Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[F:7][C:8]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=1[CH:10]=O.C(O)(=O)[CH2:18][C:19]([OH:21])=[O:20].Cl>N1C=CC=CC=1>[F:7][C:8]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=1[CH:10]=[CH:18][C:19]([OH:21])=[O:20]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(F)ccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(F)ccc1F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
Piperidine (2 mL, 20.2 mmol, 0.168 vol) was added to a stirred mixture of 2,5-difluorobenzaldehyde (12.07 g, 85.0 mmol, 1 wt) and malonic acid (18.28 g, 175.6 mmol, 1.51 wt) in pyridine (50 mL, 4.14 vol). The reaction mixture was heated under nitrogen and held at reflux (oil bath 100° C.) for 2 hours, effervescence was observed for about 90 minutes—initially vigorous then diminishing. The reaction mixture was then allowed to cool to 20 to 25° C. and poured into stirred 2 M hydrochloric acid (310 mL, 25.7 vol) (pH recorded as 1). The resulting precipitate was aged at 20 to 25° C. for 1 hour then filtered. The filter cake was washed with water (2×50 mL, 4.1 vol) then left to dry for a further 1 hour. The solid product was dried by dissolving it in TBME (250 mL, 20.7 vol), separating the phases and the water phase washed with TBME (100 mL, 8.3 vol). The TBME phases were combined, dried over magnesium sulphate (25 g, 2 wt), filtered and concentrated on a rotary evaporator to afford the product as a white solid (13.4 g, 85.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[CH:13][N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-:23].[Na+].[Na+].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N+:8]([O-:23])=[CH:7][C:6]3[N:12]=[CH:13][N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1
Reactant: Clc1ccc2ncc3ncn(-c4ccccc4Cl)c3c2c1
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc2ncn(-c3ccccc3Cl)c2c2cc(Cl)ccc21
Reaction time: 2 h

Procedure:
3.01 g (9.508 mmol) 8-chloro-1-(2-chloro-phenyl)-1H-imidazo[4,5-c]quinoline (Example 25), 1.22 g (11.4 mmol) sodium carbonate and 2.6 g (10.45 mmol) 3-chloroperoxybenzoic acid in 75 ml chloroform are stirred at rt for 5 h. After this time, a further amount of 254 mg of sodium carbonate, 472 mg 3-chloroperoxybenzoic acid and 50 ml chloroform are added and stirring is continued for 2 h at 50° C. The cold solution is washed with sat. sodium bicarbonate solution (2×), 0.1 N sodium thiosulfate (2×) and brine (2×). The organic phase is dried over sodium sulfate and the solvent evaporated. Purification of the title compound is achieved by chromatography (CH2Cl2-methanol 95:5→90:10) and crystallization (ethyl acetate-hexane). mp: 247-250° C.; MS: 330 (M++1); HPLC: tret=11.25 min (Grad 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C@H:9]2[C:20]([O:22]C)=[O:21])=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1>[C:16]([O:15][C:13]([N:11]1[CH2:12][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C@H:9]([C:20]([OH:22])=[O:21])[CH2:10]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Reaction time: 24 h

Procedure:
To a solution of 1-tert-butyl 3-methyl (3S,4R)-4-(4-chlorophenyl)pyrrolidine-1,3-dicarboxylate, from preparation 67 (0.98 g, 2.88 mmol) in tetrahydrofuran (8 mL) was added lithium hydroxide (0.21 g, 8.64 mmol) at room temperature. The reaction mixture was stirred for 24 hours and the solvent was removed in vacuo. The crude residue was dissolved in water (8 mL) and 1M hydrochloric acid solution (8.65 mL) was added. The suspension was extracted with dichloromethane (2×40 mL) and the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to afforded the desired product as a white solid, 705 mg (75%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:14])[CH:3]=1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:25]([F:28])([F:27])[F:26])=[C:20](B(O)O)[CH:21]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:25]([F:26])([F:27])[F:28])=[C:20]([C:2]2[CH:7]=[CH:6][N:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4](=[O:14])[CH:3]=2)[CH:21]=1
Reactant: CCOC(=O)Cn1ccc(Br)cc1=O
Reactant: OB(O)c1cc(Cl)ccc1C(F)(F)F
Product: CCOC(=O)Cn1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
2.04 g (7.8 mmol) of ethyl (4-bromo-2-oxopyridin-1(2H)-yl)acetate and 1.98 g (8.6 mmol) of 5-chloro-2-trifluoromethylphenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 2.89 g (quant.)
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]=1[C:17]([OH:19])=[O:18])(=[O:3])[CH3:2].C(Cl)(=O)C>C(OC(=O)C)(=O)C>[C:1]([NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:7]2[C:8]([O:19][C:17](=[O:18])[C:6]=12)=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c([N+](=O)[O-])ccc(C(=O)O)c1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Product: CC(=O)Nc1c([N+](=O)[O-])ccc2c1C(=O)OC2=O
Reaction time: 2 h
Yield: 58 %

