Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[N+:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([O-:32])=[O:31]>O1CCCC1>[CH2:1]([O:8][C:9](=[O:21])[CH:10]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:13][CH:12]=1)[CH2:37][C:36]1[CH:39]=[CH:40][C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)c1ccc(CC(=O)OCc2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To (4-tert-Butyl-phenyl)-acetic acid benzyl ester (92 g, 7.1 mmol) in tetrahydrofuran (50 ml) was added lithium diisopropylamide (8.5 mmol) at −78° C. After 30 min, 4-nitrobenzyl bromide (1.6 g, 7.5 mmol) was added. The cold bath was removed and the reaction mixture was allowed to warm to ambient temperature in 1 h. The reaction mixture was concentrated, partitioned between ethyl acetate and 1N ammonium chloride, washed with water, and dried over magnesium sulfate. Chromatography of the residue (5% ethyl acetate in hexane) afforded 2-(4-tert-Butyl-phenyl)-3-(4-nitro-phenyl)-propionic acid benzyl ester as a yellow oil (2.46, 83%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:31]1[CH:35]=[CH:34][CH:33]=[N:32]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C.[OH-].[Na+]>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22]([N:31]4[CH:35]=[CH:34][CH:33]=[N:32]4)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: c1cn[nH]c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(-n2cccn2)ccc1Br
Temperature: 180 °C
Yield: 82.7 %

Procedure:
To (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 32, 198 mg, 0.382 mmol) was added pyrazole (450 mg, 6.61 mmol) and p-toluenesulfonic acid (20 mg, 0.116 mmol). The mixture was heated by microwave irradiation to 180° C. for 30 minutes. The reaction was diluted with ethyl acetate and aqueous sodium hydroxide (1M). The organic was washed with water and brine and was dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by column chromatography to yield (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-bromo-6-(1H-pyrazol-1-yl)pyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (173 mg, 0.316 mmol). LCMS calc.=549.0/551.0. found=549.0/551.0.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:13][C:3]1[C:2]([Br:1])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:4]=1
Reactant: Nc1n[nH]c(-c2ccccc2)c1Br
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(-c2ccccc2)c1Br

Procedure:
Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=3/7) afforded the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): 7.74–7.78 (m, 2H), 7.24–7.36 (m, 3H), 6.86–6.92 (m, 2H), 6.74–6.78 (m, 2H), 4.9 (s, 2H), 4.22 (s, 2H), 3.64–3.74 (m, 4H), 2.86–3.04 (m, 4H). 13C NMR (400 MHz, CDCl3): 164, 146.2, 144.8, 128, 126.8, 118, 114.8, 60, 50.2, 50, 48.8, 46, 42, 20.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15]CC3C=CC=CC=3)[CH:13]=2)[NH:8][CH:7]=1)[CH3:2].[H][H]>C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[NH:8][CH:7]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)Cc1c[nH]c2ccc(O)cc12
Yield: 128.1 %

Procedure:
5-Benzyloxy-1H-indole-3-acetic acid ethyl ester (8.1 g, 20.3 mmol) was hydrogenated in ethanol using 3 g of Raney Ni in 150 mL of ethanol at approximately 40 psi (2.76×105 Pa) of hydrogen. The catalyst was filtered and the filtrate concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with a gradient, 30% ethyl acetate/hexane→50% ethyl acetate/hexane, to give 5.7 g (90% yield) of 5-hydroxy-1H-indole-3-acetic acid ethyl ester.
Reaction SMILES: CC[O-].[Na+].[Na].[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28]Br>O.C(Cl)Cl.CCO>[Br:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrCc1ccc2ccccc2c1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc2ccccc2c1Br)C(=O)OCC
Yield: 95.6 %

