Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2.[N+:23]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])([O-:25])=[O:24]>>[N+:23]([C:26]1[CH:27]=[C:28]([NH:29][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][NH:8]3)=[C:4]([NH:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[N:3]=2)[CH:30]=[CH:31][CH:32]=1)([O-:25])=[O:24]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)c1ccc(Nc2[nH]c(Cl)nc3ncnc2-3)cc1
Product: CCOC(=O)c1ccc(Nc2nc(Nc3cccc([N+](=O)[O-])c3)nc3[nH]cnc23)cc1
Yield: 54.1 %

Procedure:
The procedure is carried out as in stage 2 of Example 1, using 238 mg of the product obtained in stage 1 of Example 1 and 520 mg of 3-nitroaniline in place of trans-1,4diaminocyclohexane. 170 mg of the expected product are thus obtained.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26](Br)[CH:27]=[CH2:28]>C1(C)C=CC=CC=1>[CH2:28]([N:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH:27]=[CH2:26]
Reactant: c1ccc(Oc2ccc(C3CCCN3)cc2)cc1
Reactant: C=CCBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCN1CCCC1c1ccc(Oc2ccccc2)cc1

Procedure:
8 parts of 2-(4-phenoxyphenyl) pyrrolidine, 3.3 parts of triethylamine, 4 parts of allyl bromide and 70 parts of toluene were refluxed for 5 hours. After cooling and filtration, there were obtained by distillation 7.7 parts of 1-allyl-2-(4-phenoxyphenyl) pyrrolidine, B.P./0.2 mm Hg: 148°-150° C., nD26 =1.5695, M.P. of its acid fumarate: 115°-116° C. (isopropanol/ether).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[CH2:46][CH2:47][NH2:48]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:48][CH2:47][CH2:46][C:45]1[CH:49]=[CH:50][C:51]([O:52][CH3:53])=[C:43]([O:42][CH3:41])[CH:44]=1)=[O:16])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNC(=O)[C@H](Cc2ccc(OCC(=O)O)c(C(=O)O)c2)NC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1OC
Yield: 9.6 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and 3,4-dimethoxyphenethylamine (52 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (12 mg). 1H-NMR (400 MHz, CD3OD) δ 1.38 (s, 9H) 2.68 (t, 2H) 2.72-3.09 (m, 4H) 3.29-3.44 (m, 2H) 3.80 (s, 3H) 3.85 (s, 3H) 4.25 (m, 1H) 4.52 (m, 1H) 4.79 (s, 2H) 6.74 (d, 1H) 6.84 (s, 1H) 6.87 (d, 1H) 7.06 (d, 1H) 7.17-7.38 (m, 6H) 7.73 (s, 1H); HRMS m/z 693.2904 (calc of monoisotopic mass for C36H43N3O11 gives 693.2898).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:22])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:7]2=1.C[C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].CCN=C=NCCCN(C)C>N1C=CC=CC=1>[Cl:22][C:4]1[CH:5]=[C:6]2[C:14](=[C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[N:32][CH:24]=3)[CH:3]=1)[NH:13][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:7]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cl)cc2c1[nH]c1cncc(NC(=O)C(F)(F)F)c12)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
N-(8-amino-6-chloro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide (90 mg, 0.274 mmol, 1 equiv.) and 2-methylnicotinic acid (40 mg, 0.329 mmol, 1.2 equiv.) were dissolved in 1.5 ml of anhydrous pyridine under N2. EDCI (84 mg, 0.438 mmol, 1.6 equiv.) was added in one portion and the reaction mixture was stirred at room temperature 2 hours. The reaction was quenched and treated following the preceding protocol to obtain 38 mg (32%) of N-[6-chloro-4-(2,2,2-trifluoro-acetylamino)-9H-β-carbolin-8-yl]-nicotinamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:28])[N:10]1[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[NH:35][S:36]([CH3:39])(=[O:38])=[O:37].[CH2:40]([NH2:42])[CH3:41].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([NH:42][CH2:40][CH3:41])=[O:26])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:28])[N:10]1[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[NH:35][S:36]([CH3:39])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NCCCC(=O)O)C1c1ccc(Cl)cc1Cl
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: CCNC(=O)CCCNC(=O)C1c2ccccc2C(=O)N(C2CCCCC2NS(C)(=O)=O)C1c1ccc(Cl)cc1Cl

