Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2].[H-].[Na+].[CH3:23][N:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]=[C:25]1S(C)(=O)=O.O>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:25]3[N:24]([CH3:23])[C:28]4=[N:29][CH:30]=[CH:31][CH:32]=[C:27]4[N:26]=3)=[CH:15][CH:14]=2)[C:4]1=[O:20])[CH3:2]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a stirred solution of 1-ethyl-6-fluoro-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) in DMF (4 mL) was added 60% sodium hydride (13.2 mg) at room temperature. The mixture was stirred at room temperature for 30 min, and then 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (85 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on NH-silica gel eluting with AcOEt/Hexane. Crystallization from AcOEt/Hexane gave the title compound (96 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[S:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>CCOC(C)=O>[Cl:11][C:4]1[CH:5]=[C:6]([NH2:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[S:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a 0.1M solution 2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-napthalene (89) (774 mg, 2.2 mmol), in EtOAc was added tin(II) chloride dihydrate, obtained from Aldrich, (2.49 g, 11.05 mmol). The resulting mixture was refluxed for 2 hour. The crude reaction mixture was cooled to ambient temperature and excess 2M aqueous NaOH was added and allowed to stir for 15 minutes. Solid tin salts precipitated from the solution, were filtered off through a pad of celite and washed with EtOAc (200 mL). The organic layer was washed twice with brine (200 mL), dried over Na2SO4, and concentrated under vacuum to yield 592 mg (84%) of (90) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([N:34]5C(=O)C6=CC(C)=CC=C6C5=O)[CH2:29]4)=[N:18][C:17]=3[N:16]([CH3:46])[C:14]2=[O:15])[N:3]=1.C(CN)O>C1(C)C=CC=CC=1>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:28]2[CH2:29][C@H:30]([NH2:34])[CH2:31][CH2:32][CH2:33]2)=[N:18][C:17]2[N:16]([CH3:46])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]
Reactant: CC#CCn1c(N2CCC[C@@H](N3C(=O)c4ccc(C)cc4C3=O)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Solvent: Cc1ccccc1
Solvent: NCCO
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 92.5 °C

Procedure:
In a clean round bottom flask, 10 gm of 1-[(4-Methylquinazolin-2yl)methyl]-3-methyl-7-(2-butin-1yl)-8-(3(R)-4-methylphthalimidopiperidine-yl) xanthine and 100 ml of toluene were charged. 10 ml of ethanolamine was added to the reaction mass and heated to 90-95° C. to complete the reaction. The reaction mass was cooled to 80° C. and the layers were separated. The organic phase was distilled under vacuum to get crude linagliptin. Dry wt: 7.50 gm HPLC purity: 97.95% Impurity X: 0.69%
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:26]([NH2:29])[C:27]#[CH:28]>>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][NH:29][CH2:26][C:27]#[CH:28])=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CSc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Reactant: C#CCN
Product: C#CCNCc1cc(-c2ccc(SC)cc2)nn(CC(C)C)c1=O
Yield: 52.2 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and propargylamine were reacted to yield the title compound as a yellow oil (yield: 52.2%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:26][CH3:27])[C:10]([N:12]1[C:20]2[C:15](=[C:16]([Cl:22])[C:17]([Cl:21])=[CH:18][CH:19]=2)[CH2:14][CH:13]1[C:23]([OH:25])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([NH:32][C:23]([CH:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])[N:12]1[C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:26][CH3:27])=[O:25])[CH2:29][CH2:30][CH3:31]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(Cl)c(Cl)c2CC1C(=O)O
Reactant: CCCCN
Product: CCCCNC(=O)C1Cc2c(ccc(Cl)c2Cl)N1C(=O)[C@H](CC)NC(=O)OC(C)(C)C

Procedure:
This compound was prepared from 1-(N-t-butoxycarbonyl-2-(S)-aminobutyryl)-4,5-dichloroindoline-2-(R/S)-carboxylic acid as described in Example 1, using butylamine instead of trifluoroethylamine hydrochloride.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:19]1([C:22]2[N:33]=[C:25]3[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[C:29](I)[N:24]3[N:23]=2)[CH2:21][CH2:20]1>[Cu](I)I.CC(O)C>[CH:19]1([C:22]2[N:33]=[C:25]3[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[C:29]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[N:24]3[N:23]=2)[CH2:21][CH2:20]1
Reactant: C1CCNCC1
Reactant: COc1ccc(I)n2nc(C3CC3)nc12
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: COc1ccc(N2CCCCC2)n2nc(C3CC3)nc12
Temperature: 80 °C

