Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([OH:21])[C:12]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:28]1([S:38](Cl)(=[O:40])=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.N1C=CC=CC=1>ClCCl>[C:28]1([S:38]([O:21][C:13]2[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=2)(=[O:40])=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(O)c2-c2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(OS(=O)(=O)c3cccc4ccccc34)c2-c2ccccc2)cc1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-ol (0.1 g, 0.25 mmol, prepared according to the procedure described in PCT/IB03/01289) in dichloromethane (10 ml) was added naphthalene-1-sulfonyl chloride (0.086 g, 0.37 mmol) in dichloromethane (4 ml) at 0° C. and the mixture was stirred for 10 minutes. Subsequently pyridine (0.04 ml, 0.5 mmol) was added under stirring and the stirring was continued further for 6 hours at 37° C. Dichloromethane was removed under vacuo and the resultant mixture was diluted with water:ethyl acetate (1:1, 100 ml) and then extracted with ethyl acetate (25 ml×3). The organic layer was washed with brine (100 ml), dried over anhydrous sodium sulphate and evaporated to afford the title compound (0.096 g, yield 67%); m.p. 204-206° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([CH:12]=[O:13])[CH:3]=1.[Cl:14]N1C(C)(C)C(=O)N(Cl)C1=O>>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([CH:12]=[O:13])[C:3]=1[Cl:14]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: CCCc1nc(C=O)cc(N)c1F
Product: CCCc1nc(C=O)c(Cl)c(N)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.3 %

Procedure:
To a flask equipped with a stir bar and reflux condenser was added 4-amino-5-fluoro-6-propylpicolinaldehyde (0.250 g, 1.372 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.149 g, 0.755 mmol). The flask was sealed, evacuated and backfilled with N2. Acetonitrile (13.72 mL) was added, and the reaction mixture was stirred at room temperature for ˜5 min, then heated to reflux (˜2 h). The reaction mixture color changed from yellow to orange then green over the course of 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with H2O. The layers were separated, and the organic layer was washed with dilute sodium bisulfite followed by saturated NaCl. The organic layer was dried (Na2SO4), filtered and concentrated onto silica. Purification via flash chromatography (silica; EtOAc, Hex) yielded 4-amino-3-chloro-5-fluoro-6-propylpicolinaldehyde (97 mg, 32.6%) as an off-white solid: mp 89-91° C.; 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 4.81 (s, 2H), 2.81 (m, 2H), 1.76 (m, 2H), 0.99 (t, J=7.4 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −139.62; 13C NMR (101 MHz, CDCl3) δ 191.27, 152.80, 149.26, 146.64, 141.87, 139.82, 115.77, 37.04, 28.53.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[F:14][C:10]1[CH:9]=[C:8]([C:3]2[C:2]([N:1]=[C:15]=[S:16])=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1-c1cccc(F)c1
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: Fc1cccc(-c2ccccc2N=C=S)c1

Procedure:
Reaction of 2-amino-3'-fluorobiphenyl (10 g) and thiophosgene (9.2 g) in a mixture of dioxane (15 ml) and water (70 ml) at ambient temperature for 1.5 hours yielded 3'-fluoro-2-biphenylylisothiocyanate as a brown oil.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[OH:11][C:3]1[C:2]([I:1])=[CH:10][C:6]([C:7]([O:9][CH2:17][CH3:18])=[O:8])=[CH:5][N:4]=1
Reactant: CCO
Reactant: O=C(O)c1cnc(O)c(I)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnc(O)c(I)c1
Temperature: 25 °C

