Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]1[NH:21][C:20]2[CH:19]=[C:18]3[C:14]([CH:15]=[N:16][NH:17]3)=[CH:13][C:12]=2[N:11]=1.Cl.[NH2:23][CH2:24][C@H:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([Br:35])[CH:28]=1)[OH:26].CN1CCOCC1>C(#N)C>[Br:35][C:29]1[CH:28]=[C:27]([C@H:25]([OH:26])[CH2:24][NH:23][C:3]2[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=2[C:10]2[NH:21][C:20]3[CH:19]=[C:18]4[C:14]([CH:15]=[N:16][NH:17]4)=[CH:13][C:12]=3[N:11]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH3:34]
Reactant: COc1ccc([C@H](O)CN)cc1Br
Reactant: O=c1[nH]ccc(Cl)c1-c1nc2cc3cn[nH]c3cc2[nH]1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COc1ccc([C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4cn[nH]c4cc3[nH]2)cc1Br
Temperature: 80 °C
Yield: 63.8 %

Procedure:
The mixture of crude 4-chloro-3-(1,7-dihydro-1,2,5,7-tetraaza-s-indacen-6-yl)-1H-pyridin-2-one hydrochloric acid salt (80 mg, 0.25 mmol), (S)-2-amino-1-(3-bromo-4-methoxy-phenyl)-ethanol hydrochloric acid salt (105 mg, 0.37 mmol), N-methyl morpholine (0.5 ml, excess), and acetonitrile (15 mL) was heated to 80° C. overnight and cooled to room temperature. After concentration in vacuo, the residue was purified by prep. HPLC to yield the titled compound (79 mg, 66%). 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.85 (s, 1H), 7.69 (narrow d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.40 (dd, J=2.0, 8.5 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 6.96 (d, J=8.5 Hz, 1H), 6.22 (d, J=7.6 Hz, 1H), 4.93 (m, 1H), 3.80 (s, 3H), 3.66 (d, J=6.0 Hz, 2H). LCMS (t=1.39 min), [M+H]+ 495.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1[F:39]>C(#N)C.CN(C=O)C.CCOC(C)=O.O>[F:39][C:31]1[CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[CH:34]=[CH:35][C:30]=1[O:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1(COc2cc3nccc(O)c3cc2OC)CC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(COc2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3cc2OC)CC1
Temperature: 60 °C

