Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1.Cl[C:14]1[CH:23]=[CH:22][C:21]2[CH:20]([O:24][CH3:25])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(OCC)(=O)C.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].O1CCCC1>[CH3:25][O:24][CH:20]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([CH:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=4)[NH:3][C:2]3=[O:1])[CH:23]=[CH:22][C:21]1=2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: COC1CCCc2nc(Cl)ccc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC1CCCc2nc(C3C(=O)Nc4ccc(C#N)cc43)ccc21
Temperature: 100 °C
Yield: 22 %

Procedure:
The title compound was prepared as described for Example 1.2 using 2-oxoindoline-5-carbonitrile (60 mg, 0.379 mmol), 2-chloro-5-methoxy-5,6,7,8-tetrahydroquinoline (90 mg, 0.455 mmol), K2CO3 (105 mg, 0.76 mmol), X-PHOS (14.47 mg, 0.030 mmol), Pd2(dba)3 (6.95 mg, 7.59 μmol), and tetrahydrofuran (1.9 mL). The reaction mixture was heated in a microwave oven at 100° C. for 120 min. After cooling to RT the mixture was diluted with ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (silica gel, dichloromethane/methanol). The product containing fractions were combined, evaporated to dryness, and the resulting solid was triturated with diethylether. Amount 27 mg. Yield 22%.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(CC)CC)C.[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18](Cl)=[O:19])=[CH:14][N:13]=1>ClCCl>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([NH:3][CH2:1][CH3:2])=[O:19])=[CH:14][N:13]=1
Reactant: CCN
Reactant: O=C(Cl)c1cnc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cnc(Cl)nc1
Temperature: -15 °C
Reaction time: 1 h
Yield: 72613.2 %

Procedure:
A solution of ethylamine (4.26 g, 0.0946 mol) and triethylamine (28.7 g, 0.284 mol) in dichloromethane (75 mL), pre-cooled to −15 to −10° C., was added dropwise to a solution of 2-chloropyrimidine-5-carbonyl chloride (16.64 g, 0.0946 mmol) in dry dichloromethane (250 mL) at −15° C., then the reaction mixture was stirred at −15° C. for 1 hour. The reaction was quenched by the addition of a solution of concentrated hydrochloric acid (32.3 mL) in water (300 mL). The resulting mixture was stirred at room temperature for 1 hour. The layers were separated, and the aqueous phase was further extracted with dichloromethane (3×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via column chromatography to provide 2-chloro-N-ethylpyrimidine-5-carboxamide (12.75 g, 72%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][NH:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CN(C(=O)OC(C)(C)C)CC12CCCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CNCC12CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
To a solution of tert-butyl 4-((5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (0.35 g, 0.82 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (2.83 M, 5 mL) and the reaction mixture was stirred at rt for 16 h then added water (10 mL). The resulting mixture was adjusted to pH=8 with a saturated Na2CO3 aqueous solution, then extracted with DCM (20 mL×3). The combined organic layers were washed with brine dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as a yellow solid (0.13 g, 48.5%).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][N:19]4S(C3C=CC=CC=3)(=O)=O)=[N:12][N:11]=2)[CH2:3]1.[OH-].[Na+]>O1CCOCC1>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][NH:19]4)=[N:12][N:11]=2)[CH2:5]1
Reactant: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
To a solution of N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (106 mg, 0.162 mmol) in 1,4-dioxane (1 ml) was added 2M sodium hydroxide (1 ml, 2.000 mmol) and the mixture stirred at 20° C. for 18 h. The mixture was evaporated in vacuo and the residue partitioned between ethyl acetate (10 ml) and saturated ammonium chloride (5 ml), separated by hydrophilic frit and purified by silica (5 g) cartridge using a gradient of dichloromethane and methanol to give a pale brown solid 50 mg which was purified by MDAP to give the title compound as a white solid (32 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:21]3[C:13](=[N:14][C:15]4[N:16]=[CH:17][N:18]=[CH:19][C:20]=43)[NH:12][C:11]([CH3:22])=[C:10]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5][CH:4]=1)#[N:2].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:21]3[C:13](=[N:14][C:15]4[N:16]=[CH:17][N:18]=[CH:19][C:20]=43)[N:12]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:35]=3)[C:11]([CH3:22])=[C:10]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)Nc2nc3ncncc3n2C1c1ccc(C#N)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc3ncncc3n2C1c1ccc(C#N)cc1
Reaction time: 12 h