Procedure:
Copper iodide (1.0 mg, 0.005 mmol) and potassium phosphate (42.5 mg, 0.200 mmol), kept under argon, was added 2-propanol (200 μL), ethylene glycol (12.4 mg, 0.200 mmol), piperidine (10.1 mg, 0.12 mmol) and 2-cyclopropyl-5-iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (31.5 mg, 0.100 mmol). The resulting suspension was heated to 80° C. for 4 days. The mixture was allowed to reach room temperature before it was extracted with dichloromethane (3 mL). The organic phase was washed with brine, dried (Na2SO4) and filtered before it was concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 20% EtOAc in toluene to 40% EtOAc in toluene) to give 2-cyclopropyl-8-methoxy-5-piperidin-1-yl-[1,2,4]triazolo[1,5-a]pyridine (2.2 mg.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:21]>C1COCC1.C(OCC)(=O)C>[F:20][C:19]1[C:14]2[NH:13][C:1](=[O:2])[O:21][C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(O)cccc1F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2c(F)cccc2o1
Temperature: 60 °C

Procedure:
1,1′-Carbonyldiimidazole (11.4 g, 0.0703 mol) is added portionwise to a solution of 2-amino-3-fluorophenol (Step 3, 8.94 g, 0.0703 mol) in THF (200 ml) and warmed at 60° C. for 2 h. The reaction mixture is diluted with ethyl acetate (200 ml), washed with 2N HCl and saline, dried (MgSO4), and evaporated to give product as a white solid suitable for use in the next step (10.6 g, 99%); mp 131–3° C.
Reaction SMILES: [CH:1]([CH:4]1[C:8]2=[N:9][C:10]3[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]([OH:17])=[C:7]2[C:6](=[N:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[O:5]1)([CH3:3])[CH3:2].O.[C:29]([OH:32])(=[O:31])[CH3:30]>>[C:29]([O:32][CH:4]([C:8]1[C:7]([C:6]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:5])=[C:16]([OH:17])[C:15]2[C:10](=[C:11]([C:18]([F:19])([F:20])[F:21])[CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH:1]([CH3:3])[CH3:2])(=[O:31])[CH3:30]
Reactant: CC(C)C1OC(=Nc2nccs2)c2c1nc1c(C(F)(F)F)cccc1c2O
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)OC(c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1)C(C)C

Procedure:
10 g of product of Step B in 200 ml of acetic acid were refluxed for 57 hours and the solution was allowed to return to ambient temperature. Then, 200 ml of water were added followed by filtration. The orange product was washed with water and then was dissolved in a mixture of 250 ml of ethyl acetate and 500 ml of tetrahydrofuran. The mixture was dried and 1 g of active carbon was added. After filtering and concentrating to dryness under reduced pressure, 8.3 g of residue were obtained which was crystallized from 240 ml of ethyl acetate. The crystals were filtered hot, cooled, separated, dried under reduced pressure at 40° C. for 16 hours. 5.3 g of expected product were obtained, melting at 242° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][N:46]([CH3:55])[C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH2:52])=[CH:49][CH:48]=1>CN(C=O)C>[CH3:45][N:46]([CH3:55])[C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH:52][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])=[CH:49][CH:48]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CN(C)c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(N(C)C)cc4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 4-dimethylaminobenzylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(4-dimethylaminobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 2.98 min, MH+ 427.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[OH:12])=[O:2].S(Cl)(Cl)=O.[CH3:17]O>>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:17])=[O:8])=[CH:5][C:4]=1[OH:12])=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C=O)c(O)c1
Yield: 85 %