Procedure:
Methyl 1-((4-hydroxy-6-methoxyquinolin-7-yloxy)methyl)cyclopropanecarboxylate (600 mg, from Example 1) was mixed with Cs2CO3 (2 eq) and 1,2-difluoro-4-nitrobenzene (1.2 eq) in acetonitrile/DMF (20 ml, 1/1). The reaction was heated at 60° C. for 1 hour and diluted with EtOAc/H2O then extracted with EtOAc three times. The combined organic layer was dried, evaporated and purified with silica gel column to give methyl 1-((4-(2-fluoro-4-nitro-phenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanecarboxylate (300 mg). This product was mixed with iron powder (300 mg) and NH4Cl (30 mg) in EtOH/H2O (20 ml, 9/1). The reaction was refluxed for 3 hours and filtered through Celite followed by evaporation. The residue was mixed with EtOAc/H2O and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give methyl 1-((4-(2-fluoro-4-amino-phenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanecarboxylate (150 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:16][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]([CH:23]=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([CH2:31][CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:16][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]([CH2:23][N:37]2[CH2:38][CH2:39][CH:34]([CH2:33][CH2:32][CH2:31][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:35][CH2:36]2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CC(NC(=O)OCc2ccccc2)CC1c1ccccc1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(NC1CC(CN2CCC(CCCc3ccccc3)CC2)C(c2ccccc2)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
To a solution of 1-((SR)-(benzyloxycarbonylamino)-3-(SR)-(formyl)-4-(SR)-phenylcyclopentane (from Step F, derived from Higher Rf isomer in Step D) (450 mg, 0.1.4 mmol) in 1,2-dichloroethane (10 mL) was added 4-(3-phenylprop-1-yl)piperidine (424 mg, 2.1 mmol) and acetic acid (0.125 mL, 2.1 mmol). After 15 min, sodium triacetoxyborohydride (890 mg, 4.2 mmol) was added in portions over 30 min and the reaction was stirred at RT for 16 h. The reaction was diluted with methylene chloride, quenched with aq. sodium carbonate and extracted 3 times with methylene chloride. The organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FC (30-40% ethyl acetate in hexanes) to give the title product (698 mg) as the free amine.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][C:9]1([CH3:16])[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.CCCCCC.C(N(CC)CC)C.CN(C)P(N(C)C)(N(C)C)=O>[CH3:8][C:9]1([CH3:16])[C:13](=[O:14])[CH:12]=[C:11]([CH:15]=[CH:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[O:10]1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1=CC(=O)C(C)(C)O1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: CC1(C)OC(C=Cc2ccc(Cl)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
To a solution of dry diisopropylamine (5.0 mL, 35.7 mM) in dry tetrahydrofuran (150 mL) at -78° C., was added dropwise a 2.3 N solution of nbutyllithium in hexane (15.5 mL, 35.7 mM). After the reaction solution was stirred 15 minutes, a solution of 2,2,5-trimethyl-3(2H)-furanone (3.0 g, 23.8 mM) in tetrahydrofuran (25 mL) was added dropwise. Hexamethylphosphoramide (6.4 mL, 34.7 mM) was added dropwise after 30 minutes. Finally, p-chlorobenzaldehyde (3.0 g, 2.7.8 mM) in tetrahydrofuran (25 mL) was added in one portion. The reaction solution was stirred 15 minutes when trifluoroacetic anhydride (10.5 mL, 276 mM) was added in one portion. Again the reaction mixture was stirred 15 minutes when triethylamine (5.9 mL, 48 mM) was added and the mixture was allowed to warm to room temperature. The reaction mixture was then partitioned between saturated aqueous sodium chloride (50 mL) and diethyl ether (50 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2×25 mL) and saturated aqueous sodium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an orange liquid which was purified by chromatography (silica gel, pet. ether-ethyl acetate) to afford yellow crystals (3.8 g, 65% yield), m.p. 91°-92° C.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([CH3:9])=[CH:7][CH:8]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[S:5][C:6]([CH3:9])=[CH:7][CH:8]=1)=[O:3]
Reactant: CC(=O)c1ccc(C)s1
Reactant: COC(OC)N(C)C
Product: Cc1ccc(C(=O)C=CN(C)C)s1

Procedure:
A mixture of 56.08 g of 2-acetyl-5-methylthiophene and 250 ml of N,N-dimethylformamide dimethylacetal was heated on a steam bath under an air condenser for 16 hours. The mixture was cooled in an ice bath and filtered giving 66.82 g of the desired compound, mp 118°-121° C.
Reaction SMILES: [CH2:1]([C:8]1([NH2:14])[CH2:13][CH2:12][O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:8]1([NH:14][C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH2:13][CH2:12][O:11][C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1(Cc2ccccc2)CCOC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC1(Cc2ccccc2)CCOC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1.55 g of α-benzyl-α-amino-γ-butyrolactone in 16 ml of tetrahydrofuran is added 2.0 g of powdered sodium carbonate, followed by 1.27 ml of benzylchloroformate. After stirring at room temperature for 18 hours, water is added to dissolve the salt and the resulting mixture is diluted with 100 ml of ethyl acetate. It is washed with 50 ml of saturated aqueous sodium chloride. The aqueous phase is extracted with two 50 ml portions of ethyl acetate. The combined organic phase is dried (magnesium sulfate), filtered, and then concentrated. The residue is passed through 20 g of silica gel with ethyl acetate, and the filtrate concentrated to the title product as a white solid, 2.6 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH3:13])=[O:16])[CH:19]=[CH:20][C:21]=1[N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH2:28][CH2:27]1)#[N:24]
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(F)cc1
Yield: 29.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (0.8 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.6 g), the title compound (0.3 g) was obtained, melting point: 226° C.(decomposition).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH2:36][CH2:37][C:38]2[CH:39]=[C:40]([NH2:43])[NH:41][N:42]=2)[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1>ClCCl.CN(C=O)C>[CH3:35][O:34][C:32]1[CH:31]=[C:30]([CH2:36][CH2:37][C:38]2[CH:39]=[C:40]([NH:43][C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([F:7])=[CH:16][CH:15]=3)[NH:41][N:42]=2)[CH:29]=[C:28]([O:27][CH3:26])[CH:33]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: O=C(O)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(CCc2cc(NC(=O)c3ccc(F)cc3)[nH]n2)cc(OC)c1
Temperature: 0 °C
Yield: 3 %

Procedure:
Oxalyl chloride (2M in DCM, 1.40 ml, 2.75 mmol, 1.1 eq) was added dropwise to a mixture of 4-fluorobenzoic acid (350 mg, 2.50 mmol, 1 eq) in dichloromethane (15 ml) at 0° C. containing a few drops of DMF (10 ul, 0.12 mmol, 0.05 eq) and DIPEA (937 μl, 5.25 mmol, 2.1 eq). After stirring for 60 mins at 0° C. a solution of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (742 mg, 3 mmol, 1.2 eq) in DCM (10 ml) was added dropwise over 15 mins. The mixture was maintained at 0° C. for a further 2 h, then gradually allowed to warm to room temperature overnight. The mixture was diluted with DCM (50 ml) and washed with aqueous NaHCO3 solution (50 ml). The aqueous layer was extracted with DCM (50 ml). The combined organic layers were collected and concentrated. The crude product was purified by reverse-phase prep HPLC using a 30-50% gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The desired fractions were evaporated to afford the title compound as a beige solid. (31.5 mg, 3% yield)
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]3[N:34]=[CH:35][N:36]=[C:10]23)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl>CS(C)=O>[CH:2]([C@H:3]1[CH2:4][CH2:5][C@H:6]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]3[N:34]=[CH:35][N:36]=[C:10]23)[CH2:7][CH2:8]1)=[O:1]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](CO)CC2)c2ncnn12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C=O)CC2)c2ncnn12
Reaction time: 2 h

Procedure:
To a mixture of 4′-({4-[trans-4-(hydroxymethyl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (5.3 g), triethylamine (7.7 mL) and dimethyl sulfoxide (25 mL) was added a solution (40 mL) of sulfur trioxide-pyridine complex (5.3 g) in dimethyl sulfoxide at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (5 g, 95%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH:20][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:23]([F:26])([F:24])[F:25])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(CN)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(CNS(C)(=O)=O)cc2)cc1

Procedure:
To a solution of 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylamine hydrochloride obtained by Example 70 (150 mg) and triethylamine (0.1 ml) in dichloromethane (10 ml) was added dropwise methanesulfonyl chloride (0.06 ml) under ice cooling.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>C(O)C>[C:7]([C:11]1[N:16]=[C:15]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:14]=[C:13]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1nc(Cl)cc(C2CCC2)n1
Reactant: C1CNCCN1
Solvent: CCO
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
24.8 g of piperazine (287.9 mmol) were dissolved in 350 ml of ethanol and heated to reflux. 24.9 g of 2-tert-butyl-4-chloro-6-cyclobutyl-pyrimidine (48.06 mmol), dissolved in 50 ml of ethanol, were added dropwise to the solution. The solution was refluxed for further 3 h, cooled to room temperature and then extracted with water and ethyl acetate. The organic layer was washed with 5% citric acid (aq.), and the aqueous layer was adjusted to alkaline pH with 2 N NaOH. The alkaline aqueous layer was reextracted with ethyl acetate, and the organic phase was dried over magnesium sulfate, filtered and concentrated to dryness to yield 8.6 g (65.2%) of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15]C.C(=O)=O.CO.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[OH:15]
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: O=C=O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ccc(OCCCCl)c(O)c1
Yield: 86.4 %

