Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:18][C:19]([CH3:28])=[C:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][C:21]=23)=[O:16])=[CH:8][C:7]=1[CH3:29].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:12][C:11]1[CH:10]=[C:9]([CH2:13][CH2:14][C:15](=[O:16])[C:17]2[S:18][C:19]([CH3:28])=[C:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][C:21]=23)[CH:8]=[C:7]([CH3:29])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1OCCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of 3-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (170 mg, 0.411 mmol) in DCM (10 mL) and DIPEA (0.15 mL, 0.89 mmol) is added methane sulfonylchloride (0.04 mL, 0.49 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 3-{2,6-dimethyl-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenoxy}-propyl ester (200 mg) as a yellow oil; LC-MS: tR=1.18 min, [M+1]+=493.26.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH:24]1([CH2:27][C:28](O)=[O:29])[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][C:28]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:10][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:12]2)=[O:29])[CH2:26][CH2:25]1
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Reactant: O=C(O)CC1CC1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)CC3CC3)C2)cc1

Procedure:
68 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 22 mg (0.22 mmol, 1.1 eq.) of cyclopropylacetic acid were reacted according to General Method 1.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([CH2:9][CH3:10])([CH3:8])[CH2:6][CH3:7].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:6]([C:5]([CH3:8])([CH2:9][CH3:10])[CH2:4][CH2:3][OH:2])[CH3:7]
Reactant: CCC(C)(CC)CC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(C)(CC)CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 106.2 %

Procedure:
Step C To a solution of 3-ethyl-3-methyl-pentanoic acid methyl ester (1.5 g, 9.4 mmol) in anhydrous tetrahydrofuran (30 mL) at 0° C. was added a tetrahydrofuran solution (2 M) of LiAlH4 (5 mL, 10 mmol) under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HCl solution, brine, dried over MgSO4, and concentrated to give 3-ethyl-3-methyl-pentan-1-ol as a yellow oil (1.3 g, 100%).
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>C1C=CC=CC=1>[CH2:1]([O:17][C:18](=[O:21])[CH:19]=[CH2:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: C=CC(=O)Cl
Solvent: c1ccccc1
Product: C=CC(=O)OCCCCCCCCCCCCCCCC
Temperature: 80 °C

Procedure:
Hexadecanylacrylate was prepared by dissolving 10 g of hexadecanol in 50 ml of benzene. A 1.2 molar excess of acryloylchloride was added to the mixture and refluxed at 80° C. for 24 hours with stirring. The reaction mixture was allowed to cool to room temperature and the solvent was removed by roto-evaporation and room temperature water bath. The product was redissolved and 100 ml of diethyl ether and extracted five times with an equal volume of 10% NaHCO3 in a separatory funnel. The ether fraction was isolated and the solvent was removed by roto-evaporation at room temperature followed by vacuum drying in a room temperature oven. Hexadecanylacrylate is represented by the formula (XI): ##STR13##
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:13][O:12][C:8]1[C:6]2[N:7]=[C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: COc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: COc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-methoxy-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 218°-221° C.) and piperazine.
Reaction SMILES: [F-].[C:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][N:15]=1)[CH:12]=[N+:11]([CH3:16])[C:10]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:9]2=1)(=[O:4])[CH3:3].[BH4-].[Na+]>C1COCC1.CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:9]2[C:8]3[C:13](=[CH:14][N:15]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[CH:7]=3)[CH2:12][N:11]([CH3:16])[C:10]=2[CH:17]=1
Reactant: CC(=O)Nc1cc2c(cn1)c[n+](C)c1cc(Cl)ccc21
Agent: [BH4-]
Agent: [F-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1cc2c(cn1)CN(C)c1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.7 %

