Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[S:22][CH2:23][CH3:24].C1C=C(Cl)C=C(C(OO)=[O:34])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:25][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[S:22]([CH2:23][CH3:24])=[O:34]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(SCC)c1CC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(=O)CC)c1CC(C)C

Procedure:
Prepared from product of Example 6 (7.0 g, 18.1 mmol) and MCPBA (3.7 g of an 85% mixture with MCBA, 18.1 mmol) as described above. Recrystallization (ether/petroleum ether) afforded the product as a white solid (6.23 g).
Reaction SMILES: [O:1]=[C:2]1[CH:12]=[N:11][CH:10]2[CH:13]3[N:3]1[CH2:4][CH:5]([CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1)[N:6]3[C:7](=[O:14])[CH:8]=[CH:9]2.C(O)(C(F)(F)F)=O>ClCCl>[NH2:22][CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH:5]2[N:6]3[CH:13]4[CH:10]([CH:9]=[CH:8][C:7]3=[O:14])[N:11]=[CH:12][C:2](=[O:1])[N:3]4[CH2:4]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CN3C(=O)C=NC4C=CC(=O)N2C43)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CC2CN3C(=O)C=NC4C=CC(=O)N2C43)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl {1-[(3,8-dioxo-1,2,5a,8b-tetrahydro-3H,8H-2a,5,8a-triazaacenaphthylen-1-yl)methyl]-4-piperidinyl}carbamate (37 mg, 0.092 mmol) in anhydrous dichloromethane (2 ml) was treated with TFA (1 ml) and stirred at room temperature for 1 hour, evaporated to dryness, mixed with anhydrous dichloromethane and evaporated to a dark gum. This gum was dissolved in 1:1 dichloromethane:methanol (10 ml) and treated with MP-carbonate resin (600 mg) and stirred for 1.5 hours. The reaction was filtered and the resin was washed with 1:1 dichloromethane:methanol (30 ml) and the filtrate was evaporated to dryness. Purification on a 5 g SCX column eluting with a methanol to 2N methanolic ammonia gradient gave the product as a gum. Further evaporation from diethyl ether gave the product as a brown solid (22.8 mg, 82%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1([CH3:12])[CH2:10][O:9][C:8](=[O:11])[CH2:7][CH2:6]1>CO>[CH3:1][O:2][C:8](=[O:11])[CH2:7][CH2:6][C:5]([CH3:12])([CH3:4])[CH2:10][OH:9]
Reactant: CC1(C)CCC(=O)OC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC(C)(C)CO
Temperature: 50 °C
Reaction time: 4 h
Yield: 933.6 %

Procedure:
To a solution of sodium methoxide (6.32 mg, 0.117 mmol) in anhydrous MeOH (346 mL), 5,5-dimethyl-tetrahydro-pyran-2-one (150 mg, 1.17 mmol) is added dropwise at room temperature under nitrogen. The mixture is stirred at 50° C. for 4 hours and filtered through a silica gel short column (eluent: diethyl ether). The filtrate is concentrated under reduced pressure to give 5-hydroxy-4,4-dimethyl-pentanoic acid methyl ester (175 mg, 93%); TLC (hexane/AcOEt, 2:1) Rf 0.27, 1H NMR (400 MHz, chloroform-d) δ ppm 0.89 (s, 6H), 1.63 (m, 2H), 2.32 (m, 2H), 3.28 (d, 2H), 3.68 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[C:17]([F:23])[C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[H-].[Na+].Cl[C:27]1[CH:28]=[C:29]2[N:36]([CH3:37])[CH2:35][CH2:34][N:30]2[C:31](=[O:33])[N:32]=1>CN(C=O)C>[F:1][C:2]1[CH:20]=[C:19]([CH2:21][O:22][C:27]2[CH:28]=[C:29]3[N:36]([CH3:37])[CH2:35][CH2:34][N:30]3[C:31](=[O:33])[N:32]=2)[CH:18]=[C:17]([F:23])[C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1ccc(Oc2c(F)cc(CO)cc2F)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(C#N)c(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 4-(2,6-difluoro-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrile (280 mg, 0.850 mmol) in DMF (5 mL), sodium hydride (61.2 mg, 2.55 mmol) and 7-chloro-1-methyl-2,3-dih-ydroimidazo[1,2-c]pyrimidin-5(1H)-one (158 mg, 0.850 mmol).
Reaction SMILES: C(OC(N[C@H]1[C@@H](N2C=CN=N2)[C@@H](C)CN(C2C=CN=CC=2NC(C2C([NH:40][C:41](=[O:50])[O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=CC3C(=CC(N4CCN(C)C(=O)C4)=CC=3)N=2)=O)C1)=O)(C)(C)C.[H][H]>CO.[Pd]>[C:41](=[O:50])([O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[NH2:40]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)OCc1ccccc1

