Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.[NH3:12]>C(O)C>[NH2:12][C:8]1[CH:9]=[C:2]([Br:1])[CH:3]=[C:4]([F:11])[C:5]=1[C:6]#[N:7]
Reactant: N
Reactant: N#Cc1c(F)cc(Br)cc1F
Solvent: CCO
Product: N#Cc1c(N)cc(Br)cc1F
Temperature: 90 °C

Procedure:
5.0 g (22.9 mmol) 4-bromo-2,6-difluorobenzonitrile are dissolved in 200 ml of a solution of NH3 in ethanol and heated in a pressure vessel to 90° C. for 20 h. After cooling to RT the solvent is evaporated and the residual taken in up in water/DCM. The organic phase is separated, dried and evaporated.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:6][C:7]([N:10]([CH3:14])[C:11](Cl)=[O:12])=[N:8][N:9]=1)(=[O:4])=[O:3].[O:15]1[CH2:20][CH2:19][CH2:18][O:17][CH:16]1[CH2:21][NH2:22].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][S:2]([C:5]1[S:6][C:7]([N:10]([CH3:14])[C:11]([NH:22][CH2:21][CH:16]2[O:17][CH2:18][CH2:19][CH2:20][O:15]2)=[O:12])=[N:8][N:9]=1)(=[O:4])=[O:3]
Reactant: CN(C(=O)Cl)c1nnc(S(C)(=O)=O)s1
Reactant: NCC1OCCCO1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C(=O)NCC1OCCCO1)c1nnc(S(C)(=O)=O)s1
Temperature: 25 °C

Procedure:
N-(2-Methylsulfonyl-1,3,4-thiadiazol-5-yl)-N-methylcarbamoyl chloride (0.05 mole), N-(1,3-dioxan-2-ylmethyl)amine (0.05 mole), triethylamine (0.07 mole) and benzene (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 4 hours. After this time the mixture is cooled to room temperature and is filtered. The filtrate is washed with water and is dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure to yield the desired product N-(2-methylsulfonyl-1,3,4-thiadiazol-5-yl)-N-methyl-N'-(1,3-dioxan-2-ylmethyl)urea.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1>[Zn]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: CN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Product: CN(C)CCN(C)c1ccc(N)cc1

Procedure:
The compound was prepared by zinc dust reduction of N,N,N′-trimethyl-N′-(4-nitrophenyl)ethane-1,2-diamine in analogy to the method in example 3. The product with the molecular weight of 193.29 (C11H19N3); MS (ESI): 194 ([M+H]+), was obtained in this way.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([Cl:29])=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[Cl:21][C:22]1[N:27]=[C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)[C:25]([Cl:29])=[CH:24][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Nc3nc(Cl)ncc3Cl)cc2)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (100 mg, 0.36 mmol), 2,4,5-trichloropyrimidine (66 mg, 0.36 mmol) and diisopropylethylamine (70 mg, 0.54 mmol) was dissolved in 2-propanol (1.5 ml) and shaken at 80° C. overnight. Most of the solvent was evaporated. Ammonium chloride solution was added and the mixture was extracted with ethyl acetate twice. The combined organic layers are dried (MgSO4) and evaporated.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li:15])CCC>CCOCC>[CH3:1][C:2]1[CH:10]([Li:15])[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: [Li]CCCC
Reactant: CC1=Cc2ccccc2C1
Solvent: CCOCC
Product: [Li]C1C(C)=Cc2ccccc21
Reaction time: 2.5 h
Yield: 85 %

Procedure:
2-methylindene (47.2 g) was dissolved in ether (400 ml) and n-butyl lithium (145.2 ml, 2.5M in Hexane) was added dropwise over 3 hours. The mixture was stirred for 2.5 hours. After evaporation of the solvent, the residual solid was washed twice with n-pentane (400 ml). Drying under vacuum gave 2-methylindenyl lithium (42 g, 85%) as a pale brown powder.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[O:14][CH:11]1[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([Mg]Cl)[CH:16]=[CH2:17]>O1CCCC1>[CH2:17]([C:10]([OH:14])([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:11][CH2:12][OH:13])[CH:16]=[CH2:15]
Reactant: OCC1OC1COCc1ccccc1
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CCC(O)(CCO)COCc1ccccc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of 4-benzyloxy-2,3-epoxy-1-butanol (6.28 g, 32.37 mmol) in anhydrous tetrahydrofuran (75 mL) was added dropwise at -40° C. over a period of 45 minutes, to a 2M solution of allyl magnesium chloride (48.5 mL, 97 mmol) and tetrahydrofuran (50 mL). The solution was stirred at -40° C. for 1 hour, warmed to 0° C. and quenched by addition of aqueous ammonium chloride solution. The tetrahydrofuran layer was separated and the aqueous layer was extracted with ethyl acetate (three times). The combined organic extract was dried (magnesium sulfate), filtered and concentrated to obtain a mixture of compounds A and B.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([C:20]3[C:24]4[CH:25]=[N:26][CH:27]=[CH:28][C:23]=4[N:22]([CH:29]([CH3:31])[CH3:30])[CH:21]=3)=[O:19])[CH:15]=[CH:14][N:13]=2)=[O:10])=[N:6][CH:7]=1.[CH3:32][N:33](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:32]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([C:20]3[C:24]4[CH:25]=[N:26][CH:27]=[CH:28][C:23]=4[N:22]([CH:29]([CH3:31])[CH3:30])[CH:21]=3)=[O:19])[CH:15]=[CH:14][N:13]=2)=[O:10])=[N:6][CH:7]=1)#[N:33]
Reactant: CN(C)C=O
Reactant: CC(C)n1cc(C(=O)c2ccnc(NC(=O)Cc3ccc(Br)cn3)c2)c2cnccc21
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)n1cc(C(=O)c2ccnc(NC(=O)Cc3ccc(C#N)cn3)c2)c2cnccc21
Temperature: 100 °C

Procedure:
A mixture of 2-(5-bromopyridin-2-yl)-N-(4-{[1-(propan-2-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl]carbonyl}pyridin-2-yl)acetamide (Example 237, 40 mg, 0.083 mmol), zinc cyanide (29 mg, 0.251 mmol), Pd2(dba)3 (3 mg, 0.003 mmol) and DPPF (7.5 mg, 0.013 mmol) in DMF (1 mL) was heated to 100° C. under microwave irradiation for 25 minutes. The reaction was cooled and diluted with ethyl acetate. The organic layer was collected, washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using preparative TLC eluting with 5% MeOH in DCM to afford the LCMS (5 minute run) Rt=2.78 minutes MS m/z 425 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:25](=[O:35])[NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:25](=[O:35])[NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-{[5-(3-hydroxy-benzylcarbamoyl)-3-isopropyl-thiophene-2-carbonyl]-amino}-propionic acid methyl ester (0.085 g, 0.16 mmol) in DCM (5 mL) was added TFA (1.0 mL). The mixture was stirred at room temperature 1 h and evaporated. Isolate 0.067 g of crude product which was used without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]2[C:11]([C:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=3)=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([NH:4][C:5]1[N:10]=[C:9]2[C:11]([CH:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc2[nH]cc(C3=CCN(C)CC3)c2n1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1

Procedure:
A mixture of 0.30 gm (1.1 mMol) 5-(N-acetylamino)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.05 gm 10% palladium on carbon in 15 mL ethanol was hydrogenated at room temperature for 18 hours at an initial hydrogen pressure of 50 p.s.i. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate containing 20% methanol and 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[NH2:13][C:14]1[CH:19]=[N:18][C:17]([Br:20])=[CH:16][N:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(O)(=O)C.ClCCl>[Br:20][C:17]1[N:18]=[CH:19][C:14]([NH:13][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:15][CH:16]=1
Reactant: Nc1cnc(Br)cn1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: Brc1cnc(NCc2ccc3ccccc3c2)cn1
Yield: 48.7 %

