Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][OH:11])[C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:5][N:4]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:4]2[CH:5]=[C:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:7]([CH2:9][CH2:10][OH:11])=[CH:8][C:3]2=[O:2])=[CH:23][CH:24]=1
Reactant: COc1ccc(-c2cnc(OC)cc2CCO)cc1
Reactant: Clc1ccc(CBr)cc1
Product: COc1ccc(-c2cn(Cc3ccc(Cl)cc3)c(=O)cc2CCO)cc1
Yield: 35.5 %

Procedure:
According to Scheme 30 Step 3: The title compound was prepared from 2-(2-methoxy-5-(4-methoxyphenyl)pyridin-4-yl)ethanol (1 eq, 0.62 mmol, 0.16 g) and 1-(bromomethyl)-4-chlorobenzene (1.5 eq, 0.93 mmol, 0.19 g) according to the procedure described for Example 6 Step 2. Reaction conditions: 19 hours under 90° C. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 10 g SiO2) using CH2Cl2/MeOH 98/2 as eluent afford 1-(4-chlorobenzyl)-4-(2-hydroxyethyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (0.22 mmol, 82 mg, 36%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:3]=1
Reactant: COc1ccc(N)cc1
Reactant: COC(=O)c1cccc(Br)c1
Product: COC(=O)c1cccc(Nc2ccc(OC)cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with p-anisidine according to general procedure A provided methyl ester of Compound 11 as a yellow oil (93% yield). 1H NMR (CDCl3, 500 MHz): δ=7.57 (s, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.28 (m, 1H), 7.07-7.12 (m, 3H), 6.90 (d, J=8.8 Hz, 2H), 5.62 (s, 1H), 3.90 (s, 3H), 3.83 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=167.5, 156.0, 145.8, 135.2, 131.5, 129.5, 123.1, 120.7, 119.7, 116.4, 115.0, 55.8, 52.2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:36]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][CH2:38][CH2:37]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:36]3[CH2:42][CH2:41][C:40](=[O:43])[NH:39][CH2:38][CH2:37]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCNCCN1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)CC1
Product: Cl

Procedure:
1-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-5-one hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and [1,4]diazepan-5-one (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 607.4 [(M+H)+]
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[NH2:47][C:48]1([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>ClCCl>[CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([C:6]([NH:47][C:48]3([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)=[O:8])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1(N)CCCCC1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(NC(=O)c2ccc3c(c2)OCO3)CCCCC1
Reaction time: 18 h
Yield: 98.9 %

Procedure:
2.74 g (16.5 mmol) of 3,4-methylenedioxybenzoic acid was dissolved in anhydrous dichloromethane and then was ice cooled. 4.62 ml (33.0 mmol) of triethylamine, 2.53 g (16.5 mmol) of 1-hydroxybenzotriazole hydrate, 3.57 g (17.3 mmol) of N,N'-dicyclohexylcarbodiimide and 3.20 g (16.5 mmol) of ethyl 1-aminocyclohexanecarboxylate hydrochloride were successively added to the above reaction mixture and were stirred for 18 hours gradually rising the temperature up to the room temperature. The reaction mixture was concentrated under reduced pressure and was dissolved in ethyleacetate, and the insoluble components were removed therefrom by filtration. After the ethyl acetate solution was washed successively with 1N-hydrochloric acid, saturated brine, aqueous solution of saturated sodium hydrogen carbonate and saturated brine, the resultant organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, whereby 5.21 g of ethyl 1-[N-(3,4-methylenedioxyphenylcarbonyl)amino]cyclohexanecarboxylate was obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1.[Cl-].[NH4+]>C1C=CC=CC=1.[Cl-].[Cd+2].[Cl-]>[C:1]1([CH2:7][CH2:8][C:9]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Cd+2]
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Product: O=C(CCc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58 %

Procedure:
Phenylpropionyl chloride (33.7 g) in benzene was added dropwise to a stirred mixture of 4-chlorophenyl magnesium bromide (derived from 38 g of 4-chlorobromobenzene) and cadmium chloride (37 g) in benzene at 0°. The mixture was stirred at room temperature for 6 hours and aqueous ammonium chloride solution then added. Ether extraction yielded p-chlorophenyl phenylethyl ketone (25 g) m.p. 78°-79°.
Reaction SMILES: C1(C#C)C=CC=CC=1.[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]#[CH:11].[N:19]([C:22]1[S:23][C:24]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[C:25]([CH3:27])[N:26]=1)=[N+:20]=[N-:21]>>[CH2:31]([NH:30][C:28]([C:24]1[S:23][C:22]([N:19]2[CH:11]=[C:10]([CH2:9][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:21]=[N:20]2)=[N:26][C:25]=1[CH3:27])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C#CCOc1ccccc1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Solvent: C#Cc1ccccc1
Product: Cc1nc(-n2cc(COc3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 36 %

