Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.CN(C)[CH:34]=[O:35].II>O1CCCC1.CCOCC.C(OCC)(=O)C.O>[CH2:23]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][C:16]2[S:17][C:18]([CH:34]=[O:35])=[CH:19][CH:20]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN(CCCC)c1ccc(C=CC=Cc2cccs2)c(OC)c1
Reactant: CN(C)C=O
Agent: II
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)c1ccc(C=CC=Cc2ccc(C=O)s2)c(OC)c1
Temperature: -69 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
In a stream of argon, in 13 ml of tetrahydrofuran was dissolved 0.83 g (2.25 mmol) of dibutyl[3-methoxy-4-[4-(thiophene-2-yl)-1,3-butadienyl]phenyl]amine, and 2.1 ml of n-butyllithium (1.6 mol solution in hexane) (3.36 mmol) was added dropwise thereto under cooling at −68 to −70° C. After the mixture was stirred for 30 minutes, 0.21 ml (2.87 mmol) of N,N-dimethylformamide was added dropwise thereto. The reaction mixture was stirred for 1.5 hours and the temperature was allowed to rise. To this mixture, 5 ml of water was added dropwise. After the reaction mixture was poured into 50 ml of water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was purified by silica gel column chromatography to give a dark reddish brown oily matter. After this oily matter was dissolved in 100 ml of ether, 600 mg of iodine was added thereto and the mixture was stirred. The mixture was washed with a 5% sodium bisulfite solution and then with a saturated saline solution. Drying over anhydrous sodium sulfate and concentration were performed. The residue was purified by silica gel column chromatography to give 715 mg of a dark reddish brown liquid (yield: 80.1%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([O:28][CH3:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:31]1([NH2:37])([CH:34]2[CH2:36][CH2:35]2)[CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C)C=O>[C:31]1([NH:37][C:21]([C:20]2[C:15]([NH:14][C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([O:28][CH3:29])[CH:11]=3)=[O:22])=[C:16]([CH3:27])[CH:17]=[C:18]3[C:19]=2[NH:24][N:25]=[CH:26]3)=[O:23])([CH:34]2[CH2:36][CH2:35]2)[CH2:33][CH2:32]1
Reactant: NC1(C2CC2)CC1
Reactant: COc1cc(-c2nc3c(C)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)Nc2c(C)cc3cn[nH]c3c2C(=O)NC2(C3CC3)CC2)n(-c2ncccc2Cl)n1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 8 mL of N,N-dimethylformamide is added 244 mg (1.83 mmol) of bicyclopropyl-1-ylamine hydrochloride and 340 μL (2.44 mmol) of triethylamine. The reaction is stirred at 70° C. for 16 hours and then concentrated in vacuo. The residue is taken-up with water and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed several times with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 3:7) affords 90 mg (15% over two steps) of product as a pale yellowish solid; LC/MS:506/508 (M+H)+, m.p.: 150-154° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[O:4].CC1N=C(N)C=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:36]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:36][CH2:12][C:8]1[N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:13])[F:14])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(NC(=O)C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1cccc(N)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(Nc1cccc(CBr)n1)C(F)(F)F

Procedure:
2,2,2-trifluoro-N-(6-methyl-pyridin-2-yl)-acetamide xxii can be prepared from 6-methyl-pyridin-2-ylamine and trifluoroacetic anhydride in DCM. Radical bromination of xxii with N-bromosuccinimide and benzoyl peroxide in refluxing carbon tetrachloride affords N-(6-bromomethyl-pyridin-2-yl)-2,2,2-trifluoro-acetamide xxiii.
Reaction SMILES: [C-]#N.[K+].C[N:5](C)C=O.[CH3:9][N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13](=O)[O:12][C:11]1=O>O>[NH:5]=[C:9]1[C:13](=[O:12])[C:14]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:10]1[CH3:11]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CN1C(=N)C(=O)c2ccccc21
Yield: 49 %

