Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[Cl:2][C:3]1[C:4]([Cl:20])=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[N:10]=[C:9]([N:14]3[CH:18]=[CH:17]N=C3)[NH:8][C:7]=2[CH:19]=1.[CH2:21](N)[CH2:22][CH2:23][CH2:24]CC>>[Cl:2][C:3]1[C:4]([Cl:20])=[CH:5][C:6]2[S:11](=[O:12])(=[O:13])[N:10]=[C:9]([NH:14][CH2:18][CH2:17][CH2:21][CH2:22][CH2:23][CH3:24])[NH:8][C:7]=2[CH:19]=1
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2cc(Cl)c(Cl)cc21
Reactant: CCCCCCN
Solvent: O
Product: CCCCCCNC1=NS(=O)(=O)c2cc(Cl)c(Cl)cc2N1

Procedure:
6,7-Dichloro-3-(imidazol-1-yl)-4H-1,2,4-benzothiadiazine 1,1-dioxide monohydrate was treated with hexylamine according to the general procedure Method B to give the title compound; m.p. 282-286° C.; IR (KBr): 3332, 3173, 3074, 2956, 2930, 2854, 1637, 1580, 1562, 1464, 1241, 1168, 1143, 1132 cm−1.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][O:8][N:30]2[C:31](=[O:40])[C:32]3=[CH:39][CH:38]=[CH:37][CH:36]=[C:33]3[C:34]2=[O:35])[CH2:4][O:3]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC1(C)OC[C@H](CO)O1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](CON2C(=O)c3ccccc3C2=O)O1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (27 g, 0.2 mol), triphenylphosphine (53.5 g, 0.2 mol) and N-hydroxyphthalimide (33.3 g, 0.2 mol) in dry tetrahydrofuran (500 ml) cooled to 0° C. was added diethylazodicarboxylate (38.5 g, 0.22 mol). After stirring for 18 hours at 20° C. the originally dark red solution turned pale yellow and was then evaporated to dryness under reduced pressure. The residue was loaded onto a silica column in chloroform and eluted with hexane-acetone (3:1), yielding (R)-N-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)phthalimide as white plates (31.2 g, 55%), m.p. 100°-2° C. [α]D20 =+15.6° (C 0.98 in methanol); 1R: υmax (nujol) 1790, 1770, 1720, 1600 cm-1 ; 1H NMR: δH (CDCl3), 1.35 (3H, s, CH3), 1.41 (3H, s, CH3), 3.97 (1H, q, J=5.5, 8.8 Hz, CH2ON/CH2OC), 4.17 (2H, m, 1H of CH2ON+1H of CH2OC), 4.32 (1H, q, J=5.5, 10.0 Hz, CH2ON/CH2OC), 4.50 (1H, m, CH), 7.74-7.87 (4H, m, aromatic); m/z 262 (M+-CH3, 50%).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([CH:21]([OH:29])[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=1.O>CN(C)C=O>[Si:6]([O:29][CH:21]([C:19]1[CH:20]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[N+:30]([O-:32])=[O:31])[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CCOC(=O)CCC(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(O[Si](C)(C)C(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
Imidazole (5.4 g) and tert-butyldimethylsilyl chloride (3.98 g) were added to a solution of ethyl 4-(5-chloro-2-nitrophenyl)-4-hydroxybutanoate (3.8 g) in anhydrous dimethylformamide (25 mL), and stirred at room temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water three times and dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off and the residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=20:1→10:1) to obtain 5.3 g of ethyl 4-(tert-butyldimethylsilyloxy)-4-(5-chloro-2-nitrophenyl)butanoate with a quantitive yield.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.CC([O-])(C)C.[K+].[CH2:18]([OH:22])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([O:22][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH2:11])[N:3]=1)[CH2:19][CH2:20][CH3:21]
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: CCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCOc1nc(N)c2nc[nH]c2n1
Temperature: 170 °C
Yield: 70 %

Procedure:
2-chloroadenine (1) (1.53 g, 9.03 mmol) was divided among three microwave vials (10-20 mL), each containing 1-butanol (10 mL) and t-BuOK (5 mL, 1M in THF). Each vial was heated to 170° C. for 40 minutes. After reaction completion the solvent was removed by rotary evaporation and the product was purified on flash column eluting 10% methanol in ethylacetate. Evaporation of solvent gave 1.33 g (70%) of 59 as an off white solid. 1H NMR (300 MHz, DMSO) δ 0.919 (t, 3H), 1.39 (m, 2H), 1.62 (m, 2H), 4.09 (t, 2H), 6.00 (s, 2H), 7.44 (s, 1H). LCMS: m/z for C9H13N5O++H observed 208.1 at 1.34 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[CH3:18][C:19]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([C:31](O)=[O:32])=[CH:21][N:20]=1>>[C:9]([NH:8][C:6]1[CH:7]=[C:2]([NH:1][C:31]([C:22]2[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:24][C:19]([CH3:18])=[N:20][CH:21]=2)=[O:32])[CH:3]=[CH:4][C:5]=1[Cl:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1
Reactant: Cc1ncc(C(=O)O)c(-c2ccccc2)n1
Product: Cc1ncc(C(=O)Nc2ccc(Cl)c(NC(=O)c3ccccc3)c2)c(-c2ccccc2)n1

Procedure:
N-(5-amino-2-chlorophenyl)benzamide (0.24 mmol) was used in general procedure 2 with 2-methyl-4-phenylpyrimidin-5-carboxylic acid (0.30 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-2-methyl-4-phenylpyrimidin-5-carboxamide. MS (Q1) 443.1 (M)+
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:16]([O-])=O)[CH:5]=1)[CH3:2].[Cl-].[NH4+].O>[Fe].CO>[NH2:16][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:13]([O:14][CH3:15])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCOc1cc(N)c(C(=O)OC)cc1OC
Yield: 82.7 %

Procedure:
A mixture of 24.110 g (94.5 mmol) methyl 4-ethoxy-5-methoxy-2-nitrobenzoate, 15.81 g (283 mmol) iron powder, 25.28 g (472 mmol) ammonium chloride, 135 ml water, and 350 ml methanol was heated to reflux under N2. At both 3 and 5.5 hours added the same amount of iron and ammonium chloride. Removed heat at 6.5 hours, added ethyl acetate and saturated sodium bicarbonate, filtered through celite and separated layers. Washed organic layer with saturated sodium bicarbonate, dried with magnesium sulfate, stripped solvent, and dried in vacuo, giving 17.594 g of pink solid: : mass spectrum (electrospray m/e): M+H=226.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12](=[O:15])[CH:13]=[CH2:14])[CH3:2].[CH3:16][C:17]([C:20]1[CH:25]=[C:24]([SH:26])[CH:23]=[C:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]=1[OH:31])([CH3:19])[CH3:18].C(N(CC)CC)C>CO>[CH3:30][C:27]([C:22]1[CH:23]=[C:24]([S:26][CH2:14][CH2:13][C:12]([NH:11][C:4]2[C:5]([CH2:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])=[O:15])[CH:25]=[C:20]([C:17]([CH3:19])([CH3:18])[CH3:16])[C:21]=1[OH:31])([CH3:28])[CH3:29]
Reactant: C=CC(=O)Nc1c(CC)cccc1CC
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCc1cccc(CC)c1NC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared by the method of Example 4 from N-(2,6-diethylphenyl)-2-propenamide (1.01 g, 0.005 mole), 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 0.005 mole) and triethylamine (0.5 ml) in methanol, m.p. ca. 150.5°-151.5° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][C:13]([Br:16])=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C([O-])([O-])=O.[K+].[K+].[SH:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>CN(C=O)C.O>[OH:33][C:30]1[CH:31]=[CH:32][C:27]([S:26][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[S:12][C:13]([Br:16])=[CH:14][CH:15]=3)=[O:10])=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])=[CH:28][CH:29]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1ccc(Br)s1
Temperature: 80 °C
Yield: 78.6 %

Procedure:
The product of Example 241b (1.50 g, 4.34 mmol) was dissolved in DMF to which K2CO3 (1.20 g, 8.69 mmol), and 4-mercapto-phenol (548 mg, 4.34 mmol) were added. The reaction mixture was then heated to 80° C. for 2 hrs. At this point the reaction mixture was cooled to room temperature and diluted with water which was then extracted with ethyl acetate to isolate the desired compound (1.54 g, 78%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:46])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:33]([CH3:45])[N:34]=[CH:35][C:36]=2[CH2:37][O:38]C2CCCCO2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:46])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[N:33]([CH3:45])[N:34]=[CH:35][C:36]=4[CH2:37][OH:38])[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3c(COC4CCCCO4)cnn3C)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3c(CO)cnn3C)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-{3-[2-methyl-4-(tetrahydro-pyran-2-yloxymethyl)-2H-pyrazol-3-yl]-phenyl}-3-oxo-propionyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M63) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (272 mg).
Reaction SMILES: C(OC([N:8]1[CH:15]2[CH:11]([N:12]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:13][CH:14]2[C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:28]([O:27][C:25]([N:12]1[CH2:13][CH:14]([C:16](=[O:24])[NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:15]2[NH:8][CH2:9][CH2:10][CH:11]12)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)Nc1ccccc1)CN2C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)C1CN(C(=O)OCc2ccccc2)C2CCNC12
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A solution of 37 (410 mg, 0.88 mmol) in DCM (10 mL) was cooled to 0° C. and treated with TFA (4 mL). After 2 h, the solution was concentrated, diluted with EtOAc and washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 38 (305 mg) as a white foam that was used without further purification. Mass spectrum, m/z [366.4] (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)(=[O:17])=[O:16].B(Br)(Br)[Br:25].CCOC(C)=O.C([O-])(O)=O.[Na+]>ClCCl>[Br:25][CH2:20][CH2:19][N:18]([CH2:23][CH2:22][OH:21])[S:15]([C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([OH:2])[CH:4]=2)[NH:8][C:7]=1[C:12]([NH2:14])=[O:13])(=[O:17])=[O:16]
Reactant: BrB(Br)Br
Reactant: COc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N(CCO)CCBr
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 5-methoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (416 mg, 1.23 mmol) in 15 mL of dichloromethane at −78° C. was added boron tribromide solution (1 M in dichloromethane, 6.13 mmol). After 10 minutes the mixture was allowed to warm to room temperature, and stir for an additional 60 hours. The reaction was poured into a mixture of EtOAc and saturated aqueous NaHCO3 solution. The organic phase was washed with water and brine, dried with Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography through silica gel (3-10% MeOH/dichloromethane) provide the titled product, along with 5-hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C13H17BrN3O5S (M+H+): 406.0067. Found 406.0081.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[O:10]1[C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:17]2([OH:20])[CH2:18][CH2:19][C:14]3([O:13][CH2:12][CH2:11][O:10]3)[CH2:15][CH2:16]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COc1cccc(Br)c1
Product: COc1cccc(C2(O)CCC3(CC2)OCCO3)c1

Procedure:
The title compound was prepared as a white solid from 1-bromo-3-methoxy-benzene (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: CC1C=C(C)NC(=O)C=1C[NH:11][C:12](=[O:33])[C:13]1[CH:18]=[C:17](N2CCCCC2)[N:16]=[C:15](C2C=CC(C=O)=CC=2)[CH:14]=1.CNC.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:12]([NH2:11])(=[O:33])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)nc(N3CCCCC3)c2)c(=O)[nH]1
Agent: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 314.8 %

Procedure:
To a solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-formylphenyl)-6-(piperidin-1-yl)isonicotinamide (0.2 g, 0.45 mmol) in methanol (12 mL), dimethyl amine (2.6 mL, 4.5 mmol, 2M solution in THF) and acetic acid (0.02 g, 0.45 mmol) were added and reaction mass stirred at rt for 90 min. Then reaction mass was cooled to 0° C. and sodium cyanoborohydride (0.056 g, 0.9 mmol) was added. Reaction stirred at 0° C. for 2 h and then stirred at rt for overnight. On completion, solvent was removed under reduced pressure, residue treated with water and extracted with ethyl acetate. Combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel obtaining N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-((dimethylamino)methyl)phenyl)-6-piperidin-1-yl)isonicotinamide as light green solid (0.173 g, 79%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[N:27][CH:26]=[CH:25]3)=[O:20])[CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:32]>C(Cl)Cl.O>[ClH:32].[ClH:32].[NH2:11][CH2:10][CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:19]([NH:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[N:27][CH:26]=[CH:25]2)=[O:20]
Reactant: CC(C)(C)OC(=O)NCCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: NCCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-(4-hydroxyphenyl)-4-(isoquinolin-6-ylamino)-4-oxobutylcarbamate (E307) in CH2Cl2 was added HCl (4 N in dioxane) and 2 drops of H2O and the solution was stirred overnight at room temperature. The solvents were evaporated to give 4-amino-2-(4-hydroxyphenyl)-N-(isoquinolin-6-yl)butanamide dihydrochloride (E308).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7](#[N:9])[CH3:8].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]>C1COCC1>[OH:15][CH:14]([C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([OH:10])[CH:12]=1)[CH2:8][C:7]#[N:9]
Reactant: CC#N
Reactant: O=Cc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCC(O)c1cccc(O)c1
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of KOtBu (68.5 g, 614 mmol) in THF (350 mL), cooled to −50° C., was added acetonitrile (30.3 mL, 540 mmol), dropwise over a period of 5 min. The resulting mixture was stirred at −50° C. for 30 min following which a solution of 3-hydroxybenzaldehyde (30.0 g, 244 mmol) in THF (150 mL) was added slowly, over a period of 10 min. This was then allowed to warm to 0° C. and stirred for another 3 h during which the reaction was found to be complete. The reaction was quenched by slow addition of ice-water followed by extraction with EtOAc. The combined organics were washed with water, brine and dried over Na2SO4. The solution was concentrated under reduced pressure to give 3-hydroxy-3-(3-hydroxyphenyl) propanenitrile (127) as yellow oil which was purified by flash column chromatography (0 to 20% EtOAc-hexanes gradient). Yield (25.0 g, 62%): 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.90-6.93 (m, 1H), 6.82 (dd, J=8.0, 2.4 Hz, 1H), 4.91-5.03 (m, 1H), 2.76 (d, J=6.4 Hz, 2H).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][C@H:6]1[N:13]1[CH:20]=[CH:19][C:17]([NH2:18])=[N:16][C:14]1=[O:15])[CH2:2][CH3:3].C[Si](Cl)(C)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[NH4+].[OH-]>O.N1C=CC=CC=1>[C:26]([NH:18][C:17]1[CH:19]=[CH:20][N:13]([C@@H:6]2[O:7][C@H:8]([CH2:11][OH:12])[C@@H:9]([OH:10])[C@H:5]2[O:4][CH2:1][CH2:2][CH3:3])[C:14](=[O:15])[N:16]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Reaction time: 0.5 h

Procedure:
To the 2'-O-propylcytidine reaction mixture of Example 82 in an ice bath was added pyridine (60 ml) and trimethylsilyl chloride (60 ml). The reaction was stirred for 30 mins followed by the addition of benzoyl chloride (55 ml). The resulting reaction mixture was stirred for 2.5 hrs and then cooled in an ice bath. H2O (100 ml) and conc. NH4OH (100 ml) were added. After stirring for 30 mins, the reaction mixture was evaporated and the residue partition between H2O and CH2Cl2. The organic phase was washed once with dil Na2CO3, once with dil HCl, dried over MgSO4 and evaporated. The resulting residue was loaded on a silica gel column (150 g) and eluted with first CH2Cl2 then 5 to 10% MeOH in CH2Cl2 as the elution solvent. The product containing fractions were evaporated to a foam. The foam was crystallized from EtOAc/Hexanes to give the product (6.5 g total) in several crystal batches.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].O=[C:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1>CN(C=O)C.CCOCC>[Br:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
To [(3-bromophenyl)methyl](triphenyl)phosphonium bromide (1.13 mg, 2.2 mmol) in DMF (4 mL) was added NaH (52.8 mg, 2.2 mmol) after which the mixture was stirred at RT for 5 min before 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (400 mg, 2.0 mmol) was added. This mixture was stirred at RT for 1 h. The resultant mixture was diluted with Et2O (25 mL), washed with H2O (12+2×8 mL), brine (8 mL), dried over NaSO4, and filtered. The filtrate was concentrated and purified with CombiFlash chromatograph to afford the title compound (0.2014 g, 28%). LC-MS m/z 352 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=3)[CH2:20][CH2:21]2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)cn1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Yield: 82.4 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 5-bromo-2-picolinic acid (5.0 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (4.7 g) described in Preparation Example 47, the title compound (7.6 g) was obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[C:9]2[C:10]3([CH2:19][CH:20](C(C)(C)C(=O)C4C=CN=CC=4)[NH:21][CH:22]=2)[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]([CH:17]=O)C3.[CH2:34]1[CH2:38][O:37][CH2:36][CH2:35]1>>[CH3:36][O:37]/[C:38](/[C:34]1[CH:35]=[CH:14][N:13]=[CH:12][CH:17]=1)=[C:12](\[N:13]1[C:14]2[CH:15]=[CH:16][C:8]([CH3:7])=[CH:9][C:10]=2[C:19]2[CH2:20][N:21]([CH3:22])[CH2:16][CH2:8][C:7]1=2)/[CH3:17]
Reactant: C1CCOC1
Reactant: CC1=CC=C2NC(C=O)CC23CC(C(C)(C)C(=O)c2ccncc2)NC=C13
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CO/C(=C(/C)n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Reaction time: 0.17 h

Procedure:
LAH (87 mg, 52.63 mmol) was taken in dry THF (10 mL) under inert atmosphere stirred for 10 min, 8-methyl-5-(2-methyl-1-oxo-1-(pyridin-4-yl)propan-2-yl)-3,4-dihydro-1H-pyrido[4,3-d]indole-2(5H)-carbaldehyde (0.33 g, 0.914 mmol) was added portionwise and stirred at RT for 1 h. The reaction was monitored by TLC. LAH was quenched with sat. sodium sulfate (aqueous) at 0° C., filtered the reaction mass. The filtrate was extracted with EtOAc, dried over anhydrous sodium sulfate and evaporated to dryness to afford 0.24 g of the title compound as a yellow sticky solid. 1H NMR (CDCl3, free base) δ (ppm): 8.36 (d, 2H), 7.20 (s, 1H), 7.10 (d, 1H), 7.0 (d, 1H), 6.78 (d, 2H), 3.78 (s, 2H), 3.60 (s, 3H), 2.82 (m, 1H), 2.74 (m, 1H), 2.60 (m, 1H), 2.50 (s, 3H), 2.42 (s, 3H), 2.30 (m, 1H), 2.19 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCCCCO
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: OCCCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 4-aminobutan-1-ol according to general procedure 1 providing the intermediate (150 mg, 82%) as a yellow solid: Rf=0.45 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.53 (d, J=9.7 Hz, 1H), 7.38 (s, 1H), 6.68 (d, J=9.7 Hz, 1H), 3.62 (t, J=6.6 Hz, 2H), 3.40 (t, J=6.9 Hz, 2H), 1.77-1.72 (m, 2H), 1.69-1.64 (m, 2H).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[OH:8][C@@H:9]([C@H:11]1[C:17](=[O:18])[N:16]2[CH:12]1[S:13][C:14](=[S:32])[CH:15]2[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])[CH3:10].ICC>O1CCCC1>[CH2:1]([S:32][C:14]1[S:13][CH:12]2[N:16]([C:17](=[O:18])[C@@H:11]2[C@H:9]([OH:8])[CH3:10])[C:15]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])[CH3:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=S)SC12
Reactant: CC(C)NC(C)C
Solvent: CCI
Solvent: C1CCOC1
Product: CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)C2S1
Reaction time: 16 h

Procedure:
To 0.200 ml of diisopropylamine was added to 0.426 g of 4-nitrobenzyl 6(S)-[1(R)-hydroxyethyl]-7-oxo-3-thioxo-4-thia-1-azabicyclo[3,2,0]heptane-2-carboxylate in dry tetrahydrofuran with stirring. 0.252 ml of iodoethane was then added and stirring was continued for 16 hours at room temperature. The reaction mixture was then evaporated to dryness and chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures, to give the title product as a mixture of 5R and 5S isomers.