Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1.Br[C:16]1[N:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:18][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COCCSc1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COCCSc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)cc1
Yield: 61.1 %

Procedure:
1-Methylethyl 4-({[6-(4-{[2-(methoxy)ethyl]thio}phenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate (0.19 g, 61%) was prepared as a light yellow solid from (4-{[2-(methoxy)ethyl]thio}phenyl)boronic acid (0.23 g, 75% pure, 0.80 mmol), 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (from Step 1, 0.25 g, 0.70 mmol), 2M Na2CO3 (2 mL) and PdCl2(PPh3)2 (50 mg, 0.07 mmol) in DME (3 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, CDCl3): δ 8.34 (d, 1H, J=2.7 Hz), 7.86 (d, 2H, J=8.3 Hz), 7.64 (d, 1H, J=8.7 Hz), 7.42 (d, 2H, J=8.3 Hz), 7.30-7.25 (m, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.23 (bs, 2H), 3.89 (d, 2H, J=6.3 Hz), 3.59 (t, 2H, J=6.7 Hz), 3.37 (s, 3H), 3.15 (t, 2H, J=6.8 Hz), 2.95-2.80 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 445 (M+H).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([OH:12])=[C:8]([N+:13]([O-])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].CO>[NH2:13][C:8]1[CH:7]=[N:6][N:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:10](=[O:11])[C:9]=1[OH:12]
Reactant: CC(C)(C)n1ncc([N+](=O)[O-])c(O)c1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)n1ncc(N)c(O)c1=O
Reaction time: 8 h
Yield: 96.6 %

Procedure:
Into 40 ml of an absolute methanol solution of 5.3 g of 2-tert-butyl-4-hydroxy-5-nitropyridazin-3-(2H)-one, 0.5 g of palladium-carbon (containing 5% of Pd) was added in a few times at room temperature with stirring. Then, catalytic reduction was carried out overnight under hydrogen gas pressure. After completion of the reaction, the palladium-carbon was separated by filtration with celite and washed a few times with absolute methanol. The methanol was combined with the filtrate, followed by distillation under reduced pressure to obtain 4.4 g of powdery 5-amino-2-tert-butyl-4-hydroxypyridazin-3-(2H)-one.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@H:24]([C:27](=[O:32])N(OC)C)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].O>C1COCC1>[CH2:9]([O:8][P:7]([CH2:6][C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:23]1)=[O:32])([O:11][CH2:12][CH3:13])=[O:14])[CH3:10]
Reactant: CON(C)C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: CCOP(C)(=O)OCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)C1CCN(C(=O)OC(C)(C)C)C1)OCC
Yield: 46.5 %

Procedure:
Add butyl lithium (98.0 mL, 157 mmol) dropwise to a solution of diethyl methylphosphonate (23.6 g, 155 mmol) in THF (194 mL) under nitrogen at −78° C. over 15 minutes. Add (S)-3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert butyl ester (5.0 g, 19.4 mmol) in THF and stir at −78° C. for about 3.5 hrs. Pour into water and extract with ethyl acetate (3×). Wash the combined organics with water and brine. Dry (MgSO4), filter, and concentrate. Subject the residue to silica gel chromatography, eluting with 0-50% acetone in chloroform followed by another silica gel chromatography eluting with 0-30% acetone in dichloromethane to afford 3.15 g (47%) of the desired compound. MS (m/z)=294.0 (M−55)
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](I)=[N:11][CH:10]=1.[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[N:11][CH:10]=1)=[O:23]
Reactant: Cc1ccccc1-c1cc(I)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccccc1-c1cc(-c2ccncc2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 60 h
Yield: 65.5 %

