Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:48]=[CH:47][C:25]([O:26][C:27]([CH3:46])([CH3:45])[CH:28]([OH:44])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:32]=2)=[CH:24][CH:23]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]([CH3:46])([CH3:45])[C:28](=[O:44])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:33][CH:32]=2)=[CH:47][CH:48]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(OCC(O)C(C)(C)Oc2ccc(CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(OCC(=O)C(C)(C)Oc2ccc(CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Temperature: 22 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
A solution of (2R and 2S)-3-[4-[3-(tert-butyldiphenysilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-3-methyl-2-butanol (0.60 g, 0.89 mmol) in dry dichloromethane (30 ml) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) (1.50 g, 3.57 mmol) and the resulting mixture was stirred at 22° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with 5% sodium thiosulfate, saturated sodium bicarbonate and brine. After drying (magnesium sulfate), the organic phase was concentrated and chromatographed on silica gel. Elution with a mixture of toluene and ethyl acetate (98:2) gave 0.587 g (98%) of the title material as a clear oil.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:31]=[CH:30][C:29]([S:32]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)(=[O:33])=[O:34])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1)N1CCOCC1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 4-(4-bromo-benzenesulfonyl)-morpholine (example B.26) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (420 mg, 74%). MS (ISP) 563.4 [(M+H)+]; mp 227–228° C.
Reaction SMILES: [CH2:1]1[C@H:14]2[C@@H:5]([NH:6][C:7]3[C:12]([CH2:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.C1[C@@H]2[C@H:18]([NH:19]C3C=CC=CC=3C2)[CH2:17]C1>>[CH2:11]1[C@H:12]2[C@@H:7]([N:6]([CH2:17][C:18]#[N:19])[C:5]3[C:14]([CH2:13]2)=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:8][CH2:9][CH2:10]1
Reactant: c1ccc2c(c1)C[C@@H]1CCC[C@H]1N2
Reactant: c1ccc2c(c1)C[C@H]1CCCC[C@@H]1N2
Product: N#CCN1c2ccccc2C[C@H]2CCCC[C@@H]21

Procedure:
The title compounds were prepared according to the procedure of Example 1 step 3 except that Cis and Trans-1,2,3,4,4a,9,9a,10-octahydroacridine were used instead of Cis and Trans 2,3,3a,4,9,9a-Hexahydro-1H-cyclopenta[b]quinoline, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4](F)[CH:3]=1.[C-:15]#[N:16].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4]([C:15]#[N:16])[CH:3]=1
Reactant: [C-]#N
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1C#N
Yield: 7.1 %

Procedure:
4-Bromo-2-fluoro-N,N-dimethylbenzenesulfonamide (1.0 g, 3.5 mmol) and sodium cyanide (350 mg, 7.1 mmol) were dissolved in DMF (3 mL) and irradiated in the microwave at 150° C. for 20 minutes. DMF was removed in vacuo and the residue was redissolved in dichloromethane (5 mL). The organics were washed with 5 mL of each 1N aqueous HCl, saturated aqueous NaHCO3, and brine. Organics were dried over Na2SO4 and evaporated to dryness. Crude product was purified by chromatography on silica gel (eluting with 0-50% ethyl acetate in hexanes) to afford 4-bromo-2-cyano-N,N-dimethylbenzenesulfonamide (72 mg, 7%). ESI-MS m/z calc. 288.0, found 288.9 (M+1)+; retention time 1.44 minutes.
Reaction SMILES: [C:1](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1](/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][Br:14])=[CH:11][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)/C=C/c1ccc(C)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C/c1ccc(CBr)cc1
Yield: 99.3 %

