Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:28][C:27]2[CH:29]=[CH:30][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Solvent: Cc1ccccc1
Product: COc1ccc(N=C(C)c2cccc(C(C)=Nc3c(C)cc(C)cc3C)n2)cc1
Reaction time: 144 h

Procedure:
Monoimine (1, 280 mg, 1 mmol) and 4-methoxyaniline (123 mg, 1 mmol) were dissolved in 20 ml of toluene. To this solution 4 Å molecular sieves were added. After standing for 6 days at room temperature the reaction mixture was filtered and the solvent was removed in vacuo. The residue was recrystallised from ethanol. Yield 148 mg (38%) of mixed diimine (6). 1H-NMR (CDCl3) δ 8.42 (dd, 1H), 8.34 (dd, 1H), 7.86 (t, 1H), 6.93 (d, 2H), 6.88 (s, 2H), 6.81 (d, 2H), 3.82 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H), 2.22 (s, 3H), 2.00 (s, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]3[C:23]([C:14]=2[S:13][C:12]1=S)=[CH:22][CH:21]=[CH:20][CH:19]=3.C1(C)C=CC(S(OC)(=O)=O)=CC=1.[CH2:37]([N:39]1[C:43](=[O:44])[CH2:42][S:41][C:40]1=[S:45])[CH3:38].C(#N)C>C(N(CC)CC)C>[CH2:37]([N:39]1[C:43](=[O:44])[C:42](=[C:12]2[N:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:15]3[CH:16]=[CH:17][C:18]4[C:23]([C:14]=3[S:13]2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:41][C:40]1=[S:45])[CH3:38]
Reactant: COCCOCCOCCn1c(=S)sc2c3ccccc3ccc21
Reactant: CCN1C(=O)CSC1=S
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(=C2Sc3c(ccc4ccccc34)N2CCOCCOCCOC)SC1=S
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.9 g of 3-methoxyethoxyethoxyethylnaphtho[2,1-d]thiazoline-2-thion and 1.8 g of methyl p-toluenesulfonate were fed into a 50 ml short-neck flask provided with a reflux condenser. The resultant mixture was heated at 120° C. for 4 hours. After cooling the reaction mixture to room temperature followed by addition of 0.8 g of 3-ethylthiazolidine-4-on-2-thion and 24 ml of acetonitrile, the resultant mixture was cooled to 5° C., and 1.0 g of triethylamine was added thereto. After stirring at 10° C. for 24 hours, yellow precipitates thus obtained were suction-filtered, washed with 10 ml of acetonitrile three times, and dried to obtain the intended compound.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([NH2:18])=[O:17])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.C(Cl)Cl.[Pd]>[C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([NH2:18])=[O:17])[CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Cc1ccccc1C(=Cc1ccnc(NC(N)=O)c1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccccc1C(Cc1ccnc(NC(N)=O)c1)c1ccccc1
Yield: 14 %

Procedure:
[4-(2-Phenyl-2-o-tolyl-vinyl)-pyridin-2-yl]-urea (140 mg, 0.43 mmol) is dissolved in methanol (2 mL) and DCM (2 mL). Then 5% palladium on carbon (90 mg, 0.043 mmol) is added. The reaction is stirred for 16 hours under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is concentrated to give the crude product. Purification by Gilson preparative HPLC affords 20 mg of the titled product.
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[NH2:8]/[C:9](=[N:17]\[OH:18])/[CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>N1C=CC=CC=1>[CH3:1][C:2]1[O:18][N:17]=[C:9]([CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(C)/C(N)=N/O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)c1noc(C)n1

