Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:12][CH:11]=1)([CH3:9])[CH2:6][CH2:7][OH:8])(=O)C.[OH-].[K+].CO.O>C(Cl)(Cl)Cl>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([C:5]([OH:4])([CH3:9])[CH2:6][CH2:7][OH:8])=[CH:11][CH:12]=1
Reactant: CC(=O)OC(C)(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
3.20 g. of 3-acetoxy-3-(2',4'-difluoro-4-biphenylyl)butan-1-ol and 2 g. of KOH in 50 ml. of methanol are heated under reflux for 2 hours. Water and chloroform are added and the reaction mixture is worked up to give 3(2',4'-difluoro-4-biphenylyl)butane-1,3-diol, m.p. 82°-84°.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:12]=[C:11](Br)[C:10]2[C:5](=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Si:20]([O:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=[O:33])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:12]=[C:11]([CH:32]([C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([CH2:28][O:27][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH:30]=2)[OH:33])[C:10]2[C:5](=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C=O)c1
Reactant: FC(F)(F)c1cc(Br)c2cccc(C(F)(F)F)c2n1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(C(O)c2cc(C(F)(F)F)nc3c(C(F)(F)F)cccc23)c1

Procedure:
This was prepared from 2,8-bis(trifluoromethyl)-4-bromoquinoline by the method of Example 1 using 3-(tert-butyldimethylsilyloxymethyl)benzaldehyde in place of benzaldehyde and the crude product used directly in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17](Cl)(=[O:27])[C:18]1[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:20](Cl)=[O:21]>O1CCCC1.CCCCCC>[C:12]([C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[O:16][C:17](=[O:27])[C:18]1[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:20]([O:16][C:6]1[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C(C)(C)C)c(OC(=O)c2ccccc2C(=O)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred, ice-cold solution of 11.6 g (0.05 mol) 2,6-di-tert-butyl-4-methylphenol in 100 mL dry tetrahydrofuran was added dropwise under argon 25 mL 23M n-butyllithium in hexane. After 2.5 hours, 5.3 g (0.026 mol) fresh phthaloyl chloride was added dropwise and the mixture stirred overnight at room temperature. Product was isolated by extraction, washed with ligroin and recrystallized from acetonitrile to give 4 g nearly pure Compound 6, as white crystals, m.p. 262°-5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[O:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1.C1COCC1.[Br-].[Mg+2].[Br-].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Br-].[Mg+2].[Br-]>C(Cl)Cl>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:6]([C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([O:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:4]=1)=[O:7]
Reactant: CNc1nccc(-c2cccnc2Oc2cc(C(=O)Cl)ccc2C)n1
Reactant: COc1ccccc1
Agent: [Br-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNc1nccc(-c2cccnc2Oc2cc(C(=O)c3ccccc3OC)ccc2C)n1
Temperature: -78 °C

Procedure:
To 4-methyl-3-[3-(2-methylamino-pyrimidin-4-yl)-pyridin-2-yloxy]-benzoyl chloride (50 mg, 0.14 mmol) in a flame dried, round-bottom flask under nitrogen and cooled to −78° C. was added 4 ml of THF, 2 ml methylene chloride and magnesium-bromide-2-methoxy-benzene in THF (0.3 ml, 0.6 mmol). After addition of the magnesium-bromide, the −78° C. dry ice bath was removed and the reaction allowed to warm to room temperature over 4 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with methylene chloride and brine. The organic layers were combined, dried with sodium sulfate and filtered. The solvent was removed under vacuum and the product was purified via preparative HPLC (Gilson). MS m/z=427 [M+H]+. Calc'd for C25H22N4O3: 426.48.
Reaction SMILES: [NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20](S(C4C=CC(C)=CC=4)(=O)=O)[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[OH-].[K+].C(O)(=O)C>CO>[NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:7])[CH3:8])=[O:5]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)N(C)C)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(F)c(N)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 62.2 %

Procedure:
222 mg (0.397 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide was dissolved in 5 mL methanol and 200 μL of a 50% w/v potassium hydroxide aqueous solution was added. The mixture was stirred at room temperature for 5.5 hours and then neutralized with acetic acid. The material was filtered through a 0.45 μm syringe filter and purified by mass-triggered reverse phase HPLC in a gradient of acetonitrile and water (containing 0.1% formic acid). The clean fractions were lyophilized to afford 100 mg (0.247 mmol, 62% yield) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as an off-white powder. 1H NMR (500 MHz, DMSO-d6) δ 11.79 (d, 1H), 8.41 (d, 1H), 8.02 (d, 1H), 7.65 (d, 1H), 7.56 (dd, 1H), 7.45 (dd, 1H), 7.22 (t, 1H), 7.15 (d, 1H), 7.07 (d, 1H), 6.99 (t, 1H), 5.17 (s, 2H), 3.75 (s, 3H), 2.90 (s, br., 6H); MS: m/z 405.1 (M+H+).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:10][C:1]1[CH:6]=[C:5]2[C:4]([CH2:7][CH2:8][NH:9][CH:11]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(CCN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(c1ccccc1)NCC2
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 82 %

Procedure:
A mixture of 12.0 g (89 mmol) of 2-p-tolylethylamine and 11.21 ml (111 mmol) of benzaldehyde in PPA (300 g) was heated at 100° C. for 5 days. After cooling to RT it was poured into a saturated aqueous K2CO3 solution (1200 ml). Following the addition of DCM (300 ml) it was stirred for 50 min at RT. Then the phases were separated and the aqueous phase was extracted with DCM (2×500 ml). The organic phases were combined, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 16.3 g of 7-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline were obtained as the crude product, which was reacted further with no additional purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[CH2:28]([CH:30]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([CH2:45][NH2:46])[CH:38]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:29]>ClCCl>[CH2:28]([CH:30]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([CH2:45][NH:46][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=2)[CH:38]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:29]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(CN)c1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(CC)Cc1ccc(OC)c(CNC(=O)c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a solution of 4-(trifluoromethyl)benzoic acid (114 mg, 0.600 mmol) and triethylamine (0.21 mL, 1.51 mmol) in dichloromethane (3 mL), ethyl chlorocarbonate (0.063 mL, 0.659 mmol) was added under stirring and cooling with ice, and the mixture was stirred for 20 minutes. Next, after ethyl 2-ethyl-3-[3-(aminomethyl)-4-methoxyphenyl]propanoate hydrochloride (200 mg, 0.663 mmol) was added, the mixture was stirred for 1 hour under cooling with ice and for 3 hours at room temperature. Dichloromethane (20 mL) was added to the reaction mixture, which was washed with 1 mol/L hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=4:1 v/v) to afford 245 mg (93%) of the title compound as colorless crystals.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([F:26])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[CH:37]=O.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([F:26])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:37][C:29]3[N:28]([CH3:27])[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1c(C=O)nc2ccccc21
Reactant: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ccccc4n3C)C(=O)O2)cc1F

Procedure:
The title compound was prepared by coupling 6-Cyclopentyl-6-[2-(3-fluoro-4-isopropoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione from Step 1 of Example B(14), to 1-Methyl-1H-benzoimidazole-2-carbaldehyde using the AlCl3/reduction procedure described for Example B(13).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][O:38][CH3:39])[N:31]=[CH:30][N:29]=[C:28]2[S:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([S:40][C:28]3[C:27]4[C:32](=[CH:33][C:34]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:25]([O:24][CH3:23])[CH:26]=4)[N:31]=[CH:30][N:29]=3)[CH:42]=2)=[O:22])[CH:6]=[CH:7][C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COc1cc(NC(=O)Oc2ccccc2)ccc1C(F)(F)F
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4ccc(C(F)(F)F)c(OC)c4)c3)c2cc1OC

Procedure:
The procedure for Example 138B was used to react phenyl 3-methoxy-4-(trifluoromethyl)phenylcarbamate described in Example 190B (144 mg, 0.46 mmol) with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (110 mg, 0.31 mmol). To this solution was added diisopropylethyl amine (80 μL, 0.46 mmol) and DMAP (4.0 mg, 0.03 mmol). The reaction was concentrated to dryness and purified by silica gel chromatography eluting with ethyl acetate/dichloromethane 0-50% over 75 minutes. The main peak collected and concentrated, then triturated with dichloromethane to give a solid weighing 43 mg. 1H (DMSO-d6) 9.19 (s, 1H), 9.04 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.6-7.40 (m, 4H), 7.35 (m, 2H), 7.25 (m, 1H), 7.00 (m, 1H), 4.34 (m, 2H), 4.00 (s, 3H), 3.84 (s, 3H), 3.78 (m, 2H). LCMS (ESI) m/z 575 (M+H)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=[C:2]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Reactant: OB(O)c1ccccc1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(-c3ccccc3)c2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and phenylboronic acid to give (7-methoxy-1-phenyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 331(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([OH:19])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20][NH2:21]>>[CH3:20][NH:21][C:17]([C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])=[O:19]
Reactant: CN
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Product: CNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared by a similar method to Preparation 39 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid [see Preparation 38] and methylamine to afford N2-methyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxamide as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][CH:26]=2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:28])[C:18](=[O:27])[NH:19][N:20]=2)[CH:9]1[CH3:29])=O)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH3:28][CH:17]1[N:16]2[C:21]([CH2:22][O:23][C:24]3[C:15]2=[CH:14][C:13]([NH:12][CH:10]2[CH2:11][NH:8][CH:9]2[CH3:29])=[CH:26][CH:25]=3)=[N:20][NH:19][C:18]1=[O:27]
Reactant: CC1C(Nc2ccc3c(c2)N2C(=NNC(=O)C2C)CO3)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1NCC1Nc1ccc2c(c1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 2-methyl-3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.016 g, 0.040 mmol) in DCM (2 mL) was added TFA (0.4 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give 4-methyl-6-(2-methyl-azetidin-3-ylamino)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.012 g, 100%) LC/MS (Table 1, Method 5) Rt=1.582 min.; MS m/z: 302 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:12]([N:16]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:18]=2)[CH:13]=[CH:14][CH:15]=1.Cl[CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:12]([N:16]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:30][CH2:31]4)=[CH:22][CH:21]=3)[N:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)c1F
Product: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCN(CC(=O)N(C)C)CC5)cc4)nc23)c1F

Procedure:
2-(4-{4-[8-(2-Fluoro-3-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(2-fluoro-3-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine (0.150 g, 0.359 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.055 mL, 0.539 mmol) in a manner analogous to Example 313 to give product (0.075 g, 42%). MP=237-240° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.62 (s, 1H), 8.82 (d, 1H), 7.60 (m, 3H), 7.25 (m, 3H), 7.10 (m, 3H), 3.90 (s, 3H), 3.15 (s, 2H), 3.05 (s, 3H), 2.95 (m, 2H), 2.85 (s, 3H), 2.35 (m, 1H), 2.10 (m, 2H), 1.65 (m, 4H). MS=503 (MH)+.
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[C:11]([OH:20])(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>O>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]([O:10][C@H:2]1[C@H:3]2[O:8][CH2:7][C@H:6]([O:9][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:20])[C@H:4]2[O:5][CH2:1]1)=[O:20]
Reactant: CCCCCCCC(=O)O
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Solvent: O
Product: CCCCCCCC(=O)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2OC(=O)CCCCCCC
Temperature: 180 °C

Procedure:
In a stirred 1 liter apparatus under a stream of nitrogen, 219.0 g (1.5 mol) of isosorbide and 461.4 g (3.2 mol) of caprylic acid are heated with stirring and under a stream of nitrogen to 180° C. The reaction mixture was heated at 180° C. until no more water of reaction distilled off (about 28 h). The temperature was then gradually increased to 210° C. (altogether over about 30 h). The reaction has ended when a residual acid value of <2 mg KOH/g is reached. This gives a clear red-brown solution.
Reaction SMILES: C(N[C@@H](C(O)=O)C)(OC(C)(C)C)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl-].[Mg+2].[Cl-].C(OC)(=O)CC([O-])=O.[K+].[C:38]([O:42][C:43]([NH:45][C@H:46]([CH3:54])[C:47](=[O:53])[CH2:48][C:49]([O:51][CH3:52])=[O:50])=[O:44])([CH3:41])([CH3:40])[CH3:39]>CCOC(C)=O.C1COCC1>[C:38]([O:42][C:43]([NH:45][C@H:46]([CH3:54])/[C:47](/[OH:53])=[CH:48]/[C:49]([O:51][CH3:52])=[O:50])=[O:44])([CH3:40])([CH3:41])[CH3:39]
Reactant: COC(=O)CC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: COC(=O)CC(=O)[O-]
Agent: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C=C(\O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a 1-L 3-neck round-bottomed flask, connected to a mechanical stirrer, was added N-Boc-D-alanine (20.00 g, 106 mmol) followed by THF (529 mL). Then 1,1′-carbonyldiimidazole (25.7 g, 159 mmol) was slowly added into the reaction mixture (note: gas evolution was observed). The mixture was stirred under inert atmosphere for 3 h. Then magnesium chloride (20.13 g, 211 mmol), followed by potassium methyl malonate (33.0 g, 211 mmol) were added into the reaction mixture. The reaction mixture was heated at 50° C. in an oil bath for 16 h. It was cooled to RT, diluted with EtOAc (1 L) and filtered through a pad of celite. The filtrate was concentrated in-vacuo. The organic residue was diluted with CHCl3 (400 mL) and washed with sat. aq. NaHCO3 (300 mL). The aq. layer was extracted with CHCl3 (2×300 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in-vacuo. The crude material was purified by chromatography through two Interchim puriFlash UP (25 micron) pre-packed silica-gel column (300 gram), eluting with a gradient of 0-18% EtOAc in hexane. The mixed fractions were combined and purified by chromatography through an Interchim puriFlash UP (15 micron) pre-packed silica-gel column (120 grams), eluting with a gradient of 0-18% EtOAc in hexane. The fractions with desired material were combined and concentrated in-vacuo, to provide a mixture of (R)-methyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate and (R,Z)-methyl 4-((tert-butoxycarbonyl)amino)-3-hydroxypent-2-enoate (21.03 g, 86 mmol, 81% yield) as white solid. ee % was not determined. m/z (ESI, +ve) 268.0 (M+23)′.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]#[N:12].F[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[C:11]#[N:12])#[N:17]
Reactant: Cc1c(C#N)[nH]c2ccccc12
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C#N)n(-c2ccccc2C#N)c2ccccc12
Temperature: 60 °C
Yield: 94.7 %

Procedure:
A mixture of 3-methyl-1H-indole-2-carbonitrile (500 mg, 3.2 mmol), 2-fluorobenzonitrile (388 mg, 3.2 mmol) and Cs2CO3 (1.05 g, 3.2 mmol) in DMF (10 mL) was heated at 60° C. overnight. The mixture was poured into H2O and a precipitate formed. The solid was collected by filtration, washed with H2O and hexane, and dried under vacuum to give 1-(2-cyanophenyl)-3-methyl-1H-indole-2-carbonitrile (780 mg, 94.6%) as an off white solid that was used without purification.
Reaction SMILES: [CH:1]([Si:3]([Cl:6])(Cl)[Cl:4])=[CH2:2].[CH3:7][SiH:8]([Cl:10])[Cl:9]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[CH3:7][Si:8]([Cl:10])([Cl:9])[CH:2]1[CH2:1][Si:3]([Cl:6])([Cl:4])[CH:2]([Si:8]([CH3:7])([Cl:10])[Cl:9])[CH2:1][Si:3]1([Cl:6])[Cl:4]
Reactant: C=C[Si](Cl)(Cl)Cl
Reactant: C[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: C[Si](Cl)(Cl)C1C[Si](Cl)(Cl)C([Si](C)(Cl)Cl)C[Si]1(Cl)Cl
Yield: 51.2 %

Procedure:
In the same manner as that of Embodiment 1, 80 g (0.50 mol) of vinyltrichlorosilane, 171.4 g (1.49 mol) of methyldichlorosilane, and 14.7 g of tetrabutylphosphonium chloride were put in a 500 ml stainless steel tube and reacted at 180° C. for six hours. The reactant was vacuum-distilled to obtain 61.4 g (yield: 51.2%) of 2,5-bis(methyldichlorosilyl)-1,1,4,4-tetrachloro-1,4-disilacyclohexane. The obtained product was analyzed with 300 MHz 1H magnetic resonance.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10](Cl)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10]([C:41]1[CH:40]=[C:39]([F:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1

Procedure:
Following general procedure II, tert-butyl (1-{5-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)amino]pyridin-2-yl}piperidin-3-yl)carbamate (100 mg, 0.20 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.24 mmol) to afford crude product which was carried forward without any purification: ESI MS m/z 607 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1>C(O)C>[NH2:1][CH:2]1[CH2:7][NH:6][C:5](=[O:8])[NH:4][C:3]1=[O:9]
Reactant: Nc1c[nH]c(=O)[nH]c1=O
Solvent: CCO
Product: NC1CNC(=O)NC1=O
Reaction time: 5 h
Yield: 101 %

Procedure:
A suspension of 5-aminouracil (0.3 g, 2.3 mmol) in ethanol: water (25:5 ml) was degassed with nitrogen gas, then palladium hydroxide on carbon was added. The reaction was charged with hydrogen (65 PSI). The reaction was shaken for 5 h, filtered to remove the catalyst and concentrated to give 5-aminodihydro-2,4(1H,3H)-pyrimidinedione (0.3 g, 100%) as a white solid. MS found: (M+H)+=130.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17]C(=O)C3C=CC=CC=3)=[S:16])=[CH:10][C:8]=2[N:9]=1>CO>[NH2:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[CH:10][C:8]=2[N:9]=1
Reactant: Nc1nc2cc(NC(=S)NC(=O)c3ccccc3)ccc2s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=S)Nc1ccc2sc(N)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of anhydrous methanol (213 mL) was added sodium methoxide (1.15 g) and 1-(2-amino-benzothiazol-5-yl)-3-benzoyl-thiourea (Example 17, 3.5 g). The resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated and the residue was poured into water (300 mL). The mixture was extracted using ethyl acetate (3×200 mL). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated (1.61 g, 67%). 1H-NMR (DMSO d6) δ: 9.64 (s, 1H), 760–7.37 (m, 6H), 6.96 (d, 1H, J=8.3 Hz); MS (ESI) 224.8 (M+1, 100%).