Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:16])[CH2:14][CH3:15].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:16])[CH2:14][CH3:15])=[C:2]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(N)cn2)C1
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 84.9 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)propan-1-one (500 mg, 1.96 mmol) was reacted with (R)-tert-butyl (1-(5-aminopyridin-2-yl)piperidin-3-yl)carbamate (860 mg, 2.94 mmol) to afford the desired product (850 mg, 84%) as a light brown solid: ESI MS m/z 511 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:22]3[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][N:23]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)N=C(N)OC[C@H]1F

Procedure:
The condensation of (4R,5S)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.1) and 5-chloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=381.1 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][C@H:59]([OH:62])[C@@H:58]([CH3:63])[CH2:57]2)CC1>>[ClH:1].[ClH:1].[OH:62][C@H:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:57][C@@H:58]1[CH3:63]
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Agent: Cl
Product: C[C@H]1CN(CCN2CCC(NC(=O)c3cc4c(OCc5coc6cc(F)ccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106, see example 55) and amine 14 analogously to the method described in example 1.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[CH:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[C:16]([F:29])[CH:15]=2)[CH2:9]1)(C)(C)C.Br[C:33]1[CH:34]=[CH:35][C:36]([C:39]2([CH3:50])[O:43][C:42]3=[N:44][C:45]([N+:47]([O-:49])=[O:48])=[CH:46][N:41]3[CH2:40]2)=[N:37][CH:38]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:29][C:16]1[CH:15]=[C:14]([N:10]2[CH2:9][CH:8]([CH2:7][OH:6])[O:12][C:11]2=[O:13])[CH:19]=[CH:18][C:17]=1[C:33]1[CH:38]=[N:37][C:36]([C:39]2([CH3:50])[O:43][C:42]3=[N:44][C:45]([N+:47]([O-:49])=[O:48])=[CH:46][N:41]3[CH2:40]2)=[CH:35][CH:34]=1
Reactant: CC1(c2ccc(Br)cn2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(c2ccc(-c3ccc(N4CC(CO)OC4=O)cc3F)cn2)Cn2cc([N+](=O)[O-])nc2O1

Procedure:
The titled compound was prepared using the same procedure as described previously (see Example 2-1, Step 3), except that 5-(tert-Butyl-dimethyl-silanyloxymethyl)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-2-one, and 2-(5-Bromo-pyridin-2-yl)-2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazole were used as the starting materials, and TBAF deprotection required. The titled compound was obtained as slightly yellow solid (60 mg). ESI MS m/z 456 (M+H). 1H NMR (DMSO-d6) δ 8.79 (s, 1H), 8.14 (s, 1H), 8.05-8.12 (m, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.63 (dd, J=5.2, 2.8 Hz, 1H), 7.48 (dd, J=8.8, 2.0 Hz, 1H), 5.24 (t, J=5.6 Hz, 1H), 4.85 (d, J=10.8 Hz, 1H), 4.69-4.77 (m, 1H), 4.49 (d, J=10.8 Hz, 1H), 4.12 (t, J=8.8 Hz, 1H), 3.86 (dd, J=8.8, 5.6 Hz, 1H), 3.64-3.72 (m, 1H), 3.50-3.59 (m, 1H), 1.97 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH2:16][CH:17]3[CH2:19][CH2:18]3)=[O:14])[CH:8]=2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[CH:17]1([CH2:16][NH:15][C:13]([C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:20]=[CH:21][C:2]([NH:1][C:30]([NH:29][C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)=[O:31])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:14])[CH2:19][CH2:18]1
Reactant: Nc1ccc(Oc2ccnc(C(=O)NCC3CC3)c2)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ccnc(C(=O)NCC3CC3)c2)cc1
Reaction time: 1 h

