Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][C:29]([NH:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:30])[C:14]3=[O:40])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=4)[CH2:16][N:15]([CH2:28][C:29]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:30])[C:14]3=[O:40])=[CH:11][CH:12]=2)=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)CN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)CN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-(2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)-imidazolidin-1-yl)acetamido)acetate (20.0 mg, 0.0332 mmol) is dissolved in a mixture solvent of DCM (0.4 mL) and TFA (0.4 mL). The reaction mixture is stirred at room temperature for 3 h before removal of the solvent. The residue is purified by reparative LC/MS to provide the title compound; HPLC-MS calculated for C26H21ClF3N3O5 (M+H+) 548.1, found 548.1.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f29) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[CH2:14]([NH2:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:16]([CH2:14][CH3:15])[CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN1Cc2cc(Br)ccc2C1=O

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (0.5 g, 2 mmol) (AstaTech Cat. No. 27012), ethylamine in THF (1.0 mL, 2.0 M) (Aldrich Cat. No. 395072), and potassium carbonate (0.34 g, 2.4 mmol) in ethanol (5 mL) in a sealed vial was stirred at 40° C. overnight. The solid was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.28 g). LCMS (M+H)+=240.0/242.0.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([O:19]CC)=[O:18])[N:6]=1)=[O:4].O.[OH-].[Na+]>CO>[CH3:1][C:2]([CH3:23])([CH3:22])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([OH:19])=[O:18])[N:6]=1)=[O:4]
Reactant: CCOC(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.30 g ethyl [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetate from the Step D above in 20 mL MeOH and 2 mL water was added 0.50 mL of 5 N NaOH solution. After the solution was stirred at room temperature for 16 hours, the solvents were removed under reduced pressure. The residue was partitioned between cold water and EtOAc with 3 mL 1 N HCl. Separate the layers. Extract the aqueous layer with EtOAc (4×). The combined EtOAc extract was washed with saturated brine (2×), dried over anhydrous Na2SO4, and evaporated to give the title compound as yellowish solid. 1H NMR (CDCl3, 500 MHz) δ 8.27 (d, J=8.9 Hz, 1H), 7.00 (dd, =2.1 & 8.9 Hz, 1H), 6.68 (d, =2.1 Hz, 1H), 5.21 (s, 2H), 3.90 (s, 3H), 1.50 (s, 9H). LC-MS: 3.40 min. (m/Z=245.1, 291.1).
Reaction SMILES: [N:1]1([C:7](=[O:31])[CH2:8][O:9][C@H:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@@H:13]([N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.NN>CO>[NH2:20][C@@H:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([O:9][CH2:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:31])[CH2:11][CH2:12]1
Reactant: O=C(CO[C@@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)c2ccccc21)N1CCOCC1
Agent: NN
Solvent: O
Solvent: CO
Product: N[C@H]1CC[C@@H](OCC(=O)N2CCOCC2)c2ccccc21

Procedure:
A solution of Intermediate 32b (100 mg, 0.23 mmol) and hydrazine hydrate (74 μL, 2.4 mmol) in dry MeOH (6 mL) was stirred at RT for 5 h. The reaction mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20% [2M NH3 in MeOH] in DCM, to give the title compound as an off white foam (50 mg, 72%). LCMS (Method 3): Rt 1.70 min, m/z 291 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][NH2:34]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[NH:34][CH2:33][CH:29]3[CH2:30][CH2:31][CH2:32][O:28]3)=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: NCC1CCCO1
Solvent: CO
Product: N=C(NCC1CCCO1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with (tetrahydrofuran-2-yl)methanamine (23 μl, 0.23 mmol) via procedure W to afford 76 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-((tetrahydrofuran-2-yl)methyl)carbamimidoyl)benzamide. MS (Q1) 435 (M)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:14])(=[O:13])=[O:12].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]([S:11]([OH:14])(=[O:13])=[O:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)O)c1
Agent: Cl
Product: O=[N+]([O-])c1ccc(N2CCCC2)c(S(=O)(=O)O)c1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
72.4 Grams 2-chloro-5-nitrobenzenesulfonic acid was added in portions to 134 ml pyrrolidine, while keeping the temperature below 65° C. After the addition, the reaction was heated at reflux temperature with stirring for 7 hours and allowed to stand overnight at room temperature. The reaction was poured into 800 ml ice water and the solution made strongly acidic with concentrated HCl until light yellow crystals separated. The product was filtered, washed with a little dilute HCl and the moist cake was recrystallized from about 800 ml water to give 70.7 grams 5-nitro-2-pyrrolidinylbenzenesulfonic acid. m.p. = 178°-179° C. The nitro compound was reduced catalytically in ethanol with 5% palladium on carbon catalyst to give 5-amino-2-pyrrolidinyl-benzenesulfonic acid. m.p. = 255°-256° C.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[CH:8]=1.[N+:15]([O-])([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[C:8]=1[N+:15]([O-:17])=[O:16]
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1c(Br)cc(Br)cc1Br
Temperature: 50 °C

