Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N1CC2CC1CN2C(=O)N(CC)CC)C1C=CC=CC=1.I.I.[CH2:25]([N:32]1[CH2:37][CH:36]2[CH2:38][CH:33]1[CH2:34][NH:35]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>>[CH2:25]([N:32]1[CH2:37][CH:36]2[CH2:38][CH:33]1[CH2:34][N:35]2[C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Reactant: CCOC(=O)Cl
Agent: CCN(CC)C(=O)N1CC2CC1CN2Cc1ccccc1
Agent: Cl
Agent: I
Product: CCOC(=O)N1CC2CC1CN2Cc1ccccc1
Yield: 68 %

Procedure:
Using the procedure for preparation of 2-benzyl-5-(N,N-diethylcarbamyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride as related in Example 11, 29.0 g of 2-benzyl-2,5-diazabicyclo[2.2.1]heptane dihydroiodide, prepared according to the procedure given in Example 11, was treated with 1.5 equivalents of ethyl chloroformate to yield crude product. Dry column chromatography, a technique described by B. Loev and M. M. Goodman in Chem. Ind. (London), p 2026, 1967, on 1700 g alumina using chloroform development provided 11.6 g (68%) of pure product, characterized as the maleate salt, melting point 124°-128° C.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O1C2C=CC(O)=CC=2OC1.[F:51][C:52]([F:62])([F:61])[O:53][C:54]1[CH:55]=[C:56]([OH:60])[CH:57]=[CH:58][CH:59]=1>>[C:35]1([CH:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([OH:33])([C:57]3[CH:58]=[CH:59][C:54]([O:53][C:52]([F:61])([F:62])[F:51])=[CH:55][C:56]=3[OH:60])[C:25]2=[O:34])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(OC(F)(F)F)cc1O

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-(diphenylmethyl)-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 3-(trifluoromethoxy)phenol, the title compound was obtained (75%): MS (ES+) m/z 514.5 (M+23).
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]2[N:15]=[C:14]3[S:18][C:19]([C:22](=[O:24])[NH2:23])=[C:20]([NH2:21])[C:13]3=[C:12]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)(=O)C.N>CO>[NH2:21][C:20]1[C:13]2[C:14](=[N:15][C:16]3[CH2:17][NH:8][CH2:9][CH2:10][C:11]=3[C:12]=2[C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[S:18][C:19]=1[C:22]([NH2:23])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc3sc(C(N)=O)c(N)c3c2-c2cccs2)C1
Agent: N
Solvent: CO
Solvent: CC(=O)Cl
Product: NC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CCNC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-amino-2-carbamoyl-4-thiophen-2-yl-5,8-dihydro-6H-1-thia-7,9-diaza-cyclopenta[b]naphthalene-7-carboxylic acid tert-butyl ester (100 mg) in 10 ml of anhydrous methanol under argon 0.5 ml of acetyl chloride was added dropwise, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 7N ammonia in methanol and evaporated to dryness under vacuum. The residue was purified by silica gel column (chloroform/methanol, 30:1) to give a yellow solid. 1H-NMR (300 MHz, DMSO-d6): δ 7.88 (d, J=5.1 Hz, 1H), 7.28 (dd, J=3.6, 5.1 Hz, 1H), 7.16 (d, J=3.6 Hz, 1H), 7.01 (brs, 2H), 5.64 (brs, 2H), 4.84 (brs, 1H), 3.16 (s, 2H), 2.94 (m, 2H), 1.86 (m, 2H). ES MS m/z 331 (M+H)+, 329 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[CH:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[NH:1][C:2]3[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=3[N:12]=2)=[CH:16][CH:15]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2nc(Nc3ccc(Br)cc3)[nH]c2c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
1,2-Diamino-5-trifluoromethylbenzene (0.25 g, 1.42 mmol) was diluted in toluene (5 mL) and treated with 4-bromophenylisothiocyanate (0.30 g, 1.42 mmol). The dark solution was stirred at 100° C. for 15 minutes, then treated with 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol). The reaction was maintained at 100° C. for 5 h. The reaction was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4), and concentrated under reduced pressure. The dark brown oil was purified by flash chromatography on silica gel, eluting with a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The title compound was obtained as a light pink solid (0.50 g, 30%). 1H NMR (300 M, DMSO-d6) δ 11.3 (broad d, 1H), 9.87 (d, 1H) 7.50 (d, 2H), 7.61 (d, 1H), 7.55-7.42 (m, 3H), 7.35-7.30 (m, 1H); LC/MS m/z 356.2 (MH+), retention time 2.33 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].Br[CH2:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>>[C:6]([C:5]1([C:4]([O:3][CH2:1][CH3:2])=[O:8])[CH2:12][CH2:11][CH2:10]1)#[N:7]
Reactant: CCOC(=O)CC#N
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C1(C#N)CCC1