Procedure:
Following the procedure as described in Example 10, making variations as necessary to replace phenylacetylene with phenyl propargyl ether to react with 2-azido-N-benzyl-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 36% yield: mp 140-143° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 7.38-7.26 (m, 7H), 7.02-6.98 (m, 3H), 6.15 (t, J=6.0 Hz, 1H), 5.28 (s, 2H), 4.63 (d, J=6.0 Hz, 2H), 2.68 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.8, 157.9, 155.3, 153.2, 145.6, 137.4, 129.6, 128.9, 127.9, 127.9, 124.7, 121.5, 120.3, 114.7, 61.5, 44.4, 17.4; MS (ES+) m/z 406.3 (M+1).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].[CH3:15][C:16]1[C:17]([NH2:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1>C(Cl)Cl>[NH2:13][N:18]1[C:19]([CH3:22])=[CH:20][CH:21]=[C:16]([CH3:15])[C:17]1=[NH2+:23].[CH3:8][C:3]1[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:14])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Cc1ccc(C)c(N)n1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Cc1ccc(C)n(N)c1=[NH2+]
Reaction time: 1 h

Procedure:
A solution of O-(mesitylsulfonyl)hydroxylamine (5.3 g, 24.6 mmol) in DCM (20 mL) was slowly added to a solution of 3,6-dimethylpyridin-2-amine (1.0 g, 8.2 mmol) in DCM (5 mL). A yellow precipitate was formed gradually, and after stirring for 1 h, the precipitate was collected by filtration and used for the next step without further purification. ESI MS: m/z 138 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([SH:34])[NH:25][C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:18][CH:17]=1.[H-].[Na+]>CN(C)C=O>[CH3:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]2[N:25]=[C:24]([S:34][C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[NH:23][C:22]=2[C:19]2[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=2)=[CH:32][CH:31]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: Cc1ccc(-c2nc(S)[nH]c2-c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(Sc3ccc(C(F)(F)F)cc3[N+](=O)[O-])[nH]c2-c2ccc(C)cc2)cc1
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
Under agitation and covering with argon, a solution of 4.52 g of 4-chloro-3-nitrotrifluoromethylbenzene in 25 ml of dimethylformamide is added dropwise to a solution of 5.61 g of 4,5-bis(4-methylphenyl)-2-mercaptoimidazole and 0.6 g of sodium hydride (80% strength in white oil) in 200 ml of dimethylformamide. The solution is further stirred for 30 minutes, concentrated under vacuum, and the residue distributed between water and ethyl acetate. The organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized from ethanol, thus producing 8.26 g of 4,5-bis(4-methylphenyl)-2-(2-nitro-4-trifluoromethylphenylthio)imidazole in fine yellow needles having a decomposition point of 252°.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.CON(C)[C:44](=[O:46])[CH3:45].[NH4+].[Cl-]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:44](=[O:46])[CH3:45])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(C)=O
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Reaction time: 1 h

Procedure:
To a stirred solution of (2R,6S)-4-[6-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3, 15.0 g, 30.0 mmol) in THF (150 mL) was added sec-butyllithium (1.4 M in cyclohexane, 66.4 mL, 93 mmol) at −78° C. under a nitrogen atmosphere. After stirring for 1 h, N-methoxy-N-methyl-acetamide (3.4 mL, 45 mmol) was added and, after stirring for ½ h at −78° C., the solution was allowed reach room temperature with stirring continuing for 12 hours. The reaction mixture treated with saturated aqueous NH4Cl solution and the aqueous layer extracted by EtOAc (2×100 mL). The organic phases were combined, dried (Na2SO4) and concentrated. The residue was purified over a silica gel flash column using a gradient of ethyl acetate in pet. ether to give the title compound as yellow solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1)[C@@H:10]([CH3:13])[CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P([N:68]=[N+:69]=[N-:70])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[N:68]([CH2:11][C@H:10]([CH3:13])[C@H:9]([C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1)[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:69]=[N-:70]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of (2S,3R)-3-(tert-butyldimethylsilyloxy)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropan-1-ol (1.0 equiv.), DIAD (2.0 equiv.), and PPh3 (2.0 equiv.) in THF (0.18 M) was added DPPA (1.0 equiv., 1M solution in THF). The reaction mixture was stirred at room temperature overnight. Upon removal of the volatiles under vacuo, the residue was purified by silica gel column chromatography (2-3-5% EtOAc/n-heptanes) yielding ((1R,2S)-3-azido-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropoxy)(tert-butyl)dimethylsilane (62%). 1H-NMR (400 MHz, CDCl3): δ 4.04-4.10 (m, 1H), 3.94 (dd, J=8.0, 6.4, 1H), 3.72 (d, J=7.2, 1H), 3.53 (t, J=8.0, 1H), 3.36 (dd, J=12, 8.0, 1H), 3.19 (dd, J=12.0, 6.7, 1H), 1.52-1.60 (m, 1H), 1.41 (s, 3H), 1.34 (s, 3H), 0.92 (d, J=7.2, 3H), 0.90 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:35](N)=[O:36])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:22])=[CH:14][CH:13]=3)[C:6]=2[CH:34]=1.[OH-:38].[K+].O.Cl>CO>[Cl:1][C:2]1[C:3]([C:35]([OH:36])=[O:38])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:25])=[O:26])=[O:22])=[CH:16][CH:17]=3)[C:6]=2[CH:34]=1
Reactant: [OH-]
Reactant: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1nc2cc(C(=O)O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 25.6 %

