Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3](=[O:17])[N:4]([C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5][O:6][C:7]=1[CH3:8].C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)CCC.[Cl-].[Li+].O>O1CCCC1>[CH3:8][C:7]1[O:6][CH2:5][N:4]([C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3](=[O:17])[C:2]=1[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCOC(=O)C(C)(C)N1COC(C)=C(I)C1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)(C)N1COC(C)=C(c2cccs2)C1=O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 2-(2,3-dihydro-5-iodo-6-methyl-4-oxo-4H-1,3-oxazin-3-yl)-2-methylpropanoate (30.0 g), 2-(tributylstannyl)thiophene (33.5 ml), palladium bis-triphenylphosphine chloride (3.08 g) and lithium chloride (20.5 g) in tetrahydrofuran was heated at 50° C. for 24 hours. Further 2-(tributylstannyl)thiophene (2.8 ml) was added and the mixture heated for a further 18 hours. Palladium bis-triphenylphosphine chloride (0.62 g) was added and heating continued for 18 hours. The mixture was poured into water, extracted (ether) and the organic phase washed (brine), dried (magnesium sulphate) and evaporated. Purification by chromatography on silica gel gave ethyl [2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazine-3-yl]-2-methylpropanoate (14.5 g), NMR 1.15(t,3H), 1.55(s,6H), 2.1(s,3H), 4.15(q,2H), 5.25(s,2H), 6.9-7.4(m,3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:20]([C:22]3[O:23][C:24](=[O:45])[C:25]4[C:30]([C:31]=3[C:32]3[CH2:33][N:34](CC5C=CC=CC=5)[CH2:35][CH2:36][CH:37]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[CH:13]=3)[C:4]=12.CCN(C(C)C)C(C)C.C(Cl)(=O)OC(Cl)C>C(Cl)Cl>[CH:24]([OH:45])=[O:23].[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:20]([C:22]3[O:23][C:24](=[O:45])[C:25]4[C:30]([C:31]=3[C:32]3[CH2:33][NH:34][CH2:35][CH2:36][CH:37]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:21])[N:10]=[C:11]([C:12]3[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[CH:13]=3)[C:4]=12
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCCN(Cc2ccccc2)C1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Agent: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1oc(=O)c2ccccc2c1C1=CCCNC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Product: O=CO
Temperature: 25 °C
Yield: 31.3 %