Procedure:
The method described in Part A of Example 64 was used to treat ethylcyanoacetate (45 mL, 420 mmol) with 1,3-dibromopropane (51 mL, 510 mmol) and potassium carbonate (146 g, 1.06 mol) to provide ethyl 1-cyanocyclobutanecarboxylate as an orange oil containing about 15 mole % 1,2-dibromopropane.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([O:9][CH3:18])=[O:8])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1ccc(Br)cc1

Procedure:
4-Bromomandelic acid, with sulfuric acid added thereto, is reacted in methanol, to give methyl 2-(4-bromophenyl)-2-hydroxyacetate.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:19][CH2:18][C:17]2([CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20]2)[CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:19][CH2:18][C:17]4([CH2:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20]4)[CH2:16]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: c1ccc2c(c1)CC1(CCNC1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(N3CCC4(Cc5ccccc5O4)C3)nn2)n1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A mixture of 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (39 mg) obtained in Example 43(2), 3H-spiro[1-benzofuran-2,3′-pyrrolidine] hydrochloride (42 mg) and potassium carbonate (55 mg) was stirred in DMF (5 mL) at 120° C. overnight. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated. The residue was washed with a small amount of acetic acid to give the object product (35 mg, 52%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1>>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(O)c1cccc2cc(O)ccc12
Product: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Yield: 68.4 %

Procedure:
The title compound (1.95 g, 68% yield) was prepared as a brown solid from 6-hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 4-chloro-6,7-dimethoxyquinoline (2.04 g, 9.14 mmol) by an analogous procedure to that described in example 1. LC-MS (m/z) 376 (M+1).
Reaction SMILES: Cl.Cl.[O:3]=[C:4]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:7][CH2:6][N:5]1[CH2:16][C:17]([C:19]1[CH:33]=[CH:32][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])=[CH:21][CH:20]=1)=[O:18].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:51]([O:53][CH:54]([Cl:56])[CH3:55])=[O:52].O>C(Cl)Cl>[Cl:56][CH:54]([O:53][C:51]([N:13]1[CH2:12][CH2:11][CH:10]([N:8]2[CH2:7][CH2:6][N:5]([CH2:16][C:17]([C:19]3[CH:33]=[CH:32][C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])=[CH:21][CH:20]=3)=[O:18])[C:4](=[O:3])[CH2:9]2)[CH2:15][CH2:14]1)=[O:52])[CH3:55]
Reactant: CCCCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCNCC3)CC2=O)cc1
Reactant: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCOC(=O)COc1ccc(C(=O)CN2CCN(C3CCN(C(=O)OC(C)Cl)CC3)CC2=O)cc1
Temperature: 0 °C

Procedure:
To a suspension of 99.6 mg of n-butyl 4-[[2-oxo-4-(piperidin-4-yl)-piperazin-1-yl]acetyl]phenoxyacetate dihydrochloride synthesized according to the method described in WO962503 in 2 ml of methylene chloride were added 151 mg of proton sponge and 26 μl of 1-chloroethyl chloroformate with stirring at 0° C., and the mixture was stirred at room temperature for 18 hours. The reaction mixture thus obtained was poured into 2 ml of water, and extracted three times with 4 ml of ethyl acetate. The organic layer collected was dried over magnesium sulfate, and the solvent was removed by distillation to give 82.7 mg of n-butyl 4-[[4-[1-(1-chloroethyl)oxycarbonylpiperidin-4-yl]-2-oxopiperazin-1-yl]acetyl]phenoxyacetate as a crude crystalline product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:18]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 74 h

