Azzindani/Open_Reaction_Data huggingface dataset:
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.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=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:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(F)cc1
Yield: 70.9 %

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 4-fluorophenylboronic acid (available from Frontier Scientific, Inc.; 56 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]-4′-fluoro-biphenyl-2-carboxylic acid (63 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 13.18 (br s, 1H), 8.46 (s, 1H), 8.35 (d, J=8.5 Hz, 2H), 8.22 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.73-7.81 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.40-7.48 (m, 2H), 7.24-7.34 (m, 2H).
Reaction SMILES: [N+:1]1([O-:10])[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:23][C:24]1[CH:25]=[C:26]([NH2:31])[CH:27]=[CH:28][C:29]=1[Cl:30]>CN(C)C=O>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:7]([C:4]2[CH:3]=[CH:2][N+:1]([O-:10])=[CH:6][CH:5]=2)=[O:9])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=C(O)c1cc[n+]([O-])cc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70.6 %

Procedure:
A suspension of 4-pyridinecarboxylic acid-1-oxide (3.74 g, 26.9 mmol) and 1,1'-Carbonyldiimidazole (4.80 g, 29.6 mmol) in dry dimethylformamide (50 ml) was stirred for 40 minutes under an air-lock and treated with 3,4-dichlorobenzenamine (4.79 g, 29.6 mmol). The reaction mixture was heated at 100° for 5.3 hours and cooled to room temperature. The solution was evaporated in vacuo and the residue triturated with ethanol (80 ml) to give the title compound (5.38 g), m.p. 259°-265°.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:29]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CCOC(=O)CCCOc1ccccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCBr
Reaction time: 0.07 h
Yield: 50 %

Procedure:
To a solution of (4) (2.60 g., 11 mM) and 11-bromoundecanoic acid (2.65 g., 10 mM) in anhydrous methylene chloride (90 mL) is added 4-(dimethylamino)pyridine (1.22 g., 10 mM) followed by N,N'-dicyclohexylcarbodiimide (2.3 g., 11 mM) (4×5 mL of methylenechloride rinses). Precipitation of dicyclohexylurea (DCU) begins within 4 minutes. When TLC analysis indicates the reaction is complete, the mixture is filtered, the filtrate concentrated in vacuo and the residue extracted with ether. The combined ether extracts are washed 1× with 1N hydrochloric acid, 1× saturated sodium chloride solution, dried (Na2SO4) and concentrated to a residue which is stirred, filtered, and concentrated alternately with ether and methylene chloride until all DCU is removed. Concentration of the final solution yields the title product (32) (2.35 g.) as an oil that goes readily to a waxy solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][N+:24]([O-])=O)=[CH:18][CH:17]=1>C(N)C1C=CC=CC=1>[CH2:22]([N:24]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:22]([C:19]2[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=2)=[CH:23]1)[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccc(Br)cc1
Solvent: NCc1ccccc1
Product: Brc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Yield: 74.9 %

Procedure:
The title compound (0.38 g) was prepared from 0.66 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 300 μL of benzylamine, and 0.63 g of 1-bromo-4-(2-nitro-vinyl)-benzene. MS (ESI): exact mass calculated for C20H19BrN2, 366.07. found, m/z 367.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.51-7.48 (m, 2H), 7.36-7.32 (m, 2H), 7.30-7.25 (m, 3H), 7.19-7.16 (m, 2H), 5.14 (s, 2H), 4.35 (s, 2H), 3.50 (t, J=6.3 Hz, 2H), 2.87 (t, J=6.3 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:9][OH:10])[C:5]([F:8])=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][C@H:23]([CH3:25])[N:22]([C:26](Cl)=[O:27])[C@H:21]([CH3:29])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[C:3]([F:11])=[C:4]([C:5]([F:8])=[CH:6][CH:7]=1)[CH2:9][O:10][C:26]([N:22]1[C@H:23]([CH3:25])[CH2:24][N:19]([C:17]([O:16][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:18])[CH2:20][C@@H:21]1[CH3:29])=[O:27]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: OCc1c(F)ccc(Br)c1F
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)OCc1c(F)ccc(Br)c1F