Procedure:
4-Formyl-3-hydroxybenzoic acid (5 g, 30 mmol) was suspended in methanol (70 mL), and treated with thionyl chloride (3.29 mL 45 mmol) dropwise. The mixture was heated to reflux overnight. Concentrated to dryness, and 50 mL of toluene was added, and concentrated again. The residue was recrystallized from ethyl acetate-hexane. A total of 4.8 g (85%) of methyl 4-formyl-3-hydroxybenzoate was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@@H:13]3[C@@H:11]([CH2:12]3)[C@H:10]2[CH2:15][OH:16])=[O:8])[N:6]=1.[H-].[Na+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>C1COCC1>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][O:16][CH2:15][C@H:10]2[N:9]([C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][C:4]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:8])[CH2:14][C@@H:13]3[C@H:11]2[CH2:12]3)=[CH:28][CH:27]=1
Reactant: Cc1nc(C(=O)N2C[C@H]3C[C@H]3[C@H]2CO)c(-c2ccccc2)s1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2C[C@H]3C[C@H]3[C@H]2COCc2ccc(F)cc2)c(-c2ccccc2)s1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of {(1R,2S,5S)-3-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]-3-azabicyclo[3.1.0]hex-2-yl}methanol (0.025 g, 0.080 mmol) in THF (0.50 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.008 g, 0.206 mmol) followed by 4-fluorobenzylbromide (0.039 g, 0.206 mmol) and the system was stirred at 0° C. for 3 h. The mixture was then quenched with ice, extracted with EtOAc, purified using reverse phase conditions (5%→85% 0.1% TFA in water: 0.1% TFA in acetonitrile) followed by free basing with saturated sodium carbonate to afford the title compound as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.43-7.42 (m, 2H), 7.36-7.33 (m, 4H), 7.08-7.02 (m, 3H), 4.64 (m, 1H), 4.52 (m, 1H), 4.43 (m, 2H), 3.42 (m, 1H), 3.29 (m, 1H), 3.14 (m, 1H), 2.71 (s, 3H), 1.84 (m, 1H), 1.60 (m, 1H), 1.43 (m, 1H), 0.560 (m, 1H). HRMS [M+H] C24H23F1N2O2S1 calc'd 423.1537, found 423.1542.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][NH2:9].[CH3:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH:17]=[CH:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([NH:28][C:29]4[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=4[C:31](O)=[O:32])=[CH:25][CH:26]=3)[N:21]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[N:20]=2)[CH:12]=1>C(Cl)Cl>[CH3:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][NH:9][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[NH:28][C:24]1[CH:23]=[C:22]2[C:27]([C:19]([CH:18]=[CH:17][C:13]3[CH:12]=[C:11]([CH3:10])[CH:16]=[CH:15][N:14]=3)=[N:20][N:21]2[CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[CH:26][CH:25]=1
Reactant: Cn1ccnc1CN
Reactant: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)NCc4nccn4C)ccc23)c1