Procedure:
Acetic anhydride (4.6 mL, 49 mmol) was added to a pyridine (50 mL) solution of the intermediate from Step A (2.6 g, 16.2 mmol). The solution was heated at reflux for 1 hour and then at room temperature overnight. The solution was then concentrated to remove most of the pyridine. The concentrated solution was diluted with EtOAc and washed twice with water. The organic layer was concentrated and the residue purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR δ (ppm) (CHCl3-d): 4.19 (2H, dd, J=72, 3.6 Hz), 3.94 (1H, m, J=7.3 Hz), 2.58 (3H, s), 1.60 (3H, t, 7.3 Hz), 1.25 (3H, t, J=7.1 Hz). m/z=185.1 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:5][N:4]=1)(=[O:24])=[O:23]
Reactant: OCc1nnc(-c2ccccn2)s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1nnc(-c2ccccn2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(5-hydroxymethyl-1,3,4-thiadiazol-2-yl)-pyridine (6 gm), and triethylamine (13.1 ml) in dichloromethane (150 ml) was added methanesulfonylchloride (5.31 gm) at 0° C. The reaction mixture was stirred at 0° C. over a period of 1 h. The reaction was quenched by addition of water and layers were separated. Aqueous layer was extracted with dichloromethane (50 ml×2). Combined organic layer was washed with aqueous sodium bicarbonate solution followed by water and evaporated under vacuum to provide title compound in 7.5 gm quantity (88%) as oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([OH:11])=[CH:6][N:5]=1.[CH3:12]I.O>CN(C=O)C>[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([O:11][CH3:12])=[CH:6][N:5]=1
Reactant: CI
Reactant: Cc1cc(O)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(Cl)c(C)c1
Yield: 101.5 %

Procedure:
Into a flame dried flask under N2 was placed DMF (150 mL), NaH (50% oil dispersion, 4.0 g, 0.08 mol) and 2-chloro-5-hydroxy-3-methylpyridine (11.7 g, 0.08 mol). The solution was stirred at 0°-5° C. until the evolution of H2 ceased and then a solution of CH3I (5.6 mL, 0.09 mol) in DMF (50 mL) was added dropwise. After the addition, the solution was allowed to stir at room temperature overnight. The resulting slurry was added to H2O and extracted with Et2O (3X). The organic layer was concentrated and the residue distilled at 85° C. (0.6 mm) to yield 12.8 g of 2-chloro-5-methoxy-3-methylpyridine (95%) as an oil; 1H NMR (CDCl3) δ 2.35 (3H, s), 3.8 (3H, s), 7.1 (1H, d, J=3) and 7.9 (1H, d, J=3 ); MS m/e (M+) 157.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.[C:26](Cl)(=[O:30])[O:27][CH2:28][CH3:29]>>[C:26](=[O:30])([O:27][CH2:28][CH3:29])[O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:2]([NH2:1])=[N:3][C:4]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:5]=4[C:6]=3[CH:7]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Oc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl ethyl carbonate was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for Example 138, but using ethyl carbonochloridate. LRMS [M+H]=402.2
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][C:25]([NH2:27])=[O:26])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: OB(O)c1ccncc1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccncc2)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide and pyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.906 min, m/z=448.1; 1H NMR (CDCl3) 1.59 (d, 3H), 2.15 (m, 1H), 2.24-2.32 (m, 4H), 2.45 (m, 1H), 3.07 (m, 2H), 5.66 (m, 1H), 5.71 (m, 1H), 5.84 (m, 1H), 7.03 (m, 2H), 7.05 (m, 2H), 7.22 (m, 1H), 7.25 (m, 1H), 7.50 (d, 2H), 7.93 (d, 2H), 8.84 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.C(N(CC)CC)C.Cl.[NH:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH2:28]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:28]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O

