Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:32])[N:8]2[C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([F:27])[C:20]=3[F:28])[C:14]([O:29][CH3:30])=[CH:13][C:12]=2[Cl:31])=[C:4]([O:33][CH3:34])[N:3]=1.C(N(CC)C(C)C)(C)C.C([O:47][CH2:48][C:49](Cl)=[O:50])(=O)C.Cl>C(OCC)(=O)C>[Cl:31][C:12]1[CH:13]=[C:14]([O:29][CH3:30])[C:15]([O:17][CH2:18][C:19]2[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([F:27])[C:20]=2[F:28])=[CH:16][C:11]=1[N:8]1[C:7](=[O:32])[NH:6][C:5]2[C:9]1=[N:10][C:2]([NH:1][C:48](=[O:47])[CH2:49][OH:50])=[N:3][C:4]=2[O:33][CH3:34]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(N)nc32)cc1OCc1c(OC)ccc(F)c1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(NC(=O)CO)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-amino-9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (40 mg) and N,N-diisopropyl-ethylamine (0.15 mL) in ethyl acetate (4 mL) was added acetoxyacetyl chloride (0.078 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (1 mL)-tetrahydrofuran (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.05 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate) to give the title compound (4 mg).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:33][O:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:38]3[CH:39]=[N:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reactant: COc1ccc(B(O)O)cn1
Product: CCCCCCc1cccc(-c2nc(-c3ccc(OC)nc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with 6-methoxy-pyridin-3-yl-boronic acid to give the title compound as light yellow oil. MS: 530.3 (MH+).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=C[CH:2]=1.[NH2:12][C:13]1[C:18]([NH2:19])=[C:17]([CH3:20])[N:16]=[C:15]([Cl:21])[N:14]=1>C(Cl)(Cl)Cl>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([NH:19][C:1]([CH3:2])=[N:12]2)=[C:17]([CH3:20])[N:16]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1nc(Cl)nc(N)c1N
Solvent: ClC(Cl)Cl
Product: Cc1nc2nc(Cl)nc(C)c2[nH]1
Temperature: 100 °C
Yield: 635.5 %

Procedure:
After adding 10.1 ml of ortho-triethyl acetate, 0.23 g of para-toluenesulfonic acid and 73 ml of 2-methylpyrrolidone to 7.6 g of 4,5-diamino-2-chloro-6-methylpyrimidine, the mixture was heated at 100° C. and then heated and stirred while removing out of the system the ethanol produced during the reaction. After disappearance of the 4,5-diamino-2-chloro-6-methylpyrimidine, the reaction solution was further heated and stirred at 180° C. for 2 hours. After cooling to room temperature, chloroform was added thereto for dilution. The mixture solution was washed with water and then washed with saturated brine, after which the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=95:5) to obtain 1.55 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C@@H:11]([CH3:14])[CH2:10][C@@H:9]1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:20]([OH:24])[C:21]([NH2:23])=[O:22].O[NH-].O=[N-]>>[NH2:23][C:21](=[O:22])[C:20](=[O:24])[CH:19]([NH:18][C:15]([C@H:9]1[CH2:10][C@H:11]([CH3:14])[C:12](=[O:13])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:17])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: C[C@H]1C[C@H](C(=O)O)N(Cc2ccccc2)C1=O
Agent: [N-]=O
Agent: [NH-]O
Product: C[C@H]1C[C@H](C(=O)NC(Cc2ccccc2)C(=O)C(N)=O)N(Cc2ccccc2)C1=O

Procedure:
Coupling of (2R,4S)-1-Benzyl-4-methyl-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)(C(C)(C)C)(C)C.[H-].[K+].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.ClCCl>CO>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:14]2[C:15]3[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)[C:12]([CH:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)=[CH:13]2)=[CH:30][CH:29]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(O[Si](C)(C)C(C)(C)C)cc23)CC1
Agent: [H-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(c2cn(Cc3ccc(F)cc3)c3ccc(O)cc23)CC1
Yield: 89.9 %