Procedure:
3-(1-(4-Amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-isochromen-1-one hydrochloride (example 169, 0.5 g, 0.799 mmol), was dissolved in DCM (3 ml) at 0° C.; DIPEA (0.395 ml, 2.262 mmol) and 1-chloroethyl carbonochloridate (0.651 ml, 6.03 mmol) were added at 0° C. under vigorous stirring and the reaction was stirred for 5 min at 0° C. and for 2 hrs at 60° C. The reaction was allowed to cool to RT and quenched with 5 ml of MeOH; the mixture was stirred for further 2.5 hrs at 60° C. and evaporated under reduced pressure to give a crude which was purified by reverse phase flash chromatography on C-18 cartridge (H2O:CH3CN=95:5 to 50:50, with 0.1% HCOOH) to afford title compound (0.068 g, 0.125 mmol, 16%).
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].[CH2:5]([C:7]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH:24]=[C:23]([CH2:25][OH:26])[N:22]=[CH:21]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][CH3:9])[CH3:6].C(N(CC)CC)C>ClCCl>[ClH:4].[C:1]([O:26][CH2:25][C:23]1[N:22]=[CH:21][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:7]([CH2:8][CH3:9])([CH2:5][CH3:6])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:24]=1)(=[O:3])[CH3:2]
Reactant: CCC(CC)(NCCCn1cnc(CO)c1)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)(NCCCn1cnc(COC(C)=O)c1)c1ccccc1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of acetyl chloride (0.24 ml) in dichloromethane (6 ml) was added dropwise to a solution of 1-[3-(1-ethyl-1-phenylpropylamino)propyl]imidazol-4-yl-methanol (10 g, from Example 86b) in dichloromethane (18 ml) containing triethylamine (0.46 ml), with stirring, at 0° C. The mixture was stirred at 0° C. for 30 minutes and then at ambient temperature for 2 hours. Work-up as described in Example 98b, but without treatment with ethereal hydrogen chloride, gave 1-[3-(α,α-diethylbenzylamino)propyl]imidazol-4-ylmethyl acetate as an oil.
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH3:26])[CH:19]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl>CN(C=O)C.O>[CH2:1]([O:5][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH3:26])[CH:19]([CH:23]([CH3:24])[CH3:25])[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCO
Reactant: CC(C)C(C(=O)O)N(C)S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 3.17 mL (0.042 mol) of 2-butyn-1-ol in 60 ml of DMF at room temperature was added 1.70 g (0.040 mol) 60% sodium hydride. The resulting mixture was stirred for 0.5 h and then a solution of 2.45 g (8.478 mmol) the product of Example 11 dissolved in 20 mL of DMF was added to the reaction. The reaction mixture was then heated to reflux for 24 h, cooled to room temperature and then acidified to pH 2 with 10% HCl solution. After stirring for 1 h the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organics were then dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:2) to provide 1.67 g (58%) of the desired carboxylic acid product as a white solid identical to the product of Example 8.
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[CH:5]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:30])[C:14]2[O:20][C:19]3[C:21]([Cl:26])=[CH:22][C:23]([NH2:25])=[CH:24][C:18]=3[CH2:17][S:16](=[O:28])(=[O:27])[C:15]=2[CH:29]=1)=[O:10])([CH3:7])[CH3:6].COC(C1C=C(C)C2OC3C(Cl)=CC(N)=CC=3CS(=O)(=O)C=2C=1)=O>C(O)=O>[CH:5]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:30])[C:14]2[O:20][C:19]3[C:21]([Cl:26])=[CH:22][C:23]([NH:25][CH:1]=[O:2])=[CH:24][C:18]=3[CH2:17][S:16](=[O:28])(=[O:27])[C:15]=2[CH:29]=1)=[O:10])([CH3:7])[CH3:6]
Reactant: Cc1cc(C(=O)OC(C)C)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Reactant: O=C[O-]
Agent: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Agent: [Na+]
Solvent: O=CO
Product: Cc1cc(C(=O)OC(C)C)cc2c1Oc1c(Cl)cc(NC=O)cc1CS2(=O)=O
Temperature: 0 °C

Procedure:
Sodium formate (0.040 g, 0.581 mmol) was added to a suspension of 2-amino-4-chloro-6-methyl-10,10-dioxo-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid isopropyl ester (0.23 g, 0.581 mmol) [prepared by hydrolysis of compound of Example 1 and followed by esterification using isopropanol/H2SO4] in formic acid (20 mL) and refluxed for 1.5 h. The reaction mixture was cooled and poured into ice water (100 mL). The solid precipitated was filtered, washed with water and dried. The crude product was crystallised with ethylacetate/pet. ether 60-80° C. to obtain the title compound. Yield: 0.12 g (48%); mp: 212-215° C.; 1H NMR (DMSO-d6, 300 MHz): δ 1.30 (d, 6H, OCH(CH3)2), 2.64 (s, 3H, CH3), 5.12 (m, 1H, OCH(CH3)2), 5.25 (s, 2H, CH2, trans minor isomer), 5.32 (s, 2H, CH2, cis major isomer), 7.33 (d, 1H, Ar, trans minor isomer), 7.50 (d, 1H, Ar, trans minor isomer), 7.69 (d, 1H, Ar, cis major isomer), 7.86 (d, 1H, Ar, cis major isomer), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar), 8.30 (s, 1H, CHO, cis major isomer), 8.80 (d, 1H, CHO, trans minor isomer), 10.40 (d, 1H, NH, trans minor isomer), 10.57 (s, 1H, NH, cis major isomer); MS: m/e (ES−) 422 (M−1); analysis: C19H18ClNO6S requires C, 53.84,H, 4.28, N, 3.30, Cl, 8.36, S, 7.56; found: C, 54.27,H, 4.45, N, 2.94, Cl, 8.76, S, 7.77%.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[C:13]([CH2:15][OH:16])[N:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:32]([O:16][CH2:15][C:13]1[N:14]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[NH:11][C:12]=1[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)(=[O:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(CO)c(Sc2cccc(Cl)c2)[nH]1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1nc(CO[Si](C)(C)C(C)(C)C)[nH]c1Sc1cccc(Cl)c1
Yield: 78.3 %