Procedure:
After adding 100 mg of 4-(4-Aminophenoxy)-2-[(cyclopropylmethyl)aminocarbonyl]pyridine to 5 ml of tetrahydrofuran, 0.075 ml of p-fluorophenyl isocyanate was added at room temperature and the mixture was stirred for 1 hour. NH type silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (hexane:ethyl acetate=1:1, followed by ethyl acetate and ethyl acetate:methanol=10:1). The solvent was distilled off under reduced pressure, ethyl acetate and hexane were added to the residue, and the precipitated solid was filtered out to obtain 25 mg of the target substance as a light yellow powder.
Reaction SMILES: [CH3:1][C:2]([OH:16])([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:3].N1C=CC=CC=1.[C:23]1([O:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:30](=[O:31])([O:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:16][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(O)c1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(OC(=O)Oc1ccccc1)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 2-(4-biphenyl)-2-propanol (53 g, 250 mmol) in dry CH2Cl2 (250.0 mL) was added pyridine (24.6 mL, 305 mmol) and phenylchloroformate (35.0 mL, 280 mmol) in CH2Cl2 (125.0 mL) at −5° C. After addition forms a thick precipitate, which, after the reaction mixture is allowed to stand overnight at 0° C. is mostly dissolved. The mixture is poured onto ice and diluted with CH2Cl2 (1000 mL). The organic phase is separated and washed three times with cold water. After drying over Na2SO4 the organic layer is evaporated at reduced pressure at a bath temp of <30° C. The crystalline residue is dissolved in diethyl ether (1000 mL) and the solution is then concentrated with a stream of nitrogen at atmospheric pressure at bath temperature of 60° C. to approximately 200 mL and then rapidly cooled to 0° C. to produce a pure crystalline product 55.0 g (66% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](COCCO)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:32][O:33][CH2:34][C:35](=[O:37])[CH3:36]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C:35]([OH:37])([CH3:36])[CH2:34][O:33][CH3:32])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Reactant: COCC(C)=O
Agent: [Li]CCCC
Product: COCC(C)(O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to Example 51, intermediate, from (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b), n-butyllithium and methoxy-2-propanone.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:31])[N:12]=[C:13]3[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][O:24]C4CCCCO4)=[CH:17][N:14]3[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.Cl>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:31])[N:12]=[C:13]3[CH:20]=[CH:19][C:18]([C:21]#[C:22][CH2:23][OH:24])=[CH:17][N:14]3[C:15]=2[OH:16])=[O:9])=[CH:32][CH:33]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1c(O)n2cc(C#CCOC3CCCCO3)ccc2nc1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1c(O)n2cc(C#CCO)ccc2nc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-oxo-7-(3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl)-2H-pyrido[1,2-a]pyrimidine-3-carboxamide (Preparation 7, 12 mg) is dissolved in CH2Cl2 and treated with 0.5 M HCl in methanol (0.5 mL). The reaction mixture is stirred for 16 h at room temperature. The mixture is concentrated, and the residue is crystallized from ether/hexanes and dried to afford 7 mg of the title compound as a brown solid. Physical characteristics: 1H NMR (CD3OD) δ9.2, 8.35, 7.75, 7.4-7.5, 4.80, 4.50; MS (ESI+) m/z 386 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[CH:4][N:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1COCC1>[C:12]([NH:16][C:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cnc(Cl)nc1Cl
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 24.85 g (117.5 mmol) of 2,4-dichloro-pyrimidine-5-carbonyl chloride in 125 ml of THF is cooled to −15° C. It is slowly mixed with a solution of 13.2 ml (124.5 mmol) of tert-buylamine and 17.4 ml (125.7 mmol) of triethylamine in 50 ml of THF, so that the temperature of the reaction mixture remains less than −10° C. It is stirred for another 2 hours at −10° C., then the cooling bath is removed, and the reaction mixture is heated to room temperature while being stirred. After 1 hour, the precipitate that is formed is filtered off, and the filtrate is completely concentrated by evaporation. The residue that is obtained is purified by chromatography (hexane/ethyl acetate 4:1). 14.01 g (56.6 mmol, corresponding to 50% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]3)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]3[CH2:37][CH2:36][CH:35]([NH:38][CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]4=[O:16])[CH2:34][CH2:33]3)=[CH:30][C:25]=2[O:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1cc(=O)n(CC=O)c2cc(OC)ccc12
Reactant: NC1CCN(Cc2ccc3c(c2)OCCO3)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(=O)n(CCNC2CCN(Cc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To 10 mL of a chloroform solution containing 111 mg of methyl 7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinoline-4-carboxylate and 93 mg of 1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-ylamine, 23 μL of acetic acid was added and stirred at room temperature for 1 hour. To the reaction mixture, 132 mg of sodium triacetoxyborohydride was added and stirred for 0.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added and the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=3:1], to give 134 mg of methyl 1-(2-(1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-ylamino)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylate.
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1>>[CH2:1]([C@H:8]1[C@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)[CH:15]=2)[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Cc1ccccc1)CO2
Reactant: Cc1cccc(CBr)n1
Product: Cc1cccc(COc2ccc3c(c2)[C@@H](O)[C@H](Cc2ccccc2)CO3)n1