Procedure:
A suspension of 4.6 g (17.36 mmol) of 5-iodo-6-hydroxynicotinic acid and 7.0 mL of concentrated sulfuric acid in 40 mL of ethanol was refluxed for 16 h. The reaction mixture was cooled to rt and filtered to afford 3.0 g of a white solid as the title compound: 1H NMR (500 MHz, DMSO) δ 1.25 (t, J=6.9, 3H), 4.21 (q, J=6.6, 2H), 8.05 (d, J=1.4, 1H), 8.33 (d, J=1.3, 1H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:11])=[C:8]([OH:10])[CH:9]=1.I[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[N:21]=2)[N:18]=1>CN(C)C=O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:11])=[C:8]([CH:9]=1)[O:10][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([NH:22][C:23]([CH:25]3[CH2:26][CH2:27]3)=[O:24])[N:21]=2)[N:18]=1
Reactant: Cc1ccc(N)cc1O
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
To a suspension of sodium hydride (56 mg, 1.40 mmol) in N,N-dimethylformamide (2.0 mL) was added a solution of 5-amino-2-methylphenol (173 mg, 1.40 mmol) in N,N-dimethylformamide (1.0 mL), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (306 mg, 0.933 mmol) in N,N-dimethylformamide (1.5 mL), and the mixture was stirred at 110° C. for 24 hr. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the residue. The aqueous layer was extracted three times with ethyl acetate. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=17/83→90/10) to give the title compound (94 mg, 31%) as a brown powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.Cl[C:34]([O:36][CH2:37][CH2:38]Cl)=[O:35]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[N:2]3[CH2:38][CH2:37][O:36][C:34]3=[O:35])=[CH:17][CH:16]=2)=[O:20])=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: O=C(Cl)OCCCl
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: O=C(Nc1ccc(-n2cnc3c(N4CCOC4=O)ncnc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and 2-chloroethyl chloroformate by using the same method as in Example 107.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]([O:23]CC)=[O:22])[N:12]=2)[CH3:10])=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([C:21]([OH:23])=[O:22])[N:12]=2)[CH3:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(N(C)c2nc(C(=O)O)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 4-(N-(4-methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate (560 mg, 1.66 mmol) and sodium hydroxide (126 mg, 3.15 mmol) in 25 mL of methanol and water (1:3) was stirred at room temperature for 5 h. The solvents were removed under vacuum, and the residue was dissolved in 50 mL of water and acidified to pH 3. The white precipitate was collected and washed with water and dried (380 mg, 1.23 mmol, 74%). 1H NMR (CDCl3): 8.02-8.05 (m, 1H), 7.68 (ddd, J=1H, 8.4, 6.9, 1.5), 7.14-7.20 (m, 3H), 7.02-7.05 (m, 1H), 6.94-6.99 (m, 2H), 3.87 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].O[Li].O.Cl>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Temperature: 80 °C
Yield: 71.1 %

Procedure:
To the solution of methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoate (0.29 g, 0.623 mmol) in MeOH/H2O (2/1 mL) was added LiOH.H2O (0.131 g, 3.12 mmol). The mixture was heated with a microwave at 80° C. for 30 min. Then HCl (1 N) was added to adjust the about pH 4˜5. The solvent was removed. The residue was washed with H2O and a little EtOAc and dried under vacuum to afford the title compound 0.20 g (70%). LC-MS m/z 452 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][CH2:39][NH:40][CH3:41]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:40]([CH2:39][CH2:38][O:37][CH3:36])[CH3:41])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNCCOC
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: COCCN(C)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (367 mg, 0.72 mmol) and 2-methoxyethylmethyl amine (130 mg, 1.45 mmol) as starting materials.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.[CH2:11]([O:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26](=O)[CH2:27][CH2:28][C:29](O)=[O:30])[CH2:22][CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C1(C)C=CC=CC=1>[CH2:11]([O:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C@@:26]23[CH2:27][CH2:28][C:29](=[O:30])[N:10]2[C@@H:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:8][O:9]3)[CH2:22][CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C(O)CCC(=O)[C@H]1CC[C@H](COCc2ccccc2)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CC[C@@]2([C@H]3CC[C@H](COCc4ccccc4)CC3)OC[C@H](c3ccccc3)N12

Procedure:
To a stirred solution of (S)-(+)-phenylglycinol (6.85 g, 50 mmol) in toluene (150 mL) is added trans-4-[4-(benzyloxymethyl)cyclohexyl]-4-oxobutyric acid (15.2 g, 50 mmol), and the resulting mixture is heated to reflux for 4 hours with continuous water removal by using Dean-stark apparatus. The resulting mixture is concentrated, and the resulting residue is purified by silica gel column chromatography to afford trans-(3S,7aS)-7a-[4-(benzyloxymethyl)cyclohexyl]-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5-one.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C1NCCCn2c1cc1cc(F)cc(Br)c12
Reactant: OB(O)c1ccccc1
Product: O=C1NCCCn2c1cc1cc(F)cc(-c3ccccc3)c12

