Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:38][C:37](Cl)=[N:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:38][C:37]([C:14]#[C:13][C:12]2[CH:11]=[N:10][N:9]3[C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:5][C:6]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)=[N:7][C:8]=23)=[N:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cnc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 2-chloro-thiazole-5-sulfonic acid(2-hydroxy-1,1-dimethyl-ethyl)-amide (68 mg, 0.25 mmol) (Example B.14) according to general procedure II. Obtained as a yellow solid (24 mg, 17%). MS (ISP) 562.0 [(M+H)+]; mp 243–245° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.O.[NH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1OC

Procedure:
The title compound was prepared from 3,4-dimethoxybezenesulfonyl chloride and 4-piperidone monohydrate hydrochloride according to the procedure of Intemediate 22 as a white solid; 1H NMR (CDCl3) δ 2.55 (t, J=6.15 Hz, 4H), 3.40 (t, J=6.15 Hz, 4H), 3.93 (s, 3H), 3.95 (s, 3H), 6.97 (d, J=8.46 Hz, 1H), 7.23 (d, J=2.04 Hz, 1H), 7.41 (dd, J=2.10 Hz, 8.49 Hz, 1H); MS (ES) m/z 299.9 (MH+); HRMS for C13H17NO5S: 299.0834; Anal. Calcd. for C13H17NO5S: C, 52.16; H, 5.72; N, 4.68. Found: C, 52.13; H, 5.80; N, 4.59.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([CH3:18])[C:3]=1[C:4]#[N:5].Cl.Cl[C:21]([NH2:23])=[NH:22].COCCOCCOC>O>[NH2:23][C:21]1[N:22]=[C:4]([NH2:5])[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:6]=2[CH3:18])[N:1]=1
Reactant: CCCCCCC=Cc1ccc(N)c(C#N)c1C
Reactant: N=C(N)Cl
Agent: Cl
Solvent: O
Solvent: COCCOCCOC
Product: CCCCCCC=Cc1ccc2nc(N)nc(N)c2c1C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A mixture of 0.64 g of the 2-aminobenzonitrile of Example 4, 0.30 g of chloroformamidine hydrochloride, and 5.0 ml of diglyme was heated at 140°-150° C. for 5 h. The mixture was diluted with 50 ml of water and stirred for 1 h. The precipitated solid was collected by filtration, washed with water and acetone, and dried to leave 0.58 g (78%) of a white solid. (Mixture of cis-trans isomers.) Anal. calc'd for C17H24N4.2/3HCl: C, 66.2; H, 8.05 N, 18.1. Found: C, 66.2, H; 8.05; N, 18.2.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]([F:19])([F:18])[C:8]1[C:16]2[C:11](=[N+:12]([O-])[CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1.[OH-].[Na+]>>[Cl:3][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:10][N:9]=[C:8]([C:7]([F:19])([F:18])[F:6])[C:16]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2c(C(F)(F)F)n[nH]c21
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1n[nH]c2nccc(Cl)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
Phosphorus oxychloride (76.4 g) was gradually added to compound (1b) (33.2 g), followed by stirring at 100° C. for 1 hr. The reaction solution was poured into ice water, and sodium hydroxide was added thereto to adjust the pH to 10. The precipitate was collected by filtration to obtain compound (1c) (9.76 g, 270) as a light pink solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][O:6][C:7]1[C:12]([Br:13])=[CH:11][C:10]([CH:14]2[C:23]3[C:22](=[O:24])[CH2:21][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:19][C:18]=3[NH:17][C:16]([CH3:28])=[C:15]2[C:29]#[N:30])=[CH:9][C:8]=1[NH:31][S:32]([CH3:35])(=[O:34])=[O:33].N1C=CC=CC=1.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl.C(OCC)(=O)C>[Br:13][C:12]1[C:7]([O:6][CH2:5][C:4]2[CH:36]=[CH:37][CH:38]=[C:2]([NH:1][S:46]([CH3:45])(=[O:48])=[O:47])[CH:3]=2)=[C:8]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:9]=[C:10]([CH:14]2[C:23]3[C:22](=[O:24])[CH2:21][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:19][C:18]=3[NH:17][C:16]([CH3:28])=[C:15]2[C:29]#[N:30])[CH:11]=1
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(N)c2)c(NS(C)(=O)=O)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(NS(C)(=O)=O)c2)c(NS(C)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a solution of N-[2-(3-amino-benzyloxy)-3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinolin-4-yl)-phenyl]-methanesulfonamide (709 mg) and pyridine (286 μl) in dichloromethane (20 ml) was added methanesulfonyl chloride (138 μl). After stirring for 18 h, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Reaction SMILES: F[C:2]1[C:3]([CH3:14])=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:15][O-:16].[K+]>C1COCC1.CO>[CH3:15][O:16][C:2]1[C:3]([CH3:14])=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: C[O-]
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(C(=O)O)c1C
Temperature: 100 °C

