Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]([C:13]1([N:18]([CH:20]=[O:21])[CH3:19])[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12].Cl[CH2:23][C:24]([N:26]1[CH2:31][CH:30]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25]>O1CCOCC1>[CH3:9][O:10][C:11]([C:13]1([N:18]([CH:20]=[O:21])[CH3:19])[CH2:17][CH2:16][N:15]([CH2:23][C:24](=[O:25])[N:26]2[CH2:27][CH:28]=[C:29]([C:32]3[CH:33]=[CH:34][C:35]([C:38]4[N:39]=[CH:40][CH:41]=[CH:42][N:43]=4)=[CH:36][CH:37]=3)[CH2:30][CH2:31]2)[CH2:14]1)=[O:12]
Reactant: O=C(CCl)N1CC=C(c2ccc(-c3ncccn3)cc2)CC1
Reactant: COC(=O)C1(N(C)C=O)CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C1(N(C)C=O)CCN(CC(=O)N2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1

Procedure:
Added triethylamine (0.3 ml, 2.15 mmol) to a solution of (3-(Formyl-methyl-amino)-pyrrolidine-3-carboxylic acid methyl ester, Hydrochloride.(4T) (90 mg, 0.405 mmol) and 2-Chloro-1-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethanone (140 mg, 0.447 mmol) in dioxane (5 ml) at room temperature, then stirred at 90° C. for 5 hours. The reaction was cooled and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 7% MeOH/MeCl2 containing 2% NH4OH yielding 5T as a white solid (100 mg, 53%) ESMS (MH 464).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[C:19]([O:21]C)[CH:18]=[CH:17][C:16]=1[F:23])([CH3:4])[CH3:3].B(Br)(Br)Br>C(Cl)Cl>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=1[F:23])([CH3:1])[CH3:3]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(C)(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc(O)ccc2F)c(C(C)(C)C)c1
Reaction time: 6 h
Yield: 48 %

Procedure:
To a cooled solution of 8.8 (0.500 g, 2.00 mmol) in dry DCM (32.0 mL) at 0° C. was added boron tribromide (7.00 mL, 7.00 mmol). Stirring was continued for 6 hours, and the reaction was monitored by TLC and LCMS. Upon completion, pH 7 buffer was added to the mixture at 0° C. The resulting solution was extracted with DCM (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-20% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 35.1 as a colorless oil (0.29 g, 61%). MS ESI (pos.) m/e: 335.1 (M+Na)+, 320.1 (M+H2O)+, 303.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:15])[CH3:14])=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=1)=[O:33])(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CN
Reactant: Cc1cccc(N=C=O)c1
Product: CC(=O)Nc1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CNC(=O)Nc1cccc(C)c1
Yield: 54.2 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-{2-amino-N-[2-(acetylamino)phenyl]acetamido}acetate (4.7 g) and 3-methylphenyl isocyanate (2 g), and after recrystallisation in ethyl acetate, tert-butyl 2-{N-[2-(acetylamino)phenyl]-2-[3-(3-methylphenyl)ureido]acetamido}acetate (3.6 g), m.p. 185° C., is obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[CH3:14])=[C:9]([CH:11]=1)[NH2:10])(=[O:4])=[O:3].[H][H]>CO.[Pd]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:12][CH2:13][CH3:14])=[C:9]([CH:11]=1)[NH2:10])(=[O:3])=[O:4]
Reactant: [H][H]
Reactant: C/C=C/c1ccc(S(C)(=O)=O)cc1N
Agent: [Pd]
Solvent: CO
Product: CCCc1ccc(S(C)(=O)=O)cc1N

Procedure:
A mixture of 5-(methylsulfonyl)-2-[(1E)-prop-1-en-1-yl]aniline (Intermediate 60; 1.50 g; 6.84 mmol) and 10% Pd/C (196 mg) in MeOH (39 ml) was placed in a PARR reactor and treated with a pressure of 20 atm of hydrogen for 3 hours.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[CH3:11])[CH3:2].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.CC(C)([O-])C.[K+]>[CH2:1]([N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCn1c([N+](=O)[O-])cnc1C
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCn1c([N+](=O)[O-])cnc1C=Cc1ccccc1