Procedure:
A solution of benzyl [2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(4-methyl-3-oxopiperazin-1-yl)quinolin-3-yl]carbamate (12.0 mg, 0.015 mmol) in MeOH (1.0 mL) was hydrogenated in the presence of 10% palladium on carbon (6.0 mg) under a balloon of hydrogen for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a benzyl carbamate deprotected intermediate. The intermediate was treated with 4.0 M HCl in dioxane (0.15 mL, 0.6 mmol) at room temperature for 1 h. The solution was concentrated under reduced pressure and the resulting residue was diluted with MeOH and NH4OH, filtered. The filtrate was purified by preparative LCMS (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to give the title compound as a yellow powder (5.1 mg, 60%). LCMS calc. for C28H34N11O2 (M+H)+: m/z=556.3. Found: 556.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:21])([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[CH3:5].[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:35][CH2:36][CH3:37])[C:33]=1[F:34])[CH:29]=O)[CH3:24].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:20])[NH:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:29][C:28]3[CH:31]=[C:32]([O:35][CH2:36][CH3:37])[C:33]([F:34])=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=3)[CH2:18][CH2:19]2)=[CH:10][CH:11]=1)([CH3:5])[CH3:21]
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)NC2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C(C)(C)C(=O)OC)cc3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 50k), 2-methyl-2-[4-(piperidin-4-ylcarbamoyl)-phenyl]-propionic acid methyl ester (example 60e) was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 501.2 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH2:24][NH2:25]>C(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][NH:25][CH2:24][C:23]3[C:22]([F:21])=[CH:29][CH:28]=[CH:27][C:26]=3[F:30])=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: NCc1c(F)cccc1F
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Solvent: CCO
Product: O[C@H](CNCc1c(F)cccc1F)COc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from a mixture of 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane, 2,6-difluorobenzylamine and ethanol essentially as described above in Example 94. Purity by LC/MS=99%, [M+H]+=426.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:13][NH:14][CH3:15]>CS(C)=O>[CH:10]1([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:14]([CH3:15])[CH3:13])=[CH:3][CH:4]=2)=[O:9])[CH2:12][CH2:11]1
Reactant: O=C(c1ccc(F)cc1)C1CC1
Reactant: CNC
Solvent: CS(C)=O
Product: CN(C)c1ccc(C(=O)C2CC2)cc1
Temperature: 0 °C
Yield: 93.4 %

Procedure:
Cyclopropyl p-fluorophenyl ketone (1.12 g, 6.9 mmol) is added to 3 ml of dimethylsulfoxide (DMSO). The flask is sealed with a septum and the solution stirred and cooled to 0° C. in an ice bath. Anhydrous dimethylamine (3.4 g, 75.5 mmol) is added by syringe and the solution is gradually warmed to room temperature and allowed to stir at room temperature for 72 hrs. The precipitate is filtered and washed with DMSO and ether. Recrystallization from acetone-pentane (1:1) yielded p-N,N-dimethylaminophenyl cyclopropyl ketone as a white crystalline solid (1.22 g, 92.8%); m.p. 139°-141° C.; IR (KBr):158 cm-1 (C=O); NMR (CDCl3) δ:0.99 (m,2H); 1.16 (m,2H ) 2.60 (m,1H); 3.05 (s,6H); 6.67 (d,2H); 7.96 (d,2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[C:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[N:20][C:19](Br)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CN(C=O)C.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[C:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[N:20][C:19]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1C#C[Si](C)(C)C
Reactant: C1CNCCN1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2CCNCC2)nc1C#C[Si](C)(C)C
Temperature: 100 °C
Yield: 76.4 %

Procedure:
Tert-butyl N-tert-butoxycarbonyl-N-[5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-yl]carbamate (640 mg, 1.360 mmol) was dissolved in DMF (5 mL) and treated with piperazine (351.4 mg, 4.080 mmol). The reaction was allowed to heat at 100° C. for 15 minutes and then allowed to cool to ambient temperature and diluted with EtOAc/water. The aqueous layer was extracted with EtOAc and the combined organics washed with water (2×) and brine (2×). This was dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/Petrol to 10% MeOH/DCM/1% NH4OH) to afford the title compound as a yellow oil (494 mg, 76% Yield). 1H NMR (400.0 MHz, DMSO) d 0.03 (s, 9H), 1.18 (s, 18H), 2.99 (m, 4H), 3.29 (m, 4H) and 7.88 (s, 1H) ppm; MS (ES+) 476.08
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)=[CH:7][N:6]=[CH:5][C:4]=1[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)#[N:2].[C:28](O)(=[O:30])[CH3:29].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[C:28]([N:25]1[CH2:26][CH2:27][CH:22]([C:4]2[CH:5]=[N:6][CH:7]=[C:8]([C:9]3[CH:10]=[C:11]4[C:16](=[N:17][CH:18]=3)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]4)[C:3]=2[C:1]#[N:2])[CH2:23][CH2:24]1)(=[O:30])[CH3:29]
Reactant: CC(=O)O
Reactant: N#Cc1c(-c2cnc3c(c2)CCCN3C(N)=O)cncc1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2C#N)CC1
Reaction time: 16 h
Yield: 42.7 %

Procedure:
The crude 6-(4-cyano-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (0.22 mmol), acetic acid (0.025 mL, 0.43 mmol) and triethyl amine (0.091 mL, 0.65 mmol) are mixed in acetonitrile (2.5 mL). Then TBTU (104 mg, 0.33 mmol) is added and the mixture is stirred for 16 hrs. All the solvent is removed and the residue is purified by flash column chromatography to give 38 mg of the titled product.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:12]=2[N:13]=1)=[O:7])(=O)C.N>CO>[OH:4][CH2:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:12]=2[N:13]=1)=[O:7]
Reactant: COc1cccc2sc(NC(=O)COC(C)=O)nc12
Agent: N
Solvent: CO
Product: COc1cccc2sc(NC(=O)CO)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
2-(Acetoxyacetylamino)-4-methoxybenzothiazole (1.0 g) prepared in Example 4 is dissolved in methanol (40 ml) and thereto is added 28% aqueous ammonia (4 ml) and the mixture is stirred at room temperature for 1 hour. The solvent is distilled off and the resulting solids are washed with water, dried and recrystallized from ethanol to give the title compound (0.7 g) having the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([F:16])([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C@@H:19]([C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42](=[O:61])[CH2:43][C@@H:44]([O:59][CH3:60])[C@@H:45]([N:50]([CH3:58])[C:51](=[O:57])[C@H:52]([CH:54]([CH3:56])[CH3:55])[NH2:53])[C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@@H:20]([CH3:36])[C:21]([NH:23][C@H:24]([C:32]([O:34][CH3:35])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]([C:13]([NH:53][C@H:52]([C:51]([N:50]([CH3:58])[C@@H:45]([C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@H:44]([O:59][CH3:60])[CH2:43][C:42]([N:38]2[CH2:39][CH2:40][CH2:41][C@H:37]2[C@H:19]([O:18][CH3:17])[C@@H:20]([CH3:36])[C:21]([NH:23][C@H:24]([C:32]([O:34][CH3:35])=[O:33])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:22])=[O:61])=[O:57])[CH:54]([CH3:55])[CH3:56])=[O:15])([F:16])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@](F)(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(F)CCN(C(=O)OC(C)(C)C)C1)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of #169 (36.9 mg, 0.158 mmol, 1 eq.) and #114 (100 mg, 0.158 mmol, 1 eq.) in dichloromethane (3.6 mL) and N,N-dimethylformamide (0.8 mL), was added diisopropylethylamine (0.083 mL, 0.474 mmol, 3 eq.) followed by HATU (60.7 mg, 0.158 mmol, 1 eq.). The reaction was allowed to stir at room temperature for 18 hours, diluted with ethyl acetate (25 mL), washed with water (1×), 10% citric acid (1×) and brine (1×). The organic layer was dried over sodium sulfate, filtered, and the filtrate concentrated in vacuo to provide crude #218 (180 mg, 134% of theory) which was used in next step without further purification. HPLC (protocol Q): m/z 848.6 [M+H+], retention time=2.10 minutes.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:8]1[N:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1>>[N+:14]([C:11]1[CH:10]=[N:9][C:8]([N:4]2[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]2)=[N:13][CH:12]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: O[C@@H]1CCNC1
Product: O=[N+]([O-])c1cnc(N2CC[C@@H](O)C2)nc1

