Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=Cc1cccc(O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OCc1cccc(O)c1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-3-hydroxybenzaldehyde (8.10 g, 51.7 mmol) in MeOH was added NaBH4 (1.96 g, 51.7 mmol) at 0° C. The reaction was allowed to stir for 30 minutes. TLC showed clean conversion to a more polar spot. The reaction was diluted with EtOAc (400 mL), washed with water and brine, dried over sodium sulfate, and concentrated. The crude 2-chloro-3-(hydroxymethyl)phenol was used in Step B without further purification.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[I:7][C:8]1[N:9]=[N:10][C:11](I)=[CH:12][CH:13]=1.O>C1COCC1>[I:7][C:8]1[N:9]=[N:10][C:11]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:12][CH:13]=1
Reactant: CC(C)O
Reactant: Ic1ccc(I)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(I)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.50 mL (6.6 mmol) isopropanol are added to 289 mg (7.23 mmol) sodium hydride (60%) in 100 mL THF and the mixture is stirred for 30 min at rt. After that time, 2.0 g (6.0 mmol) 3,6-diiodo-pyridazine are added and the mixture is stirred for 14 h at rt and for 14 h at 50° C. After that time, the mixture is poured into water and extracted with EtOAc. The organic layer is washed with water (2×) and dried over sodium sulphate. The solvent is removed in vacuo and the residue is purified by column chromatography (silicia gel; heptane:EtOAc gradient 0 to 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[CH2:22][NH:21][CH2:20]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[CH2:22][N:21]([CH2:28][CH2:27][C:26]([O:30][CH3:31])=[O:29])[CH2:20]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc4c(c3)CNC4)n2)cc1Cl
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCN1Cc2ccc(-c3nc(-c4ccc(OC(C)C)c(Cl)c4)no3)cc2C1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 104 %

Procedure:
3-(3-chloro-4-isopropoxyphenyl)-5-(isoindolin-5-yl)-1,2,4-oxadiazole (16.7 mg, 0.047 mmol) was added to a 2 mL microwave vial equipped with a stirring bar. Methyl acrylate (8.45 μL, 0.094 mmol), and methanol (1.0 mL) were added, the vial capped, and the reaction heated to 90° C. for 20 min under microwave irradiation (300 W). After 20 minutes, another aliquot of methyl acrylate (8.45 μL, 0.094 mmol) was added, the vial was re-sealed, and heated to 110° C. for 40 min under microwave irradiation (300 W). Reaction was then concentrated and dried under vacuum overnight to give crude methyl 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)isoindolin-2-yl)propanoate as a yellow oil (21.6 mg, 104%). The product was used without further purification. LCMS (Table 1, Method c) Rt=2.85 min, m/z 442.45 (M+H)+
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[CH:8]1([CH2:14][C:15]([NH:17][CH2:18][CH2:19][S:20][CH2:21][CH:22]([C:27](=[O:34])[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:23][C:24]([OH:26])=O)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.ClC(OCC)=O.CNC>ClCCl.O1CCCC1>[CH:8]1([CH2:14][C:15]([NH:17][CH2:18][CH2:19][S:20][CH2:21][CH:22]([C:27](=[O:34])[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:23][C:24]([N:3]([CH3:4])[CH3:1])=[O:26])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCN(CC)CC
Reactant: O=C(O)CC(CSCCNC(=O)CC1CCCCC1)C(=O)c1cccnc1
Agent: CCOC(=O)Cl
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)CC(CSCCNC(=O)CC1CCCCC1)C(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (14.7 tL) was added to a solution of 3-{[2-(N-cyclohexylacetylamino)ethylthio]methyl}-4-oxo-4-(3-pyridyl)butanoic acid (44.6 mg) in dichloromethane (1.1 mL) and stirred for 30 min. The solution was cooled to 0° C. and ethyl chloroformate (10.5 μL) was added and stirred for 10 minutes. Dimethylamine in tetrahydrofuran (2M, 53 μL) was added and stirred at room temperature overnight. The solution was concentrated and purified on preparative HPLC (C-18 prep column, 10% to 90% acetronitrile in water both containing 0.1% TFA) to give 6.8 mg of the title compound; ESMS (M+1)+420.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22]([NH2:27])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.[ClH:29].CO>>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22]([NH2:27])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:15])=[O:16])[CH2:10]1.[ClH:29]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3c(N)ncc(Cl)c23)C1
Agent: Cl
Solvent: CO
Product: Nc1ncc(Cl)c2c(S(=O)(=O)N3CC[C@H](N)C3)cccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Intermediate 28s (30 mg) obtained in Step A mentioned above was added with 10% hydrogen chloride/methanol (4 ml), and the mixture was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure to obtain the title compound as hydrochloride (25 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].ClCC#CC[N:32]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[C:33](=[O:35])[O-:34]>>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:7][CH2:8][N:9]([CH2:4][C:6]#[C:7][CH2:8][O:34][C:33]([NH:32][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)=[O:35])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Reactant: O=C([O-])N(CC#CCCl)c1cccc(Cl)c1
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(CC#CCOC(=O)Nc3cccc(Cl)c3)CC2)cc1
Yield: 128.3 %

