Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[Br-:7].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:42])[CH2:16][N+:17]23[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]2)[C@@H:19]([O:25][C:26](=[O:41])[C@@H:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:18]3)=[CH:11][CH:10]=1>C(Cl)Cl>[Br-:7].[CH2:3]([O:2][C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:42])[CH2:16][N+:17]23[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24]2)[C@@H:19]([O:25][C:26](=[O:41])[C@@H:27]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:18]3)=[CH:11][CH:10]=1)=[O:5])[CH3:4]
Reactant: Nc1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Reactant: CCOC(=O)Cl
Agent: [Br-]
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
Ethyl carbonochloridate (10.5 μl, 0.11 mmol) was added to a solution of (R)-1-(2-(4-aminophenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (diastereomer 1 of I74) (60 mg, 0.11 mmol) in TEA (15.2 μl, 0.11 mmol) and DCM (2 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the product was purified by preparative HPLC (eluents: CH3CN/H2O) to obtain (R)-1-(2-(4-(ethoxycarbonylamino)phenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (14 mg, 20.6% yield).
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]([CH2:7][CH2:8][CH2:9][C:10](OC)=[O:11])[C:4](=[O:14])[CH:3]=1.Cl.C(O)(=[O:18])C>>[Cl:1][C:2]1[S:6][N:5]([CH2:7][CH2:8][C:9](=[C:10]=[O:11])[OH:18])[C:4](=[O:14])[CH:3]=1
Reactant: COC(=O)CCCn1sc(Cl)cc1=O
Reactant: CC(=O)O
Agent: Cl
Product: O=C=C(O)CCn1sc(Cl)cc1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The methyl ester of the isothiazolones were hydrolyzed to the free acids. 5-Chloro-2-(3-methoxycarbonylpropyl)-3-isothiazolone (4.0 g) was taken up in 6 ml of acetic acid. To this stirred solution at room temperature was added 6M aqueous HCl (7 ml). This solution was then stirred at room temperature for 24 hours, during which time a white precipitate formed. The solution was filtered and the filtrate further concentrated to yield more of the same precipitate (5-chloro-2-(3-hydroxy-carbonylpropyl)-3-isothiazolone). The combined yield was 2.95 g (m.p. 158°-161° C.).
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>CS(C)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCCc1ccc(N)cc1
Solvent: CS(C)=O
Product: CCCCc1ccc(Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Yield: 63 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser, and a nitrogen inlet was added 4-n-butylaniline (48.5 grams, 0.325 moles), 1-fluoro-4-nitrobenzene (15.3 grams, 0.108 moles) and anhydrous methyl sulfoxide (120 ml). The contents of the flask were heated at 100° C. for 3 days; cooled to room temperature; partitioned between diethyl ether (300 ml) and water (100 ml). The ether extract was washed with water (4×100 ml) followed by brine (2×50 ml). The ether extract was dried over anhydrous magnesium sulfate, filtered and concentrated m vacuo to yield a brown oily residue. The residue was re-crystallized from hexane (300 ml) to yield 18.4 grams of product as a yellow solid. 