Procedure:
Sulfuric acid was poured into a solution of 1,3,5-tribromobenzene in chloroform, then, to this was added nitric acid and the mixture was heated for 5 hours at 50° C. After completion of the reaction, the organic layer was neutralized with a 5% aqueous potassium carbonate solution, then washed with water, and dried over magnesium sulfate. The solvent was removed to obtain a white solid which was re-crystallized from ethanol, to give 2,4,6-tribromonitrobenzene.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:27]=[O:28].O>O1CCCC1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:27]=[O:28])[C:12]=1[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1F)OCc1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Into a round bottom flask was added (2,4-difluoro-phenyl)-carbamic acid benzyl ester (21, 3.83 g, 14.5 mmol) in 148 mL of tetrahydrofuran. The solution was chilled to −78° C. and n-butyllithium (19.1 mL, 1.60 M in hexane, 30.0 mmol) was added over 30 minutes, followed by the addition of N,N-dimethylformamide (1.12 mL, 14.5 mol). The reaction mixture was allowed to warm to ambient temperature and was stirred overnight, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was crystallized from ether to provide the desired compound (22, 3.0 g, 71%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][N:10]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:11]([NH:14][C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)(=[O:13])=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:45]1([S:51](Cl)(=[O:53])=[O:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>ClCCl>[CH2:31]([N:10]([CH2:9][CH:6]1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][S:51]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)(=[O:53])=[O:52])[CH2:8][CH2:7]1)[S:11]([NH:14][C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1)(=[O:12])=[O:13])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCC1CCC(CN(Cc2ccccc2)S(=O)(=O)NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NS(=O)(=O)N(Cc1ccccc1)CC1CCC(CNS(=O)(=O)c2ccccc2)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
Amine (22) (23.5mg, 40 μmole, 1.0 eq) was suspended in dichloromethane, then triethylamine (16.7 μL, 120 μmole, 3.0 eq) and benzenesulfonylchloride (5.4 μL, 42 μmole, 1.05 eq) were added and the reaction stirred 30 minutes. Silica gel chromatography provided the title compound. 1H NMR (500 MHz, DMSO-d6): δ 8.44 (s, 2H), 8.17 (t, 1H), 7.72 (dd, 2H), 7.55 (m, 4H), 7.35 (d, 2H), 7.25 (t, 2H), 7.18 (t, 1H), 4.37 (s, 2H), 3.30 (water), 2.93 (t, 2H), 2.48 (DMSO), 2.44 (t, 2H), 1.61 (m, 4H), 1.21 (m, 1H), 1.11 (m, 1H), 0.51 (m, 4H).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>CCO>[OH:26][CH:23]([CH2:24][OH:25])[CH2:22][N:21]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2[C:14]([N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]2=[O:20])=[CH:15]1
Reactant: NCC(O)CO
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n(CC(O)CO)cc2n(C)c1=O

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C)(670 mg, 1.987 mmol), 3-aminopropane-1,2-diol (0.231 ml, 2.98 mmol) and TEA (0.554 ml, 3.97 mmol) were combined in EtOH (15 ml) and heated at reflux for 15 mins.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][C@H:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:18]([NH2:20])=[O:19])=[C:5]([F:28])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[C:5]([F:28])=[CH:4][C:3]([C:1]([NH2:2])=[O:35])=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:7]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3ccccn3)C(N)=O)c(F)cc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccccn3)C(N)=O)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-3-(pyridin-2-yl)propanamide (53 mg, 0.133 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (16 mg). MS 415.1 (M+H); UV 214.4, 278.0, 302.6 nm.
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[C:22]([C:34]([F:37])([F:36])[F:35])[C:21]=2[CH2:20][CH2:19]1>>[C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]3[N:25]=[C:26]4[C:21]([CH2:20][CH2:19][C:18](=[O:17])[NH:27]4)=[C:22]([C:34]([F:36])([F:35])[F:37])[CH:23]=3)[CH2:13][CH2:12]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cc2c(c(N3CCNCC3)c1)CCCC2
Reactant: O=CCCCOc1cc(C(F)(F)F)c2c(n1)NC(=O)CC2
Product: O=C1CCc2c(C(F)(F)F)cc(OCCCCN3CCN(c4cccc5c4CCCC5)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine was coupled by reductive amination to 4-(7-oxo-4-trifluoromethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 503.1 (Exact Mass: 502.26).
Reaction SMILES: CCO.C([O:11][C:12]1[CH:13]=[C:14]([C:24]([O:26][CH3:27])=[O:25])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[OH:11][C:12]1[CH:13]=[C:14]([C:24]([O:26][CH3:27])=[O:25])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(-c2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cc(O)cc(-c2ccccc2)c1

