Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([CH2:9][NH2:8])[CH:15]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(-c2ccnc(CNC(=O)OC(C)(C)C)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccnc(CN)c2)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-[2-(tert-butoxycarbonylamino-methyl)-pyridin-4-yl]-benzoic acid methyl ester (1.96 g, 5.72 mmol, reference example 56) in CH2Cl2 (19 ml) was added TFA (6 ml). The reaction solution was stirred 3 hrs then concentrated under reduced pressure. The residue was purified by trituration with ether. The solids were collected by filtration, washed with ether and dried under vacuum to give 1.68 g of product. MS (EI) m/z 243 (M+H)+.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:23][F:24])[CH:8]=[C:7]([N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=S)[C:6]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:5]=2[O:4]1.CI.[N:27]#[C:28][NH2:29].[H-].[Na+]>C(Cl)Cl.O1CCCC1>[C:28]([N:29]=[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]1[C:7]1[C:6]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:5]=2[O:4][C:3]([CH2:23][F:24])([CH2:2][F:1])[CH:8]=1)#[N:27]
Reactant: N#CN
Reactant: O=[N+]([O-])c1ccc2c(c1)C(n1ccccc1=S)=CC(CF)(CF)O2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CI
Product: N#CN=c1ccccn1C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Yield: 54.3 %

Procedure:
A mixture of 0.09 g of 2,2-bisfluoromethyl-6-nitro-4-(1,2-dihydro-2-thioxo-1-pyridyl)-2H-1-benzopyran, 0.20 g of methyl iodide and 5 ml of tetrahydrofuran was refluxed for 50 minutes. To the mixture were added 57 mg of cyanamide and 13 mg of sodium hydride (60%) and the mixture was refluxed for 1.5 hours. Methylene chloride was added thereto and the mixture was filtered to remove insoluble materials. The mother liquor was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, AcOEt:hexane=1:1) to obtain 0.05 g of 4-(2-cyanoimino-1,2-dihydro-1-pyridyl)-2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran represented by the following formula having a melting point of 238-240° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:12])=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:13]([O:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:14]>>[CH2:13]([O:15][C@@H:16]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:11][CH2:10]/[CH:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)\[CH3:12])=[CH:27][CH:28]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:14]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(I)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(I)cc2)cc1)OCC
Yield: 80.5 %

Procedure:
The title compound (398 mg, 80%) was prepared as a colourless gum, from (E)-3-(4-iodophenyl)-but-2-en-1-ol (example 107a) (275 mg, 1.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (256 mg, 1.07 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:21])[C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OCC[C@@H](O)[C@@H](C1C=CC=CC=1Cl)O)([C:25](C)([CH3:27])[CH3:26])(C)C>>[C:4]([Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[O:13][C:25]([CH3:27])([CH3:26])[O:21]1)([CH3:3])[CH3:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](O)[C@@H](O)c1ccccc1Cl
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H](O)[C@H](O)c1ccccc1Cl
Product: CC1(C)O[C@@H](CCO[Si](C)(C)C(C)(C)C)[C@H](c2ccccc2Cl)O1
Yield: 70 %

Procedure:
The substantially same method as described in Example 351 was conducted, except that (1S,2S)-4-(tert-butyldimethylsilyloxy)-1-(2-chlorophenyl)butane-1,2-diol (Preparation example 353) was used instead of 1R, 2R)-4-(tert-butyldimethylsilyloxy)-1-(2-chlorophenyl)butane-1,2-diol (Preparation example 349), to obtain the title compound (0.7 g, 70˜95%)
Reaction SMILES: [N:1]([CH:4]1[CH2:16][N:7]2[CH2:8][CH2:9][CH2:10][CH:11]([C:12]([O:14]C)=[O:13])[N:6]2[C:5]1=[O:17])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[NH2:1][CH:4]1[CH2:16][N:7]2[CH2:8][CH2:9][CH2:10][CH:11]([C:12]([OH:14])=[O:13])[N:6]2[C:5]1=[O:17]
Reactant: COC(=O)C1CCCN2CC(N=[N+]=[N-])C(=O)N12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: NC1CN2CCCC(C(=O)O)N2C1=O
Yield: 67 %

