Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:34]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([CH3:37])([CH3:36])[CH3:35]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:41]4[CH2:42][CH2:43][N:38]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:39][CH2:40]4)=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)N1CCNCC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Product: CC(C)(C)N1CCN(c2ccc(S(=O)(=O)[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)[C@H](C(=O)N4CCC(F)(F)C4)C3)c(Cl)c2)CC1

Procedure:
The title compound was prepared in analogy to example 127 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 186 step 7) and N-tert-butylpiperazine. Light yellow solid (63%). MS (EI): 624.2 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:6]([C:5]4[CH:4]=[N:3][C:2]([F:1])=[C:10]([CH3:11])[CH:9]=4)=[O:8])[CH2:25][CH2:26]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: Cc1cc(C(=O)O)cnc1F
Product: Cc1cc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)cnc1F
Yield: 52.6 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 6-fluoro-5-methylnicotinic acid (1 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (1.4 g) described in Preparation Example 96, the title compound (1.2 g) was obtained.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10]([NH2:12])=[O:11])=O)(C)(C)C.[OH-].[K+]>Cl>[NH2:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[N:16]=[CH:17][CH:18]=[CH:19][N:20]=1)[C:10]([NH2:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN(c1ccccc1)c1ncccn1)C(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: NC(=O)[C@@H](N)CN(c1ccccc1)c1ncccn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid amide (48.5 g, 136 mmol, >99.9% ee) is introduced at 40° C. in portions into hydrochloric acid (16% strength, 80 ml), and the resulting solution is stirred for 1 h at this temperature. After cooling to 5° C., the pH is adjusted to 10 by adding concentrated potassium hydroxide solution. The precipitated solid is filtered off with suction and dried to give (S)-2-amino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid amide (35.3 g, 80% yield, 79% content, 99.8% ee) as a colorless solid, which can be further reacted or else crystallized again from aqueous solution, as desired.
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].[C:7]([C:10](=[C:16]=CN(C)C)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=O)[CH3:8]>>[CH:2]([N:5]1[C:7]([CH3:8])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:16]=[N:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)NN
Reactant: CCOC(=O)C(=C=CN(C)C)C(C)=O
Agent: Cl
Product: CCOC(=O)c1cnn(C(C)C)c1C

Procedure:
In a procedure analogous to Example B6, isopropylhydrazine hydrochloride (896 mg, 8.10 mmol) and ethyl 2-acetyl-3-(dimethylaminomethylene)acrylate (1.50 g, 8.10 mmol) were combined and purified by chromatography (ethyl acetate/hexane) to afford ethyl 1-isopropyl-5-methyl-1H-pyrazole-4-carboxylate (faster elution, 537 mg), 1H NMR (300 MHz, DMSO-d6): δ 1.30 (t, 3 H), 1.39 (d, 6 H), 4.23 (q, 2 H), 4.61 (hp, 1 H), 7.82 (s, 1 H); MS (ESI) m/z: 197.0 (M+H+) and ethyl 1-isopropyl-3-methyl-1H-pyrazole-4-carboxylate (slower elution, 91 mg), 1H NMR (300 MHz, DMSO-d6), δ 1.29 (t, 3 H), 1.42 (d, 6 H), 2.36 (s, 3 H), 4.21 (q, 2 H), 4.49 (hp, 1 H), 8.24 (s, 1 H); MS (ESI) m/z: 197.0 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:8]=1)=[O:6].C(C1C=CC(C(CCC)CCCCCCC(C2C3C(=CC=CC=3)N(CCCC(OCC)=O)C=2)=O)=CC=1)C(C)C>>[CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:8]=1)=[O:6]
Reactant: CCOC(=O)CCCn1cc(C(=O)CCC(C)C)c2ccccc21
Agent: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Product: CC(C)CCC(=O)c1cn(CCCC(=O)O)c2ccccc12

Procedure:
The procedure of Ex. 16 was repeated except that ethyl 4-[3-(4-methylvaleryl)-1-indolyl]butyrate obtained in Ex. 25 was used in place of ethyl 4-[3-[8-(4-isobutylphenyl)undecanoyl]1-indolyl]butyrate to give 4-[3-(4-methylvaleryl)-1-indolyl]butyric acid.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]#[C:4]B1C2CCCC1CCC2.[CH3:16][C:17]([CH3:21])([CH3:20])[CH:18]=[O:19].C(OCC)C.C(CN)O>CCCCC.CO>[CH3:16][C:17]([CH3:21])([CH3:20])[CH:18]([OH:19])[C:4]#[C:3][Si:2]([CH3:1])([CH3:14])[CH3:15]
Reactant: C[Si](C)(C)C#CB1C2CCCC1CCC2
Reactant: CC(C)(C)C=O
Solvent: CO
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C)C(O)C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 120 h
Yield: 93 %