Procedure:
3-Acetamido-4-nitrophthalic acid (0.538 g, 2.00 mmol) was dissolved in acetic anhydride (10 ml) at 80° C., and the solution was added with acetyl chloride (1 ml) and stirred for 2 hours. The solvent was evaporated, and a small amount of anhydrous dichloromethane was added to the residue, and precipitates were collected by filtration to obtain the title compound (0.29 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1Br.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29]>O>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1[NH:29][CH2:28][CH2:27][N:26]([CH3:30])[CH3:25]
Reactant: CN(C)CCN
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Solvent: O
Product: CC(C)n1nc(-c2nc(NCCN(C)C)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 122.5 °C

Procedure:
A mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg) and N,N-dimethyl-1,2-ethanediamine (0.127 ml) in 1,2-dimethyl-2-imidazolidinone (0.3 ml) was heated at 120-125° C. for 50 hours. After addition of water (3 ml), the mixture was extracted with CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel [Chromatorex® NH] eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a syrup. The syrup was crystallized from a mixture of acetone and n-hexane to give 6-(5-amino-6-{[2-(dimethylamino)ethyl]amino}-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (36 mg).
Reaction SMILES: [C:1]1([CH:7]([NH2:15])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:16]1[CH2:20][CH2:19][N:18]=[C:17]1S(O)(=O)=O>CC(O)CC.O>[NH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[N:15][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1
Reactant: NC(Cc1ccncc1)c1ccccc1
Reactant: O=S(=O)(O)C1=NCCN1
Solvent: O
Solvent: CCC(C)O
Product: c1ccc(C(Cc2ccncc2)N=C2NCCN2)cc1
Temperature: 110 °C

Procedure:
A mixture of 1-phenyl-2-(pyridin-4-yl)ethanamine (0.23 g, 1.18 mmol), and 4,5-dihydro-1H-imidazole-2-sulfonic acid (0.18 g, 1.16 mmol) in 2-butanol (5 mL), water (1 mL) were heated at 110° C. for 3 hours. The solution was cooled to room temperature. The solvents were removed under vacuum. The residue was dissolved in methanol, and added amino modified silica gel. The solvent was removed under vacuum. Purification by chromatography on amino modified silica gel (100% ethyl acetate to 7% methanol in dichloromethane) gave N-(imidazolidin-2-ylidene)-1-phenyl-2-(pyridin-4-yl)ethanamine Compound 3 as a while solid (0.21 g, 0.80 mmol, 67% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([OH:15])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:26][CH2:27][CH2:28][CH2:29]Br)=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:5]=[C:4]([O:15][CH2:29][CH2:28][CH2:27][CH2:26][S:24]([C:19]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=2)=[O:25])[CH:3]=1
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)Nc2c(Cl)cc(O)cc21
Product: CC1(C)OC(=O)Nc2c(Cl)cc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 4 from 8-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(3,4-dichloro-phenylsulfinyl)-butylbromide.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ncc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](Nc1ncc(N)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 5.7 %