Procedure:
To a stirred solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (10.0 g, 41 mmol) in methylene chloride (120 ml) cooled to -50° C. (dry ice-methanol) was added, dropwise, 1M boron tribromide in methylene chloride (123 ml, 120 mmol). The temperature was kept between -40° C. and -50° C. After complete addition, the reaction was permitted to reach -30° C., and the TLC checked (ca. 15 min. after final boron tribromide was added). Saturated NaHCO3 was added, dropwise, never allowing the temperature to go above 0° C. during most of the addition. When sufficient NaHCO3 had been added to make the solution basic, the organic layer was collected. The layer was washed with brine, dried (MgSO4), and concentrated to yield 8.1 g of dark brown oil, which solidified on standing. This was chromatographed on a Waters Prep 500 LC (2 silica columns, 2% methanol-methylene chloride as eluent). Upon concentration of the appropriate fractions, 5.8 g of a brown tacky solid were obtained. This was recrystallized from isopropyl ether (with decanting of the yellow isopropyl ether supernatant from the dark brown oily residue) to give initially 2.5 g of a yellow solid. Concentration of the mother liquor gave an additional 0.5 g, m.p.=110°-113° C.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]2[C:8]([C:11]3([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12]3)=[N:9][N:10]=[C:6]2[C@@H:5]([NH2:18])[CH2:4][C@H:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O:25]=[C:26]1[NH:34][C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[C@:27]21[CH2:42][C:41]1[C:36](=[CH:37][CH:38]=[C:39]([C:43](O)=[O:44])[CH:40]=1)[CH2:35]2.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH3:1][C@H:2]1[N:7]2[C:8]([C:11]3([C:14]([F:15])([F:16])[F:17])[CH2:13][CH2:12]3)=[N:9][N:10]=[C:6]2[C@@H:5]([NH:18][C:43]([C:39]2[CH:40]=[C:41]3[C:36](=[CH:37][CH:38]=2)[CH2:35][C@:27]2([C:28]4[C:29](=[N:30][CH:31]=[CH:32][CH:33]=4)[NH:34][C:26]2=[O:25])[CH2:42]3)=[O:44])[CH2:4][C@H:3]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)c2nnc(C3(C(F)(F)F)CC3)n21
Reactant: O=C(O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)c2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)c2nnc(C3(C(F)(F)F)CC3)n21
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
To a solution of (5R,6S,8S)-5-methyl-6-phenyl-3-[1-(trifluoromethyl)cyclopropyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-amine (19.0 mg, 0.056 mmol) in N,N-dimethylformamide (565 μL) was added (2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (19.0 mg, 0.68 mmol), 1-hydroxy-7-azabenzotriazole (0.77 mg, 5.7 μmol), N-methylmorpholine (14.9 μL, 0.136 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.0 mg, 0.068 mmol). The mixture was stirred 30 min. Water was added, and the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→15% water/acetonitrile with 0.1% trifluoroacetic acid) giving the title compound (21 mg). HRMS 599.2367 (M+1). 1H NMR (400 MHz, DMSO): δ 11.12 (s, 1H); 9.19 (d, J=8.2 Hz, 1H); 8.08-8.05 (m, 1H); 7.85 (s, 1H); 7.82 (d, J=8.0 Hz, 1H); 7.41 (t, J=6.9 Hz, 3H); 7.36-7.27 (m, 3H); 7.23 (dd, J=7.3, 1.6 Hz, 1H); 6.89 (dd, J=7.3, 5.3 Hz, 1H); 5.43 (dt, J=10.7, 7.8 Hz, 1H); 4.69-4.61 (m, 1H); 3.70 (d, J=13.5 Hz, 1H); 3.43 (d, 16.3 Hz, 2H); 3.21 (d, J=16.3 Hz, 2H); 2.67-2.56 (m, 1H); 2.36-2.25 (m, 1H); 1.73 (d, J=10.3 Hz, 1H); 1.63-1.51 (m, 2H); 1.25 (d, J=9.3 Hz, 1H); 1.17 (t, J=6.5 Hz, 3H).
Reaction SMILES: C=CC(=C)C.[CH3:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][CH:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:25][CH2:26][CH2:27][CH:28]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH3:29])[CH3:24])[CH3:18])[CH3:13])[CH3:8]>C([Li])(CC)C.C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.[Ni+2].[Ni].C1CCCCC1>[CH3:35][C:33](=[CH:32][CH2:31][CH2:30]/[C:28](=[CH:27]/[CH2:26][CH2:25]/[C:23](=[CH:22]/[CH2:21][CH2:20]/[CH:19]=[C:17](/[CH2:16][CH2:15]/[CH:14]=[C:12](/[CH2:11][CH2:10][CH:9]=[C:7]([CH3:8])[CH3:6])\[CH3:13])\[CH3:18])/[CH3:24])/[CH3:29])[CH3:34]
Reactant: CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C
Agent: [Ni+2]
Agent: [Ni]
Agent: O=C([O-])c1ccc2ccccc2c1
Solvent: C=CC(=C)C
Solvent: C1CCCCC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C=C(\C)CC/C=C(\C)CCC=C(C)C