Procedure:
4-Cyanophenol (5.0 g) is dissolved in DMF (6 ml), and thereto are added ethyl 4-bromobutanate (7.94 ml) and potassium carbonate (6.4 g), and the mixture is stirred at room temperature for 74 hours. The reaction mixture is poured into water, and the colorless precipitates are collected by filtration and washed with water to give the title compound (9.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:21](/[CH:20]=[CH:19]/[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[O:16][CH3:15])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1ccccc1C=CC(=O)O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccccc3OC)nc2n(CC)c1=O
Yield: 23.1 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.48 g (13.9 mmol) of 2-methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 990 mg (yield 24%) of Compound 157 as yellow grains.
Reaction SMILES: [CH2:1]([C:7]1[N:8]=[C:9]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[S:10][C:11]=1[CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[C:18]([CH3:28])[CH:17]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[OH-].[Li+].Cl>C(O)C.O>[CH2:1]([C:7]1[N:8]=[C:9]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[S:10][C:11]=1[CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:18]([CH3:28])[CH:17]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1nc(-c2ccc(C)cc2)sc1CCC(=O)c1ccc(CCC(=O)OC)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCc1nc(-c2ccc(C)cc2)sc1CCC(=O)c1ccc(CCC(=O)O)c(C)c1
Yield: 86.9 %

Procedure:
The obtained methyl 3-[4-[3-[4-hexyl-2-(4-methylphenyl)thiazol-5-yl]propionyl]-2-methylphenyl]propionate (45 mg, 0.0915 mmol) was suspended in ethanol (2 mL) and water (1 mL). Lithium hydroxide monohydrate (12 mg, 0.275 mmol) was added to the suspension. The mixture was refluxed for 1 hour. 1N hydrochloric acid (5 mL) and ice-cooled water (2 mL) were added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure. The obtained residue was recrystallized with hexane and ethyl acetate to give the desired compound (38 mg) as while crystalline product (yield 87%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[S:22][C:10]2[N:11]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12](=[O:17])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=2[C:8]=1[S:23][CH:24]([CH3:26])[CH3:25]>ClCCl>[Cl:3][CH2:6][C:7]1[S:22][C:10]2[N:11]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12](=[O:17])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=2[C:8]=1[S:23][CH:24]([CH3:26])[CH3:25]
Reactant: O=S(Cl)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(CO)sc21
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(CCl)sc21
Reaction time: 24 h

Procedure:
Thionyl chloride (145 μl) was added to 6-(hydroxymethyl)-3-methyl-5-[(1-methylethyl)thio]-1-(2-methylpropyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.45 g) in dry dichloromethane (20 ml) and the mixture was stirred for 24 hours. The solvent was evaporated to give the subtitle compound as a an oil.
Reaction SMILES: N[C:2]1[C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.N([O-])=[O:15].[Na+].S(=O)(=O)(O)O>Cl>[OH:15][C:2]1[C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1cccc2c1C(=O)NS2(=O)=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1NS(=O)(=O)c2cccc(O)c21
Yield: 40 %

Procedure:
A solution of 1,2-benzoisothiazol-3(2H)-one-1,1-dioxide-4-diazonium chloride, which was prepared by diazotization of 1.98 gm (10 mmols) of 4-amino-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide with sodium nitrite in dilute hydrochloric acid, was reacted with 150 ml of aqueous 10% sulfuric acid, and the reaction mixture was heated on a water bath until the evolution of nitrogen had ceased. After cooling, the reaction mixture was strongly acidified with concentrated aqueous hydrochloric acid and extracted with ether. The organic phase was evaporated, the residue was dissolved in a little sodium hydrochloride, filtered and again acidified with hydrochloric acid. The crystals formed were recrystallized from water, yielding 0.98 gm (40% of theory) of 4-hydroxy-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)=[C:6]([N+:22]([O-])=O)[CH:5]=[N:4]1)[CH3:2].[C:25]([O:29][C:30]([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[F:45][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:38]=1[C:36]1[S:37][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:34]([C:46](=[O:47])[NH:22][C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=2[N:8]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:9]2)[N:35]=1
Reactant: CCn1ncc([N+](=O)[O-])c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: CCn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 76 %