Procedure:
(rac)-Ethyl 6-(4-cyanophenyl)-8-methyl-6,9-dihydropyrimido[2,1-f]purine-7-carboxylate (30 mg, 0.08 mmol), 3-(trifluoromethyl)phenylboronic acid (31 mg, 0.17 mmol, 2 eq.), anhydrous copper(II) acetate (30 mg, 0.17 mmol, 2 eq.) and molecular sieve (100 mg, 4 Å) were initially charged. Under an atmosphere of argon, abs. dichloromethane (5 ml), pyridine (27 μl, 0.33 mmol, 4 eq.) and triethylamine (23 μl, 0.17 mmol, 2 eq.) were added. After 12 h of stirring, the mixture was filtered over kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (5.6 mg, 13% of theory).
Reaction SMILES: Br[C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C@@H:18]([C:25]#[C:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)=[CH:9][N:4]2[N:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C@@H:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([C:37]4[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=4)[N:28]=3)[CH:9]=2)=[CH:13][CH:14]=1)[C:25]#[C:26][CH3:27])[CH3:24]
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(Br)nn3c2)cc1
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: C1COCCO1
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(C#N)cc4)nn3c2)cc1
Temperature: 100 °C
Yield: 73.2 %

Procedure:
To a stirred solution of ethyl (3S)-3-[4-[(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methoxy]phenyl]hex-4-ynoate (0.25 g, 0.57 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (0.14 g, 0.5 mmol) in dioxane (115 mL) is added K2CO3 (0.15 g, 1.134 mmol). The mixture is purged with argon for 30 minutes, Pd(PPh3)4 (0.032 g, 0.027 mmol) is added and the mixture is heated at 100° C. for 5 hours. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth. The filtrate is evaporated under reduced pressure and concentrated to dryness. The crude material is purified by silica gel chromatography (combiflash) eluting with 30% EtOAc/hexane to give the title compound as a brown liquid (0.170 g, 68.75%). LCMS m/z 464 (M+H).
Reaction SMILES: [C:1]([N:4]([C:17]1[N:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=1)[C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[N:13][OH:14])=[CH:8][C:7]=1[CH3:15])(=[O:3])[CH3:2].ClN1C(=O)CCC1=O.[Cl:32][C:33]1[CH:34]=[C:35]([C:41]([C:43]([F:46])([F:45])[F:44])=[CH2:42])[CH:36]=[C:37]([Cl:40])[C:38]=1[Cl:39].C(=O)([O-])O.[K+]>COCCOC.O>[C:1]([N:4]([C:17]1[N:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=1)[C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:42][C:41]([C:35]3[CH:36]=[C:37]([Cl:40])[C:38]([Cl:39])=[C:33]([Cl:32])[CH:34]=3)([C:43]([F:46])([F:45])[F:44])[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(=O)c1ccc(C=NO)cc1C)c1ncc(Cl)cn1
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C)c1ncc(Cl)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
In a solution of 30 mg of N-acetyl-N-(5-chloro-2-pyrimidinyl)-4-hydroxyiminomethyl-2-methyl benzoic acid amide in 5 mL of 1,2-dimethoxyethane, 16 mg of N-chlorosuccinic acid imide was added and stirred at 40° C. for 30 minutes. Then the reaction mixture was left and cooled to room temperature, and 24 mg of 3,4,5-trichloro-1-(1-trifluoromethylethenyl)benzene, 10 mg of potassium hydrogen carbonate and 1 drop of water were added, and continued to stir at room temperature for 1.5 hour. After the completion of the reaction, the reaction mixture was poured in 10 mL of water, and extracted with ethyl acetate (10 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 1:3 to 1:1) to obtain 11 mg of the aimed product as colorless resinous substance.
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[CH3:22][O:23][C:24]1[CH:25]=C([CH:29]=[CH:30][CH:31]=1)CN>>[CH3:22][O:23][C:24]1[CH:25]=[C:2]([CH:29]=[CH:30][CH:31]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6]
Reactant: COc1cccc(CN)c1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Product: COc1cccc(CNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)c1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using 3-methoxybenzylamine instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 379 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.48 (1H, br. s.) 10.24 (1H, br. s.) 8.17 (1H, br. s.) 8.02 (1H, d, J=5.47 Hz) 7.79 (1H, d, J=5.27 Hz) 7.44-7.54 (1H, m) 7.31 (1H, d, J=2.73 Hz) 6.82 (1H, br. s.) 6.41 (1H, br. s.) 3.93 (1H, br. s.) 3.39 (1H, br. s.) 3.23 (2H, br.s.) 1.67-1.88 (4H, m) 1.39 (9H, s)
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=2)[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5]1)([CH3:3])[CH3:2].Br[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[CH3:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([C:6]2[C:7]3[C:12](=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[C:29]([CH3:36])[CH:30]=1)#[N:33]
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)c2ccc(NS(C)(=O)=O)cc21
Reactant: Cc1cc(C#N)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(C#N)ccc1-c1cn(C(C)C)c2cc(NS(C)(=O)=O)ccc12

