Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[C:16]([C:18]1[CH:19]=[C:20]([S:25]([NH:28][C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1F)#[N:17].Cl>CN(C=O)C>[C:16]([C:18]1[CH:19]=[C:20]([S:25]([NH:28][C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])#[N:17]
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Reactant: Cc1cccc(Br)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Br)c1Oc1ccc(S(=O)(=O)Nc2ncns2)cc1C#N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-6-methylphenol (6.0 mmol, 1120 mg) and K2CO3 (10.5 mmol, 1450 mg) in DMF (15.0 mL) was added 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 65, 4.5 mmol, 1280 mg). The reaction mixture was heated at 80° C. After stirring for overnight at 80° C., the reaction was cooled to room temperature and poured into 1 N aqueous HCl (100 mL) to precipitate which was filtered to obtain solid. The solid was washed with water (100 mL) and heptane (100 mL) and the solid was dried under vacuum to furnish the title compound. LCMS Rt=3.05 minutes MS m/z 451 [M(79Br)H]+, 453 [M(81Br)H]+ 1HNMR (d6-DMSO): δ 2.17 (s, 3H), 6.70 (d, 1H), 7.25-7.31 (m, 1H), 7.44-7.48 (m, 1H), 7.64-7.69 (m, 1H), 8.01 (dd, 1H), 8.34 (d, 1H), 8.52 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9]O)[CH:5]=[CH:6][CH:7]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CS(C)=O.O>[N:22]([CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: OCCc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
A mixture of 3-bromobenzeneethanol 4-methylbenzenesulphonate [Example H(b)] (3.96 g, 11.2 mmol) and sodium azide (22.4 mmol, 1.46 g) in DMSO (50 ml) was stirred at room temperature for 16 h, diluted with water (200 ml), extracted with diethyl ether (2×40 ml), the combined extracts washed with saturated aqueous sodium chloride (40 ml), dried over sodium sulphate and evaporated, to give the product as a pale yellow oil (2.46 g). M+ 227; 360 MHz 1H n.m.r (CDCl3) 7.52 (1H, s), 7.45-7.42 (1H, m), 7.31-7.25 (2H, m), 3.58 (2H, t, 7.0 Hz), 2.85 (2H, t, J 7.0 Hz).
Reaction SMILES: COC1C=CC(N2C[C@H](C[N:15]3[CH2:20][CH2:19][CH:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)OC2=O)=CC=1>CS(C)=O>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(N2C[C@H](CN3CCC(Oc4ccc(O)cc4)CC3)OC2=O)cc1
Solvent: CS(C)=O
Product: Oc1ccc(OC2CCNCC2)cc1

Procedure:
3-p-methoxyphenyl-5(S)-[(4-p-hydroxyphenoxypiperidino)methyl]-2-oxazolidinone (hydrochloride), m.p. 190°-191°; [α]D =-30.3° (DMSO);
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:6][N:5]=1)([O-])=O.[Cl-].[NH4+]>[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)cn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1ccc(Sc2ccc(Cl)cc2)cn1

Procedure:
2-Nitro-5-(4-chlorophenylthio)pyridine (10.5 grams), ammonium chloride (50.0 grams), and powdered iron (30.0 grams) were reacted in the same procedures reported in Example 3. The reaction mixture was filtered hot solvents were removed. The product was extracted with ethyl acetate, washed with water, the ethyl acetate removed, and the product crystallized from ethyl acetate-hexanes, yield 4.5 grams, m.p. 157°-159° C.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[F:17][C:18]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:19]=1[O:20][CH2:21][CH2:22]Br.C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[F:2][C:3]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:22][CH2:21][O:20][C:19]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:18]=2[F:17])[CH2:10][CH2:11]1
Reactant: Cc1ccc(CC2CCNCC2)c(F)c1
Reactant: Fc1ccc(OCCBr)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2CCN(CCOc3ccc(F)cc3F)CC2)c(F)c1