Procedure:
2-Napthaldehyde (0.6 g, 3.84 mmol) and 2-amino-5-bromopyrazine (0.56 g, 3.201 mmol) were treated with Na(OAc)3BH (1.02 g, 4.802 mmol) in dichloroethane (15.0 mls) and acetic acid (0.5 mls) for 18 hours at room temperature. The mixture was diluted with dichloromethane, washed with 1.0 N NaOH, washed with brine, dried over MgSO4, and concentrated. Chromatography (SiO2, EtOAc:Hex, 1:1) gave 0.49 g 5-bromo-N-(naphthalen-2-ylmethyl)pyrazin-2-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH:14]=O)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH2:22].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:22][CH3:21])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCC=O)CC2
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Dissolve 50 g (0.18 mol) of 3-(7,8-dimethoxy-2-oxo-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)propanal in 625 ml of methanol. Cool the resulting solution to 0° C. and then add 62.5 ml (0.81 mol; 4.5 equivalents) of an aqueous 40% methylamine solution. Stir for one hour at 0° C. and then add 7.5 g (0.2 mol; 1.1 equivalent) of NaBH4. Stir for 30 minutes at 0° C. and then stir for 12 hours at ambient temperature. Evaporate off the methanol. The residue is taken up in aqueous hydrochloric acid solution (1N), and washed with ethyl acetate. The aqueous phase is then adjusted to pH=8 by adding 20% sodium hydroxide solution and extracted with dichloromethane. The organic phase is washed with water, dried over MgSO4, filtered and then evaporated to dryness to obtain 52 g of an oil, which is purified by flash chromatography on 1.5 kg of silica (eluant=dichloromethane/−ethanol/NH4OH:80/20/2). 42 g of the expected product are obtained in the form of a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.[C:9]([C:11]1[C:12](=[O:21])[N:13]([CH2:19][CH3:20])[N:14]=[CH:15][C:16]=1C#N)#[N:10]>C(O)C>[C:9]([C:11]1[C:12](=[O:21])[N:13]([CH2:19][CH3:20])[N:14]=[CH:15][C:16]=1[NH:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)#[N:10]
Reactant: CCn1ncc(C#N)c(C#N)c1=O
Reactant: NCc1ccncc1
Solvent: CCO
Product: CCn1ncc(NCc2ccncc2)c(C#N)c1=O
Yield: 14.6 %

Procedure:
Into 305 ml of an absolute ethanol solution of 1.9 g of 4-picolylamine, 30 ml of an absolute ethanol suspension of 1.4 g of 4,5-dicyano-2-ethylpyridazin-3-(2H)-one was dropwise added under cooling with ice over a period of 30 minutes. After completion of the dropwise addition, the mixture was reacted at room temperature overnight. Then, ethanol was distilled off under reduced pressure. To the residue, 250 ml of ethyl acetate and 100 ml of water were added, followed by shaking. The ethyl acetate layer was dried over anhydrous sodium sulfate and then distilled under reduced pressure. The residue was subjected to column chromatography, and using an eluent (ethyl acetate:methanol=40:1), 0.3 g of the desired product (Compound No. 47) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([N:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:31]4[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=4)[CH:28]=3)[C:23]2=[O:37])[CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[B-](F)(F)(F)[F:39].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>O1CCCC1.O>[F:39][C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:37])[N:22]([C@@H:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:10][N:11]1[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])[CH2:30]2
Reactant: F[B-](F)(F)F
Reactant: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(F)c1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 2-{(2S)-3-(3-fluorophenyl)-2-[5-(1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]propyl}-1H-isoindole-1,3(2H)-dione (200.0 mg, 0.4044 mmol) [prepared in Example 1] in tetrahydrofuran (7 mL) and water (0.5 mL) was added SELECTFLUOR® fluorinating reagent (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]-octane bis(tetrafluoroborate) (212.0 mg, 0.60 mmol). The reaction mixture was sealed and stirred at 70° C. for 1 h and then additional SELECTFLUOR® fluorinating reagent (212.0 mg, 0.60 mmol) was added. The reaction mixture was sealed again and stirred at 70° C. overnight. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep.—HPLC. The purification afforded 61 mg (30% yield) of the desired product as white solid. LC/MS found: 513.0 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:53]([CH3:55])[CH3:54])C2C=CC=CC=2N=N1.CNC>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:11])[N:53]([CH3:55])[CH3:54])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 13.8 %

