Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].CCN(C(C)C)C(C)C.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:37]([F:40])([F:39])[F:38])[O:27][N:26]=[C:25]([C:28]3[S:32][C:31]([CH:33]([NH2:35])[CH3:34])=[C:30]([CH3:36])[CH:29]=3)[CH2:24]2)[CH:19]=[C:20]([Cl:22])[CH:21]=1>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:37]([F:39])([F:38])[F:40])[O:27][N:26]=[C:25]([C:28]3[S:32][C:31]([CH:33]([NH:35][C:1](=[O:4])[CH2:2][CH3:3])[CH3:34])=[C:30]([CH3:36])[CH:29]=3)[CH2:24]2)[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: CCC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(C)N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)NC(C)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reaction time: 19 h
Yield: 30.9 %

Procedure:
Propionyl chloride (20 mg) and Hünig base (70 μl) are added to a solution of 1-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-ethylamine (60 mg) in dichloromethane (1 ml). After 19 hours at room temperature, the reaction is quenched with water. The reaction mixture is extracted three times with dichloromethane. The combined organic phases are dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield N-(1-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-ethyl)-propionamide (21 mg, compound 1.49 in Table 1) as a light yellow oil. MS (HPLC/MS): 479 (MH+). Retention time: 2.01 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)N([O])C(C)(C)CCC1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[CH2:82]1[C:84]2([CH2:89][CH2:88][NH:87][CH2:86][C@H:85]2[OH:90])[CH2:83]1.C([O-])(O)=O.[Na+]>C(#N)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([CH2:19][CH2:20][CH2:21][C:22]([N:87]2[CH2:88][CH2:89][C:84]3([CH2:82][CH2:83]3)[C@H:85]([OH:90])[CH2:86]2)=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CCN1CCCCO
Reactant: O[C@@H]1CNCCC12CC2
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)OCc2ccccc2)CCN1CCCC(=O)N1CCC2(CC2)[C@H](O)C1
Temperature: 0 °C
Yield: 55 %

Procedure:
To an ice cold solution of 0.44 g (1.4 mmol) of 4-(4-hydroxy-butyl)-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester in 5 ml of acetonitrile:water (1:1) was added 0.043 g (0.3 mmol) TEMPO and 0.97 g (3.0 mmol) of (diacetoxyiodo)benzene. The mixture was stirred allowed to reach room temperature and was stirred for a further 3 h after which time it was evaporated to dryness. The crude residue was redissolved in 5 ml of DMF, 0.68 g (2 mmol) of HATU and 0.6 ml (4.0 mmol) of triethylamine added followed by addition of 0.25 g (2.0 mmol) of (S)-6-aza-spiro[2.5]octan-4-ol. hydrochloride (intermediate 2). The reaction was stirred for 16 h after which time the mixture was poured onto sat. aq. NaHCO3, extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated. Purification on a SiO2-column (CH2Cl2/MeOH 95:5), afforded the titled compound in 55% yield as a colorless foam. MS: 444.3 (MH+).
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]CO)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:2][Br:5])=[CH:9][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Oc1ccc(CCCBr)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
A solution of tetrabromomethane (1.125 eq.) in dichloromethane (0.5 ml/mole) was added dropwise to the solution of the commercially available 3-(4-hydroxyphenyl)-1-propanol 1B (1 eq.) and triphenylphosphine (1.125 eq.) in dichloromethane at 0° C. The reaction mixture was stirred at room temperature for 2 days, extracted with dichloromethane, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. the crude reaction mixture was filtered through silica gel, eluting with 10% ethyl acetate in hexane, to give 3-(4-hydroxyphenyl)-1-bromopropane 2 as a brown oil in 62% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[CH:9][NH:10][C:4]=2[CH:3]=1.CC1(C)CCCC(C)(C)N1.Cl[C:22]1([C:28]([O:30][CH3:31])=[O:29])[C:26](=[O:27])[CH:25]=[CH:24][S:23]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]([C:24]3[S:23][C:22]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([OH:27])[CH:25]=3)[CH:9]=[N:10][C:4]=2[CH:3]=1
Reactant: COC(=O)C1(Cl)SC=CC1=O
Reactant: Clc1cc2[nH]cnc2cn1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-n2cnc3cc(Cl)ncc32)cc1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 0.68 g of 6-chloro-1H-imidazo[4,5-c]pyridine and 0.65 g of 2,2,6,6-tetramethylpiperidine in 100 ml chloroform were slowly added a solution of 0.87 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate in 40 ml chloroform. The reaction mixture was stirred for 12 h at room temperature. After washing with water (3×50 ml) the organic layer was separated, dried with MgSO4 and concentrated to a volume of about 100 ml. The residue was treated with n-hexane until precipitation takes place. The solid was filtered and the procedure was repeated once again. The combined solids were dried under vacuum to yield the title compounds as an isomeric mixture, which was used for the next step (example B3) without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@H:12]1[CH2:21][N:20]2[C@H:14]([CH2:15][O:16][C:17]3[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=3[C:19]2=[O:22])[CH2:13]1.C(N(CC)CC)C>ClCCl.O.C(OCC)(=O)C>[O:11]=[C:12]1[CH2:21][N:20]2[C@H:14]([CH2:15][O:16][C:17]3[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=3[C:19]2=[O:22])[CH2:13]1
Reactant: O=C1c2ccccc2OC[C@@H]2C[C@@H](O)CN12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1C[C@H]2COc3ccccc3C(=O)N2C1
Reaction time: 0.17 h
Yield: 22.2 %

Procedure:
To a stirred solution of oxalyl chloride (0.52 ml; 5.94 mmol) in dry dichloromethane (15 ml) cooled to −78° C. was added a solution of dimethylsulfoxide (0.81 ml, 11.42 mmol) in dry dichloromethane (2 ml). Stirring was continued for 10 minutes followed by dropwise addition of a solution of the material (1 g) prepared in Example 25 (4.57 mmol) in dry dichloromethane (10 ml). The mixture was stirred for a further 15 minutes then triethylamine (3.8 ml; 27.3 mmol) was added. After stirring at −78° C. for a further 10 minutes the mixture was allowed to warm to 0° C. before ethyl acetate (50 ml) and water (50 ml) were added. After thorough mixing the organic layer was separated, washed sequentially with 1M HCl (50 ml) and brine (50 ml), and dried (Na2SO4). The solvent was removed under reduced pressure and the residue purified by flash chromatography eluting with 3% MeOH in methylene chloride to give the title product (220 mg) which was recrystallised once from the minimum of hot ethyl acetate, 1H NMR (CDCl3) δ 2.41 (dd, 1H), 2.87-2.93 (m, 1H), 4.15-4.33 (m, 3H), 4.45-4.49 (m, 2H), 7.06 (d, 1H), 7.18 (t, 1H), 7.44 (dd, 1H), 8.03 (dd, 1H); EIMS: m/z=218.4 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[CH3:25][CH:26]([C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([CH3:39])[CH3:38])[C:29]=1[C:30](O)=[O:31])[CH3:27]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:30]([C:29]1[C:28]([CH:26]([CH3:25])[CH3:27])=[CH:36][CH:35]=[CH:34][C:33]=1[CH:37]([CH3:39])[CH3:38])=[O:31]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: CC(C)c1cccc(C(C)C)c1C(=O)O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(C(C)C)cccc1C(C)C

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[[2,6-bis-(1-methylethyl)phenyl]carbonyl]-L-phenylalanine methyl ester was prepared from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2,6-bis-(1-methylethyl)benzoic acid using the general procedure described in example 3. LR MS: 555 (M+).
Reaction SMILES: [F:1][C:2]1[C:3]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][CH:14]([C:17]([O:19]CC)=[O:18])[CH2:13][CH:12]=3)[N:8](S(C3C=CC=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[C:3]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)C1CC=C(c2cc3c(-c4cc(F)ccc4OC)c(F)cnc3n2S(=O)(=O)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CCC(C(=O)O)CC3)cc12