Procedure:
A mixture of 6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide (Example 111, 140 mg, 0.26 mmol) and KOH (63 mg, 0.8 mmol) in methanol (10 mL) was stirred at 100° C. for 1 day. The mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL), dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane/mathanol (10:1) to afford 36 mg (25%) of the title compound as white solids: mp 145–150° C.; MS (ESI) m/z 541 (M+H)+; 1H-NMR (DMSO-d6) δ 8.10 (1H, s), 7.76 (2H, d, J=7.9 Hz), 7.36–7.47 (6H, m), 7.10 (1H, s), 3.28 (2H, m), 2.69–2.81 (4H, m), 2.34 (3H, s), 1.24 (3H, t, J=7.5 Hz); IR (KBr) v.,: 3450, 1701, 1517, 1340, 1163, 1091, 900 cm−1.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:24][NH:25][O:26][CH3:27].Cl>C1(C)C=CC=CC=1.C(OC)(C)(C)C>[CH3:27][O:26][N:25]([CH3:24])[C:3](=[O:4])[C:2]([CH3:6])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:1]
Reactant: CNOC
Reactant: CC(C)(C(=O)O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CON(C)C(=O)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
Dissolve 2-methyl-2-phenyl-propionic acid (15.0 g, 91.2 mmol) in toluene (80 mL) and add, by dropwise addition over 5 minutes, thionyl chloride (15 mL, 206 mmol). Stir at room temperature overnight, add additional thionyl chloride (3 mL, 41.1 mmol) and heat to reflux for 1 hour. Remove excess thionyl chloride by azeotropic distillation with toluene (40 mL). Add toluene (20 mL) to the reaction mixture along with a solution of potassium carbonate (28.0 g, 203 mmol) in aster (40 mL). Add, by dropwise addition, a solution of N,O-dimethylhydroxylamine hydrochloride (8.9 g, 91.2 mmol) in cater (20 mL) without cooling and stir for 2 hours. Add tert-butylmethyl ether (75 mL) following by slow addition of aqueous HCl (2N, 75 mL) with vigorous stirring. Separate the organic layer and wash with aqueous HCl (2N. 75 mL), saturated sodium hydrogen carbonate (25 mL) and brine (50 mL). Dry the organic layer over (Na2SO4), filter, evaporate the filtrate in vacuo and purify by vacuum distillation to give 2-methyl-2-phenyl-propionic acid. N-methoxy-N-methylamide (18.0 g, 95%): by 91-103° C./5 mm Hg. MS (CI, CH4) m/e 208 (M++1, 100), 119.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]1=[O:16].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[CH2:17]([C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[CH2:31][CH2:30]2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]1=[O:16])[CH3:18]
Reactant: CCC1(CCCCCl)C(=O)Nc2ccc(F)cc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: CCC1(CCCCN2CCN(c3ccc(F)cc3)CC2)C(=O)Nc2ccc(F)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-(4-fluorophenyl)-piperazine.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([O:24]C4C=CC=CC=4)=O)[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:31])=[N:9]2)=[CH:4][CH:3]=1.[C:32](#[N:34])[CH3:33]>>[CH2:8]([NH2:9])[CH3:7].[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:22]([NH:34][CH2:32][CH3:33])=[O:24])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:31])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Product: CCN
Product: CCNC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1

