Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[NH2:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:53]=[CH:54][CH:55]=1)[CH2:24][N:25]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)=[CH:41][CH:40]=1)[S:26]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[C:30]=1[OH:37])(=[O:28])=[O:27]>C(Cl)Cl>[Cl:36][C:31]1[C:30]([OH:37])=[C:29]([S:26]([N:25]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]3[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=3)=[CH:41][CH:40]=2)[CH2:24][C:23]2[CH:53]=[CH:54][CH:55]=[C:21]([CH2:20][NH:19][S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:22]=2)(=[O:28])=[O:27])[CH:34]=[C:33]([Cl:35])[CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1cccc(CN(Cc2ccc(Oc3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCc2cccc(CN(Cc3ccc(Oc4ccc(F)cc4)cc3)S(=O)(=O)c3cc(Cl)cc(Cl)c3O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a suspension of 4-methylbenzene-1-sulfonyl chloride (25 mg, 0.13 mmol) in CH2Cl2 (3 mL) were added Et3N (0.10 ml, 075 mmol) and N-(3-(aminomethyl)benzyl)-3,5-dichloro-N-(4-(4-fluorophenoxy)benzyl)-2-hydroxybenzenesulfonamide (70 mg, 0.13 mmol). The reaction mixture was stirred at rt. under nitrogen for 2 h. The mixture was concentrated and dissolved in MeOH, purified by preparative HPLC. The fractions containing the desired product were combined, concentrated and lyophilized to give white solid (52 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH:7]=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[BH4-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:12][CH:13]3[CH2:14][CH2:15]3)[CH2:7][NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)N=CN(CC2CC2)c2ccc(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=S1(=O)NCN(CC2CC2)c2ccc(Cl)cc21
Temperature: 50 °C

Procedure:
To a solution of 7-chloro-4-cyclopropylmethyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.7 g) in isopropanol (50 mL) there is added sodium borohydride (0.2 g) and the mixture is heated at 50° C. for 5 minutes. The reaction mixture is evaporated under reduced pressure and the residue is taken up in water (30 mL). The pH of the medium is adjusted to 5-6 by addition of 6N hydrochloric acid and the suspension is extracted three times with chloroform (30 mL). The organic phases are collected, dried over anhydrous MgSO4 and filtered. The filtrate is evaporated under reduced pressure and the residue is taken up in methanol (5 mL). Water (50 mL) is added to the methanolic solution and the precipitate which appears is collected by filtration, washed with water and dried.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:21][CH2:20][CH2:19][CH2:18][C:9]=2[N:10]=[C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:12]=1)(=O)=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH2:34])=[O:33])=[CH:27][CH:26]=1>>[CH:13]1([C:11]2[N:12]=[C:7]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][C:32]([NH2:34])=[O:33])=[CH:29][CH:30]=3)[C:8]3[S:21][CH2:20][CH2:19][CH2:18][C:9]=3[N:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: O=S(=O)(Oc1nc(C2CCCC2)nc2c1SCCC2)C(F)(F)F
Product: NC(=O)Cc1ccc(Nc2nc(C3CCCC3)nc3c2SCCC3)cc1
Yield: 54.3 %

Procedure:
Following general procedure H, 2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.133 g, 0.36 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.063 g, 0.43 mmol) to afford the title compound (0.072 g, 54%) as an off-white solid. MW=368.50. 1H NMR (DMSO-d6, 300 MHz) δ 7.91 (s, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.44 (s, 1H), 7.16 (d, J=8.5 Hz, 2H), 3.31 (s, 2H), 3.13-3.07 (m, 2H), 3.00 (quin, J=8.0 Hz, 1H), 2.75 (t, J=6.5 Hz, 2H), 2.17-2.06 (m, 2H), 1.97-1.48 (m, 8H); APCI MS m/z 369 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.[F:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]1[N:21]=[N:22][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[C:16]1[N:15]=[C:14]2OS(C1C=CC(C)=CC=1)(=O)=O>>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([C:14]3[C:13]4[C:18](=[CH:19][CH:20]=[C:11]([F:10])[CH:12]=4)[N:17]4[N:21]=[N:22][C:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[F:30])=[C:16]4[N:15]=3)[CH2:6][C:5]=12
Reactant: c1cn2c(n1)CNCC2
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3c(-c4ccccc4F)nnn3c3ccc(F)cc23)cc1
Product: Fc1ccc2c(c1)c(N1CCn3ccnc3C1)nc1c(-c3ccccc3F)nnn12

Procedure:
Prepared from 5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine and 7-fluoro-3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)-[1,2,3]triazolo[1,5-α]quinazoline as described for Example 1, step c (0.031 g, 26%). Found: C, 61.72; H, 3.79; N, 23.14. C21H15F2N7.0.33(H2O) requires C, 61.65; H, 3.86; N, 23.96%. δH (360 MHz; CDCl3) 4.09 (2H, dd, J=5 and 5), 4.05 (2H, dd, J=5 and 5), 4.97 (2H, s), 6.93 (1H, d, J=1), 7.07 (1H, d, J=1), 7.21-7.32 (2H, m), 7.37-7.40 (1H, m), 7.67-7.74 (2H, m), 8.06 (1H, ddd, J=7, 7 and 2), 8.75 (1H, dd, J=8 and 5); m/z (ES+) 404 (M+H+).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:8][C:9]([OH:14])=[C:10]([CH:13]=1)[C:11]#[N:12].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:5][C:6]1[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:8][C:9]([O:14][CH:2]([CH3:4])[CH3:3])=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: CC(C)Br
Reactant: N#Cc1cc(Br)c(-c2ccc(F)cc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1nc(-c2ccc(F)cc2)c(Br)cc1C#N

Procedure:
2-Bromopropane (3.32 mL) was added to a mixture of 5-bromo-6-(4-fluorophenyl)-2-hydroxynicotinonitrile (5.18 g), potassium carbonate (4.89 g), and DMF (30 mL), and the resultant mixture was stirred at 80 C for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (5.92 g)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[O:9]([CH:17]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)[CH2:22][CH2:21]1)[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[O:9]([CH:17]([CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([N:26]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=2)[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:22][CH2:21]1)[Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:11])[CH3:12]
Reactant: Cc1ccc(NC2CCN(CCC(O[Si](C)(C)C(C)(C)C)C3CCCCC3)CC2)nc1
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC(O[Si](C)(C)C(C)(C)C)C3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
After adding 2-furoyl chloride (0.14 mL, 1.4 mmol) dropwise to a solution of 1-(3-tert-butyldimethylsiloxy-3-cyclohexylpropyl)-4-(5-methylpyridin-2-yl)aminopiperidine (423 mg, 0.95 mmol) and triethylamine (0.264 mL) in methylene chloride (4 mL) while cooling on ice, the mixture was stirred at room temperature for 18 hours. NH silica Chromatorex DM1020 was added to the reaction mixture, which was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60 g NH silica Chromatorex DM2035, hexane:ethyl acetate=4:1) to obtain the title compound as an oil (458 mg) (89.4% yield).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1.[N+:10]([O-])([O-])=O.[K+].O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>S(=O)(=O)(O)O.O>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH2:3][O:2]1
Reactant: c1ccc2c(c1)COC2
Reactant: O=[N+]([O-])[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Nc1ccc2c(c1)COC2
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,3-dihydro-isobenzofuran (83.2 mmol) in sulfuric acid (75 mL), cooled in an ice bath, add a solution of potassium nitrate (83.2 mmol) in sulfuric acid (25 mL) dropwise. After stirring for 30 min, pour the reaction mixture over ice and collect the resulting precipitate on a glass frit. Wash the precipitate with water (200 mL) and dry under vacuum. Dissolve the precipitate in ethanol (250 mL) and add tin chloride dihydrate (273.6 mmol). After heating at 70° C. for 2 h, dilute with water (200 mL), cool to room temperature, and neutralize the reaction with 5 N NaOH. Extract the mixture with ethyl acetate (3×200 mL) and dry the organic portion over sodium sulfate. Remove the solvent in vacuo to afford the title compound as a tan solid. 1H NMR (CDCl3, 400 MHz) δ 3.50 (bs, 2H), 5.02 (s, 4H), 6.56 (d, J=2.4 Hz, 1H), 6.60 (dd, J=2.4, 8.0 Hz, 1 H), 7.01 (d, J=8.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(O)(=O)C.CO[C:17](OC)([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[CH:17]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])([CH3:19])[CH3:18]
Reactant: COC(=O)c1ccsc1N
Reactant: COC(C)(C)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COC(=O)c1ccsc1NC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 18359.7 %

Procedure:
To a solution of methyl 2-aminothiophene-3-carboxylate (1.76 kg, 11.2 mol) in glacial acetic acid (1.34 kg, 22.3 mol) and dichloromethane (8 L) were added trifluoroacetic acid (17.8 g, 156 mmol), 2,2-dimethoxypropane (6.83 kg, 65.6 mmol) and sodium triacetoxyborohydride (3.9 kg, 18.4 mol). The reaction mixture was stirred for 18 h at room temperature, quenched with saturated aqueous potassium carbonate solution (13.5 L) over 3 h and diluted with water (21 L). The organic layer was collected and the aqueous layer was extracted with dichloromethane (2×6 kg). The combined extracts were washed with aqueous sodium chloride solution (10 kg) and concentrated under reduced pressure to afford a dark black-red liquid (2.4 kg). This residue was purified on a 15-kg silica gel flash chromatography column eluted with 3% ethyl acetate-heptane to afford the title compound as a slightly yellow liquid.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:4][C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)CBr)cc1
Yield: 97.6 %

Procedure:
A solution of bromine (0.31 mL, 5.9 mmol) in carbon tetrachloride (10 mL) was added to a suspension of N-(4-acetylphenyl)acetamide (1 g, 5.6 mmol) (Lancaster Synthesis) in carbon tetrachloride (20 mL). The reaction mixture was stirred for several hours but TLC indicated only starting material. Acetic acid (10 mL) was added, and the reaction mixture was stirred overnight. Filtration gave N-[4-(bromoacetyl)phenyl]acetamide (1.4 g) as a solid. HPLC indicated that the purity was approximately 80%. This material was used directly in subsequent steps without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.Br[C:10]1[N:11]=[CH:12][C:13]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:14][C:15]=1[Cl:16]>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:13]1[C:12]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:11][CH:10]=[C:15]([Cl:16])[N:14]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Nc1cnc(Br)c(Cl)n1)c1cccc(Cl)c1Cl
Reactant: OCc1cccnc1
Product: O=S(=O)(Nc1nc(Cl)cnc1OCc1cccnc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31 using pyridine-3-methanol (0.22 g) and N-(3-bromo-6-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (Example 98) (0.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:24][O:25][CH2:26][CH3:27])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1>C(#N)C>[Cl:1][C:2]1[C:3](/[C:9](=[N:24]\[O:25][CH2:26][CH3:27])/[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:20])[F:22])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Solvent: CC#N
Product: CCO/N=C(/CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Yield: 21.7 %

Procedure:
190 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(ethoxyimino)ethyl]-2-(trifluoromethyl)benzamide was dissolved in 4 ml of acetonitrile, and the solution was irradiated with light for 2.5 hours in a quartz cell (manufactured by Fine, 4 clear windows for spectroscopy) using a 100 W high-pressure mercury lamp (manufactured by USHIO INC., lamp: UM-102, power supply: UM-103B-B). After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 41.3 mg of the desired product as white crystals.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:27].O1CCOCC1>CO>[ClH:27].[NH2:7][C@@H:8]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Route A: To a solution of [1 (S)-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]carbamic acid tert-butyl ester (Preparation 19, 11.6 g, 31.7 mmol) in methanol (40 mL) was added hydrochloric acid in dioxane (24 mL, 4N, 95.0 mmol) and the reaction mixture stirred at rt for 6 h. The solvent was removed in vacuo and the residue was dissolved in water (100 mL) and extracted into ethyl acetate (2×50 mL). The aqueous phase was evaporated to dryness to give the title compound as a white solid. δH (D2O): 0.52–0.63 (0.5H, m), 1.12–1.23 (0.5H, m), 1.26–1.38 (1H, m), 1.42–1.50 (0.5H, m), 1.59–1.69 (0.5H, m), 1.72–1.82 (1H, m), 2.61–2.71 (0.5H, m), 2.91–3.15 (4H, m), 3.33–3.47 (1H, m), 3.69–3.78 (1H, m), 3.88–3.96 (1H, m), 4.60–4.72 (1H, m), 7.02–7.11 (2H, m), 7.14–7.26 (2H, m).
Reaction SMILES: CO.CCN(CC)CC.[NH2:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][C:14]([C:20]2[CH:21]=[N:22][C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:24][CH:25]=2)=[C:13]([F:30])[C:12]=1[CH:31]1[CH2:35][CH2:34][CH2:33][O:32]1>[Pd].C1COCC1>[NH2:10][C:11]1[C:16]([NH2:17])=[CH:15][C:14]([C:20]2[CH:21]=[N:22][C:23]([C:26]([OH:29])([CH3:27])[CH3:28])=[N:24][CH:25]=2)=[C:13]([F:30])[C:12]=1[CH:31]1[CH2:35][CH2:34][CH2:33][O:32]1
Reactant: CC(C)(O)c1ncc(-c2cc([N+](=O)[O-])c(N)c(C3CCCO3)c2F)cn1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)c1ncc(-c2cc(N)c(N)c(C3CCCO3)c2F)cn1
Yield: 402.8 %

Procedure:
Placed 5% palladium on carbon (14.21 g, 50% wet, 3.339 mmol, Aldrich 330116) in a Parr bottle under nitrogen, followed by MeOH (242 mL, JT-Baker 909333) and NEt3 (46.54 mL, 333.9 mmol, Sigma-Aldrich 471283). Dissolved 245-(4-amino-2-fluoro-5-nitro-3-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-ol (20) (121.0 g, 333.9 mmol) in hot THF (360 mL), allowed to cool, added to the reaction mixture, and rinsed with another portion of THF (124 mL). Placed the vessel on a Parr shaker and saturated with H2. Added 45 psi H2 and shook until consumption was complete (HPLC and LCMS showed complete reaction). The reaction mixture was purged with nitrogen, filtered through Celite™ and rinsed with EtOAc. It was re-filtered through paper (glass microfibre) and the filtrate concentrated in vacuo. Repeated the reaction three more times on the same scale and the batches were combined giving 21 as a brown solid (447 g, 99% yield; 93% HPLC purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 333.46 (1.79 min). 1H NMR (300 MHz, CDCl3) δ 8.81 (d, J=1.4 Hz, 2H), 6.69 (d, J=7.3 Hz, 1H), 5.27-5.20 (m, 1H), 4.73 (s, 1H), 4.70 (s, 2H), 4.23-4.14 (m, 1H), 3.94-3.86 (m, 1H), 3.22 (s, 2H), 2.32-2.22 (m, 1H), 2.18-199 (m, 3H), 1.63 (s, 6H) ppm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:5].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[C:21](F)[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>CN(C)C=O.C(OCC)(=O)C>[Cl:14][C:15]1[CH:22]=[C:21]([O:1][CH2:2][CH2:3][N:4]([CH3:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: CN(CCO)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCOc1ccc(C=O)c(Cl)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
To a solution of 2-[N-(2-hydroxyethyl)-N-methylamino]pyridine (3.87 g) in dry N,N-dimethylformamide (39 ml) was added sodium hydride (60% in oil, 1.12 g), and the reaction mixture was stirred at room temperature for 30 min. 2-Chloro-4-fluorobenzaldehyde (4.43 g) was added to the reaction mixture and the mixture was stirred for 3 days. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give the objective compound (3.30 g) as a pale-yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl-].[NH4+].[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[CH3:24][S:23][C:20]1[N:21]=[CH:22][C:11]2[C:10](=[O:25])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]4[N:28]=[N:29][NH:30][N:2]=4)[CH:4]=3)[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]=2[N:19]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C#N)c1)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn[nH]n3)c1)C2=O
Temperature: 100 °C
Reaction time: 9.5 h
Yield: 27.4 %

Procedure:
(S)-5-(3-Cyanophenyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (366 mg, 1.04 mol) obtained in Step 1 of Example 71 was dissolved in DMF (7 mL), and the mixture was stirred at 100° C. for 9.5 hours after adding ammonium chloride (222 mg, 4.16 mmol) and sodium azide (176 mg, 2.71 mmol). The mixture was extracted by addition of ethyl acetate and water. The aqueous layer was collected, and the pH was adjusted to 5 with 1 mol/L hydrochloric acid. After extraction with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and reslurried with diethyl ether to give (S)-9-methylthio-5-[3-(2H-tetrazol-5-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (293 mg, 71%).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:39]([Si:43]([CH3:46])([CH3:45])Cl)([CH3:42])([CH3:41])[CH3:40].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:10]([O:31][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:46])[CH3:45])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
In analogy with Example 1j), 28.8 g (54.8 mmol) of 5(S)-(Boc-amino)4(S)-hydroxy-6-cyclohexyl-2(R)-[(4-benzyloxyphenyl)methyl]hexanoic acid in 288 ml of DMF, are converted into the title compound with 35.8 g (237.6 mmol) of tert-butyldimethylchlorosilane and 30 g (440 mmol) of imidazole. The title compound is purified by column chromatography (SiO2, hexane/ethyl acetate: 4:1 to 1:1); TLC Rf (E)=0.34; tRet (gradient from 75 to 100% (a) in (b) over 20 min)=25.06 min; FAB-MS (M+H+)=526.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)[NH:11][C:6]=2[CH:7]=[C:8]([F:10])[CH:9]=1)=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cc(F)cc(N=Cc2cccc(Br)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(F)cc2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred mixture solution of 3-[(3-bromo-benzylidene)-amino]-5-fluoro-benzoic acid methyl ester (51.7 g, 153.8 mmol) and ytterbium(III) triflate hydrate (14.3 g, 23.1 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (14 mL, 153.8 mmol) and water (2.8 mL, 153.8 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-7-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (63.0 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrFNO3 (M+H)+: 409.27, observed: 390.0 & 392.0.
Reaction SMILES: C(O[CH:4]=[CH:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])C.[CH3:12][S:13][CH2:14][CH:15]=[CH:16][N:17]1CCCC1.C([O-])(=O)C.[NH4+]>C(#N)C>[CH3:12][S:13][CH2:14][C:15]1[CH:4]=[CH:5][C:6]([C:7]([F:8])([F:9])[F:10])=[N:17][CH:16]=1
Reactant: CSCC=CN1CCCC1
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: CSCc1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a dry 1 L round bottom flask equipped with a magnetic stir bar, liquid addition funnel, thermometer, and nitrogen inlet were added 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (M) (67.4 g, 401 mmol) and 133 mL of anhydrous acetonitrile, and the resulting solution was cooled to 0° C. in an ice bath. To this solution was added 1-[3-(methylthio)prop-1-enyl]pyrrolidine (L) (63.0 g, 401 mmol, dissolved in 50 mL of anhydrous acetonitrile) dropwise via the addition funnel at a rate which maintained the reaction temperature at 0-7° C. The ice bath was removed and the resulting burgundy solution was warmed to room temperature and stirred for 2 hours. Ammonium acetate (46.3 g, 601 mmol) was added and the reaction was heated to reflux and stirred for 5 hours, and then stirred at room temperature for 16 hours. The acetonitrile was evaporated on the rotary evaporator and the residue was dissolved in 1 L of Et2O, washed with water (3×200 mL), dried (Na2SO4), filtered, and the Et2O removed on the rotary evaporator to give 83.4 g of the crude pyridine as a dark-red oil. Flash chromatography (SiO2, 25→70% EtOAc/Hexanes) afforded 70.8 g (85%) of 5-[(methylthio)methyl]-2-(trifluoromethyl)pyridine (N) as an orange oil. 1H NMR (CDCl3) δ 8.64 (d, 1H), 7.86 (dd, 1H), 7.66 (d, 1H), 3.73 (s, 2H), 2.02 (s, 3H). GC-MS (EI) m/z 207 (M+).