Procedure:
The compound, 2-tert-butoxycarbonylamino-3-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-propionic acid (4.2 g, 8.63 mmol) was dissolved in CH2Cl2 (30 mL) and stirred at room temperature under an atmosphere of argon. Triethylamine (1.44 mL, 0.014 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 4.19 g, 9.5 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 5.6 mL, 11.2 mmol) was added and the resulting solution was stirred at room temperature for about 1 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (100 mL). The organic layer was extracted with 0.5 N NaOH (1×50 mL), water (1×100 mL) and brine (1×100 mL). Silica gel chromatography of the crude product with CHCl3-MeOH (19:1) yielded pure amide, (1-dimethylcarbamoyl-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-ethyl)-carbamic acid tert-butyl ester (0.61 g, 13.8%). 1H NMR (400 MHz, CDCl3): 7.17 (overlapped d, J=8.4 Hz, 2H), 7.16 (overlapped d, J=8.4 Hz, 2H), 6.92 (overlapped d, J=8.4 Hz, 2H), 6.90 (overlapped d, J=8.4 Hz, 2H), 5.51 (d, J=8.4 Hz, 1H), 4.81 (m, 1H), 3.02-3.13 (m, 2H), 2.83-2.95 (m, 5H), 2.76 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CCCCCC>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
A 100 mL of reactor equipped with magnetic stir bar was charged with 3.39 mg (0.00499 mmol) of {[(t-Bu)2P(OH)]PdCl2}2 (from Experiment 7), 1.57 g (10.0 mmol) of bromobenzene, 1.46 g (12.0 mmol) of PhB(OH)2 and 1.66 g (12.0 mmol) of K2CO3 in 7.0 mL of THF and 2.0 mL of H2O. The resulting mixture was stirred at room temperature for 5 h. The reaction was transferred to a separatory funnel, and diluted with 300 mL of hexane and 50 mL of H2O. The layers were separated, and organic layer was washed with H2O (2×100 mL), brine (100 mL), and dried over mgSO4, filtered, and the hexane and THF removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel using hexane as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to give 1.0 g (65% yield) of biphenyl.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([NH2:27])[CH3:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:27][CH2:25][CH3:26])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCN
Product: CCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and ethanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.33 Hz, 3H) 2.36 (s, 3H) 3.16-3.37 (m, 2H) 7.59 (d, J=8.08 Hz, 1H) 7.66 (s, 1H) 7.71 (br. s., 1H) 7.99-8.22 (m, 1H) 8.34 (d, J=7.58 Hz, 2 H) 8.65 (t, J=5.05 Hz, 1H) 8.78-8.90 (m, 1H) 12.84-13.41 (m, 1H). MS m/z [M+H]+348.1.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=NS[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](OCC2OC2)=[CH:13][CH:12]=1)=O)C.[CH2:22](O)C>Cl.C1C2C(=CC=CC=2)CCC1NCC(O)COC1C=CC(C2SN=NC=2C(OCC)=O)=CC=1>[NH2:7][CH:6]1[CH2:4][CH2:22][C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10]1
Reactant: CCOC(=O)c1nnsc1-c1ccc(OCC2CO2)cc1
Reactant: CCO
Agent: CCOC(=O)c1nnsc1-c1ccc(OCC(O)CNC2CCc3ccccc3C2)cc1
Agent: Cl
Product: NC1CCc2ccccc2C1

Procedure:
Following the procedure of Example 27, but starting from 4-(4-ethoxycarbonyl-1,2,3-thiadiazol-5-yl)-1-(2,3-epoxypropoxy)benzene (2.94 g) and 2-aminotetralin (1.49 g) in absolute ethanol (20 ml), N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-[4-(4-ethoxycarbonyl-1,2,3-thiadiazol-5-yl)phenoxy]propanamine hydrochloride is obtained ((i): R=H, Ar=radical 63, wherein Z is a 4-COOC2H5 group, and the chain is attached to position 2 of the tetralin moiety).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][C:22]1[N:23]=[C:24]([NH2:28])[S:25][C:26]=1[CH3:27]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][C:24]2[S:25][C:26]([CH3:27])=[C:22]([CH3:21])[N:23]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Cc1nc(N)sc1C
Product: Cc1nc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)sc1C

