Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:7][CH2:8][C:9]([NH:11][CH2:12][C@@H:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14]2)=[O:10])=[CH:5][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].C[O:35][C:36]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)=[O:37]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:36]([C:38]1[CH:43]=[CH:42][C:41]([C:2]2[S:3][C:4]([S:7][CH2:8][C:9]([NH:11][CH2:12][C@@H:13]3[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:10])=[CH:5][CH:6]=2)=[CH:40][CH:39]=1)([OH:37])=[O:35]
Reactant: O=C(CSc1ccc(Br)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(CSc1ccc(-c2ccc(C(=O)O)cc2)s1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 130 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
The resultant product (200 mg) of Example 31, tetrakistriphenylphosphinepalladium (25 mg), sodium carbonate (200 mg) and 4-methoxycarbonylphenylboronic acid (105 mg) were dissolved in a mixed solution of ethylene glycol dimethylether (4 mL) and water (250 μL), and the mixture was heated under reflux at 130° C. for 6 hrs. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was evaporated under reduced pressure, and the residue was purified by column chromatography using chloroform as an eluent. The eluent was evaporated and the obtained yellow oil was dissolved in ethanol (2 mL). A 1N aqueous sodium hydroxide solution (50 μL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was adjusted to pH=5 with 1N hydrochloric acid, and the mixture was extracted with chloroform. The extract was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (90 mg) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)[N:6]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Product: CC(=O)Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1

Procedure:
30 g of 2-amino-4-(4'-nitrophenyl)-1,3-thiazole (prepared in accordance with J. Chem. Soc. 1959, (2365) and 100 ml of acetic anhydride are heated for 3 hours at 140° C. Excess acetic anhydride is removed by vacuum distillation and the residue is treated with 500 ml of warm water, filtered, washed, and dried to constant weight, affording 34 g of 2-acetamido-4-(4'-nitrophenyl)-1,3-thiazole.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cncnc3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-chloro-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M87) (0.42 g, 0.90 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light red solid (230 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].[NH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31]O)=[NH:30])=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]4[O:21][N:31]=[C:29]([C:28]5[CH:33]=[CH:34][C:25]([NH2:24])=[N:26][CH:27]=5)[N:30]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Reactant: N=C(NO)c1ccc(N)nc1
Product: Cc1cc(-c2cc(C(F)F)n3ncc(-c4nc(-c5ccc(N)nc5)no4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.13) (169 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 (68 mg, 30%). MS (EI) 453.0 [(M)+]; mp 243° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:12]([CH:13]=[O:14])[C:11]=1[OH:18].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([O:18][C:11]1[C:10]([O:9][CH3:8])=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cccc(C=O)c1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
Acetic anhydride (45.9 g, 0.45 mol) was added to a suspension of 3-methoxysalicylaldehyde (45.6 g, 0.3 mol) and K2CO3 (42.0 g, 0.6 mol) in CH2Cl2 (450 L) at rt. The reaction mixture was stirred at rt overnight then filtered, evaporated and the residue was recrystallised from cyclohexane to give 42 (42.0 g, 74%) as colourless needles:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:13]Br>O1CCOCC1>[Br:13][CH2:11][C:10]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=1)=[O:12]
Reactant: COc1ccc(C(C)=O)cc1F
Reactant: BrBr
Solvent: C1COCCO1
Product: COc1ccc(C(=O)CBr)cc1F
Reaction time: 0.17 h
Yield: 62.4 %

Procedure:
To a solution of 3′-fluoro-4′-methoxyacetophenone (1 g, 5.9 mmol) (Aldrich) in dioxane (10 mL) was added dropwise a solution of bromine (1.13 g, 7.1 mmol) in dioxane (30 mL). After stirring for 10 minutes, the mixture was concentrated in vacuo and the residue was purified by flash chromatography, with 10:4 hexanes/dichloromethane as an eluant, to provide 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone as a white powder (910 mg, 63% yield).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][CH2:10][C:9](=[O:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:1][C:4]1[C:12]2[O:11][CH2:10][C:9](=[O:13])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1COc2c1cccc2[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccc2c1OCC2=O

