Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:51])[CH2:25][CH2:26][C:27]3[N:31]=[CH:30][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=3)[CH:18]=1)=[O:14])[NH:7][C:6]2=[O:52])#[N:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:51])[CH2:25][CH2:26][C:27]3[N:31]=[CH:30][NH:29][N:28]=3)[CH:18]=1)=[O:14])[NH:7][C:6]2=[O:52])#[N:2]
Reactant: N#Cc1ccc2nc(C(=O)NCc3cccc(NC(=O)CCc4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(NC(=O)CCc4nc[nH]n4)c3)[nH]c(=O)c2c1
Yield: 71 %

Procedure:
A solution of 6-cyano-4-oxo-N-{[3-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propanoyl}amino)phenyl]methyl}-3,4-dihydroquinazoline-2-carboxamide (215 mg, 0.314 mmol), triethylsilane (0.053 mL, 0.330 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (3 mL) was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from IPE. The resulting powder was recrystallized from ethanol to give is the title compound as a white powder (98.6 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.[P:38](=[O:42])([OH:41])([OH:40])[OH:39]>C(C(C)=O)C>[CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.[P:38]([O-:42])([O-:41])([O-:40])=[O:39]
Reactant: O=P(O)(O)O
Agent: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Solvent: CCC(C)=O
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Maraviroc (10 gm) was dissolved in methyl ethyl ketone (100 ml) and stirred for 30 minutes at room temperature. To the solution was added phosphoric acid (2 gm) and stirred for 11 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 10 gm of crystalline form 1 of maraviroc phosphate.
Reaction SMILES: [C:1]([C:4]1[C:5]([I:21])=[N:6][N:7]2[CH2:12][CH:11]([CH3:13])[N:10]([C:14]([O:16][C:17]([CH3:20])(C)C)=[O:15])[CH2:9][C:8]=12)(=[O:3])[NH2:2].Cl[C:23]1C=C(B(O)O)C=C[C:28]=1F.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([C:4]1[C:5]([I:21])=[N:6][N:7]2[CH2:12][CH:11]([CH3:13])[N:10]([C:14]([O:16][CH2:17][CH2:20][CH2:23][CH3:28])=[O:15])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: CC1Cn2nc(I)c(C(N)=O)c2CN1C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCOC(=O)N1Cc2c(C(N)=O)c(I)nn2CC1C
Temperature: 80 °C
Reaction time: 6 h
Yield: 84.3 %

Procedure:
To a stirred suspension of Intermediate 340F (0.32 g, 0.788 mmol) in 1,4-dioxane (8.0 mL) was added (3-chloro-4-fluorophenyl)boronic acid (0.179 g, 1.024 mmol), K3PO4 (1.292 g, 2.58 mmol) and the contents of the flask were purged with N2 for 10 min. PdCl2(dppf)-CH2Cl2 (0.042 g, 0.052 mmol) was then added and the reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was cooled to RT; diluted with ethyl acetate (10 mL), washed with water, dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 2% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 340G as a pale yellow solid (0.27 g, 84%). MS(ES): m/z=408 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.85-7.92 (m, 1H), 7.71 (ddd, J=8.69, 4.91, 2.27 Hz, 1H), 7.46 (d, J=17.75 Hz, 1H), 7.24-7.38 (m, 2H), 4.99 (d, J=17.75 Hz, 1H), 4.72 (br. s., 1H), 4.44 (d, J=17.75 Hz, 1H), 4.08-4.28 (m, 2H), 1.46 (s, 9H), 1.15 (s, 3H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17].[C@@H:18]12[CH2:24][C@@H:21]([CH:22]=[CH:23]1)[CH2:20][C@H:19]2[CH2:25][C:26](O)=[O:27]>>[C@@H:18]12[CH2:24][C@@H:21]([CH:22]=[CH:23]1)[CH2:20][C@H:19]2[CH2:25][C:26]([NH:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17])=[O:27]
Reactant: Nn1nc(-c2cccs2)c2ccccc2c1=O
Reactant: O=C(O)C[C@@H]1C[C@@H]2C=C[C@H]1C2
Product: O=C(C[C@@H]1C[C@@H]2C=C[C@H]1C2)Nn1nc(-c2cccs2)c2ccccc2c1=O

