Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5]1[S:6][C:7]([CH3:12])=[CH:8][C:9]=1[C:10]#[N:11].O1[CH2:21][CH2:20]CC1.O>CN1CCNCC1.C(O)(=O)C>[CH3:12][C:7]1[S:6][C:5]2[NH:4][C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[N:1]=[C:10]([N:11]3[CH2:21][CH2:20][N:4]([CH3:5])[CH2:3][CH2:2]3)[C:9]=2[CH:8]=1
Reactant: C1CCOC1
Reactant: Cc1cc(C#N)c(Nc2ccccc2N)s1
Agent: CN1CCNCC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
2-(2-Aminoanilino)-5-methylthiophene-3-carbonitrile (2.0 g) is taken in N-methyl-piperazine (12 ml) and acetic acid (2 ml). The solution is heated at 120° C. until completion of reaction. The reaction mass is cooled and tetrahydrofuran is added. The reaction mixture is stirred for 30 minutes. The water is added at 45-50° C., the mixture is cooled up to room temperature and the solid is precipitated out. The solid is filtered off and washed with tetrahydrofuran-water mixture.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CCC)=[N+:2]=[N-:3].C1C2C(=CC=CC=2)C=CC=1C(Cl)=O.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7]([C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=1)=[O:21])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: O=C(Cl)c1ccc2ccccc2c1
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NCCNC(=O)c1ccc2ccccc2c1
Yield: 77 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 2-naphthoyl chloride (0.237 g, 1.24 mmol) was reacted with 2-azidoethanamine (0.107 g, 1.24 mmol) and triethylamine (0.252 g, 2.49 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-2-naphthamide (0.234 g, 77% yield). 1H NMR (300 MHz, CDCl3) δ 8.69 (s, 1H), δ 7.84 (m, 4H), δ 7.50 (m, 2H), 6.97 (t, J=4.2 Hz, 1H), δ 3.68 (q, J=4.8, 1.2 Hz, 2H), 3.56 (t, J=3.0 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.3, 135.1, 132.8, 131.5, 129.2, 128.8, 128.0, 127.9, 127.1, 123.8, 51.2, 39.8 ppm; HRMS (ESI) calcd for C13H12N4O (M+) 240.1011. found 240.1007.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[S:18]([C:21]1[CH:22]=[C:23]([C:27]2[C:36]([CH3:38])([CH3:37])[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:39]([O:41][CH3:42])=[O:40])[CH:33]=3)[N:28]=2)[CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19]>ClCCl>[CH3:37][C:36]1([CH3:38])[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:39]([O:41][CH3:42])=[O:40])[CH:33]=2)[N:28]=[C:27]1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18](=[O:20])(=[O:19])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:22]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Nc3ccccc3)c1)=N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
To a stirred solution of aniline (50 mg, 0.52 mmol) and N,N-diisopropylethylamine (122 mg, 0.86 mmol) in dichloromethane (4 mL) was added methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (170 mg, 0.43 mmol) in dichloromethane (2 mL). The mixture was stirred for 18 h at room temperature and purified on preparative Thin layer chromatography to afford 170 mg of methyl 3,3-dimethyl-2-(3-(N-phenylsulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate, which was used directly.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]([NH2:9])=[S:8])=[O:5])[CH2:3][CH2:2]1.Br[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[NH:20][C:19](=[O:24])[C:18]3[NH:25][CH:26]=[CH:27][C:17]=3[C:16]=2[CH:15]=1)=O.[CH2:28]([C:30]([O-:32])=[O:31])[CH3:29]>C(O)C>[CH:1]1([C:4]([NH:6][C:7]2[S:8][CH:11]=[C:12]([C:14]3[CH:23]=[CH:22][C:21]4[NH:20][C:19](=[O:24])[C:18]5[NH:25][CH:26]=[CH:27][C:17]=5[C:16]=4[CH:15]=3)[N:9]=2)=[O:5])[CH2:3][CH2:2]1.[CH2:28]([C:30]([O-:32])=[O:31])[CH3:29]
Reactant: NC(=S)NC(=O)C1CC1
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Solvent: CCO
Product: O=C(Nc1nc(-c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cs1)C1CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 27.9 %