Procedure:
To a solution of 700 mg (1.8 mmol) of [2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1H-imidazol-4-yl]methanol (46) in methylene chloride (14 ml), was added 1.29 g (12.8 mmol) of triethylamine, and then, 1.00 g (12.8 mmol) of acetyl chloride was added dropwise under ice-cooling with stirring. The reaction mixture was stirred at room temperature for 15 minutes, and added to a cooled saturated aqueous sodium hydrogen carbonate solution to neutralize and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was dissolved in 5 ml of methanol, to which was added 5 ml of 50% aqueous acetic acid, and the mixture was stirred at room temperature for1 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution to neutralize, and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:2) to give 602 mg of [2-t-butyldimethylsilyloxymethyl-5-(3-chlorophenylthio)-1H-imidazol-4-yl]methyl acetate as oil (yield 78%).
Reaction SMILES: [C:1]([CH:3]([OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)#[CH:2].C=O.[CH:20](NC(C)C)(C)C.Cl>O1CCOCC1>[CH:1]([CH:3]([OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)=[C:2]=[CH2:20]
Reactant: CC(C)NC(C)C
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Agent: C=O
Agent: Cl
Solvent: C1COCCO1
Product: C=C=CC(O)c1cccc(Oc2ccccc2)c1
Temperature: 20 °C

Procedure:
10 g of α-ethynyl-3-phenoxybenzyl alcohol, 2.1 g of paraformaldehyde, 5.3 g of diisopropylamine, 0.215 g of CuBr and 50 ml of dioxane are refluxed for 2 hours. The reaction mixture is cooled to 20° C., poured into a solution of 2 N HCl and extracted with ether. The organic phase is washed with 10% potassium carbonate and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is chromatographed over silica gel with a 7:3 mixture of hexane/ether as eluant, affording the compound of the formula ##STR5## with a refractive index of nD20° =1.5942.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.Cl.[F:16][CH2:17][CH2:18][NH2:19].C(N(CC)CC)C>CN(C=O)C>[F:16][CH2:17][CH2:18][NH:19][C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: NCCF
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FCCNc1ccn2c(n1)nc1ccccc12
Temperature: 25 °C

Procedure:
To a microwave vial equipped with a magnetic stir bar, containing DMF (1 mL) was 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.02 g, 0.081 mmol, 1.0 equiv), 2-fluoroethylamine hydrochloride (0.012 g, 0.121 mmol, 1.5 equiv) and triethylamine (0.034 ml, 0.242 mmol, 3.0 equiv). The suspension was irradiated in a Biotage Initiator microwave reactor (250 W) at 100° C. for 10 min. After cooling to room temperature, the crude product was purified by HPLC to afford 0.015 g (81%) of T802 as an off-white solid. MS (ESI, Pos.) m/z 331.1 (M+H)+.
Reaction SMILES: Cl[P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4](Cl)[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH2:15]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C([N:54]([CH2:57][CH3:58])[CH2:55][CH3:56])C>C1(C)C=CC=CC=1>[CH2:34]([N:33]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4]([N:54]([CH2:55][CH2:56][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[CH2:57][CH2:58][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: CC(C)(C)N1P(Cl)N(C(C)(C)C)P1Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)P1N(C(C)(C)C)P(N(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC)N1C(C)(C)C
Yield: 89.2 %

Procedure:
The procedure of Example 1 is repeated using 5 g (18 mmol) of 2,4-dichloro-1,3-di-tert-butyl-1,3,2,4-diazadiphosphetidine, 18.8 g (36 mmol) of dioctadecylamine, 5 mL (36 mmol) of triethylamine and 200 mL of toluene to give 20 g of a wet solid. Recrystallization of the crude solid with a mixture of 45 mL of acetonitrile and 5 mL of toluene gives 10 g (50% yield) of the title compounds as a white solid melting at 48°-55° C.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.S(Cl)(Cl)=O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:14][CH:13]=2)=[CH:23][C:22]=1[N:28]1[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]1
Reactant: O=C(O)c1ccc(-n2cncn2)cc1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)c2ccc(-n3cncn3)cc2)cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Ethyl 4-(1,2,4-triazol-1-yl)benzoate (520 mg, 2.4 mmol) was heated at reflux in 5N HCl (40 ml) for 1 h, and the product filtered off and dried in vacuo to afford the acid (88%). 4-(1,2,4triazol-1-yl)benzoic acid (0.395 g, 2.1 mmol) was suspended in dry toluene (40 ml) and thionyl chloride (2 ml) added under argon. The mixture was heated to reflux for 1.5 h and then evaporated to dryness under reduced pressure. The oil was dissolved in dichloromethane under argon and 4-methoxy-3-(4-methyl-1-piperazinyl)phenylamine (460 mg, 2.1 mmol) was added followed by triethylamine (2 ml). The mixture was stirred at room temperature under argon for 2 h and then partitioned between dichloromethane (50 ml) and saturated potassium carbonate (50 ml), and the organic extracts dried (sodium sulphate). The organic solution was filtered, evaporated to dryness under reduced pressure and purified by column chromatography (silica, chloroform/methanol 5-10%) to afford the amide (757 mg, 92%) which was crystallised from methanol diethyl ether as the oxalate salt.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[ClH:12].[CH2:13]=O>>[Cl:12][CH2:13][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Cl
Reactant: C=O
Product: O=C(O)Cc1ccc(O)c(CCl)c1

Procedure:
4-Hydroxybenzeneacetic acid, 0.5 mole, is added to concentrated hydrochloric acid, 50 ml, then 0.5 mole of formaldehyde in the form of a 34-38% solution of formalin is added. Hydrogen chloride is bubbled through the reaction mixture for 60 minutes while maintaining the temperature of the reaction mixture at 35° to 45° C. The reaction mixture is poured into water and the title compound is extracted from the aqueous solution with ethyl acetate. The ethyl acetate is dried over magnesium sulfate, filtered and removed to give the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2([CH2:22][OH:23])[CH2:21][CH2:20][C:17]3([O:19][CH2:18]3)[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOC(C)=O>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:15][CH2:16][C:17]([CH2:18][OH:19])([CH2:20][CH2:21]2)[O:23][CH2:22]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1(c2cccc(Oc3ccccc3)c2)CCC2(CC1)CO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: OCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
To a solution of (6-(3-phenoxyphenyl)-1-oxaspiro[2.5]octan-6-yl)methanol (55.9 mg, 0.180 mmol) in CH2Cl2 (2 mL) at 0° C. was added p-toluenesulfonic acid monohydrate (3.43 mg, 0.018 mmol). The solution was warmed to rt and stirred for 1 h. The reaction was then diluted with EtOAc, washed successively with sat'd aq NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (0 to 100% EtOAc:hexanes) to afford the title compound (15 mg, 27% yield) as an oil. LCMS, [M+Na]+=333.0.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[CH2:4]1.C([N:35]1[CH:39]=[C:38]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=2)[N:37]=[CH:36]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(Cl)[Cl:74]>>[ClH:74].[C:47]([C:44]1[CH:43]=[CH:42][C:41]([CH2:40][C:38]2[N:37]([CH2:2][CH:3]3[CH2:8][CH2:7][N:6]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:5](=[O:15])[CH2:4]3)[CH:36]=[N:35][CH:39]=2)=[CH:46][CH:45]=1)#[N:48]
Reactant: O=C1CC(CO)CCN1c1ccccc1
Reactant: ClCCl
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: N#Cc1ccc(Cc2cncn2CC2CCN(c3ccccc3)C(=O)C2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The product from Step D (0.205 g, 1.00 mmol) and the product from Step E (0.425 g, 1.00 mmol) were dissolved in methylene chloride (2 mL) containing diisopropylethylamine (0.191 mL, 1.10 mmol) and cooled to -78° C. under argon. Trifluoromethane sulfonic anhydride was added (0.173 mL, 1.03 mmol) and the reaction stirred at -78° C. for 1 h, followed by warming to room temperature over 2 h. The solvent was evaporated, and the residue dissolved in methanol. After refluxing for 30 min, the methanol was evaporated, and the residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase is washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The free base product was chromatographed on silica gel with 3% methanol in methylene chloride follwed by 7% 9:1 methanol:ammonium hydroxide in methylene chloride. The title compound was obtained after conversion to the hydrochloride salt. FAB ms: 371 (M+1). Anal. Calc for C23H22N4O·HCl·H2O, C, 65.01; H, 5.93; N,13.19. Found: C, 64.77; H, 5.89; N, 13.11.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].Cl[CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>O>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][CH2:22][CH:21]([OH:30])[CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[CH:6][CH:7]=2)[CH:25]=1
Reactant: Oc1ccc(-c2cccnc2)cc1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC(CCc1cccnc1)COc1ccc(-c2cccnc2)cc1
Yield: 38.2 %

Procedure:
Prepared according to the method as described in Example 24b) from 3-(4-hydroxyphenyl)pyridine (1.68 g), ethanol (30 ml), sodium hydroxide (0.393 g), water (10 ml) and (±)-α-(chloromethyl)-3-pyridinepropanol (0.91 g, Example 24a)) to give the title compound as a pale yellow solid (0.6 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[F:17])=[CH:4][CH:3]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28](C(OC(C)(C)C)=O)[C:27]([CH3:37])([CH3:36])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:19]3[CH:20]=[C:21]4[NH:28][C:27]([CH3:37])([CH3:36])[CH2:26][N:22]4[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:17])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Oc2ccc(Cl)nc2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4ccc(Cl)nc4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((6-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and tert-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: CN(C)C=O.[C:6]([CH2:9][N:10]1[C@H:13]([C@H:14]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[S:17])[CH3:15])[C@@H:12]([C@H:25]([OH:27])[CH3:26])[C:11]1=[O:28])([OH:8])=[O:7].[C:29]([O:35][CH2:36]Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].[I-].[Na+].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]([C@@H:14]([C@H:13]2[N:10]([CH2:9][C:6]([O:8][CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:7])[C:11](=[O:28])[C@@H:12]2[C@H:25]([OH:27])[CH3:26])[CH3:15])=[S:17])=[CH:23][CH:22]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N(CC(=O)O)[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N(CC(=O)OCOC(=O)C(C)(C)C)[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Reaction time: 20 h
Yield: 92.7 %

Procedure:
In18 ml of dimethylformamide, was dissolved 8.18 g (22.0 mmol) of (3S,4S)-1-carboxymethyl-4-[(1R)-1-(p-chlorophenylthiocarbonyl)ethyl]-3-[(1R)-1-hydroxyethyl]-2-azetidinone at room temperature. To the resulting solution, were successively added 5.5 ml (40.0 mmol) of pivaloyloxymethyl chloride and 5.75 g (40.3 mmol) of sodium iodide, and was added dropwise 4.2 ml (25.3 mmol) of diisopropylethylamine, followed by stirring the mixture for 20 hours at the same temperature. The reaction mixture was diluted with 120 ml of toluene. The toluene solution was washed with 2.5% aqueous sodium bicarbonate solution and water, each several times. The resulting toluene solution was dried over sodium sulfate, and then the solvent was removed by evaporation. The resulting oily residue was dissolved in 60 ml of toluene at room temperature. To the resulting solution was added 120 ml of hexane, precipitating a crystal, which was filtered and washed to obtain 9.46 g of a white crystal of the title compound (yield: 92.7%).