Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([O:19]C)=O)=[CH:16][C:11]=3[N:10]=[CH:9]2)C=CC=CC=1.Cl.[Cl:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[CH:41]=[C:40]([S:45]([N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:47])=[O:46])[CH:39]=[CH:38]2>>[ClH:34].[N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([N:51]3[CH2:52][CH2:53][CH2:54][N:48]([S:45]([C:40]4[CH:39]=[CH:38][C:37]5[C:42](=[CH:43][CH:44]=[C:35]([Cl:34])[CH:36]=5)[CH:41]=4)(=[O:47])=[O:46])[CH2:49][CH2:50]3)=[O:19])=[CH:16][C:11]=2[NH:10][CH:9]=1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCCNCC1
Reactant: COC(=O)c1ccc2c(c1)ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: O=C(c1ccc2nc[nH]c2c1)N1CCCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In a similar manner to Example 71 except for the use of methyl N-triphenylmethyl-5-benzimidazolecarboxylate and 1-[(6-chloronaphthalen-2-yl)sulfonyl]homopiperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: FC1C=CC(NCC2C(CO)=C(O)C(C([NH:18][OH:19])=O)=NC=2)=CC=1.[F:23][C:24]1[CH:46]=[CH:45][C:27]([CH2:28][CH2:29][NH:30][CH2:31][C:32]2[C:33]([CH2:43][OH:44])=[C:34]([OH:42])[C:35]([C:38](OC)=[O:39])=[N:36][CH:37]=2)=[CH:26][CH:25]=1>>[OH:19][NH:18][C:38]([C:35]1[C:34]([OH:42])=[C:33]([CH2:43][OH:44])[C:32]([CH2:31][NH:30][CH2:29][CH2:28][C:27]2[CH:45]=[CH:46][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:37][N:36]=1)=[O:39]
Reactant: COC(=O)c1ncc(CNCCc2ccc(F)cc2)c(CO)c1O
Reactant: O=C(NO)c1ncc(CNc2ccc(F)cc2)c(CO)c1O
Product: O=C(NO)c1ncc(CNCCc2ccc(F)cc2)c(CO)c1O

Procedure:
Product 22 was synthesized following a procedure similar to the one described above for the synthesis of 5-((4-fluorophenylamino)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide starting from methyl 5-((4-fluorophenethylamino)methyl)-3-hydroxy-4-(hydroxymethyl)picolinate (compound 22b). 1H-NMR (500 MHz, DMSO-d6) δ ppm 8.08 (s, 1H), 7.24 (m, 2H), 7.09 (t, J=7.2 Hz, 2H), 4.58 (s, 2H), 3.92 (s, 2H), 2.80 (m, 2H), 2.76 (m, 2H). MS-ESI m/z 336 [MH]+
Reaction SMILES: S(Cl)(Cl)=O.O[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[N:8][C:7]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[C:16]1([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[N:8][C:7]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:6]3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1nnc2ccc(-c3ccccc3)cc2c1O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc2cc(-c3ccccc3)ccc2nn1

Procedure:
Thionyl chloride (15 ml.) and dimethylformamide (1 drop) were added to ethyl 4-hydroxy-6-phenylcinnolin-3-yl carboxylate (0.30 g.). The mixture was gradually heated to boiling point and then heated under reflux until the evolution of gases ceased. The solution was evaporated under reduced pressure. The residue was dissolved in dry toluene (20 ml.) and the solution evaporated; this operation was then repeated. The residue was dissolved in a mixture of dimethylformamide (5 ml.) and ethyl acetate (30 ml.). The solution was stirred and sodium borohydride (0.25 g.) was added. The mixture was stirred for 2 hours and then added to a mixture of N-hydrochloric acid (10 ml.) and ethyl acetate (50 ml.). The mixture was separated and the ethyl acetate layer was washed with water (3 × 20 ml.), dried (MgSO4), filtered, and the filtrate evaporated under reduced pressure. The residue (which comprised ethyl 6-phenyl-1,4-dihydrocinnolin-3-yl carboxylate) was dissolved in dry toluene (50 ml.). Lead tetraacetate (1 g.) was added, and the mixture was stirred for 2 hours. The mixture was shaken with water (50 ml.), and separated. The organic layer was washed with water (3× 50 ml.), dried (MgSO4), filtered, and the filtrate evaporated under reduced pressure. The residue was crystallised from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.) to give ethyl 6-phenylcinnolin-3-yl carboxylate, m.p. 160°-2° C.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([C:23]1([C:33]([OH:35])=[O:34])[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:18]2.C([O-])(O)=O.[Na+]>>[F:7][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([C:23]1([C:33]([OH:35])=[O:34])[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:18]2