Procedure:
Following the procedure for Example 517 starting with (R)—N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid gave (R)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (0.148 g, 76%). 1H-NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.76 (s, 1H), 7.95 (s, 1H), 7.43-7.34 (m, 1H), 7.12-7.02 (m, 2H), 6.37 (d, J=8 Hz, 1H), 4.23-4.16 (m, 1H), 4.05 (q, J=7 Hz, 2H), 3.43-3.31 (m, 2H), 3.25-3.15 (m, 2H), 2.22-2.05 (m, 2H), 2.03-1.89 (m, 2H), 1.89-1.72 (m, 2H), 1.57 (m, 12H).
Reaction SMILES: [CH2:1]([OH:5])[C@H:2]([OH:4])[CH3:3].[C:6](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CC=CN=1)C>[C:6]([O:5][CH2:1][C@H:2]([OH:4])[CH3:3])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[C@@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Dimethylaminopyridine (82 mg, 0.67 mmol) was added to a solution of (R)-propane-1,2-diol (5.17 g, 67.9 mmol) and trityl chloride (19.2 g 68.9 mmol) in DCM (200 mL) at 0° C. Triethylamine (23.5 mL, 168.6 mmol) was then added dropwise to this mixture. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with 1.0 N aq HCl (50 mL), washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give (R)-1-(trityloxy)propan-2-ol (18.6 g, 86%) as a white solid. 1H NMR (DMSO-d6): δ 7.43-7.22 (m, 15H), 4.64 (d, 1H), 3.78 (m, 1H), 2.94 (dd, 1H), 2.70 (dd, 1H), 1.06 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)c(F)c5)cc34)cn2)c1
Yield: 19.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (150 mg, 0.263 mmol) was deprotected in TFA/DCM (2/5 ml). This afforded 30 mg (19.6% yield) of the titled. 1H NMR (CD3OD, 400 MHz): δ 8.67-8.66 (d, 1H), 8.60 (s, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 7.78 (s, 1H), 7.58-7.54 (m, 2H), 7.47-7.43 (t, 1H), 7.39-7.33 (q, 1H), 7.12-7.10 (d, 1H), 7.05-7.00 (m, 2H), 5.43 (s, 2H), 3.55-3.52 (d, 2H), 3.28-3.16 (m, 3H), 2.21-2.03 (m, 4H). MS: m/z=470.4 (M+1), HPLC: 98.34% in method A.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH2:29])[C:24]=1[N+:30]([O-:32])=[O:31]>CN(C=O)C.C(OCC)(=O)C>[NH2:29][C:25]1[C:24]([N+:30]([O-:32])=[O:31])=[C:23]([O:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][CH:7]=2)[CH:28]=[CH:27][N:26]=1
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
Tert-butyl 4-hydroxyphenylcarbamate (3.63 g, 17.4 mmol) was dissolved in dry DMF (150 mL). Potassium tert-butoxide (2.62 g, 23.4 mmol) was added and the stirring was continued for 30 minutes at room temperature. 4-Chloro-3-nitropyridin-2-amine (3.0 g, 17.3 mmol) was added as a solid in one portion and the reaction mixture was subsequently heated at 85° C. for 4 hours. The reaction mixture was cooled, diluted with ethyl acetate (800 ml) and washed with water (1×800 ml) and brine (2×800 ml). The organic layer was dried with magnesium sulphate and evaporated. The crude was chromatographed over silica (eluant ethyl acetate:cyclohexane 1:2) to yield 4.0 g (63% yield) of tert-butyl 4-(2-amino-3-nitropyridin-4-yloxy)phenylcarbamate.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[C:21]1([S:27][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CO
Product: COC(=O)C(Sc1ccccc1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
Methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate (7.11 g) is reacted with 2.75 g of thiophenol in methanol, as in Example 16, to yield a yellow oil. After a brief distillation at 0.02 mm to remove volatile impurities, the residue is evaporatively distilled (173° C. @ 0.01 mm) to afford the product as a colorless oil which solidifies, mp 64°-68.5° C. A portion is recrystallized from hexane to give white plates, mp 71.5°-72.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][F:14])[C:6](=[O:15])[CH2:5]2.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]1[CH2:26][O:25]1)([CH3:19])([CH3:18])[CH3:17].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]([OH:25])[CH2:26][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][F:14])[C:6](=[O:15])[CH2:5]2)([CH3:18])([CH3:17])[CH3:19]
Reactant: Nc1cc(F)c2c(c1)CC(=O)N2CCF
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2CCF

Procedure:
5-Amino-7-fluoro-1-(2-fluoro-ethyl)-1,3-dihydro-indol-2-one (0.39 g, 1.84 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (0.319 g, 1.84 mmol) and lithium trifluoromethanesulfonate (0.283 g, 1.84 mmol) in acetonitrile (4 ml) are heated at 90° C. for 6 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% Ethyl acetate/hexane) gives the title compound as a yellow-brown foamy solid. HPLC r.t. 3.92 min; MS for C18H25F2N3O4 m/z 386.1 (M+H)+.