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (200 mg, 0.57 mmol) and 4,5-dimethyl-thiazol-2-amine (87 mg, 0.68 mmol). The title compound was obtained as a yellow solid (8 mg, 3% yield). 1H NMR (400 MHz, d6-DMSO) δ: 12.85 (1H, m), 9.01 (2H, m), 2.08 (6H, m). MS m/z: 459.03, 461.02 [M+H]+.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].Cl[CH:7]([CH3:10])[C:8]#[N:9]>>[CH2:1]=[CH:2][C:3](=[CH2:4])[CH3:5].[C:8](#[N:9])[CH:7]=[CH2:10]
Reactant: CC(Cl)C#N
Solvent: C=CC(=C)C
Product: C=CC#N
Temperature: 80 °C
Reaction time: 137 h

Procedure:
Then, were added thereto 68.2 parts of isoprene and 1.79 parts of 2-chloropropionitrile as an organic halide and stirred under heating at 80° C. to conduct a polymerization reaction. After 137 hours, the same post-treatment as in Example 1 was carried out to give a random (isoprene/acrylonitrile) copolymer. The conversion rate of isoprene was 84% and the conversion rate of acrylonitrile was 79%. The analysis results of the random (isoprene/acrylonitrile) polymer obtained are shown in Table 3. The polymer was confirmed to have a chlorine atom at the terminal of the polymer chain.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>O>[S:5]([CH2:4][CH2:3][CH2:2][O:1][S:12]([CH2:15][CH2:9][CH2:10][OH:11])(=[O:14])=[O:13])([OH:8])(=[O:7])=[O:6]
Reactant: O=S(=O)(O)CCCO
Reactant: O=S1(=O)CCCO1
Solvent: O
Product: O=S(=O)(O)CCCOS(=O)(=O)CCCO

Procedure:
1 mol of 3-hydroxy propane sulfonic acid is heated to 137° C. with 3 mol of water for 2 hours. Further treatment as described under (a) results in a crystallizing oil which has a water content of 8% and is also free from 1,3-propane sultone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH3:20])[C:10]([NH:12][C:13]([NH:15]C(C)(C)C)=[O:14])=[NH:11].Cl>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]([CH3:20])[C:10]([NH:12][C:13]([NH2:15])=[O:14])=[NH:11]
Reactant: Cc1cccc(C)c1N(C)C(=N)NC(=O)NC(C)(C)C
Agent: Cl
Product: Cc1cccc(C)c1N(C)C(=N)NC(N)=O

Procedure:
A mixture of 27 g. (0.106 mole) of 1-(2,6-dimethylphenyl-N-methylamidino)-3-(t-butyl)urea and 200 ml. of conc. hydrochloric acid is refluxed for 1/2 hour. The reaction mixture is cooled, the precipitated solid filtered and washed with 10 ml. of 1:1 HCl/H2O and dried. The product is then recrystallized from ethanol-ether to obtain 1-(2,6-dimethylphenyl-N-methylamidino)urea.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][CH:18]2[C:23]([OH:25])=[O:24])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:26](O)[CH3:27]>>[C:6]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][CH:18]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(c1ccccc1)c1cccc2c1CCC2C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2c(C(=O)c3ccccc3)cccc21

Procedure:
To 250 ml. of ethanol is added 20 ml. of concentrated sulfuric acid, followed by the addition of 13.3 g. of 4-benzoylindan-1-carboxylic acid. The mixture is refluxed for 5.5 hours. After cooling, the ethanol is distilled off under reduced pressure and water is added to the residue, followed by extraction with ether. The ethereal layer is washed with a 5% aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride and, then, dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (eluted with chloroform). The described procedure gives ethyl 4-benzoylindan-1-carboxylate as an oily product. Infrared absorption spectrum (neat)