15 mmole) 4-hydroxybenzaldehyde was dissolved in 35 ml dichloromethane under argon atmosphere. 1.5 g (7.5 mmole) 2-[4-(methylsulfonyl)phenyl]-1-ethanol was added followed by 3.93 g (15 mmole) triphenylphosphine and 3.78 g (15 mmole) 1,1-(azodicarbonyl)dipiperidine. The reaction mixture was stirred at room temperature and after 2 hours a precipitate is observed. The reaction was disrupted after 5 hours and the reaction mixture was filtered. The filtrate was purified by chromatography on silica gel using dichloromethane:methanol (98:2) as eluent giving 1.66 g (yield 54.5%) of 4-[2-(4-formylphenoxy)ethyl]phenyl methyl sulfone.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.CS(C)=[O:16]>>[F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH:9]=[O:16])[N:7]=1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Reactant: CS(C)=O
Product: O=CC(=O)c1csc(C(F)(F)F)n1
Temperature: 25 °C

Procedure:
3 g (0.011 mol) of 2-Trifluoromethyl-4-bromoacetylthiazole are dissolved in 30 ml of dimethyl sulphoxide and the solution is maintained at room temperature for 70 hours. It is then poured onto 100 g of ice, and the mixture is extracted several times with ether, the organic phase is dried over sodium sulphate and concentrated, and the residue is purified on a silica gel column using toluene/ethyl acetate=7/3 as eluant.
Reaction SMILES: [C:1]([Cl:4])(=O)C.[NH2:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[ClH:4].[CH3:1][O:15][C:14](=[O:16])[C@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:5]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccccc1
Product: Cl
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Anhydrous methanol (50 mL) is taken in a 100 mL 2-necked round bottom flask fitted with a reflux condenser and an additional dropping funnel and cooled to ice temperature. Acetyl chloride (3 mL) is added drop wise through the dropping funnel. After 15 min, L-phenylalanine (3 g, 18.16 mmol) is added and the reaction mixture is refluxed at 70° C. for overnight. The reaction mixture is vacuo dried to obtain L-phenylalanine methylester hydrochloride in quantitative yield and used for further reaction without purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:32][O:33][C:34]([CH:36]1[CH:41](OS(C(F)(F)F)(=O)=O)[CH2:40][CH2:39][N:38]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:37]1)=[O:35].C([O-])(=O)C.[K+]>C(Cl)Cl.O>[CH3:32][O:33][C:34]([C:36]1[CH2:37][N:38]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:39][CH2:40][C:41]=1[C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:18]=3)=[O:35]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1OCC2
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1=C(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CCN(C(=O)OC(C)(C)C)C1
Temperature: 120 °C
Yield: 91.2 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (0.20 g, 0.49 mmol), 4-trifluoromethanesulphonyloxy-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.29 g, 0.75 mmol), potassium acetate (0.12 g, 1.22 mmol), Pd(dppf)2C12.DCM (0.04 g, 0.05 mmol), DME:IMS:water 7:2:1 (5 mL), were sealed in a microwave vial and heated by microwave irradiation at 120° C. for 10 min. The reaction mixture was cooled to RT, water and DCM were added, the organic layer separated, washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 5% methanol in DCM) to give 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (239 mg, 91%). 1H NMR 300 MHz (CDCl3) δ: 8.49 (1H, d, J=8.30 Hz), 7.87 (1H, d, J=0.64 Hz), 7.64 (1H, s), 6.92 (1H, dd, J=8.31, 1.80 Hz), 6.84 (1H, d, J=1.77 Hz), 6.00 (1H, m), 4.49-4.47 (4H, m), 4.27 (2H, s), 3.62 (2H, t, J=5.69 Hz), 3.57 (2H, s), 2.50 (3H, s), 1.59 (6H, d, J=6.63 Hz), 1.51 (9H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]3=2)[C:3](=O)[C:2]1=[O:15].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)COC(=O)C)=[CH:20][CH:19]=1)#[N:17].[C:32]([OH:35])(=[O:34])C>C(O)C.[OH-].[Na+]>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:2]([OH:15])=[C:3]([C:32]([OH:35])=[O:34])[C:4]3[C:9](=[C:8]4[CH2:10][CH2:11][CH2:12][CH2:13][C:7]4=[CH:6][CH:5]=3)[N:1]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: CC(=O)O
Reactant: O=C1Nc2c(ccc3c2CCCC3)C1=O
Reactant: CC(=O)OCC(=O)Cc1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(Cc2nc3c4c(ccc3c(C(=O)O)c2O)CCCC4)cc1
Temperature: 25 °C
Yield: 20 %