Procedure:
The product from Example 10B and 2-((1S,2S,4S)-bicyclo[2.2.1]hept-5-en-2-yl)acetic acid was processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 8.41 (dd, J=7.8, 1.4 Hz, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.92-8.10 (m, 2H), 7.80 (dd, J=5.1, 1.1 Hz, 1H), 7.65 (dd, J=3.6, 1.1 Hz, 1H), 7.29 (dd, J=5.1, 3.6 Hz, 1H), 6.23 (dd, J=5.7, 3.0 Hz, 1H), 6.07 (dd, J=5.7, 2.8 Hz, 1H), 2.89-2.92 (m, 1H), 2.77-2.81 (m, 1H), 2.42-2.50 (m, 1H), 2.10 (dd, J=14.3, 7.9 Hz, 1H), 2.08 (dd, J=14.1, 8.0 Hz, 1H), 1.91 (ddd, J=11.5, 9.0, 3.8 Hz, 1H), 1.34-1.37 (m, 1H), 1.27 (d, J=8.1 Hz, 1H), 0.61 (ddd, J=11.5, 4.3, 2.5 Hz, 1H); MS (APCI) M/Z 392 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:12]Br>[OH-].[Na+]>[Br:12][C:3]1[C:2]([OH:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: BrBr
Reactant: Oc1cnc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc2ccccc2nc1Br
Temperature: -5 °C
Reaction time: 3 h

Procedure:
6.0 mg (41 mmol) of 3-hydroxyquinoline are dissolved in 50 ml of 10% strength sodium hydroxide solution, giving a yellowish brown color. The reaction mixture is cooled to -5° C. using an ice/common salt mixture. A mixture comprising 6.6 g (2.1 ml, 41 mmol) of bromine dissolved in 50 ml of 10% strength sodium hydroxide solution is added dropwise to this solution over a period of 1 hour. During this the temperature of the reaction solution must never exceed 0° C. After this time, the cooling is removed and the reaction solution is stirred at room temperature for another 3 hours. The reaction solution is then cooled to -10° C. The reaction solution cooled to -10° C. [sic]. The reaction solution is then brought to a pH of 3 with 2N hydrochloric acid, during which the temperature of the reaction solution must never exceed -5° to 0° C. This gives the crude product as a light yellow solid. The crude product is recrystallized from 180 ml of ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH2:19][C:20]([N:22]([CH2:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21])[C:5](=[O:18])[N:6]2[CH3:17].Cl.[CH3:32][NH:33][CH3:34].C(N(CC)CC)C>CN(C)C=O>[CH2:29]([N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](=[O:21])[CH2:19][N:4]1[C:3]2[C:7](=[N:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:2]=2[N:33]([CH3:34])[CH3:32])[N:6]([CH3:17])[C:5]1=[O:18])[CH3:30]
Reactant: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)nc(Cl)c21)c1ccccc1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)nc(N(C)C)c21)c1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
A mixture of 6-chloro-N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purin-7-acetamide obtained in Example 45 (0.6 g), dimethylamine hydrochloride (0.2 g), triethylamine (0.4 g) and dimethylformamide (20 ml) is stirred at 100° C. for four hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added water and chloroform. The chloroform layer is separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from diisopropyl ether to give the desired compound (0.34 g).
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1.P(Br)(Br)[Br:13].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:13][CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)c1ccc(CO)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of methyl 5-(hydroxymethyl)thiophene-2-carboxylate (375 mg, 2.17 mmol) in methylene chloride (9.0 mL) is added phosphorus tribromide (100 μL, 1.08 mmol) and the reaction mixture is stirred at 0° C. for 0.5 h. Saturated sodium bicarbonate (10 mL) is carefully added to the reaction mixture and the phases are separated. The organic phase is washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield the title compound in pure form. ESI MS m/z 235 [M+H]+.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([OH:15])[CH2:13][OH:14].Cl.[CH3:17][O:18][C:19]([CH:21]1[C:26](=O)[CH2:25][CH2:24][NH:23][CH2:22]1)=[O:20]>C1C=CC=CC=1>[CH3:17][O:18][C:19]([CH:21]1[CH2:22][NH:23][CH2:24][CH2:25][C:26]21[O:15][CH2:12][CH2:13][O:14]2)=[O:20]
Reactant: OCCO
Reactant: COC(=O)C1CNCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Product: COC(=O)C1CNCCC12OCCO2
Yield: 63.8 %