Procedure:
By the method of Example 5, 500 mg (1.96 mmol) of trans-3-benzyl-4,6-chromandiol and 401 mg of 2-(bromomethyl)-6-methyl pyridine were converted to present title product, purified by flash chromatography on silica gel using 1:1 ethyl acetate:hexane as eluant to yield 0.38 g (53%) of present title product as white crystals, m.p. 87-90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:25]([O:26][CH3:27])=[CH:24][C:6]2[N:7]([C:10]3[S:11][C:12]([C:21]([OH:23])=O)=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C)C=O.C(OCC)(=O)C>[C:61]1([NH:60][C:21]([C:12]2[S:11][C:10]([N:7]3[C:6]4[CH:24]=[C:25]([O:26][CH3:27])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[N:9]=[CH:8]3)=[N:14][C:13]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:23])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: COc1cc2ncn(-c3nc(-c4ccccc4)c(C(=O)O)s3)c2cc1OC
Reactant: Nc1ccccc1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2ncn(-c3nc(-c4ccccc4)c(C(=O)Nc4ccccc4)s3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
To a solution of 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid (30 mg, 0.075 mmol) in dimethylformamide (1 ml) was added diethylisopropylamine (15.6 μL, 0.09 mmol) and HATU (28.5 mg, 0.075 mmol). The mixture was stirred under ambient temperature for 5 min. Aniline (6.8 μL, 0.075 mmol) was added. The mixture was stirred for 1 hr. Ethyl acetate (5 ml) was added. The mixture was washed with water (2×3 ml), brine, dried with magnesium sulfate and concentrated in vacuo. The crude was purified with flash chromatography (0 to 2% methanol dichloromethane) to afford 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid phenylamide (30 mg, 86.4%) as a yellow solid. MS m/z 457 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].[NH2:11][C:12]([NH2:14])=[O:13].S(=O)(=O)(O)O>CS(C)=O>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:4]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[N:14]=[C:12]([OH:13])[N:11]=1
Reactant: NC(N)=O
Reactant: N#Cc1ccccn1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Oc1nc(-c2ccccn2)nc(-c2ccccn2)n1
Temperature: 25 °C

Procedure:
1.0 g (approximately 60% dispersion in paraffin oil, about 25 mmol) of sodium hydride is added in portions to a solution of 5.21 g (50 mmol) of 2-cyanopyridine and 1.50 g (25 mmol) of urea in 100 ml of dimethyl sulfoxide. The resulting suspension is maintained at room temperature for 3 hours and then heated at 75° C. for 23 hours, cooled and poured into 100 ml of ice-water. The mixture is rendered neutral with 2N sulfuric acid, and the crude product is filtered off and recrystallised from 55 ml of methanol, yielding 4,6-di-pyrid-2-yl-[1,3,5]triazin-2-ol in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].C1(C)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH2:15][OH:16])[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C(CO)CO)CC1

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidin-4-ol, triethylamine, benzenesulfonyl chloride, and methylene chloride was stirred at ambient temperature for 2 days to yield 1-tert-butoxycarbonylpiperidin-4-yl benzenesulfonate. A mixture of 1-tert-butoxycarbonylpiperidin-4-yl benzenesulfonate obtained, diethyl malonate, 20% NaOEt-EtOH, and EtOH was heated under reflux with stirring for 22 hours to yield diethyl[1-(tert-butoxycarbonyl)piperidin-4-yl]malonate. A mixture of diethyl [1-(tert-butoxycarbonyl)piperidin-4-yl]malonate obtained, lithium borohydride, toluene, and THF was stirred at 60° C. for 18 hours to yield 2-(1-tert-butoxycarbonylpiperidin-4-yl)propane-1,3-diol, which was stirred together with 4M HCl-dioxane solution in MeOH at ambient temperature for 1 hour to yield 2-piperidin-4-ylpropane-1,3-diol hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH2:17].O>N1C=CC=CC=1>[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH:17][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2Cl)cc1OC
Temperature: 100 °C
Yield: 35.8 %