Procedure:
51.5 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 30.5 ml of triethylamine and 33.4 g of ethyl hydrazinoacetate hydrochloride are boiled under reflux for 0.5 h in 450 ml of ethanol. On cooling, the product precipitates in crystalline form. It is filtered off and washed with ethanol. After drying, ethyl [3,5-bis(2-hydroxyphenyl)-(1,2,4]triazol-1-yl]acetate remains as colorless crystals of m.p. 172-174° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[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.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:52]=1[C:63]([NH2:65])=[O:64]>C(Cl)Cl>[C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:50][C:51]2[C:52]([C:63](=[O:64])[NH2:65])=[C:53]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH:54]=[CH:55][CH:56]=2)=[O:16])[N:13]=1)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)c1c(N)cccc1-c1ccccc1
Reactant: CC(C)(C)NS(=O)(=O)c1nc(C(=O)O)cs1
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: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1nc(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
To a solution of 2-(N-tert-butylsulfamoyl)thiazole-4-carboxylic acid (0.56 g, 2.1 mmol) in DCM (50 mL) was added HATU (1.41 g, 2.8 mmol) and DIPEA (1.04 ml, 5.6 mmol). The reaction mixture was stirred at room temperature for 1 h and then 3-aminobiphenyl-2-carboxamide (from example 218, 0.3 g, 1.4 mmol) was added. The resulting solution was stirred for an additional 16 h. After this time, the reaction mixture was washed with water, dried, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel chromatography (30% EtOAc in hexane) to provide 2-(N-tert-butylsulfamoyl)-N-(2-carbamoylbiphenyl-3-yl)thiazole-4-carboxamide (0.11 g, 17% yield) as white solid. LCMS Method V: retention time 1.85 min; [M+1]=459.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1/C(=N\O)/C.[CH3:13][C:14]([N:16](C)C)=O.P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>C(#N)C>[CH3:13][C:14]1[O:1][C:2]2[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=2[N:16]=1
Reactant: CC(=O)N(C)C
Reactant: C/C(=N/O)c1ccc(O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1nc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (ice-water) solution of (1Z)-1-(2,4-dihydroxyphenyl)ethanone oxime (9.7 g, 57.7 mmol) and dimethylacetamide (11 mL) in acetonitrile (65 mL) was added phosphorous oxychloride (5.6 mL, 60.3 mmol) dropwise. The temperature was not allowed to exceed 10° C. during the reaction. After 1 hour stirring at room temperature the yellow slurry was poured into a mixture of aqueous NaHCO3 and ice. The resulting precipitate was filtered off and dried to give the sub-title compound (6.3 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[NH:5][N:4]=1.C(O)C.N>O>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][N:4]=[C:3]2[NH:2][CH3:1]
Reactant: CNc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: N
Solvent: CCO
Solvent: O
Product: CNc1n[nH]c2ccc(N)cc12
Yield: 23.7 %

Procedure:
5-Amino-3-methylamino-1H-indazole can be obtained as described in Example 4 from 0.5 g of 3-methylamino-5-nitro-1H-indazole, 25 ml of ethanol, 5.2 g of ferrous sulfate, 8 ml of water and 6.2 ml of 32% aqueous ammonia. 0.1 g of 5-amino-3-methylamino-1H-indazole is thus obtained in the form of a cream powder melting at 215° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22](OC(C)=O)=[O:23].[Al+3].[Cl-].[Cl-].[Cl-]>>[C:22]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[C:11]=1[CH3:20])(=[O:23])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ccc(Cl)cc12
Yield: 86 %

Procedure:
1-Benzenesulfonyl-5-chloro-2-methylindole prepared in accordance with the literature (J. Org. Chem., 47, 757 (1982) was reacted with Ac2O/AlCl3 in a similar manner described in Reference example 2 (3) to give 3-acetyl-1-benzenesulfonyl-5-chloro-2-methylindole. Yield: 86%.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[OH-].[Na+].O.[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20](Cl)(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[C:12]1([CH3:24])[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:21])=[O:22]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(OS(=O)(=O)c2c(C)cc(C)cc2C)cc1
Reaction time: 1 h

