Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:33]2[C:2]([OH:3])([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[CH:28][CH:29]=1
Reactant: NCc1ccccc1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (1.042 g, 3.84 mmol) followed by triethylamine (777.1 mg, 7.68 mmol, 1.06 mL)) and benzylamine (616 mg, 5.76 mmol, 0.79 mL) resulting in the formation of a yellow/cream precipitate. The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (3×10 mL), water (3×10 mL) and dried (Na2SO4). Recrystallisation of the cream precipitate from a minimum amount of boiling ethyl acetate and excess petrol to yielded the title product as a white crystalline solid (1.0378 g, 2.96 mmol, 77% yield). 1H NMR: (300 Hz, CDCl3) δ ppm 4.24 (d, 1H, J=15.48 Hz, H9), 4.42 (d, 1H, J=15.48 Hz, H9′), 7.16 (m, 5H, H10-H14), 7.25 (m, 5H, H1-H5), 7.56 (m, 2H, H6-H7), 7.75 (d, 1H, H8). 13C NMR: (75 Hz, DMSO); δ 42.80 (N—CH2), 90.60 (O—C—N), 122.95, 123.18, 126.78, 128.07, 128.35, 128.41, 128.51, 129.70, 130.81, 132.97, 133.07, 138.42, 139.46, 149.59 (Ar), 167.20 (C═O). IR: 1463, 1664, 2936, 3285 cm−1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:7]([Cl:19])=[CH:6][N:5]=1.[CH3:20]I>C1COCC1.O>[Cl:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:20])[CH:11]=2)[C:7]([Cl:19])=[CH:6][N:5]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2nc(Cl)ncc2Cl)c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
NaH (0.795 g, 19.88 mmol) was added to 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (Intermediate 11, 5.0 g, 18.9 mmol) in THF (200 mL) at 0° C. under N2 and the mixture was stirred at 0° C. for 0.25 h. CH3I (1.243 mL, 19.88 mmol) was then added and the mixture was allowed to warm to r.t. and was stirred for 1 h. The mixture was cooled again in an ice bath and further NaH (0.795 g, 19.88 mmol) was added. The suspension was stirred at 0° C. for 10 minutes then CH3I (1.243 mL, 19.88 mmol) was added and the mixture was stirred for 1 h. The mixture was then diluted with water (100 mL) which resulted in the formation of some solid. The solid was collected by filtration and was washed with water and EtOAc and then dried, to give the title compound (3.67 g, 70%) as a beige solid. The organic solution was further washed with water and sat. brine and then dried (MgSO4) and concentrated in vacuo. Trituration of the residue with diethyl ether gave a solid which was collected by filtration and dried in vacuo to give the title compound (477 mg, 9%) as a brown solid: This material was only 71% pure so it was kept separate from the earlier batch; 1H NMR: 3.97 (3H, s), 7.34 (2H, dtd), 7.59-7.65 (1H, m), 8.56 (1H, dd), 8.73 (1H, s), 8.79 (1H, s); m/z: ES+ MH+ 278.06.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1CS/[C:13](=[N:15]\[C:16](=[O:22])[CH2:17][C:18](OC)=[O:19])/[CH3:14].[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1>C1COCC1>[OH:22][C:16]1[N:15]=[C:13]([CH3:14])[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:25]([O:24][CH3:23])=[O:34])=[CH:27][CH:28]=2)[C:18](=[O:19])[CH:17]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: COC(=O)CC(=O)/N=C(/C)SCc1ccc2ccccc2c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cn2c(C)nc(O)cc2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
To a solution of methyl 3-({(1Z)-1-[(2-naphthylmethyl)thio]ethylidene}amino)-3-oxopropanoate (1.9 g, 0.006 mol, from step 1) in THF (25.0 mL), at 0° C., is added methyl-4-aminomethylbenzoate (1.1 g, 0.0067 mol). The reaction mixture is stirred at room temperature for 1 hour, and then concentrated to dryness. The resulting residue is dissolved in dioxane (20.0 mL), DBU (0.1 mL) is added, and the resulting reaction mixture is heated at 70° C. for 1 h under an argon atmosphere. After removing the solvent under reduced pressure, the residue is purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=275) are combined and freeze-dried to afford the title compound (0.33 g) as a white powder: 1H NMR (CD3OD/400 MHz) δ 7.99 (d 2H, J=8.4 Hz), 7.29 (d, 2H, J=8.4 Hz), 5.42 (s, 1H), 5.36 (s, 2H), 3.88 (s, 3H), and 2.42 (s, 3H); ES-HRMS m/z 275.1021 (M+H calcd for C14H15N2O4 requires 275.1026).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[S:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:21]([CH:23]1[CH:26](OC(=O)C)[NH:25][C:24]1=[O:31])[CH3:22]>[OH-].[Na+].O1CCOCC1>[CH2:21]([CH:23]1[CH:26]([S:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][NH:12][C:10]([O:9][CH2:8][C:7]2[CH:19]=[CH:20][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])[NH:25][C:24]1=[O:31])[CH3:22]
Reactant: CCC1C(=O)NC1OC(C)=O
Reactant: O=C(NCCCC(O)=S)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC1C(=O)NC1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution, prepared in the cold, of 7.95 g (26.7 mmole) of 4-p-nitrobenzyloxycarbonylaminothiobutyric acid in 26.7 ml of 1N sodium hydroxide solution is added dropwise to a pre-cooled solution of 3.24 g (20 mmole) of 3-ethyl-4-acetoxyazetidin-2-one (racemic cis-trans compound in a ratio of 6:4) in 50 ml of dioxan and the mixture is stirred for 2 hours at room temperature. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (9:1, 4:1 and 1:1) and yields the title compound with the following physico-chemical properties.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19](Cl)=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:19]([C:15]3[C:16]4[C:11](=[CH:10][C:9]([O:8][C:4]5[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=5)=[CH:18][CH:17]=4)[CH:12]=[CH:13][CH:14]=3)=[O:20])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1
Reactant: O=C(Cl)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(Cc2ccc(NC(=O)c3cccc4cc(Oc5cc(Cl)ncn5)ccc34)cc2)CC1
Reaction time: 0.5 h

Procedure:
A solution of 2.2 mMol 6-(6-chloropyrimidin-4-yloxy)-naphthalene-1-carbonyl chloride (Step 19.3) in 15 ml CH2Cl2 is added to a stirred solution of 410 mg (2.0 mMol) 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine and 680 μl (4.0 mMol) diisopropylethylamine in 15 ml CH2Cl2. After 30 min, the reaction mixture is poured into a mixture of NaHCO3 and CH2Cl2. The aq. phase is separated off and extracted with CH2Cl2. The combined organic layers are washed with water and brine, dried (Na2SO4) and concentrated to give the crude product which is purified by column chromatography (SiO2; CH2Cl2/EtOH/NH3 95:4.5:0.5) to afford the title compound as a yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][CH:28]([NH:31][S:32]([C:35]1[S:36][C:37](Br)=[CH:38][CH:39]=1)(=[O:34])=[O:33])[CH2:29][OH:30]>>[OH:26][CH2:27][CH:28]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)=[CH:38][CH:39]=1)(=[O:34])=[O:33])[CH2:29][OH:30]
Reactant: O=S(=O)(NC(CO)CO)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: O=S(=O)(NC(CO)CO)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.54) (158 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (117 mg, 40%). MS (ISN) 589.3 [(M−H)−]; mp 210° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:17]O)[CH:14]=[CH:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1.O=S(Cl)[Cl:37].N1C=CC=CC=1>O1CCOCC1>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:8]3[CH:9]=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][Cl:37])[CH:12]=4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ncnn2c(-c3cccc(CO)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Nc1ncnn2c(-c3cccc(CCl)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 1.5 h
Yield: 24.5 %

Procedure:
{3-[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-methanol (254 mg, 0.57 mmol) was suspended in 2 mL of dioxane and SOCl2 (83 μL, 1:1 mmol) was added followed by the dropwise addition of pyridine (0.14 mL, 1.7 mmol). The mixture was stirred for 1.5 hours and carefully quenched by the addition of 2M aqueous Na2CO3. The mixture was diluted with water and extracted with 3×10 mL of 10% MeOH/EtoAc. The combined organic fractions were washed with 1M aqueous H3PO4, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by ISCO® Redi-sep 12, 80% to 100% EtOAc/hexanes to provide 65 mg (24%) of the title compound as a crusty solid. 1H-NMR (DMSO-d6) 8.55 (s, 1H), 8.19 (s, 1H), 8.08, (d, 1H) 7.99 (s, 1H) 7.83 (d, 1H) 7.70 (s, 1H), 7.46 (t, 1H), 7.40 (t, 1H), 7.38-7.26 (m, 4H), 7.24 (d, 1H), 7.22 (s, 1H), 5.72 (s, 2H), 4.60 (s, 2H); LC-MS [M+H]+=465.3, 467.2, RT=3.24 min.
Reaction SMILES: [Cl:1]C1C=CC(C[C:7]2[C:16]([C:17]([NH2:19])=[O:18])=[C:15]([OH:20])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]#[C:22][CH2:23][OH:24])[CH:13]=3)[N:8]=2)=CC=1.C([O-])([O-])=O.[K+].[K+].[ClH:33].[CH:34]([N:37]([CH2:41][CH2:42]Cl)[CH:38](C)C)(C)C.O>CN(C=O)C>[ClH:1].[Cl:33][C:9]1[CH:14]=[CH:13][C:12]([CH2:21][NH:19][C:17]([C:16]2[C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]#[C:22][CH2:23][OH:24])[CH:13]=3)[N:8]([CH2:42][CH2:41][N:37]([CH3:34])[CH3:38])[CH:7]=2)=[O:18])=[CH:11][CH:10]=1
Reactant: NC(=O)c1c(Cc2ccc(Cl)cc2)nc2ccc(C#CCO)cc2c1O
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-chlorobenzyl-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.515 g) is dissolved in DMF (10 mL), and K2CO3 (0.778 g) and diisoproplyaminoethyl chloride-hydrochloride (0.56 g) are added. The reaction mixture is heated to 95° C. for 14 h, then allowed to stir at room temperature overnight. The mixture is then poured into H2O and an oil formed, which is isolated by decanting the liquid. The oil is dissolved in MeOH/CH2Cl2, and etheral HCl is added to adjust the pH to 2. The mixture is concentrated in vacuo to give the title compound as the hydrochloride salt.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([NH:16]C(=O)C)=[CH:12][CH:11]=1)(=[O:9])=[O:8].C([O-])([O-])=O.[Na+].[Na+]>Cl>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:2]2[S:1][CH:5]=[N:4][N:3]=2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2nncs2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1ccc(S(=O)(=O)Nc2nncs2)cc1
Yield: 50 %

Procedure:
Compound 102 (1.0 g, 3.6 mmol) was suspended in 3N HCl (10 mL) and heated to reflux for 30 min. The acidic mixture was neutralized with Na2CO3 solution. The precipitated product was collected by filtration, washed with water, and dried to give the product (450 mg, 1.8 mmol, 49%), mp 226° C. (lit2 mp 221-222° C.); 1H NMR (250 MHz, CDCl3) δ 5.95 (2, s), 6.57 (2, d, J=6.5 Hz), 7.41 (2, d, J=6.5 Hz), 8.68 (1, s), 14.03 (1, br s).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:19]
Reactant: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1ccccn1
Agent: [Pd]
Solvent: CO
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O)c1ccccn1
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-7-oxo-N′-picolinoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 216 (0.30 g, 0.76 mmol) and Pd/C (0.40 g) in methanol (100 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 217 (0.23 g, quant. yield) as a white foam.
Reaction SMILES: [NH2:1][C:2]1([C:14]([OH:16])=[O:15])[CH2:5][CH:4]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.[CH3:17][CH2:18]N(CC)CC.O=S(Cl)Cl>C(O)C>[CH2:17]([O:15][C:14]([C:2]1([NH2:1])[CH2:5][CH:4]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:3]1)=[O:16])[CH3:18]
Reactant: CCN(CC)CC
Reactant: NC1(C(=O)O)CC(OCc2ccccc2)C1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1(N)CC(OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a reactor charged with 1-amino-3-benzyloxy-cyclobutanecarboxylic acid (202.7 g, 0.94 mol) was added ethanol (7.0 l); the mixture was stirred at ambient temperature with mechanical stirring under an N2-atmosphere for 18 minutes. To the reaction mixture was added Et3N (350 ml, 2.51 mol), cooled to −1.8° C. and SOCl2 (170 ml, 2.4 mol) was added carefully keeping the reaction temperature <10° C. The reaction mixture was refluxed for 20 hours 10 minutes (reaction progress followed by TLC monitoring). Upon complete reaction the reaction mixture was cooled to 20° C. and evaporated in vacuo at 35° C. The weight of crude product including salts was 631.2 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[CH3:22]O>>[CH3:22][O:15][C:14]([C:12]1[N:11]=[CH:10][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:13]=1)=[O:16]
Reactant: O=C(O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cn(-c2ccc(Cl)c(Cl)c2)cn1
Yield: 81 %

Procedure:
A mixture of 1-(3,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid (7.0 g, 27 mmol), methanol (150 ml) and conc. sulfuric acid (25 ml) was refluxed for 3 h. The solution was then concentrated to 80 ml and a solution of sodium carbonate (60 g) in H2O at 0° C.(500 ml) was added. Extraction with CH2Cl2, drying of the organic phase and evaporation of the solvent gave a brown residue, which upon triturating with ether gave the title compound (6.0 g, 81%) as a light brown solid. MS: m/e=269.9 (M+).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:13][CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2].[C:19]([O-:22])(=[S:21])[CH3:20].[K+]>C(#N)C>[C:19]([S:21][C@@H:11]1[CH2:12][CH2:13][N:9]([C:6]2[S:7][CH:8]=[C:4]([C:1](=[O:3])[NH2:2])[N:5]=2)[CH2:10]1)(=[O:22])[CH3:20]
Reactant: CS(=O)(=O)O[C@H]1CCN(c2nc(C(N)=O)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC#N
Product: CC(=O)S[C@@H]1CCN(c2nc(C(N)=O)cs2)C1
Yield: 89.8 %

Procedure:
To a solution of (3S)-1-(4-carbamoyl-1,3-thiazol-2-yl)-3-methanesulfonyloxypyrrolidine (1.15 g) (obtained as described in Reference Example 20(8)) in acetonitrile (35 ml) was added potassium thioacetate (1.35 g, 11.8 mmol) at room temperature, and the mixture was heated under reflux for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→2% methanol in ethyl acetate as the eluant to afford (3R)-3-acetylthio-1-(4-carbamoyl-1,3-thiazol-2-yl)pyrrolidine (962 mg, yield 90%) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[CH:8][CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:36])=[C:31]([CH2:33][CH2:34]O)[N:32]=2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH2:34][CH2:33][C:31]2[N:32]=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[O:29][C:30]=2[CH3:36])=[CH:8][CH:7]=1
Reactant: COc1ccc(-c2nc(CCO)c(C)o2)cc1
Reactant: COC(=O)C(Cc1ccc(O)c2ccccc12)OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(OC)cc3)oc2C)c2ccccc12)OC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-3-(4-hydroxy-naphthalen-1-yl)-2-methoxy-propionic acid methyl ester was reacted with 2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethanol [J. Med. Chem. (1998), 41(25), 5037-5054] in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-methoxy-3-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-methoxy-3-(4-{2-[2-(4-methoxy-phenyl-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-propionic acid as colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:24]([O:26][CH3:27])=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:29][CH2:30][OH:31]>CN(C=O)C>[CH2:7]([N:14]1[C:22]2[C:17](=[C:18]([O:23][CH2:29][CH2:30][OH:31])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:24]([O:26][CH3:27])=[O:25])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc2c(O)cccc2n1Cc1ccccc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(OCCO)cccc2n1Cc1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Potassium carbonate (0.2 g) was added to a stirred solution of methyl N-benzyl-4-hydroxyindole-2-carboxylate (0.2 g) and 2-Bromoethanol (98 mg) in DMF (15 ml). The reaction was then stirred for 16 hours at 80° C. under an atmosphere of argon. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. Combined organic extracts were washed with water, dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography using 70% ethyl acetate: isohexane as eluent to give the product as a colourless crystalline solid. (64 mg, 27%); NMR d (CD3SOCD3) 3.74-3.82 (m, 5H), 4.10 (m, 2H), 4.88 (m, 1H), 5.80 (s, 2H), 6.58 (m, 1H), 6.98 (d, 2H), 7.09 (m, 1H), 7.14-7.27 (m, 4H), 7.38 (m, 1H); M/z (+) 326 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([N:10]=[S:11]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19][CH3:20])=[O:18])([CH3:13])=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:24]([C:26]1[CH:27]=[C:28]([NH:32][C:33]([C:35]2[N:39]([CH3:40])[N:38]=[C:37]([CH3:41])[CH:36]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1)#[CH:25]>>[CH3:40][N:39]1[C:35]([C:33]([NH:32][C:28]2[CH:27]=[C:26]([C:24]#[C:25][C:2]3[CH:3]=[C:4]([C:8]([N:10]=[S:11]([C:14]4[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=4)[C:17]([O:19][CH3:20])=[O:18])([CH3:13])=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=3)[CH:31]=[CH:30][CH:29]=2)=[O:34])=[CH:36][C:37]([CH3:41])=[N:38]1
Reactant: COC(=O)c1cccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)c1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Product: COC(=O)c1cccc(S(C)(=O)=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4cc(C)nn4C)c3)c2)c1

Procedure:
In a manner similar to that described in Example 460, methyl 3-{N-[(5-bromopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}benzoate and N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide were reacted to give the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:23]=[O:24])(=O)=O>CN(C)C=O>[O:7]([CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:23]=[O:24])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OCc1cc(C=O)ccc1OCc1ccccc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(COc2ccccc2)c1
Yield: 75.5 %

Procedure:
Phenol (100 mg), cesium carbonate (100 mg) and 3-[[(methylsulfonyl)oxy]methyl]-4-phenylmethoxybenzaldehyde (120 mg) were heated in dimethylformamide (1 ml) at approx. 80° C. for about 30 minutes. TLC showed that the reaction was almost complete so the reaction mixture was partitioned between diethyl ether and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give an oil. The residue was purified via flash column chromatography, using dichloromethane:diethyl ether (10:1) as eluant to give 3-[(phenoxy)methyl]-4-phenylmethoxybenzaldehyde (90 mg) as off-white crystals. 1H NMR (CDCl3) δ 9.95 (s, 1H, CHO); 5.27 (s, 2H); 5.24 (s, 2H). TLC (silica gel): Rf=0.7 (petroleum ether: diethyl ether, 1:1).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].O[C@@H]1[C@H:15]2[C@H:16]3[C@H:25]([CH2:26][CH2:27][C@:12]2([CH2:13][CH3:14])[C:11](=[O:29])C1)[C@@H:24]1[C:19](=[CH:20][C:21](=[O:28])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3>N1C=CC=CC=1>[C:5]([O:4][C@@H:1]1[C@H:15]2[C@H:16]3[C@H:25]([CH2:26][CH2:27][C@:12]2([CH2:13][CH3:14])[C:11](=[O:29])[CH2:2]1)[C@@H:24]1[C:19](=[CH:20][C:21](=[O:28])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
200 ml of acetic anhydride is added dropwise to 100 g of 15α-hydroxy-18-methyl-4-estrene-3,17-dione in 350 ml of pyridine. After one hour, the reaction mixture is stirred into ice water. The thus-precipitated product is suctioned off, washed neutral with water, and dried under vacuum at 50° C., thus obtaining 100 g of 15α-acetoxy-18-methyl-4-estrene-3,17-dione. A sample recrystallized from acetone/hexane melts at 165° C.