Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH:6]1([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:18]4[C:26]5[C:21](=[N:22][C:23]([C:27]6[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[C:28]=6[F:37])=[CH:24][CH:25]=5)[N:20](C5CCCCO5)[N:19]=4)[CH:15]=3)[C:10]2=[O:44])[CH2:8][CH2:7]1>C(Cl)Cl.CO>[Cl:4][C:32]1[C:31]([O:33][CH3:34])=[CH:30][C:29]([O:35][CH3:36])=[C:28]([F:37])[C:27]=1[C:23]1[N:22]=[C:21]2[NH:20][N:19]=[C:18]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[C:10](=[O:44])[N:9]([CH:6]3[CH2:8][CH2:7]3)[CH2:17]4)[C:26]2=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc(OC)c(F)c(-c2ccc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)nn(C4CCCCO4)c3n2)c1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)n[nH]c3n2)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sulfuryl chloride (10. μL, 0.12 mmol) was added to a stirring solution of 2-cyclopropyl-5-[6-(2-fluoro-3,5-dimethoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]isoindolin-1-one (65 mg, 0.12 mmol) in methylene chloride (1 mL). The mixture was stirred at r.t. for 30 min. It was concentrated to dryness. The solid was dissolved in methanol (0.3 mL). To the solution was added a solution of HCl previously prepared from acetyl chloride (0.15 mL) and methanol (0.15 mL). The mixture was stirred at r.t. for 1 h and then diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=479.1.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[N:51]([C:52]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:50]=[N:49][N:48]=2)=[CH:37][CH:36]=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1[N:14]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]3[N:51]([C:52]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)([C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[N:50]=[N:49][N:48]=3)=[CH:39][CH:40]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(=O)c2cc(C=CC(=O)OCC)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(C=CC(=O)OCC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
To a suspension of 1.75 g of ethyl 3-(2-butyl-1,4-dihydro-4-oxo-6-quinazolinyl)-2-propenoate in 25 ml of dry tetrahydrofuran at room temperature is rapidly added 6.70 g of a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran. After stirring for 20 minutes at room temperature 3.899 g of 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole is rapidly added in one portion and the reaction mixture heated at reflux for 48 hours. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and the organic layer washed with 5% HCl, water and brine. The organic layer is dried with MgSO4 and concentrated in vacuo to a residue which is purified by column chromatography on silicagel by eluting with 1:4 ethyl acetate-hexanes to give 1.732 g of the desired product as a solid. FAB MASS SPEC 799 (M+Na)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([CH:11]=1)[NH:7][CH:8]([CH3:10])[CH3:9].[Cl-].[NH4+].C1C[O:20][CH2:19]C1>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:19](=[O:20])[N:7]([CH:8]([CH3:10])[CH3:9])[C:6]=2[CH:11]=1
Reactant: C1CCOC1
Reactant: CC(C)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)n1c(=O)[nH]c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 10 h
Yield: 40 %