Procedure:
To a suspension of (S)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-[1-(4-fluorophenyl)ethyl]-5-nitropyrimidine-2,4-diamine (Method 9; 0.8 g, 2.0 mmol) and zinc dust (0.7 g, 10.0 mmol) in MeOH:THF (1:1, 50 ml) was slowly added saturated NH4Cl solution (10 ml) at 25° C. After 3 hours, the reaction mixture was treated with saturated aqueous NH4OAc solution (40 ml) and allowed to stir for 30 minutes. The reaction was then filtered through a plug of celite with EtOAc (100 ml), and the resulting aqueous layer was extracted with EtOAc (2×100 ml), dried, filtered, and concentrated to give the title compound (0.04 g, 5%). MS: Calcd.: 353; Found: [M+H]+ 354.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[N:11]([C:12]2[CH:13]=[C:14]([CH2:22][OH:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=2)[N:10]=[N:9][N:8]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:23][CH2:22][C:14]1[CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=[C:12]([N:11]2[C:7]([CH3:6])=[N:8][N:9]=[N:10]2)[CH:13]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nnnn1-c1cc(CO)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nnnn1-c1cc(COS(C)(=O)=O)cc(C(F)(F)F)c1
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 93.1 %

Procedure:
Methanesulfonyl chloride (0.26 ml, 0.39 g, 3.4 mmol) was added dropwise to a stirred, cooled (-30° C.) solution of 3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethanol (725 mg, 2.8 mmol) and triethylamine (0.59 ml, 0.43 g, 4.2 mmol) in dichloromethane (15 ml). The mixture was stirred at -30° C. for 45 minutes, diluted with dichloromethane (20 ml), washed with aqueous citric acid (10%, 20 ml) and saturated aqueous sodium hydrogen carbonate (20 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to give 1-(methanesulfonyloxymethyl)-3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)benzene as a yellow oil (877 mg, 93%), 1H (CDCl3) δ 7.86 (1H, s), 7.81 (2H, s), 5.38 (2H, s), 3.14 (3H, s), and 2.69 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[C:10]([O:14][C:15](=[O:37])[CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:34][CH2:35][CH3:36])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:10]([O:14][C:15](=[O:37])[CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([N:26]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[CH3:1])=[O:8])=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:34][CH2:35][CH3:36])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccsc1C(=O)Cl
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3sccc3C)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methyl-thiophene-2-carbonyl chloride (41 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C29H33N3O3S+H: 504, observed: 504.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:25](=[O:26])[CH2:24][O:23][CH3:22])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Product: COCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a stirred suspension of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (101 mg, 0.348 mmol) and piperidinomethyl polystyrene resin (110 mg) in 2 mL of dry CH2Cl2 was added methoxyacetyl chloride (97%, 34 μL, 1.05 eq.) at room temperature. After being shaken at room temperature for 4 hours, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2 Removal of CH2Cl2 afforded methoxyacetic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenylamide 38 (70 mg, 56%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]O)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].S(Cl)([Cl:19])=O.ClCCl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][Cl:19])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc(CCO)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)C(C)(C)c1ccc(CCCl)cc1
Yield: 92.3 %

Procedure:
In a reaction vessel, 2-[4-(2-hydroxy-ethyl)-phenyl]-2-methyl-propionic acid methylester (1 g) prepared in the Examples 1-3, thionyl chloride (2.7 g) and dichloromethane (15 mL) were introduced, and the mixture was reacted at room temperature for 2 hours. Toluene (30 mL) was added, the mixture was condensed under reduced pressure, and the solvent was removed. Dichloromethane (50 mL) and sodium hydrogen carbonate solution (30 mL) were added thereto, and the mixture was stirred to separate layers. The separated organic layer was dehydrated with Na2SO4, and then condensed by filtration to obtain 2-[4-(2-chloro-ethyl)-phenyl]-2-methyl-propionic acid methylester (1.0 g, yield 92%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH2:21]([C:23]1[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=1)[CH3:22]>>[CH2:21]([C:23]1[CH:24]=[C:25]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:26]=[CH:27][CH:28]=1)[CH3:22]
Reactant: CCc1cccc(N)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: CCc1cccc(Nc2nc(Nc3cc(C)[nH]n3)cc3cc(OC)ccc23)c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-ethyl-phenylamine give N1-(3-ethyl-phenyl)-6-methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 374(MH+).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[OH-].[K+].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C(O)(C)C>[CH2:11]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(O)[C@@H]1CCCN1Cc1ccccc1