Procedure:
This compound was prepared with the same method described before using (R)-3-hydroxypyrrolidine and 2-chloro-5-nitropyrimidine to give (R)—N-(5-nitro-pyrimidin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C8H10N4O3 m/e 210.19, obsd 211.0 (ES, M+H). Hydrogenation of the nitro compound, as above, provided (R)—N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[N:20]=[C:19]([C:21]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[C:22]=3[O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40](C)(C)C)=[O:38])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH:18]=[CH:17][N:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53].CCN(C(C)C)C(C)C.ClC(OC)=O.C(=O)([O-])N.[OH-].[Li+].Cl>C(Cl)Cl.O1CCOCC1.C(#N)C>[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53].[CH3:40][O:39][C:37]([N:34]1[CH2:33][CH2:32][CH:31]([C:28]2[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:22]3[C:44]([C:48]([F:49])([F:50])[F:51])=[CH:45][CH:46]=[CH:47][C:21]=3[C:19]3[CH:18]=[CH:17][N:16]=[C:15]([N:9]4[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]4)[N:20]=3)=[CH:30][CH:29]=2)[CH2:36][CH2:35]1)=[O:38]
Reactant: CCOC(=O)c1cnn(-c2nccc(-c3cccc(C(F)(F)F)c3OCc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)F
Agent: COC(=O)Cl
Agent: Cl
Agent: NC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCC(c2ccc(COc3c(-c4ccnc(-n5ncc(C(=O)O)c5C(F)(F)F)n4)cccc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of the title compound from Example 167 Step C (198 mg, 0.30 mmol) in DCM (3 mL) was added TFA (0.5 mL). After 3 min, the reaction mixture was concentrated in vacuo, and the crude TFA salt was used without further purification: LCMS m/z 619.9 [M+1-1]+. To a portion of the crude TFA salt (−0.15 mmol) in DCM (1.5 mL) were added DIEA (262 μL, 1.50 mmol) and methyl chloroformate (34 μL, 0.45 mmol), and the resulting mixture was allowed to stir at room temperature. After 90 min, the reaction mixture was quenched by addition of sat aq NaHCO3 and the aqueous phase was extracted with DCM. The organic phase was separated and concentrated in vacuo to provide the crude carbamate, which was used without further purification: LCMS m/z 677.9 [M+H]+. To a solution of the carbamate in dioxane (2 mL) was added lithium hydroxide (1 mL, 2N aqueous, 2 mmol), and the mixture was stirred at 50° C. After 1 h, the reaction mixture was rendered acidic by addition of HCl (2N aqueous), then was diluted with acetonitrile and purified by reverse phase HPLC (30 to 100% acetonitrile/water, both 0.1% v/v TFA) to provide the title compound: LCMS m/z 649.9 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 9.07 (d, J=5.5 Hz, 1H), 8.35 (s, 1H), 8.16 (d, J=5.5 Hz, 1H), 8.07 (dd, J=8.0, 1.5 Hz, 1H), 7.96 (dd, J=8.0, 1.5 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.17 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 4.63 (s, 2H), 4.10-4.04 (m, 2H), 3.58 (s, 3H), 2.88-2.62 (m, 3H), 1.72-1.68 (m, 2H), 1.50-1.42 (m, 2H).
Reaction SMILES: [CH2:1]([CH:5]1[C:9]2=[N:10][C:11]3[C:12]([C:19]([F:22])([F:21])[F:20])=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([OH:18])=[C:8]2[C:7](=[N:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[O:6]1)[CH2:2][CH2:3][CH3:4].Cl.[OH2:30]>>[OH:18][C:17]1[C:16]2[C:11](=[C:12]([C:19]([F:22])([F:20])[F:21])[CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH:5]([OH:30])[CH2:1][CH2:2][CH2:3][CH3:4])[C:8]=1[C:7]([NH:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)=[O:6]
Reactant: O
Reactant: CCCCC1OC(=Nc2nccs2)c2c1nc1c(C(F)(F)F)cccc1c2O
Agent: Cl
Product: CCCCC(O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 50 °C