Procedure:
To a stirred solution of 2-acetamido-8-chloro-6-methylbenzo[c][2,7]naphthyridin-6-ium fluoride (2.1 g, 2.47 mmol) in a mixture of THF (20 mL) and MeOH (5 mL) at 0° C. was added NaBH4 (0.199 g, 5.27 mmol) in three portions and the reaction was stirred at rt for 45 min. The volatile organics were removed under reduced pressure; saturated ammonium chloride solution (30 mL) was added and the solution extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford N-(8-chloro-6-methyl-5,6-dihydrobenzo[c][2,7]naphthyridin-2-yl)acetamide (0.71 g, 2.29 mmol, 93% yield) as a yellow solid. LC/MS (ESI) m/e 288.2 [(M+H)+, calcd for C15H15ClN3O 288.1]; LC/MS retention time (method C); tR=1.87 min; HPLC retention time (method A): tR=12.76 min; HPLC retention time (method B): tR=13.07 min; 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.36 (s, 1H), 8.16 (d, J=0.40 Hz, 1H), 7.63 (d, J=8.40 Hz, 1H), 6.88 (dd, J=2.00, 8.00 Hz, 1H), 6.82 (d, J=2.00 Hz, 1H), 4.26 (s, 2H), 2.89 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[Cl:8][CH2:9][CH2:10][CH2:11]/[C:12](=[CH:20]\[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]2)=[C:23]([F:33])[CH:22]=1)/[C:13]([O:15]C(C)(C)C)=[O:14]>C(Cl)(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[Cl:8][CH2:9][CH2:10][CH2:11]/[C:12](=[CH:20]\[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]2)=[C:23]([F:33])[CH:22]=1)/[C:13]([OH:15])=[O:14]
Reactant: Cc1cn(-c2ccc(/C=C(\CCCCl)C(=O)OC(C)(C)C)cc2F)cn1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn(-c2ccc(/C=C(\CCCCl)C(=O)O)cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
chloroform (5 mL) and TFA (10 mL) were added to tert-butyl(E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valerate (1.96 g), and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure. The residue was solidified with methylene chloride, ethyl acetate, and heptane and separated by filtration to obtain 2.19 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [H-].[Na+].C(S)C.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17]C)[C:13]([CH3:20])([CH3:19])[CH2:12][CH:11]=[C:10]2[CH3:21].Cl>CN(C=O)C.O>[Br:6][C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:13]([CH3:20])([CH3:19])[CH2:12][CH:11]=[C:10]([CH3:21])[C:9]=2[CH:8]=1
Reactant: COc1cc2c(cc1Br)C(C)=CCC2(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCS
Product: CC1=CCC(C)(C)c2cc(O)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.5 %

Procedure:
To a suspension of sodium hydride 60% w/w (0.12 g, 3.0 mmol) in 10 mL of DMF under the argon atmosphere was added slowly ethanethiol 98% (0.2 mL, 3.0 mmol), and the resulting solution was stirred for 15 min. A solution 6-bromo-7-methoxy-1,1,4-trimethyl-1,2-dihydronaphthalene (Compound 93, 0.24 g, 0.84 mmol) in 2 mL of DMF was added, and the reaction mixture was refluxed for 4 h, then cooled to room temperature, acidified with 2 N HCl, diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, and filtered. The solvent was removed to afford 0.23 g (100%) of the title compound as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(O)=O)[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1.[F:47][C:48]([F:75])([C:65]([F:74])([F:73])[C:66]([F:72])([F:71])[C:67]([F:70])([F:69])[F:68])[CH2:49][CH2:50][CH2:51][CH:52]([CH2:58]CCCCC=C)[C:53]([O:55]CC)=[O:54]>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:58][CH:52]([CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:75])[C:65]([F:73])([F:74])[C:66]([F:71])([F:72])[C:67]([F:70])([F:68])[F:69])[C:53]([OH:55])=[O:54])[C:7]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: C=CCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 13 and the ethyl 2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-8-nonenoate prepared in Example 4, a procedure analogous to that as shown in Example 13 was repeated to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)decanoic acid.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CCCCCC>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Yield: 98.6 %

Procedure:
In a 1000 ml three-neck flask with thermometer, reflux condenser, 50 ml dropping funnel, mechanical stirrer, bubble counter, exhaust pipe and oil bath 0.5 ml of dimethylformamide were added with stirring to a suspension of 97.05 g of 2,3,4,5-tetrafluorbenzoic acid (8; 0.5 mol) in 100 ml of n-hexane. In the course of 10 min. 44 ml of thionyl chloride (0.61 mol) were added, and the reaction mixture was heated for 17 hours at reflux temperature. After cooling to room temperature, the n-hexane was evaporated off at 55° C. and increasing vacuum for 30 min. (at the end 3 min. at 55° C./40 torr). 104.8 g of 2,3,4,5-tetrafluoro-benzoic acid chloride (9) were obtained as a yellow, clear liquid, which was directly used in the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10](C(OC)=O)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C(O)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1C(=O)CCN(Cc2ccccc2)C1=O
Agent: O=C(O)C(=O)O
Product: O=C1CCN(Cc2ccccc2)C(=O)C1
Temperature: 25 °C
Yield: 27.4 %

