Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH2:19]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:22][CH2:23]2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Product: CCCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure A-1, 1-{6-bromo-4-[trans-4-((dimethylamino)methyl)cyclohexylamino]quinolin-3-yl}butan-1-one (48 mg, 0.110 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (45 mg, 0.165 mmol) to afford the desired product (36 mg, 67%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.14 (s, 1H), 8.47 (s, 1H), 8.26 (dd, J=8.7, 1.8 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J=11.3 Hz, 1H), 4.52 (s, 1H), 3.16-3.05 (m, 4H), 2.95 (s, 6H), 2.49-2.43 (m, 2H), 2.08-2.01 (m, 2H), 1.85-1.74 (m, 4H), 1.41-1.32 (m, 1H), 1.09-1.02 (t, J=7.4 Hz, 3H); ESI MS m/z 498 [C28H33ClFN3O2+H]+; HPLC>99% (AUC), tR=11.08 min.
Reaction SMILES: C([O:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:23]3[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:22]3=[O:24])[CH2:15][N:14]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:13]2)=[O:11])[CH2:7][C:6](=[O:38])[O:5]1)C.FC(F)(F)C(O)=O>C(#N)C.O>[OH:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:23]3[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:33])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:22]3=[O:24])[CH2:15][N:14]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:13]2)=[O:11])[CH2:7][C:6](=[O:38])[O:5]1
Reactant: CCOC1OC(=O)CC1NC(=O)[C@@H]1CN(S(C)(=O)=O)C[C@@H]2CCCC[C@H](NC(=O)c3ccccc3)C(=O)N21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CS(=O)(=O)N1C[C@@H]2CCCC[C@H](NC(=O)c3ccccc3)C(=O)N2[C@H](C(=O)NC2CC(=O)OC2O)C1
Reaction time: 0.5 h

Procedure:
A solution of (4S,6S,10aS)-6-benzoylamino-2-methanesulfonyl-5-oxo-decahydro-2,4a-diaza-benzocyclooctene-4-carboxylic acid (2-ethoxy-5-oxo-tetrahydrofuran-3-yl)amide, 15, (70 mg, 0.13 mmol) in acetonitrile/water is treated with trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated in vacuo and the crude product purified by preparative reverse phase HPLC to afford the desired product. 1H NMR (CD3OD) δ 7.90–7.88 (d, J=6.9 Hz, 2H), 7.52–7.55 (t, J=7.2 Hz, 1H), 7.52–7.47 (d, J=6.9 Hz, 2H), 5.14–5.11 (m, 2H), 4.69–4.67 (m, 1H), 4.54–4.49 (broad, d, J=12.6 Hz, 1H), 4.34–4.30 (m, 1H), 4.24–4.19 (broad d, J=12.9 HZ, 1H), 3.69–3.65 (d, J=12 Hz,1H), 3.40–3.28 (m, 3H), 3.09–3.04 (m,1H), 3.01 (s, 3H), 2.71–1.28 (m, 11H); MS 522.8 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[C:12](I)=[CH:11][N:10]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:6]=3[N:7]=[CH:8][N:9]=2)[CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[C:29]([O:33][C:34](=[O:52])[N:35]([C:45]1[CH:46]=[N:47][C:48]([Cl:51])=[CH:49][CH:50]=1)[C:36]1[CH:41]=[CH:40][C:39]([CH:42]=[O:43])=[C:38]([F:44])[N:37]=1)([CH3:32])([CH3:31])[CH3:30].O>O1CCCC1>[C:29]([O:33][C:34](=[O:52])[N:35]([C:45]1[CH:46]=[N:47][C:48]([Cl:51])=[CH:49][CH:50]=1)[C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:12]2[C:5]3[C:4]([CH:1]4[CH2:2][CH2:3]4)=[N:9][CH:8]=[N:7][C:6]=3[N:10]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])[CH:11]=2)[OH:43])=[C:38]([F:44])[N:37]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)nc1)c1ccc(C=O)c(F)n1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2c(C3CC3)ncnc21
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(N(C(=O)OC(C)(C)C)c3ccc(Cl)nc3)nc2F)c2c(C3CC3)ncnc21
Temperature: -5 °C
Yield: 55.4 %

Procedure:
To 4-cyclopropyl-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (19, 0.72 g, 1.64 mmol) in 6.0 mL of tetrahydrofuran at −40° C. under nitrogen, isopropylmagnesium chloride (0.82 mL, 2.01 M in tetrahydrofuran, 1.65 mmol) is added slowly. The reaction is allowed to warm to −5° C. in 75 minutes, then cooled to −45° C. and (6-chloro-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (80, 0.48 g, 1.38 mmol) in 5.0 mL is added. The reaction is allowed to warm to room temperature in 2 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (81, 0.51 g). MS (ESI) [M+H+]+=667.2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[CH3:22])O)[CH3:2].S(=O)(=O)(O)O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:26])/[C:5](/[O:23][CH2:24][CH3:25])=[CH:6]/[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)C(OCC)C(O)c1ccc(OCc2ccccc2)cc1C
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)cc1C)OCC
Temperature: 100 °C
Yield: 99.4 %

Procedure:
To a solution of 3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethyl ester (mixture of stereoisomers; 48.8 g, 136.2 mmol) in N,N-dimethylformamid (500 ml) was added sulfuric acid (19.6 ml, 96%). The reaction mixture was heated to 100° C. for 2.5 h, cooled to ambient temperature, poured onto ice water/saturated aqueous NaHCO3 solution 1/1 and extracted two times with ethyl acetate. The combined extracts were washed with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give 46.1 g (135.4 mmol) of crude (Z)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-acrylic acid ethyl ester which was used in the next step without further purification.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([CH2:11][NH:12]C(=O)OC(C)(C)C)[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1>Cl.CCOC(C)=O>[NH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]2[CH2:4][O:3][B:2]([OH:1])[C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)B(O)OC2
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
tert-Butyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methylcarbamate (CXI) (0.27 g, 1.02 mmol) was dissolved in HCl/EtOAc (4.2 M, 7 mL/mmol) and stirred for 30 minutes at room temperature. The solvent was removed under vacuum and residue was triturated with Et2O to give 6-(aminomethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CXII) as a white solid (0.15 g, 0.75 mmol, 74% yield). 1H NMR (DMSO-d6) δ ppm 4.00 (s, 2H), 4.69 (s, 2H), 7.21-7.51 (brs, 1H), 7.52-7.66 (brs, 1H), 7.67-7.88 (brs, 1H), 8.06-8.98 (brs, 3H); ESIMS found for C8H10BNO2 m/z 146.7 (M−H2O+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:25]=1[Cl:24])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(=O)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a ice-cold solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester 1 (5 g, 21.5 mmol) and triethylamine (4.56 g, 45.0 mmol) in dichloromethane (100 ml) was added 2,4-dichlorobenzoyl chloride (3.90 g, 19.4 mmol). The reaction mixture was stirred for 30 min a 0° C. and 16 h at room temperature. Then, the reaction mixture was partitioned between 25 ml of H2O, 50 ml sat. NaHCO3 and 50 ml of CH2Cl2. The organic layer was separated and the aqueous phase was washed twice with CH2Cl2 (2×50 mL). The combined dichloromethane layer was dried (MgSO4), concentrated and the residue was purified by recrystallization in CH2Cl2 to obtain 5.832 g (74%) as a white solid of 3-(2,4-Dichloro-benzoylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 8.30 ppm (s, 1H, Haro); 7.74-7.66 ppm (m, 3H, Haro); 7.51 ppm (d, 1H, Haro); 7.46-7.34 ppm (m, 4H, Haro); 3.91 ppm (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:6][NH:7][C:8](=[O:23])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C@H:19]([CH3:22])[CH2:20][OH:21].C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>CN(C)C1C=CN=CC=1.ClCCl>[C:36]([O:21][CH2:20][C@H:19]([NH:18][C:10]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=1[C:8]([NH:7][CH2:6][C:5]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:23])[CH3:22])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H](C)CO)cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H](C)COC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of (R)-N-(3,4-dimethoxybenzyl)-2-(2-hydroxy-1-methylethylamino)-5-nitrobenzamide (5.00 g), 4-dimethylaminopyridine (1.57 g, 12.8 mmol) and triethylamine (1.79 mL) in dichloromethane (150 mL) was added acetyl chloride (1.83 mL), and the mixture was stirred for 5 hours at ambient temperature. The mixture was washed with 1N-hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether. The obtained product was recrystallized from a mixture of ethyl acetate and hexane (1:1) to give (R)-2-(2-acetoxy-1-methylethylamino)-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide as yellow crystals (5.10 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].[C:15]([O:18][CH2:19]Br)(=[O:17])[CH3:16].Cl>CN(C)C=O.O>[C:15]([O:18][CH2:19][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OCBr
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCn1cc(C(=O)O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
1H-Indole-3-carboxylic acid (400 mg) was dissolved in N,N-dimethylformamide (6 ml) and cooled to 0° C. Sodium hydride (500 mg) was added to the solution in two divided portions, and the mixture was stirred as such for 30 minutes. Bromomethyl acetate (0.32 ml) was added slowly dropwise thereto, and the mixture was stirred for 15 minutes at 0° C., warmed to room temperature and stirred for 45 minutes. The mixture was cooled to 0° C., and water was added to the mixture which was then acidified by 2 N hydrochloric acid and extracted with ethyl acetate. The extract was dried over sodium sulfate anhydrous and concentrated under reduced pressure. The residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 50:1) to give the title compound (354 mg, Y.:61%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:6]([CH2:16][OH:17])=[CH:5][C:4]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C-:25]#[N:26].[Na+].O>CN(C=O)C>[CH2:19]([O:18][C:4]1[CH:5]=[C:6]([CH2:16][OH:17])[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][C:3]=1[CH2:2][C:25]#[N:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCOc1cc(CCl)c(OCCCCCC)cc1CO
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1cc(CC#N)c(OCCCCCC)cc1CO
Yield: 88.5 %

Procedure:
A solution of the chloride (31) (1.52 g) and sodium cyanide (0.22 g) in DMF (50 ml) was stirred at 60° C. for 3 h. It was poured into water (100ml), and extracted with ether -hexane (1:1, 150 ml ). The organic fraction was washed with water, dried (MgSO4) and the solvent evaporated to give an oil, which was crystallised from hexane (80 ml) to give (32), (1.31 g, 88%), as needles, m.p 63°-66° C., Found C. 73.0, 9.7, N 3.8, C21H33NO3 requires C 72.6, 9.6, N 4.0%!; vmax (KBr)/cm-1 3334 m, 2250 m, 1511 s, 1425 s, 1395 s, 1216 s, 1192 s, 1034 s, 998 s, 871 m, 724 m; δH (250.1 MHZ; CDCl3) 0.9-1.9 (22H, m), 4.36 (4H, m), 2.42 (1H, t, J=5), 3.68 (2H, s), 4.66 (2H, d, J=5), 6.84 (1H, s), 6.89 (1H, s); δC (62.9 MHz; CDCl3) 14.1, 18.7, 22.7, 25.9, 29.4, 31.7, 62.0, 69.1, 112.4, 112.7, 118.3, 130.2, 150.2, 150.7, m/z (CI) 347 (M+, 43), 330 (100), 263 (5).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:24][C:25]([F:32])([F:31])[C:26](OCC)=[O:27]>C1COCC1>[F:24][C:25]([F:32])([F:31])[C:26](=[O:27])[CH2:10][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:12])([F:13])[F:1])=[O:11]
Reactant: CC(=O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1ccccc1C(F)(F)F
Temperature: -78 °C
Yield: 98.5 %

Procedure:
To a stirred solution of 2′-trifluoromethyl-acetophenone (225 mL, 15.0 mmol) in THF (20 mL, anhyd) at −78° C. added dropwise a 1.0M solution of lithium hexamethyldisilazide (LiHMDS) (15.8 mL, 15.8 mmol). After 1 h the reaction mixture was cooled to −78° C. and charged dropwise with ethyl trifluoroacetate (3.6 mL, 30 mmol). After addition was complete, the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was quenched by slow addition of H2O (20 mL) and concentrated under reduced pressure. The resulting material was transferred to a separatory funnel, diluted with Et2O (60 mL), washed with 1N HCl and brine, then dried (MgSO4) and concentrated to yield the title compound (4.2 g, 99%) as an amber liquid, which was used in the next step without purification. Rf: 0.15 (20% EtOAc/Hex).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:26][CH:27]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:28](O)=[O:29].CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:32]([CH:31]([CH2:34][CH3:35])[CH:27]([OH:26])[C:28]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:14]([NH:13][CH2:12][C:11]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=1[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:29])[CH3:33]
Reactant: CCC(CC)C(O)C(=O)O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC(CC)C(O)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (171 mg, 0.47 mmol), 2-hydroxy-3-ethylpentanoic acid (68 mg, 0.47 mmol), and NMM (51 μL, 0.47 mmol) in DMF (5 mL) at ambient temperature under nitrogen atmosphere was added BOP reagent (247 mg, 0.56 mmol). The mixture was stirred at ambient temperature for 18 h. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by preparative thick layer silica gel plate chromatography (2000 μM×20 cm×20 cm) developed with 5% MeOH in dichloromethane. Desired bands were removed and eluted with 5% MeOH in dichloromethane. The filtrate solvent was concentrated in vacuo to obtain 1-(3-ethyl-2-hydroxypentanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide was obtained as a yellow oil (200 mg; HPLC RT=3.45 min, method A; LC-MS m/z=496.1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[C:12]([OH:15])[CH2:13][F:14])[C:10]#[N:11].[CH2:16](I)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[C:12]([O:15][CH2:16][CH3:17])[CH2:13][F:14])[C:10]#[N:11]
Reactant: CCI
Reactant: N#CC(=C(O)CF)c1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CF)=C(C#N)c1cccc(Cl)c1Cl

Procedure:
Alkylation of 2-(2,3-dichlorophenyl)-4-fluoro-3-hydroxy-2-butenenitrile can suitably be achieved using ethyl iodide in dimethylformamide in the presence of potassium carbonate to afford crude 2-(2,3-dichlorophenyl)-3-ethoxy-4-fluoro-2-butenenitrile.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17]C)=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:7]2.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:3]([OH:17])=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1N)C(CCNC(C)=O)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)NCCC1CCc2ccc(O)c(N)c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To a solution of N-[2-(7-amino-6-methoxyindan-1-yl)ethyl]acetamide (1.1 g, 4.4 mmol.) in dichloromethane (20 mL) was added dropwise gradually boron tribromide (2.1 mL, 22.1 mmol.). The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was poured into ice-water, which was subjected to extraction with 10% methanol/chloroform. The extract solution was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography (chloroform:methanol=10:1) to afford N-[2-(7-amino-6-hydroxyindan-1-yl)ethyl]acetamide (yield 630 mg, 61%). A portion of the product was dissolved in ethanol, to which was added a saturated hydrochloric acid/ethanol solution. The solvent was distilled off under reduced pressure. The resulting crystalline precipitate was recrystallized from ethanol to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1cccc(O)c1
Product: COc1cccc(Oc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-methoxyphenol (27 μl, 0.243 mmol) similar to Example 13 and isolated as a white oil (24 mg, 34%). 1H NMR (CDCl3): 8.79-8.76 (m, 1H), 8.26-8.23 (m, 1H), 7.75-7.69 (m, 1H), 7.33-7.28 (m, 2H), 6.82-6.72 (m, 3H), 6.58 (s, 1H), 3.77 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: CC1N=C(N2C(=O)NN=C2)SC=1C(OCC)=O.[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19].Br[CH2:34][CH2:35][CH2:36][C:37]([F:40])([F:39])[F:38]>>[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][N:28]([CH2:34][CH2:35][CH2:36][C:37]([F:40])([F:39])[F:38])[C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19]
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: FC(F)(F)CCCBr
Agent: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Product: CC(=O)c1sc(N2CCN(CCCC(F)(F)F)C2=O)nc1C
Yield: 60 %

Procedure:
Following the procedure as describe in Preparation 16, making variations as required to replace ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one to react with 4-bromo-1,1,1-trifluorobutane instead of bromomethyl-2,2-difluorocyclopropane, the title compound was obtained as a yellow solid in 60% yield: mp 108-110° C.; 1H NMR (300 MHz, DMSO-d6) δ 3.97 (t, J=9.0 Hz, 2H), 3.57-3.47 (m, 2H), 3.28 (t, J=9.0 Hz, 2H), 2.50 (s, 3H), 2.40 (s, 3H), 2.32-2.19 (m, 2H), 1.76-1.62 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 155.9, 155.8, MS (ES+) m/z 336.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)([CH3:19])[CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1
Reactant: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(CCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
2.78 g. of 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol are dissolved in 30 ml. of acetic acid and hydrogenated at 20° and under 1 atmosphere on 0.5 g. of 10% Pd-C until the reaction has ceased. Filtering and evaporating gives 3-(2',4'-difluoro-4-biphenylyl)butan-1-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:22]1([C:28]2[N:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[CH:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:34]([C:32]4[CH:31]=[CH:30][N:29]=[C:28]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:33]=4)=[O:35])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccnc(-c2ccccc2)n1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccnc(-c3ccccc3)n2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.9 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (53 mg, 0.189 mmol) and 2-phenylpyrimidine-4-carboxylic acid (99.5 mg, 0.50 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 15 min at room temperature. Carbodiimde resin (500 mg) was added and shaking continued for 48 h. The solution was filtered off and concentrated under vacuum. The residue was chromatographed on a silica gel flash column eluting with ethyl acetate/hexane (1:1) and the solvent evaporated under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6methyl-1,1′-biphenyl-3-yl)-2-phenylpyrimidine-4-carboxamide (13 mg). NMR; δH CDCl3 9.98,(1H, s), 9.09,(1H, d), 8.50-8.47,(2H, m), 8.08,(1H, d), 7.86,(2H, d), 7.70,(1H, dd), 7.63,(1H, d), 7.56-7.54,(3H, m), 7.45,(2H, d), 7.33,(1H, d), 7.26,(1H, m), 3.36,(2H, m), 2.26,(3H, s), 1.09,(1H, m), 0.58,(2H, m), 0.30,(2H, m). LCMS: retention time 3.88 min, MH+463.
Reaction SMILES: [CH:1]1([C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(O)[CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])[CH2:3][CH2:2]1.[BrH:17]>>[BrH:17].[Br:17][CH2:3][CH2:2][CH2:1][C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5][CH2:6][N:7]([CH3:9])[CH3:8]
Reactant: CN(C)CCC(O)(c1ccccc1)C1CC1
Agent: Br
Product: CN(C)CC=C(CCCBr)c1ccccc1

Procedure:
A solution of 30 g. (0.14 mole) of 1-cyclopropyl-3-dimethylamino-1-phenyl-1-propanol in 200 ml. of 48% hydrogen bromide was heated at 100°C. for several minutes and then concentrated on a rotating evaporator. The residual oil was dissolved in isopropanol and treated with ether to give an amorphous solid. Recrystallization of the solid from ethyl acetate gave a nearly pure isomer which after additional recrystallization from isopropylmethyl ketone melted at 128°-130°C. The yield was 2.6 g. (5.2%). The nuclear magnetic resonance spectrum showed the double bond to be in position 2 of the hexenylamine.