Procedure:
A suspension of Example 279B (1.1 g, 1.991 mmol) in 20 mL dioxane was treated with 6M aqueous sodium hydroxide (4.98 mL, 29.9 mmol) at 80° C. for 1 hour and at 100° C. for 2 hours. The mixture was cooled and most solvent removed in vacuo. The residue was diluted with 15 mL water and the basic layer extracted with ethyl acetate (twice). The organic layer was discarded. The basic aqueous layer was adjusted to ˜pH 7 with 1M hydrochloric acid, and extracted with ethyl acetate (twice) and dichloromethane (twice). The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Trituration with ethyl acetate, filtration and drying in vacuo gave the title compound. 1H NMR (500 MHz, DMSO-d6) δ 1.60-1.78 (m, 1H) 1.95-2.11 (m, 1H) 2.27-2.48 (m, 3H) 3.39-3.52 (m, 1H) 3.53-3.62 (m, 1H) 3.67-3.81 (m, 3H) 6.12 (s, 1H) 6.54 (s, 1H) 7.07-7.44 (m, 3H) 8.17 (d, J=2.14 Hz, 1H) 11.86 (s, 1H). MS (ESI): 385.2 (M+H)+.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=O)=O.O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([O:35][CH2:36][CH3:37])[C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:20]1[C:21]2[N:8]([CH2:7][CH2:6][O:5][C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH:30]([O:35][CH2:36][CH3:37])[C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:28]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:15][C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(Cc1ccc(O)cc1)C(=O)OC
Reactant: CS(=O)(=O)OCCN1c2ccccc2Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)OC
Temperature: 80 °C
Reaction time: 12 h
Yield: 390.1 %

Procedure:
A mixture of 2-(phenoxazin-10-yl)ethyl methanesulfonate (1.75 g, 5.0 mmol), methyl 3-(4-hydroxyphenyl)-2-ethoxypropanoate (1.5 g, 0.68 mmol) and potassium carbonate (3.16 g) in dry dimethylformamide (20 mL) was stirred for 12 h at 80° C. The reaction mixture was cooled to room temperature (ca. 25° C.). Water (30 mL) was added and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (50 mL), dried (Na2SO4) and evaporated. The residue was chromatographed using a mixture of ethyl acetate and pet. ether (1:9) to afford the title compound (1.15 g, 47%) as a white solid. mp 89-90° C. 1H NMR data matches with the desired product (see above).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:11]2([CH2:14][NH2:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCC1(Cc2ccc(Cl)cc2)CCNCC1
Reaction time: 19 h

Procedure:
To a solution of 4-(4-chlorobenzyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester (0.500 g, 1.493 mmol) in methanol (3 ml) was added 4M HCl in dioxane (10 ml). After stirring for 19 hours, the solution was concentrated to give the deprotected amine as the hydrochloride salt (0.405 g).
Reaction SMILES: O[C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[N:17][OH:18])[C:13]([F:16])([F:15])[F:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.O>C1COCC1.CCOC(C)=O>[F:16][C:13]([F:14])([F:15])[C:12]1[C:3]2[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=2[O:18][N:17]=1
Reactant: CCCc1c(O)ccc(C(=NO)C(F)(F)F)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
1-(2,4-Dihydroxy-3-propylphenyl)-2,2,2-trifluoroethanone oxime (4.2 g, 15.96 mmol, prepared by the method described in WO9728137) and PPh3 (8.82 g, 33.6 mmol) were dissolved in THF (250 mL), and the mixture was cooled to 0° C. A solution of DEAD (5.02 mL, 32.0 mmol) in THF (150 mL) was slowly added over a period of 30 min. The reaction mixture was stirred for 1 h at 0° C. After addition of water (500 mL) and extraction with EtOAc (3×300 mL), the combined organic phases were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel flash chromatography (1:6 EtOAc/hexane) to yield 1.96 g (50%) of the title compound as a light yellow powder. 1H NMR (300 MHz, CDCl3): δ 1.00 (t, 3H), 1.73 (m, 2H), 2.88 (t, 2H), 5.34 (s, 1H), 6.93 (d, 1H), 7.48 (d, 1H).
Reaction SMILES: C([S:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([C:8](=[CH2:25])[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=O)C>CO.[OH-].[Na+]>[SH:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:7]([C:8](=[CH2:25])[CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CC[C@@H](SC(C)=O)CC12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CC[C@@H](S)CC12
Yield: 99.7 %

Procedure:
To a solution of 3α-acetylthio-6-methyleneandrostane-17-one (210 mg) in MeOH (3 mL), 1N NaOH (0.6 mL) was added. After 1 h at room temperature 5% NaH2PO4 aqueous solution was added and the mixture extracted with Et2O (2×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness to give 3α-mercapto-6-methyleneandrostane-17-one (185 mg, 100%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([C:11]2[N:12]=[C:13]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:14]3[S:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[C:6]([F:26])[CH:5]=1.[OH:27][CH2:28][C:29](O)=[O:30].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>O.CN(C=O)C.C(N(CC)CC)C>[ClH:3].[Cl:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([C:11]2[N:12]=[C:13]([N:20]3[CH2:21][CH2:22][N:23]([C:28](=[O:27])[CH2:29][OH:30])[CH2:24][CH2:25]3)[C:14]3[S:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[C:6]([F:26])[CH:5]=1
Reactant: Fc1cc(-c2nc(N3CCNCC3)c3sccc3n2)c(F)cc1Cl
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CO)N1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 185.7 %

Procedure:
A mixture of 500 mg of 2-(4-chloro-2,5-difluorophenyl)-4-piperazine-1-ylthieno[3,2-d]pyrimidine dihydrochloride, 104 mg of hydroxyacetic acid, 0.32 ml of triethylamine, 184 mg of HOBt, 261 mg of EDCI and 10 ml of DMF was stirred for two days at room temperature. 70 ml of water was added to the reaction mixture. After the precipitate was filtered and washed with water, it was dried at 50° C. under reduced pressure. The obtained solid was dissolved in 10 ml of THF and was added to 2 ml of 4M HCl-dioxane aq. The resultant was concentrated under reduced pressure to give a solid. This solid was recrystallized from EtOH-EtOAc to give 487 mg of 2-{4-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperazine-1-yl}-2-oxoethanol hydrochloride.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[OH-].[K+].[O:13]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14]1>CO.O>[O:13]1[CH:17]=[CH:16][C:15]([CH:18]=[C:3]2[C:4](=[O:10])[CH:5]3[CH2:8][CH2:9][N:2]2[CH2:7][CH2:6]3)=[CH:14]1
Reactant: O=Cc1ccoc1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2ccoc2)N2CCC1CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Furan-3-carboxaldehyde (2.83 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 ml water and cooled to 0° C. yielding 2-((3-furyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Furyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (2.1 g, 100 mmol) was dissolved in methanol (100 ml) and 10% palladium on charcoal (0.2 g) was carefully added under nitrogen. The suspension was hydrogenated at 50 psig in a Parr hydrogenation apparatus for 8 hrs followed by quenching of the catalyst with a small amount of chloroform. The entire slurry was filtered through a pad of Celite filter aid followed by additional washing of the pad with methanol. Rotary evaporation of the pooled solvents gave the desired product, 2-((3-oxolanyl)methyl)-1-azabicyclo[2.2.2]octan-3-one, as a clear oil that solidified upon cooling (2.05 g, 96.7%).
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[CH2:29]([N:26]1[CH2:25][CH2:24][CH:23]([O:22][C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:6]([C:5]3[O:1][C:2]4[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=4[CH:4]=3)=[O:8])=[CH:21][C:18]=2[C:19]#[N:20])[CH2:28][CH2:27]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N#Cc1cc(N)ccc1OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1cc2ccccc2o1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3o2)ccc1OC1CCN(Cc2ccccc2)CC1
Yield: 40.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]furan-2-carboxylic acid (1.2 g) and 5-amino-2-(1-benzylpiperidin-4-yloxy)benzonitrile (2.2 g), the title compound (1.3 g) was obtained. melting point: 175° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14](CO)=[CH:13][CH:12]=1)=[CH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26]C(C1C=CC=C(CO)C=1)=C)C1C=CC=CC=1>>[CH3:19][O:26][C:5]1[CH:4]=[CH:3][C:2]([CH2:1][O:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH2:10])=[CH:7][CH:6]=1
Reactant: C=C(OCc1ccccc1)c1cccc(CO)c1
Reactant: C=C(OCc1ccccc1)c1ccc(CO)cc1
Product: C=C(OCc1ccc(OC)cc1)c1ccccc1