Procedure:
A slurry of β-(1-ethyl-5-nitro-2-imidazolyl)styrene (42.7 g. or 0.175 mole) in 350 ml. of methanol containing 14.6 ml. of water at 25° C. is treated with ozone until a nearly clear, pale-yellow solution is obtained. Subsequently, the mixture is treated with 42 g. of sodium iodide in 138 ml. of water and 20.3 ml. of glacial acetic acid at 25° C. The mixture is stirred for 40 minutes and 44.1 g. (0.288 mole) of sodium thiosulfate in 242 ml. of water added. The mixture is filtered, and the filtrate concentrated at 70°-75° C. under 15-20 mm. of pressure to give 450 ml. of solution. The solution is acidified with 50 ml. of 6N hydrochloric acid and the benzaldehyde removed at 70°-75° C. under 15-20 mm. of pressure. The residue is then neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate to give an 81.5% yield of solid aldehyde, melting point 61°-67° C. after stripping. A sublimed sample of the aldehyde melts at 68°-69° C. with softening at 65° C. When the aqueous ozonized solution, after benzaldehyde is removed, is treated with thiosemicarbazide and mineral acid or semicarbazide hydrochloride and heated, the 1-ethyl-5-nitro-2-imidazolecarboxaldehyde thiosemicarbazone, melting point 241° C., or semicarbazone, melting point 223°-226° C., is obtained. The compound β-(1-ethyl-5-nitro-2-imidazolyl)styrene is prepared by treating 1-ethyl-2-methyl-5-nitroimidazole with benzaldehyde in absolute ethanol and potassium tertiary butoxide in nitrogen atmosphere below 37° C. A sample purified from 95% ethanol melts at 136.5°-137.5° C.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[C:32]([CH:38]=[CH:39][CH:40]=3)[C:33]([O:35]CC)=O)[CH2:26][CH2:25]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH:43]1([NH:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:50]([N:49]([CH:43]1[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1)[C:33](=[O:35])[C:32]1[CH:38]=[CH:39][CH:40]=[C:30]([N:27]2[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][CH2:21][CH2:20][C:7]3([C:5](=[O:6])[NH:4][CH2:3][C:2]([F:42])([F:1])[F:41])[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:13]4[C:8]3=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:25][CH2:26]2)[CH:31]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: c1ccc(CNC2CCCCC2)cc1
Reactant: CCOC(=O)c1cccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)c1
Product: O=C(c1cccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)c1)N(Cc1ccccc1)C1CCCCC1

Procedure:
Steps (c) and (d) of Example 1 were repeated, except that the compound prepared in step (b) of Example 87 was used and N-cyclohexylbenzylamine was used instead of N-methylbenzylamine. Thus, the title compound was prepared.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[C:25]=1[CH3:31].[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>CO>[CH:23]1[CH:22]=[CH:21][N:13]2[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:24]4[CH2:29][CH2:28][CH2:27][CH:26]([OH:30])[C:25]=4[CH3:31])=[C:2]([CH3:1])[CH:7]=3)=[O:9])[CH2:11][C:12]=12
Reactant: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCCC1=O
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCCC1O
Temperature: 25 °C
Yield: 88.1 %