Procedure:
By the method of Example 1, Step E, 2.51 g (0.014 mole) of 2,3-dihydro-7-nitro-3-benzofuranone is reacted with 3.1 g (0.056 mole) of powdered iron in 45 mL of glacial acetic acid and 8 mL of water, yielding 7-amino-2,3-dihydro-3-benzofuranone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][OH:27])[NH:10][CH:9]2[C:30](O)=[O:31])[CH:5]=[CH:6][CH:7]=1.CC1(C)[O:39][C@@H:38]([CH2:40][CH2:41][NH2:42])[CH2:37][O:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:39][C@H:38]([CH2:37][OH:36])[CH2:40][CH2:41][NH:42][C:30]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:33])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:28])([CH3:29])[CH2:25][CH2:26][OH:27])[NH:10]1)=[O:31]
Reactant: CC(C)(CCO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(CCO)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 47.5 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid prepared in Example 116c (0.18 g, 0.36 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.16 g, 1 mmol), HATU (0.25 g, 0.65 mmol) and iPr2NEt (0.07 mL, 0.43 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-hydroxy-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 54%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11]1)([O-])=O.CC(O)=O.O>CCO.[Fe]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2[N+](=O)[O-])C1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a solution of tert-butyl [(3S)-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate (2.69 g, 8.34 mmol) in EtOH (30.0 mL), iron powder (2.335 g, 41.81 mmol) was added, followed by AcOH (7.04 g, 117 mmol) and water (7.00 mL, 388 mmol). The reaction mixture was stirred at room temperature for 3 h then concentrated under reduced pressure. EtOAc (100 mL) was added to the residue and the resulting mixture was filtered through a pad of diatomaceous earth. The diatomaceous earth pad was washed with 10 wt % aq. K3PO4 (150 mL) and EtOAc (100 mL). The organic layer was separated and was then washed with brine (150 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-30% MeOH in DCM) to give the sub-title compound as an off-white solid (2.13 g, 87%). LCMS calc. for C15H25N4O2 (M+H)+: m/z=293.2. found 293.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.[CH3:12][C:13]1([CH2:17][OH:18])[CH2:16][O:15][CH2:14]1.[H-].[Na+].Cl>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[O:18][CH2:17][C:13]1([CH3:12])[CH2:16][O:15][CH2:14]1
Reactant: CC1(CO)COC1
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(COc2nc(C(=O)O)ccc2Br)COC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.1 %

Procedure:
To a solution of 5-bromo-6-chloropicolinic acid (Example 280a) (0.75 g, 3.17 mmol) in dry DMF (18 ml) under argon was added (3-methyloxetan-3-yl)-methanol (389 mg, 3.81 mmol) and NaH (279 mg, 6.98 mmol) was added by portions. The reaction mixture was stirred at room temperature for 20 min until gas release ceased. The reaction mixture was then stirred at 110° C. for 16 h. The reaction mixture was diluted with ethyl acetate, and the solution was poured into a separatory funnel with 10 ml aq. solution 1.0M HCl. After extraction, the organic phase was collected and the aqueous phase was back extracted with ethylacetate. The organic phases were combined, dried over Na2SO4 and evaporated down in vacuo. The residue was purified by preparative HPLC to give the title compound (260 mg, 27%), MS (EI): m/e=302.0 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.C1(C)C=CC(S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O)=CC=1.Cl>O.CN(C)C=O>[F:27][C:26]([F:29])([F:28])[CH2:25][S:14][C:11]1[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(SCC(F)(F)F)cc1
Reaction time: 3 h
Yield: 80.8 %

Procedure:
With stirring in an atmosphere of nitrogen, 110 g of anhydrous potassium carbonate was added to a solution composed of 51 g of 4-hydroxybenzenethiol and 250 ml of dimethylformamide. Furthermore, 112 g of 2,2,2-trifluoroethyl p-toluenesulfonate was added at a temperature of 25° to 30° C. The mixture was stirred at the same temperature for 3 hours, then at 30° to 40° C. for 4 hours, and finally at 50° C. for 6 hours. After cooling, the solution was poured into 2 liters of water, and concentrated hydrochloric acid was added at a temperature lower than 20° C. to adjust the pH of the solution to 3. The resulting oily product was extracted with toluene. The toluene layer was washed with water, and stirred together with 600 ml of a 10% aqueous solution of potassium hydroxide. The aqueous layer was separated, and hydrochloric acid was added at a temperature lower than 20° C. to adjust the pH of the aqueous layer to 2. The resulting oily product was extracted with toluene. The toluene layer was separated, washed with water, and then dried over anhydrous sodium sulfate. The toluene was evaporated, and the residue was distilled under reduced pressure to give 68 g of the desired 4-(2,2,2-trifluoroethylthio)phenol. b.p. 102°-105° C./0.8 mmHg.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([O:11][CH2:12][CH2:13][N:14]([C:22]1[CH:23]=[C:24]([CH:42]=[CH:43][CH:44]=1)[C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH2:29][CH2:28]1)=[O:26])C(OC(C)(C)C)=O)([CH3:10])[CH3:9]>ClCCl>[ClH:41].[CH:8]([O:11][CH2:12][CH2:13][NH:14][C:22]1[CH:23]=[C:24]([CH:42]=[CH:43][CH:44]=1)[C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:10])[CH3:9]
Reactant: CC(C)OCCN(C(=O)OC(C)(C)C)c1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OCCNc1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1
Product: Cl
Reaction time: 0.08 h