Reactant: CC(C)(C)N1CCNCC1(C(=O)O)c1ccc2c(CCO)cccc2n1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)N1CCNCC1(C(=O)O)c1ccc2c(CCF)cccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a -78° C. solution of Diethylaminosulfur trifluoride (DAST) (0.06 ml, 0.42 mmol) in dry CH2C2 was slowly added a solution of 13 (50 mg, 0.14 mmol) in dry CH2C2 (3 ml). The solution was allowed to warm to room temperature and stirred for 1 h. Saturated aqueous NaHCO3 was added and the mixture was extracted with CH2Cl2. The organic phase was dried (MgSO4) and concentrated. The residue was purified by HPLC (Whatman Partisil M9 column, 90:10 CH2Cl2 :EtOAc) to afford the fluoroethyl derivative 14 (33 mg, 66%). 1H NMR d (ppm): 1.48 s (3 CH3), 3.36 dt (CH2), 3.56 dd (NCH2), 3.71 dd (NCH2), 4.69 dt (CH2), 6.99 d (CH arom), 7.11 d (CH arom), 7.46 dd (CH arom), 7.61 d (CH arom), 8.10 d (CH arom).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=S)[O:11][C:7]=2[CH:6]=1)=[O:4].Cl.Cl.[NH:18]1[CH2:22][CH2:21][C@@H:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19]1>C1(C)C(C)=CC=CC=1.ClCCl>[CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:19]3)[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: C1CCN([C@@H]2CCNC2)CC1
Reactant: CN(C)C(=O)c1ccc2[nH]c(=S)oc2c1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: CN(C)C(=O)c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)oc2c1
Temperature: 150 °C

Procedure:
N,N-Dimethyl-2-thioxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide (Example 92C, 44 mg, 0.119 mmol) and (R)-1-(pyrrolidin-3-yl)piperidine dihydrochloride (Reference Example 5c, 54 mg, 0.238 mmol) were combined in xylene (1 mL) and heated to 150° C. for 30 minutes. The mixture was diluted with dichloromethane, washed with water, and the organic layer was absorbed on silica gel. The crude mixture was purified by silica gel chromatography eluting with a gradient of methanol in dichloromethane (2-20%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.43-1.53 (m, 2 H) 1.59-1.70 (m, 4 H) 1.91-2.07 (m, 1 H) 2.23-2.35 (m, 1 H) 2.40-2.62 (m, 4 H) 2.93-3.13 (m, 7 H) 3.41-3.51 (m, 1 H) 3.55-3.66 (m, 1 H) 3.80-3.90 (m, 1 H) 3.96 (dd, J=10.00, 7.29 Hz, 1 H) 7.22-7.28 (m, 1 H) 7.30-7.35 (m, 1 H) 7.37-7.40 (m, 1 H); MS (ESI+) m/z 343.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH3:15])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:16]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[CH:16]1([NH:21][C:2]2[C:3]3[N:4]([C:12]([CH3:15])=[N:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1nnc2c(Cl)nc3ccccc3n12
Reactant: NC1CCCC1
Solvent: CN(C)C=O
Product: Cc1nnc2c(NC3CCCC3)nc3ccccc3n12
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.2 %

Procedure:
A reaction mixture of 4-chloro-1-methyl[1,2,4]triazolo[4,3-a]quinoxaline (1.0 g; 0.004 mole) and cyclopentanamine (1.17 g; 0.013 mole) in 15 ml of DMF was stirred at room temperature for 20 hours. The reaction mixture was poured over ice-water and the precipitated solid was filtered, washed with water and dried affording 0.9 g (74%) of N-cyclopentyl-1methyl-[1,2,4]triazolo[4,3-a]quinoxalin-4-amine having a mp of 196°-198° C.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+].Cl>O1CCCC1>[C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH:7]2[N:8]3[CH:9]=[N:10][CH:11]=[C:12]3[CH2:13][CH2:14][CH:15]2[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C=CCCc1cncn1Cc1ccc(C#N)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCc2cncn2C1c1ccc(C#N)cc1