Procedure:
To a suspension of 1.3 g. (0.021 moles) of pulverized potassium cyanide in 75 ml. of dimethylformamide (distilled over calcium hydride) at 100° C. is added dropwise, over a period of 15 minutes, a solution containing 3.6 g (0.02 moles) of 1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione in 35 ml. of dimethylformamide (distilled over calcium hydride), after which time the reaction mixture is stirred at 100° C. for an additional 5 minutes. The resultant mixture is then poured into cold water and extracted into three 250 ml. portions of ether. After drying the organic phase over sodium sulfate, the excess solvent is removed and the resultant precipitate is filtered, washed with ether and dried in vacuo to yield 2-imino-1-methyl-3-indolinone, m.p. 99°-102° C. (Yield: 49%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([C:24]2[N:25](C(OCC)=O)[C:26]3[C:31]([C:32]=2[NH:33][C:34](=[O:37])[CH2:35][CH3:36])=[CH:30][CH:29]=[C:28]([Cl:38])[CH:27]=3)=[O:23])[CH:17]=1)C(OC(C)(C)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[C:1]([O:5][C:6]([NH:8][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([C:24]2[NH:25][C:26]3[C:31]([C:32]=2[NH:33][C:34](=[O:37])[CH2:35][CH3:36])=[CH:30][CH:29]=[C:28]([Cl:38])[CH:27]=3)=[O:23])[CH:17]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)n1c(C(=O)c2cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccn2)c(NC(=O)CC)c2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCC(=O)Nc1c(C(=O)c2cc(NC(=O)OC(C)(C)C)ccn2)[nH]c2cc(Cl)ccc12
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of 2-[4-[N,N-bis(tert-butoxycarbonyl)amino]-2-pyridine-2-carbonyl]-6-chloro-1-ethoxycarbonyl-3-(propionylmino)indole (step 3, 240 mg, 0.391 mol) in ethanol (10 ml) was added a solution of potassium carbonate (260 mg, 3.91 mmol) in water (5 ml) at room temperature. After stirring for 8 h, the mixture was concentrated. The residue was diluted with ethyl acetate (100 ml) and washed with (50 ml×2), dried (Na2SO4). Removl of solvent gave an oily residue, which was purified by flash column chromatography eluting with ethyl acetate/hexane (1/3) to afford 118 mg (68%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)O.C(N(CC)CC)C.S(Cl)(Cl)=O.[CH2:37]([Mg]Br)[CH:38]=[CH2:39].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(Cl)Cl.C(OCC)(=O)C>[CH2:39]([C:5]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[NH:8][C:7](=[O:12])[N:6]1[CH2:13][C:14]([F:17])([F:16])[F:15])[CH:38]=[CH2:37]
Reactant: O=C1Nc2ccc(Cl)cc2C(O)(c2ccc(F)cc2)N1CC(F)(F)F
Reactant: C=CC[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCC1(c2ccc(F)cc2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a −40° C. solution of 6-chloro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (21.2 g, 56.6 mmol) in anhydrous THF (170 mL) was added triethylamine (39.4 mL, 283 mmol). The reaction was stirred for 5 min and then thionyl chloride (4.4 mL, 59.4 mmol) was added drop wise maintaining the temperature <−20° C. After 25 min, 1.0M allylmagnesium bromide in THF (170 mL, 170 mmol) was added over 35 min maintaining the temperature <−10° C. The reaction was stirred <−5° C. over 30 min and then poured into a vigorously stirred mixture of aqueous 10% citric acid (150 mL), ice (50 g), and ethyl acetate (200 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organics were washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a crude brown oil. The oil was dissolved in methylene chloride (100 mL) and stirred 1 hr. The resulting precipitate was collected by vacuum filtration and dried under vacuum for 16 h to give racemic 4-allyl-6-chloro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[C:7]([OH:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:14](=[O:27])[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23]C)=[C:17]([O:25][CH3:26])[CH:16]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[OH:23][C:18]1[C:19]([O:21][CH3:22])=[CH:20][C:15]([C:14]([C:3]2[C:4]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[C:5]=3[O:6][C:2]=2[CH3:1])=[O:27])=[CH:16][C:17]=1[O:25][CH3:26]
Reactant: COc1cc(C(=O)c2c(C)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C(=O)c2c(C)oc3c(O)c(OC)ccc23)cc(OC)c1O