Procedure:
65 ml of trifluoroacetic acid are introduced into 100 ml of dichloromethane. A solution of 7.2 g of 1-{3-[N-(2-isopropyloxyethyl)-N-tert-butoxycarbonylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine is added thereto within a period of 5 minutes. After 2 hours at RT, the reaction solution is concentrated by evaporation and the residue is neutralised with sodium hydroxide solution and extracted with ether. Concentration by evaporation and treatment with ethereal hydrochloric acid yield 1-[3-(2-isopropyloxyethylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine hydrochloride having a melting point of 157°-159°.
Reaction SMILES: [CH3:1][CH:2]([S:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)[CH3:3].Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=3)[CH2:25][CH2:24]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:36][CH:34]([C:31]1[N:30]=[C:29]([N:26]2[CH2:25][CH2:24][CH:23]([CH2:22][O:21][C:18]3[CH:17]=[CH:16][C:15]([C:8]4[CH:9]=[CH:10][C:5]([S:4][CH:2]([CH3:3])[CH3:1])=[CH:6][CH:7]=4)=[CH:20][CH:19]=3)[CH2:28][CH2:27]2)[O:33][N:32]=1)[CH3:35]
Reactant: CC(C)Sc1ccc(B(O)O)cc1
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)cc3)CC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)Sc1ccc(-c2ccc(OCC3CCN(c4nc(C(C)C)no4)CC3)cc2)cc1
Yield: 5.2 %

Procedure:
1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-[({4′-[(1-methylethyl)thio]-4-biphenylyl}oxy)methyl]piperidine (20 mg, 5%) was prepared as a white solid from {4-[(1-methylethyl)thio]phenyl}boronic acid (167 mg, 0.85 mmol), 4-{[(4-bromophenyl)oxy]methyl}-1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidine (322 mg, 0.85 mmol), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol), 2M Na2CO3 (5 mL) and DME (5 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.57-7.39 (m, 6H), 6.94 (d, 2H, J=8.9 Hz), 4.28-4.18 (m, 2H), 3.87 (d, 2H, J=6.4 Hz), 3.46-3.30 (m, 1H), 3.20-3.08 (m, 2H), 2.98-2.85 (m, 1H), 2.16-2.03 (m, 1H), 2.03-1.93 (m, 2H), 1.55-1.39 (m, 2H), 1.36-1.24 (m, 12H); LRMS (ESI), m/z 452 (M+H).
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4[CH2:16][CH2:17][CH2:18][CH:5]([C:6]=42)[O:4][CH2:3][C:2]1=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9]3.[CH3:20]C(C)([O-])C.[K+].CI>O1CCCC1>[CH3:20][N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4[CH2:16][CH2:17][CH2:18][CH:5]([C:6]=42)[O:4][CH2:3][C:2]1=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: O=C1COC2CCCc3nc4ccccc4c(c32)N1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)COC2CCCc3nc4ccccc4c1c32
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a solution of 1,3,4a,5,6,7-hexahydro-2H-quino[4,3,2-ef][1,4]-benzoxazepin-2-one (4.09 g) in tetrahydrofuran (100 ml) was added potassium t-butoxide (2.17 g) followed by methyl iodide (1.25 ml). The reaction mixture was stirred for 2 hrs at ambient temperature and then concentrated. The residue was stirred in water/ethyl ether, the precipitate was collected and dried to give 2.0 g (46%) of 1,3,4a,5,6,7-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].Cl.Cl.NC[C:10]1[CH:36]=[CH:35][C:13]([CH2:14][N:15]([C:17]([CH3:34])([CH3:33])[CH2:18][O:19][CH: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)[CH3:16])=[CH:12][CH:11]=1.[N:37]1C=CC=CC=1>>[ClH:5].[C:27]1([CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:19][CH2:18][C:17]([N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([NH:37][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:36][CH:35]=2)[CH3:16])([CH3:33])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccncc1
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1ccc(CN)cc1)C(C)(C)COC(c1ccccc1)c1ccccc1
Agent: Cl
Product: CN(Cc1ccc(NS(C)(=O)=O)cc1)C(C)(C)COC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulphonyl chloride (40 μl) was added dropwise to a stirred solution of 2-[N-(4-aminomethylbenzyl)-N-methylamino]-1-diphenylmethoxy-2-methylpropane (140 mg -- see Example 46) in pyridine (5 ml) and the mixture was stirred at room temperature or 16 hours and evaporated. The residue was azeotroped twice with toluene, dissolved in 2M hydrochloric acid, washed with ether, basified with saturated aqueous sodium hydrogen carbonate solution and extracted into ethyl acetate. The organic extract was dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica (3 g) using methylene chloride plus 0-5% methanol as the eluant. Appropriate fractions were combined and evaporated and the residue was dissolved in ether and treated with excess saturated ethereal hydrogen chloride. The resulting precipitated gum was collected and triturated with ether to give the title compound as a colourless solid which was characterised as a hemihydrate (31 mg, 17%), m.p. 150°-155°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([NH2:12])=[C:7]([Cl:13])[CH:6]=1)[CH3:2].[C:15](OC(=O)C)(=[O:17])C>C(O)=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([NH:12][CH:15]=[O:17])=[C:7]([Cl:13])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)c(N)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(=O)c1cc(Cl)c(NC=O)c(Cl)c1
Yield: 78.9 %