Procedure:
3,4-Dimethoxybenzoyl chloride (2 g) was added to a stirred suspension of 2-chloro-5-nitroaniline (1.72 g) in pyridine (10 ml) at 20° C. The reaction mixture was heated to 100° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was poured into water (100 ml). The resulting precipitate was collected, washed with water and dried. The solid was triturated under methylene chloride (20 ml) to give N-(2-chloro-5-nitrophenyl)-3,4-dimethoxybenzamide (1.2 g), m.p. 231-232° C.; NMR Spectrum: (DMSOd6) 3.82 (s, 6H), 7.08 (d, 1H), 7.62 (m, 1H), 7.82 (d, 1H), 8.08 (m, 1H), 8.54 (d, 1H), 10.07 (m, 1H);
Reaction SMILES: [N+](=[C:3]([CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5])=[N-].[CH2:16]=[CH:17]/[CH:18]=[CH:19]\[CH3:20]>CCCCC>[CH3:20][C@@H:19]1[CH:18]=[CH:17][CH2:16][C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C@H:9]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(C=Cc1ccccc1)=[N+]=[N-]
Reactant: C=C/C=C\C
Solvent: CCCCC
Product: COC(=O)C1=C[C@@H](c2ccccc2)[C@H](C)C=CC1
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A solution of (E) Methyl 2-diazo-4-phenyl-3-butenoate (0.26 g, 1.3 mmol) in dry pentane (20 mL) is added dropwise to a stirred solution of Rh2 (TBSP)4 (0.0195 g, 13.5 mmol) and cis-1,3-pentadiene (0.45 g, 6.7 mmol) in dry pentane (50 mL) under an argon atmosphere at room temperature. After stirring for 2 hours the solvent is removed under reduced pressure. Purification by silica gel column chromatography (1/99; diethyl ether/petroleum ether, Rf =0.05) gave the product as a yellow oil (0.25 g, 79%). IR (neat) 3025.0, 2952.4, 2872.3, 1712.2, 1652.4, 1455.8, 1435.7, 1240.3; 1H NMR (CDCl3)d 7.43-7.21 (m, 5H), 7.05 (d, 1H, J=5.1 Hz), 5.82 (dp, 1H, J=5.7, 2.0 Hz), 5.58 (dd, 1H, J=5.3, 3.8 Hz), 3.74 (s, 3H), 3.60 (dd, 1H, J=9.8, 5.2 Hz), 3.29 (d, 1H, J=5.7 Hz), 2.90-5.70 (m, 1H), 0.83 (d, 3H, J=7.0 Hz); 13C NMR (CDCl3)d 168.0, 146.3, 143.5, 136.7, 131.9, 128.6, 128.2, 126.7, 126.6, 51.9, 51.0, 36.3, 25.3, 20.8; MS m/z (relative intensity) 242 (100), 91 (70); HRMS calcd for C16H18O2 : 242.1307. Found: 242.1314.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].[CH3:15][O:16][CH2:17][CH2:18][NH2:19]>ClCCl>[CH3:15][O:16][CH2:17][CH2:18][NH:19][C:10](=[O:13])[CH:11]=[CH2:12]
Reactant: COCCN
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)NCCOC
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
N,N-Diisopropylethylamine (3.21 g, 25 mmol) was added to a stirred, ice-cooled solution of acryloyl chloride (2.25 g, 25 mmol) in dichloromethane (30 ml) under nitrogen followed, 2 minutes later, by 2-methoxyethylamine (1.92 g, 25.6 mmol) added dropwise over 1 hour. The cooling bath was removed, then the reaction mixture stirred for 18 hours at room temperature and washed twice with water. The combined aqueous washings were saturated with sodium chloride and exhaustively extracted with dichloromethane. All the dichloromethane solutions were combined, washed twice with 2M aqueous sodium carbonate solution, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of ethanol: dichloromethane (0:100 to 5:95), to yield the required amide as an oil. Rf 0.63 (SS 7). Found: C,54.97; H,9.24; N,10.68. C6H11NO2 ; 0.10 H2O requires C,55.04; H,8.62; N,10.70%. LRMS: m/z 130.4 (M+1)+.
Reaction SMILES: [NH:1]=[C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][N:3]1[NH2:12].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[OH-].[Na+].[OH:28][CH2:29][C:30](OC)=O>CCO>[N:1]1[C:30]([CH2:29][OH:28])=[N:12][N:3]2[C:2]=1[C:11]1[N:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:5]=[CH:4]2
Reactant: COC(=O)CO
Reactant: N=c1c2ncccc2ccn1N
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1nc2c3ncccc3ccn2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a suspension of 8-imino-1,7-naphthyridin-7(8H)-amine-2,4,6-trimethylbenzenesulfonate (1.2 g, 2.83 mmol) in EtOH (30 mL) was added NaOH (227 mg, 5.67 mmol). The mixture was stirred at 60° C. for 1 h. Then methyl 2-hydroxyacetate (773 mg, 8.50 mmol) was added. The resulting mixture was stirred at reflux for 2 h. The mixture was concentrated and purified by silica gel column chromatography (eluting with DCM/MeOH v/v 30:1) to give [1,2,4]triazolo[1,5-h][1,7]naphthyridin-2-ylmethanol as a yellow solid (280 mg, yield 49%). ESI MS: m/z 201.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:15][CH3:16])[C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5](Cl)=[O:6].O1CCCC1.[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(N(CC)CC)C>[CH:22]1([CH2:28][NH:29][C:5](=[O:6])[C:4]2[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:11][CH2:12][C:13]#[CH:14])=[C:2]([F:1])[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1OC
Reactant: NCC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCOc1c(F)cc(C(=O)NCC2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A mixture of 200 mg of 3-fluoro-5-methoxy-4-(2-propynyloxy)benzoyl chloride and 1 ml of tetrahydrofuran was added dropwise under ice cooling to a mixture of 5 ml of tetrahydrofuran, 93 mg of cyclohexylmethylamine and 100 mg of triethylamine. Then, the mixture obtained was stirred at room temperature for 0.5 hour. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 223 mg of N-cyclohexylmethyl-3-fluoro-5-methoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 45 of the present invention) represented by the formula: