Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]2[CH2:18][C:17]3[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=3[O:19][CH3:20])[CH2:11]2)=[CH:30][CH:29]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCI)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCOc1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.4 %

Procedure:
The mixture of 2-(8-iodooctyl)-4,5,6,7-tetramethoxyindan (830 mg), 4-chlorophenol (269 mg), and potassium carbonate (481 mg) in DMF (8 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=10:1) to yield the entitled compound (776 mg) as crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=2)[NH:18][CH:17]=1)[C:8]([O:10][CH3:11])=[O:9].[CH3:28]I>O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=2)[N:18]([CH3:28])[CH:17]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: CI
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Reaction time: 0.17 h
Yield: 96 %

Procedure:
Sodium hydride (212 milligrams) was added to a solution of methyl 3-methoxy-4-(5-nitroindol-3-ylmethyl)benzoate (1.8 grams) in 60 mL of dry tetrahydrofuran. After stirring for 10 minutes, methyl iodide (753 milligrams) was added and the reaction was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulfate and evaporated. The residue was purified on silica gel with dichloromethane to give 1.8 grams product, m.p. 151°-153°.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].Cl[CH2:9][CH2:10][CH2:11][CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1C=CC=CC=1.CN(C)C=O>[C:19]([O:18][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10][CH2:9][NH:7][S:4]([CH3:3])(=[O:6])=[O:5])(=[O:21])[CH3:20]
Reactant: CS(N)(=O)=O
Reactant: CCCCCC(CCCCl)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCCC(CCCNS(C)(=O)=O)OC(C)=O
Reaction time: 1 h

Procedure:
Sodium hydride (2 g., 0.083 mole) is suspended in benzene (60 ml.) and dimethylformamide (120 ml.). Methanesulfonamide (7.6 g., 0.08 mole) is added and the suspension is heated on the steam bath for two hours. After the mixture is cooled in an ice bath, 1-chloro-4-acetoxynonane (18.5 g., 0.084 mole) is added dropwise with stirring over one hour. The suspension is heated on the steam bath for twenty hours and separated between ethyl acetate and water. After being washed with water, the organic layer is dried over anhydrous magnesium sulfate. Evaporation of the ethyl acetate in vacuo and distillation through a short path column gives the title compound, 11.6 g. (52%), b.p. 182°-185° C./0.08 mm. Anal. Calcd. for C12H25NO4S: C, 51.58; H, 9.02; N, 5.01. Found: C, 52.33; H, 8.84; N, 4.91.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[NH:8][C:9]([C:11]1[N:12](CC2C=CC=CC=2)[CH:13]=[C:14]([O:18]CC2C=CC=CC=2)[C:15](=[O:17])[CH:16]=1)=[O:10].FC(F)(F)C(O)=O.[H][H]>CN(C)C=O.[Pd]>[O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([OH:18])[C:15](=[O:17])[CH:16]=1)=[O:10]
Reactant: [H][H]
Reactant: O=C(NN1C(=O)CNC1=O)c1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NN1C(=O)CNC1=O)c1cc(=O)c(O)c[nH]1

Procedure:
To a solution of 10.8 g (0.025 mol) of N-(2,5-dioxo-1-imidazolidinyl)-1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinecarboxamide in 200 ml of dimethylformamide was added 3.83 ml of trifluoroacetic acid (0.05 mol) and 6 g of palladium on charcoal (10%). With vigorous stirring, hydrogen was passed through the solution for 45 minutes. The catalyst was removed by filtration and the filtrate evaporated. The remaining syrup solidified on trituration with ether. Yield: 6.1 g, melting point 260°-270° C., dec.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].Br[CH2:13][CH2:14][CH2:15][Cl:16]>CS(C)=O.CCOC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: ClCCCBr
Reactant: c1ccc2[nH]nnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: ClCCCn1nnc2ccccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
To a solution of benzotriazole (303 mg, 2.54 mmol) and powdered NaOH (101 mg, 2.52 mmol) in DMSO was added 1-bromo-3-chloro propane (437 mg, 2.77 mmol). The reaction mixture was stirred for 16 h at 20° C. The reaction mixture was then diluted with EtOAc (100 mL) and washed with H2O (100 mL) and saturated NaCl (100 mL), dried over MgSO4 and concentrated in vacuo. Column purification (hexanes:EtOAc 4:1) yielded 1-(3-chloropropyl)-1H-1,2,3-benzotriazole (167 mg, 34%). The title compound was prepared according to Example 286, Step C as a yellow oil (21 mg, 42%) from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b]l[1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 1-(3-chloropropyl)-1H-1,2,3-benzotriazole (48 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.88-1.98 (m, 3H), 1.99-2.18 (m, 2H), 2.20-2.41 (m, 5H), 2.51-2.60 (m, 1H), 2.64-2.71 (m, 1H), 2.89-3.00 (m, 1H), 3.03-3.13 (m, 2H), 3.21-3.27 (m, 1H), 3.47-3.60 (m, 1H), 3.76-3.88 (m, 1H), 4.73 (t, 2H, J=6.6 Hz), 6.61 (t, 1H, J=7.4 Hz), 6.84 (d, 1H, J=6.6 Hz), 6.94 (dd, 1H, J=1.1, 8.1 Hz), 7.37 (td, 1H, J=1.1, 7.4 Hz), 7.49 (td, 1H, J=1.1, 7.8 Hz), 7.57 (d, 1H, J=8.0 Hz), 8.07 (d, 1H, J=8.4 Hz) ppm.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([OH:9])=[O:8].CN(C=O)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([O:9][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(O)c(O)c1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A solution of sodium hydroxide (6.4 g) in water (40 ml) was added to a mixture of 3,4-dihydroxybenzoic acid (24.8 g) and DMF (200 ml) which had been cooled in an ice-bath. The mixture was stirred for 20 minutes and then benzyl bromide (19.1 ml) was added dropwise. After the addition was complete, the mixture was allowed to reach ambient temperature and was stirred for 20 hours. The mixture was then warmed to 50° C. for 2 hours. The solvent was removed by evaporation and the residue was partitioned between water (300 ml) and ethyl acetate (100 ml). The ethyl acetate layer was separated and the aqueous layer extracted with ethyl acetate (100 ml). The combined ethyl acetate extracts were washed with water (100 ml), saturated sodium hydrogen carbonate solution (100 ml), water (100 ml) and with saturated sodium chloride solution (100 ml) and dried (MgSO4). The solvent was removed by evaporation to give a brown solid which was crystallised from toluene to give benzyl 3,4-dihydroxybenzoate (19 g) as a solid; m.p. 147°-149° C.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16]([CH2:19][C:20]#[N:21])(=[O:18])=[O:17]>>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:19](/[S:16]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)(=[O:18])=[O:17])\[C:20]#[N:21])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: N#CCS(=O)(=O)c1cccs1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)c1cccs1

Procedure:
Reaction of 2-nitrothiophen-5-carboxaldehyde and thien-2-ylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-nitrothien-5-yl)-2-(thien-2-ylsulfonyl)acrylonitrile
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:11])[N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:3]=1.[Cl:21][C:22]1[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:23]=1>N1C=CC=CC=1>[Cl:21][C:22]1[S:26][C:25]([S:27]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[F:11])[N:4]([CH2:12][C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=3)[N:3]=2)(=[O:29])=[O:28])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: N#Cc1cccc(Cn2nc(N)c3c(F)cccc32)c1
Solvent: c1ccncc1
Product: N#Cc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(F)cccc32)c1
Temperature: 0 °C

Procedure:
To a solution of 3-[(3-amino-4-fluoro-1H-indazol-1-yl)methyl]benzonitrile (for a preparation see Intermediate 37) (695 mg, 2.61 mmol) in anhydrous pyridine (3 mL) cooled in an ice/water bath was added 5-chloro-2-thiophenesulfonyl chloride (567 mg, 2.61 mmol) dropwise over 1 minute and the reaction mixture was stirred in the ice/water bath for 1 hour. The reaction mixture was partitioned between ethyl acetate (150 mL) and 2N hydrochloric acid (100 mL). The organic layer was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield a dark red oil (1.264 g). The oil was dissolved in the minimum volume of dichloromethane, applied to a 100 g silica SPE cartridge and purified by chromatography on Flashmaster II using a 0-50% ethyl acetate in cyclohexane gradient over 60 min. Fractions 66-69 were combined and evaporated in-vacuo to yield a white foam (540 mg), which was further purified by chromatography on 100 g silica SPE cartridge on Flashmaster II using a 0-10% methanol in dichloromethane gradient over 60 min. Fractions 23-26 were evaporated in-vacuo to yield the title compound as a white foam (493 mg, 42%). LCMS (SystemB) RT=3.01 min, ES+ve m/z 447/449 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH:16][C@:17]([CH3:23])([CH2:21][CH3:22])[C:18](O)=[O:19])[CH:13]=[CH:12][N:11]=2)=[CH:2]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[F:42][C:43]([F:47])([F:46])[CH2:44][NH2:45].C([O-])([O-])=O.[Na+].[Na+]>CC1OCCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:15]=[C:14]([NH:16][C@:17]([CH3:23])([CH2:21][CH3:22])[C:18]([NH:45][CH2:44][C:43]([F:47])([F:46])[F:42])=[O:19])[CH:13]=[CH:12][N:11]=2)=[CH:2]1
Reactant: CC[C@@](C)(Nc1ccnc(-c2c[nH]c3ncccc23)n1)C(=O)O
Reactant: NCC(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: CC[C@@](C)(Nc1ccnc(-c2c[nH]c3ncccc23)n1)C(=O)NCC(F)(F)F
Temperature: 62.5 °C
Reaction time: 0.5 h

Procedure:
To (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a) (limiting reagent) charge 2-methylTHF (7.5 vol), then charge T3P® (2.0 eq, 50% w/w in 2-MeTHF). Heat the mixture to 60-65° C. and maintain this temperature for no less than 3 hrs and the solids are completely dissolved. Cool to 20-25° C. then charge 2,2,2-trifluoroethylamine (2.0 eq). Continue agitation for no less than 6 hrs at 20-25° C. and until HPLC analysis showed <1.0% of (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a). Slowly charge a Na2CO3 solution (15 vol, 1.165M) while maintaining a batch temperature<30° C. Stir the mixture for 30 min then separate the phases. Wash the organic phase with water (4 vol). Emulsions have been observed at this point and can be addressed through addition of NaCl solution. Charge methanol (7 vol) then distill to 4 vol. Repeat 3 times. Prior to crystallization, adjust the total volume to approximately 11 vol. Heat the mixture to 50-55° C. then add water (2.45 vol, final solvent composition 22% water in methanol) over 30 min. Seed the batch with (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (Ia) (1 wt % seed based on the compound of Formula (4a)). Stir for 4 hrs at 50-55° C. then add water over 24 h until the mixture is approximately 58 wt % water in methanol. Cool to 20-25° C., stir 1 h, then filter. Wash the cake with water (2 vol). Dry the solids at 60-65° C. to give (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (Ia).
Reaction SMILES: C1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([Cl:9])[Cl:8])C=CC=CC=1.[Cl:16][SiH2]Cl>Cl>[C:10]1([Si:7]([Cl:8])([Cl:9])[Cl:16])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cl[SiH2]Cl
Agent: Cl
Product: Cl[Si](Cl)(Cl)c1ccccc1
Temperature: 70 °C
Yield: 279.6 %

Procedure:
380 g of diphenyldichlorosilane (in which 0.7 g of hydrogen chloride has been dissolved beforehand by bubbling in the gas) and 22.5 g of aluminium chloride are introduced into the flask. 80 cm3 of trichlorosilane are run in, the mixture is heated to 70°C and then 477 g of trichlorosilane are introduced gradually over the course of 7 hours 30 minutes, whilst distilling the resulting dichlorosilane as it is formed. A distillate weighing 79 g, containing 60.8 g of dichlorosilane, is obtained. 356 g of phenyltrichlorosilane are obtained on distilling the mixture remaining in the flask.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]3)[C:7]=2[CH:29]=1)#[N:2].I([O-])(=O)(=O)=[O:31].[Na+].COC1C=CC2OCC(=O)N(CCN3CCC(NC(=O)OC(C)(C)C)CC3=O)C=2C=1>O.[Ru](=O)=O.C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:19][C:20]3=[O:31])[C:7]=2[CH:29]=1)#[N:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(C#N)cc32)CC1
Agent: O=[Ru]=O
Agent: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1=O)C(=O)CO2
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(C#N)cc32)C(=O)C1

Procedure:
tert-Butyl {1-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 59, 835 mg, 2.1 mmol) was reacted with sodium periodate (2.8 g, 13.1 mmol) and ruthenium (IV) oxide hydrate (30 mg, 20.1 mmol) as described for Intermediate 115 for 16 hours, except, chloroform was used for aqueous workup. The product was obtained as a colorless solid, 230 mg (27%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH:20]=[C:19]([O:22][Si](C)(C)C)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(#N)C.C(OCC)(=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([Br:8])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
NBS (1.4 g) was added to a solution of 1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethylsilyloxy)pyridine (2 g) in acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solution was diluted with ethyl acetate(50 ml) and washed with water (50 ml), sodium bicarbonate solution (50 ml) and brine (50 ml), dried (MgSO4) and evaporated to give the title compound as a colourless solid (1.8 g).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([CH:14]3[O:18][CH2:17][CH2:16][O:15]3)[S:11][C:10]=2[CH2:19][CH3:20])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:29])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:29][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([CH:14]2[O:18][CH2:17][CH2:16][O:15]2)[S:11][C:10]=1[CH2:19][CH3:20]
Reactant: CCc1sc(C2OCCO2)cc1C(O)C1CCCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCc1sc(C2OCCO2)cc1C(Cl)C1CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of cyclohexyl[5-(1,3-dioxolan-2-yl)-2-ethylthiophen-3-yl]methanol (3.00 g) synthesized above in toluene (60 mL) were added pyridine (979 μL) and thionyl chloride (883 μL) at 0° C., and the mixture was stirred at 0° C. for 1.5 hr, and then at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (3.28 g, quantitative) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][N:22]([CH3:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([N:22]([CH3:32])[CH3:21])=[CH:24][CH:25]=2)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N(C)C)cc3)ccn2c1=O
Yield: 39.8 %

Procedure:
Methyl 1-cyclopropyl-8-(4-(dimethylamino)-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (77 mg, 0.26 mmol) and (4-(dimethylamino)-phenyl)-boronic acid (56 mg, 0.34 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (39 mg, 31%). ESI-MS m/z: 377 (M+H)+.
Reaction SMILES: Cl[C:2]1[O:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[CH2:22][O:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:8])[N:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[O:33]1[CH2:34][CH2:35][N:30]([C:2]2[O:3][CH:4]=[C:5]([C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]3[CH2:22][O:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:8])[N:6]=2)[CH2:31][CH2:32]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(Cl)n2)C(COc2cccnc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(N3CCOCC3)n2)C(COc2cccnc2)C1
Temperature: 25 °C
Yield: 125.8 %

Procedure:
A solution of tert-butyl 4-(2-chlorooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (117 mg, 0.277 mmol), morpholine (48 mg, 0.554 mmol) and potassium carbonate (76 mg, 0.554 mmol) in THF (2 mL) was heated to 70° C. overnight. Upon cooling to rt, the reaction mixture was filtered and concentrated under reduced pressure. The material was purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient), yielding 165 mg (1000%) of the title compound as the TFA salt. LC-MS: RT=6.60 min, [M+H]+=474.1.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20]>C(Cl)Cl.CN1CCOCC1.ClC(OCC(C)C)=O>[O:20]=[C:19]1[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26]([F:27])([F:28])[F:29])[C:17]=2[N:16]=[C:10]([C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[O:12]1
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c(C(F)(F)F)cccc2c(=O)o1

Procedure:
Using the procedure of Step A of Example 7, a solution of 16.14 ml of BOC-L-proline in 150 ml of methylene chloride, 20.6 ml of N-methyl-morpholine, 19.5 ml of isobutyl chloroformate in 75 ml of methylene chloride and 15.4 g of 2-amino-3-trifluoromethylbenzoic acid in 150 ml of methylene chloride and 8.3 ml of N-methyl-morpholine were reacted for 20 hours. The mixture was extracted with methylene chloride and the residue was chromatographed on silica gel and was eluted with methylene chloride to obtain 16.4 g of 1,1-dimethylethyl (2S) 2-[4-oxo-8-(trifluoromethyl)-4H-3,1-benzoxazin-2-yl]-1-pyrrolidine carboxylate having a specific rotation of [α]D =-75°±2.5° (c=0.6% in CH3COOH).
Reaction SMILES: CS(C)=O.[H-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>C(OCC)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:15]#[N:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1
Reactant: BrCCOCCBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Cl)cc2)CCOCC1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Into a round-bottom flask under argon fitted with an addition funnel and thermometer was added anhydrous dimethylsulfoxide (60 mL) and sodium hydride (1.17 g, 48.8 mmol, 95%). Then a solution of (4-chlorophenyl)acetonitrile (G) (3.37 g, 22.2 mmol) and 2-bromoethyl ether (90%, 3.41 mL, 24.4 mmol) in diethyl ether (15 mL) was added slowly, while maintaining the reaction temperature at 20-30° C. The reaction mixture was maintained at room temperature for overnight. The reaction mixture was carefully quenched with water (50 mL) and then extracted with hexane (3×100 mL). The organic extracts were combined, washed with water (3×75 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to give a pale yellow oil. The oil was purified by column chromatography on silica gel using hexane/ethyl acetate (80:20) to give 4.7 g of 4-(4-chlorophenyl)tetrahydropyran-4-carbonitrile, H, as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 2.00-2.15 (m, 4H); 3.89 (dt, 2H, J1=12.6 Hz, J2=3 Hz); 4.05-4.11 (m, 2H); 7.37-7.45 (m, 4H); 13C NMR (CDCl3, 75 MHz): δ 36.66 (2C), 41.51, 64.98 (2C), 121.40,127.03, 129.37, 134.31, 138.46.