Procedure:
3-[2-Methyl-4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl-carbonyl)phenyl]-2-methyl-cyclohex-2-en-1-one of Example 4 (0.350 g, 0.853 mmol), and cerium (III) chloride (0.210 g, 0.853 mmol) were combined in methanol (4.3 mL) followed by addition of sodium borohydride (0.032 g, 0.853 mmol). The reaction was stirred at room temperature until gas evolution ceased (approximately 2 minutes), then quenched with 0.1 N hydrochloric acid (100 mL), causing a white precipitate to form. The precipitate was filtered and purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexane to afford 0.310 g of the title alcohol as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=O)[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([O:27][CH3:28])[CH:16]=1.[CH:30]1([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:32][CH2:31]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1([CH3:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([NH:36][S:33]([CH:30]3[CH2:32][CH2:31]3)(=[O:35])=[O:34])=[O:14])[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([O:27][CH3:28])[CH:16]=1
Reactant: COc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc(N2CCOCC2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(C2Nc3ccc(C(=O)NS(=O)(=O)C4CC4)cc3CC2(C)C)cc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 34.7 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-methoxy-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.3 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (87 mg, 0.45 mmol), 4-dimethylaminopyridine (55 mg, 0.45 mmol), cyclopropane sulfonamide (109 mg, 0.9 mmol) in dichloromethane (10 mL) was heated for at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [3,3-dimethyl-2-(3-methoxy-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (52 mg, 35%) as a light yellow solid: LC/MS m/e calcd for C26H33N3O5S (M+H)+: 500.6, observed: 500.2.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=O)(C)(C)C.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([O:43][CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[C:32]([CH:34]=[N:35][C:36]([O:38][Si](C)(C)C)=[CH2:37])[CH:33]=1>C1(C)C=CC=CC=1.ClCCl>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([O:43][CH:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[C:32]([CH:34]2[C:10]3([C:11]4[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=4)[NH:8][C:9]3=[O:26])[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH2:37][C:36](=[O:38])[NH:35]2)[CH:33]=1
Reactant: C=C(N=Cc1cc(Br)ccc1OC1CCOCC1)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2OC2CCOCC2)N1
Yield: 49.3 %

Procedure:
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 5b (1.0 g, 2.5 mmol) was reacted with 1-[5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (4 g, 10 mmol) in toluene at 140° C., then treated with trifuloroacetic acid in dicloromethane to give racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 0.76 g, 49%)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:20][N:21]([O:24]C3CCCCO3)[CH:22]=[O:23])[C:10]=2[F:38])[N:6]=1.CC(O)=O>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:20][N:21]([OH:24])[CH:22]=[O:23])[C:10]=2[F:38])[N:6]=1
Reactant: Cc1nc(NCc2csc(N)n2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(NCc2csc(N)n2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)n1
Yield: 19.3 %

Procedure:
[(2R)-3-[2-(6-{[(2-Amino-1,3-thiazol-4-yl)methyl]amino}-5-fluoro-2-methyl-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (114 mg, 0.2 mmol) in 4:1 AcOH:water (5 mL) was stirred at room temperature overnight. The solvents were removed in vacuo, and the resulting crude product was purified by RP-HPLC to provide [(2R)-3-[2-(6-{[(2-amino-1,3-thiazol-4-yl)methyl]amino}-5-fluoro-2-methyl-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (18 mg, 18%). LCMS: (M+H)+: 481.2.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][CH2:15]3)[N:3]=1.[H-].[Na+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1.O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:4]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][CH2:15]3)[N:3]=1
Reactant: Clc1nc(Nc2ccc3c(c2)CCC3)c2nc[nH]c2n1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nc(Nc2ccc3c(c2)CCC3)c2ncn(C3CCCC3)c2n1
Reaction time: 1 h
Yield: 69.5 %