Procedure:
By condensing 4-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)butanoic acid and ethylamine using WSC and HOBt in accordance with Example 1, (3RS,4RS)-3-(2,4-dichlorophenyl)-N-[4-(ethylamino)-4-oxobutyl]-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide was obtained as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32](=[O:36])(=[O:35])[NH:33][CH3:34])=[N:4][C:5]([NH:8][C:9]2[CH:24]=[CH:23][C:12]3[N:13]([CH2:19][C:20](O)=[O:21])[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.OC1C2N=NNC=2C=CC=1>CN(C=O)C.CO.C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:33][CH3:34])(=[O:36])=[O:35])=[N:4][C:5]([NH:8][C:9]2[CH:24]=[CH:23][C:12]3[N:13]([CH2:19][C:20]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)=[O:21])[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3CC(=O)O)ncc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CO
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3CC(=O)N2CCN(C)CC2)ncc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
{7-[5-Chloro-4-(2-methylsulfamoyl-phenylamino)-pyrimidin-2-ylamino]-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-acetic acid (227 mg, 0.43 mmol), N-methylpiperazine (48 μl, 0.43 mmol), 1-[3-(dimethylamino)propyl]3-ethylcarbodiimide hydrochloride (98 mg, 0.51 mmol), N-methylmorpholine (119 μl, 2.5 mmol), and hydroxybenzotriazole (69 mg, 0.51 mmol) were dissolved in anhydrous DMF, and the solution was stirred 18 hours at room temperature. It was then partitioned between ethyl acetate and water, and washed once with aqueous sodium bicarbonate and once with water. Concentration afforded a yellow foam. Preparative TLC (10% MeOH/CH2Cl2) gave 2-(5-Chloro-2-{1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino}-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide as a white solid, 147 mg. (56% yield) 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.27 (s, 1H), 8.43-8.51 (m, 1H), 8.23 (s, 1H), 7.70-7.83 (m, 2H), 7.58-7.64 (m, 1H), 7.41-7.48 (m, 2H), 7.23-7.30 (m, 1H), 7.08-7.12 (m, 1H), 4.58 (s, 2H), 3.34-3.43 (m, 4H), 2.62-3.10 (m, 2H), 2.39 (s, 3H), 1.96-2.32 (m, 11H); MS (m/e) 613 (M+1); retention time 5.99 minute; mp 148-151° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[CH2:12][N:13]([CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[C:37]1[CH:42]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:40]=[CH:39][C:38]=1[O:46][CH3:47])[C:14]1[N:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][N:15]=1)C1C=CC=CC=1>CO.[C].[Pd]>[CH:43]([C:41]1[CH:40]=[CH:39][C:38]([O:46][CH3:47])=[C:37]([C:28]2[CH:29]=[CH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[CH:32][C:27]=2[CH2:26][N:13]([CH2:12][C:11]2[CH:10]=[C:9]([OH:8])[CH:50]=[C:49]([C:51]([F:54])([F:52])[F:53])[CH:48]=2)[C:14]2[N:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][N:15]=2)[CH:42]=1)([CH3:45])[CH3:44]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(O)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
(3-Benzyloxy-5-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (215 mg) is dissolved in methanol (10.5 ml), and thereto is added 10% palladium-carbon and the mixture is stirred under hydrogen atmosphere at room temperature for 1 hour. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=4:1→1:2, and chloroform:methanol 19:1→9:1) to give 3-{[(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-phenol (98 mg). MS (m/z): 661 [M+H]+
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH:25]1([CH2:29]Br)[CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C(=O)C>[CH:25]1([CH2:29][N:18]([CH2:17][C:13]2[CH:12]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=3)[CH:16]=[CH:15][CH:14]=2)[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:20])=[O:21])[CH2:28][CH2:27][CH2:26]1
Reactant: BrCC1CCC1
Reactant: CC(C)S(=O)(=O)NCc1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)S(=O)(=O)N(Cc1cccc(-c2cccc(S(C)(=O)=O)c2)c1)CC1CCC1

