Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])=[O:4].[O:14]=[C:15]1[N:19]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[NH:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:23]1[CH2:22][CH2:21][CH:20]([N:19]2[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[NH:16][C:15]2=[O:14])[CH2:25][CH2:24]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C(CBr)Nc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)Nc1ccc(F)cc1F

Procedure:
4 g (16 mmol) of the bromoacetanilide from Example I and 4.2 g (19 mmol) of 4-(2-oxo-1-benzimidazolinyl)piperidine in 50 ml of dimethylformamide are stirred at RT for 18 h with 2.6 g (19 mmol) of potassium carbonate. The solid is then filtered off with suction, the filtrate is partitioned between ethyl acetate and water, and the aqueous phase is extracted 3 times with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried (MgSO4) and concentrated. The residue obtained is triturated with ether, and the solid is filtered off and then recrystallized from methanol.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([N:30]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:39])[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:42][N:41]=[N:40][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([N:30]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]3=[O:39])[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-butyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][S:27][CH3:28])(=[O:5])[CH2:2][CH2:3][CH3:4].C1C=C(Cl)C=C(C(OO)=[O:37])C=1>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][S:27]([CH3:28])=[O:37])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1C
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 43.3 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-(2-methylthioethoxy)quinoline (0.15 g, 0.38 mmol) was dissolved in methylene chloride (3 ml) and cooled to -20° C. A solution of 71% m-CPBA (0.089 g, 0.36 mmol) in 1 ml of methylene chloride was added dropwise. The temperature was allowed to rise to room temperature whereafter the solution was stirred for 15 min at room temperature. The reaction mixture was washed with a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. Chromatography with methylene chloride:methanol 10:1 as the eluent gave 0.064 g (41%) of the desired product.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[N:14]=[N:13]2)=[C:8]([O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)=[O:5])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[N:14]=[N:13]2)=[C:8]([O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)OCC)nn2)c(OCCCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2cc(C(=O)O)nn2)c(OCCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
To a solution of ethyl 1-{4-[(ethylamino)carbonyl]-2-(3-phenylpropoxy)phenyl}-1H-1,2,3-triazole-4-carboxylate (0.22 g) obtained in Example 133d) in ethanol (6 ml) was added 1N aqueous sodium hydroxide solution (1.0 ml), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was diluted with water. The obtained aqueous solution was washed with ethyl acetate, acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale-yellow oil (0.21 g, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:6][CH2:5][CH:4]([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[O:3]1.[OH-].[Na+].[Cl:15][CH:16]([Cl:20])[C:17](Cl)=[O:18].[Cl-]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[N:6]([C:17](=[O:18])[CH:16]([Cl:20])[Cl:15])[CH2:5][CH:4]([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[O:3]1
Reactant: C=CCOCC1CNC(C)(C)O1
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: C=CCOCC1CN(C(=O)C(Cl)Cl)C(C)(C)O1

Procedure:
To a reaction mixture of 25 percent w/v, 34.2 milliliters of 2,2-dimethyl-5-allyloxymethyl oxazolidine solution in 100 milliliters benzene with 4 grams of 50% sodium hydroxide solution, was added dropwise, 7.4 grams of dichloroacetyl chloride. Cooling in an ice bath and vigorous stirring was maintained during the addition of the chloride. Upon completion of the reaction the mixture was washed with water, dried, separated and the organic solvent removed in vacuo. There was obtained 10.0 grams of the title compound, nD30 1.4705. Analytical data supports the structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:17][N:12]2C(=O)[O:14][CH2:15][C:11]2([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1.[OH-].[Na+].Cl.N1C=CN=C1.[CH3:32][C:33]([Si:36](Cl)([CH3:38])[CH3:37])([CH3:35])[CH3:34].N#N>CCO.CN(C=O)C.C(Cl)Cl.O>[Si:36]([O:14][CH2:15][C:11]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:17][NH:12]1)([C:33]([CH3:35])([CH3:34])[CH3:32])([CH3:38])[CH3:37]
Reactant: O=C1OCC2(c3ccccc3)C=C(c3cc(F)ccc3F)CN12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A suspension of 109.4 g (349 mmol) 1-7 in 2.2 L of EtOH and 105 mL (1.05 moles) of 10 M NaOH in a 10 L round bottom was heated at 60° C. for 4 h, cooled to room temperature and aged overnight. To this mixture was added 90.2 mL (1.08 moles) of concentrated HCl and the solvents were removed by rotary evaporation. The residue was suspended in 2 L of acetonitrile and again taken to dryness by rotary evaporation. The solids were suspended in 3.8 L of CH2Cl2 and 200 mL of DMF, 118.7 g (1.75 moles) of imidazole was added, followed by 110.5 (733 mmol) of TBSCl. After stirring for 15 h under a gentle stream of N2, the reaction was dumped into 4 L of water and 2 L of CH2Cl2, the layers were separated, and the aqueous layer was extracted with 2 L of CH2Cl2. The combined organic extracts were then washed with 4×4 L of water, dried over Na2SO4, and concentrated by rotary evaporation. The residue was dissolved in 500 mL of MeOH and 500 mL of 2M MeNH2 in MeOH, stirred for 4 h, and then concentrated by rotary evaporation. The residue was placed under high vacuum until a constant weight was obtained, and the material was crushed with a mortar and pestle to provide 1-8 as a beige solid. Data for 1-8: 1HNMR (500 MHz, CDCl3) δ 7.6-7.3 (m, 5H), 7.1-6.9 (m, 3H), 6.75 (s, 1H), 4.25 (d, 1H), 4.1 (d, 1H), 3.95 (d, 1H), 3.75 (d, 1H), 0.9 (s, 9H), 0.1 (s, 3H), 0.05 (s, 3H) ppm.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:14]([OH:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:26][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCCCCCO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOC(=O)c1ccc(OC(C)=O)cc1
Yield: 68.4 %