Procedure:
By a method similar to Preparation 32, using 5-(t-butyldimethylsilanyloxy)-3-(1-methylpiperidin-4-yl)-1H-indol (400 mg, 1.16 mmol), potassium hydride (139 mg of a 35% dispersion oil, 1.21 mmol) and 4-fluorobenzyl bromide (148 μL, 1.21 mmol), and chromatographic purification with a 9:1 mixture of dichloromethane and methanol provided 353 mg (90%) of the desired compound as an orange foam: 1H NMR (dmso-d6): 8.61 (s, 1H), 7.25-7.00 (m, 6H), 6.82 (d, 1H, J=2.0 Hz), 6.54 (dd, 1H, J=8.8, 1.6 Hz), 5.20 (s, 2H), 2.84 (br d, 2H, J=11.6 Hz), 2.62-2.50 (m, 1H), 2.19 (s, 3H), 2.01 (br t, 2H, J=11.0 Hz), 1.85 (br d, 2H, J=13.2 Hz), 1.62 (qd, 2H, J=12.0, 2.4 Hz). MS (APCI): m/e 339.2 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:6](O)=[O:7])[CH3:2].[OH-:13].[Na+].[C:15](O)(=O)[CH3:16]>C(OC(=O)C)(=O)C>[CH2:15]([N:3]1[C:4]2[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]([OH:7])=[CH:2][C:1]1=[O:13])[CH3:16]
Reactant: CCNc1ccccc1C(=O)O
Reactant: CC(=O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCn1c(=O)cc(O)c2ccccc21

Procedure:
A solution of N-ethyl anthranilic acid (12.0g; 0.073 mole) in acetic acid (37 ml) and acetic anhydride (37ml) was refluxed for 4 hrs. The red solution was cooled, poured onto crushed ice and made alkaline with aqueous sodium hydroxide. After filtering the yellow filtrate was neutrallised with concentrated hydrochloric acid (pH 5) and the yellow solid filtered and washed with water. Recrystallisation from acetic acid in the presence of charcoal gave the title compound as an orange solid, m.p. 273°-275°C. (Found: C, 69.85; H, 6.04; N, 7.29; C11H11NO2 requires: C, 69.83; H, 5.86; N, 7.40%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:28]=[CH:27][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH2:23][CH2:24][O:25][CH3:26])=O)[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H][H]>C1COCC1>[CH3:26][O:25][CH2:24][CH2:23][NH:22][CH2:20][C:16]1[CH:15]=[C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[CH:5]=[C:4]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:3]=[C:2]([NH2:1])[N:7]=3)=[CH:28][CH:27]=2)[CH:19]=[CH:18][N:17]=1
Reactant: COCCNC(=O)c1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Reactant: [H][H]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCNCc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1

Procedure:
A solution of 4-{4-[(2-amino-6-phenylpyrimidin-4-yl) amino]phenoxy}-N-(2-methoxyethyl)pyridine-2-carboxamide from Example 23 (50 mmol) in anhydrous THF (50 mL) is added in portions to a pre-cooled in ice-bath solution of lithium aluminum hydride (100 mmol, 1.0 M in THF) in anhydrous THF (150 mL). The reaction is stirred at 0° C. for 30 min until evolution of hydrogen subsides. The reaction mixture is refluxed under nitrogen for 48 h. The mixture is brought to 5-10° C. and carefully quenched with water (3.8 mL), 15% NaOH (3.8 mL) and water (12 ruL). The mixture is extracted with EtOAc and the organic layer is dried and concentrated to give a crude product which is purified by chromatography on a silica column to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH2:22][CH3:23].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:22]([N:10]1[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][C:13]=2[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:9]1)[CH3:23]
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2ncccc12
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1nc(-c2cccc(Cl)c2)c2ncccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 8-(3-chlorophenyl)pyrido[2,3-d]pyridazin-5-one (0.32 g, 1.24 mmoles) in tetrahydrofuran (50 ml) was added sodium hydride (0.06 g, 1.4 mmoles). The mixture was stirred for 1 hour at room temperature. Iodoethane (0.48 g, 3.1 mmoles) was added and the solution was refluxed for 18 hours under an inert atmosphere. The mixture was cooled and acidified by the addition of 50 ml of 1N HCl. The desired compound was isolated by extraction with ethyl acetate (extracted until no product detected in aqueous layer), washed with sodium bicarbonate, brine and dried over magnesium sulfate. The solution was filtered and the solvent removed yielding 0.85 g of the crude desired product. The product was purified by recrystallization from methanol to yield 0.24 g of 6-ethyl-8-(3-chlorophenyl)pyrido-[2,3-d]pyridazin-5-one (67.8%), mp. 117°-118° C.
Reaction SMILES: Cl[CH2:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.[K].[C:14]([NH2:25])(=[O:24])[C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17](N)=[O:18]>CN(C=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3](=[O:12])[CH2:2][N:25]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:18])=[CH:6][CH:7]=1
Reactant: O=C(CCl)Cc1ccc(F)cc1
Reactant: NC(=O)c1ccccc1C(N)=O
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of example 23 (85 mg, 0.45 mmol) in DMF (1 mL), under a nitrogen atmosphere, was added potassium salt of phthalamide (96 mg, 0.52 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with a mixture of ice-water and filtered. The slightly pink solid was washed with water to give the titled compound as a white product (79 mg, 62% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:7]2[CH2:8][CH2:9][CH:4]([CH:5]([CH2:10][CH2:11]O)[CH2:6]2)[C:3]1=[O:13].S(Cl)([Cl:17])=O.O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[CH:7]2[CH2:8][CH2:9][CH:4]([CH:5]([CH2:10][CH2:11][Cl:17])[CH2:6]2)[C:3]1=[O:13]
Reactant: CC1(C)C(=O)C2CCC1CC2CCO
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)C(=O)C2CCC1CC2CCCl
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a stirred solution of 50 g of 3,3-dimethyl-6-(2-hydroxyethyl)-bicyclo(2.2.2)-octan-2-one (produced according to Example II) in 200 ml of dry pyridine is added 30 g of thionyl chloride. The mixture is stirred at 50° C. for 2 hours and then poured into 50 g of water. The resulting aqueous solution is extracted with three 200 ml portions of ether. The combined ether layers are washed with two 100 ml portions of 5% aqueous HCl and dried over anhydrous sodium sulfate. The ether is stripped and the residue is vacuum distilled, yielding about 42 g of 3,3-dimethyl-6-(2-chloroethyl)-bicyclo(2.2.2)-octan-2-one, having the structure: ##STR33##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH2:23])=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]#[N:23])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1c(C(N)=O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C#N)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Added dropwise to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (1.57 g, 4.1 mmol) obtained in Step 1 dissolved in dimethylformamide (10 ml) at 0° C., was phosphoryl chloride (0.72 ml, 8.2 mmol). The resulting mixture was stirred for 20 minutes at 0° C. and then stirred for 1 hour at room temperature. The reaction mixture was quenched with water at 0° C., and an mixture was extracted with ethyl acetate (30 ml twice). After removing the solvent, 5-(4-chloro phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonitrile was obtained by column chromatography as white solid (1.47 g, quantativly).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[N:8]2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl[C:26]([O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])=[O:27]>C(OCC)(=O)C>[Cl:31][C:30]([Cl:33])([Cl:32])[CH2:29][O:28][C:26](=[O:27])[NH:12][C:11]1[N:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=2)[N:8]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=1
Reactant: Cc1ccc(-n2nc([Si](C)(C)C)cc2N)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc([Si](C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Yield: 96 %

