Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH:8]1[C:17](=[O:18])[C:16]2[NH:15][CH:14]=[N:13][C:12]=2[N:11]=[C:9]1[NH2:10].P(=O)(O)(O)O.[CH3:24][C:25](OC(C)=O)=[O:26].CC(O)=O.N1C(=O)C2NC=NC=2N=C1N.OP(O)(O)=O>C(O)(=O)C>[C:25]([N:10]([C:5](=[O:7])[CH3:6])[C:9]1[NH:8][C:17](=[O:18])[C:16]2[NH:15][CH:14]=[N:13][C:12]=2[N:11]=1)(=[O:26])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: CC(=O)N(C(C)=O)c1nc2nc[nH]c2c(=O)[nH]1
Yield: 94 %

Procedure:
The effect of the ratio of acetic anhydride and acetic acid on the reaction time and yield was also studied. In general, any range of acetic anhydride, acetic acid, guanine and phosphoric acid can be used that provides the desired results. In the present work, it was found that a ratio of 15/10/1/0.05 (ml) of Ac2O/AcOH/guanine/H3PO4 is preferred. It was discovered that guanine could be acetylated using this ratio of reactants at reflux for 15 hours to give diacetylguanine with minimal discoloration in approximately 94% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:13]([N:17]2[CH:21]=[C:20]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH:19]=[N:18]2)[CH2:14][C:15]#[CH:16])[CH2:12][CH2:11][CH2:10][CH2:9]1.[H][H]>CO.[Pd]>[CH:8]1([CH:13]([N:17]2[CH:21]=[C:20]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH:19]=[N:18]2)[CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: C#CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
4-[1-(1-Cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt (prepared in Example 729) (20 mg, 0.048 mmol) was dissolved in methanol (2 mL) and a catalytic amount of 5% Pd—C was added. The mixture was stirred under 1 atmosphere of hydrogen via an affixed balloon. After 2 hours, the mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) to afford the product (14 mg, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[N:7]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.[O-:34][C:35]#[N:36].[K+]>O>[C:23]1([C:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:7]3[C:6](=[O:29])[C:5]4[C:10](=[CH:11][C:2]([NH:1][C:35]([NH2:36])=[O:34])=[CH:3][CH:4]=4)[NH:9][C:8]3=[O:12])[CH2:18][CH:19]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N#C[O-]
Reactant: Nc1ccc2c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)[nH]c2c1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc2c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)[nH]c2c1
Reaction time: 3 h
Yield: 27.7 %

Procedure:
To a mixture of 7-amino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.39 g), acetic acid (5 ml) and water (10 ml) was added a solution of potassium cyanate 0.16 g) in water (2 ml) and the resulting mixture was stirred for additional 3 hours. The reaction mixture was poured into water and precipitated solid was filtered, washed in turn with water and ethanol and dried to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-ureido-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.12 g).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])=[C:2]=[S:3].[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[CH3:30][CH:29]([CH3:31])[C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][CH2:12][NH:11][C:2]([NH:1][C:4]3[C:5]([CH3:10])=[CH:6][CH:7]=[CH:8][CH:9]=3)=[S:3])[CH2:20][CH2:19]2)[CH:22]=1)=[O:32]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: Cc1ccccc1N=C=S
Product: Cc1ccccc1NC(=S)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure P and Scheme AB using 1-isothiocyanato-2-methylbenzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 453.2 (M+H)+.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][C:4]#[CH:5].[CH2:7]([SH:11])[CH2:8][CH2:9][SH:10].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:2]([CH:1]1[S:11][CH2:7][CH2:8][CH2:9][S:10]1)[CH2:3][C:4]#[CH:5]
Reactant: C#CCCC=O
Reactant: SCCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C#CCCC1SCCCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a solution of pent-4-ynal (6.99 g, 85.1 mmol) dissolved in methylene chloride (85 mL) was added 1,3-propanedithiol (8.54 mL, 85.1 mmol). The solution was stirred at room temperature for 1 hour and then cooled to -20° C. Boron trifluoride etherate (10.46 mL, 85.1 mmol) was added and, after warming to room temperature, the solution was stirred for 16 hours. The solution was washed with water (2×20 mL) and the aqueous extract was washed with additional methylene chloride (2×40 mL). The combined organic extracts were washed with 10% potassium hydroxide solution (4×30 mL) and the aqueous extract was washed with additional methylene chloride (2×40 mL). The combined organic extracts were washed with 10% potassium hydroxide solution (4×30 mL) and the aqueous extract was back-extracted with methylene chloride (2×40 mL). The combined organic extracts were washed with brine (2×40 mL) and dried (K2CO3). The solvent was removed by rotary evaporation to afford 9.14 g (62%) of 2-(but-3-ynyl)-1,3-dithiane as a pale yellow oil. 1H NMR (CDCl3)δ: 4.2 (t, 1H), 3.1-2.8 (m, 4H), 2.6-2.4 (m, 1H), 2.3-2.0 (m, 6H); IR (neat): 3286, 2908, 1421, 1272, 907 cm-1 ; GC retention time=3.11 min (88% area); TLC (silica gel, 90% hexane: 10% ethyl acetate) Rf=0.74.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7](=[O:14])[O:8][CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])[C@H:3]1[C:15]([OH:17])=[O:16].[O:19]([C:26]1[CH:27]=[C:28]([C@H:32](O)[CH3:33])[CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7](=[O:14])[O:8][CH2:9][C:10]([Cl:13])([Cl:11])[Cl:12])[C@H:3]1[C:15]([O:17][C@H:32]([CH3:33])[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=1)=[O:16]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Reactant: C[C@@H](O)c1cccc(Oc2ccccc2)c1
Product: C[C@@H](OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Step D of Example 9, 6 g of (1R,cis)2,2-dimethyl-3-[3-oxo-3-(2,2,2-trichloroethoxy)-1-propynyl]-cyclopropane-carboxylic acid and 4.1 g of 1-(R)(3-phenoxy-phenyl)-ethanol were reacted to obtain after chromatography and elution with an 8--2 mixture of cyclohexaneethyl acetate 4.38 g of (R)α-methoxy-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[3-oxo-3-(2,2,2-trichloroethoxy)-1-propynyl]-cyclopropane-carboxylate.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=1)[CH3:12].C(=O)([O-])O.[Na+].O>C(O)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[CH:4][CH:3]=2)[CH:16]=1)[CH3:12]
Reactant: Ic1ccc2cn[nH]c2c1
Reactant: CCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCNC(=O)c1ccc(C)c(-c2ccc3cn[nH]c3c2)c1
Temperature: 150 °C
Yield: 48.5 %

Procedure:
A stirred mixture of 6-iodo-1H-indazole (0.45 g), N-ethyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 10, 0.54 g) tetrakis(triphenylphosphine)palladium(0) (0.05 g) and aqueous sodium hydrogen carbonate (1M, 1 ml) in isopropanol (10 ml) was heated at 150° C. for 30 min in a microwave oven. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (3×25 ml). The extracts were washed with water (25 ml) dried (Na2SO4) and concentrated under vacuum. The residual oil was purified by column chromatography on silica (50 g) eluting with ether/ethyl acetate (7:3) to give the title compound as a pale yellow foam (0.25 g).
Reaction SMILES: CSC.[Cl:4][C:5]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:6]=1[CH2:7]O.C(Cl)[Cl:17]>>[Cl:4][C:5]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:6]=1[CH2:7][Cl:17]
Reactant: ClCCl
Reactant: CN(C)c1ccc(Cl)c(CO)c1
Solvent: CSC
Product: CN(C)c1ccc(Cl)c(CCl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
23.8 g of N-chlorosuccinimide provided in 600 ml of absolute methylene chloride is cooled to 0° C. and is slowly mixed with 15.6 ml of dimethyl sulfide. Thereafter the suspension thus produced is cooled to -30° C. and carefully mixed with 20 g of 2-chloro-5-dimethylaminobenzyl alcohol. The reaction mixture is then warmed to 0° C. and stirred at this temperature for 3 hours. Thereafter the mixture is diluted with methylene chloride and poured into ice water. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulfate solution and concentrated in vacuo. The residue is chromatographed with hexane over aluminum oxide (neutral, stage III). A yield of 17.2 g of 2-chloro-5-dimethylaminobenzyl chloride is obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[C:4]([CH3:18])[CH:3]=1.CCN(C(C)C)C(C)C.Cl.[CH2:29]([O:31][NH2:32])[CH3:30]>CN(C=O)C>[CH2:29]([O:31][NH:32][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][N:16]=[CH:17][C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[CH3:18])[CH3:30]
Reactant: CCON
Reactant: Cc1cc(I)ccc1Nc1cnccc1C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCONC(=O)c1ccncc1Nc1ccc(I)cc1C
Reaction time: 4 h
Yield: 53 %

Procedure:
3-[(4-iodo-2-methylphenyl)amino]isonicotinic acid 2c (60 mg, 0.17 mmol) was dissolved in 6 ml dry DMF followed by the addition of DIPEA (0.20 mmol, 37 μl), ByBOP (0.20 mmol, 107 mg) and O-ethylhydroxylamine hydrochloride (0.34 mmol, 34 mg). The mixture was stirred for 4 h and the volatiles were removed in vacuo. The crude material was purified by preparative reversed phase HPLC to give 36 mg (91 μmol; 53% yield) of pure desired product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Li]CCCC.CN([CH:29]=[O:30])C>>[CH3:1][C:2]1[N:3]=[C:4]([CH:29]=[O:30])[N:5]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Cc1ncn(COCC[Si](C)(C)C)c1-c1ccccc1
Agent: [Li]CCCC
Product: Cc1nc(C=O)n(COCC[Si](C)(C)C)c1-c1ccccc1
Yield: 96.7 %

Procedure:
Reaction of 4-methyl-5-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (187 mg, 0.65 mmol), 2.5 M n-BuLi (338 uL, 0.84 mmol), and DMF (151 uL, 1.95 mmol) for 2 h at −40° C. gave the title compound (199 mg, 99%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.94 (t, 2H, J=7.5 Hz), 2.54 (s, 3H), 3.61 (t, 2H, J=7.5 Hz), 5.88 (s, 2H), 7.33–7.38 (m, 1H), 7.46 (dd, 2H, J=7.5, 7.5 Hz), 7.68 (d, 2H, J=6.0 Hz), 9.82 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][O:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[N:18]=[C:17](S(C)(=O)=O)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:44][N:45]([CH2:47][CH2:48][NH2:49])[CH3:46].[Cl-].[NH4+]>CS(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][O:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[N:18]=[C:17]([NH:49][CH2:48][CH2:47][N:45]([CH3:46])[CH3:44])[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)CCN
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(S(C)(=O)=O)nc1OCCOC1CCCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(NCCN(C)C)nc1OCCOC1CCCCO1

Procedure:
##STR143## (1) A mixture of 4-tert-butyl-N-{5-(2-methoxyphenoxy)-2-methylsulfonyl-6-[2-(tetrahydropyran-2-yloxy)ethoxy]pyrimidin-4-yl}benzenesulfonamide obtained in Reference Example 10-(2) (200 mg), dimethylaminoethylamine (138.8 mg) and dimethylsulfoxide (1 ml) is reacted at 100° C. for 15 hours, and then reacted at 120° C. for five hours. The reaction mixture is treated with ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated under reduced pressure. The residue is purified by preparative silica gel thin layer chromatography (solvent; chloroform:methanol=10:1) to give 4-tert-butyl-N-{2-(2-(N,N-dimethylamino)-ethylamino)-5-(2-methoxyphenoxy)-6-[2-(tetrahydropyran-2-yloxy)ethoxy]-pyrimidin-4-yl}benzenesulfonamide (99.7 mg) as a crystal.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30]>C[O-].[Na+].CO>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:7]
Reactant: CCCCOC(=O)c1ncc2ccc(Oc3ccccc3)cc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCNC(=O)c1ncc2ccc(Oc3ccccc3)cc2c1O
Yield: 94.9 %

Procedure:
A mixture of 4-hydroxy-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester (200 mg, 0.59 mmol) (prepared according to U.S. Pat. No. 7,629,357) and beta-alanine (792 mg, 8.9 mmol) in 0.5 M NaOMe/MeOH solution was refluxed overnight. Reaction mixture was concentrated and residue was dissolved in water (150 mL). It was cidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 196 mg (0.56 mmol) in 94% yield. LC-MS ESI−: 351.05 (M−1)−.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[O:16])=[C:13]([NH:26][C@H:27]([C:29]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:33](=[O:41])[C:32]4=[C:42]([CH3:45])[CH:43]=[CH:44][N:31]4[N:30]=3)[CH3:28])[N:12]=[CH:11][N:10]=2)=CC=1>FC(F)(F)C(O)=O>[NH2:8][C:9]1[C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[O:16])=[C:13]([NH:26][C@H:27]([C:29]2[N:34]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:33](=[O:41])[C:32]3=[C:42]([CH3:45])[CH:43]=[CH:44][N:31]3[N:30]=2)[CH3:28])[N:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2C(=O)Nc2cccc(OC)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(NC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
(S)-4-((4-Methoxybenzyl)amino)-N-(3-methoxyphenyl)-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carboxamide (120 mg, 0.19 mmol) was dissolved in 5 mL trifluoroacetic acid. The reaction mixture was stirred at room temperature overnight. The trifluoroacetic acid was evaporated and the crude was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulphate, filtered and concentrated. The residue was purified by reverse phase using SP1® Purification System to obtain 27 mg (28% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[SH:17]>>[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S:17][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Sc1nccs1
Product: O=[N+]([O-])c1ccc(Sc2nccs2)c(Cl)c1
Yield: 26 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 8 which is concerned with the preparation of starting materials, 3-chloro-4-fluoronitrobenzene was reacted with 2-thiazolethiol to give a precipitated solid which was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated to give 2-chloro-4-nitrophenyl 2-thiazolyl sulphide in 26% yield.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:32])[CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:7]4[C@@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[CH:11][C:12]=3[F:32])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: O=C1CC[C@H](CO)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@@H]4CO)cc3F)CC2)c(C)c1
Yield: 77.4 %

Procedure:
Using (R)-5-hydroxymethylpyrrolidin-2-one (138 mg) and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (392 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 1, (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-hydroxymethylpyrrolidin-2-one (330 mg) was obtained. To a mixture of the obtained (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-hydroxymethylpyrrolidin-2-one (330 mg) and sodium hydride (37 mg) were added tetrahydrofuran and N,N-dimethylformamide, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added methyl tosylate (117 μL), and the mixture was further stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-methoxymethylpyrrolidin-2-one. The obtained (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-methoxymethylpyrrolidin-2-one was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate was added and the mixture was stirred. The reaction mixture was concentrated under reduced pressure, diethyl ether was added, and the precipitate was collected by filtration to give the title compound (48 mg).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:17].CN(C=O)C>ClCCl>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: COc1ccc(OC)c(C(=O)O)c1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(C(=O)Cl)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a mixture of 2-fluoro-3,6-dimethoxybenzoic acid (4.8 g, 24 mmol) in anhydrous dichloromethane (75 mL) at 0° C., SOCl2 (14.2 g, 120 mmol) was slowly added followed by DMF (0.1 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated in vacuo to give 2-fluoro-3,6-dimethoxybenzoyl chloride (5.2 g). To a solution of ethyl 2-(3-methoxyphenyl)acetate (4.7 g, 24 mmol) in anhydrous THF (40 mL) at −78° C., LiHMDS (1.0 M in THF, 36 mL) was added dropwise. The resulting solution was stirred at −78° C. for 30 min and a solution of 2-fluoro-3,6-dimethoxybenzoyl chloride (5.2 g, 24 mmol) in anhydrous THF (60 ml) was added dropwise. The reaction mixture was stirred for additional 2 h at −78° C. and quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound (7.8 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C@H:5]1[CH2:27][C@@:26]2([CH3:28])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:25]2[C:24](=[O:29])[CH2:23][C@@:22]2([CH3:30])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16]2(OCC[O:18]2)[CH3:17])[CH2:7][C@@H:6]1[OH:31].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[OH:31][C@@H:6]1[C@@H:5]([O:4][CH2:3][CH2:2][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:27][C@@:26]2([CH3:28])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:25]2[C:24](=[O:29])[CH2:23][C@@:22]2([CH3:30])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16](=[O:18])[CH3:17])[CH2:7]1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](OCCCl)C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Reactant: C1COCCN1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCN5CCOCC5)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2β-(2'-Chloroethoxy)-20,20-ethylenedioxy-3α-hydroxy-5α-pregnan-11-one (500 mg.) was dissolved in morpholine (15 ml.) and the solution heated on a steam-bath for 24 hours. The morpholine was removed by evaporating in vacuo and the resulting red oil was dissolved in 35% aqueous acetic acid (25 ml.). This solution was heated on a steam-bath for 21/2 hours. Water (50 ml.) was added and the slightly turbid solution filtered through Kieselguhr. The filtrate was made alkaline with 10N-potassium hydroxide and the precipitate extracted into ether (100 ml.). The ether extract was washed with water until the aqueous layer was neutral, dried over anhydrous sodium sulphate and evaporated to give the title compound as a white foam (250 mg.) [α]D + 82° (c 0.98).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=4)[NH2:25])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([NH:25][C:41]([CH:38]5[CH2:40][CH2:39]5)=[O:42])[CH:26]=[CH:27][CH:28]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1)C1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 103.6 %

Procedure:
A mixture of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)aniline (10 mg, 0.025 mmol), diisopropylethylamine (13 mg, 0.10 mmol), and dichloromethane (2 mL) was treated with cyclopropanecarbonyl chloride (30 mg, 0.028 mmol) and stirred at room temperature for 6 hours. The solvent was removed in vacuo and the remaining residue was dissolved in ethyl acetate (25 mL), washed with aqueous sodium bicarbonate solution (2×20 mL), and the organic fraction was separated and concentrated. The product was purified by column chromatography over silica gel using 1% methanol and 0.01% ammonia in 1:1 ethyl acetate/hexanes to give 12 mg (quantitative yield) of N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)phenyl]cyclopropanecarboxamide as a yellow gum. MS [M+H] 464.0,