Procedure:
57 mg (1.2 mmol) of cyclopropanecarbonyl-thiourea is added to a suspension of 124 mg (0.33 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3.5 mL of ethanol. The mixture is stirred at 90° C. for 6 hours then the mixture is cooled to room temperature. The solvent is evaporated, then the product is purified by preparative LCMS. After drying, 39 mg (28%) of 8-[2-(cyclopropanecarbonyl-amino)-thiazol-4-yl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH:14]=[C:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH:12]=[C:11]2[C:20]([OH:22])=O)=[CH:4][CH:3]=1.[CH2:24]([NH2:27])[CH2:25][NH2:26]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[NH:27][CH2:24][CH2:25][N:26]2[C:20](=[O:22])[C:11]2[N:10]([CH:14]=[C:13]([C:15]([N:16]([CH3:17])[CH3:18])=[O:19])[CH:12]=2)[CH2:9]3)=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: CN(C)C(=O)c1cc(C(=O)O)n(CC(=O)c2ccc(Cl)cc2)c1
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cc2n(c1)CC1(c3ccc(Cl)cc3)NCCN1C2=O
Yield: 26.8 %

Procedure:
To a suspension of 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(dimethylcarbamoyl)-1H-pyrrole-2-carboxylic acid (90 mg, 0.27 mmol) in 1,4-dioxane (10 mL) was added ethane-1,2-diamine (0.1 mL, 1.5 mmol). The reaction mixture was heated at reflux 4 h (monitored by LCMS). The reaction mixture was then concentrated in vacuo to give an oil that was purified using flash chromatography (Biotage SP4, 12 g cartridge, 0-20% MeOH gradient in CH2Cl2) to give 10a-(4-chlorophenyl)-N,N-dimethyl-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-7-carboxamide as a light brown solid (26 mg, yield 27%) 1H NMR (400 MHz, d6-acetone): δ 2.75-2.84 (m, 1H), 2.95-3.21 (m, 6H), 3.33 (ddd, 1H, J 11.2, 7.7, 3.3 Hz), 3.49 (ddd, 1H, J 11.0, 7.7, 3.2 Hz), 3.72 (dt, 1H, J 11.0, 8.0 Hz), 4.41 (d, 1H, J 12.6 Hz), 4.75 (d, 1H, J 12.6 Hz), 7.01 (d, 1H, J 1.6 Hz), 7.13 (d, 1H, J 1.6 Hz), 7.26-7.35 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([O:17][CH3:18])=[O:16])=[N:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1.N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].C(OCC)(=O)C>CN(C=O)C>[Si:28]([O:14][CH:11]1[CH2:10][CH2:9][CH:8]([C:7]2[N:6]=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[CH:3][C:2]=2[F:1])[CH2:13][CH2:12]1)([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29]
Reactant: COC(=O)c1ccc(F)c(C2CCC(O)CC2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c(C2CCC(O[Si](C)(C)C(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
To a solution of methyl 5-fluoro-6-(4-hydroxycyclohexyl)picolinate (1.0 equiv.) in DMF (0.15 M) was added imidazole (4.0 equiv.) and TBDMSCl (2.5 equiv.). The reaction mixture was stirred at room temperature for 2 days, then added to ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give methyl 6-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-5-fluoropicolinate in 97% yield as a mixture of isomers (3:1). LC/MS=368.3 (M+H), Rt=1.4 and 1.42 min.
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[O:34]1C[CH2:37][CH2:36][C@H:35]1C(NN)=O>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([C@@H:32]4[CH2:37][CH2:36][CH2:35][O:34]4)=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NNC(=O)[C@@H]1CCCO1
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Product: Cc1cc(C2CCC2)c(-c2nnc([C@@H]3CCCO3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152), using (S)-tetrahydrofuran-2-carbohydrazide (compound 172.1) in place of acetohydrazide. m/z (ES+) 496 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[N+:3]=1[O-].P(Cl)(Cl)Cl>C(Cl)CCl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)[n+]([O-])c(Cl)c1
Solvent: ClCCCl
Solvent: ClP(Cl)Cl
Product: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Reaction time: 8 h