Procedure:
In a nitrogen atmosphere, 10% palladium-carbon (900 mg) was added to a mixed solution of EtOH (40 mL)-THF (8 mL) of methyl 5-benzyloxybiphenyl-3-carboxylate (1.55 g), and stirred in a hydrogen atmosphere at room temperature for 2 hours. The reaction liquid was filtered through Celite, and concentrated under reduced pressure to obtain the title compound as a white powder. Not purified, this was used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[C:20]([NH2:28])(=[S:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:28]=[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[S:27][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: NC(=S)c1ccncc1
Solvent: CC#N
Product: CSc1ccc(-c2sc(-c3ccncc3)nc2-c2ccc(F)cc2)cc1

Procedure:
A solution of the intermediate from Example 1, Step 3, 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromoethanone, (1.58 g, 4.66 mmol) and thioisonicotinamide (670 mg, 4.84 mmol) in 25 mL of acetonitrile was heated to reflux for 23 hours. The solution was filtered, concentrated in vacuo and the residue taken up in dichloromethane. The dichloromethane solution was washed with sat. aq. NaHCO3, and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a brown oil that was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to provide the desired thiazole as an oil that solidified upon standing (640 mg, 36%): mp 107°-109° C. 1H NMR (CDCl3) 300 MHz 8.75 (br s, 2H), 7.85 (d, J=5.9 Hz, 2H), 7.56 (m, 2H), 7.26 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.01 (t, J=8.5 Hz, 2H), 2.50 (s, 3H); 19F NMR (CDCl3) -113.23 (m). High resolution mass spectrum Calc'd. for C21H15FN2S2 : 379.0661. Found: 379.0691.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1.O1CCOCC1.Cl>C(OCC)(=O)C>[ClH:11].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:25]=[CH:24][C:22]([NH:23][CH:4]3[CH:5]4[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]4)[CH2:3]3)=[CH:21][CH:20]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1ccc(Oc2ccc(NC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Quinuclidinone hydrochloride (Aldrich, 1.61 g, 10 mmol) was treated with 4-(4-chlorophenyloxy) aniline (Aldrich, 1.10 g, 5.0 mmol) according to the procedure of Example 30A. The free base of the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.10) as a solid (1.52 g, yield, 93%). MS (DCl/NH3) m/z 329 (M+H)+, 331 (M+H)+. The free base (200 mg, 0.61 mmol) was treated with 4M HCl 1,4-dioxane (0.5 mL, 2.0 mmol) in ethyl acetate (5 mL). The hydrochloride salt of the title compound was obtained as a solid (195 mg, yield, 80%). 1H NMR (MeOH-d4, 300 MHz) δ 1.90–2.18 (m, 3H), 2.35–2.45 (m, 2H), 3.24 (ddd, J=12.5, 5.4, 2.3 Hz, 1H) 3.30–3.50 (m, 4H), 3.82 (ddd, J=12.2, 9.8, 2.7 Hz, 1H), 3.95–4.10 (m, 1H), 6.91 (dt, J=9.1, 2.3 Hz, 2H), 6.95–7.02 (m, 4H), 7.30(dt, J=9.2, 2.4 Hz, 1H), 7.26–7.32 (m, 2H) ppm. MS (DCl/NH3) m/z 329 (M+H)+, 331 (M+H)+. Anal Calculated for C19H21ClN2O.2.0HCl.0.5H2O: C, 55.56; H, 5.89; N, 6.82. Found: C, 55.78; H, 5.28; N, 6.62.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.CI.[C:19]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[N:6]([CH3:19])[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21

Procedure:
2,2-Dimethyl-6-nitro-4H-benzo[1,4]oxazin-3-one (1.1 g) was mixed with MeI (850 mg, Aldrich), K2CO3 (1.38 g, Aldrich) and DMF (30 ml, Aldrich) at 40° C. for 48 h. The DMF was removed in vacuo and the residue was diluted with EtOAc (80 ml). The organic phase was washed with H2O (50 ml), aqueous Na2SO3 (50 ml) and brine (50 ml). The resulting solution was dried (MgSO4) and concentrated to provide the compound which was used as is.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:5]=1[C:6]([OH:8])=[O:7].[C:14](Cl)(Cl)=[O:15].C1(C)C=CC=CC=1>O>[Cl:13][C:9]1[C:5]2[C:6](=[O:8])[O:7][C:14](=[O:15])[NH:3][C:4]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of potassium hydroxide (1.68 g, 30 mmol) and 2-amino-6-chlorobenzoic acid (3.43 g, 20 mmol) in water (25 mL) at 0° C. was treated dropwise with 20% phosgene in toluene (16.8 mL, 32 mmol) resulting in a precipitate. The mixture was stirred for 1 hour and the solid was collected by filtration, washed with water and dried to give the title compound (3.6 g, 91%). 1H NMR (300 MHz, DMSO-d6) δ 7.11 (d, J=7.35 Hz, 1H), 7.31 (d, J=6.99 Hz, 1H), 7.66 (t, J=8.09 Hz, 1H), 11.83 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2([C:17]3[S:18][CH:19]=[CH:20][N:21]=3)[CH2:14][O:13]C(C)(C)[O:11][CH2:10]2)=[CH:5][CH:4]=1>CO.O.O.[Cu](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)([CH2:14][OH:13])[CH2:10][OH:11])=[CH:22][CH:23]=1
Reactant: COc1ccc(COC2(c3nccs3)COC(C)(C)OC2)cc1
Agent: Cl[Cu]Cl
Solvent: CO
Solvent: O
Product: COc1ccc(COC(CO)(CO)c2nccs2)cc1
Temperature: 70 °C

Procedure:
To a solution of the 2-(5-(4-methoxybenzyloxy)-2,2-dimethyl-1,3-dioxan-5-yl)thiazole (Example 11B) (8.0 g, 23.85 mmol) in methanol (239 mL) was added copper(II) chloride dihydrate (12.20 g, 71.6 mmol) in a single portion. The mixture was heated to 70° C. for 1 hour. The reaction was cooled to room temperature and concentrated to a volume of ˜50 mL under reduced pressure. The solution was diluted with saturated aqueous ammonium chloride solution (100 mL) and ethyl acetate (150 mL). The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×100 mL). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound. MS ESI(+) m/z 296.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N+]=[N-])=[CH:4][CH:3]=1.[O:18]=[CH:19][C:20](=[CH2:22])[CH3:21]>ClCCl.CCCCCCC.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH2:21][C:20]2([CH3:22])[CH:19]=[O:18])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C=C(C)C=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCCCCCC
Product: CC1(C=O)CC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 40 °C

Procedure:
A solution of bis(4-fluorophenyl)diazomethane, prepared as above from the action of activated manganese dioxide (32.3 g) on 4,4'-difluorobenzophenone hydrazone (23.2 g) in dichloromethane (105 mL), was added to a solution of methacrolein (12.5 mL) in heptane (100 mL). The mixture was heated at 40° C. for 6 hours then the amber colored solution was evaporated in vacuo. The resulting solid was triturated with hexane (100 mL) to give 22.0 g of 2,2-bis(4-fluorophenyl)-1-methylcyclopropanecarboxaldehyde, mp 110°-113° C. Recrystallization of a sample from hexane provide the analytical specimen, mp 111°-113° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([C:9]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=[C:11]([C:12]([NH2:14])=O)[C:10]=1[OH:21])([CH3:8])[CH3:7]>N1C=CC=CC=1>[OH:21][C:10]1[C:9]([CH:6]([CH3:7])[CH3:8])=[CH:17][C:16]([CH:18]([CH3:20])[CH3:19])=[CH:15][C:11]=1[C:12]#[N:14]
Reactant: CC(C)c1cc(C(N)=O)c(O)c(C(C)C)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)c1cc(C#N)c(O)c(C(C)C)c1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of phosphorous oxychloride (1.35 g, 8.8 mmole) and dry pyridine (12 mL) cooled to 0° C., a solution of 3,5-diisopropyl salicylamide (1.10 g, 5 mmole) and dry pyridine (5 mL) was slowly added drop by drop. The reaction mixture was stirred at room temperature, whereat the colour changed from colourless over violet to red. After extraction with ethyl acetate and washing with a saturated sodium chloride solution and 2N hydrochloric acid, the organic layer was dried and evaporated under reduced pressure. The obtained solid residue was recrystallized from acetonitrile, whereat there were obtained 610 mg (60%) of 2-hydroxy-3,5-diisopropyl benzonitrile.