Procedure:
The title compound was prepared from 4-(2-fluoro-4-methylbenzyl)piperidine hydrochloride (300 mg, 1.23 mmol), 2-(2,4-difluorophenoxy)ethyl bromide (321 mg, 1.35 mmol) and K2CO3 (357 mg, 2.58 mmol) as colorless flakes (326 mg): mp 180-182° C.; 1H NMR (CDCl3) 1.65-1.90 (m, 3H), 1.95-2.13 (m, 2H), 2.30 (s, 3H), 2.61 (d, J=6.9 Hz, 2H), 2.65-2.87 (m, 2H), 3.30-3.55 (m, 2H), 3.69 (d, J=12 Hz, 2H), 4.59 (t, J=4.2 Hz, 2H), 6.75-7.02 (m, 6H), 12.61 (bs, 1H); Anal Calcd. for C21H,25ClF3NO: C, 63.08; H, 6.30; N, 3.50. Found: C, 62.94; H, 6.34; N, 3.36.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]1[CH2:12][O:11][C:10]2[CH:13]=[CH:14][C:15]3[CH2:16][CH2:17][C:18](=O)[C:19]=3[C:9]1=2.[C:21]([CH2:23]P(=O)(OCC)OCC)#[N:22].C[O-].[Na+]>CO.O>[CH2:8]1[CH2:12][O:11][C:10]2[CH:13]=[CH:14][C:15]3[CH2:16][CH2:17]/[C:18](=[CH:23]\[C:21]#[N:22])/[C:19]=3[C:9]1=2
Reactant: O=C1CCc2ccc3c(c21)CCO3
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: N#C/C=C1\CCc2ccc3c(c21)CCO3
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of toluene (184 g), 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (8.5 g, 48.9 mmol) and diethyl cyanomethylphosphonate (10.4 g, 58.7 mmol) was added dropwise 28% sodium methoxide solution in methanol (11.3 g) over 1 hr under ice-cooling, and reacted for 4 hrs. To the reaction solution was added dropwise water (85 μg), and warmed, then the layers were separated. The organic layer was washed with water, and filtered to remove dusts under pressurization. The organic layer was concentrated under reduced pressure, and to the residue was added methanol and concentrated under reduced pressure to substitute the solvent. After stirring for 1 hr under heating with reflux, the solution was cooled and matured for 1 hr. The crystallization solution was filtered, and the crystals were dried under reduced pressure to give title compound (amount 8.1 g, yield 84.4%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[C:17]1([CH2:23][CH2:24][CH2:25]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]#[N:15])=[C:4]([S:16][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: BrCCCc1ccccc1
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(SCCCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, 3-phenylpropyl bromide and sodium ethylate in ethanol. ES-MS m/e (%): 347 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1([CH3:27])[CH:8](Br)[CH:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[O:6][C:4](=[O:5])[CH2:3]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[OH:1][C:2]1([CH3:27])[CH2:8][CH:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[CH:16][CH:17]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccc(F)cc3)cc2)C1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccc(F)cc3)cc2)C1
Yield: 60.4 %

Procedure:
The product obtained by reducing 200 mg of 3-hydroxy-3-methyl-4-bromo-7-[p-(p-fluorobenzyloxy)-phenyl]-5-heptanolide with 400 mg of tri-n-butyltin hydride in 2 ml of anhydrous tetrahydrofuran according to the method described in Example 2 (a), was recrystallized from a mixture of acetone and n-hexane (1:5) to give 99 mg of the desired compound melting at 143.5°-144.5° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH:22](OC)[O:23]C)=[CH:18][C:17]=3[F:27])=[N:13][C:12]=2[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.C(Cl)Cl>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:17]=3[F:27])=[N:13][C:12]=2[CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)c1ccc(-c2nc3cc(Cc4ccccc4)ccc3o2)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1ccc(-c2nc3cc(Cc4ccccc4)ccc3o2)c(F)c1
Reaction time: 1 h