Procedure:
Ethyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-1-(4-{[(3 chloroanilino)carbonyl]oxy}-2-butynyl)-4-piperidinecarboxylate was prepared according to the general method as outlined in Example 37 (step 1). Starting from 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester (0.291 g,0.7 mmol) and 4-chloro-2-butynyl-(3-chlorophenyl)carbamate (0.19 g, 0.735), 0.27 g (64%) of the desired product was isolated as pale yellow oil. Electrospray Mass Spec: 601.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([S:51](=[N:55][CH3:56])([NH:53][CH3:54])=[O:52])=[CH:47][CH:46]=1>O1CCOCC1>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:43])[CH3:41])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:46]=[CH:47][C:48]([S:51](=[N:53][CH3:54])([NH:55][CH3:56])=[O:52])=[CH:49][CH:50]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CN=S(=O)(NC)c1ccc(Br)cc1
Solvent: C1COCCO1
Product: CN=S(=O)(NC)c1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and 4-bromo-N,N′-dimethyl-benzenesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3) using 1,4-dioxane as a solvent. LC (method 1): tR=1.01 min; Mass spectrum (ESI+): m/z=686 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.[CH:73]([O:76][CH2:77][CH2:78]O)([CH3:75])[CH3:74]>C1COCC1>[CH:73]([O:76][CH2:77][CH2:78][O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])([CH3:75])[CH3:74]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CC(C)OCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)OCCOc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 55.9 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.102 g, 0.221 mmol) was dissolved in THF (5.1 mL), and the solution was treated with triphenylphosphine (0.116 g, 0.442 mmol), 40% DEAD-toluene solution (0.201 mL, 0.442 mmol) and 2-isopropoxyethanol (0.126 mL, 1.10 mmol), followed by purification by flash column chromatography (chloroform/methanol=4/1) to obtain 4-(2-isopropoxyethoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0677 g, yield 59%).
Reaction SMILES: [N:1]([N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][N:6]([CH:11]([CH3:13])[CH3:12])[CH2:5][C:4]1([CH3:15])[CH3:14])=O.Cl>>[NH2:1][N:3]1[C:4]([CH3:14])([CH3:15])[CH2:5][N:6]([CH:11]([CH3:12])[CH3:13])[CH2:7][C:8]1([CH3:9])[CH3:10]
Reactant: CC(C)N1CC(C)(C)N(N=O)C(C)(C)C1
Agent: Cl
Product: CC(C)N1CC(C)(C)N(N)C(C)(C)C1

Procedure:
The 1-nitroso-2,2,6,6-tetramethyl-4-isopropylpiperazine obtained in the preceding stage is reacted analogously to 3b. The resulting aqueous HCl phase is used in the next stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([CH:15]=2)[NH2:14])[CH:4]=1.[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:14][C:13]1[CH:15]=[C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[CH:10]=[CH:11][C:12]=1[CH3:16])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1ccnc(-c2ccc(C)c(N)c2)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(-c2ccc(C)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a suspension of 5-(4-methoxypyridin-2-yl)-2-methylaniline (200 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (310 mg) and diisopropyl-ethylamine (0.374 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (310 mg), and the mixture was stirred for 2 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:ethyl acetate=3:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(5-(4-methoxypyridin-2-yl)-2-methylphenyl)guanidine (357 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C(C)C
Yield: 27.5 %

Procedure:
Using the general method of Example 197, 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) was reacted with isobutyryl chloride (0.41 mL, 3.9 mmol) to provide 0.34 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-methylpropanamide as an off white solid, m.p. 155.4-156.3° C. Analysis: Calculated for C20H27N5O.0.75 H2O: % C, 65.46; % H, 7.83; % N, 19.08. Found: % C, 65.84; % H, 7.87; % N, 18.73.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:37])=[C:17]([C:19]23[CH2:26][N:25]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:24][CH:23]2[CH2:22][O:21][NH:20]3)[CH:18]=1>O1CCCC1>[C:1]([NH:9][C:10]([N:20]1[C:19]2([C:17]3[CH:18]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=3[F:37])[CH2:26][N:25]([C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:28])[CH2:24][CH:23]2[CH2:22][O:21]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: O=C(OCc1ccccc1)N1CC2CONC2(c2cc(Br)ccc2F)C1
Solvent: C1CCOC1
Product: O=C(NC(=S)N1OCC2CN(C(=O)OCc3ccccc3)CC21c1cc(Br)ccc1F)c1ccccc1
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Benzoyl isothiocyanate (2.87 mL, 21.28 mmol) is added drop wise to a solution of benzyl 6a-(5-bromo-2-fluoro-phenyl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (5.977 g, 14.2 mmol) in tetrahydrofuran (95 mL) and stirred overnight under nitrogen. The solvent is removed in vacuo. The crude product is purified over silica gel with a 30 minute 5% to 100% EtOAc in hexanes gradient to give the title compound (6.05 g, 73%). ES/MS (m/e): (79Br/81Br) 584/586 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.Cl.Cl[CH2:36][CH2:37][N:38]([CH3:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:39][N:38]([CH3:40])[CH2:37][CH2:36][O:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[CH:13]([C:11]([N:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:33])[CH3:1])=[CH:4][CH:5]=1)[C:24]1[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=1)=[O:12])[CH2:14][CH2:15][CH2:16]2
Reactant: CN(C)CCCl
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3cc(O)ccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3cc(OCCN(C)C)ccc32)cc1
Temperature: 50 °C
Yield: 13.1 %

Procedure:
To a solution of N-[(4-dimethylaminophenyl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) in dimethylformamide (10 mL) were added 2-chloro-N,N-dimethylethylamine hydrochloride (0.26 g) and potassium carbonate (0.62 g), and the mixture was stirred with heating at 50° C. for 3 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 6-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide ⅕ hydrate (0.1 g). melting point: 132.6° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[C:12](O)=[N:13][CH:14]=[N:15][C:16]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[C:12]([Cl:21])=[N:13][CH:14]=[N:15][C:16]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncnc(O)c1CCOCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ncnc(Cl)c1CCOCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 160 (4.1 g, 17 mmol) and POCl3 (10 ml) is heated at 100° C. for 3 hours. The solvent is removed in vacuo and EtOAc (30 ml) and water (30 ml) are added to the residue. NaHCO3 (aq.) is carefully added until the pH of the aqueous layer is greater than 7. The layers are separated and the aqueous layer is extracted with EtOAc (2×30 ml). The combined extracts are washed with brine (50 ml), dried (Na2SO4) and solvent evaporated. Flash column purification of the residue (EtOAc:hexane=1:2) provides the product (161) as a light yellow oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10]Br)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I-:12].[Na+]>CC(C)=O.CN(C)C=O>[Si:1]([O:8][CH2:9][CH2:10][I:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCI
Reaction time: 4 h

Procedure:
Combine 2-(t-butyldimethylsilyloxy)ethyl bromide (116.2 g, 486 mmol), and sodium iodide (100 g, 663 mol) in acetone (350 mL) and dimethylformamide (25 mL). Heat to reflux. After 4 hours, cool, filter, and evaporate in vacuo to give a residue. Distill the residue to give 2-(t-butyldimethylsilyloxy)ethyl iodide: bp; 60° C. at 0.5 mm Hg. Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (3.06 g, 9.67 mmol) and sodium hydride (0.43 g, 60% in oil, 10.64 mmol) in tetrahydrofuran (60 mL) and dimethylformamide (6 mL). After 2 hours, add 2-(t-butyldimethylsilyloxy)ethyl iodide (2.78 g, 9.67 mmol). After 20 hours, heat to reflux. After 4 hours, cool to ambient temperature and add ice to quench. Evaporate in vacuo to remove most of the tetrahydrofuran. Partition the evaporated reaction mixture between ethyl acetate (250 mL) and water (200 mL). Separate the layers and extract the organic layer with water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give 1-(t-butoxycarbonyl)-4-(1-(2-(t-butyldimethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.58 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([F:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:2][CH3:1])[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution (100 mg) of methylamine and 1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) were added to pyridine (2 ml), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, ethanol was added to the residue, and the mixture was left to stand overnight. Solids deposited were collected by filtration to obtain the title compound (40 mg) as a colorless powder.
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([C:17](Cl)=[O:18])([CH2:10]3)[CH2:8]1)[CH2:14]2)=[O:6].CO.[Cl-].[NH4+]>[Cu]I.CCOCC>[C:17]([C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([C:5]([O:4][CH3:3])=[O:6])([CH2:14]3)[CH2:8]1)[CH2:10]2)(=[O:18])[CH3:1]
Reactant: [Li]C
Reactant: COC(=O)C12CC3CC(CC(C(=O)Cl)(C3)C1)C2
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C12CC3CC(CC(C(C)=O)(C3)C1)C2
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Under nitrogen, a chilled (0° C.) diethyl ether suspension of copper (I) iodide (3.0 eq) was treated with methyl lithium (6.0 eq, 1.4 M in ethyl ether). The resulting solution was chilled to −78° C. and after ten minutes a chilled (−30° C.) diethyl ether solution of 3-methoxycarbonyladamantane-1-carboxylic acid chloride was added dropwise over a five minute period. The reaction was stirred for 45 minutes at −78° C. and then quenched with MeOH (11.0 eq) and allowed to warm to room temperature. After addition of Et2O and saturated aqueous ammonium chloride solution, the mixture was stirred for ten minutes and then the organic phase was washed with saturated NH4Cl, saturated NaHCO3, brine, dried (MgSO4), filtered and concentrated to a volatile oil, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([C@@H:10]([CH3:13])[CH2:11]O)[CH3:9])[NH:5][C:4](=[O:14])[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH3:9])[C@@H:10]([CH3:13])[CH2:11][N:5]2[C:4](=[O:14])[N:3]=1
Reactant: C[C@@H](CO)N(C)c1cc(Cl)nc(=O)[nH]1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-4-chloro-6-((1-hydroxypropan-2-yl)(methyl)amino)pyrimidin-2(1H)-one (700 mg, 3.22 mmol) and triethylamine (1.35 mL, 9.65 mmol) in tetrahydrofuran (THF) (20 mL) was added methanesulfonyl chloride (0.508 mL, 6.43 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h and concentrated. Purification via Prep-HPLC (column: YMC-Actus Triart C18 150×30 mm; 2 M NH3 in methanol) afforded the title product.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[C:15]([N+:18]([O-:20])=[O:19])=[C:14]([N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)[N:13]=[C:12]1[CH3:34])(C)(C)C.F>C(#N)C.ClCCl>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:14]3[N:13]=[C:12]([CH3:34])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][OH:6])[C:16](=[O:17])[C:15]=3[N+:18]([O-:20])=[O:19])[CH2:22][CH2:23]2)=[CH:28][CH:29]=1
Reactant: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)n1CCCCO[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)n1CCCCO

Procedure:
In analogy the procedure described in example 17b, the 3-[4-(tert-butyl-dimethyl-silanyloxy)-butyl]-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3H pyrimidin-4-one (example 17a) was treated with hydrofluoric acid (47-51% in water) in acetonitrile and dichloromethane at room temperature to yield the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-3-(4-hydroxy-butyl)-2-methyl-5-nitro-3H-pyrimidin-4-one as a yellow solid; m.p. 154-156° C.; MS: [M+H]+=405
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.[C:13]([O-])(O)=[O:14].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:10]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]([CH2:5]3)[CH:3]1[N:2]=[C:13]=[O:14])[CH2:9]2
Reactant: O=C([O-])O
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C=NC1C2CC3CC(C2)CC1C3
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
A vigorously stirred mixture of 2-aminoadamantane hydrochloride (5.01 g, 26.7 mmol), CH2Cl2 (50 mL) and satd aq NaHCO3 (50 mL) was cooled in an ice bath. After 15 min, solid triphosgene (2.64 g, 8.9 mmol) was added. The mixture was stirred in the ice bath for 30 min and the layers were separated. The aqueous layer was extracted with CH2Cl2 (100 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4 and concentrated under reduced pressure to afford the title compound (3.55 g, 75%) as a white solid.