Procedure:
As the oligomer (D) represented by the formula: ##STR2## When m is 0 and R is ##STR3## is a hydrogenated product of polyisoprene. For obtaining a hydrogenated product of polyisoprene, it can be easily produced by carrying out anion polymerization of isoprene in a cyclohexane solution under the copresence of sec-butyl lithium catalyst and then hydrogenating the polymer in the presence of a nickel naphthenate catalyst. On the other hand, when m is 1, n and pare 2, and R is ##STR4## it is squalane obtained by hydrogenation of squalene with a nickel catalyst. Squalene which is a starting material of squalane is contained in liver oil of a deep sea shark, and it can be obtained by subjecting the unsaponified product of shark liver oil to fractional distillation, deacidification and further to fractional distillation in the presence of metallic sodium, or condensing farnesyl chloride or farnesyl bromide in the presence of metallic magnesium, or carrying out Wittig reaction on transgeraniol acetone.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Cl:9][C:10]([Cl:18])=[CH:11][CH:12](Br)[C:13](Br)([CH3:15])[CH3:14].[Ca].C(=O)([O-])[O-].[Mg+2].[Cl-].Cl>O.[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.[Cl-].C[N+](CC)(CC)CC.[Cu].C(OCCCC)(=O)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:12]([CH:11]=[C:10]([Cl:18])[Cl:9])[C:13]1([CH3:15])[CH3:14])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)(Br)C(Br)C=C(Cl)Cl
Agent: [Cu]
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: CC[N+](C)(CC)CC
Solvent: CCCCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl cyanoacetate (24.88 parts), 1,1-dichloro-3,4-dibromo-4-methylpent-1-ene (62.2 parts), calcium or magnesium carbonate and metal chloride is heated in water (100 parts) in the presence of a phase transfer catalyst (either cetyl trimethyl ammonium bromide (CTMAB) or methyl triethyl ammonium chloride (MTEAC)]] and a copper salt as catalyst. The reaction mass is cooled to room temperature, n-butyl acetate (100 parts by volume) water (100 parts) and hydrochloric acid (100 parts by volume) are added and the mixture is stirred for 30 minutes, filtered from extraneous matter and the filtrates separated. The butyl acetate layer is washed with water (4×100 parts) and evaporated under reduced pressure to remove the butyl acetate and yield the crude ethyl 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylate. The yield, strength and composition of the product is given in the following table, together with other details.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>ClCCl>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:7][CH2:8][C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(C#CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC#Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C

Procedure:
4.4 ml (54 mmol) of pyridine are added dropwise to a solution of 5.8 g (33 mmol) of 4-(3-hydroxyprop-1-ynyl)-nitrobenzene and 5.2 g (27 mmol) of p-toluenesulphonic acid chloride in 50 ml of dichloromethane at 0° C. After 2 hours at 0° C. about 25 g of ice and 8 ml of conc. hydrochloric acid are added. The organic phase is separated off and washed with water. After removal of the solvent in vacuo and chromatography of the residue on silica gel (dichloromethane/methanol=1:1) the product is obtained as an oil.