Procedure:
To a solution of NaOEt prepared from 9.66 g of sodium and 210 mL of dry EtOH was added 63.76 mL of diethyl malonate and the reaction mixture refluxed for 2 h. To the resulting yellow solution was added in small portions 126 g of 1-bromo-2-bromomethylnaphthalene and the reaction mixture refluxed for 16 h. Distillation of ethanol from an oil bath (100°-110° C.) through a simple Claisen head gave a yellow suspension, to which was added 350 mL of CH2Cl2 and 350 mL of H2O. The aqueous layer was extracted twice with 120-mL portions of CH2Cl2, and the combined organic layer was washed three times with 100-mL portion of H2O, dried (MgSO4) and evaporated to give 152 g (95.6%) of the ester as a yellow solid, mp 60°-65° C. Recrystallization from acetic acid gave 137 g (86.2%) of the pure diester as a colorless solid, mp 77°-79° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([NH2:24])=[CH:19][C:20]=3[NH:21]2)=[CH:13][CH:12]=1.[CH2:25]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[F:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([NH:24][CH3:25])=[CH:19][C:20]=3[NH:21]2)=[CH:13][CH:12]=1
Reactant: Nc1ccc2c(c1)[nH]c1cc(OCCOCCOCCF)ccc12
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc2c(c1)[nH]c1cc(OCCOCCOCCF)ccc12
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A mixture of 7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-2-amine (95 mg, 0.28 mmol), paraformaldehyde (43 mg, 1.43 mmol), and NaOMe (492 mg, 25% MeOH solution, 2.3 mmol) in 8 mL of MeOH was heated at reflux for 1.5 h under Ar atmosphere and cooled to rt. To this mixture was added NaBH4 (54 mg, 1.43 mmol) and the mixture was heated at reflux for 2 h. After cooling to rt, the mixture was quenched onto ice. It was extracted with ether (3×30 mL) and the combined organic phase was dried over MgSO4 and concentrated. The crude product was purified with chromatography (hexane/EtOAc) to afford 7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-N-methyl-9H-carbazol-2-amine (AD-CB-003P-WZ0141) as a light-brown solid (55 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6](=[CH:9]NC1C=CC=CC=1)[C:7]#[N:8])=[O:5].FC(F)(F)C(O)=O.[CH:28]1([NH:31][C:32](=[O:42])[C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([NH:40][NH2:41])[CH:34]=2)[CH2:30][CH2:29]1.C(N(CC)CC)C>C(O)C>[NH2:8][C:7]1[N:40]([C:35]2[CH:34]=[C:33]([CH:38]=[CH:37][C:36]=2[CH3:39])[C:32]([NH:31][CH:28]2[CH2:30][CH2:29]2)=[O:42])[N:41]=[CH:9][C:6]=1[C:4](=[O:5])[C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[Cl:1]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NN
Reactant: N#CC(=CNc1ccccc1)C(=O)c1ccccc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2ccccc2Cl)c1N
Yield: 38.4 %

Procedure:
A solution of 2-(2-chlorobenzoyl)-3-phenylaminoacrylonitrile (93 mg, 0.33 mmol, 1.0 eq), N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate (104 mg, 0.33 mmol, 1 eq), and triethylamine (31 μL, 0.22 mmol, 1.0 eq) in 20 mL of ethanol was heated to 60° C. for 48 h. After cooling, the mixture was concentrated and the residue was dissolved in minimal ethyl acetate. 100 ml diethyl ether was added and the precipitate was filtered and dried to provide desired product (50 mg, 39%). HPLC (4 minute 10-90 gradient) tR 2.51 min; MS m/z 395.1 [M+H]+; 1H NMR (DMSO), δ 8.50 (d, J=3.8 Hz, 1 H), 7.93 (d, J=8.0 Hz, 1 H), 7.84 (s, 1 H), 7.57 (m, 5 H) 7.32 (s, 1 H), 7.01 (s, 2 H) 3.37 (m, 2 H), 2.86 (m, 1 H), 2.14 (s, 3 H), 1.09 (t, 2H), 0.68 (m, 2 H), 0.58 (m, 2 H) ppm
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10](=[NH:14])OCC)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][O:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)=[N:20][C:21]=1N.Cl.Cl.NC1C=CC(N2CCO[C@@H](C(N3CCCC3)=O)C2)=NC=1N>>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:14][C:21]4=[N:20][C:19]([N:23]5[CH2:28][CH2:27][O:26][C@@H:25]([C:29]([N:31]6[CH2:32][CH2:33][CH2:34][CH2:35]6)=[O:30])[CH2:24]5)=[CH:18][CH:17]=[C:16]4[N:15]=3)[CH:7]=[N:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccc(N2CCO[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)c1cncc(C2CC2)n1
Agent: Cl
Product: O=C([C@H]1CN(c2ccc3nc(-c4cncc(C5CC5)n4)[nH]c3n2)CCO1)N1CCCC1