Procedure:
10.8 g of p-cresol is added to a mixture containing 9.17 g of 48% NaOH, 50 ml of water and 50 ml of toluene. To the resulting mixture is added 22.9 g of mesitylenesulfonyl chloride, and reaction is carried out at 60° to 65° C. for 1 hour. After separating the aqueous layer, toluene is removed from the toluene layer by distillation. The resulting desired compound is purified with methanol.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:64])([CH3:63])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[N:56]([CH3:57])[C:55]3[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=3[N:53]=2)[C:47]1=[O:62])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:64])([CH3:63])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[N:56]([CH3:57])[C:55]3[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=3[N:53]=2)[C:47]1=[O:62])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cn1c(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)nc2ccccc21
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2nc3ccccc3n2C)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A solution containing the product from Example 1H (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 59F(0.070 mmol), DEPBT (0.021 g, 0.070 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.240 mmol) and the mixture was stirred at 25° C. for 2 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The reaction was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated, to give the title compound (0.021 g, 50% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.81 (s, 9 H), 0.88 (s, 9 H), 1.38 (m, 1 H), 1.53 (m, 1 H), 2.40 (m, 1 H), 2.64 (m, 3 H), 2.83 (m, 1 H), 3.12 (m, 4 H), 3.54 (m, 4 H), 3.82 (m, 3 H), 3.95 (m, 1 H), 4.03 (s, 1 H), 4.18 (m, 1 H), 4.43 (d, J=6.99 Hz, 1 H), 4.60 (m, 2 H), 6.92 (m, 4 H), 7.04 (m, 2 H), 7.21 (m, 4 H), 7.32 (m, 1 H), 7.58 (m, 3 H), 7.89 (m, 5 H), 8.65 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([O:11][CH2:12][CH3:13])[C:7]=1[C:14]#[N:15])=[O:4].S(=O)(=O)(O)[OH:17]>>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([O:11][CH2:12][CH3:13])[C:7]=1[C:14](=[O:17])[NH2:15])=[O:4]
Reactant: CCOc1nsc(NC(=O)NC)c1C#N
Reactant: O=S(=O)(O)O
Product: CCOc1nsc(NC(=O)NC)c1C(N)=O
Temperature: 0 °C

Procedure:
A solution of 5.6 g of 1-methyl-3-(4-cyano-3-ethoxy-5-isothiazolyl)urea (from Example I) in 10 ml of concentrated sulfuric acid was heated at 50° during 1.5 hours. The reaction mixture was poured into 200 ml of ice-water and stirred for one half hour. The resultant precipitate was collected by filtration and was allowed to air-dry overnight. The solid was slurried with 50 ml of saturated sodium bicarbonate solution. The resulting white solid was collected by filtration and recrystallized from ethanol to give 4.3 g of 1-methyl-3-(4-carbamoyl-3-ethoxy-5-isothiazolyl)urea, m.p. 240°-241°.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[CH3:19][CH:20]1[NH:24][C:23](=O)[CH2:22][CH2:21]1.P(Cl)(Cl)(Cl)=O>>[CH3:19][CH:20]1[N:24]=[C:23]([N:6]2[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:16]=[CH:15][C:14]=3[O:13][C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:22][CH2:21]1
Reactant: CC1CCC(=O)N1
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1O2
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCC(N2c3ccccc3Oc3ccc(C(F)(F)F)cc32)=N1