Procedure:
A mixture of 100 mg (0.173 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-iodo-N-methyl-4-o-tolyl-nicotinamide, 21 mg (0.17 mmol) 4-pyridylboronic acid, 5 ml dimethoxyethane and 5 ml of a 2 M aqueous solution of sodium carbonate was deoxygenated by three freeze-thaw cycles. After addition of 20 mg (0.017 mmol) tetrakis(triphenylphosphine)palladium(0) the reaction mixture was stirred at 90° C. for 60 h. Cooling to room temperature was followed by dilution with water and extraction with 3 portions of ethyl acetate. The organic extract was washed with water, dried with magnesium sulfate and concentrated. Column chromatography afforded 59 mg (64%) of the title compound as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:20]1([C:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:4]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[N:1][N:2]=[N:3]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CCCCCc1nnn[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCCCCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
A solution of 1H-tetrazole-5-pentanenitrile (30 g, 198 mmol) in a mixture of methylene chloride (200 mL) and triethylamine (30 mL, 218 mmol) was stirred as trityl chloride (61 g, 218 mmol) was added. After 16 h, the reaction was treated with an aqueous solution of sodium bicarbonate and extracted with methylene chloride. The combined organic layers were dried and concentrated. The residue was dissolved in ether and hexane was added. The resulting solid was isolated by filtration to give 1-(triphenylmethyl)-1H-tetrazole-5-pentanenitrile as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:33]=[C:34]([CH2:36][CH2:37][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:35]=3)[C:10]([C:13]3[CH:32]=[CH:31][C:16]([C:17]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([O:26]C(C)(C)C)=[O:25])=[O:18])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49].C(Cl)Cl>>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([CH:33]=[C:34]([CH2:36][CH2:37][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:35]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([OH:26])=[O:25])=[O:18])=[CH:31][CH:32]=3)=[CH:11][N:12]=2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H]1CCCN1C(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1
Yield: 30 %

Procedure:
A solution of compound 17b (350 mg, 0.550 mmol) in TFA/DCM (10 mL, 1:4 v/v) was stirred at rt for 3 h. Solvent was evaporated and Et2O (30 mL) was added. The resulting solids were collected by filtration and washed with Et2O to obtain the title compound 35 as a yellow solid (142 mg, 30% yield). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (d, J=8.8 Hz, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.16-8.09 (m, 2H), 8.02 (d, J=8.8 Hz, 1H), 7.94-7.90 (m, 1H), 7.80 (s, 1H), 7.72-7.53 (m, 4H), 7.38-7.34 (m, 1H), 4.44-4.35 (m, 1H), 3.81-3.73 (m, 4H), 3.61-3.50 (m, 4H), 3.45-3.31 (m, 6H), 2.43-2.28 (m, 1H), 1.90-1.78 (s, 3H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C33H32N6O4: 577.2 (M+H). Found 577.1.
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(N(CC)CC)C.[CH3:16][C:17]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([O:20][C:21]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:22])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCCC(=O)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCCCC(=O)O
Yield: 52.7 %

Procedure:
Prepared as described for L3 from stirring 5-aminopentanoic acid (3.40 g, 29.1 mmol) in 50% aqueous dioxane with triethylamine (6.0 mL, 43.1 mmol) and BOC-ON (7.91 g, 32.1 mmol) to yield a cream solid (3.10 g, 48.8%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25](B(O)O)[CH:26]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:30][CH3:31])=[C:23]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)[CH:22]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: COc1ccc(F)cc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Example 11 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and (5-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: Sc1ccccn1
Reactant: CC(=O)Nc1ncc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccccn2)s1
Temperature: 130 °C
Yield: 75.6 %

Procedure:
A mixture of 2-acetylamino-5-chlorothiazole (5.3 g), 2-mercaptopyridine (3.5 g) and potassium carbonate (6.2 g) in N,N-dimethylformamide (50 ml) was heated at 130° C. for 3.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(2-pyridylthio)thiazole (5.70 g, yield: 76.0%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH3:40])[C:18]3[N:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[C:20]([CH3:39])[CH:19]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH3:40])[C:18]3[CH:19]=[C:20]([CH3:39])[C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[CH:22][N:23]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N(C)C(=O)c2ccc(Oc3ccc(F)cc3)nc2)ncc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N(C)C(=O)c2ccc(Oc3ccc(F)cc3)nc2)ncc1CN1CCN[C@@H](C)C1
Temperature: 25 °C
Yield: 71 %