Procedure:
PTSA (24.7, 130 mmol) and ethylene glycol (24.8 mL, 439 mmol) were added to methyl-4-oxo-3-piperidine carboxylate hydrochloride (90) (25.1 g, 130 mmol) in benzene (52 mL, 2.5 M). The solution was stirred and heated to reflux overnight. H2O was removed using a Dean Stark trap. When the reaction was judged complete by TLC, 5% aqueous NAHCO, and CH2Cl2 were added, and the organic layer was removed. The aqueous layer was extracted with CH2Cl2 (5×), and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo, and purified by silica gel chromatography with 20:1 CH2Cl2:2N NH, in EtOH to provide 91 (16.7 g, 64%). 1H NMR (CDCl3) 3.82-3.70 (4H, m), 3.48 (3H, s), 3.00-2.50 (4H, m), 2.43 (1H, t), 1.76 (1H, m), 1.30 (1H, m) ppm. 13C NMR (CDCl3): 171.83, 106.57, 64.34, 64.17, 51.36, 48.91, 46.54, 43.69, 33.97 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([S:22][CH2:23][CH2:24][N:25]4[CH2:34][CH2:33][C:32]5[C:27](=[CH:28][C:29]([O:37][CH3:38])=[C:30]([O:35][CH3:36])[CH:31]=5)[CH2:26]4)=[CH:18][CH:17]=3)[N:15]=2)=[C:5]([N+:39]([O-])=O)[CH:4]=1.Cl.[H][H]>[Fe].CO>[CH3:36][O:35][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:37][CH3:38])[CH2:26][N:25]([CH2:24][CH2:23][S:22][C:19]1[CH:20]=[CH:21][C:16]([N:14]3[N:13]=[N:12][C:11]([C:6]4[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[NH2:39])=[N:15]3)=[CH:17][CH:18]=1)[CH2:34][CH2:33]2
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)CN(CCSc1ccc(-n3nnc(-c4cc(OC)c(OC)cc4[N+](=O)[O-])n3)cc1)CC2
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COc1cc(N)c(-c2nnn(-c3ccc(SCCN4CCc5cc(OC)c(OC)cc5C4)cc3)n2)cc1OC
Yield: 79.1 %

Procedure:
0.2 g of the compound obtained in Step 3, 0.1 g of Iron and 0.15 ml of concentrated HCl were added to 3 ml of methanol, and stirred under 1 atmospheric hydrogen atmosphere for 18 hours. The reaction mixture was filtrated through a cellite pad, the pad was washed with methanol, the filtrate and wash solution were combined, and distilled under a reduced pressure to obtain a residue that gave 0.15 g of the title compound (yield 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([OH:14])=O)=[O:7].[CH2:23]([NH2:29])[C:24]1[O:28][CH:27]=[CH:26][CH:25]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([NH:29][CH2:23][C:24]1[O:28][CH:27]=[CH:26][CH:25]=1)=[O:14])=[O:7]
Reactant: NCc1ccco1
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cc(C(=O)O)ccn1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cc(C(=O)NCc2ccco2)ccn1
Yield: 25.3 %

Procedure:
To solution of 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinic acid (16 mg, 0.047 mmol), furfuryl amine (9.1 mg, 0.094 mmol) and DMAP (8.6 mg, 0.07 mmol) in DMF 4 ml was added PyBOP (36 mg, 0.07 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-furan-2-ylmethyl-isonicotinamide as a colorless solid (5 mg, 25.3% yield).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:28][C:29]1([C:34]2([CH:37]=O)[CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31][O:30]1>>[CH3:28][C:29]1([C:34]2(/[CH:37]=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31][O:30]1
Reactant: CC1(C2(C=O)CC2)OCCO1
Reactant: CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCCCC/C=C\C1(C2(C)OCCO2)CC1