Procedure:
(2-Chloro-9H-purin-6-yl)-indan-5-yl-amine (857 mg, 3 mmol) was dissolved in dry DMF (10 mL). NaH (94 mg, 3.9 mmol) was added in portions and the resulting mixture was stirred for 1 h. Cyclopentyl bromide (760 mg, 5.1 mmol) was then added and the reaction was stirred overnight at 80° C. under N2. After cooling, H2O (50 mL) was added and the mixture was extracted with CH2Cl2 (3×25 mL). The combined extracts were washed with brine (2×25 mL), dried over MgSO4, and evaporated. The residue was purified by flash chromatography (95:5 CH2Cl2/Et2O) to afford the title compound as a white powder (738 mg, 69.5%). TLC (95:5 CH2Cl2/Et2O): RF=0.38.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].CN([Si:17]([CH3:20])([CH3:19])[CH3:18])C(=O)C(F)(F)F>ClCCl>[CH3:18][Si:17]([N:6]([Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]1[CH:7]=[CH:8][NH:1][C:2](=[O:3])[N:4]=1)([CH3:20])[CH3:19]
Reactant: Nc1cc[nH]c(=O)n1
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCl
Product: C[Si](C)(C)N(c1cc[nH]c(=O)n1)[Si](C)(C)C
Temperature: -30 °C

Procedure:
A bis-trimethylsilylcytosine solution was prepared by suspending 5.78 g of cytosine in 75 ml of dichloromethane and adding 20.57 ml of N-methyl-N-trimethylsilyltrifluoroacetamide and cooling the resulting solution to -30° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH3:13])[C:8]3[C:14](=[O:23])[CH:15]=[C:16]([C:18]([O:20]CC)=[O:19])[O:17][C:7]=3[C:6]=2[N:5]=[C:4]([C:24]([O:26]C)=[O:25])[CH:3]=1.Cl>C(O)(=O)C>[Cl:1][C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH3:13])[C:8]3[C:14](=[O:23])[CH:15]=[C:16]([C:18]([OH:20])=[O:19])[O:17][C:7]=3[C:6]=2[N:5]=[C:4]([C:24]([OH:26])=[O:25])[CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2c(OC)cc3c(Cl)cc(C(=O)OC)nc3c2o1
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc2c(Cl)cc(C(=O)O)nc2c2oc(C(=O)O)cc(=O)c12
Temperature: 25 °C
Yield: 34.5 %

