Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([Cl:18])=[CH:13][CH:14]=2)[C:9]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:17][CH2:16][C:15]1[CH:14]=[CH:13][C:12]([Cl:18])=[CH:11][C:10]=1[CH2:9][OH:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)cc2C1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1ccc(Cl)cc1CO
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Into a stirred solution of 2-(tert-butoxycarbonyl)-7-chloro-3,4-dihydro-2H-isoquinolin-1-one (18.4 g, 64.38 mMol) in 50 mL of anhydrous tetrahydrofuran under inert atmosphere at 0° C. was added 2.0M LiBH4 in tetrahydrofuran (64.38 mL, 128.76 mMol, 2 eq). This was stirred at 0° C. for 1.5 hours, quenched with saturated ammonium chloride solution, then partitioned between ethyl acetate and water. The organics were dried(Na2SO4) and concentrated in vacuo. This afforded 2-(tert-butoxycarbonylaminoethyl)-5-chlorobenzyl alcohol as a clear colorless oil (hplc rt=3.21 min, method A; mass spec m/z=286.2).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:34]1(=[O:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@@H:15]([C:34]1([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reactant: O=C1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc([C@@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)C2(O)CCCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
A solution of (4S)-4-benzyl-3-[2-(4-methoxyphenyl)acetyl]-1,3-oxazolidin-2-one (2.5 g, 7.68 mmol) in dry methylene chloride (50 mL) was cooled to −78° C. and treated with diisopropylethylamine (1.09 g, 8.45 mmol) followed by titanium tetrachloride (0.88 mL, 8.06 mmol). The resulting reaction was warmed to 0° C. where it was stirred for 1 h, during which time the reaction turned dark purple. The reaction was then re-cooled to −78° C. and was treated with another portion of titanium tetrachloride (0.88 mL, 8.06 mmol) followed by a solution of cyclohexanone (0.91 mL, 8.83 mmol) in methylene chloride (10 mL). After addition, the reaction was warmed to 0° C. where it was stirred for 2 h, after which time the reaction was carefully quenched with the addition of a saturated aqueous solution of sodium bicarbonate and the mixture was stirred at 0° C. for 30 minutes. The reaction was filtered to remove the titanium salt that had precipitated, and the layers of the filtrate were then separated. The aqueous layer was washed with methylene chloride (3×30 mL). The solid precipitate was then collected and stirred vigorously in a 2N aqueous solution of hydrochloric acid (50 mL) for 20 minutes, after which time, the remaining product was extracted from the aqueous layer with methylene chloride (3×60 mL), and the combined organic extracts (from the filtrate and the liberated salt) were dried over magnesium sulfate and concentrated in vacuo. The product was purified via Biotage™ Horizon chromatography (FLASH 40 M, silica, gradient from 10% ethyl acetate/hexane to 45% ethyl acetate/hexane) to yield 2.67 g (82%) (4S)-4-benzyl-3-[(2R)-2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetyl]-1,3-oxazolidin-2-one as a colorless foam. MS (ESI) m/z 406; [α]D25=+109° (c=0.010 g/mL, EtOH).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:7]1[C:8]([CH3:13])=[N:9][CH:10]=[CH:11][CH:12]=1)=O)#[N:2].N>C(O)C.[Ni]>[CH3:13][C:8]1[N:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:5]1[NH:2][CH2:1][CH2:3][CH2:4]1
Reactant: Cc1ncccc1C(=O)CCC#N
Agent: [Ni]
Agent: N
Solvent: CCO
Product: Cc1ncccc1C1CCCN1
Reaction time: 15 h
Yield: 71.6 %

Procedure:
To a solution of 3.15 g 2-methyl-3-pyridyl 2-cyanoethyl ketone (Preparation III) in 180 ml of ethanol saturated with ammonia was added 20 g of freshly prepared Raney nickel. The mixture was hydrogenated in a Parr apparatus at about 50 psi for 15 h. The reaction mixture was filtered to remove the catalyst and concentrated under reduced pressure. The residue was taken up in hexane and dried over Drierite. After filtration and removal of the solvent the residue was distilled. The fraction boiling at 100°-105°/0.175 mm Hg, was collected to give 2.1 g (75%) of 2-methylnornicotine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[Al](C)C.[NH2:12][C:13]1[C:14]2[N:15]([C:19]([C@H:31]3[CH2:36][CH2:35][C@H:34]([C:37](OC)=[O:38])[CH2:33][CH2:32]3)=[N:20][C:21]=2[C:22]2[NH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]=[CH:17][N:18]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:12][C:13]1[C:14]2[N:15]([C:19]([C@H:31]3[CH2:32][CH2:33][C@H:34]([C:37]([NH:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[O:38])[CH2:35][CH2:36]3)=[N:20][C:21]=2[C:22]2[NH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]=[CH:17][N:18]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn32)CC1
Reactant: Nc1cccnc1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](C(=O)Nc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A suspension of 3-aminopyridine (40 mg, 0.43 mmol) in toluene (1.3 mL) was treated with a 2M toluene solution of trimethylaluminum (0.3 mL, 0.60 mmol). After 25 min, the resulting solution was treated with methyl trans-4-(8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate (30 mg, 0.08 mol) and the mixture stirred at rt overnight. The mixture was then stirred with 2M NaOH (20 mL) and ethyl acetate (20 mL) for 10 min., then the organic phase was separated and the aqueous extracted EtOAc (3×15 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo to give crude product which was subjected to mass-directed preparative HPLC to afford pure desired product. 1H NMR (d6-DMSO, 400 MHz): δ 11.45 (br s, 1H), 10.12 (s, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.25 (d, J=4.8 Hz, 1H), 8.14 (s, 1H), 8.08 (dd, J=8.0, 1.6 Hz, 1H), 7.71 (d, J=5.2 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.34 (m, 1H), 7.15-7.00 (m, 3H), 6.65 (s, 1H), 6.42 (br s, 2H), 3.22 (m, 1H), 2.47 (m, 1H), 2.15-1.95 (m, 4H), and 1.85-1.65 (m, 4H). MS (ES+): m/z 452.17 [MH+].
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][CH2:12][C:7]=2[CH:6]=1)[OH:4].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:14][C:10]1([CH3:13])[O:9][C:8]2[CH:15]=[CH:16][C:5]([C@H:3]3[O:4][C:17](=[O:18])[NH:1][CH2:2]3)=[CH:6][C:7]=2[CH2:12][O:11]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a solution of (R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (2.53 g, 11.3 mmol) in chloroform (12 mL) was added carbonyldiimidazol (2.75 g, 17 mmol) and triethylamine (2.37 mL, 17 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue diluted with ethyl acetate (25 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried (Na2SO4), and the solvent reduced under reduced pressure. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (1:2) as eluent yielded the title compound (1.63 g, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[CH3:24]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)c(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(Cl)c(Br)c1
Yield: 78 %

Procedure:
A mixture of 3-[5-(3-bromo-4-chlorophenyl)-4-isoxazolyl]propionic acid (2.74 g), conc. sulfuric acid (0.2 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(3-bromo-4-chlorophenyl)-4-isoxazolyl]propionate (2.22 g, yield 78%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 54–55° C.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:36][C:35]4[CH:34]=[N:33][N:32]([CH3:37])[C:31]=4[NH:30][C:29]4[CH:38]=[CH:39][CH:40]=[CH:41][C:28]3=4)=[O:26])=[CH:21][C:20]=2[CH3:42])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.CO>[ClH:1].[CH3:37][N:32]1[C:31]2[NH:30][C:29]3[CH:38]=[CH:39][CH:40]=[CH:41][C:28]=3[N:27]([C:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][CH:12]4[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]4)=[C:20]([CH3:42])[CH:21]=3)=[O:26])[CH2:36][C:35]=2[CH:34]=[N:33]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC1CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
4M HCl solution in dioxan (1 ml) was added to a solution of 4-{3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenoxy]-propyl}-piperidine-1-carboxylic acid tert-butyl ester from Example E68.4 (71 mg, 0.13 mmol) in methanol (3 ml). The mixture was stirred for 20 h at room temperature then solvents were concentrated in vacuo. The residue was triturated with diethyl ether to yield the title compound (61 mg, 97%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][Br:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCc1ccccc1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 4-phenyl-1-butanol (5.00 g, 33.3 mmol) and CH2Cl2 (250 mL) at 0° C. was added triphenylphosphine (13.1 g, 50.0 mmol) followed by NBS (8.90 g, 50.0 mmol). After stirring at this temperature for 2 h, the mixture was quenched with H2O (50 mL) and extracted with CH2Cl2 (150 mL) The organic layer was washed with brine (40 mL) and dried (Na2SO4). After concentration, the residue was flushed through two quick columns of silica gel using 2% EtOAc/petroleum ether as an eluant to afford 4-phenylbutyl bromide (6.22 g, 88%) as an intermediate.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:26][C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]([N:20]3[CH2:21][CH2:22][N:23]([C:29]4[CH:30]=[CH:31][N:32]=[C:27]([CH3:26])[N:28]=4)[CH2:24][CH2:25]3)=[O:19])[CH2:16][CH2:17]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(C1CCN(S(=O)(=O)c2ccc(Cl)cc2)CC1)N1CCNCC1
Reactant: Cc1nccc(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nccc(N2CCN(C(=O)C3CCN(S(=O)(=O)c4ccc(Cl)cc4)CC3)CC2)n1

Procedure:
The crude 1-(4-chlorophenylsulphonyl)-4-(piperazin-4-ylcarbonyl)piperidine hydrochloride, 2-methyl-4-chloro-pyrimidine (299 mg) and triethylamine (1.47 ml) were heated under reflux in ethanol (12 ml) for 5 hours. The solvent was removed by evaporation. Purification by filtration column chromatography (silica) eluting with 2% methanol/dichloromethane increasing to 10% methanol/dichloromethane gave 1-(4-chlorophenylsulphonyl)-4-[1-(2-methylpyrimidin-4-yl)piperazin-4-ylcarbonyl]piperidine as a solid (0.87 g); NMR (CDCl3): 1.7-2.0 (m, 5H), 2.5 (m, 5H), 3.5-3.8 (m, 10H), 6.3 (m, 1H), 7.5 (m, 2H), 7.7 (m, 2H), 8.2 (m, 1H).
Reaction SMILES: [N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3][C:2]=1[C:14]([NH:16][NH2:17])=[O:15].[N:18]([O-])=O.[Na+].N([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3][C:2]=1[C:14]([N:16]=[N+:17]=[N-:18])=[O:15]
Reactant: O=N[O-]
Reactant: NNC(=O)c1ncc2[nH]c3ccccc3c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=NC(=O)c1ncc2[nH]c3ccccc3c2n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under heating, 0.3 g of 5H-pyrimido[5,4-b]indole-2-carboxylic acid hydrazide (Example 5) is dissolved in a mixture of 6 ml of glacial acetic acid and 2.4 ml of water. Then, a solution of 0.33 g of sodium nitrite in 1 ml of water is added gradually thereto at 0° C. After adding the nitrite, the mixture is stirred for another 4 hours at 0° C., thereafter rendered alkaline with sodium carbonate solution, and the thus-crystallized 5H-pyrimido[5,4-b]indole-2-carboxylic acid azide is vacuum-filtered. The yield is 0.3 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:25])[CH2:15][O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:25])[CH2:15][O:16][CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)COCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-phenethyloxy-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: CCN=C=NCCCN(C)C.CN(C=O)C.[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[C:24]2[C:32](O)=[O:33])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:35][C@H:36]([C:40]([NH:42][CH:43]([CH:52]([OH:55])[CH2:53][F:54])[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:41])[CH:37]([CH3:39])[CH3:38]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17]1([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[C:24]2[C:32]([NH:35][C@H:36]([C:40]([NH:42][CH:43]([CH:52]([OH:55])[CH2:53][F:54])[CH2:44][C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])=[O:41])[CH:37]([CH3:38])[CH3:39])=[O:33])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc2ccccc2n1-c1ccccc1
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2ccccc2n1-c1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
DMAP (122 mg, 1.0 mmol) and EDAC (249 mg, 1.3 mmol) were added as solids to a DMF solution of 1-phenylindole-2-carboxylic acid (237 mg, 1.0 mmol in 2 ml, DMF), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at 0° C. A methylene chloride solution of N-(valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (306 mg, 1.0 mmol in 2 mL of methylene chloride) was added to the reaction mixture and the mixture was stirred for 1 hour under a nitrogen atmosphere at 0° C. and 4 hours at room temperature. The yellow reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated to give a colorless film (0.827 g). The film was subjected to flash chromatography on silica gel with ethyl acetate/hexanes (1:2) to yield the title product as a white foam (400 mg, 78%). TLC: (ethyl acetate/hexanes 1: 1): Rf=0.27.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[N:4][C:5]([O:9][CH3:10])=[CH:6][C:7]=1[CH3:8].C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.[Cl-].[NH4+]>C1COCC1>[CH3:10][O:9][C:5]1[N:4]=[C:3]([CH3:11])[C:2]([B:17]([OH:20])[OH:18])=[C:7]([CH3:8])[CH:6]=1
Reactant: COB(OC)OC
Reactant: COc1cc(C)c(Br)c(C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C)c(B(O)O)c(C)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-bromo-6-methoxy-2,4-dimethylpyridine (150 mg) was added to THF (3 mL). The solution was cooled to −78° C., and n-butyllithium (1.63 M solution in n-hexane, 0.468 mL) was added, followed by stirring at the same temperature for 30 minutes. Trimethyl borate (0.108 mL) was added to the reaction mixture, and the mixture was stirred at −78° C. for 10 minutes and at room temperature for 50 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the reaction mixture was concentrated under reduced pressure. THF was distilled off. The resulting residue was filtered. The solid collected by filtration was washed with water and n-heptane to give the title compound (41 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([S:22]([NH:1][C:2]2[C:7]([I:8])=[CH:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CSc1cnc(N)c(I)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 56 %

Procedure:
To a solution of 2-amino-3-iodo-5-methylthiopyridine (7.63 g) in pyridine (30 ml), benzenesulfonyl chloride (7.9 ml) was added at 15 to 30° C. under nitrogen atmosphere and the mixture was stirred at 60° C. for 15 hours. The reaction solution was then poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. A solution of the resulting crude bis(benzenesulfonyl) product in a mixture of methanol/dioxane (1:1, 200 ml) was added a 1N aqueous potassium hydroxide solution (64 ml) at 15 to 30° C. and the mixture was stirred at 60° C. for 1 hour. The reaction solution was then poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (methanol:chloroform=1:50) to obtain 6.4 g (56%) of the desired product as a white powder.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].OS([O-])(=O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][Cl:20])[CH3:2]
Reactant: CCOC(CCN)OCC
Reactant: O=C(Cl)CCCCCl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CCNC(=O)CCCCCl)OCC

Procedure:
A solution of [3,3-bis(ethyloxy)propyl]amine (9.02 g, 61 mmol) and diisopropylethylamine (13.3 mL, 76.4 mmol) in CH2Cl2 (50 mL) was added dropwise to a cooled (0° C.) solution of 5-chloropentanoyl chloride (10.35 g, 61 mmol) in CH2Cl2 (50 mL) over 2 h. After addition was complete the mixture was treated with 1N NaHSO4 (75 mL) and separated the layers in a separatory funnel. Back extracted the aqueous with CH2Cl2 then combined the organics, washed them with brine, dried them over MgSO4, filtered, and concentrated in vacuo. The resulting oil was chromatographed on silica gel using a gradient between 50 and 100% EtOAC in Hexanes over 100 min. Collected, combined, and concentrated in vacuo pure fractions to provide the desired product as a yellow viscous oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.09 Hz, 6 H), 1.44-1.55 (m, 2 H), 1.59-1.75 (m, 4 H), 2.04 (t, J=7.23 Hz, 2 H), 3.01-3.08 (m, 2 H), 3.41 (dq, J=9.55, 7.07 Hz, 2 H), 3.50-3.64 (m, 4 H), 4.48 (t, J=5.69 Hz, 1 H), 7.74 (t, J=4.98 Hz, 1 H); ES+ MS: 288 (M+Na+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)([O-:3])=[O:2].[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:23]([O:22][C:21](=[O:27])[NH:20][CH2:19][CH2:18][NH:17][CH:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:11][CH2:12]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C1CCN(c2ccccc2[N+](=O)[O-])CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 8 (945 mg, 4.29 mmol), 1 (695 mg, 4.33 mmol), and acetic acid (1.31 g, 21.8 mmol) in methanol (10 mL) was treated with sodium cyanoborohydride (270 mg, 4.29 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. PCTLC (SiO2, 6 mm, 10% EtOH-90% CHCl3) afforded the title compound (9).
Reaction SMILES: Cl[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH:18]=[O:19].[H-].[Na+].[CH3:22][CH:23]([SH:25])[CH3:24]>CN(C)C=O.O>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([S:25][CH:23]([CH3:24])[CH3:22])=[C:3]([CH:18]=[O:19])[S:4][C:5]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]1=[O:13]
Reactant: CC(C)S
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)c(C=O)sc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SC(C)C)c(C=O)sc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
To a solution of 5-chloro-1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrinidine-6-carboxaldehyde (Example 50 step b; 2 g) in dimethylformamide (20 ml) was added sodium hydride (0.3 g of 60% dispersion) followed by the addition of 2-propanethiol (0.6 g). The mixture was stirred for 24 hours at ambient temperature then the reaction was diluted with water (100 ml) and extracted thrice with ethyl acetate (3×100 ml). The organic phase was washed with water (100 ml), then with brine (100 ml) and then dried, filtered and evaporated to leave the subtitle compound as a pale yellow solid (2.24 g).