Procedure:
0.95 g of methyl 2-azido-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (racemate B) and 1.05 g of triphenylphosphine in 20 ml of dioxane were stirred at room temperature for 1 hour and the mixture was then evaporated. The residue was treated with 40 ml of 2N aqueous ammonia at 50° C. for 2.5 hours and the precipitated triphenyl phosphine oxide was removed by filtration. Evaporation then yielded 0.53 g (66%) of 2-amino-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (racemate B) in the form of a white solid which, after recrystallization from aqueous methanol, melted at 228°-230° C. (decomposition).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].Cl>O.C(Cl)(Cl)(Cl)Cl>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:5](=[O:7])[CH3:6])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Yield: 97.3 %

Procedure:
514 grams (3.85 mol) of anhydrous aluminum chloride was put into 2 liters of carbon tetrachloride. While stirring vigorously, 302 grams (3.85 mol) of acetylchloride was added over a period of 1 hour at a temperature below 10° C. Subsequently, 469 grams (3.5 mol) of tert.butylbenzene was added to the reaction mixture over a period of 3 hours at a temperature below 5° C. After stirring for 1 hour without cooling, the reaction mixture was poured into a mixture of 500 milliliters of water, 1.7 kilograms of ice and 150 milliliters of 35% hydrochloric acid. The organic phase was separated, washed to neutrality and dried. After the solvent had been distilled off, 600 grams of 4'-tert.butylacetophenone was obtained having a refractive index nD20 = 1.5212. 444 grams (2.02 mol) of the above-described 4'-tert.butylacetophenone was mixed with 1.25 liters of glacial acetic acid and heated to 60° C. while stirring. Subsequently, at a reaction temperature of about 60° C., 375 grams (5.28 mol) of gaseous chlorine was passed into the reaction mixture for 41/2 hours. After the reaction mixture had been freed from hydrogen chloride gas and the excess of chlorine by passing through nitrogen, 414 grams (5.05 mol) of anhydrous sodium acetate was added and then the reaction mixture was heated to 95° C. Subsequently, another 185 grams (2.60 mol) of gaseous chlorine was passed into the reaction mixture for 2 hours at a temperature of about 95° C. The excess of chlorine was again removed with the aid of nitrogen and then the hot reaction mixture was filtered. After the addition of 63 milliliters of water, the clear filtrate was cooled to room temperature, which caused 2,2,2-trichloro-4'-tert.butylacetophenone to crystallize out. After filtering off by suction, washing and drying, 530 grams of white crystalline final product was obtained, having a melting point of 61.5° - 62.5° C.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:3]=1[CH2:4][N:5]([CH3:16])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[S-2:24].[Na+].[Na+].O>CS(C)=O>[SH:24][C:2]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:3]=1[CH2:4][N:5]([CH3:16])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1Cl)C(=O)OCc1ccccc1
Reactant: [S-2]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(Cc1cc([N+](=O)[O-])ccc1S)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 44.6 %

Procedure:
To a partially dissolved mixture of 6A (7.00 g, 20.91 mmol) in DMSO (40 mL), was added sodium sulfide (3.26 g, 41.8 mmol). The mixture was stirred at 50° C. for 45 min. The reaction mixture was cooled to rt, poured into water (500 mL). The mixture was extracted with EtOAc (3×). The combined organic phase was washed with water and brine, filtered though a pad of SiO2 and concentrated to a red oil. The crude product was purified by flash chromatography (loaded in chloroform onto a 40 g column and eluted with a gradient from 0 to 100% ethyl acetate/hexanes). The desired fractions were collected, concentrated to give 6B (3.10 g, 9.33 mmol, 44.6% yield) as an orange solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.99 (d, J=7.15 Hz, 2H) 7.27-7.48 (m, 6H) 5.20 (br. s., 2H) 4.56 (br. s., 2H) 2.96 (br. s., 3H); MS (ESI) m/z: 333.1 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:23])[C:7]2=1.Cl.[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29]Cl)[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][O:23][C:8]1[C:7]2[C:6]3[C:14](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1)[CH3:26]
Reactant: CCN(CC)CCCl
Reactant: Oc1cccc2c1c1cccc(F)c1n2Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1c1cccc(F)c1n2Cc1ccc(F)cc1
Yield: 74.4 %

Procedure:
8-Fluoro-9-(4-fluorobenzyl)-9H-carbazol-4-ol (0.0226 g, 0.073 mmol), 2-diethylaminoethylchloride hydrochloride (0.0202 g, 0.12 mmol), potassium carbonate (0.0330 g, 0.24 mmol), sodium iodide (0.0018 g, 0.012 mmol) and DMF (1 mL) are heated at 80° C. for 3 h. After the mixture had cooled, it is partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (20 mL) using methanol/dichloromethane (2/98 and 4/96) to give 0.0222 g (74%) of the title compound; mp 59-60° C.; MS (ESI+) for C25H27F2N2O m/z 409.3 (M+H)+; 1H NMR (CDCl3) δ1.21, 2.87, 3.22, 4.45, 5.67, 6.74, 6.94, 7.02, 7.14, 7.39, 8.11. Anal. Calcd for C25H26F2N2O: C, 73.51; H, 6.41; N, 6.86. Found: C, 73.05; H, 6.61; N, 6.83.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N:25]([CH3:49])[CH:26]2[C:30]3[C:31](C)=[C:32]4[C:37](=[CH:38][C:29]=3[CH2:28][CH2:27]2)[N:36]=[C:35]([CH3:39])[N:34](OC(=O)C(C)(C)C)[C:33]4=[O:47])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@@H:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9])=[O:5].[OH-].[Na+]>CO>[F:1][C:2]1[CH:24]=[C:23]([N:25]([CH3:49])[CH:26]2[C:30]3[CH:31]=[C:32]4[C:37](=[CH:38][C:29]=3[CH2:28][CH2:27]2)[N:36]=[C:35]([CH3:39])[NH:34][C:33]4=[O:47])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@@H:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9])=[O:5]
Reactant: Cc1c2c(cc3nc(C)n(OC(=O)C(C)(C)C)c(=O)c13)CCC2N(C)c1ccc(C(=O)N[C@H](C(=O)O)c2ccc(CC(=O)O)cc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2cc3c(cc2c(=O)[nH]1)C(N(C)c1ccc(C(=O)N[C@H](C(=O)O)c2ccc(CC(=O)O)cc2)c(F)c1)CC3
Yield: 92.2 %

Procedure:
A solution of (2S)-2-{o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-3-pivaloyloxy-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzamido}-2-[p-(carboxymethyl)phenyl]acetic acid (0.14 g, 0.2 mmol) in 1 ml of methanol containing 0.6 ml of 1N NaOH was stirred for 90 minutes at room temperature. After dilution with water and filtration the pH was adjusted to 2.5 with 2N HCl . The resulting solid was filtered off, washed with water, dried and triturated with ether to give (2S)-2-{o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzamido}-2-[p-(carboxymethyl)phenyl]acetic acid (0.103 g, 93%) as a white solid, m.p. 196°-200° C.;
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[C:7]([C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=1)=[O:8].C(O)(C(F)(F)F)=O>ClCCl>[CH:3]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[C:7]([C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=1)=[O:8])=[O:2]
Reactant: CCOC(=O)c1cnc(SC)nc1C(=O)c1cccc(C(OC)OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc(SC)nc1C(=O)c1cccc(C=O)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of Example 215A (500 mg, 1.32 mmol) in dichloromethane (20 ml) was added TFA (5 mL). The mixture was stirred at 40° C. overnight. The reaction mixture was concentrated and the crude product was used in the next step without further purification. MS (DCI/NH3) m/z 331 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[C:9]([O:12][CH2:13][CH:14]([O:20][CH2:21]OC(=O)C)[CH2:15][O:16][C:17](=[O:19])[CH3:18])(=[O:11])[CH3:10]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:9]([O:12][CH2:13][CH:14]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:20][CH2:21][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCOC(COC(C)=O)COC(C)=O
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(=O)OCC(COC(C)=O)OCn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.1 %