Procedure:
The compound was prepared from (3-bromo-2,6-difluoro-phenyl)-methanol and 4-chlorocarbonyl-cis-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedures described in Example 121 and 54 to give the product as a colorless oil (9.75 g); MS (ISP): 482.3 (M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[Si:23]([O:30][CH2:31][CH:32]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:33]OS(C)(=O)=O)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C)C=O.O>[Si:23]([O:30][CH2:31][CH:32]([CH2:39][O:40][Si:41]([C:44]([CH3:45])([CH3:47])[CH3:46])([CH3:42])[CH3:43])[CH2:33][O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)COS(C)(=O)=O
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCC(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)c(C=O)cc1-c1cccs1
Temperature: 80 °C
Reaction time: 1 h
Yield: 329.3 %

Procedure:
Ex-13D: To a solution of 2-hydroxy-4-methoxy-5-thien-2-ylbenzaldehyde (Ex-13C, 0.10 g, 0.43 mmol) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.18 g, 1.3 mmol) and the resulting yellow slurry was heated to 80° C. Methanesulfonic acid 3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propyl ester (Ex-13A, 0.24 g, 1.3 mmol) was then added dropwise in three equal portions with stirring at 1 h intervals. After the last addition, the reaction was stirred for an additional 1 h at 80° C. and cooled to room temperature. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic phase was sequentially washed with a saturated ammonium chloride solution (15 mL), water (15 mL), and brine (15 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography (ethyl acetate/hexanes, 1:6) gave 0.78 g (90%) of 2-[3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propoxy]-4-methoxy-5-thien-2-ylbenzaldehyde as a pale green solid, mp 91–92° C. 1H-NMR (300 MHz, CDCl3) δ 10.34 (s, 1H), 8.13 (s, 1H), 7.41 (dd, 1H, J=3.6, 1.2 Hz), 7.28 (dd, 1H, J=5.1, 1.2 Hz), 7.05 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 4.22 (d, 2H, J=5.7 Hz), 3.96 (s, 3H), 3.80 (d, 4H, J=5.7 Hz), 2.33 (pentet, 1H, J=5.7 Hz), 0.88 (s, 18H), 0.012 (s, 12H). HRMS (EI) Calcd. for C28H46O5SSi2: 550.2604 (M+); Found: 550.2593.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[S:14][C:13]([NH2:15])=[N:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][N:5]=1)=O.[I:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>B(F)(F)F.CCOCC>[NH2:15][C:13]1[S:14][C:10]([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:23]([I:22])[CH:24]=3)[N:9]=2)=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1
Reactant: Nc1cccc(I)c1
Reactant: CS(=O)c1nccc(-c2sc(N)nc2-c2ccccc2)n1
Agent: FB(F)F
Solvent: CCOCC
Product: Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3cccc(I)c3)n2)s1

Procedure:
A mixture of 5-(2-methylsulfinyl-pyrimidin-4-yl)-4-phenyl-2-amino-thiazole (2.0 g, 6.3 mmol) and m-iodoaniline (7.0 g, 31.6 mmol) is heated at +100° C. After the addition of boron trifluoride diethyl etherate (3 drops) the solution is heated at +150° C. for half an hour. On cooling the product starts to crystallize. The N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-iodo-phenyl)-amine after chromatography (eluent: 2:1 mixture of ethyl acetate/hexane) has a m.p. of 243–244° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=2)([OH:27])[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2cccc(Br)c2)CCN(Cc2ccccc2)CC1
Temperature: -75 °C
Reaction time: 2.5 h
Yield: 81.7 %

