Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2](=[C:13]1[C:18](=[O:19])OC(C)(C)OC1=O)[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:5]=1[F:12].Cl.[F:24][C:25]([F:36])([F:35])[C:26]1[N:30]2[CH2:31][CH2:32][NH:33][CH2:34][C:29]2=[N:28][N:27]=1.C(N(C(C)C)CC)(C)C>C(OC(C)C)(=O)C>[O:19]=[C:18]([N:33]1[CH2:32][CH2:31][N:30]2[C:26]([C:25]([F:36])([F:24])[F:35])=[N:27][N:28]=[C:29]2[CH2:34]1)[CH2:13][C:2](=[O:1])[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:5]=1[F:12]
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: CC1(C)OC(=O)C(=C(O)Cc2cc(F)c(F)cc2F)C(=O)O1
Agent: Cl
Solvent: CC(=O)OC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 85 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
A mixture of 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)-ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g), 3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine hydrochloride (7.2 g), diisopropyl ethylamine (4.5 g), and isopropyl acetate (100 mL) are heated to about 85° C. and stirred for about 4 hours. The reaction mass is then cooled to about 30° C. and quenched with water (90 mL). The organic layer is separated, washed with 5% sodium chloride solution (3×50 mL) and distilled off completely under vacuum to afford 12 g of the title compound. (Yield: 93.3%; purity by HPLC: 95.7%)
Reaction SMILES: [N:1]1([C:7](=[O:25])[CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([C:15]3[CH:16]=[N:17][C:18]4[NH:19][CH2:20][CH2:21][CH2:22][C:23]=4[CH:24]=3)[CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl.CCOC(C)=O>[C:32]([N:19]1[C:18]2[N:17]=[CH:16][C:15]([C:13]3[CH:14]=[C:9]([CH2:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:25])[CH:10]=[N:11][CH:12]=3)=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)(=[O:34])[CH3:33]
Reactant: O=C(Cc1cncc(-c2cnc3c(c2)CCCN3)c1)N1CCOCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCCc2cc(-c3cncc(CC(=O)N4CCOCC4)c3)cnc21
Reaction time: 16 h

Procedure:
1-Morpholin-4-yl-2-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-ethanone (62.4 mg, 0.184 mmol) is dissolved in DCM (2 mL). Pyridine (0.089 mL, 1.11 mmol) is added. Acetyl chloride (1.0M in DCM, 0.55 mL, 0.55 mmol) is added dropwise and the mixture is stirred for 16 h. The mixture is diluted with EtOAc (50 mL), washed with water (3×5 mL), and brine, dried over sodium sulfate, filtered, and concentrated. The resulting crude product is purified by normal phase chromatography using 0-6% MeOH in DCM as the gradient to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[C:26]([CH3:32])=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[C:26]=2[CH3:32])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Cc1c(O)cccc1Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(Cl)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-chloro-2-methylphenol: 1H-NMR (CDCl3) δ 8.57 (1H, dd, J=2.6, 0.7 Hz), 8.18–7.99 (4H, m), 7.44–7.34 (3H, m), 7.23 (1H, d, J=8.1 Hz), 7.02 (1H, d, J=8.1 Hz), 5.45–5.35 (1H, m), 3.90 (3H, s), 2.19 (3H, s), 1.60 (3H, d, J=6.9 Hz); MS (ESI) m/z 459 (M+H)+, 457 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Clc1ncnc2c1ncn2C1CCCCO1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 6-chloropurine (2.70 g, 17.5 mmol) and p-toluenesulfonic acid monohydrate (0.14 g, 0.71 mmol) in methylene chloride (30 mL) was added dihydropyran (2.39 mL, 26.2 mmol). The suspension was stirred for 3 h. The reaction mixture was washed with 2.5% Na2CO3 solution (100 mL×2), and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated. The oil was treated with hexanes (100 mL) and stirred. The hexanes layer was decanted. The oil solidified upon standing to give the desired product (4.17 g, 98%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](N)=[O:9])=[C:6]([O:13][CH:14]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]2)[CH:5]=1.Cl.S(Cl)([Cl:23])=O>O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]2[C:8](=[O:9])[N:16]([CH3:19])[CH2:15][CH:14]([CH2:18][CH2:17][Cl:23])[O:13][C:6]=2[CH:5]=1