Reaction time: 2 h

Procedure:
A solution of 1.27 g of ethyl 5-[1-(4-cyanobenzyl)imidazol-5-yl]-1-pent-2-enoate in 27 ml of tetrahydrofuran at 5° under nitrogen is treated with 0.52 g of potassium tert-butoxide. The reaction mixture is stirred at 5° for 2 h and 10 ml of 1N hydrochloric acid is added. The layers are separated. The organic phase is extracted with 1N hydrochloric acid (2×10 ml). The combined aqueous layers are extracted with ether, adjusted to pH=8 and extracted with methylene chloride (3×15 ml). The organic phase is dried and evaporated to yield the product which is treated with one molar equivalent of ethereal hydrogen chloride. The resulting solid is recrystallized from acetone to yield 5-(4-cyanophenyl)-6-ethoxycarbonylmethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine. m.p. 126°-127°.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[NH:10][C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:21]([N:23]([CH2:35][CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:22]>>[CH2:1]([NH:8][C:9](=[O:18])[NH:10][C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([NH:19][C@@H:20]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[CH:46][CH:45]=1)[C:21]([N:23]([CH2:35][CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Product: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)(C)NC(=O)NCc1ccccc1)OCC
Yield: 88.6 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, 3-(3-benzylureido)-3-methylbutanoic acid (Compound VI-2) (170 mg, 0.68 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) (223 mg, 0.45 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethylacetate=50:50 to 0:100) to obtain the title compound (289 mg, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[CH:3]=1.OS(O)(=O)=O.[N+:24]([O-])([OH:26])=[O:25]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])[N:5]=[C:4]([NH2:18])[C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: Nc1cc(Cl)cc(-c2ccccc2C(F)(F)F)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (617.5 mg, 2.27 mmol, prepared as described in STEP A above) was cooled to 0° C. and treated slowly with H2SO4 (10 mL). The mixture was stirred at 0° C. for 1 h. Nitric acid (133 μL, 2.94 mmol) was added slowly, and the mixture continued to stir at 0° C. for an additional 1.5 h. Ice (50 mL) was added. A precipitate formed and was filtered, dissolved in DCM (70 mL), and washed with saturated aqueous NaHCO3 (70 mL). The aqueous layer was extracted with DCM (30 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 40-g SEPRA Si 35 SPE column (Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 1:19 for 15 min, then 1:19 to 1:3 over 40 min) to yield 4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine as a yellow solid. The basic mother liquor and acidic filtrate were carefully combined, made basic with 1 N aqueous NaOH, and extracted twice with DCM (100 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to yield additional product. 1H-NMR (400 MHz, CDCl3) δ: 7.76-7.90 (m, 1H), 7.55-7.71 (m, 2H), 7.46 (d, J=7.3 Hz, 1H), 6.93 (s, 1H), 6.11 (br. s., 2H). Mass Spectrum (LCMS, APCI pos.): Calculated for C12H7N3O2ClF3: 318.0 (M+H). Measured: 318.0.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH:21]=[CH2:22])=[CH:15][CH:16]=2)[C:11]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([CH2:21][CH3:22])=[CH:15][CH:16]=2)[C:11]=1[C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1
Solvent: CC#N
Solvent: O