Procedure:
In analogy to example 10, step 3, propane-2-sulfonic acid (3′-methanesulfonyl-biphenyl-3-ylmethyl)-amide (example 49, step 2) was reacted with cyclobutylmethyl bromide, tetrabutylammonium iodide and cesium carbonate in N,N-dimethylacetamide to give propane-2-sulfonic acid cyclobutylmethyl-(3′-methanesulfonyl-biphenyl-3-ylmethyl)-amide as a colorless semi-solid. MS: 436.3 ([M+H]+)
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:13][CH:12]=1)C1C=CC=CC=1.C1COCC1.CCOCC>CCO.[Pd]>[C:30]([O:29][C:27](=[O:28])[NH:26][CH2:25][C:14]1[C:15]2[C:20](=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:11]([NH2:10])=[CH:12][N:13]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1cc2c(NC(=O)OCc3ccccc3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc2c(N)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Yield: 89 %

Procedure:
A solution of [1-(tert-Butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-carbamic acid benzyl ester, in 45 mL of EtOH and 20 mL THF was hydrogenated at 1 atm (balloon) over 60 mg of 10% Pd—C for 3 h. The catalyst was removed by filtration through a plug of celite and the filtrate was concentrated to give a white film. Trituration with ether gave 534 mg (89%) of the 4-aminoisoquinoline as a white granular solid. H1-NMR (CDCl3): δ 7.84 (s, 1H), 7.36 (s, 1H), 7.02 (s, 1H), 6.00 (s, 1H), 4.78 (d, J=5.1 Hz, 1H), 4.03 (s, 3H), 4.01 (s, 3H), (s, 1H), 3.89 (s, 2H), 1.48 (s, 9H). MS: APCI (M+H) calc' d for C18H24N2O4+H 334.4; found 334.0.
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[C:7]([OH:17])=[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([Cl:12])=[CH:10][CH:11]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]=[C:27]=[O:28]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:27]([NH:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])=[O:28])=[C:7]([OH:17])[C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: COc1ccccc1N=C=O
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Agent: NC(N)=O
Product: COc1ccccc1NC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 34.4 %

Procedure:
Following the general procedure for urea formation outlined in example 12, 3-amino-6-chloro-2-hydroxybenzenesulfonamide (40 mg, 0.18 mmol) and 2-methoxyphenylisocyanate (33 mg, 0.22 mmol) ) were coupled to form the desired urea (23 mg, 34%). EI-MS (m/z) 370.3, 372.1(M).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:17]([OH:19])=O)[C:13](=[O:16])[NH:14][N:15]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2].CN(C=O)C.C(N(CC)CC)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[C:35]([NH2:40])[CH:34]=1>O>[NH2:40][C:35]1[CH:34]=[C:33]([Cl:32])[CH:38]=[CH:37][C:36]=1[NH:39][C:17]([C:12]1[C:13](=[O:16])[NH:14][N:15]=[C:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=2)[CH:11]=1)=[O:19]
Reactant: Nc1ccc(Cl)cc1N
Reactant: CCNc1nccc(-c2cc(C(=O)O)c(=O)[nH]n2)n1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCNc1nccc(-c2cc(C(=O)Nc3ccc(Cl)cc3N)c(=O)[nH]n2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 110 mg of 6-(2-ethylaminopyrimidin-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 2 ml of DMF and 0.17 ml of triethylamine is mixed with 192 mg of Hatu and stirred at room temperature for 30 minutes. Then 66 mg of 4-chloro-phenylenediamine are added, and the mixture is stirred at room temperature overnight. 5 ml of water are added to the mixture, and the precipitate is briefly stirred and then filtered off with suction and dried.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:15][CH2:16][CH2:17][CH2:18]C(O)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO>N1C=CC=CC=1>[C:5]([O:4][CH:1]([CH2:18][CH2:17][CH2:16][O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)CCCOCc1ccccc1
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)OC(C)CCCOCc1ccccc1
Yield: 36 %