Procedure:
5-Benzyl-2-(4-(dimethoxymethyl)-2-fluorophenyl)benzo[d]oxazole (0.160 g, 0.424 mmol) was dissolved in 2 mL THF and 1 mL 5N HCl was added. The mixture was stirred for 1 h, diluted with DCM, and quenched with 10N NaOH until basic. The aqueous was extracted 2×DCM. Combined organics were dried over sodium sulfate, filtered, and concentrated to give 4-(5-benzylbenzo[d]oxazol-2-yl)-3-fluorobenzaldehyde as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.09 (s, 1H), 8.43 (t, J=7.3 Hz, 1H), 7.90-8.04 (m, 2H), 7.72-7.83 (m, 2H), 7.38 (d, J=8.5 Hz, 1H), 7.26-7.33 (m, 4H), 7.17-7.24 (m, 1H), 4.11 (s, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=1[F:22].CCOC(C)=O>[Pd].CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[F:22]
Reactant: O=[N+]([O-])c1ccc(NCCc2cc3ccccc3[nH]2)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(NCCc2cc3ccccc3[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(2-(1H-indol-2-yl)ethyl)-2-fluoro-4-nitroaniline (2.32 g, 7.75 mmol) and Pd/C (0.60 g) in mixed solvents of EtOAc (25 mL) and MeOH (25 mL) was stirred at rt under H2 overnight. The mixture was then filtered, and the filtrate was concentrated in vacuo to give the crude product, which was used for next step without further purification.
Reaction SMILES: F[C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.O>CN1C(=O)CCC1>[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:2]2[C:3]([CH:8]3[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:33][CH:32]=1
Reactant: O=C1CCCC(c2nccnc2F)C1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CCCC(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)C1
Temperature: 125 °C

Procedure:
Argon was bubbled through a mixture of (rac)3-(3-fluoropyrazin-2-yl)cyclohexanone (250 mg, 1.287 mmol), cesium carbonate (1258 mg, 3.86 mmol) and 4-(benzo[d]thiazol-2-ylamino)phenol (468 mg, 1.931 mmol) in NMP (3 ml) for 5 min. The mixture was heated to 125° C. for 3 hrs and was then cooled to RT. Distilled water (100 ml) was added and the resulting mixture was extracted with EtOAc (3×50 ml). The organic layer was washed with water and brine and dried over sodium sulfate. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (20% to 50% EtOAc in hexanes) afforded (rac)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanone as a white solid. MS (ESI, pos. ion) m/z: 417.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[C:21]1(=[O:36])[N:25]([CH2:26][C:27](=[O:30])[CH2:28][NH2:29])[C:24](=[O:31])[C:23]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:22]12>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:29][CH2:28][C:27]([CH2:26][N:25]3[C:21](=[O:36])[C:22]4=[CH:35][CH:34]=[CH:33][CH:32]=[C:23]4[C:24]3=[O:31])=[O:30])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: NCC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: O=C(CNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1)CN1C(=O)c2ccccc2C1=O
Yield: 84 %

Procedure:
A suspension of 7-chloro-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione (18g, 56 mmole) and (3-phthalimidoacetonyl)amine, ethylene ketal (28.88 g, 112mmole) in 800 ml. of absolute ethanol is heated on a steambath, under nitrogen for 24 hours. The above mixture is then evaporated to dryness in vacuo to give 27 g (84%) of 7-chloro-5-(o-chlorophenyl)-2-[(3-phthalimidoacetonyl)amino]-3H-1,4-benzodiazepine, ethylene ketal as a buff-colored compound of melting point 180°-190° C. An analytical sample recrystallized from methanol ethyl acetate has a melting point of 200°-202° C.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:26]4[CH:35]=[CH:34][C:33]([O:36]CC5C=CC=CC=5)=[C:32]5[C:27]=4[CH:28]=[CH:29][C:30](=[O:44])[NH:31]5)[OH:25])=[CH:16][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[Pd]>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:26]4[CH:35]=[CH:34][C:33]([OH:36])=[C:32]5[C:27]=4[CH:28]=[CH:29][C:30](=[O:44])[NH:31]5)[OH:25])=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=c1ccc2c([C@@H](O)CNCCc3ccc(OCCC45CC6CC(CC(C6)C4)C5)cc3)ccc(OCc3ccccc3)c2[nH]1
Agent: [Pd]
Product: O=c1ccc2c([C@@H](O)CNCCc3ccc(OCCC45CC6CC(CC(C6)C4)C5)cc3)ccc(O)c2[nH]1