Procedure:
A solution of 23.6 g (100 mmol) of 1,3-dibromobenzene in 250 ml of absolute ether was cooled to -75° C. A solution of 62.5 ml (100 mmol) of n-butyllithium (1.6 M in hexane) was added dropwise within 45 minutes. The resulting suspension was stirred at -75° C. for 2.5 hours. Subsequently, a solution of 19.0 g (100 mmol) of 1-benzyl-4-piperidone in 100 ml of absolute ether was added dropwise within 30 minutes at -70° C. to -75° C. and thereafter the mixture was stirred for 2 hours. Subsequently, the mixture was partitioned between ether and saturated ammonium chloride solution, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:1 mixture of methylene chloride and hexane as the eluent. There were obtained 28.3 g (82% of theory) of 1-benzyl-4-(3-bromophenyl)-piperidin-4-ol as a yellow oil; MS: 345, 347 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][CH3:13])=[CH:4][C:3]=1F.CC(N(C)C)=[O:17]>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][CH3:13])=[CH:4][C:3]=1[OH:17]
Reactant: CC(=O)N(C)C
Reactant: COc1nccc2cc(F)c(Cl)cc12
Solvent: O
Product: COc1nccc2cc(O)c(Cl)cc12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of sodium trimethylsilanoate (149.2 mL, 1M in THF) was added to a solution of 7-chloro-6-fluoro-1-methoxyisoquinoline (10, 10 g, 47.2 mmol) in DMA (200 mL) under argon. After stirring at 60° C. for 24 hours, the solution was evaporated under reduced pressure and then freeze dried to give crude product (20.4 g). This was dissolved in water and the pH adjusted to pH=6.5. A light brown precipitate was collected by filtration and purified by reverse phase chromatography (0 to 4 minutes, 15% acetonitrile/water, 4 to 24 minutes 15 to 90% acetonitrile/water and then 100% acetonitrile) to give 7 g of the desired product. Rt=2.60 min (Method 2). Detected mass: 210.0 (M+H+).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][CH:6]=1.C(Br)(Br)(Br)[Br:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:14][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][F:1])=[CH:6][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(OCCF)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FCCOc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (4-(2-fluoroethoxy)phenyl)methanol (117 mg; 0.68 mmol) in anh. DCM (5 ml) was treated at rt with CBr4 (228 mg; 0.68 mmol), and with PPh3 (180 mg; 0.68 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 1 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 1-(bromomethyl)-4-(2-fluoroethoxy)benzene as a slightly yellow oil which was directly used for the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:45])[CH2:20][CH2:21][CH2:22][C:23](=[O:44])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)=[C:26]([CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])[CH:25]=1)C>CCCCCC.C(OCC)(=O)C>[C:39]([CH2:38][CH2:37][C:26]1[CH:25]=[C:24]([C:23](=[O:44])[CH2:22][CH2:21][CH2:20][C:19]([OH:45])=[O:18])[CH:29]=[CH:28][C:27]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15])([OH:41])=[O:40]
Reactant: CCOC(=O)CCCC(=O)c1ccc(OCCCCCBr)c(CCC(=O)OCC)c1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCOc2ccc(C(=O)CCCC(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 53.5 %