Procedure:
2-Methyl-3-(3,4,5-trimethoxybenzoyl)-7-hydroxy-6-methoxy-benzo[b]furan Example 11 (100 mg, 0.27 mmol) was dissolved in dry dichloromethane (5 mL) and solid aluminium trichloride (72 mg, 0.54 mmol) was added to it. The mixture was stirred for 2 hours when additional amount of aluminium trichloride (72 mg, 0.54 mmol) was added and the stirring was continued for 2 more hours (tlc). The reaction was quenched with saturated solution of ammonium chloride and diluted with DCM (20 mL) the organic layer was separated and washed with water, dried over magnesium sulphate and solvent was distilled to gave the crude product which was purified over silica gel column. The compound was crystallized from methanol to gave the product as white solid. (42 mg, 44%). 1H NMR (300 MHz, CDCl3) δ 7.16 (s, 2H, benzoyl Hs), 6.91 (d, J=8.58 Hz, 1H), 6.83 (d, J=8.58 Hz, 1H), 5.94 (s, 1H, OH), 5.68 (s, 1H, OH), 3.91 (s, 3H, OMe), 3.87 (s, 6H, 2×OMe), 2.54 (s, 3H, Me).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[ClH:11].[O:12]([NH2:14])[CH3:13]>C(O)C>[ClH:11].[CH3:13][O:12][N:14]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])[CH3:9]
Reactant: CC(=O)c1ccccc1N
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CON=C(C)c1ccccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.4 %

Procedure:
To a 250-mL rotted bottom flask were added 2′-aminoacetophenone (3.0 g, 22.2 mmol), methoxylamine hydrochloride (2.0 g, 24.4 mmol, 1.1 eq) and ethanol (30 mL). The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 3 h. The oil bath was removed and the reaction mixture was allowed to cool at room temperature. The reaction mixture was filtered and the filtered solid was washed with ethanol followed by diethyl ether to give 0.64 g of 1-(2-aminophenyl)-1-ethanone O-methyloxime hydrochloride as a white solid.
Reaction SMILES: [C:1]([N:4]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[C:5]1([C:18]([O:20]CC)=O)[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].O.Cl>C1COCC1.CCOC(C)=O>[CH2:11]([N:8]1[CH2:9][CH2:10][C:5]2([N:4]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:1](=[O:3])[CH2:2][C:18]2=[O:20])[CH2:6][CH2:7]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1(N(C(C)=O)c2cccc(F)c2)CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a 0° C. solution of 0.86 g (2.2 mmol) ethyl 4-[acetyl(3-fluorophenyl)amino]-1-benzylpiperidine-4-carboxylate in 1 mL THF was added 3.2 mL (6.5 mmol, 2M solution in heptane, THF, ethylbenzene) lithium diisopropylamide solution and the reaction mixture was allowed to slowly warm to rt and stirred for an additional 14 hr. To this mixture was added 50 mL water and 50 mL EtOAc and the pH was adjusted to pH=6 with 1N HCl (approx 11 mL). The aqueous layer was extracted 3×100 mL EtOAc and the combined extracts washed with 100 mL brine, dried over MgSO4, filtered, and concentrated to give 8-benzyl-1-(3-fluorophenyl)-1,8-diazaspiro[4.5]decane-2,4-dione as a solid. 1H NMR (CDCl3, 400 MHz) δ 7.44 (ddd, J=8.06, 8.06 and 6.23 Hz, 1H); 7.14-7.30 (m, 6H); 6.95 (br d, J=7.88 Hz, 1H); 6.89 (ddd, J=9.16, 2.02, and 2.02 Hz, 1H); 3.52 (s, 2H); 3.26 (s, 2H); 2.73 (m, 2H); 2.65 (m, 2H); 1.85 (br m, 4H). Electrospray mass spectrum M+H=353.1
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:28][C:29]([F:46])([F:45])[C@@H:30]([O:32][C:33](=O)[O:34]C1C=CC([N+]([O-])=O)=CC=1)[CH3:31]>>[F:28][C:29]([F:46])([F:45])[C@H:30]([CH3:31])[O:32][C:33]([N:23]1[CH2:22][CH2:21][C:20]2([CH2:19][C:18]3([O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:27]3)[CH2:26]2)[CH2:25][CH2:24]1)=[O:34]
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Product: C[C@H](OC(=O)N1CCC2(CC1)CC1(Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O1)C2)C(F)(F)F

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and (S)-carbonic acid 4-nitro-phenyl ester 2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described for Example 12. LC (method 3): tR=0.95 min; Mass spectrum (ESI+): m/z=530 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]3[O:37][CH2:36]3)[C:30]([O:32]C)=[O:31])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH:28][CH:29]([CH2:34][CH:35]([OH:37])[CH2:36][S:1][C:2]3[S:3][C:4]4[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=4[N:6]=3)[C:30]([OH:32])=[O:31])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Sc1nc2ccccc2s1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc4ccccc4s3)C(=O)O)cc2)cc1

Procedure:
Example 26 is prepared from 2-mercaptobenzothiazole and 1d using the procedure described for compound 20.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[OH:10].[Na+].OO>C(Cl)Cl.O>[CH2:1]1[O:10][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: C=Cc1ccccc1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: c1ccc(C2CO2)cc1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
0.0178 g (0.02 mmol) of the complex salt as described in Preparative Example 1 was added to a mixture of 0.208 g (2 mmol) of styrene in 20 ml of CH2Cl2 and 1.68 g (20 mmol) of sodium hydrogen carbonate in 20 ml of water. After a reaction time at room temperature of 10 minutes, 20 ml of H2O2 (30% strength) was added slowly over a period of 2.5 hours, with the temperature rising to 28° C. After a further 22 hours, the reaction was complete. The layers were separated and the organic phase was evaporated under reduced pressure. The product obtained was purified by column chromatography giving styrene oxide in a yield of 54% based on styrene.
Reaction SMILES: [CH3:1][C@H:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[C:4](=[O:24])[CH2:3]1.C[Li].[CH2:27](OCC)C>C1COCC1>[OH:24][C:4]1([CH3:27])[C:5]2[N:6]=[CH:7][N:8]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:10]=2[C@H:2]([CH3:1])[CH2:3]1
Reactant: CCOCC
Reactant: C[C@@H]1CC(=O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: [Li]C
Solvent: C1CCOC1
Product: C[C@@H]1CC(C)(O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A solution of (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (40 mg, 0.120 mmol) in THF (4 mL) was added to a 1.5M solution of methyllithium in diethyl ether (0.088 mL, 0.132 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 1 hour and quenched by saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (2×). The organic layer was dried (MgSO4) and concentrated. The residue was purified by a silica cartridge (5.0 g) eluted by EtOAc to give tert-butyl 4-((5R)-7-hydroxy-5,7-dimethyl-6,7-dihydro-5H -cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate as an off-white solid (29 mg, 69%). LCMS (APCI+) [M-Boc+H]+ 349.1; Rt: 2.49 mm.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11](CC)[CH2:12][CH:13]([OH:16])[CH2:14][CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH2:20]1[CH2:24]OC(N2C(=O)NC(=O)C(F)=C2)[CH2:21]1.[CH3:34][CH2:35][C:36]1([OH:49])[N:41]=[C:40]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[Se:39][CH2:38][CH2:37]1>C(OCC)(=O)C>[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH:13]([OH:16])[CH2:14][CH2:15][CH2:21][CH2:20][CH3:24])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:34][CH2:35][C:36]1([OH:49])[N:41]=[C:40]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[Se:39][CH2:38][CH2:37]1
Reactant: CCC(O)CC(CC)COC(=O)c1ccccc1
Reactant: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Agent: CCC1(O)CC[Se]C(c2ccc(C)cc2)=N1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCC(O)CCCOC(=O)c1ccccc1
Reaction time: 123 h

Procedure:
A comparison thermal solvent dispersion 4-hydroxy-(2'-ethylhexyl) benzoate (TS-1), a liquid at room temperature, is prepared by similar means. An aqueous solution of 10% (w/w) aqueous DA-9 (6 g), 8.3% aqueous gelatin (about 54 g), and water (74.9 g) is combined with 15 g TS-1, stirred, passed through a colloid mill 5 times, chill set, and stored in the cold until it is used for melt preparation. This colloid milled dispersion is designated a TS-1 CM dispersion. A solid particle thermal solvent dispersion of 4-hydroxy-nonyl benzoate (TS-2; Pfaltz and Bauer; melting point 90°-93° C.) is prepared similarly. About 12 g of TS-2 was dissolved in 24 g of ethyl acetate and mixed with an aqueous gelatin solution comprising 4.8 g of 10% (w/w) aqueous DA-9, 43.3 g of 8.3% (w/w) aqueous gelatin, and 35.9 g of water to give a crude dispersion. This dispersion is passed through a colloid mill 5 times, chill set, noodled, washed to remove ethyl acetate, remelted, chill set, and stored in the cold until used for melt preparation. This colloid milled dispersion is designated TS-2 (CM). Another solid particle thermal solvent dispersion of TS-2 is prepared by roller milling methods. About 18 g of TS-2 is combined with 36 g of 10% aqueous DA-9 , 66 g of water, and about 100 mL of 1.8-2.1 mm-diameter zirconia milling media and placed in a sealed glass jar. This jar is placed on a roller mill for about 123 hours, and a fine particle sized aqueous dispersion is obtained. This dispersion is passed through a cloth filter. About 110 g of this filtrate is combined with about 55.3 g of 8.3% (w/w) aqueous gelatin and 1.9 g of water at about 40° C., stirred, chill set, and stored in the cold until it is used for melt preparation. This roller milled dispersion is designated TS-2 RM.
Reaction SMILES: C(OC(N1CCC2(OCCN([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([Cl:33])=[N:21][C:20]=4[CH:19]=3)C2)CC1)=O)(C)(C)C.[C:36]([O:40][C:41]([N:43]1[CH2:48][C:47]2([CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[O:46][CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41]([N:43]1[CH2:48][C:47]2([CH2:53][CH2:52][N:51]([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([Cl:33])=[N:21][C:20]=4[CH:19]=3)[CH2:50][CH2:49]2)[O:46][CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCOC2(CCNCC2)C1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)CCO2
Product: CC(C)(C)OC(=O)N1CCOC2(CCN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2)C1

Procedure:
Prepared according to the method used in the preparation of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-oxa-4,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester using 1-oxa-4,9-diaza-spiro[5.5]undecane-4-carboxylic acid tert-butyl ester in place of 4-ethoxy-4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (110 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:25])=[O:24])=[CH:18]2.[S:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH2:43].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23]([NH:43][C:39]1[S:38][CH:42]=[CH:41][N:40]=1)(=[O:25])=[O:24])=[CH:18]2
Reactant: Nc1nccs1
Reactant: COc1cc(C(F)(F)F)ccc1-c1cccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1-c1cccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 0.08 h

Procedure:
A vial was charged with perfluorophenyl 5-(2-methoxy-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonate (77.62 mg, 0.142 mmol), THF (1415 μl), and thiazol-2-amine (21.26 mg, 0.212 mmol). The vial was cooled in an ice bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (354 μl, 0.354 mmol) was added dropwise over 1 min. LC/MS after 5 min showed mostly the desired product. After a total of 20 min, the reaction was quenched by the addition of acetic acid (0.1 mL). The resulting mixture was warmed to room temperature and concentrated. The product was purified by chromatography on silica gel (0 to 5% MeOH/DCM) to give 5-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (59.52 mg, 0.128 mmol) as an off-white foam. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.79 (br. s., 1H), 8.51 (d, J=1.9 Hz, 1H), 8.21 (d, J=8.3 Hz, 1H), 7.81-7.65 (m, 2H), 7.57-7.41 (m, 5H), 7.26 (d, J=4.6 Hz, 1H), 6.84 (d, J=4.6 Hz, 1H), 3.73 (s, 3H); m/z (ESI) 465.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[O:11][C:12]([C:16]([NH2:18])=O)=[CH:13][C:14](=[O:15])[C:3]1=2.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1C=CC=CC=1>CN(C=O)C>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[O:11][C:12]([C:16]#[N:18])=[CH:13][C:14](=[O:15])[C:3]1=2
Reactant: Cn1c2ccccc2c2oc(C(N)=O)cc(=O)c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c2ccccc2c2oc(C#N)cc(=O)c21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 10.5 g (43.3 mmole) 4,5-dihydro-5-methyl-4-oxopyrano[3,2-b]indole-2-carboxamide, 12.6 g (66.2 mmole) p-toluenesulfonyl chloride, and 10.3 g (10.5 ml, 130 mmole) of pyridine in 55 ml DMF was heated under nitrogen on a steam bath for 4 hr. The cooled mixture was added to 500 g ice/water, stirred for 20 min, and the pink solid was filtered and washed with cold water. Two recrystallizations from ethanol yielded light pink needles of mp 190°-192° C.