Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][C:16]2[C:20]([CH3:21])=[N:1][C:2]3[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[C:3]=3[C:17]=2[CH3:18])=[CH:13][CH:12]=1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Reactant: Cc1cc(N)cc(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1cc(O)c2c(C)c(Cc3ccc(Cl)cc3)c(C)nc2c1
Temperature: 160 °C

Procedure:
A mixture of 3-amino-5-methylphenol (1.0 g), 3-(4-chlorobenzyl)pentane-2,4-dione (1.7 g) and toluene-4-sulfonic acid (0.30 g) was heated at 160° C. under nitrogen for 3 hours. The mixture was cooled to room temperature and the residue triturated with methanol to give title compound, 1.5 g.
Reaction SMILES: P(Br)(Br)([Br:3])=O.CN(C=O)C.[Br:11][C:12]1[CH:19]=[C:18]([CH2:20]O)[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:11][C:12]1[CH:19]=[C:18]([CH2:20][Br:3])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: O=P(Br)(Br)Br
Reactant: O=Cc1ccc(CO)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1ccc(CBr)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.1 %

Procedure:
To a stirring cold (0° C.) solution of POBr3 (0.6 mol, 171 g) in CH2Cl2 (1.6 L) was added dropwise DMF (0.75 L) over a period of 1 h. A solution of 2-bromo-4-hydroxymethyl-benzaldehyde (0.49 mol, 107 g) in CH2Cl2 (0.75 L) was then added dropwise over a period of 0.5 h. The resulting mixture was stirred at 0° C. for another 0.5 h and was then transferred via a cannula to a cold (0° C.) stirring aqueous solution of NaHCO3 (3 L, 1M) while maintaining the temperature of the aqueous solution below 10° C. After the transfer was completed, the mixture was extracted with CH2Cl2 (2 L). The organic extract was separated and washed with H2O (3 L) and brine (3 L), dried with MgSO4 (anhyd.) and concentrated to give an oil . The residue was extracted with 10% EtOAc/hexane (2 L). The organic extract was washed with H2O (2×1 L), dried with MgSO4 (anhyd.) and concentrated to a solid which was swished with hexane to give 154 g (˜100%) of the title compound as a beige solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33](=[O:35])[CH3:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1>C1COCC1>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)([OH:35])[CH3:34])=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(-c2ccc(C(C)=O)nc2)cc1
Reactant: Ic1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(-c2ccc(C(C)(O)c3ccncc3)nc2)cc1
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To cooled (−78° C.) 4-iodopyridine (270 mg, 1.3 mmol) [Albrecht, et al., US Patent Application Publication No. 2009/0318436] in THF (15 mL) was added slowly 1.6 M n-BuLi in hexane (1.65 mL, 2.6 mmol). Stirring was continued for an additional 30 minutes at the same temperature, followed by the addition of a THF (5 mL) solution of 1-(5-(4-methoxyphenyl)pyridin-2-yl)ethanone (300 mg, 1.3 mmol). After stirring for 2 hours at the same temperature, the reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL). The aqueous layer was extracted with ethylacetate (2×150 mL). The combined organic layers were washed with brine (20 mL). Finally, the organic phase was dried over Na2SO4 and concentrated under reduced pressure to give crude product. The crude product was purified by flash chromatography (silica gel 60-120μ) using 20% ethyl acetate and hexane as eluent to afford racemic 1-(5-(4-methoxyphenyl)pyridin-2-yl)-1-(pyridin-4-yl)ethanol as an off-white solid (135 mg, 33% yield) in 99.6% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.74 (d, 1H), 8.45 (dd, 2H), 7.98 (dd, 1H), 7.68 (d, 1H), 7.62 (d, 2H), 7.48 (dd, 2H), 7.02 (d, 2H), 6.15 (s, 1H), 3.78 (s, 3H), 1.88 (s, 3H); LC-MS m/z calculated for [M+H]+307.14. found 307.3.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20])(=[O:15])=[O:14]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:17]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CS(=O)(=O)c1cccc(CN)c1
Reactant: Clc1nc2c(Br)cccn2n1
Product: CS(=O)(=O)c1cccc(CNc2cccn3nc(Cl)nc23)c1

Procedure:
3-Methanesulfonyl-benzylamine was prepared from 3-methanesulfonyl-benzonitrile (0.984 g, 5.43 mmol) in a manner analogous to Example 156b. Product isolated as a pale yellow oil (0.946 g, 94%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.93 (s, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 4.00 (s, 2H), 3.06 (s, 3H). MS=186 (MH)+. 160 b) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methanesulfonyl-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 3-methanesulfonyl-benzylamine (450.0 mg, 2.429 mmol) in a manner analogous to Example 2d. Product isolated as a pale yellow solid (0.429 g, 59%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.97 (s, 1H), 7.93-7.87 (m, 2H), 7.68 (d, J=7.7 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 6.85 (t, J=7.4 Hz, 1H), 6.35 (d, J=7.8 Hz, 1H), 5.51-5.44 (m, 1H), 4.59 (d, J=5.8 Hz, 2H), 3.07 (s, 3H). MS=337, 339 (MH)+. 160 c) N(8)-(3-Methanesulfonyl-benzyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methanesulfonyl-benzyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown lyophilate as the trifluoroacetic acid salt (0.004 g, 4%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.50 (br s, 1H), 9.17 (s, 1H), 7.98-7.93 (m, 2H), 7.81 (d, J=8.0 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.65-7.59 (m, 3H), 6.96 (d, J=8.9 Hz, 2H), 6.70 (t, J=7.5 Hz, 1H), 6.64 (br s, 1H), 6.32 (d, J=7.6 Hz, 1H), 4.65-4.60 (m, 2H), 3.72-3.65 (m, 2H), 3.23-3.13 (m, 6H), 2.92-2.82 (m, 6H). MS=492 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:11][C@H:10]([N:22]([C:27](=[O:31])[C:28]([OH:30])=O)[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:61]1[C:62]([NH2:67])=[CH:63][CH:64]=[CH:65][CH:66]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[NH:67][C:28](=[O:30])[C:27]([N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C@H:10]1[CH2:11][C@@H:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]1)=[O:31]
Reactant: CC(C)CN(C(=O)C(=O)O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCNc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCCNc1ccccc1NC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
{[(3S,5R)-1-(tert-Butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl](2-methylpropyl)amino}(oxo)acetic acid (10.3 g), HOBt (4.13 g) and WSC.HCl (6.28 g) were dissolved in DMF (50 ml), N-(4-methoxybutyl)benzene-1,2-diamine (4.67 g) and diisopropylethylamine (11.3 ml) were added, and the mixture was stirred at room temperature for 15 hr and at 60° C. for 2 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (9.11 g).
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:28])[CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([O:39][C:40]([F:43])([F:42])[F:41])=[C:34](B(O)O)[CH:35]=1>>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([O:39][C:40]([F:41])([F:42])[F:43])=[C:34]([C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[CH:16][CH:15]=3)=[O:12])[C:4](=[O:28])[CH:3]=2)[CH:35]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(Br)cc1=O
Reactant: OB(O)c1cc(Cl)ccc1OC(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2OC(F)(F)F)cc1=O

Procedure:
127 mg (purity 70%, 0.2 mmol) of tert-butyl 4-{[2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate) and 58 mg (0.24 mmol) of 5-chloro-2-trifluoromethoxyphenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 107 mg (purity 94%, 89% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([O:8][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(C)c1ccc(O)cc1F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)c1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 110.6 %

Procedure:
To a solution of compound (8) (3.69 g, 14.9 mmol) and triethylamine (4.13 mL, 29.7 mmol) in dry dichloromethane, (CF3SO2)2O (2.93 mL, 17.8 mmol) was added dropwise at 0° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 12 hours. The organic layer was washed sequentially with a 1M aqueous solution (90 mL) of hydrochloric acid, a 1M aqueous solution of sodium hydroxide (90 mL), and saline (90 mL), and dried (over sodium sulfate). The solvent was then distilled off. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (10:1) solution to give 5.44 g (96%) of compound (18) of interest as clear yellow liquid matter.
Reaction SMILES: F[C:2]1([F:10])[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH2:3]1.Cl[C:12]1[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:10])=[CH:9][CH:8]=3)[C:13]3[C:26]([CH3:27])=[CH:25][S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: NCC1=CCC(F)(F)C=C1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Product: Cc1csc2nc(-c3cccnc3)nc(NCc3ccc(F)cc3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluoro-4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:41]=[CH:40][CH:39]=[CH:38][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:38]=[CH:39][CH:40]=[CH:41][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(I)c3c(N)ncnc32)C1
Reactant: OB(O)c1ccc(Oc2ccccc2F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv) in dioxane/H2O(7/3=V/V) (30 mL), [4-(2-fluorophenoxy)phenyl]boronic acid (500 mg, 2.16 mmol, 6.99 equiv), sodium carbonate (200 mg, 1.89 mmol, 0.26 equiv), and Pd(PPh)4 (500 mg, 0.43 mmol, 3.19 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath an then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.2 g (59%) of tert-butyl 3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.CO[CH:16]([N:19]([CH3:21])[CH3:20])OC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])/[CH:9]=[CH:16]/[N:19]([CH3:21])[CH3:20])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Product: CN(C)/C=C/C(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3.62 g of 1-(4-bromo-2-nitrophenyl)ethanone and 5.3 g of (dimethoxymethyl)dimethylamine was stirred at 90° C. for 4 hours. The reaction mixture was cooled to room temperature and the precipitated solid was collected by filtration. The obtained solid was washed with diisopropyl ether and dried under reduced pressure to obtain 3.93 g of (2E)-1-(4-bromo-2-nitrophenyl)-3-(dimethylamino)prop-2-en-1-one.
Reaction SMILES: CC(CCCCCOC(C1C(C(OCCCCCC(C)C)=O)=CC=CC=1)=O)C.CC(N)C1C=CC=CC=1.[F:38][C:39]1[CH:44]=[C:43]([C:45](=[CH2:49])[C:46]([OH:48])=[O:47])[CH:42]=[CH:41][C:40]=1[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C1C=CC=CC=1.C(O)C>[F:38][C:39]1[CH:44]=[C:43]([CH:45]([CH3:49])[C:46]([OH:48])=[O:47])[CH:42]=[CH:41][C:40]=1[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: C=C(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: CC(C)CCCCCOC(=O)c1ccccc1C(=O)OCCCCCC(C)C
Agent: CC(N)c1ccccc1
Solvent: CCO
Solvent: c1ccccc1
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
DIOP (64.8 mg.) was added to a solution of DTDR (46 mg.) in benzene (9 ml.) under nitrogen and the mixture allowed to stand for 15 minutes. This complex was then added to a mixture, prepared by adding ethanol (16 ml.) followed by (-)-α-methylbenzylamine (24 mg.) in ethanol (2 ml.) to the product of Example 2 (0.5 g.), under hydrogen. The reaction mixture was stirred under hydrogen for 51/2 hours at room temperature and then kept under hydrogen overnight. The solution was concentrated under reduced pressure and the residue treated with ether and aqueous 10% potassium carbonate. The ether extract was treated with the potassium carbonate extract, which was then acidified. The oil which separated, solidified and was extracted with ether and the extract dried, filtered, evaporated and the product recrystallised from light petroleum (b.p. 60°-80° C.) to give 2-(2-fluoro-4-biphenylyl)propionic acid, m.p. 101°-103° C., having an optical rotation [α]D20 +35.5° representing 89% of the (+) isomer in the product.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[N:5]([CH3:14])[C:6](=[O:13])[N:7]2[CH3:12].[F-].[Cs+].[CH2:18](B1OC(C)(C)C(C)(C)O1)[CH:19]=[CH2:20]>O1CCOCC1.O.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>[CH2:20]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:15])[N:5]([CH3:14])[C:6](=[O:13])[N:7]2[CH3:12])[CH:19]=[CH2:18]
Reactant: Cn1c(=O)c2c(I)cccc2n(C)c1=O
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCc1cccc2c1c(=O)n(C)c(=O)n2C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a stirred solution of Step 4 intermediate (40 g, 126 mmol) in 1,4-dioxane (1.3 lit) was added cesium fluoride (38.3 g, 252 mmol) and allylboronic acid pinacol ester (42.5 ml, 225 mmol) under nitrogen atmosphere and the mixture was degassed for 10 min. Tetrakis(triphenylphosphine)palladium(0) (14.46 g, 12 mmol) catalyst was added and the mixture was stirred at 100° C. for 20 h under nitrogen atmosphere. The mixture was diluted with water (500 ml) and extracted with ethyl acetate (3×500 ml). The combined extracts were concentrated and the residue obtained was purified by silica gel column chromatography to give 26.5 g of the product as an off-white solid; 1H NMR (δ ppm, CDCl3, 300 MHz): 7.54 (t, J=7.8, 1H); 7.08 (t, J=6.9, 2H); 6.18-6.00 (m, 1H); 5.06-4.95 (m, 2H); 4.04 (d, J=6.3, 2H); 3.60 (s, 3H); 3.45 (s, 3H). MS (m/z): 231.37 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH2:25])[CH:19]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:25][CH2:24][C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(Cl)c(C#N)c(NCCO)n1
Reactant: NCc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO

Procedure:
In analogy to the procedure described in example 47a, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-methanesulfonyl-pyrimidine-5-carbonitrile was treated with 3-picolyl-amine in dioxane in the presence of N-ethyl-diisopropylamine at 40° C. to yield 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as a brown solid which was used in the next step without further purification and characterization.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[CH3:11][Si:12]([CH3:17])([CH3:16])[CH2:13][CH2:14]O.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl.Cl>[CH3:11][Si:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][O:9][C:8]([CH:4]1[CH2:5][CH2:6][CH2:7][C:2](=[O:1])[CH2:3]1)=[O:10]
Reactant: C[Si](C)(C)CCO
Reactant: O=C1CCCC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)C1CCCC(=O)C1
Yield: 99.8 %

Procedure:
3-oxo-cyclohexanecarboxylic acid (2.00 g, 14.1 mmol), 2-trimethylsilylethanol (2.5 mL, 17.4 mmol), 4-dimethylaminopyridine (148 mg, 1.21 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.44 g, 17.9 mmol) in methylene chloride (14 mL) was stirred for 18 h. The solution was diluted with 10% aqueous hydrochloric acid and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to yield 3.41 g (100% yield) of 3-oxo-cyclohexanecarboxylic acid 2-trimethylsilanyl-ethyl ester as a clear oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](O)(=[O:39])[CH2:36][CH2:37][CH3:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1)(=[O:39])[CH2:36][CH2:37][CH3:38]
Reactant: CCCC(=O)O
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 82.2 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by butyric acid (27 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction, was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give N-(cis-4-Butyrylamino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (89 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[Cl:17][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[NH:10][C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc2c(c1)NC(=O)CC2
Solvent: CC(=O)O
Product: COc1cc2c(cc1Cl)CCC(=O)N2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
35.4 Grams of 7-methoxy-3,4-dihydrocarbostyril are dissolved in 300 ml of acetic acid. This solution is stirred under ice-cooling conditions, and 100 ml of acetic acid solution containing 27 g of sulfuryl chloride are added dropwise and allowed to stand overnight. The reaction mixture is poured into 1 liter of ice-water and the precipitate thus formed is separated by filtration, washed with water and dried. Recrystallization from methanol obtains 30 g of 6-chloro-7-methoxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 212° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.C(Cl)Cl.[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([CH2:19][C:20]([C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(C(=O)Cc2ccccc2)c1
Reaction time: 3 h
Yield: 5 %

Procedure:
Under nitrogen, methyl pyrrole-3-carboxylate (920 mg., 7 mmoles) was dissolved in 25 ml. of methylene chloride. Phenylacetyl chloride (930 mg., 6 mmoles) was added and dissolved. Finally, stannic chloride (1.2 ml., 12 mmoles) was added. The reaction mixture was stirred for 3 hours, water (15 ml.) added dropwise, diluted with 50 ml. of ether, the organic phase separated, washed with 20 ml. of water and evaporated to dryness to yield methyl 5-phenylacetylpyrrole-3-carboxylate (semisolid, Rf 0.3 on silica gel thin layer chromatography with ethyl acetate-1/hexane-5/5% acetic acid as eluant). The entire batch was employed without weight determination in the next step.