Procedure:
Method Q Add N-[1-isopropyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indol-6-yl]-methanesulfonamide (50.0 mg, 0.132 mmoles), 4-bromo-3-methyl-benzonitrile (51.8 mg, 0.264 mmoles), Pd(OAc)2 (4.25 mg, 0.018 mmoles; 4.25 mg), 2-(diphenylphosphino)-2′-(N,N-dimethylamino)biphenyl (11.5 mg, 0.030 mmoles), potassium phosphate (84.2 mg, 0.396 mmoles), and 1,4-dioxane (1.00 mL) to a 10 mL microwave vessel, equipped with a stir bar. Purge the reaction mixture with nitrogen, and then seal the vessel with a cap. Place the vessel in a microwave reactor at 150° C. for 15 min at 250 W heating. Monitor the reaction using LC/MS. Cool the reaction to ambient temperature and quench with saturated aqueous ammonium chloride. Extract the resulting mixture into ethyl acetate. Wash the combined extracts with saturated aqueous ammonium chloride, water and brine. Dry the resulting solution over sodium sulfate (granular) and concentrate in vacuo. Dissolve the resulting solid in dichloromethane and purify on a chromatotron (1MM silica gel plate) 0-2% ethyl acetate gradient in dichloromethane. A second purification may be necessary. This time purify the material with 30-40% ethyl acetate gradient in hexane to provide N-[3-(4-Cyano-2-methyl-phenyl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide, 35 mg (75%) as an off white solid. 1H NMR (CDCl3) δ 7.58 (s, 1H), 7.45-7.52 (m, 3), 7.41 (d, 1H, J=8.4 Hz), 7.25 (s, 1H), 6.9 (dd, 1H, J=8.4, 1.7 Hz), 6.52 (s, 1H), 4.65 (septet, 1H, J=6.7 Hz), 2.98 (s, 3H), 2.34 (s, 3H), 1.55 (d, 6H, J=6.7 Hz); MS (IS−) m/e 377 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH2:30]1[C@@H:35]2[CH2:36][CH2:37][CH2:38][N:34]2[CH2:33][C@@H:32]([CH2:39]O)[O:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:39][C@H:32]5[O:31][CH2:30][C@@H:35]6[CH2:36][CH2:37][CH2:38][N:34]6[CH2:33]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OC[C@@H]1CN2CCC[C@H]2CO1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CN2CCC[C@H]2CO1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and [(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl]methanol (prepared as described in WO 2004/006846) following General Procedure J.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([C@H:17]3[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=O)[OH:25])[CH2:19][CH2:18]3)[CH2:7][C:6]2=1.[O:27]=[C:28]1[CH2:33][S:32][C:31]2[CH:34]=[CH:35][C:36](C(O)=O)=[N:37][C:30]=2[NH:29]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([C@H:17]3[CH2:22][CH2:21][C@H:20]([NH:23][C:24]([C:36]4[CH:35]=[CH:34][C:31]5[S:32][CH2:33][C:28](=[O:27])[NH:29][C:30]=5[N:37]=4)=[O:25])[CH2:19][CH2:18]3)[CH2:7][C:6]2=1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Reactant: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)O)CC1)CO3
Product: COc1ccc2ncc3c(c2c1)CC([C@H]1CC[C@H](NC(=O)c2ccc4c(n2)NC(=O)CS4)CC1)CO3

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 6 and in analogy to Example 1 using [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid text-butyl ester and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH2:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[C:24](Cl)(=[O:27])[CH2:25][CH3:26].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1NC(=O)CC
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.6 %

Procedure:
1-Amino-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (50 mg, 0.16 mmol) prepared in Example 20 was dissolved in dichloromethane (10 mL), and propionyl chloride (150.38 mg, 0.14 mL, 1.62 mmol) and triethylamine (180.12 mg, 0.25 mL, 1.78 mmol) were added thereto in order at 0° C. The mixture was stirred for 24 hrs at RT, and an excess amount of propionyl chloride (2 mL) was further added thereto to be stirred for 15 hrs. The resulting mixture was washed with saturated saline and extracted with dichloromethane. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 29 mg of the titled compound (yield: 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].N.Cl[N:15]1C(C)(C)C(=O)N(Cl)C1=O>>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[NH2:15]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Agent: N
Product: COC(=O)c1cccc(Cl)c1N
Yield: 49.6 %