Procedure:
Obtained from Intermediate 24 (0.1 g, 0.17 mmol) and palladium on charcoal (10%, 0.02 g) by the same procedure described in Example 1 (reaction time: overnight). The crude obtained was triturated with ether giving the title compound as a white solid (0.081 g, 95%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH2:15][C:16](O)=[O:17]>C(OCC)C>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH2:15][CH2:16][OH:17]
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCc1c(Cl)cccc1Cl
Reaction time: 3 h
Yield: 82.9 %

Procedure:
a suspension of lithium aluminum hydride (13.75 g, 365.75 mmol) in anhydrous diethyl ether (500 mL) was added via a powder addition funnel 2,6-dichlorophenylacetic acid (50 g, 243.75 mmol). The resulting reaction mixture was refluxed for 16 hours and then quenched by slow addition of a sodium sulfate saturated aqueous solution (25 mL). The resulting slurry was stirred for 3 hours and then filtered, the insoluble was carefully washed with diethyl ether (2×100 mL). The combined ether filtrates were dried over sodium sulfate and the solvent was evaporated in vacuo to yield 38.6 g (85% yield) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](/[N:11]=[C:12](/[NH:32][C:33](=[O:42])[CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)\[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]2[C:20](=[O:21])[NH:19][C@@H:18]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:43]1([N:49]=[C:50]=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]1([CH2:7][CH2:8][C:9](/[N:11]=[C:12](/[NH:32][C:33](=[O:42])[CH2:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)\[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]2[C:20](=[O:21])[N:19]([C:50](=[O:51])[NH:49][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@@H:18]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(CCc1ccccc1)/N=C(\NCCC[C@H]1C(=O)N[C@@H]1C(=O)OCc1ccccc1)NC(=O)CCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)/N=C(\NCCC[C@H]1C(=O)N(C(=O)Nc2ccccc2)[C@@H]1C(=O)OCc1ccccc1)NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 149 (50 mg, 1.0 eq.) in DCM (2 mL) was added phenylisocyanate (29 μL, 3.0 eq.), triethylamine (12 μL, 1 eq.) and DMAP (1 mg). The reaction was stirred for 18 hours at room temperature and then diluted with dichloromethane and washed with 1N HCl and water. The organic layer was then concentrated in vacuo and purified via silica gel chromatography eluting with 15% EtOAc in hexanes to give 150 (10 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C@@H:33]([CH3:36])[CH2:34][OH:35]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=[C:16]([NH:32][C@@H:33]([CH3:36])[CH2:34][OH:35])[N:17]=2)=[C:20]([CH3:26])[CH:21]=1
Reactant: C[C@H](N)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(N[C@@H](C)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 240 h

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) and (S)-2-amino-1-propanol (75 mg, 1 mmol) were dissolved in THF (10 ml) and stirred under Ar at 23° for 10 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-15% EtOAc/CH2Cl2 gave the title compound as an off-white amorphous solid. mp 96-101°, LC MS m/z=441 (MH+) Retention time=2.04 min.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:12])=[CH:7][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
25.0 g (0.15 moles) of 4-(trifluoromethyl)phenol and 23.5 g (0.17 moles) of potassium carbonate were mixed in 80 ml of acetone in a 200 ml three-necked flask. The flask was equipped with a reflux condenser, a dropping funnel and a thermometer and was connected with a calcium chloride tube for shielding the flask against moisture of the outside. After the mixing, 21.4 g (0.17 moles) of dimethyl sulfate were added at a temperature of not higher than 30° C. in a dropwise manner to the mixture under stirring. After that, the reaction mixture was refluxed at reflux temperature of acetone for 5 hrs. After completing the reaction, the reaction liquid was cooled down to room temperature. The resulting precipitates (solid) were separated by filtration. The obtained filtrate was concentrated by an evaporator. To the resulting residue 100 ml of water and 100 ml of n-hexane were added, thereby extracting the target product into the n-hexane layer. To the resulting water layer 50 ml of n-hexane were added, thereby conducting an extraction again. The resulting two n-hexane layers were combined together, followed by washing with 80 ml of 2 mol/L sodium hydroxide aqueous solution. The resulting n-hexane layer was washed two times with 50 ml of water. The obtained n-hexane layer was dried with magnesium sulfate anhydride, followed by concentration by an evaporator and then by removal of hexane by distillation under reduced pressure, thereby obtaining 22.8 g (0.13 moles) of oily 4-(trifluoromethyl)anisole (isolation yield: 84.0%). This product was found to have the following properties.
Reaction SMILES: [Br:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[OH-].[Na+]>Cl.C(O)C>[Br:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cccc(N)c1Br
Temperature: 55 °C
Yield: 99.2 %

