Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O)[NH2:2].O=[CH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:15]#[N:16]>C(O)(=O)C>[C:17]1([C:14]2[CH:13]=[N:2][N:1]3[C:3]4[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:5](=[O:7])[NH:16][C:15]=23)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: N#CC(C=O)c1ccccc1
Solvent: CC(=O)O
Product: O=c1[nH]c2c(-c3ccccc3)cnn2c2ccccc12
Temperature: 150 °C

Procedure:
A mixture of 2-hydrazinobenzoic acid (0.15 g, 0.8 mmol) and 3-oxo-2-phenyl-propionitrile (0.116 g, 0.8 mmol) in acetic acid (0.2 mL) was heated in a microwave (Personal Chemistry SmithSynthesizer) at 150° C. for 10 minutes. The precipitated product was filtered, washed with methanol and diethyl ether and dried. 1H NMR (DMSO-d6) δ 12.10 (s, 1H), 8.10-8.19 (m, 3H) 7.88-7.96 (m, 1H), 7.59 (d, J=7.3 Hz, 2H), 7.52 (t, J=7.8 Hz, 1H), 7.42 (t, J=7.6 Hz, 2 Hz), 7.28 (t, J=7.3 Hz, 1H).
Reaction SMILES: CO[C:3]1C(OC)=NS(=O)(=O)[N:4]=1.[NH:12]([C:16]1[O:17][CH:18]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]2(OC)[NH:30][S:29](=[O:32])(=[O:31])[N:28]=[CH:27]2)[N:20]=1)[C:13]([NH2:15])=[NH:14].CN>>[NH:12]([C:16]1[O:17][CH:18]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]2([NH:4][CH3:3])[NH:30][S:29](=[O:32])(=[O:31])[N:28]=[CH:27]2)[N:20]=1)[C:13]([NH2:15])=[NH:14]
Reactant: COC1(NCCCCc2coc(NC(=N)N)n2)C=NS(=O)(=O)N1
Reactant: COC1=NS(=O)(=O)N=C1OC
Agent: CN
Product: CNC1(NCCCCc2coc(NC(=N)N)n2)C=NS(=O)(=O)N1

Procedure:
When a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with an equimolar amount of 4-[(2-quanidino-4-oxazolyl]butylamine [prepared according to the procedure described in Belgian Pat. No. 866,155] and the resultant 3-{4-[(2-guanidino-4-oxazolyl]butylamino}-4-methoxy-1,2,5-thiadiazole 1,1-dioxide is treated with excess methylamine, the title compound is thereby produced.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:33]=[CH:32][C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=O)[O:26]C(C)(C)C)[CH3:23])[CH2:16][CH2:15]4)[O:13][C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.Cl.[C:35](OCC)(=O)C>>[CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:33]=[CH:32][C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:26])[CH3:35])[CH3:23])[CH2:16][CH2:15]4)[O:13][C:9]=3[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COC1CCN(c2nc3ccc(OCCC4CC4)cc3o2)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COC1CCN(c2nc3ccc(OCCC4CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To tert-butyl [(1S)-2-({1-[6-(2-cyclopropylethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate (190 mg) was added 4M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 15 min, and concentrated. Pyridine (10 mL) and acetic anhydride (5 mL) were added to the residue, and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate/methanol), and recrystallized from ethyl acetate/hexane to give the title compound (43 mg).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21]OC(C)(C)C)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1>CO.[Pd]>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)ONCCCC[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Yield: 192.3 %

Procedure:
A solution of 590 mg of CBZ-D-Trp-Lys(OtBu)-OtBu was hydrogenated at 50 PSI for 2.5 hours in 50 mL of methanol with 100 mg of 10% palladium on carbon catalyst. The catalyst was then filtered off and the solvent evaporated to yield 466 mg (95%) of D-Trp-Lys(BOC)-OtBu (see Scheme 2A, reactants 9→8).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].Cl.[S:31]1[C:35]([CH2:36][NH2:37])=[CH:34][N:33]=[CH:32]1>>[S:31]1[C:35]([CH2:36][NH:37][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([N:13]3[CH2:12][C:10]4[CH2:11][N:7]([C:5](=[O:6])[C:4]5[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=5[C:2]([F:28])([F:1])[F:29])[CH2:8][C:9]=4[CH2:14]3)=[N:16][CH:17]=2)=[CH:34][N:33]=[CH:32]1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Reactant: NCc1cncs1
Agent: Cl
Product: O=C(NCc1cncs1)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 58 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (50 mg, 0.124 mmol) were reacted with C-thiazol-5-ylmethylamine, hydrochloride analogously to example 3d. Yield: 58%, M+H+: 500.20.
Reaction SMILES: [OH-].[Na+].[O:3]1[C:8]([C:9](=[N:15][O:16][CH3:17])[C:10]([O:12]CC)=[O:11])=[CH:7][S:6][CH2:5][CH2:4]1>CO>[O:3]1[C:8]([C:9](=[N:15][O:16][CH3:17])[C:10]([OH:12])=[O:11])=[CH:7][S:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C(=NOC)C1=CSCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)C1=CSCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
1N Aqueous solution (24 ml.) of sodium hydroxide was added to a solution of ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetate (syn isomer, 4.6 g.) in methanol (50 ml.), and stirred at room temperature for 16 hours. After the resultant solution was concentrated in vacuo, the residue was dissolved in water. The solution was washed with ethyl acetate and adjusted to pH 1.0 with 10% hydrochloric acid. The solution was extracted with ethyl acetate, and the extract was washed with water and dried over magnesium sulfate. The solution was concentrated under reduced pressure at 40° C., and the residue was washed with diisopropyl ether and then dried to give 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetic acid (syn isomer, 3.8 g.), white crystals, mp. 129° to 131° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:3]2[C:4](=[CH:11][S:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH3:14]>CC(O)C>[NH2:14][C:2]1[C:3]2[C:4](=[CH:11][S:12][CH:13]=2)[N:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2cscc2c1Cl
Reactant: N
Solvent: CC(C)O
Product: Nc1c([N+](=O)[O-])cnc2cscc12
Yield: 96 %

Procedure:
To a stirred suspension of 1.25 g of 4-chloro-3-nitrothieno[3,4-b]pyridine 11 in 37 ml of 2-propanol is introduced anhydrous ammonia at room temperature during 3 hours. The mixture is concentrated in vacuo and the residue is suspended in water with stirring. The crystals are collected by filtration, washed with water and dried to give 1.09 g (96%) of Compound 12. An analytical sample is recrystallized from chloroform-methanol, giving yellow crystals melting at 307°-309° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1)=[O:6].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=2)[N:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2n[nH]c3ccccc3c2=O)cc1C
Reactant: Cc1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nc(C(=O)c3ccc(C)c(C)c3)c(=O)c3ccccc32)n1
Yield: 68.2 %

Procedure:
Compound 9a was prepared following the procedure outlined in Step 3 of Example 1. Briefly described here, 36 mg (0.13 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-cinnolin-4-one 8a, 7 mg (0.17 mmol) of 60% sodium hydride and 33 mg (0.17 mmol) of 2-bromomethyl-6-methyl-pyridine in 0.7 mL N,N-dimethylformamide at rt for 3 h. The product was purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 50 min. The HPLC fractions containing pure product were combined and lyophilized to give 34 mg of a pale yellow solid 9a as the trifluoroacetate salt: LC-MSD, m/z for C24H21N3O2 [M+H]+=384.5, HPLC retention time: 2.3 min; 1H NMR (400 MHz, CDCl3): δ 2.3 (s, 3H), 2.35 (s, 3H), 2.85 (s, 3H), 6.1 (s, 2H), 7.15-7.2 (m, 1H), 7.25-7.3 (m, 1H), 7.45-7.55 (m, 2H), 7.6-7.7 (m, 3H), 7.7-7.8 (m, 1H), 8.0-8.1 (m, 1H), 8.3-8.4 (m, 1H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH3:2].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:1]([N:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:4]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH3:2]
Reactant: CCNc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N(CC)c1ccc(Cl)cc1C(=O)c1ccccc1

Procedure:
Subsequently, a mixture of 5.2 g of 2-ethylamino-5-chlorobenzophenone thus obtained and 20 ml of ethyl chloroformate was heated at 110° C for 5 hours. Then, the reaction mixture was concentrated to dryness under reduced pressure to give 2-(N-ethyl-ethoxycarbonylamino)-5-chlorobenzophenone as brown oil.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].ClC(Cl)=C(Cl)Cl.C(O)CCC.S(=O)(=O)(O)O.Cl>>[OH:10][C:4]1[C@@H:3]([C@@H:2]([OH:12])[CH2:1][OH:13])[O:8][C:7](=[O:9])[C:5]=1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCCCO
Solvent: ClC(Cl)=C(Cl)Cl
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 85 °C
Reaction time: 2 h

Procedure:
594 g (3 mol) of anhydrous 2-keto-L-gulonic acid were suspended in a solvent mixture consisting of 72 ml (0.7 mol) of perchloroethylene and 1 l (11 mol) of n-butanol. After addition of 7 g (69 mmol) of conc. sulfuric acid, the mixture was evacuated to 300 mbar and heated to an internal temperature of 85° C. The distillate was removed. After 2 hours, 24 ml of water were removed. After addition of 725 ml (7 mol) of fresh perchloroethylene, the viscous reaction mixture was rapidly treated with 79 g (0.8 mol) of conc. hydrochloric acid and stirred at 75° C. for 17 hours. The precipitated L-ascorbic acid was filtered off with suction, washed with n-butanol and dried in vacuo. Yield: 460 g (86%) of a gray crystallizate having a vitamin C purity of 99%. Vitamin C of high purity can be obtained by processes known from the literature, e.g. recrystallization.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57]/[CH:58]=[CH:59]\[C:60]([CH3:70])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:61]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:57]/[CH:58]=[CH:59]\[C:60]([CH3:70])([O:62][Si:63]([CH2:66][CH3:67])([CH2:68][CH3:69])[CH2:64][CH3:65])[CH3:61])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C\CBr
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C\CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 97.8 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and (Z)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (125 mg, 0.428 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=30:1, developed once) to give the title compound as a colorless oil (80.7 mg, 98%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:22]3[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=3)[C:9]3[C:14]([C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:30])[O:4][N:3]=1.B(Br)(Br)Br.O.O1CCOCC1>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[C:9]3[C:14]([C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:30])[O:4][N:3]=1
Reactant: COc1ccc(-n2c(-c3c(C)noc3C)c(C(=O)C(F)(F)F)c3ccccc32)cc1
Agent: BrB(Br)Br
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1noc(C)c1-c1c(C(=O)C(F)(F)F)c2ccccc2n1-c1ccc(O)cc1
Temperature: 25 °C
Yield: 46 %

Procedure:
1-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone was dissolved in dry DCM and the mixture was cooled on an ice-bath under an atmosphere of nitrogen. BBr3 (17 μl, 0.1 mmol) was added and the temperature was allowed to warm to RT and the mixture was stirred over night. Water, DCM and some dioxane were added, the phases were separated and the solvents were evaporated. The residue was passed through a short plug of silica with EtOAc as eluent. The residue was purified by preparative HPLC to provide the title compound 1-(2-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-1H-indol-3-yl)-2,2,2-trifluoroethanone in 46% yield. ES/MS m/z: 401.1 (M+H), 399.1 (M−H); 1H NMR (methanol-d4, 500 MHz): 8.26 (m, 1H), 7.41-7.34 (m, 2H), 7.18 (m, 1H), 7.11 (m, 2H), 6.89 (m, 2H), 2.19 (s, 31-1) and 2.01 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:32](C1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C(O)=O)(=O)=O)CC3)=NC=2)=CC=1)#[N:33]>>[C:32]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:30])[CH3:31])[C:25]([NH:27][OH:28])=[O:26])(=[O:21])=[O:22])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1)#[N:33]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1)C(=O)NO
Yield: 53 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 2-(R)-{4-[5-(4-Cyanophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid (0.070 g), to provide the title compound as a white solid (0.039 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[F:9][C:10]([F:20])([F:19])[C:11](=O)[CH2:12][C:13](OCC)=[O:14].Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:11]([C:10]([F:20])([F:19])[F:9])[CH:12]=[C:13]2[OH:14]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1ccccc1F
Agent: Cl
Solvent: c1ccccc1
Product: Oc1cc(C(F)(F)F)nc2c(F)cccc12
Temperature: 110 °C
Reaction time: 5 h
Yield: 8.5 %

Procedure:
2-Fluoroaniline (10.0 g), ethyl trifluoroacetoacetate (16.6 g) and concentrated hydrochloric acid (0.1 mL) were dissolved in benzene (40 mL), and the mixture was refluxed in a reaction vessel equipped with Dean-Stark trap for 7 hr. The reaction mixture was concentrated under reduced pressure and 75% phosphoric acid (40 mL) was added thereto. The mixture was stirred at 110° C. for 5 hr. The reaction mixture was added to water, neutralized with sodium hydrogencarbonate, and extracted with ethyl acetate. The extract was concentrated under reduced pressure to give 8-fluoro-4-hydroxy-2-trifluoromethylquinoline (1.77 g).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([S:16][C:17]1[S:18][CH2:19][CH2:20][N:21]=1)C1C=CC=CC=1>CO>[CH2:1]([N:21]1[CH:20]=[CH:19][S:18][C:17]1=[S:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CSC2=NCCS2)cc1
Reactant: ClCc1ccccc1
Solvent: CO
Product: S=c1sccn1Cc1ccccc1
Temperature: 150 °C
Yield: 704.2 %

Procedure:
12.7 g (0.1 mole) of benzylchloride were added to 209.2 g (1 mole) of 2-benzylthio-thiazoline and the mixture was heated to 150° C. for eight hours. The mixture was allowed to cool down to 70° C. and 500 ml of methanol were added. The reaction mixture was allowed to cool down to room temperature and stirred for an additional hour; N-benzyl-thiazoline-thion precipitated from the medium as a white crystalline product, was isolated by filtration and washed twice with 10 ml of methanol. The crude product was recrystallized from a minimum of acetonitrile. 146 g of N-benzyl-thiazolinethion were isolated and sulfonated as described below.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]=[O:9].[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl>O>[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]=[O:9]
Reactant: O=Cc1ncc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C[Si](C)(C)CCOCn1ccnc1C=O
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
An oily suspension of 20.8 g sodium hydride in mineral oil (50%, 0.52 mol) was washed mineral oil free by stirring with hexane 3-times and suspended in 400 ml DMF. Under stirring at ambient temperature 50.0 g (0.520 mol) imidazole-2-carbaldehyde was added to the suspension. After 1.5 h, 101.0 ml (0.572 mol) 2-(trimethylsilanyl)ethoxymethyl chloride was added and the reaction was stirred a further hour. Then excess water was added to the suspension and the reaction mixture was extracted three times with ethyl acetate. The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The raw material was then purified by column chromatography (DCM) to yield 85.0 g (0.376 mol) of the SEM-protected imidazole-2-carbaldehyde.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([OH:11])[N:5]=2.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:21][CH2:22][CH2:23]Br)(=[O:20])[CH3:19].O>CN(C=O)C.[Cl-].[Na+].O>[C:18]([O:21][CH2:22][CH2:23][O:11][C:6]1[N:5]=[C:4]2[S:3][C:2]([NH2:1])=[N:10][C:9]2=[CH:8][CH:7]=1)(=[O:20])[CH3:19]
Reactant: Nc1nc2ccc(O)nc2s1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCOc1ccc2nc(N)sc2n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino[1,3]thiazolo[5,4-b]pyridin-5-ol 2 hydrobromide (10 g) in DMF (20 mL) were added potassium carbonate (25.2 g) and 2-bromoethyl acetate (4 mL) at room temperature. It was stirred at 80° C. for 2 hours. To the reaction mixture were added saturated brine and water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=1:2-1:3) to obtain 2-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]ethyl acetate (2.97 g) as a pale yellow solid.
Reaction SMILES: C(OC([NH:8][CH:9]([C:17](=[N:24][OH:25])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.Cl>CO>[NH2:8][CH:9]([C:17](=[N:24][OH:25])[C:18]1[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=1)[C:10]([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCCC1)C(=NO)c1ccncc1
Agent: Cl
Solvent: CO
Product: NC(C(=O)N1CCCC1)C(=NO)c1ccncc1
Temperature: 45 °C

Procedure:
(±)-2-tert-Butyloxycarbonylamino-3-(hydroxyimino)-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-1-one TTA 08160 (100 mg, 0.29 mmol) was dissolved in MeOH (2 mL) and a solution of 1 M HCl in MeOH (1 mL, 3.00 mmol) was added and the mixture was heated for 10 min at 45° C. MeOH was evaporated and the residue was dried to give crude (±)-2-amino-3-(hydroxyimino)-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-1-one TTA 08164. Amberlite IRA-400 (Cl−) (1 mL, 1.4 mmol) was washed successively with water (2×10 mL), NaOH 0.5 N (3×20 mL), water (2×10 mL) and MeOH (3×10 mL). A solution of TTA 08164 in MeOH (30 mL) was stirred with washed Amberlite IRA-400 for 5 min at RT. After filtration, the MeOH was evaporated and the free base form was purified by column chromatography (SiO2, CH2Cl2:MeOH=9:1). HCl Treatment in MeOH gave (±)-2-amino-3-(hydroxyimino)-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-1-one dihydrochloride Compound 224 (29 mg, 31% yield) as a beige solid.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].[Cl:7][CH2:8][CH2:9]O>O.[Cl-].[Cl-].[Zn+2]>[Cl:7][CH2:8][CH2:9][O:5][C:2]([CH3:6])([CH3:1])[C:3]#[N:4]
Reactant: OCCCl
Reactant: CC(C)(O)C#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C#N)OCCCl
Temperature: 60 °C
Reaction time: 19 h
Yield: 63.8 %

Procedure:
(Navalokina, R. Et al J. Org. Chem. USSR (Engl. Trans.), 1980, 16, 1382-1386. 2) Ramalingam, K. U.S. Pat. No. 4,864,051, 1989). A 250 mL round bottom flask was charged with ZnCl2 (68.14 g, 0.5 mole) which was then fused by heating under vacuum. After returning to room temperature the material was placed under an atmosphere of N2. To this was added acetone cyanohydrin (45.66 mL, 0.5 mole) followed by 2-chloroethanol (50.24 mL, 0.75 mole) and the mixture placed in a preheated oil bath (60° C.). After stirring for 18-20 h at 60° C., the reaction mixture was cooled, diluted with water (300 mL) and washed with CH2Cl2 (5×100 mL). The combined CH2Cl2 extracts were dried (Na2SO4), filtered and concentrated under vacuum to afford the crude product as a yellow liquid. Purification was accomplished by vacuum distillation (10 mm Hg) using a vigreux column. The fraction boiling between 65-75° C. was collected to afford the desired product as colorless oil (47.1 g, 63.8% yield). 1H NMR (500 MHz, CDCl3) δ: 3.85 (2H, t, J=5.8 Hz), 3.64 (2H, t, J=5.8 Hz), 1.60 (6H, s).
Reaction SMILES: FC1C=CC([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[N:12][CH:11]=2)=CC=1.Br.BrCC1C=CC=CN=1.[OH-].[Na+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:9]([NH2:8])(=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Agent: Br
Agent: BrCc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: NC(=O)c1cccnc1
Reaction time: 8 h
Yield: 269.2 %

Procedure:
In a round bottom flask, N-(4-fluoro-phenyl)-6-chloro-nicotinamide (0.905 g, 3.62 mmol) and 2-bromomethyl-pyridine hydrobromide (0.915 g, 3.62 mmol) was suspended in toluene (5 ml). 50% aqueous sodium hydroxide (2.0 mL) was added to the reaction mixture, followed by tetra-n-butyl-ammonium hydroxide (100 ul). The biphasic reaction mixture was vigorously stirred overnight, and the aqueous layer removed by pipette. The organic layer was diluted with ethyl acetate (20 mL) and washed with water, saturated aqueous sodium chloride and dried over sodium sulfate. The organic layer was filtered and removed by rotary evaporation to yield 1.19 g (96%) of nicotinamide intermediate X as an off white solid. ESI-MS m/z=341.9, 343.9 [M+H]+.