Procedure:
The title compound, light grey solid (62 mg, 84%), MS (ISP) m/z=295.2 [(M+H)+], mp 277° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[O:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH2:24])[CH2:17][CH2:16]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([NH:24][CH2:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)=[O:13]
Reactant: NCCCN1CCOCC1
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Product: Cc1[nH]c2c(c1C(=O)NCCCN1CCOCC1)CCCC2=O
Yield: 84.5 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 3-morpholinopropan-1-amine 0.30 g (2.1 mmol) was reacted to give 0.27 g (85%) of the titled compound as a white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C:7]1[CH:8]=[C:9]([CH:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=2)[OH:16])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C:7]1[CH:8]=[C:9]([C:15]([C:17]2[CH:18]=[C:19]([O:25][CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=2)=[O:16])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc(OC)cc(C(O)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of [3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-(3,5-dimethoxy-phenyl)-methanol (13.1 g, 32.4 mmol) in CH2Cl2 (330 mL) was added manganese dioxide (13.0 g, 150.0 mmol), and the mixture was stirred at ambient temperature for 8 h. Manganese dioxide (13.0 g, 150.0 mmol) was again added, and stirring proceeded for an additional 16 h. The mixture was filtered through Celite, and the sicciate was washed with CH2Cl2 (50 mL). The filtrate was evaporated, providing [3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-(3,5-dimethoxy-phenyl)-methanone as an oil (12.9 g, 99% yield): 1H NMR (CDCl3) δ 0.18 (s, 6H, 2SiCH3), 1.00 (s, 9H, SiC(CH3)3), 3.83 (s, 6H, 2OCH3), 3.89 (s, 3H, OCH3), 6.65 (t, J=2.4 Hz, 1H, Ar), 6.86-6.90 (m, 3H, Ar), 7.39-7.47 (m, 2H, Ar).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1.Br[CH2:16][CH2:17]Br>CS(C)=O>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:17][CH2:16]2)[N:4]=1
Reactant: BrCCBr
Reactant: CCOC(=O)Cc1cccnn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2cccnn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.2 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 830 mg, 21.66 mmol) was washed with petroleum ether under a nitrogen atmosphere to remove the mineral oil. Dimethylsulfoxide (10 mL) was added and the resulting suspension was stirred for 5 min before adding ethyl 2-(pyridazin-3-yl)acetate (600 mg, 3.61 mmol) and 1,2-dibromoethane (2.03 g, 10.83 mmol) dissolved in dimethylsulfoxide (10 mL) at 10° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was partitioned between a saturated aqueous solution of ammonium chloride and ethyl acetate. The organics were dried over sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified via column chromatography (100-200 silica gel mesh, 50-60% ethyl acetate in petroleum ether) to afford ethyl 1-(pyridazin-3-yl)cyclopropanecarboxylate (300 mg). MS (ES+APCI) (M+H) 193.0.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18]Cl>>[N:1]1([C:2]2[N:3]=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Nc1cc2ccccc2cn1
Reactant: ClCCCNCCCl
Product: c1ccc2cc(N3CCCNCC3)ncc2c1