Procedure:
Prepared in a similar manner to that described for Example 6 above except using C-(1-Methyl-1H-imidazol-2-yl)-methylamine hydrochloride and 2-[3-[2-(4-Methyl-pyridin-2-yl) -vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid. 1H NMR (DMSO-d6) δ 9.83 (1H, s 9.03 (1H, t, J=5.5 Hz), 8.45 (1H, d, J=4.7 Hz), 8.09 (1H, d, J=8.5 Hz), 7.85 (1H, d , J=16.5 Hz), 8.67 (1H, d , J=7.3 Hz), 7.53–7.39 (4H, m), 7.11 (3H, m), 6.90 (1H, d, J=6.9 Hz), 6.86 (1H, s), 5.79 (1H, d , J=8.9 Hz), 5.75 (1H, s), 4.54 (1H, d , J=5.5 Hz), 3.85–3.70 (2H, m), 3.66 (3H, s), 2.35 (3H, s), 2.10 (2H, m), 1.70 (2H, m), 1.60 (3H, m). Anal. Calcd for C32H33N7O2.0.8 CH2Cl2: C, 63.99; H, 5.672; N, 15.93. Found: C, 63.95; H, 5.72; N, 16.01.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3([CH3:24])[CH2:23][CH2:22]3)=[O:20])[CH2:15][CH2:14]2)=[N:4][CH:3]=1.C1COCC1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=[C:39]([C:41]2([CH3:44])[CH2:43][CH2:42]2)[CH:40]=1>>[CH3:24][C:21]1([C:19]([N:16]2[CH2:17][CH2:18][CH:13]([O:12][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2]([NH:1][C:34]([NH:35][C:36]4[N:37]([C:45]5[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=5)[N:38]=[C:39]([C:41]5([CH3:44])[CH2:42][CH2:43]5)[CH:40]=4)=[O:33])=[CH:3][N:4]=3)[CH2:14][CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: CC1(C(=O)N2CCC(Oc3ncc(N)c4ccccc34)CC2)CC1
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)C4(C)CC4)CC3)c3ccccc23)cc1
Temperature: 46.5 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
Add [4-(4-Amino-isoquinolin-1-yloxy)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone (Preparation 23, 331.00 g, 1.02 moles), THF (3.97 L, 48.79 moles), [5-(1-Methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Preparation 18, 410.00 g, 1.02 moles), and DIPE (159.00 g, 1.22 moles) to a 12 L Morton flask equipped with overhead stirrer, thermocouple, and reflux condenser. Reflux the mixture for 22 hours. Cool reaction to <50° C. and treat with carbon (Darco G-60; 33.00 g, 2.75 moles). Stir the slurry for 30 minutes at 43-50° C., then filter over micro fiber paper and Hyflo Super Cel® (27.00 g). Seed the filtrate and allow to cool at ambient temperature during precipitation. Pack the resulting slurry in ice and stir overnight. Filter the solids, wash with THF (300.00 mL, 3.69 moles), and dry under reduced pressure at 40° C. Subject residue to silica gel chromatography eluting with 1:3 acetone/DCM, then 30% acetone in DCM to obtain 401 g (68%) 1-{1-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yloxy]-isoquinolin-4-yl}-3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-urea as a white solid 1H NMR (300 MHz, DMSO-d6): δ 0.56 (t, J=6.0 Hz, 2H), 0.73 (t, J=6.0 Hz, 2H), 0.84 (t, J=6.0 Hz, 2H), 0.92 (t, J=6.0 Hz, 2H), 1.27 (s, 3H), 1.41 (s, 3H), 1.73-1.81 (m, 2H), 1.99-2.08 (m, 2H), 2.41 (s, 3H), 3.52-3.65 (m, 2H), 3.83-3.96 (m, 2H), 5.47-5.58 (m, 1H), 6.22 (s, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.65-7.71 (m, 1H), 7.78-7.83 (m, 2H), 8.12 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.58 (s, 1H), 8.69 (s, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[S:28][CH2:29][CH2:30]O)([CH3:21])[CH3:20])[C:13]3=[O:32])[C:9]([CH3:33])=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1.[CH2:36]([N:38](CC)CC)C.CS(Cl)(=O)=O.CN>C(Cl)Cl.C(O)C>[CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH3:20])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[S:28][CH2:29][CH2:30][NH:38][CH3:36])[CH3:21])[C:13]3=[O:32])[C:9]([CH3:33])=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2SCCO)c1=O
Reactant: CCN(CC)CC
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: CCO
Solvent: ClCCl
Product: CNCCSc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)cc(F)c2C)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Cyclopropyl-3-fluoro-5-{3-[(1-{2-[(2-hydroxyethyl)sulfanyl]phenyl}-1-methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide (Example 320g, 0.15 g) was stirred in DCM (20 mL) and cooled to −40° C. before triethylamine (0.046 mL) and methanesulfonyl chloride (0.024 mL) were added. The reaction was warmed to room temperature and methylamine (40% in water) and ethanol (5 mL) were added. The reaction was then stirred for 18 h at 100° C. The reaction was concentrated in vacuo, then purified on SCX resin eluting with methanol (discarded) and flushing with 20% ammonia in methanol. The crude product was purified by preparative HPLC (Phenomenex Gemini column, eluent: 95-5% gradient of aqueous 0.2% aqueous ammonia in acetonitrile). The fractions containing the desired compound were evaporated to dryness to afford the title compound as a solid (3 mg).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:32]=4)=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: COc1cccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)c1
Yield: 71.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 3-methoxyphenylboronic acid (available from Combi-Blocks Inc.; 61 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-3′-methoxy-biphenyl-2-carboxylic acid (65 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 13.15 (br s, 1H), 8.46 (s, 1H), 8.28-8.39 (m, 2H), 8.20 (d, J=7.8 Hz, 1H), 8.09 (dd, J=8.5, 1.8 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 6.86-7.06 (m, 3H), 3.80 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][O:10]C.[N+:12]([C:15]1[O:21][C:18]([CH2:19]O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C1C=CC=CC=1.C(OCC)C.FB(F)F>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:19][C:18]1[O:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[CH:9]=[O:10]
Reactant: COC=Cc1ccccc1Cl
Reactant: O=[N+]([O-])c1ccc(CO)o1
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=CC(=Cc1ccc([N+](=O)[O-])o1)c1ccccc1Cl
Reaction time: 1 h