Procedure:
To a stirring solution of 3-Fluoro-2-methyl-6-nitro-benzoic acid (4.2 g, 21 mmol) in THF (40 mL) and methanol (40 mL) is added potassium methoxide in methanol (15 g, 63 mmol) and the solution is heated to 100° C. for 2 hours. The reaction mixture is cooled to room temperature and then the mixture is quenched with a 1N HCl solution and partitioned between ethyl acetate. The organic layer is washed with brine and then concentrated to give 3-Methoxy-2-methyl-6-nitro-benzoic acid (4.3 g) in quantitative yields. 1H-NMR (400 MHz, δ, ppm) CDCl3: 2.32 (s, 3H), 3.98 (s, 3H), 6.95 (d, 1H), 8.15 (d, 1H).
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17](/[N:20]=[CH:21]/[C:22]4[O:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[O:5][C:4]1=[O:30])[CH3:2].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[CH2:1]([N:3]1[N:7]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][CH2:21][C:22]4[O:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)=[CH:18][CH:19]=3)[CH2:12][CH2:13]2)[O:5][C:4]1=[O:30])[CH3:2]
Reactant: CCn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)oc1=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCn1nc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3)CC2)oc1=O
Yield: 86.8 %

Procedure:
3-Ethyl-5-[1-(4[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9c, 0.41 g, 1 mmol) on reduction with sodiumcyano borohydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 3-ethyl-5-[1-(4-[(5-nitro-2-furyl)methyl]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (10c, 359 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Br:17]Br>C(Cl)Cl>[NH2:1][C:2]1[C:14]([Br:17])=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: BrBr
Reactant: COc1ccc(N)c(CN2CCOCC2)c1
Solvent: ClCCl
Product: COc1cc(Br)c(N)c(CN2CCOCC2)c1

Procedure:
N-(2-Amino-3-bromo-5-methoxy-benzyl)-morpholine was prepared from N-(2-amino-5-methoxy-benzyl)-morpholine and bromine analogous to Example 9. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [CH3:1][C:2]([CH3:59])([CH3:58])[C@H:3]([N:44]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[N:51]=2)[C:45]1=[O:57])[C:4]([NH:6][C@@H:7]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:25]C(=O)OCC1C=CC=CC=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[CH:14][CH:13]=1)=[O:5].Cl>C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[NH2:25][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[C@@H:9]([OH:36])[CH2:8][C@@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([N:44]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[N:51]=2)[C:45]1=[O:57])[C:2]([CH3:1])([CH3:58])[CH3:59])[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1ccc(-c2ccc(C[C@H](NC(=O)OCc3ccccc3)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4cccc(C)n4)C3=O)C(C)(C)C)cc2)nc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(-c2ccc(C[C@H](N)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4cccc(C)n4)C3=O)C(C)(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 74D (0.033 g, 0.041 mmol) in a mixture of ethyl acetate (0.25 mL) and methanol (0.25 mL) was treated with Pd(OH)2 on carbon (0.009 g, 20% Pd by wt.) and HCl solution (0.041 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filtered through a bed of celite® and rinsed with methanol. The solvent was concentrated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([C:15](O)=[O:16])[C:9]2=[O:18])=[CH:4][CH:3]=1.O=S(Cl)[Cl:21]>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([C:15]([Cl:21])=[O:16])[C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: O=C(O)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Yield: 95.1 %

Procedure:
A mixture of 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (200 mg, 0.557 mmol), SOCl2 (330 mg, 2.78 mmol) and one drop of DMF in toluene (30 mL) was refluxed for 2 h. The mixture was concentrated under vacuum to afford crude 1-(4-fluoro-phenyl)-4-iodo-2-oxo-1,2-dihydro-pyridine-3-carbonyl chloride (200 mg, 95%).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][C:10]#[C:11][CH2:12][C:13]#[C:14][CH2:15][C:16]#[C:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1.CC1C=CC(OCC#CCC#CCC#CCC#CCCCC(O)=O)=CC=1.O1CCCCC1OC1CCCCO1.C(O)(=O)C(O)=O>C(OCC)(=O)C>[CH3:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[O:19][CH2:18][C:17]#[C:16][CH2:15][C:14]#[C:13][CH2:12][C:11]#[C:10][CH2:9][C:8]#[C:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2]
Reactant: COC(=O)CCCC#CCC#CCC#CCC#CCOc1cccc(C)c1
Agent: C1CCC(OC2CCCCO2)OC1
Agent: Cc1ccc(OCC#CCC#CCC#CCC#CCCCC(=O)O)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: Cc1cccc(OCC#CCC#CCC#CCC#CCCCC(=O)O)c1

Procedure:
185 mg of 16-(m-methylphenoxy)hexadeca-5,8,11,14-tetraynoic acid methyl ester was treated with 21 ml of a pH 6.7 buffer solution (prepared as described in Example 1) and 1.98 g of Sigma Lipase, Type VII, from Candidacylindracea and sonicated for 30 minutes at room temperature. The reaction mixture was then transferred to a separatory funnel with ethyl acetate (200 ml) and acidified to pH ~3 with a saturated solution of oxalic acid. The organic layer was separated, dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by thin layer chromatography in silica gel with a Chromatatron (model 7924, Harrison Research, Palo Alto, CA) using hexane:ethyl acetate:acetic acid (70:30:1) as the eluant, yielding 16-(m-methylphenoxy)-hexadeca-5,8,11,14-tetraynoicacid, as an oil. The product was stored in dry ice.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[Cl:16][C:17]1[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=1[C:19](N(OC)C)=[O:20]>C1COCC1>[Cl:16][C:17]1[CH:28]=[CH:27][CH:26]=[CH:25][C:18]=1[C:19](=[O:20])[CH2:15][C:12]1[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=1
Reactant: Cc1ccncc1
Reactant: CON(C)C(=O)c1ccccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
To lithium diisopropyl amide (6.5 mL, 1.6 M in cyclohexane, 10.4 mmol) in THF (20.0 mL) at −78° C. was added a solution of 4-picoline (1.07 g mL, 11.5 mmol) in THF (10.0 mL) dropwise. The dry ice bath was removed. The reaction mixture was stirred at 0° C. for 30 minutes, and cooled back to −78° C. A solution of 2-chloro-N-methoxy-N-methylbenzamide (21) (2.39 g, 12 mmol) in THF (10.0 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. White solid was filtered off and dissolved in ethyl acetate. The organic phase was washed with water, brine, dried over dried magnesium sulfate and concentrated under vacuum to give 1-(2-chlorophenyl)-2-(pyridin-4-yl)ethanone (22) (1.09 g, 4.7 mmol, 47%) as white solid.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C=O.C(OCC)(=O)C>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:15][CH:16]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 4-(adamantan-1-yl)phenol (2.0 g, 8.76 mmol) in N,N-dimethylformamide was added potassium carbonate (3.63 g, 26.29 mmol) and ethyl 4-bromobutanoate (1.29 g, 10.51 mmol), and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give ethyl 4-(4-(adamantan-1-yl)phenoxy)butanoate as a white solid (2.7 g, 90% yield).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13]Br)=[CH:5][CH:4]=1.C[O:16][P:17]([O:20][CH3:21])[O:18][CH3:19]>C1(C)C=CC=CC=1>[CH3:19][O:18][P:17]([CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][P:17](=[O:16])([O:20][CH3:21])[O:18][CH3:19])=[CH:5][CH:4]=1)(=[O:16])[O:20][CH3:21]
Reactant: BrCc1ccc(CBr)c2ccccc12
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccc(CP(=O)(OC)OC)c2ccccc12)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
A 200 mL round bottom flask is charged with 1,4-bis(bromomethyl)naphthalene (Example 26(b), 2.07 g, 6.6 mmol) and toluene (75 mL). The flask is equipped with a Dean-Stark trap, condenser, and nitrogen inlet. The mixture is heated to reflux temperature to dry the toluene and starting material. A total of 25 mL of toluene is collected in the Dean-Stark trap and then discarded. The mixture is cooled to room temperature and then trimethyl-phosphite (4 mL, 34 mmol) is added and the reaction is heated at a gentle reflux overnight. The reaction is checked by TLC after 24 hours and found to be complete. The toluene and excess trimethylphosphite are removed at a reduced pressure to yield an oil. The product is chromatographed on 400 g of 40-63 μm silica gel. The sample is applied in ethyl acetate and elution is with 10% methanol-ethyl acetate. Fractions which contained 50 mL each are collected. The desired product (2.01 g, 0.00542 mole, 81%) is eluted in fractions 60-80 and is a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][C:10](=O)[C:9]=2[N:8]=1.N1C=CC=CC=1.[NH2:30][OH:31].Cl>C(O)C.O>[CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[N:30][OH:31])[C:9]=2[N:8]=1
Reactant: NO
Reactant: Cc1nc(-c2cccnc2)sc1-c1ccc2c(n1)C(=O)CCC2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2cccnc2)sc1-c1ccc2c(n1)C(=NO)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
A solution of 2-[4-methyl-2-(3-pyridyl)thiazol-5-yl]-6,7-dihydro-5H-quinolin-8-one (0.024 g, 0.067 mmol) was dissolved in ethanol (1 mL) and pyridine (0.054 mL, 0.053 g, 0.67 mmol) was added at ambient temperature. To this was added H2N—OH.HCl (0.0070 g, 0.10 mmol) and the resulting yellowish suspension was stirred at ambient temperature monitoring by LCMS. The reaction was complete after 2 hours. The reaction mixture was diluted with water and extracted ethyl acetate. The organic phase was then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography eluting with a 5 to 10% MeOH: CH2Cl2, gradient gave 13 mg (58%) of the title compound as a yellow solid, and as a single isomer with mp=212-215° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=1[N:6]=[C:7]2Cl.[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([CH:28]=1)[NH2:27])([CH3:21])([CH3:20])[CH3:19].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CC(N(C)C)=O>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([NH:27][C:7]2[C:8]3[C:3](=[C:2]([Cl:1])[N:11]=[CH:10][CH:9]=3)[C:4]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:5]=3[N:6]=2)[CH:28]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Fc1ccc2nc(Cl)c3ccnc(Cl)c3c2c1
Reactant: Cc1ccc(C(C)(C)C)cc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(C)(C)C)cc1Nc1nc2ccc(F)cc2c2c(Cl)nccc12
Reaction time: 0.75 h

Procedure:
To a solution of 1,5-dichloro-9-fluorobenzo[c]-2,6-naphthyridin (Example 1, Step 5) (150 mg, 0.56 mmol) and 5-tert-butyl-2-methylaniline (101 mg, 0.62 mmol) in DMA (2.8 mL) was added NaHMDS (1 M in THF, 1.2 mL, 1.2 mmol) at 0° C. After stirring for 45 minutes, the reaction was quenched by the addition of sat. aq. NaHCO3. The reaction was then extracted with EtOAc and water. The organic extracts were dried over MgSO4 and concentrated in vacuo. Column chromatography on silica gel (100% hexane to 100% EtOAc) provided the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:28]=[CH:29][N:30]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[CH:23]=O)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:28]=[CH:29][N:30]=3)[N:17]=[C:18]([C:20]3[CH:27]=[CH:26][CH:25]=[C:22]([CH2:23][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C=O)c3)nn3ccnc23)n1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(CN4CCCCC4)c3)nn3ccnc23)n1
Reaction time: 1 h
Yield: 51.9 %

Procedure:
3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzaldehyde (28 mg, 0.070 mmol) and piperidine (7 mg, 0.077 mmol) were dissolved in 1,2-dichloroethane (8 mL), stirred for 1 h, then sodium triacetoxyborohydride (44 mg, 0.21 mmol) was added followed by AcOH (0.1 mL). After 15 h, the solvent was removed and the residue was purified by chromatography (silica gel, dichloromethane/methanol 40/1) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(3-(piperidin-1-ylmethyl)phenyl)imidazo[1,2-b]pyridazin-8-amine (17 mg, 21%) as an orange solid. 1H NMR (300 MHz, CD3OD): δ 8.80 (s, 1H), 8.00 (s, 1H), 7.91-7.84 (m, 2H), 7.59 (s, 1H), 7.48-7.41 (m, 3H), 6.30 (d, 1H, J=7.8 Hz), 6.09 (d, 1H, J=8.4 Hz), 4.30-4.26 (m, 1H), 3.60-3.43 (m, 4 h), 2.51-2.47 (m, 4 h), 2.15-2.05 (m, 3H), 1.78 (brs, 1H), 1.63-1.60 (m, 4 h), 1.51-1.46 (m, 2H), 1.19 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 468, tR=1.397 min, HPLC: 99.52% at 214 nm, 98.65% at 254 nm, tR=5.76 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][C:34](=[O:43])[N:35]3[CH2:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:30][CH:29]=2)=[CH:9][CH:8]=1.Cl[C:45]1[C:50]([O:51][CH3:52])=[CH:49][N:48]=[CH:47][N:46]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH3:42][O:41][CH2:40][CH2:39][CH2:38][N:35]1[C:36]2[C:31](=[CH:30][CH:29]=[C:28]([CH2:27][O:26][CH:14]3[CH:13]([C:10]4[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:45]5[C:50]([O:51][CH3:52])=[CH:49][N:48]=[CH:47][N:46]=5)=[CH:8][CH:9]=4)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15]3)[CH:37]=2)[CH2:32][CH2:33][C:34]1=[O:43]
Reactant: COc1cncnc1Cl
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCN)cc3)cc21
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCNc4ncncc4OC)cc3)cc21
Temperature: 90 °C
Reaction time: 20 h

Procedure:
The mixture of 0.200 g of tert-butyl 4-[4-(4-aminobutoxy)phenyl]-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate, 0.058 g of 4-chloro-5-methoxypyrimidine, 0.0064 g of (±)-2,2′-bis(diphenylphosphine)-1,1′-binaphthyl, 0.387 g of sodium tert-butoxide and 0.0028 g of dipalladiumtris(dibenzylidenacetone)-chloroform complex in 10 ml of toluene is stirred under argon at 90° C. over 20 hours. The reaction mixture is cooled, admixed with brine (20 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed successively with water (100 ml) and brine (100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.25 (200:20:1 dichloromethane-methanol-conc. ammonia); Rt=4.60.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]#[N:11])=[N:3][CH:2]=1.[ClH:12]>CCO.[Pd]>[ClH:12].[ClH:12].[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([CH2:10][NH2:11])=[N:3][CH:2]=1
Reactant: N#Cc1ncnc2[nH]ccc12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ncnc2[nH]ccc12
Reaction time: 6 h

Procedure:
7H-Pyrrolo[2,3-d]pyrimidine-4-carbonitrile (86 mg, 0.597 mmol) was dissolved in EtOH (2 mL), then added concentrated HCl (0.2 mL, 2.39 mmol) and 10% Pd/C (20 mg). The reaction was put under a balloon of H2 gas and stirred for 6 h. The mixture was filtered through a pad of Celite®, washing with MeOH. The filtrate was concentrated in vacuo to yield C-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methylamine dihydrochloride as an orange solid.