Procedure:
A solution of stannous chloride (15.0 g, 76.1 mM) in 30 mL of concentrated hydrochloric acid was slowly added to a solution of methyl 2-bromo-3-nitrobenzoate (4.0 g, 15.4 mM) in 90 mL ethanol at 15-30° C. over 1 hour. The mixture was then heated at 50-60° C. for 15 minutes. The mixture was cooled to room temperature and made alkaline by slow addition of solid sodium hydroxide maintaining a temperature of 30-35° C. The resultant mixture was extracted three times with chloroform. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 3.51 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil, identical in all respects to the material derived via catalytic hydrogenation described above.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:10]=2)[N:5]=[C:4]([N:19]2[CH2:25][CH2:24][CH2:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[CH2:20]2)[CH:3]=1.[CH2:30]([NH2:33])[CH2:31][NH2:32]>>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:19]1[CH2:25][CH2:24][CH2:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[CH2:20]1)[CH:3]=[C:2]2[NH:32][CH2:31][CH2:30][NH2:33]
Reactant: NCCN
Reactant: Clc1cc(N2CCCc3ccccc3C2)nc2ccc(Oc3ccccn3)cc12
Product: NCCNc1cc(N2CCCc3ccccc3C2)nc2ccc(Oc3ccccn3)cc12
Temperature: 180 °C
Reaction time: 3 h

Procedure:
The mixture of 2-[4-chloro-6-(pyridin-2-yloxy)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine (40 mg, 0.1 mmol) and ethane-1,2-diamine (2 mL) was heated with stirring in a 5 mL microwave process vial for 3 hours at 180° C. under microwave irradiation. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 7 mg of product as a yellow powder. MS obsd. (ESI+) [(M+H)+] 426. 1H NMR (400 MHz, CD3OD) δ ppm 8.12 (d, J=3.2 Hz, 1 H), 7.82-7.78 (m, 1 H), 7.66 (d, J=2.8 Hz, 1 H), 7.61 (d, J=8.8 Hz, 1 H), 7.48 (d, J=6.8 Hz, 1 H), 7.23 (dd, J=5.2, 2.4 Hz, 1 H), 7.16-7.08 (m, 4 H), 6.90 (d, J=8.4 Hz, 1 H), 6.04 (s, 1 H), 4.83 (s, 2 H), 4.16 (brs, 2 H), 3.41 (t, J=6.2 Hz, 2 H), 3.05 (t, J=4.8 Hz, 2 H), 2.94 (t, J=6.2 Hz, 2 H), 1.96-1.91 (m, 2 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:63][C:64]([CH3:68])([CH3:67])[CH2:65][NH2:66]>C(Cl)Cl>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:66][CH2:65][C:64]([CH3:68])([CH3:67])[CH3:63])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CC(C)(C)CN
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCC(C)(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in methylene chloride (2 mL) were added HBTU (30 mg, 0.079 mmol) and (2,2-dimethylpropyl)amine (0.045 mL, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (39 mg, 86%). LC-MS m/z 591 (M+H)+.