Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:23][O:24][CH2:25][CH:26]([C:34]1[CH:35]=[CH:36][C:37]([CH:40]=[O:41])=[N:38][CH:39]=1)[O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1.C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH3:23][O:24][CH2:25][CH:26]([C:34]1[CH:35]=[CH:36][C:37]([C:40](=[O:41])[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[N:38][CH:39]=1)[O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Reactant: COCC(OC1CCCCO1)c1ccc(C=O)nc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(OC1CCCCO1)c1ccc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)nc1
Yield: 53.8 %

Procedure:
A mixture of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.07 g), 5-[2-methoxy-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyridine-2-carbaldehyde (0.97 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (90 mg), triethylamine (0.23 mL), tetrahydrofuran (8 mL) and ethanol (8 mL) was stirred with heating under reflux for 1 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (1.05 g, yield 54%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 588 (MH+).
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9](=[O:11])[CH3:10].CCN(CC)CC.[S:19]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]1[O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>ClCCCl.CCOC(C)=O>[S:19]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]1[O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:6]2[CH2:7][CH:2]3[CH2:8][CH:5]2[CH2:4][N:3]3[C:9](=[O:11])[CH3:10])=[CH:31][CH:30]=1
Reactant: CC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: O=Cc1ccc(Oc2nc3ncccc3s2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2CC1CN2Cc1ccc(Oc2nc3ncccc3s2)cc1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 88.1 %

Procedure:
To a 1-L round-bottom, 3-necked flask equipped with magnetic stirring, dynamic nitrogen inlet, and thermocouple probe were added 1-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethanone hydrochloride (53.3 g, 0.302 mol), DCE (250 mL), and Et3N (100 mL, 1.006 mol). The flask was warmed to 50° C. and aged for 20 min. An additional 100 mL of DCE was added to facilitate stirring. The solution was cooled to 40° C. and the solution was then added via cannula to a 2-L round-bottom, 3-necked flask equipped with overhead mechanical stirring, dynamic nitrogen inlet, and thermocouple probe containing 4-(thiazolo[4,5-b]pyridin-2-yloxy)-benzaldehyde (51.6 grams, 0.201 mol) dissolved in DCE (100 mL). The 1-L round-bottom flask was rinsed with DCE (100 mL). The rinse solvent was added to the reaction mixture. The resultant deep purple solution was aged at rt for 2.5 h. After such time, the sodium triacetoxyborohydride (72.5 g, 0.342) was added in 4 equal portions over a four-hour period. Once addition was complete, the resultant solution was aged at rt overnight. The reaction was quenched by the slow addition of water (1 L) over a 10-minute period. After 30 additional minutes of stirring, the solution was filtered to remove a fine rag layer of precipitate. The layers were separated and the aqueous layer was extracted with DCE (1×500 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated to yield crude product as a thick brown oil. The crude product was suspended in EtOAc (500 mL), warmed to 70° C., and cooled slowly to rt. The resultant slurry was filtered and the filtrate was concentrated to yield 1-{5-[4-(thiazolo[4,5-b]pyridin-2-yloxy)-benzyl]-2,5-diaza-bicyclo[2.2.1]hept-2-yl}-ethanone (67.2 g, 0.177 mol) as a brown glass. MS (ESI): mass calcd. for C20H20N4O2S, 380.13; m/z found, 381.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=4)[CH:16]=3)[O:11][C:10]([CH3:32])([CH3:31])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=4)[CH:16]=3)[O:11][C:10]([CH3:32])([CH3:31])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC(C)(C)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Oc3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a solution of ethyl 4-[[4-(4-methylphenyl)-2,2-dimethyl-(2H)chromen-6-yl]-ethynyl]-benzoate (Compound 266, 90.0 mg, 0.213 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was heated to 35° C., cooled to room temperature and stirred overnight. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before the solvent was removed under reduced pressure. The residual solid was recrystallized from CH3CN to give 70.0 mg (83%) the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.01 (2H, d, J=8.3 Hz), 7.57 (2H, d, J=8.3 Hz), 7.40 (1H, dd, J=2.1, 8.3 Hz), 7.30-7.20 (4H, m), 7.16 (1H, d, J=2.0 Hz), 6.90 (1H, d, J=8.3 Hz), 5.67 (1H, s), 2.38 (3H, s), 1.49 (6H, s).
Reaction SMILES: C[Mg]I.[CH2:4]([N:6]1[C:10]([C:11]2[CH:12]=[C:13]([C:17]([NH:20][S:21]([CH2:24][C:25]([F:28])([F:27])[F:26])(=[O:23])=[O:22])([CH3:19])[CH3:18])[CH:14]=[CH:15][CH:16]=2)=[CH:9][C:8]([CH:29]=[O:30])=[N:7]1)[CH3:5].[CH2:31]1COCC1>CCOCC>[CH2:4]([N:6]1[C:10]([C:11]2[CH:12]=[C:13]([C:17]([NH:20][S:21]([CH2:24][C:25]([F:26])([F:27])[F:28])(=[O:23])=[O:22])([CH3:19])[CH3:18])[CH:14]=[CH:15][CH:16]=2)=[CH:9][C:8]([CH:29]([OH:30])[CH3:31])=[N:7]1)[CH3:5]
Reactant: C1CCOC1
Reactant: CCn1nc(C=O)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Agent: C[Mg]I
Solvent: CCOCC
Product: CCn1nc(C(C)O)cc1-c1cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c1
Reaction time: 0.25 h
Yield: 58 %