Procedure:
Following the procedure in Rouot et al., in J. Med. Chem., 19, 1049 (1976), 4-amino-3,5-dichlorobenzoic acid ethyl ester (70.2 g., 030 m) is reacted with the product from acetic anhydride (61.3 g., 0.60 m) and formic acid (34.5 g., 0.75 m) to yield the desired 3,5-dichloro-4-formamidobenzoic acid ethyl ester (62.0 g., 0.237 m) in crude yield of 79% with a melting point of 168°-170° C. Reaction of this crude (16.35 g., 0.062 m) with a mixture of thionyl chloride (55.4 g., 0.47 m) and sulfuryl chloride (3.4 g., 0.062 m) leads to the desired 3,5-dichloro-4-dichloromethaniminobenzoic acid ethyl ester (14.65 g., 46 mmol) which distills at 105° C. at 250 mm of Hg after standard workup. It should be noted that this material may solidify on standing. Finally, this distilled dichloromethamine (4.35 g., 0.0138 m) is reacted with ethylene diamine (1.66 g., 0.0276 m), and 10 mL of triethylamine in approximately 25 mL of ethyl acetate for 10 hours. An immediate white precipitate is noted, but stirring is continued overnight to ensure complete reaction. This reaction mixture then is vacuum filtered to yield 5.35 g. of white powder (which is greater than 100% yield, but is probably due to the fact that, in addition to the desired compound, triethylamine hydrochloride as well as the hydrochloride of the desired compound are present at this stage). Recrystallization of the white powder from absolute ethanol produced a white crystalline solid (2.3 g., 0.0076 m) in a yield of 55% with a melting point of 238°-240° C. This compound demonstrates the expected IR absorptions at 3380 (sharp), 3150 (broad), 1710 (sharp), 1660 (sharp and most intense), 1580 (sharp), 1275 (sharp), 1105 cm-1 (sharp).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[S:5].Cl[CH2:12][S:13][C:14]#[N:15]>>[S:13]([CH2:12][O:6][C:4](=[S:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[C:14]#[N:15]
Reactant: N#CSCCl
Reactant: OC(=S)c1ccccc1Cl
Product: N#CSCOC(=S)c1ccccc1Cl
Yield: 77 %

Procedure:
28.5 g (0.14 mol) of the K salt of 2-chloro-thiobenzoic acid and 15 g (0.14 mol) of chloromethyl thiocyanate were reacted and processed as in Example 1 B. 26.3 g of a yellowish oil having a density of 1.36 (this corresponds to a yield of 77% of the theoretical conversion).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[S:9])[NH:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1.[CH3:20]I>C(O)C>[CH3:1][N:2]1[C:8]([S:9][CH3:20])=[N:7][CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1
Reactant: CI
Reactant: CN1Cc2ccccc2C(c2ccccc2)NC1=S
Solvent: CCO
Product: CSC1=NC(c2ccccc2)c2ccccc2CN1C
Yield: 61.4 %

Procedure:
A solution of 8 g (30 mmol) of the thione of Example 152 and 2.7 mL (44 mmol) of methyl iodide in 100 mL of ethanol was refluxed two hours, cooled, and the hydriodide of the product filtered off. The salt was partitioned between methylene chloride and aqueous sodium bicarbonate, the organic layer dried over magnesium sulfate, and stripped. The residue was dissolved in ethanol and 2.7 g of methanesulfonic acid was added followed by ether. The resulting precipitate was filtered off and recrystallized from ethanol to yield 5.2 g of product as the methanesulfonate salt, mp 195-196.