Procedure:
Starting with 0.135 g (0.66 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.31 g (0.64 mmol) of 4-[(5-bromopentyl)oxy]-3-(3-ethoxy-3-oxopropyl)-δ-oxobenzenepentanoic acid ethyl ester, the title compound (0.190 g; 62.8% overall yield) was obtained as a white solid, mp 151°-153.5° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: CON(C)[C:4](=[O:22])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][O:8]1.[CH:24]([Mg]Br)=[CH2:25].Cl>O1CCCC1>[CH3:21][S:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][O:8]2)[C:4](=[O:22])[CH:24]=[CH2:25])=[CH:17][CH:16]=1)(=[O:19])=[O:20]
Reactant: CON(C)C(=O)C(CC1CCCO1)c1ccc(S(C)(=O)=O)cc1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCCO1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
A solution of N-methoxy-N-methyl-2-[4-(methylsulfonyl)phenyl]-3-(tetrahydrofuran-2-yl)propanamide (1.68 g) in tetrahydrofuran (19.7 mL) was cooled to 0° C., and vinylmagnesium bromide (1.0M tetrahydrofuran solution, 19.7 mL) was added dropwise thereto. The reaction mixture was stirred at room temperature for 3 hr, and poured into 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (930 mg, yield 61%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 309 (MH+).
Reaction SMILES: Br.[NH2:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][C:6]([Br:11])=[CH:5][N:4]=1.C(N(CC)CC)C.Cl[C:20](OC(Cl)(Cl)Cl)=[O:21]>ClCCl>[Br:11][C:6]1[CH:5]=[N:4][C:3]2[NH:2][C:20](=[O:21])[O:10][CH2:9][C:8]=2[CH:7]=1
Reactant: Nc1ncc(Br)cc1CO
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1Nc2ncc(Br)cc2CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2-amino-5-bromo-3-hydroxymethylpyridine hydrobromide (Apollo, Cheshire, UK, 0.528 mmol) in dichloromethane (1.25 ml) and triethylamine (1.162 mmol) was cooled with an ice-bath. Was added to the RM trichloromethyl chloroformate (0.317 mmol) in dichloromethane and the RM was stirred for 30 min at 0° C. and 1 h at rt. The RM was diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and separated by flash chromatography (heptane/EtOAc 0% to 80%). The fractions containing product were evaporated together to give the title compound as a yellow solid. (HPLC: tR 2.16 min (Method A); M+H=229, 231 MS-ES)
Reaction SMILES: Br[C:2]1[CH:42]=[CH:41][C:5]2[NH:6][C:7]([C@@H:9]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:10][C:11](=[O:32])[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:8][C:4]=2[CH:3]=1.[Cl:43][C:44]1[CH:49]=[C:48]([C:50]#[N:51])[CH:47]=[CH:46][C:45]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[Cl:43][C:44]1[CH:49]=[C:48]([C:50]#[N:51])[CH:47]=[CH:46][C:45]=1[C:2]1[CH:42]=[CH:41][C:5]2[NH:6][C:7]([C@@H:9]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:10][C:11](=[O:32])[NH:12][C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: N#Cc1ccc(B(O)O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc2cc(Br)ccc2[nH]1
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: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc2cc(-c3ccc(C#N)cc3Cl)ccc2[nH]1
Temperature: 120 °C
Yield: 47.1 %

Procedure:
A mixture of (S)-tert-butyl (1-(5-bromo-1H-benzo[d]imidazol-2-yl)-3-oxo-3-(tritylamino)propyl)carbamate (Preparation 14, 87 mg, 0.14 mmol), 2-chloro-4-cyanophenylboronic acid (34 mg, 0.19 mmol) and aqueous sodium carbonate solution (2M, 150 μL, 0.30 mmol) in 1,2-dimethoxyethane (0.95 mL) was sparged with argon three times, then tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.007 mmol) was added. The reaction mixture was heated under microwave irradiation at 120° C. for 60 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulphate, and concentrated in vacuo to give the crude product. The residue was purified using silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (45 mg, 48%) as a pale tan solid.
Reaction SMILES: [CH2:1]([NH:5][CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)[C:7]#[N:8])[CH:2]([CH3:4])[CH3:3].S(OC)(O[CH3:26])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([N:5]([CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)[C:7]#[N:8])[CH3:26])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNC(C#N)c1cccc(Oc2ccccc2)c1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)CN(C)C(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of α-(N-isobutylamino)-3-phenoxybenzeneacetonitrile (28.0 g; 0.1 mole), dimethyl sulfate (12.6 g; 0.1 mole), anhydrous potassium carbonate (15.0 g) and anhydrous acetone (100 ml) was stirred at a temperature of 50° C. for a period of 16 hours. The mixture was filtered and the solvent was removed from the filtrate by distillation under reduced pressure. The residue was treated with anhydrous diethyl ether, the etherial solution was separated and the ether was evaporated to give α-(N-isobutyl-N-methylamino)-3-phenoxybenzeneacetonitrile as a yellow oil. Proton nuclear magnetic resonance spectrum (d6 -acetone; δ in ppm): 0.85 (6H, d of d); 1.83 (1H, m); 2.23 (3H, s); 5.19 (1H, s); 7.0-7.5 (9H, m).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[H-].[Na+].[O:9]([C:16]1[CH:35]=[CH:34][C:19]([O:20][CH2:21][CH2:22]C2C=C(S([O-])(=O)=O)C=CC=2C)=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[O:9]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH2:22][O:1][N:2]2[CH:6]=[CH:5][CH:4]=[N:3]2)=[CH:34][CH:35]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: On1cccn1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1CCOc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccc(OCCOn3cccn3)cc2)cc1
Temperature: 0 °C
Yield: 76.6 %