Procedure:
A solution of MeMgI (1.47 mmol) in Et2O (3.0 M, 0.49 mL) was added dropwise over 2 min to a stirred mixture of the aldehyde from Step 1 and THF (10 mL) at 0° C. under N2. The reaction mixture was stirred for 15 min and then quenched by the addition of NH4Cl solution (15 mL). The organics were extracted into EtOAc (40 mL), concentrated under reduced pressure, and purified by column chromatography on silica, eluting with 80% EtOAc/iso-hexane to yield the alcohol (121 mg, 58%). 1H NMR (CDCl3, 400 MHz) δ 7.60-7.45 (3H, m), 7.35 (1H, d, J=7.6 Hz), 6.23 (1H, s), 5.08 (1H, s), 4.98 (1H, q, J=6.5 Hz), 4.15-4.07 (2H, m), 3.53-3.42 (2H, m), 1.82 (6H, s), 1.57 (3H, d, J=6.5 Hz), 1.39 (3H, t, J=7.2 Hz). MS (ES+) C18H24F3N3O3S requires: 419, found: 420 (M+H+, 100%).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10](=O)[CH2:11][CH3:12].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[CH2:10]([C:11]1([CH3:12])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)[CH3:9]
Reactant: CCC(C)=O
Reactant: Oc1ccccc1O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCC1(C)Oc2ccccc2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.5 %

Procedure:
To a stirred solution of 20.0 g (0.180 mole) of catechol and 0.8 g (0.40 mole) of 2-butanone in 200 ml of methylene chloride was added 128.0 g (0.902 mole) of phosphorus pentoxide. The reaction mixture was stirred at room temperature for two days. The stirring was stopped, and the reaction solids were allowed to settle. The reaction mixture was decanted into a separatory funnel. The solid material was washed with methylene chloride, and the wash was decanted into the above separatory funnel. The combined organic phase was washed with aqueous, saturated sodium bicarbonate solution. The washed organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield 17.3 g of 2-ethyl-2-methyl-1,3-benzodioxole.
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.[N+](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Br:1][CH2:2][CH:3]1[CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[CH:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=[N+]([O-])c1cccc(/C=C/CBr)c1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1C(CBr)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 66 h
Yield: 6.1 %

