Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][C:43]=1[CH3:51]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][C:43]=5[CH3:51])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3C)cn2)cc1
Yield: 24.8 %

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 4-bromo-3-methylbenzoic acid (60 mg) instead of 4-bromobenzoic acid, in the same manner as Step A in Example 1-D-19, a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-benzoic acid (31 mg, 25%) was obtained.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].[C:14]([C:18]1[CH:22]=[C:21]([C:23](=O)[CH2:24]Br)[N:20]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[CH:22]=[C:21]([C:23]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:24]=2)[N:20]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: CC(C)(C)c1cc(C(=O)CBr)n(Cc2ccccc2)n1
Product: COC(=S)c1cc(-c2nc(-c3cc(C(C)(C)C)nn3Cc3ccccc3)cs2)c(C)s1
Yield: 81 %

Procedure:
A solution of 823 mg (3.3 mmol of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 1.36 g (3.3 mmol) of 1-[3-(tert-butyl)-1-benzylpyrazol-5-yl]-2-bromoethan-l-one in a manner similar to Example 8, step (a) to give methyl 4-{4-[3-(tert-butyl)-1-benzylpyrazol-5-yl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate (1.25 g, 79%) as a crystalline solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.11 (s, 1H), 8.05 (s, 1H), 7.28-6.99 (m, 5H), 6.70 (s, 1H), 5.88 (s, 2H), 3.86 (s, 3H), 2.70 (s, 3H), 1.30 (s, 9H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C24H25N3O2S3, 484.1 (M+H), found 483.9.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:23])[CH:8]=2)[N:3]=1.[S:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C(O)CCC>[S:24]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH2:28][N:27]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:23])[CH:8]=3)[N:3]=2)[CH2:26][CH2:25]1
Reactant: c1ccc2c(c1)CNCCS2
Reactant: Cc1ccc2nc(Cl)nc(NCCNC(=O)OC(C)(C)C)c2c1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(NCCNC(=O)OC(C)(C)C)c2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of tert-butyl {2-[(2-chloro-6-methylquinazolin-4-yl)amino]ethyl}carbamate (460 mg, 1.366 mmol) in n-butanol (6 mL) was added 2,3,4,5-tetrahydro-1,4-benzothiazepine (248 mg, 1.50 mmol) and triethylamine (276 mg, 2.732 mmol). The mixture was heated with stirring at 100° C. in a sealed tube for 4 hours, and then concentrated in vacuo. The residue was purified by flash column chromatography to afford 350 mg of the desired product as a white solid (yield was 55%).
Reaction SMILES: CI.[C:3]([C:7]1[CH:8]=[C:9]([C:25](=[O:27])[CH3:26])[CH:10]=[C:11]([N:15]2[CH2:19][C@@H:18]([O:20][CH2:21][O:22][CH3:23])[C@H:17]([OH:24])[CH2:16]2)[C:12]=1[O:13][CH3:14])([CH3:6])([CH3:5])[CH3:4].[C:28]1(C)C=CC=CC=1.C(OCC)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:3]([C:7]1[CH:8]=[C:9]([C:25](=[O:27])[CH3:26])[CH:10]=[C:11]([N:15]2[CH2:19][C@@H:18]([O:20][CH2:21][O:22][CH3:23])[C@H:17]([O:24][CH3:28])[CH2:16]2)[C:12]=1[O:13][CH3:14])([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1ccccc1
Reactant: COCO[C@@H]1CN(c2cc(C(C)=O)cc(C(C)(C)C)c2OC)C[C@H]1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: COCO[C@@H]1CN(c2cc(C(C)=O)cc(C(C)(C)C)c2OC)C[C@H]1OC
Reaction time: 64 h
Yield: 77 %

Procedure:
Tetra-n-butylammonium bromide (227 mg, 0.704 mmol) and methyl iodide (0.18 ml, 2.9 mmol) were added to a mixed solvent of 1-{3-(tert-butyl)-5-[(3R,4R)-3-hydroxy-4-(methoxymethoxy)tetrahydro-1H-1-pyrrolyl]-4-methoxyphenyl}-1-ethanone (496 mg, 1.41 mmol) in a toluene (3 ml) −50% aqueous NaOH (3 ml) mixed solvent in that order at room temperature and the mixture was stirred for 64 hours. It was then diluted with water, extraction was performed with ethyl acetate and the extract was washed with brine. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (397 mg, 77%) as a light yellow oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)(=O)=O.[CH:15]1([SH:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][S:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OCCc1ccc(Br)cc1
Reactant: SC1CCCC1
Product: Brc1ccc(CCSC2CCCC2)cc1