Procedure:
A mixture of 5-chloro-N-isopropyl-2-nitroaniline (Step 1 of Example 12, 0.76 g, 3.54 mmol), iron (0.99 g, 17.7 mmol) and ammonium chloride (0.38 g, 7.08 mmol) was suspended in ethanol (27 mL) and H2O (9 mL). Then, the mixture was heated at 80° C. for 3 h. After cooling, the insoluble materials was filtered off on a pad of Celite, and the filtrate was evaporated under reduced pressure. To the residue was added N,N′-carbonyldiimidazole (CDI, 0.57 g, 3.50 mmol) and THF (10 mL) and then stirred at 100° C. for 10 h. After cooling, the volatile materials were removed under reduced pressure and the residue was partitioned between ethylacetate and H2O. After extraction with ethylacetate (3 times), the combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (2:1) to give 0.30 g (40%) of the title compound as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([F:15])([F:14])[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.B(F)(F)F>>[F:5][C:6]([F:14])([F:15])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=1
Reactant: FC(F)(F)Oc1ccccc1
Reactant: CC(=O)Cl
Agent: FB(F)F
Product: CC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
Into a 250 ml stainless steel reactor equipped with a magnetic stirrer system, 100 ml of anhydrous HF, 23.6 g (0.3 mole) of acetyl chloride, and 32.4 g (0.2 mole) of trifluoromethoxybenzene were introduced at around 0° C. The reactor was closed and gaseous boron trifluoride (BF3) introduced until a constant pressure of 6 bars was achieved. The reaction was then allowed to proceed with stirring at ambient temperature for 3 hours. Following reaction, the reactor was decompressed to atmospheric pressure, then the reaction mixture poured over 200 g of crushed ice. The resultant heterogeneous mixture was extracted three times with 200 ml of methylene chloride. The organic phases were washed three times with 200 ml of water, once with 200 ml of 3% aqueous potassium hydroxide solution, and twice with 200 ml of water. The organic phase was dried over magnesium sulfate and the solvent eliminated by distillation under reduced pressure. 37.2 g (yield: 91%) of p-trifluoromethoxyacetophenone having a purity of 96.3% was recovered.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:25]([F:28])([F:27])[F:26])([CH2:13]OS(C2C(C)=CC=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:25]([F:28])([F:27])[F:26])([CH2:13][N:29]=[N+:30]=[N-:31])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1S(=O)(=O)OCC1(C(F)(F)F)CCN(Cc2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CC#N
Product: [N-]=[N+]=NCC1(C(F)(F)F)CCN(Cc2ccccc2)C1

Procedure:
The compound (2.43 g) from step 456c was dissolved in acetonitrile, then reacted with tetrabutylammonium azide at 80° C. for 16 hours. The mixture was diluted with methylene chloride, then washed with water and brine and dried. Removal of the solvent gave 0.751 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][C:16]([F:15])([F:25])[F:26])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(tert-Butoxycarbonyl)-L-prolinal (200 mg, 1.00 mmol) and 3-trifluoromethoxy-phenylamine (186.8 mg, 1.05 mmol) were mixed in 1,2-dichloroethane (10 mL) and treated with sodium triacetoxyborohydride (314 mg, 1.41 mmol). The mixture was stirred at RT under nitrogen overnight, then quenched by addition of water, extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated. The crude oil was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1) to give the desired material. MS (LC/MS): 361.1 [M+H]+.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[NH2:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#N.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[NH2:6][C:7]1[CH:8]=[C:9]([C:10]2[S:4][C:3]([NH2:5])=[N:2][N:1]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: N#Cc1cccc(N)c1
Reactant: NNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(-c2nnc(N)s2)c1
Temperature: 0 °C

Procedure:
Thiosemicarbazide (455.69 mg; 5.00 mmol; 1.00 eq.) and 3-aminobenzonitrile (590.69 mg; 5.00 mmol; 1.00 eq.) are heated in TFA (2.50 ml) at 60° C. for 4 h00. The mixture become a thick yellowish solution. The reaction mixture is poured into ice-water (15 mL) and neutralized with saturated NaHCO3 aqueous solution. The resulting precipitate is filtered, affording 5-(3-aminophenyl)-1,3,4-thiadiazol-2-amine as white-off solid (291.00 mg; 30.27%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[CH3:29][Si:30]([CH3:35])([CH3:34])[CH2:31][CH2:32]O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:17]([O:19][CH2:32][CH2:31][Si:30]([CH3:35])([CH3:34])[CH3:29])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C[Si](C)(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)OCC[Si](C)(C)C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A mixture of 20.1 g (75.7 mmol) of [(phenylmethoxy)carbonyl]-L-leucine, 0.925 g (7.57 mmol) of dimethylaminopyridine and 8.95 g (75.7 mmol) of 2-trimethylsilylethanol in 200 ml of dichloromethane was cooled in an ice bath under nitrogen and treated with a solution of 15.6 g (75.7 mmol) of dicyclohexylcarbodiimide in 50 ml of dichloromethane. The ice bath was removed after 30 minutes and the reaction allowed to come to room temperature overnight. The reaction mixture was filtered, concentrated in vacuo and partitioned between 800 ml of ether and 200 ml of water. The organic layer was separated and further rinsed with saturated sodium bicarbonate, water, 10% potassium bisulfate, water and brine, then dried (magnesium sulfate) and concentrated in vacuo to 26.1 g of crude product. Flash filtration over silica gel (180 g in 20:1, hexanes:ethyl acetate) yielded 22.9 g of crude product which was chromatographed using a Waters Prep 500 LC, two columns eluted with 15:1, hexanes:ethyl acetate (250 ml/minute, 200 ml fractions). Combining the pure fractions yielded 19.6 g of the title compound as an oil: [α]D =7.3° (c=1, chloroform).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH:38]3[CH2:40][CH2:39]3)=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]1([C:35]2[N:34]=[CH:33][C:32]([C:28]3[CH:27]=[C:26]([C:24]4[CH2:23][C:22](=[O:41])[NH:21][C:9]5[CH:10]=[C:11]([C:17]([F:20])([F:18])[F:19])[C:12]([CH2:14][CH2:15][CH3:16])=[CH:13][C:8]=5[N:7]=4)[CH:31]=[CH:30][CH:29]=3)=[CH:37][CH:36]=2)[CH2:39][CH2:40]1
Reactant: CCCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(C4CC4)nc3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-propyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M204) (266 mg, 0.46 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (75 mg, 35%).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C.[ClH:20]>C(OCC)C>[ClH:20].[CH2:1]([NH:5][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: CCOC(=O)CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)CNCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of isobutylamine (0.90 mL, 0.0091 mol), bromoacetic acid, ethyl ester (1.0 mL, 0.0090 mol), and triethylamine (1.28 mL, 0.00918 mol) in diethylether (15 mL) was stirred at room temperature for 24 hours. The resulting suspension was filtered off and washed with diethylether. The filtrate and washings were combined and rotary evaporated to an oil. The oil was chromatographed on silica gel (150 g, 230-400 mesh) eluting with dichloromethane-diethylether (19:1, 8×125 mL; 15:1, 7×125 mL; 10:1, 15×125 mL). Fractions containing product were combined and rotary evaporated to give an oil. The oil was dissolved in diethylether, concentrated hydrochloric acid (0.52 mL, 0.0063 mol HCl) was added, and the volatiles were rotary evaporated to give a white solid. The solid was dried in vacuo; yield 1.0 g (59%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:24][N:25]=[C:26]=[O:27]>C(Cl)Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]2[CH2:23][CH2:22][N:21]([C:26]([NH:25][CH3:24])=[O:27])[CH2:20][CH2:19]2)[C:26]([NH:25][CH3:24])=[O:27])=[CH:12][CH:13]=1
Reactant: Fc1ccc(CNC(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CCC(C(c2ccc(F)cc2)N(Cc2ccc(F)cc2)C(=O)NC)CC1

Procedure:
A solution of 2.06 g (6.5 mmol) of α-(4-fluorophenyl)-N-[(4-fluorophenyl)methyl]-4-piperidinemethanamine and 3.1 g (54.4 mmol) of methyl isocyanate in 300 mL of CH2Cl2 was stirred at room temperature for 18 h. The solvent was removed in vacuo to give a white solid. The solid was recrystallized from methylene chloride/ether to give 2.65 g (94.8%) of a white, crystalline solid containing 0.15 mole of CH2Cl2, mp 120°-162° C.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].CN(CCN(C)C)C.[Si:13]([O:20][C@H:21]([CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])/[CH:22]=[N:23]\[S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1COCC1>[Si:32]([O:31][CH2:30][C@@H:21]([O:20][Si:13]([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14])[C@H:22]([NH:23][S@:24]([C:26]([CH3:27])([CH3:28])[CH3:29])=[O:25])[CH:1]=[CH2:2])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34]
Reactant: CC(C)(C)[S@](=O)/N=C\[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: C=C[Mg]Br
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: C=C[C@@H](N[S@@](=O)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 53.3 %

Procedure:
To a 2.0 L round bottom flask containing vinylmagnesium bromide (92 ml, 92 mmol) was added THF (40 mL) and the mixture was allowed to stir at −78° C. for 5 min. At this time, TMEDA (23 ml, 154 mmol) was added via syringe followed by (S,Z)-N—((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide (13.0 g, 31 mmol) in THF. The reaction was allowed to stir at −78° C. for 4 h and then allowed to slowly warm to RT overnight. The reaction was quenched by the addition of ammonium chloride (sat, 100 ml). The aqueous layer was extracted with EtOAc, washed with brine, dried sodium sulfate, filtered and concentrated to give a crude oil that was purified by silica gel column to give (S)—N-((2S,3S)-1,2-his(tert-butyldimethylsilyloxy)pent-4-en-3-yl)-2-methylpropane-2-sulfinamide (5.45 g, 39% yield, higher Rf) and (S)—N-((2S,3R)-1,2-bis(tert-butyldimethylsilyloxy)pent-4-en-3-yl)-2-methylpropane-2-sulfinamide (7.43 g, 54% yield, lower Rf).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][CH2:11][P:12](=[O:19])([O:16]CC)[O:13]CC.C[Si](Br)(C)C>>[P:12]([CH2:11][NH:10][C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9])([OH:19])([OH:16])=[O:13]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCOP(=O)(CN)OCC
Agent: C[Si](C)(C)Br
Product: O=C(NCP(=O)(O)O)c1ccc(Br)o1

Procedure:
5-Bromofuroic acid was reacted with diethyl aminomethylphosphonate in a manner similar to that described in Step D, Example 5. The product was treated with TMSBr as described in Step D, Example 1 to provide the title compound (no. 8.01) as a solid. BPLC Rt=3.72 min; negative ion electrospray MS M-1 found: 282/284.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([O:14][C:15](=[O:35])[NH:16][CH:17]1[CH2:29][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][C:31]([F:34])([F:33])[F:32])[CH:26]=3)[NH:21][C:20]=2[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[N:39]=1>CN(C=O)C.CCOC(C)=O>[CH2:7]([O:14][C:15](=[O:35])[NH:16][CH:17]1[CH2:29][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][C:31]([F:34])([F:32])[F:33])[CH:26]=3)[N:21]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[N:39]=3)[C:20]=2[CH2:19][CH2:18]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NC1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1)OCc1ccccc1
Reactant: Fc1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1)OCc1ccccc1
Temperature: 50 °C
Yield: 56.2 %

Procedure:
Add Cs2CO3 (6.44 g, 19.8 mmol) to a solution of (6-trifluoromethoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid benzyl ester (Preparation 43) (4.00 g, 9.88 mmol) and 2-bromomethyl-6-fluoropyridine (Preparation 44) (3.11 g, 13.8 mmol) in DMF (40 mL). Heat the resulting mixture to 50° C. for 18 h and then dilute with EtOAc (120 mL). Wash the organics with water (3×40 mL), dry (MgSO4), filter, and concentrate to give the crude product (5.40 g) as a brown oil. Purify the crude product on silica gel (120 g) eluting with 2545% EtOAc/hexanes to afford 2.85 g (56%) of the title compound as a tan oil. MS (ES): m/z 514 (M+1); HPLC (Method A): Rt=4.54 min (95%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:19])[CH3:18]>CC(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Br
Reactant: Cc1cccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(OC(C)C)c1C

Procedure:
To a stirred solution/suspension of 2,3-dimethylphenol (10 g) and potassium carbonate (6.8 g) in acetone (150 ml) at reflux was added 2-bromopropane (46 ml) drop-wise over 30 min. The solution was heated at reflux for 4 days. After cooling, the solvent was evaporated and the residue was dissolved in ether and water. The ether phase was separated and was worked up according to the general procedure. Column chromatography on silica gel (eluent:ethyl acetate/heptane 1:19) afforded pure 2,3-dimethyl-1-(2-propyl)oxybenzene (13.2 g) as a mobile, slightly brown oil which was used without further purification.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[OH:5][C:6]1([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15]>>[C:1]([CH2:2][CH2:3][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([OH:5])([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[C:7]1=[O:15])#[N:4]
Reactant: C=CC#N
Reactant: Cc1cccc(C2(O)C(=O)Nc3ccccc32)c1
Product: Cc1cccc(C2(O)C(=O)N(CCC#N)c3ccccc32)c1

Procedure:
Reaction of acrylonitrile with 3-hydroxy-3-(m-tolyl)indolin- 2-one by a procedure analogous to that of Example 1 gives 1-(2-cyanoethyl)- 3-hydroxy-3-(m-tolyl)indole- 2-one. Hydrogenation of 1-(2-cyanoethyl)-3-hydroxy-3-(m-tolyl) indolin-2-one by a procedure analogous to that of Example 2 gives 1-(3-aminopropyl)-3-hydroxy-3-(m-tolyl)indolin- 2-one. Cyclodehydration of 1-(3-aminopropyl)-3-hydroxy-3-(m-tolyl) indolin -2-one by a procedure analogous to that of Example 3 gives 2,3,4,10-tetrahydro-10-(m-tolyl) pyrimido[ 1,2-a] indol-10-ol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:11][CH:10]([CH2:12][SH:13])[CH2:9][S:8]1)[CH3:2].[CH2:22]([C:25]1[C:35]([OH:36])=[C:34]([C:37](=[O:39])[CH3:38])[CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30]Br)[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:37]([C:34]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30][S:13][CH2:12][CH:10]2[CH2:9][S:8][C:7]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[S:11]2)=[C:25]([CH2:22][CH2:23][CH3:24])[C:35]=1[OH:36])(=[O:39])[CH3:38]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)SCC(CS)S1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCSCC2CSC(CCC(=O)OCC)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 31 (2.0 g, 0.0056 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane (prepared as described in U.S. Pat. No. 4,565,882, Example 14) (2.0 g, 0.006 mol) and anhydrous potassium carbonate (3.5 g) in methyl ethyl ketone (25 ml) at reflux overnight. The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 2.1 g (70%) of the product as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[N:15]1([CH2:20][C:21](O)=[O:22])[CH:19]=[N:18][CH:17]=[N:16]1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.CN(C=O)C>[N:15]1([CH2:20][C:21]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[S:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:4]=3[CH:3]=2)=[O:22])[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: O=C(O)Cn1cncn1
Reactant: Nc1ccc2sc3ccccc3c2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1cncn1)Nc1ccc2sc3ccccc3c2c1
Yield: 84.3 %

Procedure:
2-Aminodibenzthiophene (Bull. Soc. Chim. Fr. (1996), 133 (6), 597-610; 500 mg, 2.5 mmol) was dissolved DMF (10 ml) and 2-(1,2,4-triazol-1-yl)acetic acid (318 mg, 2.5 mmol) was added in one portion followed by 1-hydroxybenztriazole hydrate (383 mg, 5.0 mmol) and EDAC (960 mg, 5.0 mmol). The resultant mixture was stirred for 16 hours at ambient temperature then poured on to water (100 ml). A fine white solid was collected which was washed extensively with water, methanol (25 ml) and ether (25 ml) to leave a colourless solid (650 mg). NMR: 10.62 (brs, 1H), 8.18 (m, 2H), 8.16 (m, 1H), 7.99 (m, 3H), 7.62 (dd, 1H), 7.50 (m, 2H), 5.20 (s, 2H); m/z 309.