Procedure:
Acetic anhydride (1.86 mL) was added to a mixed solution of 5-benzyloxypentan-2-ol (957 mg, 4.93 mmol) in pyridine (1.8 mL) in an ice bath. After completion of the reaction, methanol (1.6 mL) was added to the reaction solution in an ice bath, and the solvent was evaporated. The pH was adjusted to 4 with 2 mol/L hydrochloric acid. After extraction with chloroform-water, the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 420 mg of the title compound (yield: 36%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].C[C:13]1[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1>C(O)C>[CH3:18][C:16]1[S:17][C:13](=[N:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=2[OH:10])[CH2:14][CH:15]=1
Reactant: Cc1ccc(C=O)s1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: CCO
Product: CC1=CCC(=Nc2cc([N+](=O)[O-])ccc2O)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4Nitro-o-aminophenol (30.8 g, 0.2 mole) and 5-methyl-2-thiophenecarboxaldehyde (25.2 g, 0.2 mole) are dissolved in 250 ml of absolute ethanol and stirred at room temperature for 0.5 hour. The precipitated material is filtered and washed with additional ethanol yielding 49.8 g of product, melting point 202°-204°C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]([O:11][C:12]2[CH:17]=CC=C[CH:13]=2)=[O:10])[CH:5]([CH3:18])[CH:4]=1.[CH3:19]C(C)([O-])C.[K+]>O1CCCC1>[CH3:18][CH:5]1[CH2:4][C:3](=[O:2])[CH:8]=[CH:7][N:6]1[C:9]([O:11][C:12]([CH3:13])([CH3:17])[CH3:19])=[O:10]
Reactant: COC1=CC(C)N(C(=O)Oc2ccccc2)C=C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1CC(=O)C=CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 20 h
Yield: 51.5 %

Procedure:
A 3-L four neck round-bottom flask was purged and maintained with a nitrogen atmosphere and a solution of phenyl 4-methoxy-2-methylpyridine-1(2H)-carboxylate (454.1, 70.0 g, 285 mmol, 1.00 equiv) in tetrahydrofuran (1.2 L) was added. The solution was cooled to −78° C. then potassium tert-butoxide (128 g, 1.14 mol, 4.00 equiv) was added portion-wise. The resulting mixture was stirred at 10-15° C. for 20 h then concentrated in vacuo. The residue was dissolved in EtOAc (1.5 L), then carefully quenched with ice water (200 mL). The layers were separated and the aqueous was extracted with additional ethyl acetate (100 mL). The combined organics was washed with aqueous sodium hydroxide (1.5 M, 3×100 mL), aqueous hydrochloric acid (1 M, 2×100 mL), and brine (200 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether, 1:200-1:20) as the eluent to obtain the title compound as a light yellow oil (31.0 g, 51%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CBr
Reactant: Nc1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)c(N)c1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75 %

Procedure:
To a stirred solution of 3-amino-2,4-difluorophenol (intermediate X(a)) (713 mg, 4.9 mmol, 1.0 eq) in DMF (30 mL) was added Na2CO3 (1.56 g, 14.7 mmol, 3.0 eq). The resulting mixture was stirred for 40 min at room temperature. Ethyl bromoacetate (1 g, 5.90 mmol 1.2 eq) was added and the reaction stirred overnight. The reaction was diluted with water then extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (petroleum ether: EtOAc, 25:1) to give the title compound (intermediate IV(a)) as an oil (850 mg, 71%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[N:11]=[C:12]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[C:29]([C:36]([F:39])([F:38])[F:37])[CH:28]=2)[C:13]2[CH:18]=[CH:17][N:16]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:14]=2[N:15]=1)#[N:9]>C(Cl)Cl>[C:8]([C:10]1[N:11]=[C:12]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[C:29]([C:36]([F:39])([F:38])[F:37])[CH:28]=2)[C:13]2[CH:18]=[CH:17][N:16]([CH2:19][C:20]([OH:22])=[O:21])[C:14]=2[N:15]=1)#[N:9]
Reactant: CCOc1ccc(-c2nc(C#N)nc3c2ccn3CC(=O)OC(C)(C)C)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(-c2nc(C#N)nc3c2ccn3CC(=O)O)cc1C(F)(F)F
Reaction time: 5 h
Yield: 97.9 %