Procedure:
Obtained by working as in Example 1a, starting with 2-(4-bromophenyl)ethyl methanesulfonate (Carbohydr. Res. (2003) 338, 29) and cyclopentanethiol.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[OH:10][CH:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH2:13][CH2:12]1>CCO>[OH:3][NH:2][C:20]([C:15]1[C:14]2[CH2:13][CH2:12][CH:11]([OH:10])[C:19]=2[CH:18]=[CH:17][CH:16]=1)=[NH:21]
Reactant: N#Cc1cccc2c1CCC2O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1cccc2c1CCC2O
Reaction time: 16 h
Yield: 90 %

Procedure:
Prepared using General Procedure 1. To hydroxylamine hydrochloride (0.87 g, 12.5 mmol) and sodium carbonate (1.32 g, 12.5 mmol) in EtOH (20 mL) was added 1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile INT-46 (1.80 g, 11.3 mmol) in one portion and the solution was heated to reflux. After 16 h, the reaction was cooled and filtered to remove the solids. The EtOH was removed and the compound was purified by chromatography (MeOH/DCM) to give 1.74 g (90%) of N,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide INT-47 as a white foam. LCMS-ESI (m/z) calculated for C10H12N2O2: 192.1; found: 193.1 [M+H]+, tR=0.56 min. 1H NMR (400 MHz, MeOD) δ 10.30 (s, 1H), 9.97 (s, 1H), 7.72-7.58 (m, 1H), 7.46-7.37 (m, 2H), 5.22 (t, J=6.5, 1H), 3.17-3.03 (m, 1H), 2.99-2.83 (m, 1H), 2.49 (dddd, J=11.4, 8.0, 7.0, 4.4, 1H), 2.02-1.88 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:19]=[N:18][C:5]2[N:6]=[C:7]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]=[C:9]([OH:10])[C:4]=2[CH:3]=1.[C:20]([C:22]1[CH:43]=[CH:42][C:25]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])=[CH:24][CH:23]=1)#[CH:21].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.[Pd](Cl)Cl>[C:12]([NH:11][C:7]1[N:8]=[C:9]([OH:10])[C:4]2[CH:3]=[C:2]([C:21]#[C:20][C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])=[CH:42][CH:43]=3)[CH:19]=[N:18][C:5]=2[N:6]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(Br)cnc2n1
Reactant: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A mixture of 2.0 g of 6-bromo-2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidine, 2.1 g of diethyl N-(4-ethynylbenzoyl)-L-glutamate, 2.57 ml of triethylamine, 0.11 g of palladium chloride, 0.32 g of triphenylphosphine, and 0.05 g of cuprous chloride in 150 ml of acetonitrile is heated at reflux under nitrogen for 2.5 hours. The solid which forms upon first cooling to room temperature is collected by filtration, and washed with cold acetonitrile to yield 1.91 g of diethyl N-[4-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-ylethynyl)benzoyl]-L-glutamate which is sufficiently pure for further processing. Chromatography on silica gel with 5% methanol:methylene chloride showing the following physical properties. m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 1.25 (t, 3H, J=7.20 Hz), 1.33 (t, 3H, J=7.20 Hz), 1.36 (s, 9H), 2.14-2.62 (m, 4H), 4.14 (q, 2H, J= 7.20 Hz), 4.27 (q, 2H, J=7.20 Hz), 4.79-4.86 (m, 1H), 7.30 (d, 1H, J=8.40 Hz), 7.63 (d, 2H, J=8.25 Hz), 7.86 (d, 2H, J=8.25 Hz), 8.51 (brs, 1H), 8.64 (d, 1H, J=2.40 Hz), 8.97 (d, 1H, J=2.40 Hz), 12.2 (brs, 1H); IR (KBr) 3330, 3290, 2970, 1730, 1655, 1590, 1530, 1440, 1370, 1260, 1140, 1020, 965, 925, 850, 810, and 760 cm-1 ; 13C-NMR (CDCl3, 75 MHz) delta 14.3, 27.1, 27.2, 30.7, 40.6, 52.7, 61.1, 62.0, 87.61, 92.71, 115.1, 117.3, 125.9, 127.4, 127.5, 132.0, 133.9, 138.7, 149.6, 157.8, 158.6, 160.5, 166.4, 172.1, 173.5, 180.8.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([S:27][CH3:28])[N:8]2[C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:11][CH2:10][C:9]=12)=[O:4].[CH3:29][NH2:30].[K+].[Br-]>C(O)C>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]2[N:8]3[C:7]([S:27][CH3:28])=[N:6][C:5]([C:3]([NH:30][CH3:29])=[O:4])=[C:9]3[CH2:10][N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:13]=2[CH:18]=1
Reactant: COC(=O)c1nc(SC)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reactant: CN
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: CNC(=O)c1nc(SC)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
A mixture of 2.1 g (0.005 mole) of 8-chloro-6-(2-chlorophenyl)-1-methylthio-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid methyl ester and 20 ml of a 28% solution of methylamine in ethanol was heated at 130° in a steel bomb for 18 hrs. The contents of the bomb were evaporated at reduced pressure to give a tan solid. Recrystallization from ethanol gave off-white prisms with mp 224°-227°. Uv λ max 218 mμ (ε=51,400) infl 245 (26,000) sh 275 (12,000); ir (KBr) 3410 cm-1 (NH) 1668, 1527 (CON).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:18](=[O:20])[CH3:19])=[C:5]([CH3:10])[CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(C)=O)c(C)c1
Reaction time: 1.33 h
Yield: 90.4 %