Reactant: CN1CCC(Oc2cc(Cl)ccc2C(N)=O)C1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CC(CCCl)Oc2cc(Cl)ccc2C1=O
Yield: 58.9 %

Procedure:
To a solution of 10.4 g (0.26 mole) of sodium hydroxide in 150 ml of water was added 32 g (0.13 mole) of 4-chloro-2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide and the mixture was heated at reflux for 24 hr. The reaction mixture was adjusted to pH 6 with concentrated hydrochloric acid and filtered and the filtrate concentrated. The residue was boiled with 100 ml of isopropyl alcohol and the mixture filtered. The filtrate was concentrated and heated at reflux with 98 g (0.83 mole) of thionyl chloride for 1 hr. The excess thionyl chloride was evaporated under reduced pressure. The residue was dissolved in 70 ml of chloroform and the solvent evaporated under reduced pressure. The residue was redissolved in 75 ml of chloroform and 40 ml of triethylamine was added gradually. The mixture was heated at reflux for 1 hr. The solvent was evaporated under reduced pressure to give a dark-brown solid. The solid was dissolved in ethyl acetate and the resulting solution washed twice with 200 ml of water and twice with 250 ml of 20% sodium hydroxide. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 21 g (59%) of dark-brown solid. The solid was recrystallized from isopropyl alcohol to give the title compound, m.p. 85°-87° C.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.CI>O1CCCC1.O>[CH3:1][C:20]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:22][C:17]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 500 mL round-bottomed flask was added diisopropylamine (7.98 mL) in tetrahydrofuran (233 mL). The mixture was cooled to −78° C. under N2 and n-butyllithium (2.5 M in hexanes, 22.40 mL) was added. The reaction was stirred for 30 minutes and ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (10 g) was added. The reaction was allowed to stir for 1.5 hours upon which time CH3I (4.38 mL) was added. The reaction was allowed to warm to room temperature overnight with stirring. Water was added and the aqueous layer was extracted with ethyl acetate. The combined organics were dried (Na2SO4), filtered and concentrated by rotary evaporation. The residue was purified by normal phase flash column chromatography (Analogix, 0-50% hexanes/ethyl acetate).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[C:3]([O:5][CH3:6])=[O:4].[N-:14]=[N+:15]=[N-:16].[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]([CH2:34][C@H:35]([OH:40])[C:36]([F:39])([F:38])[F:37])[C:27](=[O:33])[N:28]([CH2:30][C:31]#[CH:32])[N:29]=2)=[CH:21][CH:20]=1>C(#N)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:2]([N:14]1[CH:32]=[C:31]([CH2:30][N:28]2[C:27](=[O:33])[N:26]([CH2:34][C@H:35]([OH:40])[C:36]([F:38])([F:37])[F:39])[C:25]([C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)=[N:29]2)[N:16]=[N:15]1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Br)c1ccccc1Cl
Reactant: C#CCn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(c1ccccc1Cl)n1cc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
361 mg (1.37 mmol) of methyl bromo(2-chlorophenyl)acetate were initially charged in 10 ml of acetonitrile, and 89 mg (1.37 mmol) of sodium azide were added. The mixture was stirred at RT for 1 h. 2.7 mg (0.14 mmol) of copper(II) acetate monohydrate and 569 mg (1.64 mmol) of the compound from Example 14A were then added. The resulting mixture was stirred at 50° C. for 48 h. The reaction mixture was then filtered through a little silica gel, the product being eluted with about 10 ml of ethyl acetate, and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1→6:1→4:1→2:1→1:1). This gave 496 mg (53% of theory) of the target compound.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd].[C]>[OH:8][C:9]1[C:10]2[N:11]([C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cccn12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc2c(O)cccn12
Temperature: 25 °C

Procedure:
31.45 g (101.3 mmol) of ethyl 8-(benzyloxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylate were dissolved in 21 of ethyl acetate, 3.15 g of 10% Pd/carbon were added and the mixture was stirred at RT and atmospheric pressure with hydrogen for 5 h. The mixture was filtered through kieselguhr, the filter cake was washed thoroughly with ethyl acetate/methanol and the filtrate was evaporated to dryness. This gave 21.94 g of the target compound (98% of theory, purity 99%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][CH3:29])[C:16]2[C:17]([CH2:26][CH3:27])=[C:18]([CH:22]=[C:23]([Cl:25])[CH:24]=2)[C:19]([OH:21])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.[NH2:63][CH2:64][C:65]1[C:66](=[O:73])[NH:67][C:68]([CH3:72])=[CH:69][C:70]=1[CH3:71]>CN(C=O)C>[Cl:25][C:23]1[CH:22]=[C:18]([C:19](=[O:21])[NH:63][CH2:64][C:65]2[C:66](=[O:73])[NH:67][C:68]([CH3:72])=[CH:69][C:70]=2[CH3:71])[C:17]([CH2:26][CH3:27])=[C:16]([N:15]([CH2:28][CH3:29])[CH:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:11]2)[CH:24]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCc1c(C(=O)O)cc(Cl)cc1N(CC)C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(C(=O)NCc2c(C)cc(C)[nH]c2=O)cc(Cl)cc1N(CC)C1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
A stirred solution of 3-[(4-{[(tert-butoxy)carbonyl]amino}cyclohexyl)(ethyl)amino]-5-chloro-2-ethylbenzoic acid (139 mg, 0.33 mmol) in anhydrous DMF (2.0 ml) at 0° C. under nitrogen, was treated with HATU (149 mg, 0.39 mmol) and DIPEA (114 μl, 0.65 mmol). The resulting solution was stirred for 10 minutes and then treated with 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 61 mg, 0.36 mmol). The resulting suspension was stirred at 0° C. for 1 hour and then stirred at room temperature for 98.5 hours. The reaction mixture was treated with HATU (37 mg, 0.1 mmol), stirred for 1 hour and then 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 11 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for a further 23 hours and then partitioned between water (20 ml) and CH2Cl2 (20 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×10 ml). The combined organics were washed with a saturated solution of NaHCO3 (aq) (40 ml), water (20 ml), brine (2×20 ml), dried (MgSO4), filtered and concentrated in-vacuo. The crude residue was purified by flash column chromatography (10 g SNAP cartridge, Isolera, 0-13% MeOH/CH2Cl2) and triturated from ether/heptane (2.0 ml) with sonication and the liquor decanted. The remaining solid was dried under high vacuum to give the title compound (101 mg, 52%) as a beige solid. LC-MS 93%, 4.54 min (7 minute LC-MS method), m/z=559.2, 561.2. 1H NMR shows a mixture of cis/trans isomers.
Reaction SMILES: Br[C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[CH3:15][N:16]([CH2:21][C:22]1[O:23][C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[C:26]=1[CH3:27])[C:17](=[O:20])[CH:18]=[CH2:19].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:11][CH:10]1[CH2:9][CH2:8][C:7](=[O:12])[NH:6][C:5]2[N:13]=[CH:14][C:2](/[CH:19]=[CH:18]/[C:17]([N:16]([CH3:15])[CH2:21][C:22]3[O:23][C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[C:26]=3[CH3:27])=[O:20])=[CH:3][C:4]1=2
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Reactant: O=C1CCC(O)c2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)C(O)CCC(=O)N3)oc2ccccc12
Temperature: 130 °C
Yield: 72.5 %

Procedure:
A suspension of 3-bromo-5-hydroxy-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (40 mg, 0.16 mmol), N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (71 mg, 0.31 mmol) and (i-Pr)2EtN (0.14 mL, 0.78 mmol) in 3 mL of DMF) was de-oxygenated with Ar for 30 min in a microwave reaction vial. The mixture was treated with Pd(OAc)2 (4.0 mg, 0.02 mmol) and P(o-tol)3 (9.0 mg, 0.04 mmol) then heated to 130° C. for 5 min in the microwave. The hot mixture was filtered through a pad of celite and washed liberally with ethyl acetate. The filtrate was diluted with 20 mL H2O then extracted with 2×20 mL ethyl acetate. The resulting crude product was subjected to prep HPLC purification to yield 47 mg of product (75% pure). A second prep HPLC purification was performed to obtain pure product as a fluffy white powder. Yield 5.1 mg (8%); 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.09 (s, 1H), 7.56 (d, J=7.4 Hz, 1H), 7.47 (m, 2H), 7.35-7.21 (m, 3H), 7.14 (d, J=15.2 Hz, 1H), 5.60 (s, 1H), 4.77 (s, 2H), 3.17 (s, 3H), 2.65 (s, 3H), 2.26 (m, 4H); ESI MS m/z 406 [C23H23N3O4+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9].