Procedure:
4.0 g of 1-(2-chlorophenyl)-2-methoxyethylene are added dropwise within 20 minutes to 9.55 g of 5-nitrofurfurol in 12 cc of dry benzene at room temperature after the addition of one drop of diethyl ether/trifluoroborane. The mixture is stirred at 35°-40° for 1 hour and is then successively washed with a 5% aqueous sodium acetate solution and water, the benzene solution is dried over magnesium sulphate and concentrated by evaporation. The residue is taken up in 3 cc of concentrated hydrochloric acid, 17 cc of water and 120 cc of glacial acetic acid, and the mixture is stirred at 80°-85° for 3 hours. The mixture is concentrated in a vacuum, and, after cooling, the title compound is obtained as yellow crystals having a M.P. of 148°-151°.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].C([Li])CCC.CN(C)CCN(C)C.[C:25]([C:29]1[CH:53]=[C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:32]2[O:33][P:34](Cl)[O:35][C:36]3[C:42]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:41][C:40]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:39][C:37]=3[CH2:38][C:31]=2[CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>CCCCCC.O1CCCC1>[C:25]([C:29]1[CH:53]=[C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:32]2[O:33][P:34]([C-:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)[O:35][C:36]3[C:42]([C:43]([CH3:45])([CH3:44])[CH3:46])=[CH:41][C:40]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:39][C:37]=3[CH2:38][C:31]=2[CH:30]=1)([CH3:28])([CH3:27])[CH3:26].[C-:6]1([P:34]2[O:35][C:36]3[C:42]([C:43]([CH3:44])([CH3:45])[CH3:46])=[CH:41][C:40]([C:47]([CH3:50])([CH3:48])[CH3:49])=[CH:39][C:37]=3[CH2:38][C:31]3[CH:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:53]=[C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:32]=3[O:33]2)[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: c1cc[cH-]c1
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(Cl)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Agent: [Fe+2]
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP([c-]1cccc1)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Yield: 58.5 %

Procedure:
The general procedure of Example 1 is followed using 3.5 g (18.8 mmol) of ferrocene in 30 mL of hexane, 25 mL of a 1.6M hexane solution of n-butyl lithium, 4.5 g (38.7 mmol) of N,N,N',N'-tetramethylethylenediamine and 20 g (41 mmol) of 2,4,8,10-tetrakis(tert-butyl)-6-chloro-12H-dibenzo[d,g][1,3,2]dioxaphosphocin in 100 mL of tetrahydrofuran. The residue is triturated with hexane and the resultant solid is recrystallized from an acetonitrile/tetrahydrofuran mixture to give 12 g (58.5% yield) of a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[Br:20]Br>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[Br:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene (27.0 g, 100 mmol)in 1.10 L of chloroform at 60° C. was added bromine (15.98 g, 100 mmol) dropwise dissolved in 200 mL of chloroform. After the addition was complete, the reaction was cooled to room temperature, and the solvent removed in vacuo to provide 34.2 g (100%) of 2-(4-methoxyphenyl)-3-bromo-6-methoxybenzo[b]thiophene as a white solid. mp 83-85° C. 1H NMR (DMSO-d6) δ7.70-7.62 (m, 4H), 7.17 (dd, J=8.6, 2.0 Hz, 1H), 7.09 (d, J=8.4 Hz, 2H). FD mass spec: 349, 350. Anal. Calcd. for C16H13BrO2S: C, 55.03; H, 3.75. Found: C, 54.79; H, 3.76.