Procedure:
A mixture of 4-{(E)-2-carbomethoxyethenyl}toluene (17.6 g), N-bromosuccinimide (17.8 g) and a trace of dibenzoxylperoxide was refluxed in carbon tetrachloride under illumination until the brown-red colour disappeared. Filtration and evaporation of the solvent gave 4-{(E)-2-carbomethoxyethenyl}benzyl bromide (25.3 g). This was dissolved in dry tetrahydrofuran, heated with the sodium salt of ethyl acetoacetate (15.2 g) and a trace of potassium iodide and refluxed for 1.5 days. The solvent was removed the residue partitioned between ether and water and the ether layer dried. Removal of the solvent gave an oil (26.6 g). This was stirred with sodium hydroxide (10 g) in water (400 ml) for 2 days. The solution was extracted with ether, the aqueous layer made acidic with hydrochloric acid and this was heated on a steam bath for 1 h. The solution was extracted with chloroform and the organic layer dried (MgSO4). Removal of the solvent gave the acid of the title compound (11.0 g). This was esterified with methanol-sulphuric acid to give the title compound. τ(CDCl3) 7.9 (3H, s), 7.0-7.5 (4H, m), 6.25 (3H, s), 3.65 (1H, d, J= 16 Hz), 2.85 (2H, d, J=8 Hz), 2.6 (2H, d, J=8 Hz), 2.4 (1H, d, J=16 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2].[CH3:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([C:40](O)=[O:41])[C:29]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:40]([C:28]3[C:29]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][CH:31]=4)=[C:24]([CH3:23])[CH:25]=[CH:26][CH:27]=3)=[O:41])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2]
Reactant: N#Cc1cccc(CN2CCN(c3ccc(N)cc3)CC2)c1
Reactant: Cc1cccc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)Nc2ccc(N3CCN(Cc4cccc(C#N)c4)CC3)cc2)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.1 %

Procedure:
To a stirred solution of 4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (400 mg), 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid (460 mg), HOBt (222 mg), and Et3N (166 mg) in CH2Cl2 (20 mL) was added at room temperature EDCl (315 mg) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3 and dried over Na2SO4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with CH2Cl2/MeOH (98/2) and crystallized from AcOEt to give the title compound (122 mg) as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]([F:24])([F:23])[F:22])[NH2:16]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([O:20][C:21]([F:22])([F:23])[F:24])=[C:13]([Cl:12])[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(Cl)c1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 185.2 using 5-bromo-6-chloro-nicotinic acid and 3-chloro-4-(trifluoromethoxy)aniline to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.72 min, UPLC-MS (Condition 3) tR=1.34 min, m/z=429.0 [M−H]−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:25][C:26](O)=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([C@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([CH:36]1[CH2:40][O:39][C:38](=[O:41])[N:37]1[C:26](=[O:27])[CH2:25][C:11]1[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=2)[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: O=C(Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1)N1C(=O)OCC1Cc1ccccc1

Procedure:
The title compound was prepared from (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid and (S)-(−)-4-benzyl-2-oxazolidinone following the same procedure as for the synthesis of compound 39a.
Reaction SMILES: [NH2:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1.[C:16]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[C:16]([O:20][C:21]([NH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NC1CN(Cc2ccccc2)CC12CC2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CN(Cc2ccccc2)CC12CC2
Reaction time: 2 h
Yield: 75.3 %

Procedure:
In 30 ml of tetrahydrofuran was dissolved 800 mg of compound 6 followed by the addition of 1.2 g of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON) at room temperature and the mixture was stirred at that temperature for 2 hours. The solvent was then removed under reduced pressure and to the residue was added chloroform. The mixture was extracted with a 10% aqueous citric acid. The citric acid extract was adjusted to pH≥10 with 1N aqueous sodium hydroxide and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give 900 mg of 7-tert-butoxycarbonylamino-5-benzyl-5-azaspiro[2.4]heptane (compound 10). 870 mg of this compound 10 was dissolved in 15 ml of ethanol and catalytic hydrogenation was carried out at 40° C. and 4.5 kg/cm2 in the presence of 500 mg of 10% palladium-on-carbon for 2 hours. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure to give title compound 11. This product was used without purification in the substitution reaction.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:19])[CH2:14][C:15](=[N:17]O)[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:19][N:17]=[C:15]([CH3:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CC(=O)[C@@H]1CCCN1Cc1ccccc1)=NO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc([C@@H]2CCCN2Cc2ccccc2)on1
Temperature: 25 °C