Procedure:
In 10 ml of pyridine was dissolved 2.0 g of 4-acetoxybenzoic acid chloride, and 2.4 g of dodecyl alcohol was added to the solution. Reaction was carried out at room temperature with stirring. The reaction mixture was treated by customary procedures to obtain 2.4 g of dodecyl 4-acetoxybenzoate. In the same manner as described in Referential Example 13, the acetoxy group was selectively isolated to quantitatively obtain dodecyl 4-hydroxybenzoate. This ester was dissolved in 20 ml of pyridine and a solution of 2.2 g of 3-chloro-4-benzyloxybenzoic acid chloride in 20 ml of pyridine was added to the above solution. The mixture was reacted at room temperature with stirring overnight and the reaction mixture was treated by customary procedures to obtain 3.3 g of 4'-dodecyloxycarbonylphenyl 3-chloro-4-benzyloxybenzoate. In the same manner as described in Referential Example 10, this ester was catalytically reduced to obtain 2.7 g of 4'-dodecyloxycarbonylphenyl 3-chloro-4-hydroxybenzoate.
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N:7][C:8](Cl)=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C(B(CC)[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)C.C([O-])([O-])=O.[K+].[K+]>CN(C=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]>[NH2:1][C:2]1[C:6]2=[N:7][C:8]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1sc2ccc(Cl)nc2c1N
Reactant: CCB(CC)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccc(-c3cccnc3)nc2c1N
Temperature: 95 °C
Yield: 81 %

Procedure:
A solution of the methyl 3-amino-5-chloro-thieno[3,2-b]pyridine-2-carboxylate prepared as described in Example 5A (0.252 g), diethyl 3-pyridyl-borane (0.155 g), Pd(dppf)Cl2 (0.082 g) and K2CO3 (420 mg) in degassed DMF (5 mL) was heated to 95° C. for 1.5 h, cooled, quenched in sat'd NH4Cl, the solid precipitate collected and chromatographed 9:1 hexane/EtOAc to give 0.24 g (81%) of the title compound: 1H NMR (300MHz, CDCl3) δ 3.95 (3H, s), 6.30 (2H, br s), 7.45 (1H, dd), 7.86 (1H, d), 8.19 (1H, d), 9:1 hexane/EtOAc to give 0.24 g (81%) of the title compound: 1H NMR (300MHz, CDCl3) δ 3.95 (1H, dd), 9.32 (1H, br d).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=[O:14].[N+:15]([O-])([OH:17])=[O:16]>OS(O)(=O)=O.O>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:15]([O-:17])=[O:16])=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=[O:14]
Reactant: COc1ccc2c(c1)CCN(C)C2=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc2c(cc1[N+](=O)[O-])C(=O)N(C)CC2
Temperature: -20 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 2-methyl-6-(methyloxy)-3,4-dihydro-1(2H)-isoquinolinone (5 g, 26.17 mmol) in H2SO4(2.17 mL) was added HNO3 (1.95 g, 31.4 mmol) dropwise at −20° C. The mixture was stirred for 2 h at −20° C. The reaction was diluted with water and the aqueous layer was extracted with dichloromethane. The combined organic layer was concentrated under reduced pressure to afford 2-methyl-6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-isoquinolinone (4.7 g, 75.8%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:17]=[C:18]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][N:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)[CH:28]=[CH:27][CH:26]=2)[C:19]([C:22]#[N:23])=[N:20][CH:21]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:17]=[C:18]([NH:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([CH2:31][N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:30]=2)[C:19]([C:22]#[N:23])=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Nc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cccc(CN2CCNCC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-[(6-{[5-({(1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)-2-cyanopyridin-3-yl]amino}pyridin-2-yl)methyl]piperazine-1-carboxylate (90 mg, 0.15 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.17 mL, 2.2 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The reaction was then concentrated under reduced pressure to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-{[6-(piperazin-1-ylmethyl)pyridin-2-yl]amino}pyridine-2-carbonitrile. The material was used in the next step without further purification. MS ESI calc'd for C22H31N8 [M+H]+ 407. found 407.
Reaction SMILES: [Br:1]C1C=C2C(C=CN2)=CC=1F.[C:12]([C:15]1[C:23]2[C:18](=[CH:19][C:20](F)=[C:21]([F:24])[CH:22]=2)[N:17]([CH2:26][C:27]([OH:29])=[O:28])[CH:16]=1)(=[O:14])[NH2:13]>>[Br:1][C:20]1[CH:19]=[C:18]2[C:23]([C:15]([C:12](=[O:14])[NH2:13])=[CH:16][N:17]2[CH2:26][C:27]([OH:29])=[O:28])=[CH:22][C:21]=1[F:24]
Reactant: Fc1cc2cc[nH]c2cc1Br
Reactant: NC(=O)c1cn(CC(=O)O)c2cc(F)c(F)cc12
Product: NC(=O)c1cn(CC(=O)O)c2cc(Br)c(F)cc12