Procedure:
5.6 g of 2-nitroimidazol, 12.4 g of 1,3-diacetoxy-2-acetoxymethoxypropane and 0.5 g of p-toluenesulfonic acid monohydrate were placed in a flask connected with a trap for reducing pressure by an aspirator. The flask was heated by oil bath of 130°-140° C. under reduced pressure while stirred. Acetic acid was distilled out as the reaction proceeded. In about 15 minutes, the reaction was completed. After cooling down to room temperature, the content was added with about 300 ml ethyl acetate and subjected to extraction. The extract was washed with saturated aqueous sodium hydrogen carbonate, and with water in this order. Then it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by separable high performance liquid chromatography through silica gel columns using a mixture solvent (ethyl acetate - benzene) as an eluate to obtain 13.3 g of the title compound as a viscous oil material (yield: 88.6%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:17](Cl)=[O:18])([O-:13])=[O:12]>C1(C)C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1)[C:17]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)=[O:18])([O-:13])=[O:12]
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: -10 °C
Yield: 84.8 %

Procedure:
A solution of 10.9 g (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 12.6 g (0.055 mole) 3,5-dinitrobenzoyl chloride in 200 ml toluene was refluxed for 20 hours. The crude product precipitated from the reaction mixture upon cooling to -10° C. After isolation by filtration, the residue was washed with hot petroleum ether and finally recrystallized from methylene chloride to give 17.5 g (85% yield) of pure product; m.p. 197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[S:6][C:7]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([OH:10])[C:8](=[CH2:9])[C:4]=2[CH:3]=1.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[S:6][CH2:9][CH:8]([C:7](=[O:10])[CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1
Reactant: C=C1c2cc(Cl)ccc2SC1(O)COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(COc1ccccc1)C1CSc2ccc(Cl)cc21
Yield: 97 %

Procedure:
A solution of 5-chloro-3-methylene-2-phenoxymethyl-2,3-dihydrobenzo[b]-thiophen-2-ol (16.9 g) in dichloromethane (250 ml) was shaken vigorously for a few seconds with 5M aqueous sodium hydroxide solution (150 ml), then the organic solution was separated, washed with water (150 ml), dried (MgSO4), and the solvent removed in vacuo to leave 1-(5-chloro-2,3-dihydrobenzo[b]thiophen-3-yl)-2-phenoxyethanone as a pink solid (16.4 g) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:6]=1.[F:24][C:25]1[CH:26]=[C:27]([C@@H:32]2[O:36][C:35](=[O:37])[NH:34][C@@H:33]2[CH3:38])[CH:28]=[C:29]([F:31])[CH:30]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:34]2[C@H:33]([CH3:38])[C@H:32]([C:27]3[CH:26]=[C:25]([F:24])[CH:30]=[C:29]([F:31])[CH:28]=3)[O:36][C:35]2=[O:37])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@H]1NC(=O)O[C@H]1c1cc(F)cc(F)c1
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3cc(F)cc(F)c3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and (4R,5S)-5-(3,5-difluoro-phenyl)-4-methyl-oxazolidin-2-one.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:22]([C:33]#[N:34])[CH:21]=3)[CH:12]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[C:33]([C:22]1[CH:21]=[C:20]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]3[CH:12]=[C:11]([C:8]4[CH:7]=[CH:6][C:5]([C:4]([OH:35])=[O:3])=[CH:10][CH:9]=4)[O:19][C:18]=23)[CH:25]=[CH:24][C:23]=1[O:26][CH:27]1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)#[N:34]
Reactant: CCOC(=O)c1ccc(-c2cc3nccc(-c4ccc(OC5CCOCC5)c(C#N)c4)c3o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cc(-c2ccnc3cc(-c4ccc(C(=O)O)cc4)oc23)ccc1OC1CCOCC1

Procedure:
A solution of 4-{7-[3-cyano-4-(tetrahydro-pyran-4-yloxy)-phenyl]-furo[3,2-b]pyridin-2-yl}-benzoic acid ethyl ester (1.6 g, 3.42 mmol) in 50 ml ethanol and 1M NaOH (20 mL, 40.0 mmol) is stirred at room temperature for 14 h. Ethanol is removed in vacuum and the mixture acidified with 1M hydrochloric acid. The resulting precipitate is filtered off, washed with water and dried for 16 h; yield: 1.4 g 4-{7-[3-cyano-4-(tetrahydro-pyran-4-yloxy)-phenyl]-furo[3,2-b]pyridin-2-yl}-benzoic acid; HPLC/MS: 2.12 min, [M+H]=441;
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][N:20]=1>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:17][C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[Cl:3])=[CH:21][N:20]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: Oc1ccc(Oc2ccccc2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(COc2ccc(Oc3ccccc3)cc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a solution of 0.09 g of sodium hydride (60% oil dispersion) in 10 ml of N,N-dimethylformamide, there was added dropwise a solution of 0.45 g of 2-chloro-4-phenoxyphenol in 3 ml of N,N-dimethylformamide with stirring and ice-cooling. After 30 minutes, a solution of 0.34 g of 2-chloro-5-chloromethylpyridine in 5 ml of N,N-dimethylformamide was added thereto at room temperature, followed by stirring at the same temperature for 10 hours. The reaction mixture was poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.50 g of 2-chloro-5-(2-chloro-4-phenoxyphenoxy)methylpyridine. Yield, 71%. n22 1.6173 Yield, 71%. nD22 : 1.6173
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[C:34](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH3:34])=[O:22])[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.8 %

Procedure:
A mixture of 3-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionic acid (7.01 g), iodomethane (2.12 ml), potassium carbonate (4.70 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 48 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (6.51 g, yield: 90%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([F:16])[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[NH:24][CH:25]=[C:26]([CH3:27])[C:19]=34)=[C:12]([F:28])[CH:11]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:16][C:14]1[CH:15]=[C:10]([NH:9][C:4]2[CH:3]=[CH:2][N:7]=[C:6]([NH2:8])[N:5]=2)[CH:11]=[C:12]([F:28])[C:13]=1[O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]2[NH:24][CH:25]=[C:26]([CH3:27])[C:19]=12
Reactant: Cc1c[nH]c2nccc(Oc3c(F)cc(Nc4cc(Cl)nc(N)n4)cc3F)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2nccc(Oc3c(F)cc(Nc4ccnc(N)n4)cc3F)c12

Procedure:
50 mg (0.12 mmol) of 6-chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine are dissolved in 10 ml of ethanol. 35 μl (0.25 mmol) of triethylamine and 26 mg (0.02 mmol) of 10% palladium-on-carbon are added, and the mixture is hydrogenated under atmospheric pressure in a hydrogen atmosphere overnight. The mixture is then filtered through Celite®, and the celite is washed with methanol. The solvent is removed under reduced pressure and the crude product is purified by preparative HPLC.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]1[CH2:15][O:14]1)[C:5]([NH2:7])=[O:6].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>S1(CCCC1)(=O)=O>[OH:14][CH:13]([CH2:15][NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([NH2:7])=[O:6])=[CH:3][C:2]=1[I:1]
Reactant: CC(C)(C)N
Reactant: NC(=O)c1ccc(OCC2CO2)c(I)c1
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)NCC(O)COc1ccc(C(N)=O)cc1I
Yield: 102 %

Procedure:
A solution of 3.75 g (0.01 mole) of 3-iodo-4-(oxiranylmethoxy)benzamide and 10.5 ml (0.1 mole) of t-butylamine in 7 ml of sulfolane was heated at 90° C. in an autoclave. After 2 hr the vessel was cooled and the t-butylamine was evaporated in vacuo. The residue was crystallized from CH2Cl2 /CH3CN to give 4.0 g (100% yield) of 4-[2-hydroxy-3-[(1,1-dimethylethyl)amino]propoxy]-3-iodobenzamide as a white crystalline solid, mp 111°-114° C.