Procedure:
A mixture of 23.4 gm (89.7 mMol) methyl 1-benzyl-2,4-dioxo-3-piperidinecarboxylate in 200 mL 10% aqueous oxalic acid was stirred at reflux for 15 hours. The reaction mixture was cooled to room temperature and the solution extracted with 3×200 mL dichloromethane. The organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure to provide 4.99 gm (27%) of the desired compound.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][CH2:21][CH2:22][F:23].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:23][CH2:22][CH2:21][CH2:20][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: FCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)(CCCF)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 39.4 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.0 g of 1-bromo-3-fluoropropane were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 10 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.67 g of 2-(3-fluoropropyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (74)).
Reaction SMILES: O[C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C1OC1CO.B(F)(F)F.CCOCC.OCC(CO)O>CS(C)=O>[C:8]([OH:10])(=[O:9])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: FB(F)F
Agent: OCC1CO1
Solvent: CCOCC
Solvent: OCC(O)CO
Solvent: CS(C)=O
Product: O=C(O)C=Cc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
8.719 g of p-hydroxy cinnamic acid was dissolved in 10 ml of DMSO, and 19.7 g of glycidol was added. The mixture was stirred and heated to 90° C. Catalystic amount of boron trifluoride ethyl ether was added, heating and agitation was carried out for 2 hours and then the adduct of cinnamic acid and glycerin was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([OH:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4].[Br:22]N1C(=O)CCC1=O>ClCCl.C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([Br:22])=[C:9]([OH:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)nc(-c2ccc(Cl)c(OC)c2F)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(O)c1Br
Yield: 63.8 %

Procedure:
6-Hydroxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester(150 mg, 0.48 mmol) was combined with N-bromosuccinimide (180 mg, 1.0 mmol) in 7 mL dichloromethane plus 2 mL acetonitrile and heated to reflux for 2 hours. After cooling the volatiles were removed under vacuum and the residue was taken up in 15 mL dichloromethane plus 5 mL water. The organic phase was separated and washed with 10 mL 5% sodium bisulfite solution, washed with 10 mL brine, dried and evaporated to give 120 mg (63% yield) of 6-hydroxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-bromopyrimidine-4-carboxylic acid methyl ester: mp 192-195° C.; MS m/z 390/392; 1H NMR (DMSO-d6): δ 7.47 (m, 3H), 3.95 (d, 3H), 3.91 (s, 3H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.N#N.Cl.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([NH:37][C@H:38]([C:46](Cl)=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44])(=[O:36])=[O:35])[CH:28]=[CH:27]2>C(Cl)(Cl)Cl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([NH:37][C@H:38]([C:46]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45])(=[O:36])=[O:35])[CH:28]=[CH:27]2
Reactant: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)ccc2c1
Reactant: CCOC(=O)C1CCCCN1
Agent: Cl
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCCN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2.2 g of ethyl 2-piperidinecarboxylate and 4.1 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N2 -(6-methoxy-2-naphthalenesulfonyl)-L-arginyl chloride hydrochloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 500 ml of chloroform was added and the chloroform solution was washed twice with 50 ml of saturated sodium chloride solution, dried over Na2SO4 and evaporated in vacuo. The oily residue was washed with ether to give 2.9 g of powdery ethyl 1-[N2 -(6-methoxy-2-naphthalenesulfonyl)-L-arginyl]-2-piperidinecarboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[NH:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:19]=[O:20])[C:13]=2[CH:12]=[CH:11]1>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]1[NH:10][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:19]=[O:20])[C:13]=2[CH:12]=1
Reactant: BrCc1ccccc1Br
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2[nH]c(Cc3ccccc3Br)cc12
Yield: 96.6 %

Procedure:
The same procedures used in Example 1 were repeated except for using 3.78 g of o-bromobenzyl bromide and 2.00 g of indole-4-carbaldehyde as a starting material to give 4.18 g of (2-bromobenzyl) indole-4-carbaldehyde as pale yellow crystals. The yield thereof was found to be 97%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1.N>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: Cc1ccc(Br)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: N
Solvent: ClCCl
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5 -Bromo-2 -methyl-pyridine (71.35 g. 0.41 M) in dichloromethane (350 ml) was added a solution of m-chloroperbenzoic acid (78.83 g, 0.46 M) in dichloromethane (1100 ml), over a period of 2.5 hours. The reaction mixture was stirred at ambient temperature for a further 20 hours, cooled (ice/salt bath) and anhydrous ammonia bubbled into it for 1 hour during which time a white precipitate formed and the temperature of the solution was not allowed to rise above 151°. The reaction mixture was allowed to warm to room temperature, filtered and washed with dichloromethane. The filtrate and washings were combined and washed with Na2SO3 (5 %) solution (2×200 ml), water (2×150 ml), dried (phase separating paper) and evaporated to dryness in vacuo to give an off white solid. Recrystallisation from ethyl acetate gave 5 -bromo-2 -methylpyridine-N-oxide as white crystals, 65.66 g. 84 %. m.p. 116°-118°.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:25]([CH3:26])[CH2:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[N:7]=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43]([NH:46][CH3:47])(=[O:45])=[O:44].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][O:21][C:10]1[CH:11]=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[N:7]=[C:2]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[S:43]([NH:46][CH3:47])(=[O:45])=[O:44])[C:3]2[CH:25]([CH3:26])[CH2:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:4]=2[N:5]=1
Reactant: CNS(=O)(=O)c1ccccc1N
Reactant: COc1ccc(CN2CC(C)c3c(Cl)nc(Nc4ccc(N5CCOCC5)cc4OC)nc32)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(N3CCOCC3)cc2OC)nc2c1C(C)CN2Cc1ccc(OC)cc1
Temperature: 130 °C
Yield: 91.4 %