Procedure:
To a solution of 1-[(E)-3-bromo-1-propenyl]-3-nitrobenzene (Preparation 22, 820 mg, 3.23 mmol) in dichloromethane (3 ml) was added rhodium (II) acetate dimer (20 mg, 0.046 mmol). To the mixture was added dropwise at room temperature over 3 h a solution of ethyl diazoacetate (0.47 ml, 510 mg, 4.47 mmol) in dichloromethane (3 ml), then the mixture was stirred at room temperature for 66 h. The mixture was purified by silica (100 g) column chromatography eluting with hexane:dichloromethane 100:0 to 50:50. Product containing fractions were combined and concentrated in vacuo to afford the title compound as a colourless oil (65 mg, 7%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1.O>CN(C=O)C>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[CH:10][CH:11]=2)[N:6]([C:27]2[CH:28]=[C:23]([Cl:22])[N:24]=[CH:25][N:26]=2)[CH:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3c(Br)c[nH]c3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2ccc3c(Br)cn(-c4cc(Cl)ncn4)c3c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
Sodium hydride (60% in mineral oil, 114 mg, 2.84 mmol) was added to a mixture solution of 3-bromo-6-(3-nitrophenyl)-1H-indole (450 mg, 1.42 mmol) and 4,6-dichloropyrimidine (212 mg, 1.42 mmol) in anhydrous DMF (10 mL) at room temperature. After stirring at room temperature for 5 hours, followed by addition of ice, the mixture was added to icy water. After stirring at room temperature for 12 hours, the produced solid was filtered, washed with water, and then dried. The target compound (600 mg) was obtained as yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][F:29])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.Cl>C1COCC1.CO.O>[F:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([CH2:4][C:3]([OH:30])=[O:2])[CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OCCCCF)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(CN(CC(=O)O)S(=O)(=O)c2ccc(OCCCCF)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 1.04 g (2.37 mmol) of {[4-(4-fluorobutoxy)-benzenesulfonyl]-(4-methoxybenzyl)-amino}-acetic acid methyl ester in 15 ml of THF, 15 ml of MeOH and 7 ml of H2O, 0.24 g (5.7 mmol) of LiOH mono-hydrate is added in portions and the mixture is stirred for 30 min at 0–5° C. After stirring for additional 3.5 h, the reaction mixture is acidified with 1 N aqueous HCl and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to give ([4-(4-fluoro-butoxy)-benzenesulfonyl]-(4-methoxy-benzyl)-amino)-acetic acid; NMR (CDCl3): 1.86–1.96 (m, 4H), 3.79 (s, 3H), 3.90 (s, 2H), 4.08 (t, 2H, J=5.52 Hz), 4.38 (s, 2H), 4.48 (t, 1H, J=6.04 Hz), 4.55–4.65 (m, 1H), 6.84 (d, 2H, J=8.56 Hz), 6.98 (d, 2H, J=9.08 Hz), 7.14 (d, 2H, J=8.56 Hz), 7.81 (d, 2H, J=9.08 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Br:19][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)nc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CBr)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
Methyl 6-methylnicotinate (1.05 g, 10 mmol) was dissolved in ethyl acetate (50 ml), and NBS (3.56 g, 20 mmol) and AIBN (329 mg, 2 mmol) were added thereto. The reaction mixture was stirred at 80° C. for 3 hours, combined with an aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to give the title compound (682 mg, 28%) as an orange amorphous compound.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:21])[N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[C:10]([CH3:11])=[C:6]2[C:5]([CH3:22])=[N:4][N:3]=1.[NH2:23][NH2:24]>>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]([CH3:11])=[C:6]3[C:7]([C:2]([NH:23][NH2:24])=[N:3][N:4]=[C:5]3[CH3:22])=[C:8]2[CH3:21])=[CH:13][CH:14]=1)[CH3:20]
Reactant: CCOc1ccc(-n2c(C)c3c(C)nnc(Cl)c3c2C)cc1
Reactant: NN
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(NN)c3c2C)cc1

Procedure:
Utilizing the general procedure outlined in EXAMPLE 85, 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine and hydrazine (0.10 mL, 0.32 mmol) reacted to give 6-(4-ethoxyphenyl)-1-hydrazino-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine: 1H NMR (CDCl3, 500 MHz) δ 7.03-7.11 (m, 4H), 4.12 (q, 2H), 2.43 (s, 3H), 2.36 (s, 3H), 2.28 (s, 3H), 1.69 (s, 2H), 1.50 (t, 3H); MS (ESI) 312 (M+H)+.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.Cl[Si](C)(C)C.CCN(C(C)C)C(C)C.Cl[C:23]([O:25][CH:26](Cl)[CH:27](C)C)=[O:24].[C:31]1([CH2:37][C:38]([OH:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)(Cl)Cl>[C:31]1([CH2:37][C:38]([O:40][CH2:27][CH2:26][O:25][C:23]([NH:7][C:3]2([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]2)=[O:24])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: NC1(C(=O)O)CC1
Reactant: CC(C)C(Cl)OC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccccc1)OCCOC(=O)NC1(C(=O)O)CC1
Yield: 18.6 %