Procedure:
A mixture of 6.1 g of the product of Step C, 60 ml of water and 60 ml of 6N hydrochloric acid was heated at 50° C. for 5 hours and was then cooled to room temperature and iced and vacuum filtered. The product was washed with water and added to 100 ml of water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried, filtered and evaporated to dryness under reduced pressure. The 6.4 of residue was added to 50 ml of ether and the mixture was iced and vacuum filtered. The product was washed with ether and dried under reduced pressure at 60° C. to obtain 3.9 g of 4-hydroxy-2-(1-hydroxypentyl)-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide melting at 190° C.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[N:13]=[C:14]([NH:16][C:17]([CH3:21])([CH3:20])[CH2:18][NH2:19])[S:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:22]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[N:13]=[C:14]([N:16]4[C:17]([CH3:20])([CH3:21])[CH2:18][NH:19][C:24]4=[O:26])[S:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:22]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(CN)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: Br
Solvent: C1CCOC1
Product: CC1(C)CNC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Yield: 51 %

Procedure:
Following the Example 356, N2-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-2-methylpropane-1,2-diamine hydrobromide was reacted with triphosgene in tetrahydrofuran and purified on silicagel column eluting with 50% of ethyl acetate in heptane to give 1-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2-one. Yield 51%. MS (ESI+): 393.9
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[Cl:6][C:7]1[CH:8]=[C:9]([OH:17])[C:10](=[CH:15][CH:16]=1)[C:11](OC)=[O:12].N#N>O1CCOCC1.O>[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([NH:2][OH:3])=[O:12])=[C:9]([OH:17])[CH:8]=1
Reactant: COC(=O)c1ccc(Cl)cc1O
Reactant: NO
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NO)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
Hydroxylamine hydrochloride in solid (5.25 g, 75 mmol) is placed in an egg type flask and dissolved by drop-adding small amount of water in ice-bath. Thereafter, thereto is drop-added 15 ml of 50% NaOH solution. The reaction is stirred for 5 minutes and is drop-added 50 ml of dioxane solution of methyl 4-chloro-salicylate (9.3 g, 50 mmol) under coverage of N2. After completion of drop-addition, a reaction is carried out at room temperature for 24 hours, and then a red-brown deposit precipitates, which is filtered out and placed in an egg type flask, thereto is added 50 ml of 10% hydrochloric acid and then reflux for 0.5 hour. After cooling to room temperature, a yellow deposit precipitates, which is filtered out and recrystallized in anhydrous ethanol, to obtain 8.25 g of 4-chloro-N,2-dihydroxy-benzamide, with a yield of 88%.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[Br:10][C:11]1[S:15][N:14]=[CH:13][CH:12]=1>>[Br:10][C:11]1[S:15][N:14]=[CH:13][C:12]=1[N+:6]([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: Brc1ccns1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnsc1Br
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of concentrated H2SO4 (15 mL) and HNO3 (6 mL) at 0° C. was added 5-bromoisothiazole (O) (5.0 g, 29.4 mmol). The mixture was then stirred at 70° C. for 1.5 hours. After cooling to room temperature, it was poured into stirring ice water (120 mL). The mixture was then extracted with ethyl acetate twice (150 mL×2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo at room temperature (25° C.). The residue was purified with flash column (eluent: 5-20% ethyl acetate/petroleum ether) to afford the product 5-bromo-4-nitroisothiazole (P) (4.4 g, 21 mmol).