1H NMR (CDCl3) δ 8.1(d, 2H), 7.2(d, 2H), 7.15(d, 2H), 6.9(d, 2H), 6.3(bs, 1H), 2.6(t 2H), 1.6(pent, 2H), 1.4(hextet, 2H), 0.9(t, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2([CH2:17][CH2:16][C:15](=[CH:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]2)[S:11][CH:10]([CH2:23][C:24]([OH:26])=[O:25])[C:9]1=[O:27])([CH3:4])([CH3:3])[CH3:2].I[CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2([CH2:17][CH2:16][C:15](=[CH:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:13]2)[S:11][CH:10]([CH2:23][C:24]([O:26][CH:30]([CH3:32])[CH3:31])=[O:25])[C:9]1=[O:27])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CC=C1CCC2(CC1)SC(CC(=O)O)C(=O)N2CC(=O)OC(C)(C)C
Reactant: CC(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)C)C(=O)N2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 1.0 g of 2-[4-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetic acid. After adding 0.42 ml of 2-iodopropane and 0.67 g of anhydrous potassium carbonate at ambient temperature, the resulting mixture was stirred at ambient temperature for 17 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=17:3] gave 1.0 g of isopropyl 2-[4-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetate as a light yellow oily product.
Reaction SMILES: Br[C:2]1[O:23][C:5]2[N:6]([CH3:22])[CH:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1.[C:24]1([CH:30]([OH:34])[CH2:31][C:32]#[CH:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(N(CC)CC)C.CN(C=O)C.[Cu]I.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>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:33]#[C:32][CH2:31][CH:30]([OH:34])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:23][C:5]=3[N:6]([CH3:22])[CH:7]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: C#CCC(O)c1ccccc1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)oc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCC(O)c3ccccc3)oc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Bromo-N-(4-chlorobenzyl)-7-methyl-4-oxo-4,7-dlhydrofuro[2,3-b]-pyridine-5-carboxamide (Example 79, 0.593 g) was suspended in a mixture of triethylamine (15 mL) and DMF (3 mL). CuI (0.029 g), Pd(PPh3)2Cl2 (0.105 g), and then 1-phenyl-3-butyn-1-ol (0.36 mL) were added. The reaction mixture was stirred at room temperature for 20 min and then was partitioned between CH2Cl2 (50 mL) and water (50 mL). The aqueous layer was separated and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with a sat. aq. ammonium chloride solution (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2) followed by recrystallization from methanol to yield 0.275 g of the title compound as a yellow solid. Physical characteristics. M.p. 202-203° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 10.50, 8.58, 7.44-7.25, 7.15, 5.73, 4.85-4.81, 4.55, 3.91, 2.89; MS (ESI+) m/z 461 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][NH:15][C:16](=[O:26])[CH2:17][NH:18][C:19]1[S:20][C:21]([CH:24]=[O:25])=[CH:22][N:23]=1)[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Sn](C)(C)O>ClCCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][NH:15][C:16](=[O:26])[CH2:17][NH:18][C:19]1[S:20][C:21]([CH:24]=[O:25])=[CH:22][N:23]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](CNC(=O)CNc1ncc(C=O)s1)NC(=O)OC(C)(C)C
Agent: C[Sn](C)(C)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)CNc1ncc(C=O)s1)C(=O)O
Temperature: 80 °C
Yield: 42.9 %

Procedure:
Following the general procedure as described in Example 117, except using material from Example 106 (100 mg, 0.259 mmol), 1,2-dichloroethane (2.5 mL), trimethylstannanol (140 mg, 0.0.776 mmol), and heating in a microwave for 2.5 h at 80° C. under normal power, 41.4 mg (43%) of the title compound is isolated as a thick oil that contains 0.25 equivalents of the tin reagent. LC/MS (Condition A): ret. T=2.28 min, (M+H)+ 373.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].[Br-:23].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>O1CCCC1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Br:23])=[C:5]2[C:10]=1[NH:9][C:8](=[O:22])[CH:7]=[CH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 0 °C
Yield: 81.9 %

Procedure:
5-Acetyl-8-benzyloxy-1H-quinolin-2-one (372 g, 1.27 mol) was dissolved in tetrahydrofuran (3.6 L) and the solution was cooled to 0° C. Pyridinium tribromide (453 g, 1.27 mol) was added thereto in portions, and the mixture was heated under reflux for 3 hours. Thereafter, tetrahydrofuran (3.1 L) was added and the mixture was heated under reflux overnight. The precipitate was collected by filtration and washed with tetrahydrofuran. The solid was suspension-washed with tetrahydrofuran (2.3 L) and, thereafter, washed with purified water (3 L). Separately, the tetrahydrofuran filtrate and the washings were mixed, concentrated under reduced pressure, and the residue was suspension-washed with tetrahydrofuran (1 L). The solids were combined and dried under reduced pressure to obtain 8-benzyloxy-5-(2-bromoacetyl)-1H-quinolin-2-one (387 g).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]2)[CH2:2]1.Br[C:13]1[C:14]([Cl:40])=[C:15]([N:23]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:16]=[C:17]([O:19][CH:20]([F:22])[F:21])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:40][C:14]1[C:13]([N:1]2[CH2:4][CH:3]([N:5]3[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]3)[CH2:2]2)=[CH:18][C:17]([O:19][CH:20]([F:22])[F:21])=[CH:16][C:15]=1[N:23]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CN1CCN(C2CNC2)CC1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(OC(F)F)cc(Br)c2Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(OC(F)F)cc(N3CC(N4CCN(C)CC4)C3)c2Cl)cc1
Temperature: 105 °C
Yield: 61.7 %

Procedure:
1-(Azetidin-3-yl)-4-methylpiperazine (95 mg, 0.609 mmol), tert-butyl (3-bromo-2-chloro-5-(difluoromethoxy)phenyl)(4-methoxybenzyl)carbamate (300 mg, 0.609 mmol), cesium carbonate (397 mg, 1,218 mmol), Pd2(dba)3 (27.9 mg, 0.030 mmol) and BINAP (56.9 mg, 0.091 mmol) were suspended in toluene (6088 μl) at room temperature. The reaction was degassed under vacuum and backfilled with N2 (4 times), and then heated to 105° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through celite and concentrated. Column chromatography (24 g SiO2, 0 to 10% CH3OH—CH2Cl2 gradient elution) afforded tert-butyl (2-chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)phenyl)(4-methoxybenzyl)carbamate (213.1 mg).
Reaction SMILES: C(O[C:4]1[CH:8]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18]C)=[CH:13][CH:12]=2)[CH2:7][CH2:6][N:5]=1)C.CO[CH:22](OC)[CH2:23][NH2:24].C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.C1C=CC=CC=1>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][S:9][CH:8]2[C:4]3=[N:24][CH:23]=[CH:22][N:5]3[CH2:6][CH2:7]2)=[CH:16][CH:15]=1
Reactant: COC(CN)OC
Reactant: CCOC1=NCCC1SCc1ccc(OCC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: c1ccccc1
Product: COc1ccc(CSC2CCn3ccnc32)cc1

Procedure:
2-Ethoxy-3-p-ethoxybenzylthio-1-pyrroline (531mg) (synthesized according to the method disclosed in Japanese Patent Laid-Open No. 56987/1985), aminoacetaldehyde dimethylacetal (315mg) and acetic acid (180mg) were dissolved in 30 ml of ethanol and refluxed under heating for one hour. The reaction solution was evaporated to dryness in vacuo, the residue was distributed between benzene and 40 ml of water containing 4 ml of 1N sodium hydroxide aqueous solution, the benzene phase was washed with water and dried over MgSO4 and thereafter the solvent was distilled off in vacuo to obtain 700mg of colorless and transparent material. The oily material was dissolved in 30 ml of benzene, 1.14 g of p-toluenesulfonic acid (hydrate) was added thereto and refluxed under heating for one hour. The reaction solution was cooled, washed with 5% aqueous solution of sodium bicarbonate and water and dried, then the solvent was distilled off. The residue was purified by column chromatography using a column packed with 20 g of silica gel (eluent: Chloroform/methanol (19:1 v/v)) to obtain the objective compound as a colorless and transparent oil. The compound was crystallized during standing in a refrigerator (m.p.=65°~73° C.; yield: 0.53 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([OH:18])(=O)=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([Cl:21])(=[O:18])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Yield: 95 %

Procedure:
To a mixture of 4′-methoxy[1,1′-biphenyl]-4-sulfonic acid (30 g, 0.11 mol) and thionylchloride (90 ml), DMF (1 ml) was added and the reaction mixture was refluxed for 6 h. Excess thionylchloride was distilled off and the crude was purified by column chromatography over silica gel (pet. ether/CHCl3, 1:1) to give 4′-methoxy[1,1′-biphenyl]-4-sulfonyl chloride (30 g, 95%).
Reaction SMILES: [C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:23](O)(=O)[CH2:24]CCCCCCCCCCCCCCCC.[OH-].[Na+:44].[N+]([O-])(O)=O>O>[C:1]([O-:22])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:23][CH3:24].[Na+:44]
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 55 °C

Procedure:
In an amount of 32.4 g of behenic acids, 9.9 g of arachidic acid and 5.6 g of stearic acid were dissolved in 945 mL of pure water at 90° C. Then, the solution was added with 98 mL of 1.5 mol/L sodium hydroxide aqueous solution with stirring at high speed. Subsequently, the solution was added with 0.93 mL of concentrated nitric acid, cooled at 55° C. and stirred for 30 minutes to obtain sodium behenate solution.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])=O.[NH4+]>C(O)C.O.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCC=Cc1ccccn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCc1ccccn1
Yield: 94.1 %

Procedure:
Ethyl 5-(2-pyridyl)-4-pentenoate (1.7 g, 8.2 mmol) was dissolved in ethanol (20 ml), and 10% palladium-carbon (0.22 g) and a solution of ammonium formate (3.1 g, 49.0 mmol) in water (5 ml) were added thereto. The reaction mixture was refluxed for 2 hrs. Palladium-carbon was filtered off, and the reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (1.6 g, 94%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([OH:17])[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([OH:17])[CH2:15][CH2:14][CH:13]([N:18]4[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=5)=[O:24])[CH2:19]4)[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C1CCC(O)(c2ccc3c(c2)OCC3)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc4c(c3)OCC4)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(2,3-dihydro-benzofuran-6-yl)-4-hydroxy-cyclohexanone (as prepared in Example 3, Step B) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: N1C(=O)N=[CH:4][CH:5]=1.[CH2:7]([N:9]1[C:13]([Cl:14])=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18]C)[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:32]([C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:23][CH:22]=2)[C:10]1=[O:38])[CH3:8]>>[C:5]1([CH2:8][CH2:7][N:9]2[C:13]([Cl:14])=[C:12]([CH2:15][CH2:16][CH2:17][CH3:18])[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[C:32]([C:33]5[NH:37][N:36]=[N:35][N:34]=5)=[CH:31][CH:30]=[CH:29][N:28]=4)=[CH:23][CH:22]=3)[C:10]2=[O:38])[CH:4]=[CH:16][CH:15]=[CH:12][CH:13]=1
Reactant: O=C1N=CC=N1
Reactant: CCCCCc1c(Cl)n(CC)c(=O)n1Cc1ccc(-c2ncccc2-c2nnn[nH]2)cc1
Product: CCCCc1c(Cl)n(CCc2ccccc2)c(=O)n1Cc1ccc(-c2ncccc2-c2nnn[nH]2)cc1

Procedure:
1-methyl-4-pentyl-5-chloro-1,3-dihydro-3-[[4-3-(1H-tetrazol-5-yl)-2-pyridinyl]phenyl]methyl]-2H-imidazol-2-one, 1-ethyl-4-pentyl-5-chloro-1,3-dihydro-3-[[4-[3-(1H-tetrazol-5-yl)-2-pyridinyl]phenyl]methyl]-2H-imidazol-2-one;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:8][C:5]1[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:3][CH:2]=[CH:7][CH:6]=1
Reactant: Cc1ccc(Br)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccnc1-c1ccccn1
Temperature: 110 °C
Reaction time: 48 h
Yield: 76.2 %

Procedure:
A mixture of 2-bromo-5-methylpyridine (5.0 g, 29 mmol), 2-tributylstannylpyridine (10 g, 27 mmol) and Pd(PPh3)4 (2.0 g, 1.7 mmol) in dry toluene (250 mL) was stirred for 48 h at 110° C. The reaction mixture was filtered over Celite and evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. Flash column chromatography (0.5% MeOH in CH2Cl2) afforded methyl-2,2′-bipyridine (3.5 g, 75%) as a colorless oil. 1H-NMR (500 MHz, CDCl3): 2.47 (s, 3H), 7.35 (dd, 1H), 7.70 (dd, 1H), 7.87 (m, 1H), 8.36 (d, 1H), 8.43 (d, 1H), 8.58 (d, 1H), 8.74 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[CH2:26][C:23]3[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=Cc1ccncc1
Product: CN(Cc1ccncc1)Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Yield: 93 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine was reacted with pyridine-4-carbaldehyde using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)methylpyridin-4-ylmethylamine as a solid (93% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethyl ether and methanol to give 426 as a solid (80% yield). NMR (CDCl3, 400 MHz), 2.35 (3H, s), 3.66 (2H, s), 3.88 (2H, s), 3.91 (4H, t, J=5.2), 4.07 (4H, t, J=5.2), 5.27 (2H, s), 7.32 (1H, s), 7.36 (2H, d, J=6), 8.61-8.62 (2H, m), 9.30 (2H, s). MS: (ESI+): MH+=449
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[CH:12][C:11]([C:17](O)=[O:18])=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C(Cl)CCl.[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35]>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:28][C:22]1[CH:21]=[C:20]([C:6]2[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]3[NH:15][C:14]4[C:9]([C:8]=3[CH:7]=2)=[CH:10][C:11]([C:17]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:18])=[CH:12][CH:13]=4)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: COc1ccc(-c2cc(C(N)=O)c3[nH]c4ccc(C(=O)O)cc4c3c2)cc1F
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4ccc(C(=O)NS(C)(=O)=O)cc4c3c2)cc1F
Yield: 54.9 %

Procedure:
To a solution of 8-carbamoyl-6-(3-fluoro-4-methoxyphenyl)-9H-carbazole-3-carboxylic acid (53 mg, 0.070 mmol, Example 187) in DMF (1 ml) was added DMAP (63 mg, 0.516 mmol), then EDC (128 mg, 0.668 mmol) and methanesulfonamide (92 mg, 0.967 mmol) and the mixture stirred at room temperature for 18 hours. The reaction mixture was filtered through a 0.45 um Nylon filter and purified by prep HPLC (water/CH3CN/NH4OAc eluent system). Product containing fractions were evaporated to give 17.5 mg 3-(3-fluoro-4-methoxyphenyl)-N6-(methylsulfonyl)-9H-carbazole-1,6-dicarboxamide as an off-white solid. HPLC retention time 11.10 min (HPLC conditions as in Table 9 and Table 10). MS (ESI) m/z [M−H]− 454; [M+H]+ 456. 1H NMR (CD3OD) δ ppm 8.88 (s, 1H), 8.53 (d, 1H, J=1.3), 8.16 (m, 2H), 7.63-7.55 (m, 3H), 7.22 (t, 1H, 8.5), 3.96 (s, 3H), 3.25 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6](C)=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([N:18]3[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:20][C:19]3=[O:35])[CH3:17])=[CH:12][CH:11]=2)=[N:3]1.Cl[C:37]1[CH:38]=CC(=O)N(C2CC2)N=1>>[CH:1]1([N:2]2[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:10]3[CH:11]=[CH:12][C:13]([C@@H:16]([N:18]4[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:32])[CH3:33])([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[O:20][C:19]4=[O:35])[CH3:17])=[CH:14][CH:15]=3)=[N:3]2)[CH2:38][CH2:37]1
Reactant: O=c1ccc(Cl)nn1C1CC1
Reactant: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn(C)c1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C3CC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 3-{(S)-1-[4-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and 6-chloro-2-cyclopropylpyridazin-3(2H)-one following a procedure analogous to that described in Example 17. Mass spectrum (ESI+): m/z=488 [M+H]+