Procedure:
Pure 3-chloroanthranilic alkyl esters have previously been prepared only in a 5-step synthesis starting from anthranilic esters (U.S. Pat. No. 5,068,392). According to U.S. Pat. No. 5,068,392, (pure) 3-chloroanthranilic alkyl esters can be prepared starting from anthranilic esters by means of a 5-step synthesis. The amino group of the anthranilic alkyl ester is first acetylated, bromination then takes place in the para position to the acetylated amino group, and this is then followed by chlorination in the ortho position to the acetylated amino group. Subsequently, the bromine is removed by reduction and the acetamino group is de-acetylated. The process is fairly elaborate and is found to be problematical owing to the use of bromine chloride or elemental bromine and chlorine. In addition to this, a series of unwanted waste products is inevitably formed. Apart from this, the preparation of 3-chloroanthranilic alkyl esters has only been described in the form of a mixture together with chloroanthranilic alkyl esters substituted in the 5 or 6 positions. Thus, according to EP 20 969, 3-chlorophthalic anhydride is reacted with ammonia, alkali metal hydroxide and alkali metal hypochlorite, and the resulting mixture of 5-chloroisatoic and 8-chloroisatoic anhydrides is esterified with alkanols to give a mixture of 3-chloroanthranilic and 6-chloroanthranilic alkyl esters. 5-Chloroanthranilic and 3,5-dichloroanthranilic alkyl esters arise as by-products in the amounts of from 23 to 48% and from 2 to 6%, respectively, when 3-chloroanthranilic alkyl esters are prepared in accordance with U.S. Pat. No. 5,118,832 by the reaction of anthranilic esters with 1,3-dichloro-5,5-dimethylhydantoin. After complicated removal of the by-products, methyl 3-chloroanthranilate is obtained in 49.6% yield.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].N1C=CC=CC=1.Cl[S:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21].[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:20]([C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=2)(=[O:22])=[O:21])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
10 g (55.8 mmol) of 4-fluoro-3-trifluoromethylaniline and 6 ml (74.3 mmol) of pyridine are dissolved in 250 ml of dichloromethane. The mixture is cooled with ice water and, under agitation and exclusion of moisture, 12.7 g (57.6 mmol) of 4-chlorosulfonylbenzoic acid is added in incremental portions. The mixture is stirred overnight; the slurry is combined with 75 ml of 2N sodium hydroxide solution, and the organic phase is separated. The alkaline solution is washed with dichloromethane and then adjusted to pH 2 with hydrochloric acid. The product is taken up in ethyl acetate. The solution is washed with water, dried over sodium sulfate and concentrated to dryness. The title compounds melts at 243-°245° C. after crystallization from ethanol.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH:20]1([C:23]([C:29]2[S:33][C:32]([SH:34])=[N:31][CH:30]=2)([OH:28])[C:24]([F:27])([F:26])[F:25])[CH2:22][CH2:21]1>>[CH:20]1([C:23]([C:29]2[S:33][C:32]([S:34][C:2]3[CH:11]=[C:10]4[C:5]([C:6]([C:13]5[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=5)=[CH:7][C:8](=[O:12])[O:9]4)=[CH:4][CH:3]=3)=[N:31][CH:30]=2)([OH:28])[C:24]([F:26])([F:25])[F:27])[CH2:22][CH2:21]1
Reactant: O=c1cc(-c2ccc(F)cc2)c2ccc(Br)cc2o1
Reactant: OC(c1cnc(S)s1)(C1CC1)C(F)(F)F
Product: O=c1cc(-c2ccc(F)cc2)c2ccc(Sc3ncc(C(O)(C4CC4)C(F)(F)F)s3)cc2o1

Procedure:
Employing the procedure described in Example 1, Step 3, using 7-bromo-4-(4-fluorophenyl)-2H-chromen-2-one and (−)-1-cyclopropyl-2,2,2-trifluoro-1-(2-mercapto-1,3-thiazol-5-yl)ethanol, the titled compound was obtained. 1H NMR (400 MHz, acetone-d6): δ 8.00 (s, 1H), 7.68 (m, 2H), 7.56-7.60 (m, 2H), 7.48 (dd, 1H), 7.39 (t, 2H), 6.43 (s, 1H), 5.88 (s, 1H), 1.65 (m, 1H), 0.82 (m, 1H), 0.54-0.71 (m, 3H); [α]D=−29.6° (c=1, EtOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=3)=[CH:11][C:10]([C:21]([O:23]CC)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(F)C=3)=CC(C(O)=O)=N2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(F)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(F)c2)n(-c2cccc(Cl)c2)n1
Product: O=C(O)c1cc(-c2ccc(F)c(F)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 33A in analogy to the synthesis of the compound of Example 73A. 2.49 g (96% of theory) of the title compound are obtained.