Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5]=[N+]=[N-])[CH3:2].[CH:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1.CC(=O)OCC>C(Cl)Cl>[CH:9]1([CH2:12][O:13][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:8])[CH2:11][CH2:10]1
Reactant: OCC1CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)COCC1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
Diazoacetic acid ethyl ester (80.00 g, 0.70 mol) was added dropwise to cyclopropanemethanol (60.66 g, 0.84 mol) and [Rh(Ac2O)2]2 (3.1 g, 7.02 mmol) in anhydrous CH2Cl2 (800 mL) at 0° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 4 h. CH2Cl2 extractive work up and silica gel chromatography (PE: EA=100:1-50:1) gave the title compound (100 g, 90.4% yield) as a colorless oil. 1H NMR: (CDCl3, 400 MHz) δ 4.23-4.19 (m, 2H), 4.09 (s, 2H), 3.38-3.36 (m, 2H), 1.27 (t, J=7.2 Hz, 3H), 1.10-1.07 (m, 1H), 0.57-0.52 (m, 2H), 0.24-0.20 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C([O:12][B:13](OC(C)C)[O:14]C(C)C)(C)C>C1COCC1>[Cl:8][C:4]1[N:3]=[C:2]([B:13]([OH:14])[OH:12])[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Br)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: OB(O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.4 %

Procedure:
A solution of n-Buli (2.5 M, 24.91 mL, 62.3 mmol) in freshly distilled THF (100 mL) was cooled to −78° C., followed by the addition of a solution of 2-bromo-6-chloropyridine (10.0 g, 51.96 mmol) in 10 mL THF. The resulting dark colored mixture was stirred at this temperature for 45 min. A solution of triisopropylborate (11.72 g, 62.3 mmol) was added and the mixture was stirred at −78° C. for 2 h, and warmed to RT and stirred for an additional 1 h. The mixture was quenched by slow addition of 3% aq NaOH solution (400 mL). The resulting aqueous layer was collected and acidified down to pH 5-6 by dropwise addition of 3N HCl (180 mL), keeping the internal temperature below 5° C. The mixture was extracted with EtOAc and the combined organic layers were dried, filtered and concentrated. The residue was recrystallized from Et2O to give 6-chloropyridin-2-ylboronic acid (6 g, 73.6%) as a white solid. MS (ESI, pos. ion) m/z: 158 (M+1); 1H NMR (DMSO-d6, 300 MHz): δ ppm 8.51 (brs, 1H), 7.84 (m, 2H), 7.51-7.48 (m, 1H).
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][C:5](=O)[CH2:6][CH3:7].O.[NH2:11][NH2:12]>C(O)C>[CH2:2]([C:3]1[CH:4]=[C:5]([CH2:6][CH3:7])[NH:12][N:11]=1)[CH3:1]
Reactant: NN
Reactant: CCC(=O)CC(=O)CC
Solvent: O
Solvent: CCO
Product: CCc1cc(CC)[nH]n1
Temperature: 25 °C
Yield: 99728.3 %

Procedure:
A solution of 3,5-heptanedione (10.0 g, 0.078 mmol) in ethanol (40 ml) was treated dropwise with hydrazine hydrate (4.2 ml, 0.086 mmol) at room temperature producing an exotherm that was cooled by use of an ice bath. After the addition was complete the reaction mixture was allowed to warm to room temperature. The solution was concentrated under reduced pressure. The oil was partitioned between dichloromethane and brine. The aqueous layer was extracted with dichloromethane (×2). The combined organic phases were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to afford the title compound (9.66 g) as a pale yellow oil that partly solidified on standing.
Reaction SMILES: [CH3:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]1.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.[Br:35]N1C(=O)CCC1=O.ClC1C=CC=CC=1>O>[Br:35][CH2:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]1
Reactant: CSc1cccc(-n2nnn(C)c2=O)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: Clc1ccccc1
Solvent: O
Product: CSc1cccc(-n2nnn(C)c2=O)c1CBr
Yield: 20 %

Procedure:
To a mixture of 1-(2-methyl-3-methylsulfanylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 15) 1.50 g, 1,1′-azobis(cyclohexane-1-carbonitrile) 0.620 g, N-bromosuccinimide 1.30 g and chlorobenzene 15 ml was stirred with heating under reflux for four hours. After cooling the mixture, to the reaction solutions was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(2-bromomethyl-3-methylthiophenyl)-4-methyl-1,4-dihydrotetrazole-5-one 0.400 g.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9]C)=O.[NH2:11][C:12]([NH2:14])=[S:13].[OH-].[K+]>C(O)C.O>[SH:13][C:12]1[N:11]=[C:7]([OH:9])[C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[N:14]=1
Reactant: COC(=O)C1CCCC1=O
Reactant: NC(N)=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Oc1nc(S)nc2c1CCC2
Yield: 26.4 %