Procedure:
To the product of step (e) (2.6 g) in glacial acetic acid (20 mls) was added concentrated hydrochloric acid (5.2 mls) and the whole was heated on a steam bath for three hours, during which time a solid slowly crystallised out of solution. The reaction mixture was cooled to room temperature and the crystallised solid was filtered off, washed thrice with glacial acetic acid and twice with diethyl ether. The resulting pale yellow solid was dried over sodium hydroxide pellets at 90° C. under a reduced pressure of 1 mm Hg for 2.5 hours, affording 0.8 g of the sub-title compound. N.M.R. Spectroscopy confirmed the structure.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH3:18][O:19][C:20]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:21]=1[C:22](N(OC)C)=[O:23]>>[CH3:18][O:19][C:20]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:21]=1[C:22]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:23]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: COc1ccc(OC)c(C(=O)N(C)OC)c1
Agent: [Li]CCCC
Product: COc1ccc(OC)c(C(=O)c2ccc(OC)cc2C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 2,5-dimethoxy-N-methoxy-N-methylbenzamide. It is crystallized from diisopropyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH2:18][CH:19]([CH2:25][CH2:26][CH2:27][F:28])[C:20]([O:22]CC)=[O:21])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>O.C(O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][CH2:18][CH:19]([CH2:25][CH2:26][CH2:27][F:28])[C:20]([OH:22])=[O:21])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(CCCF)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(CCCF)C(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 1-tert-Butyl 6-ethyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-(3-fluoropropyl)-hexanedioate (1f) (90.0 mg, 0.22 mmol) and lithium hydroxide (53.0 mg, 2.22 mmol) in 1 mL water/ethanol (1:1) was stirred for 14 h at r.t. The mixture was acidified to pH 2 by addition of 2 N aqueous hydrochloric acid and extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[C:8]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[C:13](Cl)[C:7]2=[CH:6][C:5]=1[NH:17]C(C)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25].CC(O)C.Cl>CS(O)(=O)=O.O>[NH2:17][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][C:4]=1[O:3][CH2:2][CH3:1])[N:10]=[CH:11][C:12]([C:15]#[N:16])=[C:13]2[NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:29])=[C:22]([Cl:21])[CH:23]=1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1NC(C)=O
Reactant: Nc1ccc(F)c(Cl)c1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Temperature: 84 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
A stirred mixture of N-(4-chloro-3-cyano-7-ethoxy-6N-acetylquinoline (274.5 g, 0.947 mol), 3-chloro-4-fluoroaniline (180 g, 1.24 mol), methanesulfonic acid, (5.5 g, 0.057 mol), and 2-propanol (6.7 L) was warmed to reflux (84° C.) for 6.5 hours. After stirring overnight at room temperature, the mixture was warmed to 80° C. Water (3.2 L) containing concentrated hydrochloric acid (655 mL of 38% aqueous HCl) was added. The reaction was kept at reflux for 5 hours. The reaction mixture was cooled to 0° C.-10° C. for 1 hour. The yellow solid product is collected by vacuum filtration and washed with 20% 2-propanol/water (700 mL) and water (2×700 mL). Drying the product in vacuo at 60° C. gave 344.8 g (91%, 99% by HPLC) of 6-Amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitrile as a hydrochloride salt. 1H NMR (DMSO-d6+D2O) δ1.42 (t, 3H), 4.25 (q, 2H), 7.05 (m, 1H), 7.1 (s, 1H), 7.35-7.50 (m, 3H), 7.65 (dd, 1H), 8.65 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[C:28]([F:38])=[CH:29][C:30]([F:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1>>[F:37][C:30]1[CH:29]=[C:28]([F:38])[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)=[CH:32][C:31]=1[S:33]([NH2:36])(=[O:34])=[O:35]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (136 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (138 mg, 51%). MS (ISN) 545.1 [(M−H)−]; mp 264° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]/OC)([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C:22]1[CH:27]=[C:26]([OH:28])[C:25]([O:29][CH2:30][CH2:31][CH3:32])=[CH:24][N:23]=1>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[C:8]2=[CH:17][NH:20][CH2:21][C:22]1[CH:27]=[C:26]([OH:28])[C:25]([O:29][CH2:30][CH2:31][CH3:32])=[CH:24][N:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCOc1cnc(CN)cc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Solvent: CN(C)C=O
Product: CCCOc1cnc(CNC=C2C(=O)NC(=O)c3ccc(C(C)(C)C)cc32)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
An amount of 50.0 mg (0.193 mmol) of (4E)-6-tert-butyl-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione, is dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 35 mg (0.193 mmol) of 2-aminomethyl-5-propoxy-pyridin-4-ol. All solids dissolved and after the mixture is stirred at room temperature for 2 hours, the solution is evaporated to dryness in vacuo, treated with acetonitrile, filtered and washed several times with fresh acetonitrile and dried to give 52 mg of the title compound as a light pink solid (66% yield); mp 162-178° C. dec, MS data ES(+) 410.4 m/e.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])C)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:13])[CH2:10][CH2:11][CH3:12].[OH-].[Na+].BrBr.[Br-].S(OS([O-])=O)([O-])=[O:23].[Na+].[Na+].Cl>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:13])[CH2:10][CH2:11][CH3:12])[C:14]([OH:16])=[O:23]
Reactant: CCCC(C)Oc1ccc(C(C)=O)cc1F
Reactant: O=S([O-])OS(=O)[O-]
Agent: BrBr
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(C)Oc1ccc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.449 g of 1-[3-fluoro-4-(1-methylbutoxy)phenyl]ethanone in 6.8 ml of dioxane was dropped dropwise into 1.36 g of NaOH, 1.6 g of bromine in 6.8 ml of water. The mixture was stirred at room temperature for 30 minutes and then heated at 50° C. for 1 h. The excess bromide was decomposed by adding a sodium disulfite solution, and then the solution was poured into 25% strength hydrochloric acid solution and stirred for 20 minutes. The solution was extracted with ethyl acetate. The combined organic phases dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 226.1 (C12H15FO3); MS (ESI): 227 (M+H+).