Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C@@:12]([C:27]1[CH:32]=[C:31]([O:33][C:34]([F:39])([F:38])[CH:35]([F:37])[F:36])[CH:30]=[C:29]([F:40])[CH:28]=1)([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])#[N:2].[Si]([N:45]=[N+:46]=[N-:47])(C)(C)C>COCCOC>[N:2]1[NH:45][N:46]=[N:47][C:1]=1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([NH:11][C@@:12]([C:27]1[CH:32]=[C:31]([O:33][C:34]([F:38])([F:39])[CH:35]([F:36])[F:37])[CH:30]=[C:29]([F:40])[CH:28]=1)([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCCCCCNC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Solvent: COCCOC
Product: O=C(NCCCCCc1nn[nH]n1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 150 °C
Yield: 47 %

Procedure:
To a solution of (R)-1-(5-cyanopentyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea, prepared by the method described in Procedure 12 (45 mg, 0.080 mmol) in DME (161 μL) at rt was added TMSN3 (0.013 mL, 0.16 mmol), followed by n-Bu2SnO2 (2 mg, 0.008 mmol). The reaction mixture was heated at 150° C. for 10 min under microwave irradiation. An additional amount of TMSN3 (0.013 mL, 0.16 mmol) and n-Bu2SnO2 (2 mg, 0.008 mmol) was added, and the reaction mixture was heated at 150° C. for an additional 10 min under microwave irradiation. The reaction mixture was concentrated and the residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18, eluting with MeCN/H2O containing 0.1% TFA, monitoring at 220 nm) to provide (R)-1-(5-(2H-tetrazol-5-yl)pentyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea (23 mg, 47% yield) as a white solid. 1H NMR (500 MHz, MeOH-d4) δ 7.18-6.89 (m, 11H), 6.71 (d, J=5 Hz, 2H), 6.37-6.16 (m, 1H), 3.93 (d, J=15 Hz, 1H), 3.81 (d, J=15.0 Hz, 1H), 3.08 (t, J=5 Hz, 2H), 2.94 (t, J=5 Hz, 2H), 1.83-1.76 (m, 2H), 1.55-1.48 (m, 2H), 1.41-1.35 (m, 2H); LC/MS: RT=3.736 min [M+H] 607.3 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeCN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:32]=[CH:33][CH:34]=3)[CH2:19][N:20]3[C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:29]([OH:31])=O)[C:23]=4[CH:22]=[CH:21]3)=[O:15])=[C:9]([C:35]3[CH:40]=[C:39]([C:41](=[O:54])[NH:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:53])([F:52])[F:51])[CH:45]=4)[CH:38]=[CH:37][N:36]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:31]=[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[CH:22]=[CH:21][N:20]2[CH2:19][C:18]1[CH:32]=[CH:33][CH:34]=[C:16]([C:14](=[O:15])[NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:8][C:9]=2[C:35]2[CH:40]=[C:39]([C:41](=[O:54])[NH:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([F:51])([F:52])[F:53])[CH:45]=3)[CH:38]=[CH:37][N:36]=2)[CH:17]=1)[NH:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68]
Reactant: NCCOCCOCCOCCC(=O)O
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(Cn3ccc4c(C(=O)O)cccc43)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)CCOCCOCCOCCNC(=O)c1cccc2c1ccn2Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 1 h
Yield: 36.5 %

Procedure:
A mixture of 3 mg of 1-(3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)-benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)-1H-indole-4-carboxylic acid 9.1, 1.7 mg of 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoic acid, and 2.5 mg of HATU in 300 μL of DMF was treated with 1.5 μL of diisopropylethylamine. After 2 h the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate, and the combined organic extracts were washed with brine and dried (Na2SO4). The solvent was evaporated and a fraction of the product was dissolved in 1:1 dichloromethane/TFA. After stirring for 1 h the solvent was evaporated and the residue was purified by reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient to yield 1.4 mg of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 9.57 (t, J=5.7 Hz, 1H), 8.98 (d, J=5.1 Hz, 1H), 8.51 (d, J=8.7 Hz, 1H), 8.40 (s, 1H), 7.93 (s, 1H), 7.89 (d, J=5.1 Hz, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.72 (s, 1H), 7.65 (m, 2H), 7.60-7.52 (m, 3H), 7.48 (t, J=7.7 Hz, 1H), 7.24-7.14 (m, 3H), 7.03-6.94 (m, 1H), 4.64 (d, J=5.8 Hz, 2H), 4.36 (s, 2H), 3.47 (s, 4H), 2.15 (t, J=7.3 Hz, 2H), 1.83 (br, 4H), 1.81-1.67 (m, 2H), 1.64 (br, 2H). MS (ES, m/z) 935.32 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[ClH:17].Cl.[NH2:19][CH2:20][CH2:21][O:22][NH2:23].N1C=CC=CC=1>C(O)C>[ClH:17].[ClH:17].[NH2:19][CH2:20][CH2:21][O:22][N:23]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: NCCON
Reactant: O=C(CCn1ccnc1)c1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCn1ccnc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A mixture of 1-(4-fluorophenyl)-3-(1-(1H)-imidazolyl)-1-propanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.46 g), 3 equivalents of pyridine and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for two hrs. The reaction mixture was partitioned between 20% sodium hydroxide solution and ethyl acetate. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 1.9 g (40%) of product, mp 225°-226° C. (dec).
Reaction SMILES: [Mg].BrCCBr.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.C([Mg]Cl)(C)C.[CH2:26]([O:33][C:34](=[O:45])[NH:35][CH:36]([CH3:44])[CH2:37][C:38](N(OC)C)=[O:39])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([C:38](=[O:39])[CH2:37][CH:36]([NH:35][C:34](=[O:45])[O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:44])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1
Reactant: FC(F)(F)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CON(C)C(=O)CC(C)NC(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC(=O)OCc1ccccc1
Temperature: 75 °C
Reaction time: 14 h

Procedure:
To a stirred suspension of magnesium turnings (1.55 g; 63.76 mmol) in THF (50 mL) under an atmosphere of N2 was added 1,2-dibromoethane (135 uL). The mixture was heated to 75° C. and 3,5-bis(trifluoromethyl)bromo benzene (4.59 mL; 26.79 mmol) was slowly added to maintain a gentle reflux. The reaction was heated at gentle reflux for 2.5 h and then cooled to room temperature. In a separate flask, isopropyl magnesium chloride (18 mL; 36 mmol) was added dropwise to a stirred solution of benzyl-{3-[methoxy(methyl)amino]-1-methyl-3-oxopropyl}carbamate (Step B; 5 g; 17.86 mmol) in THF (30 mL) at −20° C. The resultant solution was stirred at −20° C. for 40 min prior to dropwise addition of the Grignard solution. The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was quenched with 1 N HCl (100 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% acetone/hexanes gradient) to afford benzyl {3-[3,5-bis(trifluoromethyl)phenyl]-1-methyl-3-oxopropyl}carbamate as a white solid. LCMS=434.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.39 (s, 2H), 8.07 (s, 1H), 7.37-7.29 (m, 5H), 5.16-5.04 (m, 3 h), 4.31-4.23 (m, 1H), 4.16-4.10 (m, 1H), 3.19 (dd, J=16.8, 6.5 Hz, 1H), 1.34 (d, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 33 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (33%).
Reaction SMILES: [C:1]([N:5]1[CH2:9][CH2:8][NH:7][S:6]1(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(OCC)(=O)C.CCCCCC>[C:1]([N:5]1[CH2:9][CH2:8][N:7]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[S:6]1(=[O:10])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)N1CCNS1(=O)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)N1CCN(Cc2ccc([N+](=O)[O-])cc2)S1(=O)=O
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield from 2-tert-butyl-1,2,5-thiadiazolidine-1,1-dioxide [M. Preiss, Chem. Ber., 1978, 111, 1915] and 4-nitrobenzyl bromide following the procedure described for Example 1 (Method B, Step 1); mp 113° C. (ethyl acetate-hexane, 60:40); δH (360 MHz, CDCl3) 8.21 (2H, d, J=8.7 Hz, Ar--H), 7.58 (2H, d, J=8.7 Hz, Ar--H), 4.24 (2H, s, Ar--CH2 --), 3.40 (2H, t, J=6.2 Hz, --CH2 --), 3.17 (2H, t, J=6.2 Hz, --CH2 --), 1.44 (9H, t-Bu); m/z (EI) 313 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:22]([O:24]C)=O)[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[NH3:26]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:22]([NH2:26])=[O:24])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]4)[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCN(C)CC3)ccc12
Reactant: N
Solvent: CO
Product: CN1CCN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(Br)nc23)CC1
Temperature: 80 °C
Yield: 66 %

Procedure:
A mixture of methyl 2-bromo-7-(4-methylpiperazin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (300 mg, 0.744 mmol) and 7 N NH3 in MeOH (5 mL) in a sealed microwave vial was heated in an oil bath at 80° C. for 16 h. After cooling to RT, the solid was collected by filtration, washed with MeOH, and air-dried to afford 2-bromo-7-(4-methylpiperazin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxamide (200 mg, 0.489 mmol, 66% yield). MS (ESI) m/z 390.0 (M+H); LCMS Ret Time: 1.242 min; PHENOMENEX® Luna S10 4.6×50 mm column, 3 min gradient, 0-100% B, 5 mL/min. Solvent A: 10% MeOH—90% H2O—0.1% TFA; Solvent B: 90% MeOH—10% H2O—0.1% TFA.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:9]2[N:14]3[N:15]=[C:16]([CH3:26])[C:17]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4Cl)=[C:13]3[N:12]=[C:11]([CH3:27])[CH:10]=2)[CH2:6][CH2:7][CH3:8])[CH2:3][CH2:2]1.[CH3:28]C1C=C(Cl)C=CC=1C1C(C)=NN2C(N(CCC)CCC)=CC(C)=NC=12>>[CH:1]1([CH2:4][N:5]([C:9]2[N:14]3[N:15]=[C:16]([CH3:26])[C:17]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[CH3:28])=[C:13]3[N:12]=[C:11]([CH3:27])[CH:10]=2)[CH2:6][CH2:7][CH3:8])[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C)nc2c(-c3ccc(Cl)cc3Cl)c(C)nn12
Reactant: CCCN(CCC)c1cc(C)nc2c(-c3ccc(Cl)cc3C)c(C)nn12
Product: CCCN(CC1CC1)c1cc(C)nc2c(-c3ccc(Cl)cc3C)c(C)nn12

Procedure:
cyclopropylmethyl-[3-(2,4-di-chloro-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-propyl-amine, [3-(2-methyl-4-chloro-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-di-propyl-amine;
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH:20]=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH2:20][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1cc(N)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of 4-chloro-3-methoxyaniline (1.57 g, 10.0 mmol) in methanol (27 ml) were added acetic acid (3 ml), N-(tert-butoxycarbonyl)-L-prolinal (2.40 g, 12.05 mmol) and sodium cyanoborohydride (1.56 g, 24.1 mmol). The resulting suspension was stirred for 2 hours at room temperature. Aqueous sodium bicarbonate solution (30 ml) was added and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=70:30) to yield a light yellow oil (2.31 g, 68%); MS (ISP): 341.0, 342.9 ((M+H)+.).
Reaction SMILES: [CH2:1]([C:3]1([CH3:12])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH:5]([NH2:11])[CH2:4]1)[CH3:2].C(N(CC)CC)C.[OH:20][C:21]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([C:3]1([CH3:12])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH:5]([NH:11][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:29]([N+:30]([O-:32])=[O:31])[C:21]=2[OH:20])[CH2:4]1)[CH3:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1O
Reactant: CCC1(C)CC(N)CC(C)(C)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(C)CC(NC(=O)c2cccc([N+](=O)[O-])c2O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred soution of 3-ethyl-3,5,5-trimethylcyclohexylamine (3.20 g, a 6:4 mixture of axial:equatorial ethyl diastereomers), triethylamine (2.13 g) and 4-dimethylaminopyridine (DMAP) (0.12 g) in dichloromethane (50 ml) was added, in a rapid dropwise manner, a solution of 2-hydroxy-3-nitrobenzoyl chloride (3.83 g) in dichloromethane (10 ml). After the addition was complete, the reaction mixture was stirred at room temperature for 12 hours, then poured into 1N HCl (250 ml). The organic layer was separated, and the aqueous layer washed with dichloromethane (50 ml). The organic phases were combined, dried (MgSO4) and the solvent evaporated to give a yellow solid (5.70 g). Recrystallization from methanol gave an analytical sample (m.p. 125-128° C.). The 13C NMR of this material showed it to be a mixture of diastereomers in an approximate ratio of 6:4.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])(=O)=O>C(Cl)Cl>[CH:27]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[O:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)([CH3:29])[CH3:28]
Reactant: O=C1CCC(CCO)CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OCCC1CCC(=O)CC1)(C(C)C)C(C)C

Procedure:
A solution of 4-(2-hydroxy-ethyl)-cyclohexanone (Intermediate R10, 6.8 g, 52.6 mmol, (obtainable as described in the publication by Ciufolini et. al. J. Amer. Chem. Soc. 1991, 113, 8016) was dissolved in CH2Cl2 (75 mL) and treated with diisopropylethylamine (9.2 mL, 52.6 mmol) followed by tri-isopropylsilyl trifluoromethane sulfonate (TIPSTf) (15.3 g, 50.2 mmol) at −30 EC. The reaction mixture was warmed to 0 EC for 1 h. The mixture was subjected to an aqueous work-up and purified by chromatography on SiO2 to give 4-(2-triisopropylsilanyloxy-ethyl)-cyclohexanone (Intermediate R11, 11.8 g (82%). Intermediate R11 was converted via Intermediate R12 to the unsaturated aldehyde, 5-(2-triisopropylsilanyloxy-ethyl)-cyclohex-1-enecarbaldehyde (Intermediate R13)
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[N:30]1([C:35]([C@H:37]2[CH2:41][CH2:40][NH:39][CH2:38]2)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:39]4[CH2:40][CH2:41][C@H:37]([C:35]([N:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)=[O:36])[CH2:38]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=C([C@H]1CCNC1)N1CCCC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC[C@H](C(=O)N4CCCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 93.4 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol) and pyrrolidin-1-yl-(S)-pyrrolidin-3-ylmethanone (51 mg, 0.30 mmol) in DCE (5 mL) was stirred at ambient temperature for 2 h. Sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 70:30) to afford 399 as a white solid (132 mg, 86%). LCMS (Method G): RT=6.43 min, M+H+=544. 1H NMR (CDCl3, 400 MHz) δ 7.99 (m, 1 H); 7.75 (m, 1 H); 7.27 (m, 2 H); 4.35 (m, 4 H); 3.94 (s, 2 H); 3.87 (m, 7 H); 3.50-3.38 (m, 4 H); 3.35 (q, J=7.5 Hz, 2 H); 3.20-3.10 (m, 1 H); 3.01 (m, 1 H); 2.87 (m, 2 H); 2.72 (m, 1 H); 2.16-2.07 (m, 2 H); 2.01-1.90 (m, 2 H); 1.91-1.81 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[C@H:20]2[C@@H:24]3[O:25][C:26]([CH3:29])([CH3:28])[O:27][C@@H:23]3[C@@H:22]([C:30](O)=[O:31])[O:21]2)=[C:13]([NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:12]=1.C(Cl)(=O)C(C)(C)C.[CH3:47][C:48]([CH3:54])([CH3:53])[C:49]([NH:51][NH2:52])=[O:50]>O1CCCC1>[CH3:47][C:48]([CH3:54])([CH3:53])[C:49]([NH:51][NH:52][C:30]([C@@H:22]1[C@@H:23]2[C@@H:24]([O:25][C:26]([CH3:28])([CH3:29])[O:27]2)[C@H:20]([N:17]2[CH:16]=[N:15][C:14]3[C:18]2=[N:19][C:11]([Cl:10])=[N:12][C:13]=3[NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[O:21]1)=[O:31])=[O:50]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(NC3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(C)C(=O)NN
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)NNC(=O)C(C)(C)C)O[C@H]2n1cnc2c(NC3CCOCC3)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Diisopropylethylamine (0.487 ml) was added to a stirred solution of (3aS,4S,6R,6aR)-6-[2-chloro-6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (350 mg) in dry tetrahydrofuran (8 ml) at 0° C. under nitrogen. After 5 min pivaloyl chloride (0.098 ml) was added and the mixture was stirred at 0° C. for 2.5 h. 2,2-Dimethyl-propionic acid hydrazide was added in tetrahydrofuran (2 ml) at 0°, and stirring was continued at 0-22° C. overnight. The mixture was concentrated in vacuo and partitioned between ethyl acetate (2×30 ml) and saturated aqueous sodium bicarbonate (30 ml). The organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was azeotroped with dichloromethane (10 ml) to give the title compound as a cream solid (357 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([O:10][CH3:11])[CH:3]=1.[C-:12]#[N:13].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:12]#[N:13])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(Cl)ccc1CC#N
Yield: 36.7 %

Procedure:
Step B In a manner similar to the method described in Example 57 Step B, 4-chloro-2-methoxybenzyl chloride (5.1 g, 27 mmol) was reacted with NaCN (3 g, 61 mmol) in ethanol (40 mL) and water (20 mL) at 100° C. for 8 h to give 4-chloro-2-methoxybenzyl cyanide as a colorless oil (1.8 g, 36%)
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([N:12]=[CH:13][N:14]([CH3:16])[CH3:15])(=[O:11])=[O:10].O>C(C(C)=O)C>[CH3:15][N:14]([CH:13]=[N:12][S:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][I:1])(=[O:11])=[O:10])[CH3:16]
Reactant: CN(C)C=NS(=O)(=O)CCCCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: CN(C)C=NS(=O)(=O)CCCCCI
Yield: 93.3 %

Procedure:
2.98 g of sodium iodide were added to a solution of 2.09 g of the product of Step B in 31.5 ml of methyl ethyl ketone (M.E.K.), and the mixture was refluxed for 4 hours. After cooling, water was added and extraction was carried out with ethyl acetate. The extracts were washed with water, then with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 2.69 g of the expected product.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4](/[CH:19]=[CH:20]\[CH3:21])[CH2:3]1.N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[Si:31]([O:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:4](/[CH:19]=[CH:20]\[CH3:21])[CH2:3]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: C/C=C\[C@@H]1C[C@H](O)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C/C=C\[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
A solution of benzyl (1S,2S,4R)-4-hydroxy-2-((Z)-prop-1-enyl)cyclohexylcarbamate (6.0 g, 20.7 mmol) in methylene chloride (60 mL) was treated with imidazole (2.1 g) and cooled to 0° C. The resultant solution was charged with tert-butylchlorodimethylsilane (3.4 g, 22.8 mmol) and then stirred for 18 h at 30° C. before being quenched with water. The organic phase was separated, and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with brine, dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl (1S,2S,4R)-4-(tert-butyldimethylsilyloxy)-2-((Z)-prop-1-enyl)cyclohexylcarbamate (6.0 g). MS found: (M+H)+=404.