Procedure:
Following the general procedure for the one pot synthesis, ACPC (1.02 g, 9.8 mmol) was reacted with chlorotrimethylsilane (2.48 mL, 19.7 mmol) in anhydrous chloroform in the presence of DIEA (3.64 mL, 19.7 mmol). Subsequent reaction of the intermediate with 1-chloro-2-methylpropyl chloroformate (1.6 mL, 14.8 mmol) followed by a mixture of DIEA (3.64 mL, 19.7 mmol) and phenylacetic acid (2.6 g, 19.7 mmol) provided 0.560 g (14.4% yield) the title compound (20) as a yellow solid after aqueous work-up and mass-guided preparative HPLC purification. M.p: 142.1-145.6° C. 1H NMR (CDCl3, 400 MHz): δ=7.33 (m, 5H), 6.81 (q, 1H), 5.31 (s, 1H), 3.61 (s, 2H), 1.63 (m, 2H), 1.47 (d, 3H), 1.28 (m, 2H). MS (ESI) m/z 330.08 (M+Na)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CCC1.[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>>[CH:2]1([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:43][CH2:44][C:45]4[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:7][CH2:6][CH2:5]1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(CC3CCC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CCC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 32 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclobutylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 32% yield: mp 136-137° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) 8.53-8.41 (m, 2H), 7.63-7.61 (m, 1H), 7.20-7.16 (m, 1H), 6.51-6.17 (m, 1H), 4.60-4.46 (m, 2H), 4.08-3.93 (m, 2H), 3.53-3.41 (m, 2H), 3.39-3.20 (m, 2H), 2.60-2.45 (m, 4H), 2.03-1.98 (m, 2H), 1.88-1.79 (in 2H), 1.74-1.65 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.5, 153.5, 149.2, 148.7, 135.5, 134.0, 123.5, 116.7, 49.3, 42.5, 42.0, 41.3, 33.7, 26.2, 18.3, 17.2; MS (ES+) m/z 386.3 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH:10]O.C(Cl)(Cl)Cl.O>CC(O)=O>[CH:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: OO
Reactant: CC(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1cc[n+]([O-])cc1

Procedure:
A solution of 4-isopropylpyridine and 1.5 mL of 30% H2O2 in 7 mL of AcOH was heated at 135° C. A total of 15.4 mL of H2O2 was added in 4 portions, and the solution was refluxed for 2 h. Chloroform and water were added, the layers were separated, and the aqueous layer was extracted 3 times with CHCl3. The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% MeOH/CHCl3) provided 139 mg of the 4-isopropylpyridine N-oxide as an orange oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[N:3]1.Br[C:12]1[CH:13]=[C:14]([CH:30]=[CH:31][CH:32]=1)[O:15][CH2:16][CH:17]([OH:29])[CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>O1CCOCC1.O>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH2:28][N:19]1[CH2:18][CH:17]([OH:29])[CH2:16][O:15][C:14]1[CH:30]=[CH:31][CH:32]=[C:12]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:6]=3[CH2:7]2)[CH:13]=1
Reactant: OC(COc1cccc(Br)c1)CN1CCc2ccccc2C1
Reactant: Cn1ncc2c1CNCC2
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1ncc2c1CN(c1cccc(OCC(O)CN3CCc4ccccc4C3)c1)CC2
Temperature: 100 °C
Reaction time: 16 h
Yield: 18.5 %