Procedure:
Place 2-p-tolyl-5-trimethylsilanyl-2H-pyrazol-3-ylamine (170 mg, 0.693 mmol) in ethyl acetate (10 mL). Add potassium carbonate (191 mg, 1.38 mmol) and water (2 mL). Stir the reaction and add trichloroethyl chloroformate (0.114 mL, 0.831 mmol). Stir at room temperature for 18 hours. Add water and ethyl acetate. Separate organic layer and wash with saturated aq. sodium chloride. Collect organic layer, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 0-30% EtOAc:hexane to yield 280 mg (96%) of the title compound. MS(ES+): m/z=420.2 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([OH:16])[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:3]=1.BrC1C=CC(S(O[C@@H:28]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:30]([C:40]([O:42][CH3:43])=[O:41])[CH2:29]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([O:16][C@H:28]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:30]([C:40]([O:42][CH3:43])=[O:41])[CH2:29]3)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:3]=1
Reactant: Oc1nc2ccccc2c2ccc(Br)cc12
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](Oc2nc3ccccc3c3ccc(Br)cc23)CN1C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of the product mixture from Step 2 (176 mg, 0.642 mmol) in NMP (1.5 mL) was added 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (373 mg, 0.803 mmol) and Cs2CO3 (418 mg, 1.29 mmol). The mixture was then heated to 60° C. for 18 h, and worked up with water and EtOAc. The organic layer was washed with brine, dried over MgSO4, and the solvent was removed in vacuo. The crude material was purified on silica (gradient elution, 10-50% EtOAc/hex) to yield the title compound as a 1:1 mixture with the expected regioisomer. LRMS ((M-Boc)+H)+=401.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:16]#[N:17])[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1.[C-:18]#[N:19].[Na+]>CN(C)C=O.O>[C:18]([CH2:2][CH2:3][CH2:4][C:5]1([C:16]#[N:17])[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)#[N:19]
Reactant: CCOC(=O)N1CCC(C#N)(CCCCl)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC(C#N)(CCCC#N)CC1
Temperature: 140 °C
Yield: 88.3 %