Product: CCc1ccc2cc(C)c(C(OC(C)(C)C)C(=O)O)c(-c3ccc(Cl)cc3)c2c1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-ethyl-3-methylnaphthalen-2-yl)acetic acid (93) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-vinylnaphthalen-2-yl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.74 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz, 1H), 7.59 (s, 1H), 7.53 (m, 2H), 7.29 (m, 2H), 7.04 (s, 1H), 5.07 (s, 1H), 2.60 (m, 5H), 1.15 (t, J=7 Hz, 3H), 0.94 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H2O+0.05% HOAc, 4.0 min run): tR (min)=3.81.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:56]1[CH2:60][CH2:59][C@@H:58]([OH:61])[CH2:57]1>CN(C=O)C.C(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([N:56]2[CH2:60][CH2:59][C@@H:58]([OH:61])[CH2:57]2)=[O:33])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: O[C@@H]1CCNC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (200 mg), HOBt (1 eq.), EDAC (2 eq.), TEA (3 eq.) and (R)-pyrrolidin-3-ol (3 eq.) in DMF (4 mL) was stirred at rt for overnight. The reaction was diluted with DCM, washed with water (2×) and 10% sodium carbonate (2×). The DCM was dried, concentrated and purified on a silica gel column to give 21 mg of the titled compound. MS m/z 588 [M++1].
Reaction SMILES: NCCCCCC([O:9][C:10]1[C:11](=[CH:16][CH:17]=[C:18](CN)[CH:19]=1)[C:12]([NH:14][OH:15])=[O:13])=O>C([O-])(O)=O.[Na+]>[C:12]([NH:14][OH:15])(=[O:13])[C:11]1[C:10](=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:9]
Reactant: NCCCCCC(=O)Oc1cc(CN)ccc1C(=O)NO
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NO)c1ccccc1O

Procedure:
SHA-Sepharose 4B was prepared by mixing 130 mg of (6-aminohexanoyl)-4-aminomethylsalicylhydroxamic acid (SHA-Z-NH2), dissolved in 30 mL 0.2 M NaHCO3, with. 6.5 g HCl washed CNBr activated Sepharose 4B (Pharmacia) overnight at room temperature. After the coupling reaction, 2 mL 0.5 M Tris, pH 8.5 were added and the gel slurry mixed at room temperature for 1 hour, and washed with water, 0.5 M NaCl, and water again. The resulting SHA-Sepharose 4B was suspended in 30 mL of 20% ethanol, and stored at 4° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[NH:12][N:11]=[N:10]1.[C:15](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH3:15])[N:11]=[N:10]1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(I)cccc1-n1nn[nH]c1=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: Cc1c(I)cccc1-n1nnn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the above-mentioned 1-(2-methyl-3-iodophenyl)-1,4-dihydrotetrazole-5-one, potassium carbonate 17.40 g, dimethyl sulfate 5.78 g and N,N-dimethylformamide 150 mL was stirred at 25° C. for one hour. To the reaction mixtures was added aqueous saturated sodium bicarbonate solution and the mixtures were extracted with ethyl acetate. The organic layers were washed with aqueous saturated sodium bicarbonate solution and were dried over anhydrous sodium sulfate. The resulting mixtures were concentrated under reduced pressure to give 1-(2-methyl-3-iodophenyl)-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Intermediate (PRI-P)”) 8.10 g.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:16](Br)[CH:17]=[CH2:18]>CCO>[CH2:18]([S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Solvent: CCO
Product: C=CCSc1nnc(-c2ccc3[nH]cnc3c2)o1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and allylbromide (0.093 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[N:7]=[N:8][S:9][C:10]=1[CH2:11]O.C(=O)([O-])[O-].[K+].[K+].[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH3:5][C:6]1[N:7]=[N:8][S:9][C:10]=1[CH2:11][S:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Sc1ccccc1
Reactant: Cc1nnsc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Product: Cc1nnsc1CSc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
