Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:27][CH:28]4[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]4)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:27][CH:28]4[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]4)=[N:25][CH:26]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: CC1CCC(Nc2ncc(Cc3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC1CCC(Nc2ncc(Cc3c[nH]c4ncc(Cl)cc34)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.6 %

Procedure:
To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-cyclohexyl)-amine (64, 0.120 g, 0.242 mmol) in 5.0 mL of tetrahydrofuran, tetrabutylammonium fluoride trihydrate (0.20 g, 0.63 mmol) is added. The reaction is stirred at room temperature overnight, 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 collected and concentrated under vacuum to provide the desired compound (P-3009, 1.4 mg). MS (ESI) [M+H+]+=355.95.
Reaction SMILES: C([NH:3][CH:4](/[CH:11]=[C:12](/[CH2:21][P:22]([O:28]C(C)C)([O:24]C(C)C)=[O:23])\[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.C[Si](C)(C)Br.C(O)C>ClCCl>[NH2:3][CH:4](/[CH:11]=[C:12](/[CH2:21][P:22]([OH:28])([OH:24])=[O:23])\[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CCC/C(=C\C(CC(=O)OCC)NC=O)CP(=O)(OC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCC/C(=C\C(N)CC(=O)OCC)CP(=O)(O)O
Reaction time: 20 h

Procedure:
4.3 g (9.9 mmol) of diethyl E-2-formylamino-4-diisopropylphosphonomethyl-hept-3-ene-1,7-dicarboxylate are dissolved in 14 ml of dichloromethane and 5.2 ml (40 mmol) of trimethylbromosilane are added dropwise at room temperature to the solution. The reaction mixture is allowed to stand for 20 hours and, after addition of 14 ml of ethanol, allowed to stand for a further 19 hours. The reaction mixture is concentrated on a rotary evaporator and the residue is taken up in 14 ml of ethanol. After addition of 14 ml of propylene oxide and 14 ml of ethanol, the resultant suspension is stirred for 90 minutes and then filtered with suction, affording diethyl E-2-amino-4-phosphonomethyl-hept-3-ene-1,7 -dicarboxylate of m.p. 218°-220° C. (decomp.).
Reaction SMILES: [C:1]([NH:8][C:9]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:10]S(C(F)(F)F)(=O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)Cl.[CH2:29]([N:32]1[CH2:37][CH2:36]N[CH2:34][CH2:33]1)[C:30]#[CH:31]>>[C:22]([O:21][C:19](=[O:20])[NH:18][C:9](=[N:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[N:10]1[CH2:36][CH2:37][N:32]([CH2:29][C:30]#[CH:31])[CH2:33][CH2:34]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: C#CCN1CCNCC1
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C#CCN1CCN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC1
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of N,N′-di-Boc-N″-trifluoromethanesulfonylguanidine (1.72 g, 4.40 mmol) in anhydrous CH2Cl2 (20 mL) Et3N (674 μL, 4.84 mmol) and N-propargyl piperazine (600 mg, 4.84 mmol) are added. The mixture is left reacting at room temperature for 16 h, then the solvent is evaporated. The residue is taken up in EtOAc, and treated with a saturated aqueous NaHCO3 solution and brine. Crude compound is purified by flash chromatography (2:1 EtOAc-petr. et., Rf=0.37) giving compound 4 as a yellow oil (1.01 g, 2.77 mmol) in 63% yield. 1H NMR (CDCl3, 200 MHz) δ 9.61 (br, 1H), 3.44 (m, 4H), 3.16 (d, J=2.6 Hz, 2H), 2.41 (m, 4H), 2.18 (m, 1H), 1.27 (s, 9H) ppm.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([O:16][CH3:17])[CH:6]=2.C[CH2:20][N:21](C(C)C)[CH:22]([CH3:24])[CH3:23].CNC(C)C>CS(C)=O>[CH:22]([N:21]([CH3:20])[C:2]1[C:3](=[O:18])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([O:16][CH3:17])[CH:6]=2)([CH3:24])[CH3:23]
Reactant: COC(=O)c1cc2nc(Cl)c(=O)[nH]c2cc1OC
Reactant: CCN(C(C)C)C(C)C
Agent: CNC(C)C
Solvent: CS(C)=O
Product: COC(=O)c1cc2nc(N(C)C(C)C)c(=O)[nH]c2cc1OC
Temperature: 85 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of methyl 3-chloro-7-methoxy-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.2 g, 4.47 mmol) in DMSO (20 mL) was added DIEA (1.16 g, 8.98 mmol) and methyl(propan-2-yl)amine (490 mg, 6.70 mmol) with stirring at 85° C. overnight. The reaction mixture was cooled to room temperature. The product was precipitated by the addition water and the solids were collected by filtration to afford methyl 3-(isopropyl(methyl)amino)-7-methoxy-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (1.0 g, 73%).
Reaction SMILES: [C:1]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[F:29][C:30]1[CH:31]=[CH:32][C:33]2[N:39]3[CH:40]=[N:41][C:42]([C:43](=[N:45]O)[NH2:44])=[C:38]3[C@@H:37]3[CH2:47][CH2:48][N:36]3[C:35](=[O:49])[C:34]=2[CH:50]=1>CN(C)C=O>[F:29][C:30]1[CH:31]=[CH:32][C:33]2[N:39]3[CH:40]=[N:41][C:42]([C:43]4[N:45]=[C:11]([CH2:10][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:9])[O:13][N:44]=4)=[C:38]3[C@@H:37]3[CH2:47][CH2:48][N:36]3[C:35](=[O:49])[C:34]=2[CH:50]=1
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN(Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 129.2 %

Procedure:
6.81 g (36 mmol) of BOC-sarcosine were dissolved in 30 ml of N,N-dimethylformamide and treated portionwise with 6.5 g (40 mmol) of 1,1'-carbonyldiimidazole. After completion of the CO2 evolution the solution was stirred at 40° for 30'. Then, 9.04 g (15 mmol) of (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at 90° overnight. By evaporation of the solution and chromatography of the residue on 450 g of silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 8.81 g (65%) of (S)-7-fluoro-12,12a-dihydro-1-[5-(N-BOC-N-methylaminomethyl)-1,2,4-oxadiazol-3-yl]-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was used in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccccc1-c1ccccc1
Temperature: 25 °C

Procedure:
Aqueous sodium carbonate (2 M, 100 mL), followed by tetrakis(triphenylphosphine) palladium (340. mg, 0.297 mmol), were added to a solution of 2-bromonitrobenzene (2.00 g, 9.90 mmol) and phenylboronic acid (1.27 g, 9.90 mmol) in dimethoxyethane (125 mL). The reaction mixture was heated to reflux for 3 hours. The reaction crude was then cooled to room temperature, diluted with water (100 mL) and the product extracted with CH2Cl2 (4×50 mL). The organic phase was dried over MgSO4, and concentrated under reduced pressure to yield a yellow solid, which was further purified via flash chromatography over silica, eluting with a gradient of hexanes to 20% CHCl3/80% hexanes. The nitro 2 was obtained as a yellow oil that was further dried under high vacuum for 24 h (1.79 g, 90.1%).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[C:20]([C:22]1([OH:30])[CH2:27][CH2:26][CH2:25][N:24]([CH3:28])[C:23]1=[O:29])#[CH:21]>>[F:19][C:3]1[C:2]([C:21]#[C:20][C:22]2([OH:30])[CH2:27][CH2:26][CH2:25][N:24]([CH3:28])[C:23]2=[O:29])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC1(O)CCCN(C)C1=O
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CN1CCCC(O)(C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)C1=O
Yield: 16 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-ethynyl-3-hydroxy-1-methylpiperidin-2-one (US2012/214762A 1) to give the titled compound as a white solid (20 mg, 16%).
Reaction SMILES: C(N=C=NCCCN(C)C)C.[O:12]=[C:13]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][CH2:15][N:14]1[CH2:31][C:32](O)=[O:33].[NH:35]1[CH2:40][CH2:39][CH:38]([N:41]2[C:45]3[CH:46]=[CH:47][C:48]([C:50]([F:53])([F:52])[F:51])=[CH:49][C:44]=3[N:43]=[N:42]2)[CH2:37][CH2:36]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:33]=[C:32]([N:35]1[CH2:40][CH2:39][CH:38]([N:41]2[C:45]3[CH:46]=[CH:47][C:48]([C:50]([F:53])([F:51])[F:52])=[CH:49][C:44]=3[N:43]=[N:42]2)[CH2:37][CH2:36]1)[CH2:31][N:14]1[CH2:15][CH2:16][CH2:17][C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:12]
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: FC(F)(F)c1ccc2c(c1)nnn2C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(n2nnc3cc(C(F)(F)F)ccc32)CC1
Reaction time: 23 h

Procedure:
N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.132 mL, 0.743 mmol) was added via syringe to a mixture of the product of Example 68E (230 mg, 0.743 mmol), 1-(piperidin-4-yl)-5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole (201 mg, 0.743 mmol), and 4-(dimethylamino)pyridine (9.1 mg, 0.07 mmol) in CH2Cl2 (3 mL). The reaction was allowed to proceed at ambient temperature for 23 hours. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with 1 N aqueous HCl, saturated aqueous NaHCO3 solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 50%-100% ethyl acetate/hexanes, 0-20 minutes, 30 mL/minute) to yield an amorphous solid which was triturated with 12 mL 1:1 ether/hexanes and 2 mL ether. The solid was collected by vacuum filtration and air-dried to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.37 (s, 1H), 7.73 (d, J=8.7, 1H), 7.51 (d, J=8.4, 1H), 7.39-7.14 (m, 10H), 5.10-4.95 (m, 1H), 4.82-4.66 (m, 1H), 4.34 (d, J=15.1, 1H), 4.27-4.06 (m, 2H), 3.71-3.50 (m, 2H), 3.46-3.29 (m, 1H), 3.14-2.94 (m, 1H), 2.73-2.63 (m, 2H), 2.64-2.47 (m, 1H), 2.44-2.14 (m, 3H), 1.96-1.82 (m, 2H). MS (ESI+) m/z 562 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([OH:18])[C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=C(OC)N=1.[Cl:21][C:22]1C(OC)=C(C=O)C=C[N:23]=1>>[Cl:21][C:22]1[C:3]([O:2][CH3:1])=[C:8]([CH:9]([OH:18])[C:10]#[C:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:23]=1
Reactant: COc1c(C=O)ccnc1Cl
Reactant: COc1ccc(C(O)C#Cc2ccccc2)c(OC)n1
Product: COc1c(C(O)C#Cc2ccccc2)ccnc1Cl
Yield: 100 %

Procedure:
Following the procedure used to prepare 1-(2,6-dimethoxy-pyridin-3-yl)-3-phenyl-prop-2-yn-1-ol, 2-chloro-3-methoxy-pyridine-4-carbaldehyde was reacted to give the title compound (1.60 g, 100%) as a colourless solid, LCMS (Method A): RT=4.14 min, [M+H]+=274/276.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][N:13]=1)(=[O:8])=[O:7])(C)(C)C.CS(O)(=O)=O>ClCCCl>[C:14]1([C:11]2[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[N:13][CH:12]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ncc(-c2ccccc2)s1
Agent: CS(=O)(=O)O
Solvent: ClCCCl
Product: NS(=O)(=O)c1ncc(-c2ccccc2)s1
Yield: 75 %

Procedure:
To a solution of N-t-butyl-5-phenyl-2-thiazole sulfonamide (0.25 g, 0.84 mmol) in 17 mL of 1,2-dichloroethane was added methanesulfonic acid (0.11 mL, 1.68 mmol). The reaction was heated at reflux for 6.5 h and then concentrated. The product was subjected to flash chromatography (2:1 hexane/ethyl acetate). Recrystallization from ethyl acetate/hexane afforded 0.15 g (0.63 mmol, 63%) of 5-phenyl-2-thiazole sulfonamide (white crystals).
Reaction SMILES: BrC[CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[Br:22]CCCC(C)(C1C=CC=CC=1)CO.O1C=CCCC1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:22][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Reactant: CC(CO)(CCCBr)c1ccccc1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(CCCBr)(COC1CCCCO1)c1ccccc1
Yield: 95 %

Procedure:
According to the method described for the synthesis of 207d, 206b (20.0 g, 77.8 mmol) was treated with 3,4-dihydro-2H-pyran (8.2 g, 96.5 mmol) and p-toluenesulfonic acid hydrate (0.57 g, 3.0 mmol) in CH2Cl2 (350 mL) to afford 207b (25.2 g, 95%) as an oil, which was used without further purification. 1H NMR (CDCl3): 7.26-7.08 (m, 5 H), 4.45 (m, 1 H), 3.72 (m, 1 H), 3.58 (m, 1 H), 3.35-3.05 (m, 2 H), 3.28 (t, 2 H, J=6.6), 1.95-1.39 (m, 10 H), 1.25 (s, 3 H). 13C NMR (CDCl3): δ 145.38, 128.15, 126.51, 126.03, 99.06, 98.92, 76.20, 61.91, 61.80, 41.82, 41.74, 37.58, 37.43, 34.65, 30.61, 27.88, 25.58, 23.03, 22.90, 19.39, 19.32. HRMS (LSIMS, nba): Calcd for C17H26O2Br (MH+): 341.1116, found: 341.1127.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([CH:60]1[CH2:65]COC[CH2:61]1)[C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:46](=[O:59])[CH:47]([NH:54][C:55]([O:57][CH3:58])=[O:56])[C:48]6[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=6)=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7].COC(NC(C1CCOCC1)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:46](=[O:59])[CH:47]([NH:54][C:55]([O:57][CH3:58])=[O:56])[C:48]6[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=6)=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:24][CH:25]=2)=[CH:18][N:19]=1)=[O:7])[CH:60]([CH3:65])[CH3:61]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(F)(F)CN6C(=O)C(NC(=O)OC)C6CCOCC6)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1
Agent: COC(=O)NC(C(=O)O)C1CCOCC1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(F)(F)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1

Procedure:
[1-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester was prepared following the procedure for [2-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid methyl ester, substituting 2-Methoxycarbonylamino-3-methyl-butyric acid for Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid. LCMS-ESI+: calc'd for C47H48F2N8O6: 858.37 (M+); Found: 859.88 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH2:20])=[N:16][CH:17]=1>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([NH:20][CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:22])([F:10])[F:21])=[CH:17][N:16]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(NCCc2ccc(C(F)(F)F)cn2)c1

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (3-methoxy-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 297.2 [M+H]+) was prepared from 3-bromo-anisol instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[N:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[N:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (257 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a white foam (320 mg, 67%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH2:18][CH2:19][CH2:20][OH:21])[O:11][C:10]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:9]2[CH2:8]1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][S:2]([O:21][CH2:20][CH2:19][CH2:18][C:7]1([CH3:6])[O:11][C:10]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:9]2[CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CCCO)Cn2cc([N+](=O)[O-])nc2O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(CCCOS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
Methanesulfonyl chloride (1.4 ml, 18.09 mmol) in methylene chloride (10 ml) was added dropwise to a mixture of 2-methyl-2-(3-hydroxypropyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 38 (2.1 g, 9.24 mmol), triethylamine (2.8 g, 20.09 mmol), 4-dimethylaminopyridine (50 mg, 0.41 mmol) and methylene chloride (80 ml) with cooling on ice-bath followed by stirring at room temperature overnight. The reaction mixture was concentrated. 10% hydrochloric acid was added to the residue, and the resulting mixture was stirred for 30 minutes with cooling on ice-bath. The precipitates were filtered off and washed with water to afford 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)propyl methanesulfonate (2.6 g, yield 92%) as a white powder.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>CN(C=O)C>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2-c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.00 g, 11.5 mmol) and sodium hydride (60%, 0.506 g, 12.6 mmol) in DMF (50 mL) was stirred at ambient temperature for 1 h then 4-fluorobenzaldehyde (1.36 mL, 12.6 mmol) was added. The reaction mixture was heated at 100° C. for 21 h. The reaction mixture was cooled to ambient temperature and the precipitate was collected by filtration, washed with DMF (30 mL) and ether (30 mL), and dried to afford 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzaldehyde as a tan solid (2.80 g, 7.61 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 10.03 (1H, s), 8.46 (2H, d, J=8.4 Hz), 8.39 (1H, s), 8.09 (2H, d, J=8.8 Hz); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 9.71 min. MS: MH+365.8.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C@H:7]([CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=1[F:19])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:30])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])=[C:11]([F:19])[CH:12]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1F)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(N)cc1F)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of di-tert-butyl-N (4-nitro-2-fluorobenzoyl)-(L)-glutamate (3.6 g, 8.4 mmoles) in 95% ethanol (100 mL) was mixed with 10% palladium on carbon (0.25 g) and placed on a Parr apparatus. The mixture was shaken under hydrogen atmosphere for 2 hours. The reaction mixture was filtered, spin evaporated, and dried to give a white solid, di-tert-butyl N-(4-amino-2-fluorobenzoyl)-(L)-glutamate yield, 3.0 g (91%); mp 91°-95° C.; 1H-NMR (CDCl3) δ 1.41 (s, 9H), 1.48 (s, 9H), 2.0-2.4 (m, 4H), 2.8 (br s, 2H), 4.71 (m, 1H), 6.34 (d, 1H), 6.48 (d, 1H), 7.17 (q, 1H), 7.86 (t, 1H); uv (MeOH) 280 nm max (16800), 238 min (2760), 212 sh (12100); mass spec (CI) m/e 397 (21 %), 341 (13), 285 (100).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:31][CH3:32])[CH2:25][C@@H:26]([CH:28]2[CH2:30][CH2:29]2)[OH:27])[C:5]1=[O:33])[CH:2]=[CH2:3].O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([C@@:4]1([CH3:34])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:31][CH3:32])[CH2:25][C:26]([CH:28]2[CH2:29][CH2:30]2)=[O:27])[C:5]1=[O:33])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)C[C@H](O)C2CC2)C1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(=O)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-1-hydroxypentan-3-yl)-3-methylpiperidin-2-one prepared above in Step A (175 mg, 0.350 mmol) and water (9.5 μL, 0.52 mmol) in DCM (3.9 mL) was added Dess-Martin periodinane (222 mg, 0.524 mmol) at rt. After being stirred at rt for 40 min, the reaction was quenched (1 M aq. Na2S2O3), extracted (2×DCM), and washed (2×sat. NaHCO3 and 1×sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (12 g SiO2, 15% and 25% EtOAc/Hex) provided the title compound as a colorless film.