Procedure:
A solution of 20.9 gm (0.1 mol) of 2,6-dichloro-4-nitropyridine-1-oxide (J. Chem. Soc. B 1967, 1235) in 100 ml of ethylene chloride was heated to boiling and then 27.5 gm (0.2 mol) of phosphorus trichloride were added. The solution obtained was stirred for a further 8 hours under reflux and was then concentrated by evaporation in vacuo. The oily residue which remained was poured into ice water. The crystalline residue formed was recovered by suction filtration and washed neutral with water.
Reaction SMILES: C(N=[N+]=[N-])C1C=CC=CC=1.[N:11]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[N+:12]=[N-:13].[C:22]([C:24]1[S:25][C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:27]([CH3:29])[N:28]=1)#[CH:23]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH:23]=[C:22]([C:24]3[S:25][C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:27]([CH3:29])[N:28]=3)[N:13]=[N:12]2)=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=NCc1ccc(F)cc1
Reactant: C#Cc1nc(C)c(C(=O)OCC)s1
Agent: [N-]=[N+]=NCc1ccccc1
Product: CCOC(=O)c1sc(-c2cn(Cc3ccc(F)cc3)nn2)nc1C
Yield: 62 %

Procedure:
Following the procedure as described in Example 2, making variations as necessary to replace benzylazide with 1-(azidomethyl)-4-fluorobenzene to react with ethyl 2-ethynyl-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 62% yield: 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.32-7.23 (m, 2H), 7.05-6.94 (m, 2H), 5.49 (s, 2H), 4.51 (q, J=7.1 Hz, 2H), 2.62 (s, 3H), 1.29 (t, J=7.1 Hz, 3H); MS (ES+) m/z 347.3 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:21]=[CH:20][C:9]3[CH:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25].C(O[K])(C)(C)C>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:21]=[CH:20][C:9]3[CH:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:23][C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:25])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1
Reactant: O=C(CCl)N1CCOCC1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: O=C(CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of trans-4-[6-(cyclopropylmethoxy)-1-benzofuran-2-yl]cyclohexanol (611 mg), 4-(chloroacetyl)morpholine (1.05 g) and tert-butoxy potassium (718 mg) in THF (10 mL) was stirred at room temperature overnight and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (882 mg).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:23](#[N:25])[CH3:24]>>[O:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:11]2[CH:21]=[CH:22][C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH2:24][C:23]#[N:25])=[N:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:16][CH2:17]1
Reactant: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Reactant: CC#N
Product: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1

Procedure:
In another aspect, the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride comprising the steps of: (1) reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; (3) reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; (4) converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; (5) reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide; and (6) contacting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide with hydrochloric acid to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide dihydrochloride.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([CH3:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:12])=[O:13])=[C:7]([CH3:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)ccc1S(=O)(=O)Nc1ccsc1C(=O)O
Temperature: 77.5 °C
Yield: 76.7 %