Procedure:
was prepared from 6-bromo-5-fluoro-1H-indole [259860-08-7] in a similar manner as described for the preparation of (3-carbamoyl-5,6-difluoro-indol-1-yl)-acetic acid. White solid. MS (LC/MS): 315.0 [M+H]+, 631.0 [2M+H]+; tR (HPLC conditions k): 2.79 min.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].C([O:10][C:11]([C:13]1[S:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:20][CH2:19]2)=[N:16][N:17]=1)=O)C>>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH:5][C:11]([C:13]1[S:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:22][CH2:23]2)=[N:16][N:17]=1)=[O:10]
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Reactant: CC(C)(C)CCN
Product: CC(C)(C)CCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 3,3-dimethylbutylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.053 g, yield 93%). 1H NMR (300 MHz, CDCl3) δ 7.72-7.69 (m, 1H), 7.63-7.51 (m, 2H), 7.33-7.31 (m, 1H), 6.99 (br., t, 1H), 4.07-3.99 (m, 1H), 3.89-3.81 (m, 1H), 3.74-3.59 (m, 2H), 3.53-3.49 (m, 2H), 3.44-3.37 (m, 2H), 3.33-3.29 (m, 2H), 1.51-1.49 (m, 2H), 0.92 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 174.4, 167.5, 158.1, 155.9, 133.9, 132.4, 129.6, 127.1, 126.9, 126.8, 126.7, 126.2, 125.3, 121.7, 49.5, 48.9, 45.9, 42.9, 40.7, 36.4, 29.9, 29.3. MS (ES+) m/z 470 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36](=[O:56])[CH2:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40](OS(C(F)(F)F)(=O)=O)[CH:39]=1>>[CH3:34][O:35][C:36](=[O:56])[CH2:37][C:38]1[CH:39]=[C:40]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:33])[CH2:31][CH3:32])[CH:41]=[C:42]([C:44]([F:46])([F:45])[F:47])[CH:43]=1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:52])([CH3:51])[CH2:35][CH:36]([Sn:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])O)=[CH:30][CH:29]=1>C(Cl)Cl.C(#N)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:52])([CH3:51])[CH2:35][CH:36]([I:25])[Sn:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:30][CH:29]=1
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)C(O)CC(C)(C)c1ccc(Cl)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)C(I)CC(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.4 %

