Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]>ClCCl>[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[I:1])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]
Reactant: Nc1ccccc1I
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C(=CNc1ccccc1I)C(=O)OCC
Temperature: 110 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
2-Iodoaniline (50 g, 228.3 mmol) and 2-ethoxymethylene-malonic acid diethyl ester (50 mL, 251.1 mmol) were mixed and the solution was stirred at 110° C. for 3 h. The crude was dissolved in dichloromethane and it was purified by silica plug. The product was eluted with ethyl acetate/hexanes (10-50%) and the solvent removed under reduced pressure to afford 2-[(2-iodo-phenylamino)-methylene]-malonic acid diethyl ester as an off-white powder (81.4 g, 91.6%). 1H NMR (CDCl3, 400 MHz) δ 1.49 (t, 3H), 1.54 (t, 3H), 4.40 (q, 2H), 4.52 (q, 2H), 7.01-7.05 (m, 1H), 7.36-7.39 (m, 1H), 7.52-7.56 (m, 1H), 8.59 (d, 1H). Exact mass calculated for C14H16INO4 389.01, found 390.1 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O>[CH3:12][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: OCCCc1ccc(O)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(CCCO)cc1
Temperature: 65 °C
Yield: 95.1 %

Procedure:
2.26 g (14.87 mmoles) of 3-(4-hydroxyphenyl)-1-propanol were dissolved in dry acetone (20 ml) and potassium carbonate (2.05 g, 14.87 mmoles) was added, followed by methyl iodide (MeI) (2.11 g, 14.87 mmoles). The mixture was kept at reflux in a water bath at 60-70° C. for 48 h. After that period of time, it was diluted with water and the acetone was removed at reduced pressure. Extraction was performed with diethyl ether, and the result was washed with water, dried over sodium sulphate, filtered and the solvent was evaporated in a vacuum to give an oil (2.35 g) (94.93% yield) of 3-(4-methoxyphenyl)-1-propanol.
Reaction SMILES: C(OC(=O)[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:8])(C)(C)C.[C:17](=[O:20])([O-])[O-:18].[K+].[K+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C.CCOC(C)=O>[C:9]([O:18][C:17](=[O:20])[CH2:8][CH2:7][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:13][CH:14]=1)([CH3:14])([CH3:10])[CH3:7]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CBr
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(CCC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of -(4-Hydroxy-phenyl)-propionic acid tert-butyl ester (1 g, 4.50 mmol) in dry DMF (20 ml) at room temperature under argon is added potassium carbonate (0.62 g, 4.50 mmol) followed by methyl bromoacetate (0.43 ml, 4.50 mmol) and the reaction mixture is stirred at room temperature. The reaction mixture is diluted with EtOAc and washed with water, dried (MgSO4) and evaporated in vacuo to yield a clear colourless liquid. Purification on a Waters 3000 prep HPLC system (C18, MeCN/water) yields 3-(4-Methoxycarbonylmethoxy-phenyl)-propionic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8]C)=[N:6][CH:7]=1.CC(O)=O.Br>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:17]3[N:16]=2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3OC)nc12
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Temperature: 90 °C
Yield: 75.6 %

Procedure:
To a mixture of (R)-ethyl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1.0 g, 2.60 mmol, Preparation K, Step A) and AcOH (7.44 mL, 130 mmol) was added HBr (4.76 mL, 33 wt % in acetic acid, 26 mmol) at ambient temperature. The reaction mixture was heated at 90° C. for 2 hours. After cooling, the reaction mixture was diluted with EtOAc, washed with water, saturated NaHCO3, and brine, dried with MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography, eluting with 2-3% MeOH/DCM to yield the title product (0.73 g, 76%). MS (apci) m/z=372.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Al+3].[Cl-].[Cl-].[Cl-].[Br:16]Br>CCOCC>[Br:16][CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:11]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1ccc(Cl)cc1Cl
Temperature: 0 °C

Procedure:
25 g (0.1322 mol) of 2′,4′-dichloroacetophenone was placed in a three-neck round bottom flask equipped with a magnetic stir bar, reflux condenser, and dropping funnel. Anhydrous ether (30 mL) and AlCl3 (0.20 g) were added. The solution was stoppered and cooled to 0° C. in an ice bath. Br2 (21.13 g, 0.1322 mol) was added dropwise (at a rate of approximately 0.5 mL/min). After addition of Br2 was complete, HBr and the solvent were removed under reduced pressure. The remaining HBr was removed by blowing a stream of nitrogen over the orange oily product. The resulting oil was placed under high vacuum until all the bubbling had ceased. The product was obtained as a viscous orange oil, which solidified upon standing in the refrigerator. Yield: 35.72 g (100%); TLC: 95% Hexanes/5% Acetone, Rf=0.35.
Reaction SMILES: [CH2:1](N(C(C)C)C(C)C)C.C[C:11]1[O:12][C:13](=[O:28])[C:14](=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[N:15]=1.[CH3:29][OH:30]>[C].[Pd]>[C:29]([NH:15][CH:14]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=1)[C:13]([O:12][CH3:11])=[O:28])(=[O:30])[CH3:1]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1=NC(=Cc2ccc(OC(F)(F)F)cc2)C(=O)O1
Reactant: CO
Agent: [Pd]
Product: COC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(C)=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
N-Ethyl-N,N-diisopropylamine (2.50 g, 19.4 mmol) was added to a methanol (50 mL) solution of 2-methyl-4-[4-(trifluoromethoxy)benzylidene]-1,3-oxazol-5(4H)-one (5.00 g, 18.4 mmol) prepared in Reference Example 3 (3d), at room temperature. The mixture was stirred at 60° C. for 4 hours. The reaction solution was cooled to room temperature, and then 10% palladium-carbon (wet, 2.2 g) was added thereto. The resulting mixture was stirred under a hydrogen atmosphere (rubber balloon) at room temperature for 2 hours. The reaction solution was filtered, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate, 1:1 and 4:5, V/V) to give 4.56 g of the title compound (light yellow crystal, yield: 81%).
Reaction SMILES: [CH3:1][C:2]1[C:20]([CH3:21])=[C:19]([N+:22]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[CH:6]=1.CO.[H][H]>[Pt].CC(O)=O>[NH2:22][C:19]1[CH:18]=[CH:17][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[CH:6]=2)=[C:2]([CH3:1])[C:20]=1[CH3:21]
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c(C)c2C)ccn1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: COCC(=O)Nc1cc(Oc2ccc(N)c(C)c2C)ccn1

Procedure:
A solution of N-(4-(2,3-dimethyl-4-nitrophenoxy)pyridin-2-yl)-2-methoxyacetamide (90 mg, 0.272 mmol) in a mixture MeOH (30 mL) and AcOH (2.0 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 50° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo to afford the title compound, Intermediate H5, (82 mg, 100%); Rt 1.21 min (Method 2); m/z 302 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:21])=[C:18]([NH2:20])[CH:19]=3)(=[O:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:21][C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)(=[O:13])=[O:12])=[CH:19][C:18]=1[NH:20][CH:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)c2c[nH]c3cc(Cl)ccc23)cc1N
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)c2c[nH]c3cc(Cl)ccc23)cc1NC1CCN(C)CC1
Temperature: 30 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
5-(6-Chloro-1H-indole-3-yl sulfonyl)-2-methyl phenyl amine [obtained from preparation 1, Step (v)](600 mg, 1.87 mmol) was added to a 100 mL three necked round bottomed flask, followed by the addition of 1-methyl-4-piperidone (423 mg, 3.74 mmol), sodium sulfate (2.6 grams, 18.7 mmol) and acetic acid (12 mL). The reaction mass was stirred for 4 hours at room temperature (30° C.). Then sodium tri acetoxy borohydride (1.18 grams, 5.61 mmol) was added to the reaction mass at 20-25° C. in 5 minutes. This reaction mixture was further stirred over night at room temperature. The reaction mixture was then quenched into 100 mL water, basified to pH 9 with 50% aqueous sodium hydroxide solution under cooling (10° C.) and extracted the product with ethylacetate (4×50 mL). The combined organic layer was washed with saturated brine solution (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain oily mass. The technical product was further purified by column chromatography using ethylacetate and methanol as an eluents to obtain 0.31 grams of the title product.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[CH3:16][N:17]([CH2:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)[CH3:18].[H-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:18][N:17]([CH2:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:3][CH:2]([OH:1])[CH2:4][N:5]1[C:6](=[O:15])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]1=[O:14])[CH3:16]
Reactant: CN(C)Cc1cccc(O)c1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)Cc1cccc(OCC(O)CN2C(=O)c3ccccc3C2=O)c1
Yield: 39.5 %

Procedure:
A solution of 2-(oxiranylmethyl)-1H-isoindole-1,3-(2H)-dione (20.3 g) and 3-(dimethylaminomethyl)phenol (22.3 g) in dimethylformamide (200 ml) with a catalytic amount of sodium hydride (0.2 g) was heated for 6 h at 100° under N2. The solvent was evaporated to give an oil which was dissolved in chloroform and washed with 2N sodium hydroxide and water. The organic solution was evaporated to give an oil (14 g). A portion of the oil (0.8 g) was distilled to give the title compound (0.6 g) as an oil, b.p. 250° (0.08 mmHg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:8][CH:14]=1
Reactant: NC(=O)c1ccc(Cl)s1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2ccc(Cl)s2)n1
Yield: 51 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-chloro-2-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(5-chloro-2-thienyl)oxazole. The yield was 51%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 90-91° C.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[C:7]([Cl:13])[CH:6]=1.[OH-].[Na+].S(O)(O[CH2:21][CH2:22][NH2:23])(=O)=O.C1(C)C=CC=CC=1>CO.O>[Cl:13][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[S:11][CH3:12])[CH2:4][C@H:3]1[O:14][CH2:21][CH2:22][NH:23][CH2:2]1
Reactant: NCCOS(=O)(=O)O
Reactant: CSc1ccc(C[C@@H](O)CCl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CSc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 38 %

Procedure:
The solution of 0.4 g (1.6 mmol) (R)-1-chloro-3-(3-chloro-4-methylsulfanyl-phenyl)-propan-2-ol in 1.4 mL methanol was treated with a solution of 0.39 g (1.0 mmol) sodium hydroxide in 0.7 mL water and 0.92 g (6.5 mmol) 2-aminoethyl hydrogen sulfate. The reaction was warmed to 45° C. and stirred for 2.5 h. After the addition of 0.42 g (10.5 mmol) solid sodium hydroxide and 7 mL toluene the reaction temperature was raised to 65° C. After 4 h the reaction mixture was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed using MPLC and dichloromethane: methanol: ammonia (9:1:0.1 v/v) as eluant to give the compound as a light brown oil (38%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Br:12][CH2:13][CH2:14][C:15]([C:9]1[CH:10]=[CH:11][C:6]([Br:5])=[CH:7][CH:8]=1)=[O:16]
Reactant: O=C(Cl)CCBr
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCBr)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
AlCl3 (23.8 g, 178 mmol) was added by portions to bromobenzene (155 ml, 1.47 mol) at 0° C. 3-Bromopropionyl chloride (25 g, 146 mmol) was added dropwise to the red solution kept at 0° C. over 30 min. After 1 h at RT, the reaction mixture was heated to 50° C. for 1 h. After cooling, the mixture was poured over ice/water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to yield 3-bromo-1-(4-bromophenyl)propan-1-one (36 g) which was crystallized from petroleum ether (mp=66° C.). 1H NMR (CDCl3): 7.82 (2H, d, J=8.5 Hz), 7.62 (2H, d, J=8.5 Hz), 3.73 (2H, t, J=6.5 Hz), 3.55 (2H, t, J=6.5 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[Br:17]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Br:17][C:10]1[CH:9]=[CH:8][C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCOc1ccccc1OCCOC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1ccc(Br)cc1OCCOC
Yield: 99.6 %

Procedure:
1,2-Bis(2-methoxyethoxy)benzene (8.1 g, 31.9 mmol) and N-bromosuccinimide (6.2 g, 35 mmol) were stirred in 50 mL DMF at room temperature overnight. The reaction was diluted with 200 mL EtOAc and washed with 1N NaOH and water. The organic layer was dried over magnesium sulfate and concentrated to give 9.7 g (92%) of 4-bromo-1,2-bis(2-methoxyethoxy)benzene.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([Cl:19])[N:11]=1)[CH:7]([CH3:9])[CH3:8])C.[H][H]>C1COCC1.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.O=[V]>[Cl:19][C:12]1[N:13]=[CH:14][C:15]2[NH:16][C:4](=[O:3])[CH2:5][N:6]([CH:7]([CH3:9])[CH3:8])[C:10]=2[N:11]=1
Reactant: CCOC(=O)CN(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Reactant: [H][H]
Agent: O=[V]
Agent: CC(=O)/C=C(/C)O
Solvent: C1CCOC1
Product: CC(C)N1CC(=O)Nc2cnc(Cl)nc21
Yield: 87 %

Procedure:
A suspension of [(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]-acetic acid ethyl ester (40 g; 0.132 mol), Pt/C5% (2 g) and vanadylacetylacetonate (2 g; 0.754 mmol) in THF (50 ml) was treated with hydrogen (5 bar) overnight. The reaction mixture was warmed (in order to solubilize the precipitate formed) and filtered on a celite pad, then concentrated in vacuo. The crude was diluted in ethyl acetate and the organic phase was washed with NaOH 10% solution, dried with MgSO4 and concentrated in vacuo. 28 g (0.115 mol; 87% yield) of solid material were obtained.
Reaction SMILES: [CH:1]([N:4]([CH:20]([CH3:22])[CH3:21])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:24][NH:25][C:26]([NH2:28])=[O:27]>>[CH:1]([N:4]([CH:20]([CH3:22])[CH3:21])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)/[C:10](=[N:24]\[NH:25][C:26]([NH2:28])=[O:27])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: NNC(N)=O
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Agent: Cl
Product: COc1ccc2c(c1)/C(=N\NC(N)=O)C(=O)N2CCN(C(C)C)C(C)C
Yield: 84 %

Procedure:
By using 1-(2-diisopropylaminoethyl)-5-methoxyisatin and semicarbazide hydrochloride, a method analogous to that described in Example 6 was carried out to obtain (E)-1-(2-diisopropylaminoethyl)-5-methoxyisatin 3-semicarbazone having a melting point of 157°-159° C. (yield: 84.0%, recrystallizing solvent: ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH2:20])=[O:19])[CH:8]=1)=[O:5].Cl[C:35]1[N:40]=[C:39]([NH2:41])[CH:38]=[CH:37][C:36]=1[F:42].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[NH2:41][C:39]1[N:40]=[C:35]([C:22]2[CH:23]=[CH:24][C:2]([Cl:1])=[C:3]([CH:21]=2)[C:4]([NH:6][C:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=[C:9]([C:18]([NH2:20])=[O:19])[CH:8]=2)=[O:5])[C:36]([F:42])=[CH:37][CH:38]=1
Reactant: Nc1ccc(F)c(Cl)n1
Reactant: CC1(C)OB(c2ccc(Cl)c(C(=O)Nc3cc(C(N)=O)nn3-c3ccccc3)c2)OC1(C)C
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(NC(=O)c2cc(-c3nc(N)ccc3F)ccc2Cl)n(-c2ccccc2)n1

Procedure:
A solution of 5-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxamide (Preparation 3, 50 mg, 0.11 mmol), 6-chloro-5-fluoropyridin-2-amine (47 mg, 0.32 mmol), tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol) and potassium carbonate (30 mg, 0.21 mmol) in dioxane (1.5 mL) and water (1.5 mL) was heated at 110° C. under microwave irradiation for 1 hour. The reaction was poured into water (25 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with brine (10 mL), dried over magnesium sulphate and concentrated in vacuo.
Reaction SMILES: C([C@@]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9]C1=CC(=O)CC2)C.[C:23]1(Cl)C(=O)C(Cl)=C(Cl)C(=O)[C:24]=1Cl.[C:35]1([CH3:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:41]=[C:35]1[CH2:40][CH2:39][C@@:38]2([CH2:23][CH3:24])[C:37]([CH:9]=[CH:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:21])=[CH:36]1
Reactant: Cc1ccccc1
Reactant: CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Product: C=C1C=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(CC)CC1

Procedure:
290 mg of 10β-ethyl-estra-4-ene-3,17-dione and 594 mg of chloranil are taken up in 15 ml of toluene. The mixture is refluxed for 20 hours in an atmosphere of nitrogen. The solvent is washed with several small portions of 5% sodium hydroxide and then with water. It is dried over anhydrous sodium sulfate for several hours. The solution is filtered and the solvent removed under vacuum. The amorphous solid obtained is triturated with ether, filtered and purified by chromatography over silica gel using a n-hexane-ethyl acetate solvent.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C=[O:12].[CH2:13]([Cl:15])Cl>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:12][CH2:13][Cl:15])=[O:7])=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C=O
Agent: [Zr+4]
Agent: [Cl-]
Product: O=C(OCCl)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(Mudryk, B. et al., Tetrahedron Lett. 2002, 43, 6317-6318) 4-Fluorobenzoyl chloride (3.0 g, 18.9 mmol) was added to a stirred suspension of zirconium tetrachloride (4.0 g, 17.01 mmol) in dry CH2Cl2 (40 mL) at room temperature. After 15 min, the reaction mixture was cooled to 0° C. and paraformaldehyde (0.68 g, 22.7 mmol) was added. The slurry was stirred at 0-25° C. for 2 h and the solvent was removed under vacuum. Water (50 mL) was added slowly and the mixture was agitated for 10 min. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic phase was washed with 1 N sodium bicarbonate (2×50 mL) followed by brine (1×30 mL). The solvent was removed and the product was purified by silica gel chromatography (5% EtOAc-Hexanes). Yield 3.2 g (89%). 1H NMR (500 MHz, CDCl3): δ 5.86 (s, 2H), 7.06 (m, 2H), 8.02 (m, 2H).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17].[C@H:19]1([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:39])[CH:35]=3)[N:30]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][C:1]([NH:39][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([NH:28][C@H:19]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20]1)[CH:38]=[CH:37]2)=[O:12]
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CN(C)CCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CN(C)CCNC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 2-dimethylamino-ethylamine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=390.5 (M+H+).
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:17]([CH3:19])[CH3:18]>C(#N)C>[CH3:18][CH:17]([N:1]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=[N:2]1)[CH3:19]
Reactant: COC(=O)c1ccn[nH]1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccnn1C(C)C
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 1H-pyrazole-5-carboxylate (0.6 g) (available from Fluorochem), in acetonitrile (50 ml) was added cesium carbonate (1.55 g) followed by 2-iodopropane (0.476 ml) and the mixture stirred at 20° C. for 18 h. The solvent was removed in vacuo and the residue was partitioned between water (20 ml) and DCM (20 ml) and separated by hydrophobic frit. Purification by chromatography on silica gel (50 g silica), eluting with a gradient of 0-100% ethyl acetate in cyclohexane gave methyl 1-(1-methylethyl)-1H-pyrazole-5-carboxylate (0.24 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](O)[CH2:10][CH3:11])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.P(Br)(Br)([Br:24])=O>C(OCC)(=O)C>[Br:24][CH:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)[CH2:10][CH3:11]
Reactant: CCC(O)c1cnc(Cl)nc1Cl
Reactant: O=P(Br)(Br)Br
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(Br)c1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (±)-1-(2,4-dichloro-pyrimidin-5-yl)-propan-1-ol (0.26 g; 1.26 mmol) (from Example 7a supra) in diisopropylethylamine (0.55 mL; 3.13 mmol) (Aldrich) was cooled slightly (18° C.) to help offset the exothermicity of the reaction. Neat phosphorus oxybromide (0.35 g; 1.36 mmol) (Aldrich) was added in one portion. The cooling bath was removed and reaction mixture stirred at room temperature. After 15 minutes, the reaction mixture was diluted with ice and ethyl acetate. The organic phase was then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 12M; 5:95 ethyl acetate-hexanes) gave crude (±)-5-(1-bromopropyl)-2,4-dichloro-pyrimidine which was used in subsequent steps without further purification. (Yield 0.23 g). The material showed 3 peaks for the pyrimidine ring proton in its NMR spectrum indicating some displacement of the ring chlorines with bromine.