Procedure:
To a solution of 48 (256.0 mg; 0.69 mmol) in tetrahydrofuran (15 mL) and methanol (3 mL) was added aqueous lithium hydroxide (3.5 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The organic phase was dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The crude beige residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 10% v/v over 350 mL gradient elution) to give the title product as a white solid (187 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>ClCCl>[CH3:22][CH:21]([CH3:23])[C:20]([N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:7]2[CH2:8]1)=[O:24]
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 124d (160 mg, 0.952 mmol) in dichloromethane (10 mL) was added triethylamine (197 mg, 1.90 mmol). After stirring at room temperature for 5 minutes, a solution of isobutyryl chloride (111.0 mg, 1.047 mmol) in dichloromethane (2 mL) was added and the mixture was stirred for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was then concentrated under reduced pressure to afford 148a as a white solid (220 mg, 97%), which was used in the next step without further purification. MS-ESI: [M+H]+ 239.0
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.Br[CH2:14][CH2:15][CH3:16]>C1COCC1.O>[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:14][CH2:15][CH3:16])[N:5]=1
Reactant: Ic1n[nH]c2ccccc12
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1nc(I)c2ccccc21
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
NaH (60%, 197 mg, 4.92 mmol) was added to a solution of 3-iodoindazole (1.0 g, 4.1 mmol) in THF (20 mL) at 0° C., and the reaction stirred further for 30 min. Bromopropane (605 mg, 4.9 mmol) was added to the reaction at 0° C. The solution was heated to reflux and stirred overnight. It was then cooled, diluted with water, extracted with EtOAc (3×30 mL), and the organics were washed with brine, dried (Na2SO4), and concentrated. Purification by silica gel chromatography (10%-30% EtOAc/hexanes) gave 650 mg (56%) of the title compound as a yellow solid. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.93 (3H, t, J=7.2 Hz), 1.93-1.98 (2H, m), 4.35 (2H, t, J=7.2 Hz), 7.20 (1H, t, J=7.6 Hz), 7.36-7.49 (3H, m).
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][OH:6].Cl.Cl[C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29]>C(O)(=O)C.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([O:6][CH2:5][CH2:4][O:3][CH3:2])=[C:10]([N+:28]([O-:30])=[O:29])[CH:11]=3)[N:16]=[CH:15][N:14]=2)=[C:21]([F:27])[CH:22]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1Cl
Reactant: COCCO
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Sodium (148 mg, 6.4 mmol) was added to 2-methoxyethanol (10 ml), the mixture stirred for 15 minutes to give a complete solution and the volatiles removed by evaporation. The residue was dissolved in DMSO (5 ml) and 7-chloro-4-(4-chloro-2-fluoroanilino)-6-nitroquinazoline hydrochloride (500 mg, 1.3 mmol) was added. The mixture was stirred at ambient temperature for 18 hours then diluted with a solution of acetic acid (1 ml) in water (20 ml). The resulting precipitate was collected by filtration, washed with water, dried and purified by column chromatography eluting with methylene chloride/methanol (96/4). The purified product was recrystallised from methylene chloride/isohexane to give 4-(4-chloro-2-fluoroanilino)-7-(2-methoxyethoxy)-6-nitroquinazoline (304 mg, 60%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1I.[F:12][C:13]([F:18])([F:17])C([O-])=O.[Na+]>CN1CCCC1=O.O.[Cu]I>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:13]([F:18])([F:17])[F:12]
Reactant: Cn1c(I)cc2ccccc21
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc2ccccc21
Temperature: 160 °C
Yield: 37 %