Procedure:
4-Methoxy-2-methylaniline (26.06 g, 190 mmol) and triethylamine (43 ml, 309 mmol) were dissolved in dichloromethane, acetic anhydride (25 ml, 265 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 80 min. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained solid was filtered, washed with hexane, and dried under reduced pressure to give the title compound (30.78 g, yield 90%) as a pale-pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:15](=O)[CH3:16])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([CH3:16])[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26])[CH3:10]
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(Cl)c2)c1-c1ccccc1

Procedure:
m-Chloroaniline (5 mmol, 0.6 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 12 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. Upon completion of the reaction, the crude solid was recrystallized from ethanol to provide the named product (m.p. 93.2° C.-94.6° C.).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8]CC)=O)=[O:4].[CH2:19]=[N:20][C:21]([CH3:31])([C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=1)[CH3:22]>C1(C)C(C)=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[O:4][CH2:19][N:20]([C:21]([CH3:31])([C:23]2[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=2)[CH3:22])[C:6](=[O:8])[C:5]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=NC(C)(C)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C(C(=O)C(F)(F)F)c1ccccc1
Solvent: Cc1ccccc1C
Product: CC(C)(c1cc(Cl)cc(Cl)c1)N1COC(C(F)(F)F)=C(c2ccccc2)C1=O
Yield: 83.7 %

Procedure:
Ethyl 2-trifluoroacetyl-2-phenylacetate (1.30 g) and N-methylene-1-methyl-1-(3,5-dichlorophenyl)ethylamine (1.19 g) were mixed, and xylene (10 ml) was added thereto. The mixture was allowed to react by refluxing for 30 minutes. The solvent was removed by evaporation, and the crude product was recrystallized from a mixture of hexane and ethyl acetate to afford the captioned compound (1.80 g, yield 84%).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][C@H:8]1[CH2:11][NH:10][C:9]1=[O:12])=[O:6])[CH3:3].C([Li])(CC)C.[CH3:19][S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21]>O1CCCC1.C1CCCCC1>[CH3:3][C:2]([CH3:13])([O:4][C:5]([NH:7][C@H:8]1[CH2:11][N:10]([C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:25])[C:9]1=[O:12])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC1=O
Reactant: CS(=O)(=O)N=C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)NS(C)(=O)=O)C1=O
Temperature: -75 °C