Procedure:
Following the procedure of Example 1 but starting with 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (8.6 g.) and a 33% (w/v) aqueous solution of ethylamine (d = 0.92; 9 cc.) in acetonitrile (200 cc.), 2-(7-chloro-1,8-naphthyridin-2-yl)-3-ethylaminocarbonyloxy-isoindolin-1-one (4.1 g.), melting at 212°-215° C., is obtained.
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[C:3]1[CH:7]2[C:8]3[C:13]([CH:4]1[CH2:5][CH2:6]2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH2:14].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]([Cl:15])=[C:3]1[CH:7]2[C:8]3[C:13]([CH:4]1[CH2:5][CH2:6]2)=[CH:12][CH:11]=[CH:10][C:9]=3[NH:14][C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: Nc1cccc2c1C1CCC2C1=C(Cl)Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)Nc2cccc3c2C2CCC3C2=C(Cl)Cl)c(C(F)F)n1
Temperature: 80 °C
Yield: 83.4 %

Procedure:
9-Dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-ylamine (166 g, 35% xylene solution, 0.25 mol), triethylamine (28 g, 0.275 mol) and xylene (13 g) were charged in a reactor and the mixture was heated to 80° C. 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (182 g, 26% xylene solution, 0.25 mol) was added over 2 hours. After conversion, the product was extracted, concentrated and crystallized in a mixture of xylene/methycyclohexane. 83 g of pure product were isolated. (Purity: 97%, Yield: 82%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:24].[NH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([NH:32]O)=[NH:31])=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]4[O:22][N:32]=[C:30]([C:29]5[CH:34]=[CH:35][C:26]([NH2:25])=[N:27][CH:28]=5)[N:31]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5ccc(N)nc5)no4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.6) (178 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (66 mg, 28%). MS (ISP) 471.9 [(M+H)+]; mp 262° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[OH:8][C:4]1[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Oc1cccc(-c2ccccc2)c1
Temperature: 100 °C
Yield: 84.2 %

Procedure:
A stirred mixture of 660 mg (3 mmol) of 3-iodophenol, 439 mg (3.6 mmol) phenylboronic acid, and 173 mg (0.15 mmol) tetrakistriphenylphosphine in 10 mL of toluene, 5 mL ethanol, and 6 mL 2M sodium carbonate (aqueous) was heated at 100° C. in an inert atmosphere of nitrogen for 15 minutes. The cooled mixture was partitioned between EtOAc, ice, and brine and the organic phase was separated, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by plate layer chromatography (PLC) using CH2Cl2 as the eluant to give 430 mg of the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH2:18][CH2:17][C:16](=O)[CH:15]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22]>CCO.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH2:18][CH2:17][C:16](=[N:21][OH:22])[CH:15]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C1C=C(c2ccc(Sc3ccc(F)cc3)o2)CC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1C=C(c2ccc(Sc3ccc(F)cc3)o2)CC1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a stirred solution of 3-[5-(4-fluorophenylthio)-2-furyl]-2-cyclopentenone (5.9 g; 21.5 mM) in EtOH-pyridine (50 ml-12 ml) was added hydroxylamine hydrochloride (2.24 g; 32.3 mM) at room temperature. After stirring overnight, solvent was removed. To the residue was added 0.5N aqueous HCl (80 ml), and the whole was extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with water (70 ml), brine (70 ml), dried over MgSO4, and concentrated in vacuo to give 6 g (yield 97%) of crude subtitle compound as a brown oil, which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[N:24][CH:25]=3)[NH:18][CH:19]=2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C1COCC1>[CH3:1][N:2]([CH3:7])[S:3]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:22]=[CH:21][C:20]([C:17]3[NH:18][CH:19]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)[N:16]=3)=[CH:25][N:24]=2)[CH2:31][CH2:30]1)(=[O:5])=[O:4]
Reactant: Fc1ccc(-c2c[nH]c(-c3ccc(N4CCNCC4)nc3)n2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)N1CCN(c2ccc(-c3nc(-c4ccc(F)cc4)c[nH]3)cn2)CC1
Reaction time: 8 h
Yield: 41.3 %

Procedure:
N,N-Dimethylsulfamoyl chloride (0.09 g) was added to a solution of 1-{5-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (0.2 g) and pyridine (0.05 g) in THF. The reaction mixture was held at room temperature overnight and then concentrated in vacuo. The residue was diluted with 1N NaOH and the resultant mixture extracted with dichloromethane. The organics were extracted with 6N HCl, and the acidic extracts basified with 1N NaOH. The basic aqueous layer was then extracted with dichloromethane. The organics were dried over magnesium sulfate and were concentrated. The residue was purified by flash column chromatography on silica (20% ethyl acetate in hexanes grading to ethyl acetate grading to dichloromethane) to provide 4-{5-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine-1-sulfonic acid dimethylamide (0.11 g). MS m/z 431 (M++1).