Procedure:
A solution of 10 g of L-proline and KOH (10 g) in 120 mL isopropanol was stirred at 40° C., then benzyl chloride (13.5 mL) was added dropwise. The reaction mixture was stirred for 6 additional hours, then neutralized with concentrated HCl to a pH of 5-6. The reaction mixture was extracted with CH2Cl2 (3×70 mL), the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, the solids were removed by filtration and the solvents of the filtrate were removed under reduced pressure. The residue was treated with acetone to afford N-benzyl proline (15 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33].N#N>C(Cl)Cl.CCOC(C)=O>[Br:33][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:2]=1[F:1]
Reactant: OCCOc1ccc(F)cc1F
Reactant: BrC(Br)(Br)Br
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Fc1ccc(OCCBr)c(F)c1
Reaction time: 0.5 h

Procedure:
To a cool solution 2-(2,4-difluoro-phenoxy)-ethanol (0.48 g, 2.77 mmol.) in CH2Cl2 (15 ml), triphenyl phosphine (1.3 g, 5 mmol)) was added. Carbon tetrabromide (1.65 g, 5 mmol.) in CH2Cl2 (3 ml) was added to the solution dropwise under N2. The solution was stirred for 30 minutes. EtOAc was added, then the solvent was evaporated under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:20]1[O:21][C:16]([CH3:17])([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)[O:18][CH2:19]1
Reactant: OCCO
Reactant: CC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(Cc2ccc(OCc3ccccc3)cc2)OCCO1

Procedure:
A solution of 1-(4-benzyloxyphenyl) propan-2-one (5 g), ethylene glycol (1.4 g) and a trace amount of 4-toluenesulphonic acid, in benzene (100 ml) was heated under reflux with azetropic removal of water for 2 hours. The solvent was evaporated, the residue dissolved in ethyl acetate, washed with 1.2 N sodium bicarbonate solution, dried (MgSO4) and evaporated to give a light brown oil which crystallised on standing (6.1 g) m.p. 58°-62°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:10](Cl)(=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[O:22]=[C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: OCCN1CCNCC1
Product: CCCCCCCCCCCC(=O)N1CCN(CCO)CC1

Procedure:
5.2 g of 1-(2-hydroxyethyl)piperazine and 8.8 g of dodecanoyl chloride was reacted following the procedure under Example 3. This provided 8.7 g of product, m.p. 38°-40° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)cc4)CC3)nn2C(C)(C)C)cc1

Procedure:
82 mg (76%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-(4-chlorophenyl)piperazine (60 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH:4]([Br:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of 4-chlorophenylacetic acid methyl ester (14.6 g, 79.1 mmol), N-bromosuccinimide (14.4 g, 80.7 mmol), and benzoyl peroxide (1.91 g, 7.89 mmol) in carbon tetrachloride (100 mL) was heated at reflux for 3 h. After the mixture was cooled at room temperature, hexanes (500 mL) was added. The reaction mixture was filtered and the solvent was evaporated in vacuo. The crude material was purified by column chromatography on silica (EtOAc/Hexanes, 15:85) to give the title compound as colorless oil (16.9 g, 63%): 1H NMR (400 MHz, CDCl3) δ 3.81 (s, 3H, CH3), 5.34 (s, 1H, CH), 7.44 (dd, J=60.4 Hz, J=8.4 Hz, 4H, ArH).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[C:18]1([C:24]2[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[S:26][N:25]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:28]=2)[CH2:30][CH2:31]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Product: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 83 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropylsulfanyl-5-methanesulfonyl-benzoic acid (Example A22) and 3-phenyl-5-piperazino-1,2,4-thiadiazole. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as an off-white solid (yield 83%). MS (m/e): 503.1 (M+H+, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[OH:3][CH2:4][C:6]1[N:7]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(CO)cc3ccccc32)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To stirred solution of Red-A1 (sodium dihydro-bis(2-methoxyethoxy)aluminate ≈70% in toluene) (30 mL) in dry THF (100 mL) cooled at 5° C. and under nitrogen was added dropwise and at this temperature a solution of compound of step 1 (26,8 g, 78 mmol) in dry THF (75 mL). After stirring one hour at 5° C. and then one hour at room temperature the mixture was cooled at 10° C. and treated dropwise with 2N NaOH, to effect hydrolysis of the intermediate complex. The organic phase was separated and the solvent in vacuo evaporated. The residue was solved in ethyl ether, the solution washed with water, dried over MgSO4 and evaporated to give the required alcohol (23.3 g, 98%) as a yellow oil; IR (film) 3500, 1597 cm-1.