Procedure:
To a solution of ethyl 4-(3-chloropropyl)-4-cyano-1-piperidinecarboxylate (12.7 g) in dimethylformamide (250 ml) was added sodium cyanide (24 g) under nitrogen, with stirring. The mixture was warmed at 140° C. overnight and then cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The organic extracts were washed with saturated, sodium chloride solution and water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was chromatographed, eluting with 2:1 heptane/ethyl acetate. The appropriate fractions were collected and concentrated to give 10.8 g (88.5%) of product. A portion was distilled to give the analytical sample, bp 196-201° C. (4 mm of mercury).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.P(Br)(Br)[Br:20].C(=O)([O-])O.[Na+]>N1C=CC=CC=1.CCCCCC>[Br:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1-c1ccc(CO)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCCCCC
Product: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reaction time: 2 h
Yield: 100.4 %

Procedure:
10.0 g (41 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate was dissolved in 7.9 g of pyridine and n-hexane (100 ml). 8.3 g (31 mmol) of phosphorus tribromide was dropwise added thereto under cooling with ice, followed by stirring for 2 hours as such. The reaction liquid was added to an aqueous solution of sodium hydrogencarbonate, followed by the extraction with n-hexane. The organic phase was washed with water, dried and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 9.5 g of the title compound (yield 75% ).
Reaction SMILES: [CH:1]12[C:13](=O)[CH:10]([CH2:11][CH2:12]1)[CH2:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:2]2.[C:15]1([S:21]([NH2:24])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH:1]12[C:13](=[N:24][S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[CH:10]([CH2:11][CH2:12]1)[CH2:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:2]2
Reactant: O=C1C2CCC1Cc1ccccc1C2
Reactant: NS(=O)(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=S(=O)(N=C1C2CCC1Cc1ccccc1C2)c1ccccc1

Procedure:
Tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-one (130 mg, 0.70 mmol) and benzenesulfonamide (110 mg, 0.70 mmol) were mixed in toluene (6 mL). Amberlyst-15 ion exchange resin (35 mg) was added, and the mixture was heated at reflux under Dean Stark conditions for 36 h. The mixture was concentrated and the crude sulfonylimine was used directly in the next step.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]=[CH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][CH:20]=1.C([O-])(=O)C.[Na+].O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:14][C:15]1[CH:20]=[C:19](/[C:3](/[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:2]/[C:1]([O:11][CH2:12][CH3:13])=[O:10])[CH:18]=[CH:17][CH:16]=1
Reactant: Clc1cccc(I)c1
Reactant: CCOC(=O)C=CCC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C(\CC(=O)OCC)c1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 21 h
Yield: 20.1 %

Procedure:
A mixture of diethyl glutaconate (10.0 g. 53.7 mmol), 3-chloroiodobenzene (11.5 g, 48.2 mmol), sodium acetate (4.40 g, 53.7 mmol) and palladium acetate (1.1 g, 4.9 mmol) in DMF (30 mL) was heated to 100° C., stirred for 21 hours, cooled to room temperature, poured into water, filtered, and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel 8:1 hexanes/ethyl acetate to provide 2.88 g (20%) of the desired product. MS (DCI/NH3) m/z 297 (M+H)+; 1H NMR (CDCl3) δ 7.43 (m, 2H), 7.32 (m, 3H), 6.26 (s, 2H), 4.19 (m, 4H), 1.21 (t, 3H), 1.31 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C@@:11]([NH:33][C:34](=O)[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)([C:19]2[CH:24]=[C:23]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:22]=[C:21]([F:32])[CH:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.[OH2:68].[NH2:69][NH2:70]>ClCCl>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C:34]([NH:33][C@:11]([C:8]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([C:4]([NH:69][NH2:70])=[O:5])[CH:7]=2)([C:19]2[CH:24]=[C:23]([O:25][C:26]([F:31])([F:30])[CH:27]([F:28])[F:29])[CH:22]=[C:21]([F:32])[CH:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:68])=[CH:36][C:37]=1[C:42]([F:45])([F:44])[F:43]
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(=O)O)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: O
Reactant: NN
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: NNC(=O)c1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of (R)-2-fluoro-5-(1-(4-fluoro-3-(trifluoromethyl)benzamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)benzoic acid, prepared as described in Procedures 3, 62, 5, 6, 7, 56, 57 and 23, (30 mg, 0.045 mmol) in dichloromethane (1 mL) was added hydroxybenzotriazole (8 mg, 0.058 mmol), followed by EDCI (11 mg, 0.058 mmol). The reaction mixture was stirred for 15 min at rt, then hydrazine hydrate was added (3 μL, 0.001 mmol) and the reaction mixture was stirred for an additional 15 min. The reaction mixture was loaded on an ISCO cartridge (4 g column) and eluted with 0 to 100% EtOAc in hexane to yield (R)-4-fluoro-N-(1-(4-fluoro-3-(hydrazinecarbonyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 344, 25 mg, 81% yield) as a white solid. LCMS: RT=1.78 min [M+H] 674 (Chromolith Performance RP-18e column, 4.6×100 mm eluting with 10-90% ACN/H2O over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm).