Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][NH:4][C:5]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[O:8]>CO>[CH3:3][NH:4][C:5]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:6]=1[CH:7]([OH:8])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15]
Reactant: CNc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc(Cl)cc1C(O)c1ccccc1Cl

Procedure:
750 mg of sodium borohydride are added in individual portions to a suspension of 2.8 grams of 2-methylamino-2', 5-dichlorobenzophenone in 20 ml of methanol. After reaction for about ten minutes, the solvent is evaporated in a vacuum. After absorption in ether, washing with water, and then drying, 2-methylamino-2',5-dichlorobenzhydrol is isolated by crystallization (2.52 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.O.O.O.C([O-])(=O)C.[Na+].[Br:17]Br.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[C:7]([Br:17])=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: Cc1cnc(N)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cnc(N)c(Br)n1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To acetic acid (1500 ml.), 2-amino-5-methylpyrazine (1 mole) and 326.5 g. sodium acetate trihydrate are slowly added 1.1 mole bromine in 180 ml. acetic acid at 2° C. in the absence of light. The mixture is stirred about 15 hours at 20° C., stripped of acetic acid in vacuo, poured into ice, made alkaline with sodium hydroxide, filtered, and residue extracted with ether, the extract stripped and the 2-amino-3-bromo-5-methylpyrazine crystallized from a suitable solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16].O(CCCC)CCCC.O>[Fe].CC(O)=O>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCc1cccs1
Agent: [Fe]
Solvent: O
Solvent: CCCCOCCCC
Solvent: CC(=O)O
Product: COc1cc(N)c2nccc(C)c2c1OCCCCCc1cccs1

Procedure:
A mechanically stirred mixture of 6-methoxy-4-methyl-8-nitro-5-[5-(thienyl) pentoxy] quinoline (5.50 g, 0.014 mol), Fe-filings (6 g), Bu2O (15 ml), H2O (50 ml) and HOAc (1.5 ml) was heated at 105°-110° C. for 2.5 h, allowed to cool and filtered. The residue was well washed with Et2O (200 ml) and the filtrate and the washings were combined. The organic layer was separated and the aqueous layer was extracted with Et2O (2×75 ml). The combined organic layers were washed with saturated NaCl solution (2×50 ml), dried (K2CO3), treated with carbon (Darco G-60), and concentrated to a yellow oil which on trituration with pet. ether (20°-40° C., 20 ml), at -20° C., gave 8-amino-6-methoxy-4-methyl-5-[5-(2-thienyl)pentoxy] quinoline as a yellow solid, 4.07 g (80%), m.p. 42°-44° C. This material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:13])([C:11]#[CH:12])[CH3:10])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.O>[Cu]Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:9]([CH3:13])([CH3:10])[CH:11]=[CH:12]2
Reactant: C#CC(C)(C)Nc1ccc(Br)cc1
Agent: Cl[Cu]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C=Cc2cc(Br)ccc2N1
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-N-(2-methylbut-3-yn-2-yl)benzenamine (3.30 g, 14 mmol) in toluene (14 ml, 14 mmol) was added copper(I) chloride (0.300 g, 3.0 mmol) in one portion. The reaction vessel was sealed and the resulting mixture was heated to 90 deg C. After stirring overnight, the mixture was transferred to a separatory funnel containing water and EtOAc. The aqueous layer was washed 1× with EtOAc and 3× with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated. The crude oil was purified with an MPLC (100% DCM to 10% (91/10/1 DCM:MeOH:NH4OH)) to provide the product. MS m/z: 238.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:6]=[CH:7][CH:8]=O.[C:15]([CH2:17][C:18]([N-:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])#[N:16]>>[CH2:21]([NH:20][C:18](/[C:17](=[CH:8]/[CH:7]=[CH:6]/[C:5]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1)/[C:15]#[N:16])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N#CCC(=O)[N-]Cc1ccccc1
Reactant: COc1ccc(C=CC=O)cc1OC
Product: COc1ccc(/C=C/C=C(\C#N)C(=O)NCc2ccccc2)cc1OC

Procedure:
The compound was prepared as described in Example 3, by adding 3,4-dimethoxycinnamaldehyde (Example 6, 0.04 g, 0.2 mmol) to N-(cyanoacetyl)benzylamide (Example 4, 0.036 g, 0.2 mmol). After refluxing for 1 h and recrystallization from ethanol a yellow solid was obtained (0.045 g, 62%). The product gave the following analytical data:
Reaction SMILES: O[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[F:15])[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.Cl.O.N>C(O)(=O)C>[F:15][C:9]1[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=1[C:2]1[CH2:7][CH2:6][S:5][CH2:4][CH:3]=1
Reactant: Nc1ccc(C2(O)CCSCC2)c(F)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(C2=CCSCC2)c(F)c1
Reaction time: 18 h
Yield: 95.7 %

Procedure:
4-Hydroxy-4-(2-fluoro-4-aminophenyl)tetrahydrothiopyran (11.35 g, 50 mM) and butylated hydroxytoluene (50 mg) as antioxidant were suspended in a mixture of concentrated hydrochloric acid (37%, 200 ml) and water (50 ml), and stirred at 80° under nitrogen for 18 hours. Glacial acetic acid (150 ml) was added, and reaction continued at 80° for a further 5 hours. After cooling, the reaction was made basic by the cautious addition of concentrated ammonia and ice. The mixture was extracted with diethyl ether (400 ml), the extract washed with water (100 ml), brine (100 ml), dried (magnesium sulfate), filtered and evaporated to give the title product (10 g) as a dark oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:29]=[CH:28][C:13]([C:14]([NH:16][NH:17]C(OCC2C=CC=CC=2)=O)=[O:15])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].C>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:28][CH:29]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)NNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)NN)cc1
Yield: 95.1 %

Procedure:
A solution of the product of step (a) (5.7 g) in methanol (120 ml) was hydrogenolysed over 10% palladium on carbon (0.5 g) until hydrogen uptake ceased (1 hour). Activated charcoal was added and the mixture was stirred, filtered through diatomaceous earth and concentrated to give 4-(t-butoxycarbonylaminomethyl)benzoylhydrazine (3.6 g) as a colourless solid; m.p. (from toluene) 114-116° C.; NMR Spectrum 1.4 (9H, s); 3.2-4.0 (2H, br s); 4.2 (2H, s); 7.3 (2H, d); 7.4 (1H, t); 7.8 (2H, d); 9.7 (1H, s).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:26][NH2:27]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:26][NH2:27])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(O)c1ccc2cnccc2c1
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NNC(=O)c1ccc2cnccc2c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Isoquinoline-6-carboxylic acid (1.2 g, 6.94 mmol) purchased from Gateway Chemical Technology, Inc. was mixed with CDI (1.68 g, 10.4 mmol) in DMF (20 Ml) in a round bottom flask. After the mixture was stirred for 30 minutes at 20° C., anhydrous hydrazine (2 mL) was added and the resulting mixture was stirred at 20° C. for one hour. After removing the solvent at a reduced pressure, the remaining residue was mixed with 20 mL water. After filtration, washing with water and air drying, an off-white solid was obtained as the desired product. LCMS (API-ES) m/z (%): 188.0 (100%, M++H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][CH:13](O)[CH3:14])[CH:2]=1.C(O)(=O)CC.[C:21](OCC)([O:26]CC)([O:23][CH2:24][CH3:25])[CH3:22]>[Cl-].[Na+].O>[CH2:24]([O:23][C:21](=[O:26])[CH2:22][CH:11]([C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:12]=[CH:13][CH3:14])[CH3:25]
Reactant: CC(O)C=Cc1cnc2ccccc2c1
Reactant: CCOC(C)(OCC)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCC(=O)O
Product: CC=CC(CC(=O)OCC)c1cnc2ccccc2c1

Procedure:
A solution of the allylic alcohol 22-2 (1.2 g, 6.1 mmol) in triethyl orthoacetate (50 mL) was treated with propionic acid (0.022 mL, 0.31 mmol) and refluxed for 2 h. The cooled mixture was treated with a solution of 1:1 sat. brine/1N HCl (150 mL), then extracted with CH2Cl2 (3×125 mL). The pooled organic extracts were washed with sat. NaHCO3, dried, filtered and evaporated. Chromatography on silica gel (EtOAc) afforded 22-3 as a yellow glass.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Nc1ccc(S(=O)(=O)O)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1ncc(S(=O)(=O)O)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h

Procedure:
6-Aminopyridine-3-sulfonic acid (20 g) in concentrated H2SO4 (80 mL) was heated at 50° C. until it was completely dissolved. To this solution was added fuming HNO3 slowly over 20 minutes, so the internal temperature did not exceed 55° C. After the addition was complete, the reaction mixture was heated at 50° C. for 1 hour. After it was cooled to room temperature, it was poured into 150 g of ice. The mixture was stirred for another hour. The flask was cooled to 0° C., and was kept at 0° C. for another 2 hours. The solid was collected by filtration, and washed with cold 1:1 water/ethanol (20 mL), followed by diethyl ether (10 mL). The solid was dried in a vacuum oven overnight to provide the title compound.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21].O>C(#N)C>[Si:24]([O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Nc2ccccc2)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a solution of 12 g of 4-anilinophenol (64.7 mmol) in 200 mL of acetonitrile there are added, at ambient temperature, 6.7 g of imidazole (97.05 mmol) and 11.7 g of tert-butyl(chloro)dimethylsilane (77.64 mmol). The batch is stirred at 70° C. for 4 hours. The reaction mixture is then poured into water and extracted with ether. The organic phase is then dried over magnesium sulphate, then filtered and evaporated to dryness. The crude product thereby obtained is then purified by chromatography over silica gel (petroleum ether/dichloromethane gradient). The title product is obtained in the form of a powder.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:22][CH3:23])[C:11]([C:13]([N:15]([CH:19]3[CH2:21][CH2:20]3)[CH:16]3[CH2:18][CH2:17]3)=[O:14])=[CH:12][C:7]2=[C:6]2[N:24]([CH3:27])[CH:25]=[N:26][C:5]=12.[CH3:28][O:29][CH:30]([O:39][CH3:40])[C:31](=[O:38])[CH:32]=[C:33](SC)[S:34][CH3:35]>CN(C=O)C.C(OCC)(=O)C>[CH:16]1([N:15]([CH:19]2[CH2:21][CH2:20]2)[C:13]([C:11]2[N:10]([CH2:22][CH3:23])[C:8]3=[N:9][C:4]([NH:3]/[C:33](/[S:34][CH3:35])=[CH:32]/[C:31](=[O:38])[CH:30]([O:29][CH3:28])[O:39][CH3:40])=[C:5]4[N:26]=[CH:25][N:24]([CH3:27])[C:6]4=[C:7]3[CH:12]=2)=[O:14])[CH2:18][CH2:17]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Reactant: COC(OC)C(=O)C=C(SC)SC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N/C(=C/C(=O)C(OC)OC)SC)nc21
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
Sodium hydride (142 mg, 3.55 mmol) was added to 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 400 mg, 1.182 mmol) in DMF (7 mL) at room temperature and the mixture stirred for 30 min, 1,1-dimethoxy-4,4-bis(methylthio)but-3-en-2-one (394 mg, 1.773 mmol) was added and stirring continued overnight. The reaction mixture was diluted with ethyl acetate and washed with water, 10% lithium chloride and water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 2-5% methanol/dichloromethane). (Z)-N,N-Dicyclopropyl-4-(4,4-dimethoxy-1-(methylthio)-3-oxobut-1-enylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (484 mg, 0.944 mmol, 80% yield) was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][CH2:7][C:6]=2[C:5]([CH3:13])=[CH:4][CH:3]=1.Cl.[N:15]([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl-].[K+]>O>[NH:1]([C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][CH2:7][C:6]=2[C:5]([CH3:13])=[CH:4][CH:3]=1)[NH2:15]
Reactant: O=N[O-]
Reactant: Cc1ccc(N)c2c1CCC(C)O2
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: O=S([O-])[O-]
Solvent: O
Product: Cc1ccc(NN)c2c1CCC(C)O2
Temperature: 70 °C

Procedure:
23 g of 1E was mixed with 60 ml of concentrated hydrochloric acid and the mixture was warmed to 70° C., then stirred to room temperature. Then the mixture was cooled to 0° C. and 120 g of ice water was added, followed by addition, drop-by-drop over 15 minutes, of a solution of 9.9 g of sodium nitrite in 30 ml of water. The resulting mixture was stirred at 0° C. for 30 minutes, poured into a cold (0° C.) mixture of 120 g of sodium sulfite in 450 ml of water, and stirred at room temperature for three hours. Then 22.6 g of sodium dithionite was added in portions to the stirred mixture, at room temperature and the mixture was stirred at room temperature for 18 hours. The stirred mixture was heated to 75° C., 125 g of potassium chloride was added, the mixture was stirred at 75° C. for 15 minutes and then chilled to 0° C. and filtered. The solid was dried and mixed with 300 ml of methanol. The resulting slurry was stirred and cooled to -10° C. while excess anhydrous hydrogen chloride was added. The resulting mixture was stirred to 5° C., the methanol was evaporated therefrom, and the residue was taken up in 300 ml of water. The resulting mixture was made basic with 50% aqueous sodium hydroxide, and extracted with ether. The extract was dried (MgSO4), filtered and concentrated to dryness at 25° C. and 30 Torr, to give 8-hydrazino-3,4-dihydro-2,5-dimethyl-2H-1-benzopyran (1F), as an amber syrup.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:2]1([CH3:1])[CH:18]=[CH:17][C:5]([C:6]2[O:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)NNC(=O)c1ccc(C)cc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnc(-c2ccc(C)cc2)o1
Yield: 93 %

Procedure:
6A (8.1 g, 32.4 mmol) was dissolved in toluene (200 ml) and pyridine (2.6 mL, 32.4 mmol). Thionyl chloride (9.6 g, 81 mmol) was added and the reaction was refluxed for 8 h. The solvent was evaporated and the residue was partitioned between DCM and aqueous NaHCO3 (sat.). The organic phase was further washed with 0.1 M HCl and aqueous NaHCO3 (sat.), filtered through a phase separator and the solvent was removed by evaporation. There was obtained 7.0 g (93%) of 6B as an off white solid. 1H NMR (400 MHz, CDCl3): δ 1.48 (t, 3H), 2.44 (s, 3H), 4.54 (q, 2H), 7.34 (d, 2H), 8.04 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([Cl:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:10])=[C:4]([Cl:9])[CH:3]=1
Reactant: Cc1ccc(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Br)ccc1CBr
Yield: 65.6 %

Procedure:
4-Bromo-2-chloro-1-methylbenzene (CAS 89794-02-5, 30 g, 0.15 mol) and N-bromosuccinimide (26 g, 0.15 mol) were mixed in CCl4 (300 mL). Azobis(2-methylpropionitrile) (˜0.3 g) was added in portions under vigorous stirring and refluxing. The mixture was refluxed for 30 min and cooled. The precipitate was filtered off and discarded. The filtrate was evaporated. The residue was distilled at 1 mmHg, by 75° C. to give the title compound (28 g, 65%). 1H NMR data (CDCl3): δ 7.57 (d, J=1.9 Hz, 1H ArH), 7.39 (dd, 1H, J1=1.9 Hz, J2=8.1 Hz, ArH), 7.31 (d, 1H, J=1.9 Hz, ArH), 4.53 (s, 2H, ArCH2).
Reaction SMILES: Cl.O1CCCC1.[CH2:7]([O:14][C@@H:15]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:19]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[S:18][C:16]1([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([CH:54]2OCC[O:55]2)[CH:48]=1)[OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH2:7]([O:14][C@@H:15]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:19]([CH2:38][O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[S:18][C:16]1([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[C:49]([CH:54]=[O:55])[CH:48]=1)[OH:17])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC1(c2ccc(Cl)c(C3OCCO3)c2)S[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
Then, 6M hydrochloric acid (120 mL) was added to a tetrahydrofuran (50 mL) solution of 2,3,4,6-tetra-O-benzyl-1-C-[4-chloro-3-(1,3-dioxolane-2-yl)phenyl]-5-thio-D-glucopyranose (6.01 g, 8.12 mmol) while ice-cooled, and stirred at room temperature for two days. The reaction mixture was added with an iced water and extracted with ethyl acetate and the organic phase was washed with a saturated sodium bicarbonate aqueous solution, brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain colorless amorphous 2,3,4,6-tetra-O-benzyl-1-C-(4-chloro-3-formylphenyl)-5-thio-D-glucopyranose (4.53 g, 80%).
Reaction SMILES: [CH3:1][C:2]([S:32][C:33]([C:46]1C=CC=C[CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:31])[C@H:3]([NH:13][C:14](=[O:30])[O:15][CH2:16][CH:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:4](=[O:12])[NH:5][CH2:6][CH2:7]CCC=O.C(Cl)Cl.C(O)(C(F)(F)F)=O>CCOC(C)=O>[CH3:1][C:2]1([CH3:31])[S:32][C@H:33]2[CH2:46][CH2:47][CH2:7][CH2:6][N:5]2[C:4](=[O:12])[C@H:3]1[NH:13][C:14](=[O:30])[O:15][CH2:16][CH:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2
Reactant: CC(C)(SC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCCC=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)S[C@H]2CCCCN2C(=O)[C@H]1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
To a round bottom flask was added (R)-(9H-fluoren-9-yl)methyl 3-methyl-1-oxo-1-(5-oxopentylamino)-3-(tritylthio)butan-2-ylcarbamate (35 mg, 0.050 mmol), DCM (1 mL) and TFA (0.077 mL, 1.0 mmol). The reaction mixture was stirred at rt for 15 min. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (10 mL), water (10 mL) and saturated aqueous NaCl (10 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (9H-fluoren-9-yl)methyl (3R,9aS)-2,2-dimethyl-4-oxooctahydropyrido[2,1-b][1,3]thiazin-3-ylcarbamate (12 mg, 0.027 mmol, 55% yield) as a white solid. Anal. Calcd. for C25H28N2O3S m/z 436.3. found: 437.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.78 (d, J=7.15 Hz, 2H), 7.63 (t, J=6.60 Hz, 2H), 7.41 (td, J=7.42, 3.30 Hz, 2H), 7.33 (t, J=7.42 Hz, 2H), 5.84 (d, J=8.80 Hz, 1H), 4.90 (dd, J=8.80, 3.85 Hz, 1H), 4.63 (d, J=8.80 Hz, 1H), 4.54-4.35 (m, 2H), 4.26 (t, J=7.15 Hz, 1H), 4.16-3.99 (m, 1H), 3.22 (ddd, J=13.06, 8.39, 4.40 Hz, 1H), 2.00 (dt, J=8.80, 4.40 Hz, 1H), 1.93-1.81 (m, 1H), 1.80-1.67 (m, 3H), 1.62-1.52 (m, 1H), 1.39-1.24 (m, 3H), 1.19 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:9]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[N:4][C:5](Br)=[CH:6][CH:7]=1.Cl.[CH3:28][C:29]1([OH:33])[CH2:32][NH:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[Br:1][C:2]1[C:3]([C@@H:9]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[N:4][C:5]([N:31]2[CH2:32][C:29]([OH:33])([CH3:28])[CH2:30]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(Br)ccc1Br
Reactant: CC1(O)CNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC1(O)CN(c2ccc(Br)c([C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)n2)C1
Temperature: 150 °C

Procedure:
(S)-tert-butyl (1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (150 mg, 0.3 mmol), 3-methylazetidin-3-ol hydrochloride (75 mg, 0.6 mmol) was combined with cesium carbonate (397 mg, 1.2 mmol), palladium diacetate (10 mg, 0.015 mmol) and 2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl (19 mg, 0.03 mmol) in 2 mL of toluene. The system was degassed and purged with argon and heated to 150° C. heating bath for 1 hour, the reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water and brine, and then dried over sodium sulfate. The crude was purified by flash chromatography eluting with EtOAc/hexanes to provided the title compound. MS (m/z) 499.72 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([C:10]([NH2:12])=O)=[N:4]1)[CH3:2].P(Cl)(Cl)(Cl)=O>>[CH2:1]([N:3]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([C:10]#[N:12])=[N:4]1)[CH3:2]
Reactant: CCc1cc(C(N)=O)nn1CC
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1cc(C#N)nn1CC
Yield: 101.9 %

Procedure:
1,5-Diethyl-1H-pyrazole-3-carboxamide (8.3 g, 0.050 mol) was treated with phosphorous oxychloride (35 mL) according to the method described in Part C of Example 7. The reaction was heated for 2.5 hours to provide 7.6 g of 1,5-diethyl-1H-pyrazole-3-carbonitrile as a yellow oil, which was used without purification.