Procedure:
In a 25 mL round-bottomed flask, 6,7,8,9-tetrahydrobenzo[g]indoline-2,3-dione (0.119 g, 0.590 mmol) was taken up in 1 mL ethanol and 3 mL 10 M NaOH, and the mixture heated at reflux temperature for 3 minutes. A solution of acetic acid 3-(4-cyano-phenyl)-2-oxo-propyl ester (0.167 g, 0.767 mmol) in 3 mL ethanol was then added and the reaction further heated for 10 minutes. The reaction mixture was then cooled to room temperature and acidified with glacial acetic acid, and the yellow precipitate collected by filtration. The procedure described above for the purification of example 7 was followed. Product was obtained as a bright yellow powder (42 mg, 20% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 1.74-1.87 (m, 4H) 2.83 (t, J=5.31 Hz, 2H) 3.12 (t, J=5.43 Hz, 2H), 4.40 (s, 2H), 7.28 (d, J=9.09 Hz, 1H) 7.51 (d, J=8.59 Hz, 2H) 7.75 (d, J=8.34 Hz, 2H) 8.23 (d, J=8.84 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1([CH2:6][CH2:7][C:8]([NH2:10])=[O:9])[CH2:5][CH2:4]1.C(Cl)(=O)[C:14](Cl)=[O:15].[CH3:19][N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=3)[CH:28]=[CH:27][N:26]=2)[CH:22]=[N:21]1.N1C=CC=CC=1>ClCCCl.C1COCC1>[CH3:19][N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([NH:38][C:14]([NH:10][C:8](=[O:9])[CH2:7][CH2:6][C:3]4([C:2]([F:11])([F:12])[F:1])[CH2:5][CH2:4]4)=[O:15])=[N:36][CH:37]=3)[CH:28]=[CH:27][N:26]=2)[CH:22]=[N:21]1
Reactant: NC(=O)CCC1(C(F)(F)F)CC1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)CCC4(C(F)(F)F)CC4)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
A suspension of Example B2 (0.081 g, 0.449 mmol) in DCE (6 mL) was treated with oxalyl chloride (0.039 mL, 0.449 mmol), stirred at RT for 0.5 h, then heated to 83° C. for 3 h. The mixture was cooled to RT, added drop-wise to a solution of Example A2 (0.10 g, 0.374 mmol) and pyridine (0.151 mL, 1.871 mmol) in THF (6 mL) and stirred at RT for 1 h. The mixture was treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN, sonicated for 5 min and the resulting solid collected via filtration and dried to afford N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide (98 mg, 55%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1H), 10.89 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27-8.25 (m, 2H), 8.08 (d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.73 (dd, J=9.0, 2.9 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.70 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.57 (t, J=8.0 Hz, 2H), 1.87 (t, J=8.0 Hz, 2H), 0.91 (m, 2H), 0.78 (m, 2H); MS (ESI) m/z: 475.1 (M+H+).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16](O)=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2].S(Cl)(Cl)=O.[CH2:34]([NH:36]CC)[CH3:35]>ClCCl>[CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16]([NH:36][CH2:34][CH3:35])=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCNCC
Reactant: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc2cc(C(=O)O)c(=O)oc12
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCNC(=O)c1cc2cc(/C=C/C(=O)c3ccc(C)cc3)cc(C(C)CC)c2oc1=O
Reaction time: 0.75 h

Procedure:
To a suspension of (E)-8-sec-butyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxylic acid of the formula (V) (0.5 g, 1.28 mmol) in dichloromethane (20 mL). added thionyl chloride (1.0 mL), was refluxed for 1.5 h. The resulting solution was evaporated to dryness under reduced pressure, and the residue was dispersed in dichloromethane (10 mL). The solvent was eliminated under reduced pressure. Dispersion in dichloromethane and solvent elimination was repeated twice. The residue was dissolved in dichloromethane (15 mL) and added with stirring to a solution of the diethyl amine (0.09 g, 1.28 mmol). After 45 min at room temperature, the solvent was removed by evaporation under reduced pressure and extracted 3-fold with CHCl3 (25 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane, which upon concentration provides (E)-8-sec-butyl-N,N-diethyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxamide (General Formula VI). (0.37 g, 65% yield). White solid, m. p. 146-147° C.; 1H NMR (CDCl3 300 MHz): δ 7.95, (d, J=8.1 Hz, 2H) 7.82-7.76 (m, 2H), 7.70 (d, J=1.8 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.51 (d, J=15.7 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 3.58 (q, J=7.0 Hz, 2H), 3.45-3.41 (m, 1H), 3.33 (q, J=7.1 Hz, 2H), 2.45 (brs, 3H), 1.79-1.72 (m, 2H) 1.34-1.25 (m, 6H), 1.20 (t, J=7.1 Hz, 3H) 0.89 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ 189.7, 164.3, 157.8, 152.7, 144.0, 142.6, 141.4, 136.7, 135.5, 131.7, 129.8, 129.5, 128.8, 126.7, 126.0, 122.9, 118.7, 43.4, 39.6, 33.5, 29.8, 21.8, 20.6, 14.3, 12.9, 12.1; ESI-MS (m/z): 446 (M+H)+.