Procedure:
A solution of 14.0 grams (0.053 mole) of triphenylphosphine in about 54 mL of methylene chloride was stirred, and 3.6 grams (0.053 mole) of imidazole was added. Upon completion of addition, the reaction mixture was stirred about 45 minutes until the imidazole dissolved. The reaction mixture was then cooled in an ice bath, and 13.6 grams (0.053 mole) iodine was added portionwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 15 minutes until the iodine dissolved. After this time the reaction mixture was cooled to 0° C., and a solution of 17.4 grams (0.036 mole) of 3-(4-chlorophenyl)-3-methyl-1-tributylstannylbutanol in about 36 mL of methylene chloride was added dropwise while maintaining the reaction mixture temperature below 5° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. The reaction mixture was then taken up in about 100 mL of acetonitrile and extracted with three 150 mL portions of hexane. The combined extracts were concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using petroleum ether as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of 3-(4-chlorophenyl)-3-methyl-1-iodo-1-tributylstannylbutane. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:42]1([C:48](=[O:73])[CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH2:68])[CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:58][CH:57]=2)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C=O)C>[N:42]1([C:48](=[O:73])[CH2:49][O:50][C:51](=[O:72])[C@@:52]([CH2:70][OH:71])([CH3:69])[CH2:53][C@H:54]([NH:68][C:6]([C:4]2[NH:3][N:2]=[N:1][CH:5]=2)=[O:8])[CH2:55][C:56]2[CH:61]=[CH:60][C:59]([C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[CH:58][CH:57]=2)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1
Reactant: O=C(O)c1c[nH]nn1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCC(=O)N1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-morpholin-4-yl-2-oxo-ethyl ester (54 mg, 120 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (35 mg; purity 95%). MS m/z [M+H]+ calc'd for C28H33N5O6, 536.24. found 536.2.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([CH2:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])(=[O:15])=[O:14])[CH2:9]2)C=CC=CC=1.[H][H].[ClH:31]>C(O)C.O.[OH-].[OH-].[Pd+2]>[ClH:31].[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([CH2:12][CH:10]1[CH2:11][NH:8][CH2:9]1)(=[O:14])=[O:15]
Reactant: [H][H]
Reactant: O=S(=O)(CC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1F
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S(=O)(CC1CNC1)c1ccccc1F
Yield: 91 %

Procedure:
1-(Diphenylmethyl)-3-{[(2-fluorophenyl)sulfonyl]methyl}azetidine (1.33 g, 3.37 mmol) was dissolved in ethanol (80 mL). The solution was diluted with 2M hydrochloric acid (1.8 mL) and water (20 mL). 20% Palladium hydroxide on carbon (0.63 g) was added and the mixture shaken on a Parr apparatus under 50 psi of hydrogen for 3.5 h. The catalyst was removed by filtration and the filtrate concentrated to a small volume. The solid present was redissolved by adding ethanol and the solution filtered. The filtrate was concentrated to a small volume once again to give a crystalline solid which was collected under suction, washed with cold ethanol and dried in vacuo to afford the title compound as colourless crystals (0.81 g, 91%); 1H NMR (500 MHz, CD3OD) δ 3.34–3.42 (1H, m), 3.80 (2H, d, J=7.6 Hz), 4.07 (2H, t, J=10 Hz), 4.14 (2H, t, J=10 Hz), 7.41–7.49 (2H, m), 7.80–7.84 (1H, m), 7.90–7.92 (1H, m); 19F NMR (471 MHz, CD3OD) δ −110.6; m/z (ES+) 230 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N+]=[N-])=[CH:4][CH:3]=1.[CH:18]([CH:20]=[CH2:21])=[O:19]>ClCCl.CCCCCCC.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH2:21][CH:20]2[CH:18]=[O:19])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C=CC=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=CC1CC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of bis(4-fluorophenyl)diazomethane, prepared as in Example 84 from the action of activated manganese dioxide (59.7 g) on 4,4'-difluorobenzophenone hydrazone (42.81 g) in dichloromethane (195 mL), was added to a solution of acrolein (15.7 mL) in heptane (150 mL). The deep purple reaction mixture, after being stirred at 40° C. for 2 hours then at 53° C. for 30 minutes, faded to a pale amber color. Evaporation of the solvents afforded 46 g of 2,2-bis(4-fluorophenyl)cyclopropanecarboxaldehyde as an oil. The material was used without further purification in subsequent reactions.
Reaction SMILES: O.N[C:3]1[C:30](Cl)=[CH:29][C:6]([C:7]([NH:9][C@H]2CCN(CCCOC3C=CC(F)=CC=3)C[C@H]2OC)=[O:8])=[C:5]([O:32][CH3:33])[CH:4]=1>CO>[CH3:33][O:32][C:5]1[CH:4]=[CH:3][CH:30]=[CH:29][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC
Solvent: O
Solvent: CO
Product: COc1ccccc1C(N)=O

Procedure:
40 Parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide monohydrate were boiled in 160 parts of methanol. The product was filtered off while hot and crystallized twice from a mixture of 600 parts of tetrachloromethane and 400 parts of trichloromethane. The product was filtered off, dried and recrystallized from 4-methyl-2-pentanone. The product was filtered off and dried (water-separator) yielding 18.5 parts of cis-4-amino-5-chloro-N-[2-chloro-4-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]aminocarbonyl]-5-methoxyphenyl]-2--methoxybenzamide; mp. 181.5° C. (compound 239).