Procedure:
While cooling and at 0° C., a solution of 1.0 g of N-hydroxypyrazole in 10 ml of dimethylformamide is dripped into a suspension of 0.3 g of sodium hydride in 10 ml of dimethylformamide. The mixture is stirred for a further hour, after which a solution of 4.7 g of 2-(4-phenoxyphenoxy)-ethyl-p-toluenesulfonate in 50 liters of dimethylformamide is added. The reaction batch is stirred for 12 hours at room temperature and then poured into 250 ml of ice water. The mixture is extracted three times with methyl tert-butyl ether, and the combined extracts are washed with 1N sodium hydroxide solution and then with water. The organic phase is dried with sodium sulfate, the solvent is stripped off under reduced pressure and the residue is chromatographed over silica gel using toluene as developer; there is obtained 2.7 g of N-[2-(4-phenoxyphenoxy)-ethoxy]-pyrazole of melting point 83°-85° C.
Reaction SMILES: Cl[C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][C:6]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>C(O)(C)C>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[C:9]3[C:4](=[CH:5][C:6]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:8]=3)[N:3]=2)=[CH:35][CH:34]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc2c(=O)n(-c3ccccc3)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1ccc2c(=O)n(-c3ccccc3)c(NCc3ccc(Cl)cc3)nc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
To a suspension of methyl 2-chloro-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carboxylate (0.10 g, 0.25 mmol) in isopropyl alcohol (2.8 mL) was added N,N-diisopropylethylamine (93 μL, 0.53 mmol) and p-chlorobenzylamine (77.3 μL, 0.64 mmol). The reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 30% EtOAc/hexanes) to afford methyl 2-[(4-chlorobenzyl)amino]-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carboxylate (30 mg, 30%). LC-MS: (FA) ES+ 420.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5](=[C:10]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH:11]1[CH3:17])[C:6](OC)=[O:7])#[N:4].CC(C)=O.Cl>C(O)C>[OH:7][CH2:6][CH:5]([CH:10]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH:11]1[CH3:17])[C:3]#[N:4]
Reactant: COC(=O)C(C#N)=C1CC(C)(C)CC1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CC1CC(C)(C)CC1C(C#N)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.1 eq. of sodium borohydride are placed in ethanol at 10° C. under an inert atmosphere. Methyl 2-cyano-2-(2,4,4-tri-methylcyclopentylidene)acetate B is added thereto dropwise. The reaction medium is stirred at ambient temperature overnight and is then neutralized with acetone. It is subsequently poured onto a cold 10% HCl solution. The aqueous phase is extracted twice with MTBE. The combined organic phases are washed with a sodium bicarbonate solution and then with an aqueous sodium chloride solution. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, 3-hydroxy-2-(2,4,4-tri-methylcyclopentyl)propanenitrile is obtained in the form of four diastereomers in the proportions of 11:13:23:53.