Procedure:
Reaction of 2-(trifluoromethyl)phenoxazine, 5-methyl-2-pyrrolidinone and phosphorous oxychloride according to the procedure of Example 1 provides the free base 10-(5-METHYL-1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE as a distillable oil, b.p. 145-152° C. at 0.03 mm Hg. Conversion of the free base to the hydrochloride salt affords 10-(5-METHYL-1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE HYDROCHLORIDE, m.p. 192.5-195.5° C. (dec.) (corr.), in a 45% overall yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([OH:14])[CH:8]=1)[CH3:2].C([O-])(O)=O.[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:23](=[O:24])[CH2:22][Cl:21])=[C:9]([OH:14])[CH:8]=1)[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)C=Cc1ccc(N)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C=Cc1ccc(NC(=O)CCl)c(O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 11-3 (3.38 g, 16.3 mmol) in CHCl3 (80 mL) was added saturated NaHCO3 (50 mL) and it was then chilled to 0° C. A solution of chloroacetyl chloride (1.94 mL, 24.4 mmol) in CHCl3 (30 mL) was added dropwise to the chilled biphase. Upon addition completion, the reaction was stirred at 0° C. for 1 h. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give 11-4 which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:14][N:13]([CH2:15][C:16]([NH:18]C2C=CC=CC=2)=[O:17])[C:12](=[O:25])[CH2:11][N:10]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:9]1=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC=CC=1.[CH2:44](N)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH2:44]([NH:18][C:16](=[O:17])[CH2:15][N:13]1[CH2:14][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:36])[N:10]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:11][C:12]1=[O:25])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NCc1ccccc1
Reactant: O=C(CN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)Nc1ccccc1
Solvent: Nc1ccccc1
Product: O=C(CN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)NCc1ccccc1

Procedure:
Instead of the starting material compound of Example 270, that is, aniline, benzylamine was used for the similar procedure as in Example 270 to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])[CH:11]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[CH3:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[S:33](Cl)(=[O:35])=[O:34]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:14]([CH:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([O:4][CH2:3][CH2:2][NH:1][S:33]([C:29]3[N:28]([CH3:27])[CH:32]=[CH:31][N:30]=3)(=[O:35])=[O:34])[CH:13]=2)[CH2:9][CH:10]1[NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)NC1Cc2ccc(OCCN)cc2C1Cc1ccccc1
Reactant: Cn1ccnc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)NC1Cc2ccc(OCCNS(=O)(=O)c3nccn3C)cc2C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 6-(2-aminoethoxy)-1-benzyl-2,3-dihydro-1H-inden-2-ylcarbamate (44.7 mg, 0.126 mmol; see example 193.8) in dry dichloromethane (2 ml) was added 4-dimethylaminopyridine (18.49 mg, 0.151 mmol) followed by 1-methyl-1H-imidazole-2-sulfonyl chloride (22.78 mg, 0.126 mmol). The reaction mixture was stirred at room temperature for 1 h. Added dichloromethane and washed twice with 1N hydrochloric acid. The collected organic layers were washed with water, sodium bicarbonate and brine, dried, filtered and evaporated to obtain ethyl 1-benzyl-6-(2-(1-methyl-1H-imidazole-2-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate as a white foam. m=60 mg (95%)
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[CH3:15])[CH3:2].[Br:16]NC(=O)CCC(N)=O.C(OCC)(=O)C>C1COCC1>[Br:16][C:5]1[C:6]2[C:11](=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[N:3]([CH2:1][CH3:2])[C:4]=1[CH3:15].[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[CH3:15])[CH3:2]
Reactant: NC(=O)CCC(=O)NBr
Agent: CCn1c(C)cc2ccc([N+](=O)[O-])cc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1c(C)c(Br)c2ccc([N+](=O)[O-])cc21

Procedure:
Stir a solution of 1-ethyl-2-methyl-6-nitro-1H-indole, 19 (0.36 g, 1.76 mmol) and N-bromosuccinamide (0.31 g, 1.76 mmol) in anhydrous THF (10 mL) under inert atmosphere at ambient temperature for 14 hours. Quench the reaction with saturated aqueous sodium bicarbonate, add ethyl acetate, and wash with saturated aqueous sodium bicarbonate followed by saturated aqueous brine. Dry the organic layer over sodium sulfate, filter, and concentrate in vacuo. Chromatograph over silica gel using hexanes/ethyl acetate (9:1) to afford the title compound and unreacted 1-ethyl-2-methyl-6-nitro-1H-indole (0.37 g) in a 4:1 mixture which can be used in the subsequent step without further purification. LRMS (API ES+)=: 283, 285 (M, M+2M).