Procedure:
The title compound was prepared by a method analogous to Example 105 using ethyl 6-cyclopropylpyrazine-2-carbimidate (Intermediate 30) and (R)-(4-(5,6-diaminopyridin-2-yl)morpholin-2-yl)(pyrrolidin-1-yl)methanone (Intermediate 29). MS (ESI+) (M+H) 420.2; HPLC retention time 2.432 min (Method A).
Reaction SMILES: [CH:1]([NH:4][CH:5]=[NH:6])([CH3:3])[CH3:2].Br[C:8](=[CH:12]OC)[C:9](=[O:11])[CH3:10].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[N:6][CH:12]=1)(=[O:11])[CH3:10]
Reactant: COC=C(Br)C(C)=O
Reactant: CC(C)NC=N
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)c1cncn1C(C)C
Temperature: 8 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 13.9 g (0.162 mol) of N-isopropylformamidine (which was prepared in Reference Example 4), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 8° C. under stirring for 8 hours for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluant: ethyl acetate) to give 3.28 g (yield: 20%) of 5-acetyl-1-isopropylimidazole as pale yellow liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[F:35][CH:36]([F:39])[CH2:37][NH2:38]>>[F:35][CH:36]([F:39])[CH2:37][NH:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCC(F)F
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(NCC(F)F)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (100 mg, 0.190 mmol) and 2,2-difluoroethylamine (300 μL, 3.92 mmol) the title compound was obtained as a white powder (57 mg, 0.100 mmol, 52.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.94 (s, 1H), 8.15 (d, J=5.1 Hz, 1H), 7.65-7.75 (m, 2H), 7.38-7.44 (m, 2H), 7.27 (q, J=7.5 Hz, 3H), 6.30 (bs, 1H), 3.63 (bs, 2H), 3.27-3.31 (m, 1H), 1.36 (d, J=7.0 Hz, 6H). MS (ESI): 569.9 [M+H]+.
Reaction SMILES: C[O-].[Na+].[C:4]([O:12]CC)(=O)[CH2:5][C:6]([O:8]CC)=O.[F:15][C:16]([F:25])([F:24])[CH:17]1[CH2:22][CH2:21][NH:20][C:19]([NH2:23])=[N:18]1.Cl>CO.O>[OH:8][C:6]1[N:23]=[C:19]2[NH:18][CH:17]([C:16]([F:25])([F:15])[F:24])[CH2:22][CH2:21][N:20]2[C:4](=[O:12])[CH:5]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: NC1=NC(C(F)(F)F)CCN1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=c1cc(O)nc2n1CCC(C(F)(F)F)N2
Temperature: 40 °C
Yield: 80.4 %

Procedure:
62.10 g (1150 mmol) of sodium methoxide are added to a mixture of 340 mL (2230 mmol) of diethyl malonate heated to 40° C. The mixture is heated at 100° C. until a clear solution is obtained. 59.50 g (360 mmol) of 4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine dissolved in 100 mL of methanol are then added to the reaction medium. The mixture obtained is maintained at 100° C. for 1 hour and then cooled to room temperature overnight. The reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 250 mL of water. 12 N hydrochloric acid is added to the thick suspension obtained, to pH=5-6. The suspension obtained is filtered through a sinter funnel and the insoluble matter is rinsed with acetonitrile to give 68.10 g of 2-hydroxy-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in the form of a yellow solid, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34](O)=[O:35])[CH:29]=1.Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(=O)([O-])O.[Na+].CN(C)C(=O)C>[CH3:26][C:25]1[C:20]([C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]4[N:5]([CH:27]=[C:2]([NH:1][C:34]([C:30]5[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=5)=[O:35])[N:3]=4)[CH:6]=3)[CH:12]=2)=[O:19])=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)c4cccnc4)cn3c2)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 30.7 %

Procedure:
A mixture of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (150 mg, 0.625 mmol), pyridine-3-carboxylic acid (76.9 mg, 0.625 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (132 mg, 0.689 mmol), 1H-benzotriazol-1-ol (58.0 mg, 0.429 mmol), N,N-diisopropylethylamine (143 μL, 0.835 mmol) and N,N-dimethylacetamide (5 mL) was stirred at room temperature for 13 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→75% ethyl acetate-hexane) to give the title compound (89.0 mg, 46%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][NH:15][CH:12]1[CH2:14][CH2:13]1
Reactant: O=Cc1c(F)ccc(F)c1Cl
Reactant: NC1CC1
Product: Fc1ccc(F)c(CNC2CC2)c1Cl

Procedure:
Synthesized according to typical procedure J from 2-chloro-3,6-difluorobenzaldehyde and cyclopropylamine.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O-:10])=[O:9])[O:5][C:4]2[C:11]([CH2:19][CH2:20][CH3:21])=[C:12]3[C:17](=[CH:18][C:3]1=2)[CH2:16][CH2:15][CH2:14][CH2:13]3.[Na+].Cl>O>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[O:5][C:4]2[C:11]([CH2:19][CH2:20][CH3:21])=[C:12]3[C:17](=[CH:18][C:3]1=2)[CH2:16][CH2:15][CH2:14][CH2:13]3
Reactant: CCCc1c2c(cc3c(=O)cc(C(=O)[O-])oc13)CCCC2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCc1c2c(cc3c(=O)cc(C(=O)O)oc13)CCCC2
Yield: 86.1 %