Procedure:
To a solution of the methyl 2-oxocyclopentanecarboxylate (40 g, 281 mmol) and thiourea (21 g, 281 mmol) in ethanol (200 ml) was added KOH (20 g, 356 mmol) in water (120 ml). The mixture was refluxed for 12 hour. The solvent was removed and the residue was quenched with concentrated HCl (25 mL). The precipitate was filtered, washed with water and dried to afford the 2-mercapto-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12.5 g, 26%). MS (APCI+) [M+H] +168.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].I[CH2:10][CH2:11][F:12]>CN(C=O)C>[F:12][CH2:11][CH2:10][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1
Reactant: FCCI
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FCCn1cc(I)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.9 %

Procedure:
A solution of 4-iodo-1H-pyrazole (1.10 g, 5.7 mmol) in anhydrous DMF (25 mL) is treated with NaH (0.23 g, 60% in mineral oil, 5.7 mmol). After stirring for 20 minutes at room temperature, the reaction mixture is treated with 1-iodo-2-fluoroethane (1.0 g, 5.7 mmol) and stirred over night at room temperature. The reaction is quenched with H2O and diluted with EtOAc. The two layers are separated and the aqueous is extracted with EtOAc. The combined organic extracts are washed with H2O, brine, dried (Na2SO4) and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane:15/85) to afford the title compound (1.08 g, 79%) as an oil. MS (+) ES 240 (M+H)+.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.[CH3:58][C:59]1[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:60]=1[S:66](Cl)(=[O:68])=[O:67]>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:66]([C:60]3[CH:61]=[C:62]([F:65])[CH:63]=[CH:64][C:59]=3[CH3:58])(=[O:67])=[O:68])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(N)n2)c1F
Yield: 46 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (0.082 g, 0.239 mmol) and 2-methyl 5-fluorobenzenesulfonyl chloride (0.055 g, 0.263 mmol) the title compound was obtained (57 mg, 0.11 mmol, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 7.91 (d, J=5.3 Hz, 1H), 7.44 (dd, J=8.8, 2.6 Hz, 1H), 7.29-7.42 (m, 3H) 7.16-7.29 (m, 2H), 6.71 (s, 2H), 5.73 (d, J=5.1 Hz, 1H), 2.49 (s, 3H), 1.35 (s, 9H). MS (ES+): 516 [M+H]+.
Reaction SMILES: CO.[C:3]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:22]([O:26][C:27]([NH:29][S:30]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:32])=[O:31])=[O:28])[CH2:23][CH2:24][CH3:25].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:22]([O:26][C:27]([N:29]([CH3:3])[S:30]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:31])=[O:32])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOC(=O)NS(=O)(=O)NCC(=O)OCC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOC(=O)N(C)S(=O)(=O)NCC(=O)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methanol (8.5 mmol) and triphenylphosphine (2.6 g, 8.5 mol) in dry THF is added a solution of ethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate from the previous step (2.4 g, 8.5 mol) and DIAD (2.0 g, 8.5 mmol) in dry THF dropwise at 0° C. under N2 atmosphere. The mixture is stirred at 0° C. for 2 h, warmed to RT and is stirred overnight. After the solvent is removed in vacuo, the residue is purified by column chromatography to afford ethyl 2-((N-(butyloxycarbonyl)-N-methylsulfamoyl)amino)acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:14]2([CH2:17][C:16](=[O:18])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]2([CH2:17][C:16]([OH:18])([CH3:21])[CH2:15]2)[CH2:19][CH2:20]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1
Yield: 55 %