Procedure:
To a solution of 878 mg 1-((S)-1-Benzyl-pyrrolidin-2-yl)-butane-1,3-dione 3-oxime in 50 ml dichloromethane were added 0.52 ml methanesulfonyl chloride and 0.94 ml triethylamine at 0° C. The solution was allowed to warm to RT within 5 h. The reaction mixture was extracted with 1 M HCl (3×), the aqueous extracts were neutralized with solid NaHCO3 and extracted with dichloromethane (3×) to give the crude product which was purified by chromatography on silica using ethyl acetate/heptane 1/2 as eluent.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:25])([CH2:23][OH:24])[C:19]([F:22])([F:21])[F:20])=[O:15].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.N1C=CC=CC=1>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:24][CH2:23][C:18]([CH2:17][NH:16][C:14]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=3)[C:2]=2[NH2:1])=[O:15])([OH:25])[C:19]([F:22])([F:21])[F:20])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1c(C(=O)NCC(O)(CO)C(F)(F)F)cnn1-c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(O)(CNC(=O)c2cnn(-c3ccc(F)cc3)c2N)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
To a stirred solution of 5-amino-1-(4-fluorophenyl)-N-[3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]-1H-pyrazole-4-carboxamide (2.47 g, 6.82 mmol) in anhydrous dichloromethane (20 ml) and anhydrous pyridine (20 ml) cooled in an ice bath under a nitrogen atmosphere was added p-toluenesulphonyl chloride (1.7 g, 8.9 mmol). The mixture was stirred for 6 hours at ice bath temperature before being allowed to warm to room temperature and stirred overnight. The solution was evaporated under vacuum and the residue was partitioned between ethyl acetate (100 ml) and water (30 ml). The separated organic phase was washed with 2M hydrochloric acid (2×30 ml), water (30 ml), saturated sodium hydrogen carbonate (30 ml), water (30 ml) and saturated brine (50 ml) before being dried over sodium sulphate and evaporated under reduced pressure to give a foam (3.45 g). This foam was purified on a Flashmaster column of Silica (100 g) using a 0-100% ethyl acetate in cyclohexane gradient over 1 hour. This afforded the title compound (2.8 g, 79%) as a foam.
Reaction SMILES: [CH2:1]([O:9][C:10](=[O:20])[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[C:27](Cl)(=[O:29])[CH3:28]>C1(C)C=CC=CC=1>[CH2:1]([O:9][C:10](=[O:20])[CH:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][O:13][C:27](=[O:29])[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOC(=O)C(CO)c1ccccc1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)C(COC(C)=O)c1ccccc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
To 60.4 g of 3-hydroxy-2-phenyl-propionic acid octyl ester in 150 ml of toluene is added at 4° C. 22.9 g (290 mmol) of pyridine followed by 22.8 g (290 mmol) of acetyl chloride dissolved in 50 ml of toluene. The reaction mixture is stirred for 2 hours at 4° C. The white precipitate is filtered off and washed with 100 ml of toluene to afford 70.5 g of 3-acetoxy-2-phenyl-propionic acid octyl ester used as crude material in the next step.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH:20]([O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:22])[CH3:21]
Reactant: Oc1ccc(Br)c2ccccc12
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Br)c2ccccc12
Temperature: 25 °C

Procedure:
The following is an adaptation of the method of Bringmann. A solution containing 4-bromo-1-naphthol (10.0 g, 0.045 mol), potassium carbonate (31 g, 0.224 mol), and 2-bromopropane (27.6 g, 0.224 mol) in DMF was heated at reflux for 1 h under a nitrogen atmosphere. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The resultant residue was subjected to silica gel chromatography using a 50% ethyl acetate-hexane mixture as the eluent to provide 4-isopropoxy-1-bromonaphthalene.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:9](=[O:10])[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.[H-].[Na+].Cl[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27]>O1CCCC1>[CH2:29]([O:28][C:26]([N:8]1[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]2[C:5](=[C:4]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:3]([C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])[C:2]2=[O:1])[C:9]1=[O:10])=[O:27])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOC(=O)Cl
Reactant: O=c1nc(-c2ccccc2)c2c(=O)nc(-c3ccccc3)c1=2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)N1C(=O)C2=C(c3ccccc3)N(C(=O)OCCCC)C(=O)C2=C1c1ccccc1
Reaction time: 24 h
Yield: 72.5 %