Procedure:
Trifluoroacetic acid (0.41 mL) was added to a solution of tert-butyl {2-cyano-4-[4-ethoxy-3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}acetate (160 mg) in CH2Cl2 (1.6 mL) at room temperature, and the mixture was stirred at the same temperature for 5 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (CHCl3:MeOH=100:0 to 80:20), whereby {2-cyano-4-[4-ethoxy-3-(trifluoromethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}acetic acid (137 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH3:1][C:2]1[CH:9]=[C:8]([O:10][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[C:7]([CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1cc(C=O)c(C)cc1O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
To a stirring solution of 2,5-dimethyl-4-hydroxy-benzaldehyde (0.43 g, 2.86 mmol) in DMF (8 mL) at room temperature was added imidazole (0.43 g, 6.29 mmol) and chloro-triisopropyl-silane (0.74 mL, 3.43 mmol). The mixture was stirred at room temperature for 16 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (15:75) to afford 2,5-dimethyl-4-triisopropylsilanyloxy-benzaldehyde as a colorless oil (0.7 g, 80%): 1H NMR (300 MHz, DMSO-d6): δ 10.07 (s, 1 H), 7.65 (s, 1 H), 6.69 (s, 1 H), 2.55 (s, 3 H), 2.21 (s, 3 H), 1.35 (m, 3 H), 1.10 (d, J=6.9 Hz, 18 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=5% ethyl acetate in hexanes; Rf=0.68.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:21][C:20]3[CH:19]=[C:18]([C:22]([NH:24][NH2:25])=[O:23])[NH:17][C:16]=3[CH:15]=2)=[CH:10][CH:9]=1)([O-:7])=[O:6].C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C1COCC1.O>[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:21][C:20]3[CH:19]=[C:18]4[N:17]([C:1](=[S:2])[NH:25][NH:24][C:22]4=[O:23])[C:16]=3[CH:15]=2)=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: S=C(Cl)Cl
Reactant: NNC(=O)c1cc2oc(-c3ccc([N+](=O)[O-])cc3)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH][nH]c(=S)n2c1cc1oc(-c3ccc([N+](=O)[O-])cc3)cc12
Reaction time: 12 h

Procedure:
As depicted in Scheme 29 below, a solution of thiophosgen (1.2 molequivalents) in THF is added dropwise at room temperature to a stirred solution of the corresponding hydrazide, 2-(4-nitrophenyl)-4H-furo[3,2-b]pyrrole-5-carbohydrazide, prepared as described hereinabove (1.5 molequivalents), and Na2CO3 in dry THF. The mixture is stirred for 12 hours, and thereafter a mixture of ethyl acetate and water is added. The organic phase is washed with diluted HCl and brine and concentrated wider reduced pressure. The pure product, 2-(4-nitro-phenyl)-4-thioxo-5,6-dihydro-4H-1-oxa-3b,5,6-triaza-cyclopenta[a]inden-7-one, is obtained after purification by flash chromatography.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@H:29]([CH3:34])[C:30](OC)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH2:35]([CH2:37][NH2:38])[OH:36]>>[OH:36][CH2:35][CH2:37][NH:38][C:30](=[O:31])[C@H:29]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[CH3:34]
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: NCCO
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)C(=O)NCCO
Yield: 61.7 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.55 mmol) was reacted with ethanolamine (0.332 ml, 5.5 mmol) to give the title compound as a white solid (164 mg, 62%); NMR Spectrum 1.64 (d, 3H), 3.21 (m, 2H), 3.43 (m, 2H), 4.75 (t, 1H), 5.22 (q, 1H), 5.77 (s, 2H), 6.95 (d, 1H), 7.01 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.72 (m, 4H), 8.16 (s, 1H), 8.48 (br t, 1H), 8.53 (m, 3H), 10.73 (br s, 1H); Mass spectrum MH+ 484.