Procedure:
Dissolve B-(2-(trimethylsilyl)ethynyl)-9-borabicyclo[3.3.1]nonane.tetrahydrofuran complex (2.13 g, 7.3 mmol) in pentane (25 mL) and add trimethylacetaldehyde (795 μL, 7.3 mmol). Stir at room temperature for 5 days. Remove the solvent under a positive nitrogen pressure to give a yellow solid. Add ethyl ether (30 mL) and methanol (500 μL). Cool to 0° C. and add, by dropwise addition, ethanolamine (440 μL, 7.3 mmol). Stir overnight, centrifuge the reaction mixture and separate the clear supernatant liquid. Wash the precipitate with pentane (2×10 mL) and combine the organic phases. Wash with water (2×25 mL) and dry (MgSO4). Evaporate the solvent in vacuo and purify by silica gel chromatography (19:1 hexane/ethyl acetate) to give the title compound as a clear liquid (1.25 g, 93%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1.N1C=CC=CC=1.[C:17]([CH2:21][C:22](Cl)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:22](=[O:23])[CH2:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)nc(C)c1N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(Br)nc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a mixture of 1c (0.364 g, 1.81 mmol) and pyridine (0.158 ml, 2 mmol) in dichloromethane (5 ml) was added tert-butylacetyl chloride (0.242 g, 1.8 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield 1d (0.361 g, 1.64 mmol, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[N:15]=[C:14]1[C:9]([CH:10]=[CH:11][CH:12]=[C:13]1[C:17]([OH:19])=O)=[N:8]2.O.[NH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1.S(Cl)(Cl)=O>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[N:15]=[C:14]1[C:9]([CH:10]=[CH:11][CH:12]=[C:13]1[C:17]([NH:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1)=[O:19])=[N:8]2
Reactant: Nc1nnn[nH]1
Reactant: COc1cccc2nc3cccc(C(=O)O)c3nc12
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1cccc2nc3cccc(C(=O)Nc4nnn[nH]4)c3nc12
Temperature: 70 °C

Procedure:
To a stirred solution of 0.006 mole (1.5 g) of 9-methoxyphenazine-1-carboxylic acid and 0.006 mole (0.61 g) of 5-aminotetrazole monohydrate in 50 ml of pyridine was added dropwise 0.012 mole (1.4 g) of thionyl chloride. The mixture was warmed to 70° C., maintained at 70° C. for 20 minutes, then diluted with water. A solid product was separated from the mixture by filtration, washed with water and acetone, and dried. Recrystallization from N,N-dimethylformamide provided 9-methoxy-(N-tetrazol-5-yl)phenazine-1-carboxamide, in the form of orange needles, m.p. 325°-330° C. (dec.)
Reaction SMILES: Br[C:2]1[C:3](=[O:22])[N:4]([CH3:21])[N:5]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:12][C@@H:11]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=2)[CH:7]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:31][NH2:32])=[N:28][C:29]=1[CH3:30].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(#N)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:31][NH:32][C:2]2[C:3](=[O:22])[N:4]([CH3:21])[N:5]=[C:6]([O:8][CH2:9][C@H:10]3[CH2:12][C@@H:11]3[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=3)[CH:7]=2)=[N:28][C:29]=1[CH3:30]
Reactant: COc1ccc([C@H]2C[C@@H]2COc2cc(Br)c(=O)n(C)n2)nc1
Reactant: Cc1nc(CN)ccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COc1ccc([C@H]2C[C@@H]2COc2cc(NCc3ccc(Cl)c(C)n3)c(=O)n(C)n2)nc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 15.5 %

Procedure:
To the solution of 4-bromo-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one (5) (80 mg, 0.219 mmol) in toluene (5 mL) under N2, (5-chloro-6-methylpyridin-2-yl)methanamine (4) (50 mg, 0.320 mmol), Pd2(dba)3 (15 mg, 0.0219 mmol), BINAP (20 mg, 0.0328 mmol) and NaOt-Bu (42 mg, 0.438 mmol) were added. After the reaction mixture was stirred at 85° C. for 4 h, 15 mL water was added. The mixture was extracted with EtOAc (3×10 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (X bridge Prep C18OBD, 40-60% acetonitrile in water with 10 mmol NH4HCO3 modifier) to afford the compound as an oil (15 mg, 15.5% yield). 1H NMR (400 MHz, MeOD) δ 8.05-8.04 (s, 1H), 7.75-7.73 (d, 1H), 7.30-7.27 (m, 1H), 7.20-7.15 (m, 2H), 5.72 (s 1H), 4.40 (s, 2H), 4.18-4.14 (m, 1H), 4.10-4.00 (m, 1H), 3.86 (s, 3H), 3.71 (s, 3H), 2.61 (s, 3H), 2.08-2.03 (m, 1H), 1.75-1.70 (m, 1H), 1.18-1.13 (m, 1H) 1.03-0.95 (m, 1H); LRMS m/z (M+H) 441.1 found, 441.15 required.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 80 °C
Yield: 45 %