[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:22][CH2:23][N:24]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:25][CH2:26]3)[CH2:19][CH2:20]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:31][CH2:32]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCNCC3)CC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
To a solution of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperazin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (35.4 mg, 70 μmol) in methylenehloride (0.7 mL) was added under stirring ethyldiisopropyl amine (18.3 μL, 105 μmol) and methanesulfonyl chloride (6.00 μL, 77.0 μmol). The reaction was stirred at room temperature for 5 hours and additional ethyldiisopropyl amine (18.3 μL, 105 μmol) and methanesulfonyl chloride (6.00 μL, 77.0 μmol) was added. The reaction was stirred at room temperature over night. The reaction was purified by column chromatography on silica gel using ethyl acetate as solvent to yield the title compound as a yellow solid (39 mg, 95%). MS ISP (m/e): 584.1/586.1 (100/44) [(M+H)]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:4][C:5]2[C:6](=[C:8]([C:12]([OH:14])=O)[CH:9]=[CH:10][CH:11]=2)[N:7]=1.Cl.Cl.[NH2:17][C@H:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1>>[N:20]12[CH2:19][C@@H:18]([NH:17][C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:5]4[O:4][C:3]([S:2][CH3:1])=[N:7][C:6]=34)=[O:14])[CH:23]([CH2:24][CH2:25]1)[CH2:22][CH2:21]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: CSc1nc2c(C(=O)O)cccc2o1
Agent: Cl
Product: CSc1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1

Procedure:
Following general procedure GP-C1, a mixture of 2-(methylthio)benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-(methylthio)benzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]#[N:13])[CH:3]=1.C(N)(=[S:16])C.O>CN(C)C=O.O1CCOCC1.Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12](=[S:16])[NH2:13])[CH:3]=1
Reactant: CC(N)=S
Reactant: N#Cc1cc(Br)c2ccccc2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: NC(=S)c1cc(Br)c2ccccc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of 4-bromonaphthalene-2-carbonitrile (0.57 g) in N,N-dimethylformamide (4 mL) and 4 mol/L HCl 1,4-dioxane solution (4 mL) was added thioacetamide (1.1 g) at room temperature, and the reaction mixture was stirred at 70° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel to give 4-bromonaphthalene-2-carbothioamide (0.48 g). To a suspension of this compound (0.48 g) in ethanol (6 mL) was added ethyl 2-chloro-acetoacetate (0.59 g), and the mixture was stirred at 65° C. for 24 hours. After cooling to room temperature, the precipitated solid was collected by filtration, washed with ethanol, and dried to give the title compound (0.41 g).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[C:6](O)(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>O>[C:7]1([C:6]2[NH:21][C:16]3[CH:17]=[C:18]([S:1]([OH:3])(=[O:5])=[O:2])[CH:19]=[CH:20][C:15]=3[N:22]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=S(=O)(O)c1ccc2nc(-c3ccccc3)[nH]c2c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