Procedure:
To a suspension of 0.5 g (0.00175 mol) of 1,4-diketo-3,6-diphenylpyrrolo[3,4-c]pyrrole in 17 ml of tetrahydrofuran are added, under argon, 0.28 g (0.007 mol) of solid sodium hydride. After stirring for 24 hours, 0.67 ml (0.007 mol) of n-butyl chloroformate are added and the suspension is stirred overnight. The mixture is filtered and the filtrate is concentrated under vacuum. The residue is taken up in water/diethyl ether, the organic phase is dried over MgSO4 and then concentrated under vacuum. The residue is taken up in n-hexane and the precipitated yellow powder is collected by filtration and washed with a minor amount of n-hexane, giving 0.62 g (73% of theory) of N,N'-bis(n-butoxycarbonyl)-1,4-diketo-3,6-diphenylpyrrolo[3,4-c]pyrrole as a yellow fluorescent powder.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[NH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Reactant: CN(C)CCN
Agent: Cl
Product: CN(C)CCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 20.7 mg (0.23 mmol) of N-(2-aminoethyl)-N,N-dimethylamine are reacted together by general method E. 17.4 mg (24.8% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]2[C@H:12]([OH:25])[CH2:13][CH2:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[CH2:16][C:9]2=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C(N(CC)CC)C.[O:35]=[C:36]1[NH:44][C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[N:37]1[CH:45]1[CH2:50][CH2:49][N:48]([C:51](OC2C=CC([N+]([O-])=O)=CC=2)=[O:52])[CH2:47][CH2:46]1>C1COCC1>[O:35]=[C:36]1[NH:44][C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[N:37]1[CH:45]1[CH2:46][CH2:47][N:48]([C:51]([O:25][C@H:12]2[C:10]3=[N:11][C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:7][CH:8]=[C:9]3[CH2:16][C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[F:24])[CH2:14][CH2:13]2)=[O:52])[CH2:49][CH2:50]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: CC(C)(C)Nc1ccc2c(n1)[C@H](O)CC[C@@H](c1cccc(F)c1F)C2
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)Nc1ccc2c(n1)[C@H](OC(=O)N1CCC(n3c(=O)[nH]c4ncccc43)CC1)CC[C@@H](c1cccc(F)c1F)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6R,9R)-2-(tert-butylamino)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (69.1 mg, 0.199 mmol) with stirring bar was azeotroped by benzene. Sodium hydride (47.9 mg, 1.995 mmol) was added to the THF (3 mL) suspension of (6R,9R)-2-(tert-butylamino)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (69.1 mg, 0.199 mmol) and 4-nitrophenyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate compound with triethylamine (1:3) trihydrochloride (238 mg, 0.299 mmol) at rt. The reaction was stirred at room temperature overnight. The reaction was quenched by water and partitioned between ethyl acetate and water. The ethyl acetate layer was washed by water twice before dried (Na2SO4), filtered and concentrated. Flash column by methanol in CH2Cl2 from 0 to 10% gave the desired product as a white solid. The product was further purified by prep HPLC (69.2 mg, 26%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.07 (d, J=5.19 Hz, 1H) 7.34-7.44 (m, 1H) 6.96-7.15 (m, 4H) 6.08-6.28 (m, 1H) 5.83-5.99 (m, 1 H) 4.42-4.77 (m, 3H) 3.16-3.25 (m, 1H) 2.86-3.14 (m, 3H) 2.62-2.72 (m, 1H) 2.11-2.38 (m, 5H) 1.94 (d, J=11.90 Hz, 3H) 1.52-1.60 (m, 1H) 1.46 (s, 9H).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)=[O:5].[CH2:12]([Mg]Br)[CH3:13]>O1CCCC1>[O:8]1[CH2:9][CH2:10][CH:6]([C:4](=[O:5])[CH2:12][CH3:13])[CH2:7]1
Reactant: CON(C)C(=O)C1CCOC1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)C1CCOC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
Into a 250-mL 3-neck round-bottom flask, was placed a solution of N-methoxy-N-methyltetrahydrofuran-3-carboxamide (compound 263.1, 6.71 g, 42.2 mmol) in tetrahydrofuran (100 mL). The system was purged with nitrogen, then cooled to 0° C. Ethylmagnesium bromide (3M in diethyl ether, 17 mL, 51 mmol) was added drop-wise at 0° C. over 30 min. The resulting solution was stirred overnight at 40° C., then cooled and carefully quenched with aqueous HCl (1M, 10 mL). The resulting mixture was concentrated under reduced pressure and the residue was diluted with water (10 mL). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic extracts were washed with brine (2×10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. Obtained the title compound as a light yellow oil (4.5 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32]C(OCC=C)=O)[C:27]=2[F:39])[CH:5]=[CH:4][N:3]=1.C([SnH](CCCC)CCCC)CCC.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.ClCCl>[NH2:32][C:28]1[C:27]([F:39])=[C:26]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)sc2-c2ccnc(Cl)n2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(N)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 1 h
Yield: 94.6 %

Procedure:
1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(2-fluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}phenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (855 mg, 1.489 mmol) was dissolved into dichloromethane (DCM) (8 mL). To this solution were added tributylstannane (433 mg, 1.489 mmol), tetrakis (86 mg, 0.074 mmol) and water (0.083 mL, 4.62 mmol), and the reaction mixture was stirred for 1 h and concentrated. The residue was purified using column chromatography (0 to 100% EtOAc/hexane) to give 690 mg of the title compound. MS (ESI): 490.1 [M+1]+.