Procedure:
According to General Protocol II, (±)-2-(2-(2-methoxy-4-morpholinophenylamino)-7-(4-methoxybenzyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidin-4-ylamino)-N-methylbenzenesulfonamide was prepared from (±)-4-chloro-N-(2-methoxy-4-morpholinophenyl)-7-(4-methoxybenzyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-amine (80 mg, 0.161 mmol), 2-amino-N-methylbenzenesulfonamide (Intermediate C4, 36 mg, 0.194 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), (±)-BINAP (20 mg, 0.032 mmol) and cesium carbonate (105 mg, 0.322 mmol) heated at 130° C. in a sealed tube for 12 hours, and isolated as a solid (95 mg, yield 91%). 1H NMR (400 MHz, CDCl3) δ ppm 8.32-8.38 (dd, 2H, J=8.4 Hz, 15.2 Hz), 8.00 (s, 1H), 7.85-7.87 (dd, 1H, J=1.6 Hz, 8.0 Hz), 7.50-7.54 (m, 1H), 7.22-7.27 (m, 3H), 7.07-7.10 (t, 1H, J=8.0 Hz), 6.86-6.88 (m, 2H), 6.52-6.53 (d, 1H, J=2.4 Hz), 6.40-6.43 (dd, 1H, J=1.2 Hz, 8.8 Hz), 4.49-4.60 (m, 2H), 4.44-4.46 (m, 1H), 3.87-3.89 (m, 7H), 3.81 (s, 3H), 3.54-3.59 (m, 1H), 3.27-3.28 (m, 1H), 3.09-3.11 (t, 4H, J=4.4 Hz), 2.99-3.02 (dd, 1H, J=4.0 Hz, 9.6 Hz 2.59-2.61 (d, 3H, J=5.6 Hz), 1.22-1.28 (m, 3H).
Reaction SMILES: [Mg].[C:2]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1[CH2:19][CH2:18][CH2:17]C1>>[CH:17]1([C:2]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:9])[CH2:18][CH2:19]1
Reactant: C1CCOC1
Reactant: O=C(c1ccccc1)c1ccco1
Agent: [Mg]
Product: OC(c1ccccc1)(c1ccco1)C1CC1

Procedure:
To a suspension of magnesium turnings (0.26 g, 10.5 mmol) in anhydrous tetrahydrofuran (6 ml) cyclopropyl bromide (1.28 g, 10.5 mmol) in tetrahydrofuran (5 ml) was added dropwise under nitrogen. The reaction mixture was heated at reflux for 1 h after the initial exotherm had subsided before 2-benzoylfuran (12 g, 7.0 mmol) was added as a solution in tetrahydrofuran (10 ml). The reaction mixture was worked up as described in Example 1 to give the title alcohol as an oil. T.l.c. rf=0.23 (SiO2, heptane/THF (7:3)).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:10][O-:11].[Na+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[C:1]1[CH2:2][CH2:3][O:4][C:10]1=[O:11]
Reactant: O=Cc1ccccc1O
Reactant: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1OCCC1=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 142 %

Procedure:
Salicylaldehyde (293 g) and Υ-butyrolactone (413 g) were dissolved in toluene (2.4 L) and the solution was cooled to not more than 3° C. in an ice-salt bath. Thereto was added sodium methoxide (324 g) over 20 min. The temperature of the reaction mixture rose to 24° C. After stirring at room temperature for 3 hr, the mixture was stirred for 45 min under heating at 60-65° C. The reaction mixture was cooled again in an ice-bath and 10% sulfuric acid (2.51 ml) was added dropwise. The obtained white suspension was filtrated, washed with water and dried to give the title compound (324 g), melting point 162-164° C.