Procedure:
To a stirred mixture of 1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (30 mg, 0.219 mmol) in dioxane:H2O (6 mL, 2:1) was added 1-(3-bromophenoxy)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (119 mg, 0.328 mmol), Cs2CO3 (213 mg, 0.657 mmol) and then Ruphos (2 mg) and Pd(Ruphos) (5 mg). The mixture was degassed by N2 4 times and stirred at 100° C. for 16 hours. The reaction mixture was then quenched with water (20 mL), extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated to yield a residue which was purified by prep-HPLC to afford 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(1-methyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)phenoxy)propan-2-ol (17 mg, Yield 18.6%). 1H NMR (400 MHz, MeOD) δ=7.32 (s, 1H), 7.19-7.08 (m, 4H), 7.04 (d, J=5.8 Hz, 1H), 6.70-6.61 (m, 2H), 6.50-6.43 (m, 1H), 4.29-4.22 (m, 1H), 4.20 (s, 2H), 4.09-4.01 (m, 1H), 4.01-3.92 (m, 1H), 3.76 (s, 2H), 3.73 (s, 3H), 3.61 (t, J=5.8 Hz, 2H), 2.98-2.84 (m, 4H), 2.82-2.67 (m, 4H). LCMS (m/z): 419.2 (M+1).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][C:9](=[O:11])[O:8][C:7](=O)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH2:14][OH:15]>N1C=CC=CC=1>[OH:15][N:14]1[C:9](=[O:11])[CH2:10][C:5]2([CH2:4][CH2:3][CH2:2][CH2:1]2)[CH2:6][C:7]1=[O:8]
Reactant: O=C1CC2(CCCC2)CC(=O)O1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CC2(CCCC2)CC(=O)N1O

Procedure:
A solution of 8-oxaspiro[4.5]decan-7,9-dione (5.0 g) and hydroxylamine hydrochloride (2.1 g) in 75 ml of anhydrous pyridine was heated to 80° C. with stirring under N2.
Reaction SMILES: [CH2:1]=[O:2].[CH:3]1([CH:9]=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[OH-].[Na+]>CO>[CH:9]([C:3]1([CH2:1][OH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:10]
Reactant: C=O
Reactant: O=CC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=CC1(CO)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
Methanol is added to a suspension of 37% formaldehyde solution (69 ml.) and cyclohexanecarboxaldehyde (100 g.; 0.89 mole) to afford a homogeneous solution. The mixture is cooled to 0° C. and a sodium hydroxide solution (1N; 67 ml.) is added with stirring over the course of 15 minutes. The mixture is allowed to warm to room temperature and is stirred at 25° C. overnight. The solution is then concentrated, diluted with water and extracted with ether. The ether extract is dried, evaporated in vacuo and the residual colorless liquid is distilled to afford 51% of 1-formyl-1-hydroxymethylcyclohexane (65 g.) , b.p. 120°-125° C./0.90 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:17]=[O:18].[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O1CCCC1.Cl.O>O1CCCC1>[CH:19]1([CH:17]([C:3]2[S:4][C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=3)=[CH:6][C:2]=2[CH3:1])[OH:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: Br[Mg]C1CCCCC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a solution of 3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde (0.8 g) in tetrahydrofuran (20 mL) was added dropwise 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (5 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 30 min. The reaction mixture was treated with 1N hydrochloric acid and poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (0.5 g, 51%) as a yellow crystal.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.C(O)(=O)C>O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: Brc1cccs1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(-c2cccs2)cc1
Temperature: 2 °C
Reaction time: 1.5 h

Procedure:
2-Bromothiophene (130.4 g, 0.8 mol) was dissolved in 2-Me-THF (240 ml, 0.3 L/mole) and the resulting mixture cooled to 2° C. NiCl2(dppe) (2.11 g, 4.0 mmol) was added followed by addition, over about 40 min. at ≦30° C., of the 4-fluoro-phenylmagnesium bromide solution prepared as in STEP A above to yield a dark red solution. The solution was then stirred at 22° C. for 1.5 hrs. A solution of acetic acid (91.7 ml, 1.6 mol) in water (240 ml, 0.3 L/mol) was then added and the resulting mixture stirred strongly for 15 min. The resulting layers were separated, the organic layer was washed with water (80 ml, 0.1 L/mol), then concentrated in vacuo at 75° C. to yield 2-(4-fluorophenyl)thiophene as a brown oil.