Procedure:
A mixture of 1-methyl-2-iodoindole (4.40 g, 17.3 mmole), sodium trifluoroacetate (24.0 g, 176.5 mmole) and copper(I) iodide (17.1 g, 89.8 mmole) in N-methylpyrrolidone is heated at 160° C. for 6 hours, cooled to room temperature, diluted with water and filtered through diatomaceous earth to remove copper salts. The filtrate is extracted with ether. The extracts are combined, washed with water, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is chromatographed using silica gel and 4:1 hexanes:ethyl acetate as eluent to give the title product as a pale yellow oil which crystallized on standing, 119 g (37% yield), mp 28°-32° C., identified by IR, 1HNMR and 19FNMR analyses.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[C:14](=[O:21])[CH:13]=[C:12]2[CH3:22])[CH:18]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(O)=O.[N+:32]([O-])([O-:34])=[O:33].[K+]>O>[F:5][C:4]([F:7])([F:6])[C:3]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[C:14](=[O:21])[C:13]([N+:32]([O-:34])=[O:33])=[C:12]2[CH3:22])[CH:18]=1)([OH:8])[C:2]([F:1])([F:23])[F:24]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)CC2
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([N+](=O)[O-])c(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To a stirred mixture of 7.0 g (0.02 mole) of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one and 70 ml of trifluoroacetic acid is added 4.2 g (0.042 mole) of potassium nitrate. The mixture is stirred for 16 hours at room temperature and then is refluxed for 30 minutes. The mixture is poured into 300 ml of water. The solid is filtered off, washed with water, and dried. Recrystallization from 250 ml of acetonitrile gives 3.3 g (42%) of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]-6-methyl-5-nitro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, m.p. 289°-290° (dec).
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([Br:18])[CH:13]=1.[NH2:20][C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[CH:25]=2>>[Br:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:20][C:21]2[N:22]=[CH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[C:26]([O:31][CH3:32])[CH:25]=3)=[O:19])[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1ccccc1NCc1ccnc(Br)c1
Reactant: COc1ccc2cc(N)ncc2c1
Product: COc1ccc2cc(NC(=O)c3ccccc3NCc3ccnc(Br)c3)ncc2c1

Procedure:
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(7-methoxy-isoquinolin-3-yl)benzamide was prepared from 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester and 3-amino-7-methoxyisoquinoline in analogy to the procedures detailed in WO2004/013102, particularly Example 6A; supra; 1H-NMR (300 MHz, d6-DMSO) 10.62 (1H, s), 9.10 (1H, s), 8.51 (1H, s), 8.32 (1H, d), 8.11 (1H, t), 7.83-7.90 (2H, m), 7.60 (1H, s), 7.50 (1H, m), 7.38-7.41 (2H, m), 7.27 (1H, t), 6.66 (1H, t), 6.55 (1H, d), 4.54 (2H, d), 3.91 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1c[nH]nc1C
Product: COC(=O)c1cn(-c2ccc(OC)cc2)nc1C
Yield: 64.9 %

Procedure:
Using methyl 3-methyl-1H-pyrazole-4-carboxylate (5.7 g) synthesized in Example 1(3) and 4-methoxyphenylboronic acid (12.4 g) and in the same manner as in Example 17(1), the title object compound (6.5 g, 65%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1>C1C=CC=CC=1>[C:26]([O:13][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:7][CH2:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: OCc1ccc(OCc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(OCc1ccc(OCc2ccc(Cl)cc2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 1.2g of 4-(4'-chlorobenzyloxy)benzyl alcohol, 1.0g of triethylamine and 25 ml of anhydrous benzene was added 0.9g of hydrochloride of nicotinoyl chloride at 10° C. The whole mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water. The organic layer was dried over sodium sulfate and then concentrated in vacuo to give a crystalline residue. The residue was recrystallized from ethanol to give 1.2g of 4-(4'-chlorobenzyloxy)benzyl nicotinate, mp 101°-2° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[CH2:3][OH:4].[N:14]#[C:15]Br>>[Cl:13][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:15]([NH2:14])=[N:1]2)[CH:12]=[CH:11][CH:10]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CCc1cccc(Cl)c1
Product: NC1=N[C@@H](CCc2cccc(Cl)c2)CO1

Procedure:
In analogy to example 1b (S)-2-amino-4-(3-chloro-phenyl)-butan-1-ol was reacted with cyanogen bromide to give (S)-4-[2-(3-chloro-phenyl)-ethyl]-4,5-dihydro-oxazol-2-ylamine. Light yellow viscous oil. MS (ISP): 227.2 ([{37Cl}M+H]+), 225.1 ([{35Cl}M+H]+).