Procedure:
To a stirred solution of 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (164 mg, 0.60 mmol) in dry THF (2 mL) was added dropwise a 1.4 M solution of methylmagnesium bromide in toluene/THF (0.56 mL, 0.78 mmol) under an atmosphere of nitrogen, at −78° C. After 1 h the solution was quenched with saturated NH4Cl(aq) and the resulting mixture partitioned between EtOAc and water. The organic layer was dried (Na2SO4) and evaporated to give a residue, which was purified by column chromatography (Si—PCC, 0-70% EtOAc in cyclohexane) to give 2-Hydroxy-2-methyl-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (96 mg, 55%) as a colourless oil. LCMS (Method H): RT 4.13 min, [M+H]+ 290.4
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C)C=O>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=[C:15]2[N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
Alternately, combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.7 g, 5.37 mmol) and dimethylformamide (40 mL). Add sodium hydride (0.23 g, 60% n in oil, 5.75 mmol). After 15 minutes, add 4-fluorobenzyl bromide (0.73 mL, 5.86 mmol). After 18 hours, partition the reaction mixture between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the organic layer five times with water and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-(4-fluorobenzyl-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.42 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].Br[CH2:30][CH2:31][CH2:32][CH2:33][Cl:34].[H-].[Na+].O>CN(C)C=O>[Cl:34][CH2:33][CH2:32][CH2:31][CH2:30][NH:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCCl)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 56.5 %

Procedure:
1.52 g (3.90 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 30 mL of dimethylformamide under argon atmosphere, 2.25 mL (19.5 mmol) of 1-bromo-4-chlorobutane and 470 mg (11.8 mmol) of sodium hydride (60% oil dispersion) were added under ice-cooling and the mixture was stirred at room temperature for 1.3 hours. The reaction solution was cooled on ice, water was added and the mixture was extracted three times with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=100:1) to give 1.06 g of 5-(4-chlorobutylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 57%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:17]=[C:18]([CH3:20])[CH3:19]>S(=O)(=O)(O)O.O1CCOCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(C)(C)C
Temperature: -78 °C
Reaction time: 144 h
Yield: 62 %

Procedure:
Concentrated sulfuric acid (10 drop) was added to a solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (500 mg, 2,15 mmol) in 20 ml of dioxane/chloroforme (2:3) in a sealed tube. After cooling the solution at −78° C., put 20 ml of isobutene gaz. The sealed tube was closed and then the reaction mixture was stirred for 6 days at 60° C. The solvant was removed and then partitioned between 15 ml of sat. Na2CO3 solution and 15 ml of EtOAc. The organic layer was separated, the aqueous phase was washed twice with ethyl acetate and the combined ethyl acetate layer was dried (MgSO4), concentrated and the residue was purified by flash chromatography (5% EtOAc/Hexane) to obtain 385 mg (62%) of 3-tert-Butylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.65 ppm (d, 2H, Haro); 7.44-7.38 ppm (m, 3H, Haro); 7.07 ppm (s, 1H, Haro); 3.86 ppm (s, 3H); 1.48 ppm (s, 9H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:4](C(OC(C)(C)C)=O)[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)[C:7]=1[C:8](=[O:10])[NH2:9]>O1CCOCC1.CO>[ClH:1].[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)[C:7]=1[C:8](=[O:10])[NH2:9]
Reactant: CC(C)(C)OC(=O)n1cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c(C(N)=O)c1N
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c[nH]c1N
Temperature: 50 °C
Reaction time: 15 h