Procedure:
α-Benzyloxy[4-(hydroxymethyl)styrene] and α-Benzyloxy[3-(hydroxymethyl)styrene]
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N:5]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2)=[C:6]=[S:7]>C(Cl)Cl>[NH2:3][CH2:2][CH2:1][NH:4][C:6](=[S:7])[NH:5][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2
Reactant: NCCN
Reactant: O=C1Cc2c(N=C=S)cccc2N1
Solvent: ClCCl
Product: NCCNC(=S)Nc1cccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 110.8 %

Procedure:
Ethylenediamine (0.828 mL, 12.38 mmol) is added to a solution of 4-isothiocyanatooxindole (0.471 g, 2.48 mmol) in methylene chloride (20 mL). The resulting solution is stirred at room temperature for 2.5 hours. The reaction mixture is concentrated by rotary evaporation to yield 0.688 g of crude 4-[N'-(2-aminoethyl)thioureido]oxindole as a green solid. This material is carried on directly to the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C:8]1([C:17]([O:19]C)=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(Cl)Cl.Cl>CCO.C1COCC1>[C:1]([O:5][C:6](=[O:21])[CH2:7][C:8]1([C:17]([OH:19])=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(CC(=O)OC(C)(C)C)Cc2ccccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)CC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
To a solution of methyl 2-(2-tert-butoxy-2-oxoethyl)-2,3-dihydro-1H-indene-2-carboxylate (4.5 g, 15.50 mmol) in EtOH/THF (70 mL, 1:1) at room temperature was added 1 M sodium hydroxide (35 ml, 35.0 mmol), and the mixture was stirred at room temperature for 1.5 hour. To the reaction mixture was added DCM and acidified by 1 M HCl to pH=7. The mixture was extracted with DCM, and the combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 10 to 30% EtOAc/HEP) and gave the title compound: 1.4 g (yield: 15%). LCMS (condition B): 275.2 (M−1); retention time=1.17 min.
Reaction SMILES: S1(CCCC1)(=O)=O.P(Cl)(Cl)([Cl:10])=O.C(N(CC)CC)C.O=[C:21]1[NH:26][CH:25]=[N:24][C:23]2[S:27][C:28]3[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30][C:29]=3[C:22]1=2>[Cl-].[Na+]>[Cl:10][C:21]1[C:22]2[C:29]3[CH2:30][CH2:31][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][C:28]=3[S:27][C:23]=2[N:24]=[CH:25][N:26]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3nc[nH]c(=O)c23)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To sulfolane (3.19 L) was added phosphoryl chloride (785 g, 5.12 mol) at rt. Triethylamine (518 g, 5.12 mol) was added dropwise with water-bath cooling. tert-Butyl 4-oxo-3,5,6,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(4H)-carboxylate from Example 10A (525.5 g, 1.706 mol) and additional sulfolane (1.34 L) were added, and the mixture was heated to 70° C. for 2.5 h. The mixture was cooled to it, and triethylamine (967 g, 9.56 mol) was added. A semi-saturated aqueous sodium chloride solution (10 L) was added during which the mixture was cooled with an ice-bath. After stirring at rt for 2 h, the precipitate was collected by suction filtration and washed three times with water (1.5 L). The residue was dried to yield 517 g (93%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:8]([CH3:9])[C:7]([N+:10]([O-:12])=[O:11])=[N:6][CH:5]=1.CC(C)([O-])C.[K+]>C1C=CC=CC=1>[CH3:9][N:8]1[C:4]([CH:3]=[CH2:2])=[CH:5][N:6]=[C:7]1[N+:10]([O-:12])=[O:11]
Reactant: Cn1c(CCCl)cnc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: C=Cc1cnc([N+](=O)[O-])n1C
Reaction time: 2 h

Procedure:
To a solution of 18.9 g. of 5-(2-chloroethyl)-1-methyl-2-nitroimidazole (prepared according to the procedure of British Pat. No. 1,222,486) in 2.8 liters of anhydrous benzene cooled to 5°-10° C., 16.8 g. of potassium tert-butoxide is added. Stirring is continued for 2 hours at 5°-10° C. After filtration and concentration to dryness under vacuum at a temperature lower than 50° C., the resulting yellow oily residue is washed three times with 50 ml. of ethyl ether (or light petroleum). The title product is obtained, which is dried under vacuum at 40° C.; yield 12 g. (77.7%). A sample crystallized from ethyl ether melts at 106°-108° C.