Procedure:
To a solution of 2-Chloromethyl-quinoline (1.57 g) and 4-Hydroxy-benzamide (995 mg) in dimethyl formamide (20 mL) was added cesium carbonate (7.3 g) and the reaction mixture heated at 80° C. for 18 h. The reaction mixture was poured into water and extracted with chloroform, dried magnesium sulfate, filtered and concentrated to provided the title compound (909 mg). MS: (M+H m/z=279.3).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C@H:21]([F:23])[CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][C@H:21]([F:23])[CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@H](F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1C[C@@H](F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 91.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4R*)-4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (235 mg, 0.389 mmol) prepared in Example 106e, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (162 mg, 92%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13]OC2CCCCO2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.BrCCC[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][CH2:12][CH2:13][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: BrCCCCCCCCCCCOC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)CCCOC2CCCCO2)cc1
Product: Cc1ccc(S(=O)(=O)CCCCCCCCCCCOC2CCCCO2)cc1

Procedure:
As in Example 2a 13.57 g (40.5 mmol) of 1b give, after column chromatography, 13.82 g (83%) of practically colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)(=O)=O)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.N.[CH3:40][OH:41]>>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([O:41][CH3:40])[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: CO
Agent: N
Product: COc1nccc(-c2noc3c(F)c4c(cc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)n1

Procedure:
Starting material: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169) and 2M ammonia in methanol.
Reaction SMILES: [Na+].[Na+].[O:3]=[C:4]([CH2:8][CH2:9][C:10]([O-:12])=[O:11])[C:5]([O-:7])=[O:6].[Br-].[C:14]1([S+:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.ClCCl>[O:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:5]([OH:7])=[O:6].[C:27]1([S+:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1.[C:27]1([S+:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C([O-])CCC(=O)C(=O)[O-]
Agent: [Br-]
Agent: [Na+]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-ketoglutaric acid disodium salt (0.4 g, 2.1 mmol) was dissolved in 6 mL of water. Triphenylsulfonium bromide (1.4 g, 4.1 mmol) was dissolved in 12 mL dichloromethane. The salt solution was added dropwise to the triphenylsulfonium bromide solution and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness (or on oil stage) on a rotary evaporator. The product obtained from evaporation was washed with ethyl ether and dissolved using an excess amount of dichloromethane and filtered. After the evaporation of dichloromethane, the pure compound was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Br[CH2:38][CH2:39][Cl:40]>O>[Cl:40][CH2:39][CH2:38][O:25][C:22]1[CH:23]=[CH:24][C:19]2[N:18]=[CH:17][N:16]([C:10]3[S:11][C:12]([C:13]([NH2:15])=[O:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[C:20]=2[CH:21]=1
Reactant: ClCCBr
Reactant: NC(=O)c1sc(-n2cnc3ccc(O)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCl)cc32)nc1-c1cccc(Cl)c1
Yield: 62.1 %

Procedure:
To a mixture of 0.371 g (1 mmole) of 4-(3-chloro-phenyl)-2-(6-hydroxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.25d), 1.63 g (5 mmole) of cesium carbonate and 3 mL of dimethylformamide was added 0.249 mL (3 mmole) of 1-bromo-2-chloro-ethane. The mixture was heated at 100 degrees for 30 minutes. The cooled mixture was diluted with 20 mL of water and the resulting precipitate collected by filtration and then air dried. The solid was triturated with acetonitrile to give 0.269 g of 2-[6-(2-chloro-ethoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.28a) as a yellow solid.
Reaction SMILES: C(OC([NH:8][CH:9]([CH:17]([OH:45])[CH:18]([NH:26][C:27](=[O:44])[C@H:28]([CH2:40][C:41](=[O:43])[NH2:42])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.CO.C(N)(C)C.C(Cl)(Cl)Cl>>[NH2:8][CH:9]([CH:17]([OH:45])[CH:18]([NH:26][C:27](=[O:44])[C@H:28]([CH2:40][C:41](=[O:43])[NH2:42])[NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(C)N
Product: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Yield: 95 %