Procedure:
0.575 cm3 of a 4M hydrochloric acid solution in dioxane is added at a temperature in the region of 20° C., under an argon atmosphere, to 0.06 g (0.115 mmol) of tert-butyl 2-amino-3-carbamoyl-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}pyrrole-1-carboxylate in solution in a mixture of 1.2 cm3 of dioxane and 1.2 cm3 of methanol. After stirring for 15 hours at a temperature in the region of 50° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give 2-amino-3-carbamoyl-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole hydrochloride which is taken up in 2.5 cm3 of ethyl acetate. 0.01 cm3 of triethylamine and 0.013 cm3 of acetic anhydride are added at a temperature in the region of 20° C., under an argon atmosphere. After stirring for 1 hour at a temperature in the region of 20° C., a catalytic quantity of DMAP is added and then the stirring is maintained for 30 minutes. The reaction mixture is diluted with 5 cm3 of ethyl acetate. The organic phase is washed with twice 5 cm3 of water. All the aqueous phases are combined and extracted with 5 cm3 of ethyl acetate. All the organic phases are combined, washed with 5 cm3 of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.054 g of a residue which is purified by flash chromatography [eluent: dichloromethane/methanol (98/2 by volume)]. After concentrating the fractions under reduced pressure, 0.010 g of 1-acetyl-2-amino-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-3-carboxamide is obtained, in the form of a yellow solid; 1H NMR (300 MHz, (CD3)2SO, —δ in ppm): 2.14 (s: 3H); from 5.20 to 6.10 (broad m: 1H); 6.40 (d, J=2.0 Hz: 1H); from 6.70 to 7.60 (broad m: 1H); 7.30 (broad d, J=8.5 Hz: 2H); 7.38 (mt: 1H); from 7.45 to 7.54 (m: 3H); 8.62 (dd, J=7.5 and 2.5 Hz: 1H); 8.92 (broad s: 1H); 9.25 (broad s: 1H); 10.7 (broad s: 1H); 11.4 (broad s: 1H); ES+: m/z=464 (MH+).
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1F)[C:30]#[N:31].[CH3:36][N:37]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:45]2[CH:55]=[C:54]([OH:56])[C:48]3[CH2:49][C:50]([CH3:53])([CH3:52])[O:51][C:47]=3[CH:46]=2)=[O:44])=[N:38]1>>[CH3:36][N:37]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:45]2[CH:55]=[C:54]([O:56][C:34]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=3[F:26])[C:48]3[CH2:49][C:50]([CH3:53])([CH3:52])[O:51][C:47]=3[CH:46]=2)=[O:44])=[N:38]1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Reactant: N#Cc1ccc(F)c(F)c1
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)cc3F)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 3,4-difluorobenzonitrile (11 mg, 0.080 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (23 mg, 0.080 mmol) to give a colorless oil (8 mg, 20% yield). 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1 H) 7.50 (dd, J=10.11, 1.77 Hz, 1 H) 7.42 (d, J=8.59 Hz, 1 H) 7.28 (d, J=2.02 Hz, 1 H) 7.00-7.08 (m, 2 H) 6.95 (s, 1 H) 6.77 (d, J=1.77 Hz, 1 H) 3.78 (s, 3 H) 2.97 (s, 2 H) 1.51 (s, 6 H); LCMS for C22H19FN4O3 m/z (M+H)+ 407.10.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][C:25](=[O:49])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](=O)[NH:33][CH2:34][C:35]([C:37]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=1[O:44][CH:45]([CH3:47])[CH3:46])=O>C1COCC1>[CH3:23][O:24][C:25](=[O:49])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[S:10][C:35]([C:37]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:38]=2[O:44][CH:45]([CH3:47])[CH3:46])=[CH:34][N:33]=1
Reactant: COC(=O)CCCCCCC(=O)NCC(=O)c1cc(Cl)ccc1OC(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCCCCCc1ncc(-c2cc(Cl)ccc2OC(C)C)s1
Yield: 45.7 %

Procedure:
Add Lawesson's reagent (31.03 g, 77 mmol) to a solution of 7-[2-(5-chloro-2-isopropoxyphenyl)-2-oxoethylcarbamoyl]heptanoic acid methyl ester (21.80 g, 55 mmol) in THF (550 mL) at room temperature under nitrogen. Heat the mixture at reflux for 3 hours. Remove the solvent under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:3), to afford 7-[5-(5-chloro-2-isopropoxyphenyl)thiazol-2-yl]heptanoic acid methyl ester (9.96 g, 46%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:64][CH:65]([CH2:68][OH:69])[CH2:66][OH:67]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:64][CH:65]([CH2:68][OH:69])[CH2:66][OH:67])=[O:20])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Reactant: NC(CO)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NC(CO)CO)cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Yield: 20.55 %

Procedure:
To a flask charged with 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 23) (70 mg, 0.174 mmol) and HATU (80 mg, 0.209 mmol) was added DMF (3 mL) and the resulting solution was treated with DIPEA (0.091 mL, 0.523 mmol) and after 5 min by 2-aminopropane-1,3-diol (31.8 mg, 0.349 mmol). The reaction was concentrated in vacuo, residue partitioned between water and EtOAc. the phases were separated and the aqueous extracted with EtOAc (×2). The combined organic layers were washed with saturated NaHCO3 (3×) then brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP (HpH) and the residue triturated with Et2O to give 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1,3-dihydroxypropan-2-yl)benzamide (17 mg, 0.036 mmol, 20.55% yield) as a very pale yellow solid. LCMS (HpH, 2 min), Rt=0.74 min, MH+=475.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(Cn2ccc3cc(Br)ccc32)cc1
Reactant: OB(O)c1ccccc1
Product: Fc1ccc(Cn2ccc3cc(-c4ccccc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-(4-fluorobenzyl)-1H-indole (Step 1 of Example 27) and benzeneboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 302. 1HNMR (300 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.63 (d, 2H, J=8.3 Hz), 7.56-7.51 (m, 2H), 7.45-7.37 (m, 3H), 7.30-7.22 (m, 3H), 7.20-7.08 (m, 2H), 6.54 (d, 1H, J=6.0 Hz), and 5.43 ppm (s, 2H).