Procedure:
(S)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-azetidinone (1.12 g) was dissolved in dry tetrahydrofuran (120 ml) and stirred at -75° C. under dry nitrogen. sec-Butyl lithium (4.44 ml of a 1.35 M solution in cyclohexane) was added and followed in two minutes by methylsulfonyl isocyanate (0.72 ml). After stirring for 25 minutes at -75° C., the reaction was quenched by the addition of 0.5 M pH 5.5 monobasic potassium phosphate buffer (60 ml), diluted with ethyl acetate-water, acidified to pH 2.5 with 3N hydrochloric acid, and (60 ml), diluted with ethyl acetate-water, acidified to pH 2.5 with 3N hydrochloric acid, and extracted with ethyl acetate (three times). The extract was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo to yield the desired product as a foam (1.73 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][N:6]=1.N1C=CC=CC=1.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:22][S:19]([NH:1][C:2]1[S:3][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][N:6]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1cnc(N)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Cc1cnc(NS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of ethyl 2-aminothiazol-5-ylacetate (32 g.) in methylene chloride (160 ml.) was added pyridine (27.2 g.) under ice-cooling, and to the mixture was dropwise added mesyl chloride (29.6 g.) in methylene chloride (29.6 ml.) over 30 minutes at 8° to 10° C. The mixture was further stirred for 8 hours at room temperature. After the reaction, methylene chloride was distilled off from the reaction mixture, and to the residue were added water (300 ml.) and ethyl acetate (300 ml.). The resulting mixture was adjusted to pH 2 with 10% hydrochloric acid under ice-cooling, and the precipitates were collected by filtration and washed with ethyl acetate. The precipitates were recrystallized from ethanol (600 ml.) to give ethyl 2-methanesulfonamidothiazol-5-ylacetate (27.3 g.), mp 153° to 155° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.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.[NH2:50][N:51]1[C:59]2[C:54](=[CH:55][C:56]([F:60])=[CH:57][CH:58]=2)[C:53]([CH2:61][C:62]([CH3:65])([OH:64])[CH3:63])=[CH:52]1>CN(C=O)C.CCOC(C)=O>[F:60][C:56]1[CH:55]=[C:54]2[C:59](=[CH:58][CH:57]=1)[N:51]([NH:50][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:5][CH:6]=1)=[O:10])[CH:52]=[C:53]2[CH2:61][C:62]([OH:64])([CH3:63])[CH3:65]
Reactant: CC(C)(O)Cc1cn(N)c2ccc(F)cc12
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(CC(C)(C)O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (748 mg, 3.48 mmol) in DMF (30 mL) is treated with HATU (1.3 g, 3.48 mmol) and DIPEA (1.2 mL, 6.96 mmol), and the mixture is stirred at rt for 30 min. 1-(1-Amino-5-fluoroindol-3-yl)-2-methyl-propan-2-ol (2.9 mmol) is added and the mixture is stirred at 80° C. for 12 h. The mixture is diluted with EtOAc, washed with saturated aqueous NH4Cl and saturated aqueous Na2CO3, dried (Na2SO4), filtered and concentrated in vacuo to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid [5-fluoro-3-(2-hydroxy-2-methyl-propyl)-indol-1-yl]-amide (990 mg, 81%). MS: 420 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 1.13 (s, 6H), 2.75 (s, 2H), 2.85 (s, 3H), 6.84 (m, 1H), 7.24 (m, 1H), 7.37 (m, 1H), 7.53 (m, 1H), 7.95 (s, 1H), 7.98 (m, 1H), 8.44 (m, 1H), 8.76 (m, 1H), 9.15 (s, 1H).
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[CH2:13]1[C:18](=O)[N:17](Br)[C:15](=[O:16])[CH2:14]1.CC1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28]C=1C(OC)=O>C(Cl)(Cl)(Cl)Cl>[N+:32]([C:30]1[CH:31]=[C:13]2[C:14](=[CH:28][CH:29]=1)[C:15](=[O:16])[NH:17][CH2:18]2)([O-:34])=[O:33]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1NCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
AIBN (84 mg, 0.51), NBS (1.1 gram, 6.4 mmol), and the methyl 2-methyl-4-nitrobenzoate (1 g, 5.1 mmol) from step 1 of this example were suspended in CCl4 and the mixture heated under N2 at 79 C overnight. The solution was filtered, and concentrated in vacuum. The residue was dissolved in 7 N ammonia in methanol (15 ml) and the solution stirred for 2 hours at RT. The mixture was concentrated in vacuum. and the resulting solid suspended in EtOAc (21.5 ml), heated at 80° C. for 30 minutes with stirring, cooled RT and aged at −20° C. for the 3 days. The solid was isolated by filtration to give the titled compound.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]2[C:6]=1/[C:7](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:8](=[O:17])[NH:9]2.[Cl-].[NH4+]>O.CO.[Zn]>[NH2:14][C:13]1[C:5]([C:4]#[C:3][CH2:2][OH:1])=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:17])/[C:7]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(C#CCO)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(C#CCO)c21

Procedure:
Using Method L above, (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (63 mg, 0.19 mmol) (from Example 30 above) was reduced with zinc (0.11 g, 1.67 mmol) and ammonium chloride (22.4 mg, 0.42 mmol) in 10% water in methanol (10 mL) with heating at reflux for 2 h to give (Z)-5-amino-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 18 mg, 40%).
Reaction SMILES: CN1CCN=C1C1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Br:33])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9]C=1.[N:35]1([N:40]=[C:41]2C=CC(N)=C[CH2:42]2)[CH2:39][CH2:38][CH2:37][CH2:36]1.C(Cl)CCl>CN(C=O)C.O>[N:35]1([N:40]=[C:41]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[CH:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Br:33])[NH:16][C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)=[O:18])=[CH:9][CH2:42]2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: NC1=CCC(=NN2CCCC2)C=C1
Reactant: CN1CCN=C1c1ccc(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2ccccc2Br)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: O=C(Nc1ccc(Cl)cc1)NC(C(=O)NC1=CCC(=NN2CCCC2)C=C1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of 2-(2-bromophenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (from EXAMPLE 77, 60 mg, 0.16 mmol) and 4-(pyrrolidin-1-ylimino)phenylamine (60 mg, 0.31 mmol) in DMF (4 mL) and H2O (1 mL), EDC (120 mg, 0.62 mmol) was added. After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (70 mg). MS 554.2 and 556.2 (M+H, Cl+Br pattern).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](=[O:19])([O:14][CH2:15][CH2:16][CH2:17][CH3:18])OCCCC.[CH2:20](O)[CH2:21]CC>>[C:8](=[O:19])([O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:21][CH:20]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CCCCOC(=O)OCCCC
Reactant: CCCCO
Product: O=C(Oc1ccccc1)Oc1ccccc1
Reaction time: 0.67 h

Procedure:
After 150 minutes of starting of the reaction, the reflux ratio was set to 0.2 and unreacted phenol and dibutyl carbonate were mainly distilled out in a reflux ratio of 0.2 by lowering gradually the reaction pressure from atmospheric pressure to 450 mmHg. After 40 minutes, unreacted phenol and dibutyl carbonate were almost distilled out. At this time, the bottom section temperature was 205° C. Then, dibutyl carbonate due to disproportionation was mainly distilled out by further lowering gradually the reaction pressure to 100 mmHg. After 2 hours of setting the reflux ratio to 0.2, the reaction was completed. At this time, the reaction liquid was analyzed. At this time, the bottom section temperature was 207° C. The distilled-out liquid contained 668 g of dibutyl carbonate, 774 g of phenol and 18 g of butanol. The bottom liquid was further distilled in order to remove the catalyst, whereby 133 g of diphenyl carbonate was obtained as the distillate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[CH3:41][CH:42]([CH3:51])[C:43](N1CCOCC1)=[O:44]>>[OH:16][C:12]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:11]=[C:2]([C:43](=[O:44])[CH:42]([CH3:51])[CH3:41])[CH:3]=[CH:4]2)([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)C(O)(c1ccc2cc(Br)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)C(=O)N1CCOCC1
Product: CC(C)C(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Yield: 84.4 %

Procedure:
In a similar manner to that described in Example 57-(i), the reaction of 1-(6-bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (2.0 g) with 2-methyl-1-(4-morpholinyl)-1-propanone (688 mg) was carried out to give the titled compound (966 mg) as a colorless powder.