Procedure:
3-(1,4-Diazacycloheptan-1-yl)-isoquinoline is prepared from 3-aminoisoquinoline and 2-chloroethyl-3-chloropropylamine.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[NH2:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[N:13]3[CH2:20][CH2:21][N:22]=[C:12]3[C:11]=2[CH:10]=1>N1C=CC=CC=1.CCOCC>[C:1]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[N:13]3[CH2:20][CH2:21][N:22]=[C:12]3[C:11]=2[CH:10]=1)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1ccc2c(c1)C1=NCCN1C(=O)N2
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)CC(=O)Nc1ccc2c(c1)C1=NCCN1C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.5 g (0.02 mol) of isovaleric acid chloride were added to 2.02 g (0.01 mol) of 9-amino-5-oxo-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline in 30 ml of absolute pyridine, and the mixture was stirred for 8 hours at room temperature. The mixture was then diluted with ether, and the precipitated crystals were separated off. The crystals were dissolved in water, the aqueous solution was purified with active charcoal and the free base was then precipitated by the addition of ammonia. It was filtered off under suction and dried.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.O[C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:22][CH:21]=1>>[CH2:27]([O:26][C:24](=[O:25])[C:23]1[CH:34]=[CH:35][C:20]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([C:14]([OH:16])=[O:15])[O:17][CH3:18])=[CH:8][CH:7]=2)=[CH:21][CH:22]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Product: COC(Cc1ccc(OCCCOc2ccc(C(=O)OCc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with benzyl 4-hydroxybenzoate and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18])=[O:8])[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1ccncc1N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccccc1C(=O)Nc1cnccc1C(N)=O

Procedure:
In a similar manner to Example 68 a) reaction of 2-propoxybenzoyl chloride (0.99 g), 3-aminoisonicotinamide (0.69 g) and triethylamine (0.51 g) in acetonitrile (15 ml) afforded a crude product (1.45 g) which was recrystallized from methanol to afford 3-(2-propoxybenzamido)isonicotinamide, 0.73 g, m.p. 214-7° C.
Reaction SMILES: O=[C:2]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6]CC)=O.[NH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[NH2:18]>C(O)C>[O:10]([CH2:9][C:2]1[CH:3]=[C:4]([OH:6])[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)CC(=O)COc1ccccc1
Solvent: CCO
Product: Oc1cc(COc2ccccc2)nn1-c1ccccn1
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
Ethyl 3-oxo-4-phenoxybutanoate (5a, 1.2 g, 5.4 mmol) was charged in a 25 mL round-bottom flask and dissolved in 10 mL of ethanol. A solution of 2-hydrazinopyridine (0.55 g, 5.0 mmol) in 5 mL of ethanol at 100° C. was gradually added thereto over 30 minutes, followed by stirring for 20 hours. After completion of the reaction was confirmed by TLC, the reaction solution was concentrated by evaporation, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography (n-Hex/EtOAc=9/1 (v/v)) to afford the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[BH3-]C#N.[Na+]>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropanecarboxamide (851 mg, 2.26 mmol) in acetic acid (60 mL) was added NaBH3CN (309 mg, 4.91 mmol) at 0° C. The reaction mixture was stirred for 5 min at room temperature after which no starting material could be detected by LCMS. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (5-40% ethyl acetate/hexanes) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-yl)cyclopropanecarboxamide (760 mg, 89%).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:13]([O:15][N:16]=[C:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[C:18]#[N:19])=[O:14]>C1(C)C=CC=CC=1>[C:1]([O:5][C:13]([O:15][N:16]=[C:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[C:18]#[N:19])=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CC(=NOC(=O)Cl)c1cccc2ccccc12
Reactant: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)ON=C(C#N)c1cccc2ccccc12
Reaction time: 3 h

Procedure:
The mixture was stirred for 3 hours at the same temperature and allowed to stand overnight. A solution of tert-butyl alcohol (11.1 g.) and pyridine (12 ml.) in toluene (20 ml.) was added dropwise, under ice-cooling, to the resultant mixture containing 2-chlorocarbonyloxyimino-2-(1-naphthyl)-acetonitrile. The mixture was stirred for 6 hours at the same temperature and allowed to stand overnight. The reaction mixture was then washed with water, 1N hydrochloric acid, water, a sodium bicarbonate aqueous solution and water, and dried over magnesium sulfate. The solution was concentrated under reduced pressure and n-hexane and methanol were added to the residue. The mixture was allowed to stand in a refrigerator and the precipitated crystals were collected by filtration and recrystallized twice from methanol to give 2-tert-butoxycarbonyloxyimino-2-(1-naphthyl)acetonitrile (3.3 g.), mp 90° to 92° C.