Procedure:
4.87 g of heptyltriphenylphosphonium bromide and 1.25 g of aldehyde 7 are reacted analogously to 193., and 978 mg of title substance 206 is obtained as a colorless oil (only Z-isomer).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]([C:8](=[O:25])[N:9]([CH2:21][CH2:22][CH:23]=C)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[O:19][CH3:20])=C>C(Cl)Cl.[Ru]>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[C:8](=[O:25])[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])[CH2:21][CH2:22][CH:23]=1
Reactant: C=CCCN(Cc1ccc(OC)cc1OC)C(=O)C(=C)CCC(=O)OC
Agent: [Ru]
Solvent: ClCCl
Product: COC(=O)CCC1=CCCN(Cc2ccc(OC)cc2OC)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.1 %

Procedure:
130 mg of the compound (c) (0.360 mM) prepared by the above Step 2 was added to the catalyst solution containing 20 mg of ruthenium (0.024 mM) dissolved in CH2Cl2. Then the mixture was stirred for 24 hrs at room temperature, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with methanol/chloroform (1:10) solvent mixture as an eluant to give 108 mg of the title compound (d) (yield: 90%).
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:10]3=[N:11][CH:12]=[C:13]([NH2:15])[CH:14]=[C:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH:23](Br)[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[C:17]1([CH:23]([NH:15][C:13]2[CH:14]=[C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:16][C:10]3=[N:11][CH:12]=2)[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cnc2[nH]c(-c3ccccc3)nc2c1
Reactant: CC(Br)c1ccccc1
Solvent: CN(C)C=O
Product: CC(Nc1cnc2[nH]c(-c3ccccc3)nc2c1)c1ccccc1
Reaction time: 18 h

Procedure:
100 mg 2-phenyl-3H-imidazo[4,5-b]pyridin-6-ylamine from ex. b) were dissolved in 1 mL dry dimethylformamide (DMF) and 92 mg 1-phenylethyl bromide were added at room temperature. The mixture was stirred for 18 hours (hrs), the DMF was removed under vacuum and the residue purified by chromatography on silica eluting stepwise first with dichloromethane, then dichloromethane/methanol (60:1), then dichloromethane/methanol/ammonia (60:1:0,2). Product containing fractions were pooled and further purified by preparative HPLC-MS.
Reaction SMILES: FC(F)(F)C(O)=O.O.C(OC([N:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[C:30]([CH2:34][C@@H:35]([OH:43])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=[CH:32][CH:33]=2)[CH:25]=[N:26][CH:27]=1)=O)(C)(C)C>C(Cl)Cl>[NH:16]1[CH2:19][CH2:18][C@H:17]1[CH2:20][O:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[C:30]([CH2:34][C@@H:35]([OH:43])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=[CH:32][CH:33]=2)[CH:25]=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(C[C@@H](O)Cc3ccccc3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O[C@@H](Cc1ccccc1)Cc1cccc(-c2cncc(OC[C@@H]3CCN3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
Trifluoroacetic acid (1.6 mL) and water (0.16 mL) were added to CH2Cl2 (8.0 mL). This mixture was added to a sample of 1-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]-3-phenyl-2(S)-propanol (320 mg, 0.67 mmol) in a 25 mL round-bottom flask with magnetic stirrer under N2. After stirring at room temperature overnight, the solution was concentrated in vacuo, the residue was diluted with water, and the solution was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product (300 mg) was purified by preparative HPLC (column: SunFire Prep C18, 150×19, 5 μm particle size; UV detection at 254 nm; flow 20 mL/min; mobile phase: A, water with 0.05% TFA; B, methanol; 40-100% B in A in 8 min). The product-containing eluate was partially evaporated under reduced pressure to remove MeOH. The residual solution was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine and dried over Na2SO4. Concentration gave the free amine (130 mg, 52%) as a yellow oil. LC-MS (ESI) m/z 375 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].Br[C:51]1[S:52][C:53]2[CH:59]=[CH:58][CH:57]=[CH:56][C:54]=2[N:55]=1.C([O-])([O-])=O.[K+].[K+]>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>[S:52]1[C:53]2[CH:59]=[CH:58][CH:57]=[CH:56][C:54]=2[N:55]=[C:51]1[C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:7][C:6]=2[CH:22]=1
Reactant: Brc1nc2ccccc2s1
Reactant: COC(=O)c1cc(Br)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COC(=O)c1cc(-c2nc3ccccc3s2)cc2c1OC(c1ccccc1)(c1ccccc1)O2