A 2 l four-necked flask is initially charged with 182 ml of distilled water, and 1533 g (15 mol) of 96% sulfuric acid are carefully added. 367 g (3.0 mol) of benzoic acid are introduced into the sulfuric acid, which at this point has a temperature of about 100° C., over a period of about 10 minutes while stirring vigorously (during this the temperature drops to about 80° C.). The mixture is subsequently heated to an internal temperature of 100° C., the benzoic acid dissolving almost completely. 325 g (3.0 mol) of 1,2-phenylenediamine are subsequently metered in at such a rate that the temperature of the mixture does not rise above 125° C. After completion of the addition the mixture is heated to reflux temperature (about 178° C.) and stirred for a further 6 hours at this temperature, during which a small proportion of the benzoic acid sublimes. The mixture is then stirred into 6 l of water at a temperature of 100° C. and then stirred for a further 30 minutes at 100° C. and the precipitate is then filtered off with suction and washed with 2 l of water at a temperature of 80° C. until free of sulfate. The dried crude product (580 g, 70% of theory) is suspended in 2.5 l of water and the pH is adjusted to 8 with 32% sodium hydroxide solution. After addition of 20 g of activated carbon the mixture is stirred for a further 60 minutes at room temperature and subsequently clarified by filtration. The filtrate is heated to 80° C. and the pH is adjusted to 3 with concentrated sulfuric acid. The precipitated product is filtered off with suction while hot, washed with 4 l of water at a temperature of 90° C. and dried to constant weight in a vacuum drying cabinet at 75° C. and 20 mbar. 493 g (1.8 mol, 60% of theory) of 2-phenylbenzimidazole-5-sulfonic acid are thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1I.[F:14][C:15]1[C:20]([F:21])=[CH:19][C:18](B(O)O)=[C:17]([O:25][CH3:26])[CH:16]=1>CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:18]1[CH:19]=[C:20]([F:21])[C:15]([F:14])=[CH:16][C:17]=1[O:25][CH3:26]
Reactant: COC(=O)CNc1cnccc1I
Reactant: COc1cc(F)c(F)cc1B(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CNc1cnccc1-c1cc(F)c(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-ylamino)-acetic acid methyl ester and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light yellow oil (82%). MS (ESI): m/z=309.104 [M+H]+.
Reaction SMILES: Br[C:2]1[C:9](C)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C([Li])CCC.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]=[O:23].[Cl-].[NH4+].C[CH2:27][O:28]CC>CCCCCC.C(OCC)(=O)C>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([O:28][CH3:27])[C:2]=1[CH:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=1)[OH:23]
Reactant: CCOCC
Reactant: Cc1cccc(CO)c1Br
Reactant: O=Cc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cccc(CO)c1C(O)c1ccccn1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a mixture of 12.49 g (0. 0621 mol) of o-bromo-m-methylbenzyl alcohol in 400 ml of ether cooled to -20° C. was added in portions 13.3 ml (0.1335 mol) of n-butyllithium (10M) in hexane over a 20 min period, and the reaction mixture was allowed to warm to room temperature and stirred 1 hr. The above reaction mixture was cooled to -20° C., 14.63 g (0.136 mol) of pyridine-2-carboxaldehyde in 50 ml of ether was added to the mixture over an 1 hr period (the mixture turns purple), and the resulting reaction mixture was allowed to warm to room temperature and stirred for 1 hr. Ammonium chloride solution (100 ml) and 200 ml of ethyl acetate were added to the mixture with stirring, and the mixture was extracted with ethyl acetate (2×200 ml). The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated. The diol was was triturated with 100 ml of ether, filtered, and the solid product was washed with hexane (yield: 6.6 g; 46%) to afford 2-[1-hydroxy-(2'-hydroxymethyl-6'-methyl)-benzyl]-pyridine (Formula XIII: R1 =R7 =H; R2 =6'--CH3), as a pale yellow solid, m.p. 129°-132° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([O-])([O-])=O.[Cs+].[Cs+].IC>C(#N)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:17])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc(C(=O)c2ccccc2)c(O)c1
Temperature: 25 °C

Procedure:
The above prepared (2,4-dihydroxy-phenyl)-phenyl-methanone (0.775 g, 3.62 mmol) was dissolved in 15 mL of acetonitrile and treated successively at 0° C. with Cs2CO3 (1.297 g, 1.1 eq.) and iodomethane (0.242 mL, 1.08 eq.), and the mixture was then stirred over night at ambient temperature. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, heptane/AcOEt=9/1), delivered 0.681 g of the title compound as off-white oil.