Procedure:
Using the procedure of Example 11 with the resultant compound of Example 66 gave, after silica gel chromatography using methanol/isopropylamine/chloroform, the desired compound (RF 0.3; 2.5% methanol/2% isopropylamine/chloroform) in 95% yield. Mass spectrum (M+H)+ =519.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]O)=[CH:31][CH:30]=1>C(#N)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:2]([NH:1][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[C:3]([CH:10]=1)[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5]
Reactant: COc1ccc(CO)cc1
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: COc1ccc(CNc2ccc(Cl)cc2C(=O)N(C)OC)cc1
Temperature: 70 °C
Yield: 74.2 %

Procedure:
A solution of 8 (3.75 g, 17.3 mmol) in 50 mL of acetonitrile was treated with p-toluenesulfonic acid monohydrate. The reaction mixture was heated to 70° C. with stirring. 4-Methoxybenzyl alcohol (2.63 g, 19.0 mmol) in acetonitrile (3 mL) was added dropwise via syringe keeping the reaction temperature at 70° C. The reaction was stirred at 70° C. for 12 h, allowed to cool to ambient temperature, and concentrated in vacuo. Chromatography afforded 9 (4.3 g, 75%) as light yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1>>[OH:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:9])=[CH:24][CH:25]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)C1CCOCC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: O=C(Nc1ccc(O)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
3,4,5,6-Tetrahydro-2H-pyran-4-carboxylic acid (10.0 g) solution in dimethylformamido (15 ml) was added drop-wise with carbonyl diimidazole (13.1 g) in dimethylformamido (65 ml) in an ice bath and the mixture was stirred for 30 minutes at room temperature. 4-Aminophenol (8.4 g) solution in dimethylformamido (20 ml) was added drop-wise to this mixture in ice bath and the mixture was stirred for 5 hours at room temperature. The reaction mixture was concentrated to small volume and further stirred after addition of 2N HCl (100 ml). Crystals formed were collected by filtration, washed with water and then dried under vacuum at 60° C. to obtain 4′-hydroxy-3,4,5,6-tetrahydro-2H-pyran-4-carboxanilide (13.5 g) as white crystal.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14])=O.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])/[C:5](=[N:22]\[OH:23])/[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[F:14]
Reactant: COc1ccc(C(=O)c2cc(F)ccc2F)c(O)c1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(/C(=N\O)c2cc(F)ccc2F)c(O)c1Cl

Procedure:
A mixture of 28 g of 3-chloro-2',5'-difluoro-2-hydroxy-4-methoxybenzophenone and 26 g of hydroxylamine HCl in 250 ml pyridine is refluxed for three hours. Pyridine is evaporated and the residue partitioned between ethyl acetate and 5% HCl. The ethyl acetate extract is washed with water, dried over Na2SO4 and evaporated to give a solid product as a mixture of isomers. The solid is heated at 200°-210° C. for approximately 30-45 minutes and recrystallized from toluene giving E-3-chloro-2',5'-difluro-2-hydroxy-4-methoxybenzophenone oxime, mp 209°-210° C.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH2:8]=[C:9]([CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15])[C:10]([OH:12])=[O:11]>C1(C)C=CC=CC=1.C(#N)C>[CH:1]1([CH2:4][S:5]([CH2:8][CH:9]([CH2:13][C:14]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[O:15])[C:10]([OH:12])=[O:11])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: C=C(CC(=O)N1CCOCC1)C(=O)O
Reactant: O=S(O)CC1CC1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)CC1CC1
Temperature: 85 °C
Reaction time: 4.5 h
Yield: 40.1 %

Procedure:
To a solution of cyclopropylmethylsulphinic acid (1.8 g, 15 mmol) in anhydrous toluene (45 mL) and anhydrous acetonitrile (9 mL) was added 2-Methylene4-morpholin-4-yl-4-oxo-butyric acid (2.98 g, 15 mmol). The resulting solution was warmed to 85° C. and stirred at this temperature for 4.5 h. The heterogeneous reaction mixture is then allowed to cool to room temperature then concentrated under reduced pressure. The residue is then purified by flash chromatography eluting with 7% methanol in dichloromethane to give 2-Cyclopropylmethanesulfonylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (1.92 g) as viscous oil which was re crystallized from hot ethyl acetate to give a white solid.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=1[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C.O>ClCCl>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=1[CH2:22][N:23]1[CH2:28][CH2:27][N:26]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:25][CH2:24]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(C(C)C)cc1CN1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1CN1CCN(S(=O)(=O)c2ccccc2)CC1
Reaction time: 3 h

Procedure:
Phenylsulfonyl chloride (0.24 ml) was added to a solution of the product from step (b) (396 ml) and triethylamine (0.44 ml) in dichloromethane (3 ml) and the mixture was stirred for 3 h. Water was added and the mixture was extracted with dichloromethane. The organic extracts were dried (MgSO4), evaporated in vacuo and purified by chromatography (silica, petrol—ether as eluent) to give the sub-title compound (431 mg).