Procedure:
Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (600 mg, 1.459 mmol, 1 eq.), Pd(PPh3)4 (85 mg, 0.073 mmol, 0.05 eq.), bis(pinacolato)diboron (480 mg, 1.9 mmol, 1.3 eq.) and KOAc (216 mg, 2.2 mmol, 1.5 eq.), then Pd(PPh3)4 (85 mg, 0.073 mmol, 0.05 eq.), 2-bromo-1,3-benzothiazole (375 mg, 1.75 mmol, 1.2 eq.) and K2CO3 (1 g, 7.3 mmol, 5 eq.) were used according to GP6 to yield the title product as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2([CH2:10][CH2:11][OH:12])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4][O:3]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:1][C:2]1([C:7]2([CH2:10][CH2:11][O:12][S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[CH2:9][CH2:8]2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(C2(CCO)CC2)OCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2(C3(C)OCCO3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
470 mg of 9 is dissolved in 10 ml of pyridine, and p-toluenesulfonyl chloride is added at 0° C. under nitrogen. It is stirred for 1 hour at 0° C., and then sodium bicarbonate solution is added. It is extracted with ethyl acetate, washed with dilute hydrochloric acid and then with sodium bicarbonate solution, dried on sodium sulfate and concentrated by evaporation. After the residue is chromatographed on silica gel with ethyl acetate/hexane, 670 mg of the title compound remains as a colorless oil.
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:9])[CH2:7][CH:8]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[CH3:16][C:17]1([CH3:27])[C@H:19]([CH:20]=[C:21]([Cl:23])[Cl:22])[C@H:18]1[C:24](Cl)=[O:25]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[CH3:16][C:17]1([CH3:27])[C@H:19]([CH:20]=[C:21]([Cl:22])[Cl:23])[C@H:18]1[C:24]([O:9][CH:6]1[CH2:7][CH:8]=[C:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]1)=[O:25]
Reactant: C=CCC1=CCC(O)C1
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@H]1C(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CCC1=CCC(OC(=O)[C@@H]2[C@@H](C=C(Cl)Cl)C2(C)C)C1
Yield: 57.8 %

Procedure:
To a mixture of (RS)-3-(2-propenyl)-3-cyclopenten-1-ol (100 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (82 mg) and toluene (5 ml), (1R)-trans-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarbonyl chloride (181 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 145 mg of (RS)-3-(2-propenyl)-3-cyclopenten-1-yl (1R)-trans-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylate (Compound No. 29). Yield 57% nD25 1.5100
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@H:19]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:22]([CH2:32][OH:33])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[Si:11]([O:18][C@H:19]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:22]([CH:32]=[O:33])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.5 %

Procedure:
To a solution of oxalyl chloride (2.4 mL) in methylene chloride (75 mL) at −78° C. was slowly added dimethylsulfoxide (3 mL) in methylene chloride (25 mL). After 10 minutes, a solution of tert-butyl (2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 190, 7.60 g) in methylene chloride (40 mL) was slowly added. After 30 minutes at −78° C., diisopropylethylamine (10 mL) was added and the reaction warmed to room temperature. The reaction was diluted with ethyl acetate, washed with 0.5 M HCl, NaHCO3 and brine solutions, dried (Na2SO4), filtered and concentrated. Chromatography on silica gel with a gradient of 0-30% ethyl acetate in hexanes gave 6.84 g of product.