Procedure:
A solution of the product of step (e) (0.3 g), in water (25 ml) was acidified with 2 N hydrochloric acid. The precipitated organic acid was filtered off washed with water and dried to give the title compound as a white solid, (0.24 g), mp 245°-8°.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:12][C@H:11]([C:13](OC)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[CH2:12][C@H:11]([CH2:13][OH:14])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)[C@H]1C[C@@H](c2ccc(C(F)(F)F)cc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OC[C@H]1C[C@@H](c2ccc(C(F)(F)F)cc2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of the compound prepared in Step 2, above (1.29 g, 5 mmol) in diethyl ether (100 ml) was added dropwise to a stirred suspension of LiAlH4 (0.23 g, 6 mmol) in diethyl ether (20 ml) over 30 minutes at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 3 hours, cooled to 0° C., and excess hydride was destroyed by addition of water (2.5 ml). To the resultant mixture was added 20% aqueous sulfuric acid (20 ml) and the organic phase was separated. The aqueous phase was extracted with diethyl ether (2×20 ml), and the combined extracts were washed with water (20 ml), saturated aqueous sodium bicarbonate (20 ml) and brine (20 ml), then dried over MgSO4. Evaporation of the solvent gave a clear colorless liquid (quantitative yield) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:4]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[B]1OC2C(=CC=CC=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([C@H:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:4]([O:13][S:14]([C:17]([F:19])([F:20])[F:18])(=[O:15])=[O:16])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C(=O)c1c(C)cc2cc(C)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](O)c1c(C)cc2cc(C)ccc2c1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl 2-(3,6-dimethyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (16.3 g, 40 mmol) in toluene (250 mL) cooled to an internal temperature of −40° C. was treated with (R)-(+)-2-methyl-CBS-oxazaborolidine (5.6 g, 20.1 mmol). Freshly distilled catecholborane (4.7 mL, 44.2 mmol) was diluted with toluene (20 mL) and the solution added dropwise to the reaction over 30 minutes to produce a clear yellow solution. After an additional 15 minutes, saturated Na2CO3 (300 mL) was added and the reaction allowed to warm to room temperature over 2.5 hours. The aqueous layer is extracted with EtOAc and the combined organics are washed with saturated Na2CO3 (3×300 mL), saturated NH4Cl (300 mL) and brine. Following drying over anhydrous MgSO4 and concentration in vacuo, the residue was purified using Isco silica gel column chromatography (10-75% EtOAc/hex) to produce (S)-ethyl 2-(3,6-dimethyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate that was determined to be 66% enantiomeric excess by HPLC analysis on a Chiralpak AS-H column with a 80:20 heptane/EtOH isocratic method. LCMS-ESI+ (m/z): [M+Na]+ calcd for C17H17F3O6SNa: 429.3. found: 429.3.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH:21]=[C:22]([C:28]([O:30]CC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:15]=1>C(O)C>[OH:30][C:28]1[C:15]2[C:16](=[CH:17][CH:18]=[CH:19][N:14]=2)[N:20]=[CH:21][C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(=CNc1cccnc1)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cccnc2c1O
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 265 g. of diphenyl and 735 g. of diphenyl ether is heated to 255° C., and then the above diethyl 2-([3-pyridylamino]methylene)-malonate is added all at once. The temperature of the mixture is maintained at 255° C. until ethanol is no longer evolved. The mixture is cooled to 25° C. and the precipitate is removed by filtration. It is washed liberally with hexane and dried. This affords 40.5 g. (75% yield) of ethyl 4-hydroxy-1,5-naphthyridine-3-carboxylate.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]2[C:23]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:15][CH2:14]1)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH3:44]I>CN(C)C=O>[CH3:3][C:4]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([N:19]([C:20]([C:22]2[C:23]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=3)=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH3:44])[CH2:17][CH2:18]1)[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(C)(CCCN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC(C)(CCCN1CCC(N(C)C(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)c1ccccc1
Reaction time: 1 h

Procedure:
0.095 g (0.803 mmol) of sodium hydride (55 to 65% in oil) are added to a solution of 0.4 g (0.724 mmol) of methyl 2-methyl-2-phenyl-5-{4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-piperidin-1-yl}-pentanecarboxylate in 5 ml of dimethylformamide at ambient temperature and stirred for one hour. Then 0.05 ml (0.803 mmol) of methyl iodide are added and the mixture is stirred for 14 hours. The reaction solution is poured onto water, extracted with ethyl acetate, and the organic phase is dried over sodium sulphate. The product is purified by column chromatography on silica gel (eluant: dichloromethane/methanol=5:1).