Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:10]2)=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1.[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[N:10]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: BrC1CCCC1
Reactant: CC(C)c1cc(I)ccc1N=C1NC2(CCCC2)CS1
Product: CC(C)c1cc(I)ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
4-Iodo-2-isopropylaniline was converted to 4-iodo-2-isopropylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 4-iodo-2-isopropylphenyl isothiocyanate according to Method C2a to give 2-(4-iodo-2-isopropylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodo-2-isopropylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2-(4-cyano-2-isopropylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [C:1]([C:3](=[C:9](OC(=O)C(C)(C)C)[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[NH3:22]>C(#N)C>[NH2:22]/[C:9](/[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[C:3](/[C:1]#[N:2])\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)=C(OC(=O)C(C)(C)C)C(CC)CC
Reactant: N
Solvent: CC#N
Product: CCOC(=O)/C(C#N)=C(\N)C(CC)CC
Temperature: 10 °C
Reaction time: 3 h

Procedure:
118.2 g (0.4 mol) of ethyl 2-cyano-3-[(pivaloyl)oxy]-4-ethyl-2-hexenoate were dissolved in acetonitrile and cooled to 10° C. At 10-15° C., 112 g (0.8 mol) of 25% strength ammonia solution were then added dropwise, and the mixture was stirred at 15° C. for 3 h. The organic phases is [sic] washed, dried and concentrated. Recrystallization with diisopropyl ether gave 57.5 g (68% of theory) of the title compound (m.p. 87° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:14][CH2:15][CH:16]2[CH2:18][O:17]2)=[CH:5][C:6]2[O:11][C:10](=[O:12])[CH:9]=[CH:8][C:7]=2[CH:13]=1.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.CO.Cl>C(O)(C)C>[OH:17][CH:16]([CH2:18][N:30]1[CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:33])([F:34])[F:19])[CH:22]=2)[CH2:32][CH2:31]1)[CH2:15][O:14][C:4]1[C:3]([O:2][CH3:1])=[CH:13][C:7]2[CH:8]=[CH:9][C:10](=[O:12])[O:11][C:6]=2[CH:5]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: COc1cc2ccc(=O)oc2cc1OCC1CO1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: COc1cc2ccc(=O)oc2cc1OCC(O)CN1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 80 %

Procedure:
Method C (1.5 d at 45° C.); starting materials: 6-methoxy-7-(oxiranylmethoxy)-2H-1-benzopyran-2-one (example 86) and 1-(3-trifluoromethylphenyl)piperazine; yield 80%; fusion point 133°-135° C. (from methanol). Hydrochloride: method F; yield 83%; fusion point 125°-128° C. (decomposes; from isopropanol).
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].[C:9]([OH:28])(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][N:2]([CH2:6][CH2:7][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][O:5][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: CN(CCO)CCO
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCN(C)CCOC(=O)CCCCCCC/C=C\C/C=C\CCCCC

Procedure:
Compound A-5 (348 mg, 54.0%) was obtained in the same manner as that in Reference Example 2, by using N-methyldiethanolamine (Tokyo Chemical Industry Co., Ltd.; 119 mg, 1.00 mmol) and linoleic acid (Aldrich; 617 mg, 2.20 mmol).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](I)[CH:9]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20]>CS(C)=O.[Cu]Br>[Br:7][C:8]1[CH:9]=[C:10]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCCN1
Reactant: Brc1cccc(I)c1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C1CCCN1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
To a flask charged with Cs2CO3 (4.74 g), Copper(I) bromide (99 mg), and ethyl-2-cyclohexanone-carboxylate (248 mg) was added 3 mL of DMSO under an argon atmosphere. 1-bromo-3-iodobenzene (2.0 g) was added followed by a solution of 2-pyrrolidinone (715 mg) in 3 mL of DMSO. The reaction mixture was stirred at rt for 16 h and then heated to 90° C. for 24 h. The mixture was filtered over celite, concentrated and purified by flash chromatography (65:35 hexanes:ethyl acetate) to afford 983 mg of 1-(3-Bromo-phenyl)-pyrrolidin-2-one as a brown solid.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:18]([NH:25][C:26]([NH2:28])=[S:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:18]([NH:25][C:26]1[S:27][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[N:28]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=S)NCc1ccccc1
Reactant: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Solvent: CCO
Product: CCOC(=O)c1sc(NCc2ccccc2)nc1-c1cccc(C#N)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
To a solution of ethyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (0.60 g, 2.03 mmol) in 20 mL of absolute ethanol was added N-benzylthiourea (0.34 g, 2.03 mmol). The resulting mixture was stirred at 80° C. for 3 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with saturated aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to-yield a solid. Trituration with hexanes/ethyl ether left the title compound as an off-white solid (0.36 g, 49%). MS (ESI) 364.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O)=[N:5]2.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15])=[N:5]2
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccccc1Sc1ccc2nccn2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccccc1)c1ccccc1Sc1ccc2nccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a mixture of 2-(imidazo[1,2-b]pyridazin-6-ylthio)benzoic acid (109 mg, 0.40 mmol), aniline (75 mg, 0.81 mmol), 1-hydroxybenzotriazole hydrate (61 mg, 0.40 mmol) and N,N-dimethylformamide (5 mL) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (153 mg, 0.80 mmol) and triethylamine (0.167 mL, 1.20 mmol), and the mixture was stirred at room temperature for 18 hr. A 1N aqueous sodium hydroxide solution was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→80/20) and precipitated from ethyl acetate/diisopropyl ether to give the title compound (110 mg, 0.32 mmol, yield 79%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:9].[NH2:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=1>>[NH2:16][C:17]1[C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)=[O:9])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccccc1C(=O)c1ccncc1
Reactant: Nc1cccnc1Cl
Product: Nc1cccnc1Nc1ccccc1C(=O)c1ccncc1

Procedure:
The title compound is prepared by reacting (2-aminophenyl)(4-pyridinyl)methanone as prepared by Nann, A. J. and Schofield, K., J. Chem. Soc. 1952, 583-9 with 3-amino-2-chloropyridine.
Reaction SMILES: C1C(C(N[C@H](C(O)=O)CCC(O)=O)=[O:8])=CC=C(NCC2N=C3C(N=C(N)NC3=NC=2)=O)C=1.[CH2:33]1[CH2:38][CH2:37][CH:36]([N:39]=[C:40]=[N:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:35][CH2:34]1>CS(C)=O>[C:40]([NH:39][CH:36]1[CH2:35][CH2:34][CH2:33][CH2:38][CH2:37]1)([NH:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=[O:8]
Reactant: Nc1nc(=O)c2nc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2[nH]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
The carboxylic acid group of folic add (1.0 g, 2 mmol) dissolved in 20 mL of DMSO was pre-activated with DCC (0.495 g, 2.4 mmol) and NHS (0.463 g 4 mmol) at room temperature (Scheme 2). In the reaction, dicyclohexylurea was formed and removed by filtration. The vacuum-dried precursor polymer was added to the reaction solution. The reaction was kept at room temperature for 48 hours. The resulting solution was placed in a dialysis membrane with a molecular weight cut-off of 2000 and dialyzed against DI water for one week. The final product was harvested by freeze-drying.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH2:13]([O:17][C:18]([C:20]#[C:21][C:22](OCCCC)=[O:23])=[O:19])[CH2:14][CH2:15][CH3:16]>C(O)C>[CH2:13]([O:17][C:18]([C:20]1[N:6]2[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][S:3][C:2]2=[N:1][C:22](=[O:23])[CH:21]=1)=[O:19])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOC(=O)C#CC(=O)OCCCC
Reactant: Nc1nc(-c2ccccc2)cs1
Solvent: CCO
Product: CCCCOC(=O)c1cc(=O)nc2scc(-c3ccccc3)n12
Reaction time: 48 h

Procedure:
A mixture of 8.8 g of 2-amino-4-phenylthiazole, 50 ml of absolute ethanol and 11.3 g of acetylene dicarboxylic acid di-n-butyl ester is heated to 50° to 60° C. for about 10 minutes. After standing for 2 days at room temperature the solution is evaporated to dryness. The residue is dissolved in ethyl acetate, filtered and the filtrate is mixed with an equal volume of ether. The precipitate is filtered off. 3-phenyl-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid n-butyl ester is thus obtained. Yield: 5 g=30.5% of the theoretical. Melting point 152°-154° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]([C:10](=[O:24])[NH:11][C@:12]2([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][C@H:13]2[CH:15]=[CH2:16])[CH2:8][CH:7]([OH:25])[CH:6]=1)=[O:4].[CH3:26][O:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32](O)=[CH:33][C:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:35]2)=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:9]([C:10](=[O:24])[NH:11][C@:12]2([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:14][C@H:13]2[CH:15]=[CH2:16])[CH2:8][CH:7]([O:25][C:32]2[C:31]3[C:36](=[CH:37][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[N:35]=[C:34]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:33]=2)[CH:6]=1)=[O:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)C1CC(O)C=C1C(=O)OC)C(=O)OC(C)(C)C
Reactant: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C=C1C(=O)OC)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
To an ice cooled solution of 29 (41 mg, 116 mmol) in dry THF, 7-methoxy-2-phenyl-quinolin-4-ol (150 mmol) and triphenylphosphine (150 mmol) were added. Then DIAD (160 mmol) was dissolved in THF (2 mL) and added dropwise to the solution. After one hour the mixture was concentrated and purified using flash chromatography (toluene/ethyl acetate 3:1). This gave the title compound as a yellow oil.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH2:32][OH:33])[CH2:26]1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2([C:45](O)=[O:46])[CH2:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1>C(Cl)Cl>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2([C:45]([N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH2:32][OH:33])[CH2:26]3)=[O:46])[CH2:44][CH2:43][CH2:42]2)=[CH:39][CH:40]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Reactant: OCC1CCCCNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(N1CCCCC(CO)C1)C1(c2ccc(Cl)cc2)CCC1
Yield: 95 %

Procedure:
iPrEtN (1.78 mL, 10.2 mmol) and pyBrOP (2.39 g, 5.12 mmol) were added at room temperature to a stirring solution of azepan-3-yl-methanol (0.4392 g, 3.41 mmol) and 1-(4-Chlorophenyl)-cyclobutanecarboxylic acid (1.0778 g, 5.12 mmol) in CH2Cl2 under N2. When the reaction was complete, the reaction was subjected to aqueous work-up. Silica gel purification (4:1 to 2:3 Hexanes: Ethyl acetate) provided the desired product in 95% yield (1.0395 g). LRMS: 321.91.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Reactant: ICCC1CCCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(CCC4CCCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and (2-iodoethyl)cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[C:28]([N:29]([CH3:44])[C:30](=[O:43])[CH2:31][N:32]2C(=O)C3=CC=CC=C3C2=O)=[CH:27][CH:26]=[C:25]([Cl:45])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.O.NN>C(O)C>[NH2:32][CH2:31][C:30]([N:29]([C:28]1[C:2]([Cl:1])=[C:3]([C:25]([Cl:45])=[CH:26][CH:27]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:44])=[O:43]
Reactant: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Yield: 65.2 %

Procedure:
A mixture of 8-[2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (750 mg), hydrazine monohydrate (117 mg) and ethanol was heated under reflex for 4 hours. The precipitate was removed by filtration and filtrate was evaporated in vacuo. The residue was dissolved with a mixture of chloroform and methanol (10:1, V/V), precipitate was removed by filtration and filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with chloroform - methanol to afford 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (390 mg) as an amorphous powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[CH2:13][CH2:14][NH:15][C:16](=[O:19])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]2[CH2:13][CH2:14][N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:16](=[O:19])[C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccccn1
Reactant: O=C1NCCc2ncc(OCc3ccccc3)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cc(OCc3ccccc3)cnc2CCN1c1ccccn1
Temperature: 150 °C

Procedure:
3-(Benzyloxy)-7,8-dihydro-1,6-naphthyridin-5(6H)-one, example 1.15, (10.0 mg, 0.04 mmol), 2-bromopyridine (8.0 μL, 0.08 mmol), CuI (1.1 mg, 0.006 mmol) and K2CO3 (11.0 mg, 0.08 mmol) were mixed in DMF (0.5 mL), and heated to 150° C. for 2 days. The reaction was partitioned between EtOAc (10 mL) and brine (10 mL). The organics were dried and concentrated and purified by RP-HPLC to afford the compound. LC-MS (M+H)=332.1.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[Cl:33][C:34]1[CH:35]=[C:36]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:37]=[CH:38][C:39]=1[Cl:40]>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=2)[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:36]2[CH:37]=[CH:38][C:39]([Cl:40])=[C:34]([Cl:33])[CH:35]=2)[CH2:46][CH2:45]1)=[O:20]
Reactant: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 71.2 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (652 mg, 1.31 mmol, 71%) was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13]C)=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[Cl:23].[Li+].[OH-].Cl>C1COCC1.CO>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[Cl:23]
Reactant: COC(=O)c1cc2scnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2scnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of methyl 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxylate (8.74 g, 21.02 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 5.0 M LiOH (aq., 9.5 mL). After stirring at ambient temperature for 2 h, the reaction was treated with 10% HCl (aq.) till the solution was acidic. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated to give the desired product (8.08 g, 95.7% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 9.18 (s, 1H), 8.71 (s, 1H), 8.47 (s, 1H), 7.44 (m, 1H), 7.31 (m, 1H), 6.65 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:40](=[O:41])[C:39]2[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=2)[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C=CC1CC1(NC(=O)C1CC(O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
Compound 21a (11.8 g, 32.0 mmol) and pyridine (27 ml, 305 mmol) were dissolved in DCM (200 ml) and cooled to 0° C., 4-nitrobenzoyl chloride (6.6 g, 35.6 mmol) was added and the solution was stirred at room temperature overnight. The reaction mixture was washed with NaHCO3 (aq), aqueous citric acid and brine, dried over MgSO4 and evaporated on silica. The crude product was purified by column chromatography on silica (EtOAc/n-Heptane: 50:50) to give 11.84 g, 72% of the title compound.
Reaction SMILES: ClC1C=CC2[N:6]=C(N)N=C(OCC)C=2N=1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:6])=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOc1nc(N)nc2ccc(Cl)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A mixture of 6-chloro-4-ethoxy-pyrido[3,2-d]pyrimidin-2-ylamine (0.22 g), 4-fluorobenzaldehyde (2.0 mmol), acetic acid 5.0 mmol) and molecular sieves (10 mg) in DCE (3 mL) was stirred at room temperature for 30 minutes. NaBH(OAc)3 was added portion by portion. The mixture was stirred for 16 hours, and then quenched by adding saturated aqueous NaHCO3. The solution was partitioned with DCM. The organic layer was dried over Na2SO4 and concentrated to afford the crude product which was purified by flash chromatography using hexane/ethyl acetate as eluting solvent. 0.33 g of 6-chloro-4-ethoxy-pyrido[3,2-d]pyrimidin-2-yl)-(4-fluoro-benzyl)-amine (Example 61) was obtained (yield: 50%) as a white solid which was characterized by its mass spectrum as follows: MS (m/z) 333.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH2:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].NC1C(Cl)=CC2NC(N3C=[C:39]([C:41](O)=[O:42])C=N3)=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)(=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH:26][C:41](=[O:42])[CH3:39])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2nc3cc(NC(C)=O)c(Cl)cc3n2COCCOC)c1
Reaction time: 3 h
Yield: 81 %

Procedure:
To a stirred suspension of 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.300 g, 0.762 mmol) and THF (4 mL) was added diisopropylethylamine (0.330 mL, 1.90 mmol) at 0° C. Acetyl chloride (57.0 μL, 0.800 mmol) was then added. After 3 h, the reaction was quenched with water (10 mL) and extracted with EtOAc (3×35 mL). The combined organic layers were washed with brine (15 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (5-65% EtOAc/hexanes) to yield the titled compound (0.270 g, 81%) as a 2:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C19H22ClN5O5, 435.1; m/z found, 436.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.83 (s, 1H), 8.71 (s, 1H), 8.18 (s, 1H), 7.79 (br s, 1H), 7.74 (s, 1H), 6.10 (s, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.66-3.62 (m, 2H), 3.48-3.43 (m, 2H), 3.29 (s, 3H), 2.29 (s, 3H), 1.38 (t, J=7.1 Hz, 3H).