Procedure:
1,1-Dimethylethyl (2S)-4-({6-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]-4-methyl-3-pyridinyl}methyl)-2-methyl-1-piperazinecarboxylate (D118) (26 mg, 0.047 mmol) was dissolved in dry DCM (4 mL). TFA (1 mL) was added and the reaction mixture was stirred at room temperature, under argon. The reaction mixture was concentrated, re-dissolved in methanol (2 mL) and loaded on to a 1 g SCX cartridge. Elution with methanol (20 mL) followed by 2M NH3 in methanol (20 mL) gave a colourless oil. The product was further purified by MDAP. The resulting oil was dissolved in methanol (1 mL) and loaded on to a 1 g SCX cartridge and eluted with methanol (20 mL), followed by 2M NH3 in methanol (20 mL) to give the title compound as a colourless oil (15 mg). MS (ES): MH+ 450.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([CH3:21])[N:17]=[C:18]([CH:19]=[O:20])[C:13]=3[CH2:12][CH2:11][C:10]2=[O:22])=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([CH3:21])[N:17]=[C:18]([CH2:19][OH:20])[C:13]=3[CH2:12][CH2:11][C:10]2=[O:22])=[CH:4][CH:3]=1
Reactant: Cc1nc(C=O)c2c(n1)N(Cc1ccc(Br)cc1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1nc(CO)c2c(n1)N(Cc1ccc(Br)cc1)C(=O)CC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 122.2 %

Procedure:
To a solution of 8-[(4-bromophenyl)methyl]-2-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-4-carbaldehyde (550 mg, 1.53 mmol) in tetrahydrofuran (5 mL) and isopropanol (2 mL) was added sodium borohydride (116 mg, 3.05 mmol). After 45 min, the mixture was cooled to 0° C. and CO2 was bubbled in for 5 min. The mixture was filtered and the filtrate was concentrated to give 677 mg of a yellow foam. Purification by flash chromatography (5% MeOH/CH2Cl2) gave 496 mg (90%) of product as an off-white solid, mp 159°-160° C.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].[CH3:13][N:14]1CCNC[CH2:15]1>CN(C)P(N(C)C)(N(C)C)=O>[CH3:13][N:14]([CH3:15])[C:5]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[S:1](=[O:3])(=[O:2])[N:4]=1
Reactant: CN1CCNCC1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN(C)C1=NS(=O)(=O)c2ccccc21
Reaction time: 8 h

Procedure:
10.0 g (54.6 mM) Saccharin and 10.9 g (109.2 mM) N-methylpiperazine are refluxed in 50 ml of hexamethylphosphoramide for 6.5 hours, and the reaction mixture is allowed to stand overnight at room temperature. The resulting precipitate is filtered off, washed with 100 ml toluene, to yield N,N-dimethyl-1,2-benzisothiazole-3-amine 1,1-dioxide. After standing for a day the combined filtrate and toluene washings yield the crystalline product which is filtered off, washed with toluene, and recrystallized from toluene. The resulting free base (3-(4-methyl-1-piperazinyl)-1,2-benzoisothiazole, 1,1-dioxide) is taken up in hot ethyl acetate and shaken with 10% aqueous HCl. The precipitated salt is filtered from the two phases, washed with ethyl acetate, and dried at 80°/vacuum to give 3.9 g of the title compound, m.p. 323°-324°.
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]1([CH3:19])[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=[CH:13]1.Cl>O>[CH3:11][C:12]1([CH3:19])[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH:13]1[S:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])=[O:9]
Reactant: CC1(C)C=CC(=O)CC1
Reactant: O=S([O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)CCC(=O)CC1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
Benzenesulfinic acid sodium salt (5.98 g) was added to a solution containing 3 ml of 4,4-dimethyl-2-cyclohexen-1-one and 20 ml of water. Forty ml of 1N hydrochloric acid were added dropwise to the resulting mixture. The reaction mixture was stirred at room temperature for 24 hours. The crystals so precipitated were filtered and the solid, washed with water, isopropanol and cold ethyl ether. After recrystallization from isopropanol, 4,4-dimethyl-3-(phenylsulfonyl)-cyclohexan-1-one was obtained in the form of white crystals. Yield: 89%
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[CH:6]=[O:7])=[CH:11][CH:12]=1
Reactant: O=Cc1ccc[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cccc2C=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.4 %

Procedure:
To a solution of 1H-pyrrole-2-carbaldehyde (0.58 g, 6.1 mmol) and 1-(chloromethyl)-4-methoxybenzene (1.0 mL, 7.3 mmol) in DMF (15 mL) was added K2CO3 (3.4 g, 24.5 mmol). After stirring 16 hr at room temperature, the mixture was diluted with ethyl acetate (200 mL) and washed with H2O (2×100 mL) then brine (100 mL). The organic layer was dried (MgSO4), filtered and then concentrated to provide 1.45 g (˜100%) of crude 1-(4-methoxybenzyl)-1H-pyrrole-2-carbaldehyde. This material was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:22][C:23]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([CH3:33])[NH:27]2>>[F:22][C:23]1[C:31]([O:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[N:4][CH:3]=2)=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([CH3:33])[NH:27]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COCCOCCOc1cc2nncc(Cl)c2cc1OC
Product: COCCOCCOc1cc2nncc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OC
Yield: 18.4 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)cinnoline (100 mg, 0.32 mmol) was reacted with 4-fluoro-5-hydroxy-2-methylindole (64 mg, 0.38 mmol), (prepared as described for the starting material in Example 1), to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)cinnoline (26 mg, 19%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([OH:23])=O)[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[CH:28]1([SH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](=[O:23])[S:34][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:25])([F:27])[F:26])[CH:3]=1
Reactant: SC1CCCCC1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)SC3CCCCC3)cs2)CC1

Procedure:
A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 200 mg) is reacted analogously to Example I-227 with cyclohexanethiol (64.0 mg). This gives, after chromatographic purification, S-cyclohexyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbothioate (110 mg, 44%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:3].[N:24]([CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N+:25]=[N-:26]>CN(C)C=O.CO.[Cu]I>[CH3:3][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:26]=[N:25][N:24]([CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:37])[CH:18]=3)[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:1]
Reactant: CC(C)(C)OC(=O)NCCCN=[N+]=[N-]
Reactant: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3cn(CCCNC(=O)OC(C)(C)C)nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 126 %

Procedure:
To a solution of 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 58) (250 mg, 0.795 mmol) in a mixture of N,N-dimethylformamide (DMF) (4.5 mL) and methanol (0.500 mL) were successively added 1,1-dimethylethyl (3-azidopropyl)carbamate (for a preparation, see Intermediate 74) (318 mg, 1.590 mmol) and copper(I) iodide (7.57 mg, 0.040 mmol). The resulting mixture was stirred at 100° C. under microwave irradiation for 2 h, and then cooled to room temperature and partitioned between EtOAc and brine. The two layers were separated and the aqueous phase was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over a Na2SO4 cartridge and concentrated in vacuo. Purification of the residue by SP4 column using a 10 G silica cartridge (gradient: 2 to 10% MeOH in DCM) gave 1-methylethyl((2S,4R)-1-acetyl-6-{1-[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]-1H-1,2,3-triazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (514 mg, 0.999 mmol, 126%) as a viscous yellow oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[B:9]1[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>C1COCC1>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=2)=[CH:4][C:3]=1[B:9]1[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:15])([CH3:14])[O:13]1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 equiv.) in THF (0.1 M) at 0° C. was added 3-trifluoromethylbenzoylchloride (1.0 equiv.) and the reaction was stirred at room temperature for 3 h. The solution was concentrated and dried under vacuo to give N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(trifluoromethyl)benzamide as a tan solid in 96% yield. LCMS (m/z) (M+H)=406.2, Rt=1.24 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]([N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25].C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[CH2:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[CH2:28][CH2:27]1)[CH3:25]
Reactant: CCN1CCCNCC1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCN(CC)CC2)nc1-c1ccc(C)cc1
Temperature: 110 °C
Yield: 22.6 %

Procedure:
A mixture of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.104 g; 0.312 mmol), 1-ethyl-1,4-diazepane (0.120 g; 0.937 mmol) and triethyl amine (0.220 mL; 1.56 mmol) in tetrahydrofuran (2 mL) was heated at 110° C. in a sealed tube for 5 h. The mixture was diluted with a saturated solution of sodium hydrogencarbonate, extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of methanol (1-30%) in dichloromethane furnished 0.030 g (21%) of the title compound as a brown oil.