At an ice-cooled temperature, 3 ml of thionyl chloride was added to 0.50 g (3.8 mmol) of 4-methyl-1,2,3-thiadiazol-5-ylmethanol and stirred for 4 hours. Then, the reaction mixture was concentrated under reduced pressure, and 1.30 g (11.5 mmol) of potassium carbonate, 0.38 g (3.4 mmol) of thiophenol and 10 ml of acetone were added to the concentrate and reacted for 7 hours with heating under reflux. After the reaction was completed, the reaction mixture was cooled to room temperature, the precipitated matter was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 5:1 mixture of n-hexane and ethyl acetate. Thus, 0.64 g of the objective compound was obtained.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:16][NH:17][C:18](=O)/[C:19](=[N:26]\[O:27][CH2:28][C:29]1[N:34]=[C:33]([NH:35][C:36](=[O:42])[O:37][CH2:38][CH2:39][C:40]#[CH:41])[CH:32]=[CH:31][CH:30]=1)/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1.[N-:50]=[N+:51]=[N-:52].[Na+]>C(#N)C>[CH2:38]([O:37][C:36](=[O:42])[NH:35][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:28][O:27]/[N:26]=[C:19](\[C:18]2[N:17]([CH3:16])[N:52]=[N:51][N:50]=2)/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:34]=1)[CH2:39][C:40]#[CH:41]
Reactant: C#CCCOC(=O)Nc1cccc(CO/N=C(\C(=O)NC)c2ccccc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: C#CCCOC(=O)Nc1cccc(CO/N=C(/c2ccccc2)c2nnnn2C)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
With ice cooling, 85 μl of trifluoromethanesulphonic anhydride were added to a solution of 100 mg (0.25 mmol) of but-3-yn-1-yl(Z)-{6-[({[2-(methylamino)-2-oxo-1-phenylethylidene]amino}oxy)methyl]pyridin-2-yl}carbamate (only Z diastereoisomer) and pyridine (81 μl, 4 eq.) in acetonitrile (2 ml). The mixture was heated at 50° C. for 2 h and then cooled to room temperature. Then, 49 mg of sodium azide were added and the mixture was stirred again at 50° C. for 2 h. The homogeneous orange solution was then cooled to room temperature and filtered over silica gel, and the silica gel filter layer was washed with 50 ml of EtOAc. The combined organic phases were concentrated by evaporation in vacuo, giving 87 mg (84% purity) of (Z)-but-3-yn-1-yl{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C@H:3]([O:17][CH3:18])[CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C:29]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[N:27][C:22]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][C@@H:3]([O:17][CH3:18])[C:2]([F:1])([F:19])[F:20])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:23][CH:24]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CO[C@H](CN1CCc2ccc(N)cc2CC1)C(F)(F)F
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(C[C@@H](OC)C(F)(F)F)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-((R)-3,3,3-trifluoro-2-methoxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide was prepared from 3-((R)-3,3,3-trifluoro-2-methoxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 335. Product isolated as a yellow solid (56 mg, 24%). LCMS (m/e) 567 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.74 (s, 1H), 8.08 (s, 1H), 7.36-7.25 (m, 3H), 7.19-7.11 (m, 2H), 6.91 (d, 1H, J=7.9 Hz), 6.87 (s, 1H), 6.13-6.05 (m, 1H), 3.75-3.65 (m, 1H), 3.61 (s, 3H), 2.93 (d, 3H, J=4.8 Hz), 2.89-2.65 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:10][CH:8]([CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:9])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)COc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(COc1ccc(Cl)cc1)OS(C)(=O)=O
Temperature: -8 °C
Reaction time: 1 h

Procedure:
To a solution of 37.4 g of 3-(p-chlorophenoxy)propan-2-ol and 41 ml of triethylamine in 500 ml of dichloromethane stirred and chilled at -8° C. is added dropwise 18.7 ml of methanesulfonyl chloride in 50 ml of dichloromethane. After stirring at -8° C. for 1 hour, the solution is washed with 350 ml portions of ice cold water, 1N HCl, saturated NaCl, saturated NaHCO3 and saturated NaCl. The organic layer is dried (MgSO4) and the solvent removed under reduced pressure to give 54 g of product as white crystals, mp 72°-78° C.