Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[OH:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:12]=1[CH:13]=O.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[CH:13][C:12]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]=2[OH:10])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Cc1cccc(O)c1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc(O)c1C=Nc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A solution of 4-bromo-2-fluoroaniline (19.6 g, 103.16 mmol), 2-hydroxy-6-methyl-benzaldehyde (14.03 g, 103.16 mmol) and p-toluenesulfonic acid (188 mg, 0.99 mmol) in toluene (300 mL) was heated to reflux in a Dean-Stark apparatus for 1 h and then allowed to cool to ambient temperature. After adding triethylamine (0.8 mL) the reaction mixture was concentrated to give the crude title compound (31.7 g, 99%) which was used without further purification. Data: 1H-NMR (400 MHz, CDCl3) δ 2.52 (s, 3H), 6.72 (d, J=7.6 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 5.15 (t, J=7.8 Hz, 1H), 7.26-7.38 (m, 3H), 9.03 (s, 1H), 13.63 (s, 1H).
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.[ClH:12].C(N(C(C)C)CC)(C)C.Cl.CNC.[C:26]1([C:32]#[C:33][C:34]2[CH:35]=[N:36][CH:37]=[C:38]([CH:42]=2)[C:39](O)=[O:40])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.C(OCC)(=O)C>[ClH:12].[CH3:2][N:3]([CH3:4])[C:39](=[O:40])[C:38]1[CH:42]=[C:34]([C:33]#[C:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:35]=[N:36][CH:37]=1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.34 g, 1.8 mmol) to a solution of diisopropylethyl amine (0.47 mg, 2.7 mmol), dimethylamine hydrochloride (0.11g, 1.34 mmol) and 5-phenylethynyl-nicotinic acid (0.2 g, 0.9 mmol) in tetrahydrofuran and stir at room temperature for 18 h. Dilute the reaction mixture with ethyl acetate and extract with an aqueous saturated solution of sodium carbonate. Extract the aqueous layer with ethyl acetate. Combine organic layers, dry (magnesium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 40:60 to 80:20 ethyl acetate:hexanes, to give the free base of the title compound as a colorless oil. Convert the free base to the hydrochloride salt as described in EXAMPLE 163 to give the title compound (0.18 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[N:12]1[C:21]2[C:16](=[CH:17][C:18]([CH2:22][NH2:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.ClCCl>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:23][CH2:22][C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[N:12]=[CH:13][CH:14]=[CH:15]3)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: NCc1ccc2ncccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc(Cl)nc1NCc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of 2,4-dichloro-5-nitro-pyrimidine (2.80 g, 14.4 mmol) in dioxane (20 mL) was added dropwise a solution of quinolin-6-ylmethanamine (2.28 g, 14.4 mmol) in dioxane (4 mL) and DIPEA (2.56 mL, 14.7 mmol). The reaction mixture was stirred at room temperature for 2 hours. Dichloromethane (20 mL) was then added to the reaction mixture. The solvent was removed in vacuo and the crude product was purified by flash chromatography over silica gel, using 50% EtOAc-hexane, gave the desired product (3.18 g, 70%) as a pale yellow solid. LCMS (APCI) m/z 316.0 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:19]2[O:18][CH2:17][CH2:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:2].[BH4-].[Na+].Cl>C(O)C.O1CCCC1>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:19]2[O:18][CH2:17][CH2:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C1=Cc2cccc(-c3ccccc3C=O)c2OCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C1=Cc2cccc(-c3ccccc3CO)c2OCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a solution of ethyl 2,3-dihydro-9-(2-formylphenyl)-1-benzoxepin-4-carboxylate (0.58 g) in a mixture of ethanol (5.8 ml) and tetrahydrofuran (3 ml) was added sodium borohydride (34 mg) at 0 C. The reaction mixture was stirred for 30 minutes at ambient temperature, thereto was added 1N hydrochloric acid (2 ml), and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated n vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:9) as an eluent to give a solid of ethyl 2,3-dihydro-9-(2-hydroxymethylphenyl)-1-benzoxepin-4-carboxylate (530 mg).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[NH:15][C:14]4=[O:24])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1)#[CH:26].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:24])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:26]#[C:25][C:27]3[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Reactant: C#Cc1ccc(C=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(C#Cc4ccc(C=O)cc4)n[nH]c3c1)C(=O)N2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 12.2 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro [cyclopropane-1,3′-indolin]-2′-one (862 mg, 2 mmol), 4-ethynylbenzaldehyde (286 mg, 2.2 mmol), Pd(PPh3)2Cl2 (28 mg, 0.04 mmol, 2 mmol %) and CuI (15.3 mg, 0.08 mmol, 4 mmol %) in a 50 mL of flask was added DMF (6 mL) and Et3N (10 mL). The resulting mixture was stirred at 100° C. (oil temp.) for 90 min. After removal of Et3N, H2O (20 mL) was added and the precipates were collected by suction filtration. Crystals formed in the mother liquor were collected and dried to give the title compound (106 mg) as a yellow solid. The remaining residue was combined and purified by flash chromatography (gradient: EtOAc.hex 0 to 50% to 100%), followed by trituration with H2O to give the title compound (440 mg) as a yellow solid. Total 546 mg (yield 63%). 1H NMR (400 MHz, DMSO-d6) δ 13.63 (s, 1H), 10.44 (s, 1H), 10.05 (s, 1H), 7.98 (d, J=7.6 Hz, 2H), 7.87 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.58 (d, J=8.0 Hz, 1H), 5.63 (s, 1H), 3.29 (s, 3H), 3.22 (t, J=8.4 Hz, 1H), 2.40-2.33 (m, 1H), 1.99 (dd, J=8.8 Hz, 4.8 Hz, 1H); MS ESI 434.2 [M+H]+, calcd for [C27H19N3O3+H]+ 434.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([NH:30][CH3:31])=[O:29])[N:26]=2)=[N:10]1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][C@H:33]1[C:38]([OH:40])=[O:39]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([NH:30][CH3:31])=[O:29])[N:26]=2)[NH:12][C:13]([CH2:20][N:32]2[CH2:37][CH2:36][O:35][CH2:34][C@H:33]2[C:38]([OH:40])=[O:39])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)[C@@H]1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc(CC(=O)NC)cs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nc(CC(=O)NC)cs2)=NC1c1ccc(F)cc1Br
Yield: 52.8 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(4-(2-(methylamino)-2-oxoethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.15 g, 2 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.39 g, 3 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.66 g, 53%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH2:3][CH2:2]1.[P:13]([O-:28])([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2([P:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:28])[O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: [O-]P(Oc1ccccc1)Oc1ccccc1
Product: O=P(Oc1ccccc1)(Oc1ccccc1)C1(N2CCOCC2)CCCCC1

Procedure:
To 1-morpholinocyclohexene (21.5 g; 0.13 mol) was added diphenyl phosphite (30 g; 0.13 mol) drop-wise during 20 minutes. The mixture which began to deposit a solid was heated at 100° for 30 minutes following the addition. After cooling, the resulting solid was recrystallized from benzene/hexane to yield pure diphenyl 1-morpholinocyclohexane-1-phosphonate, 37 g (70%), mp 103°-6°. NMR and IR spectra support the structure. Analysis: Calculated for C22H28NO4P; N, 3.49%; P, 7.73%. Found: N, 3.40% P, 7.70%. ##STR10##
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:21]([CH3:23])[CH3:22]>CN1C(=O)N(C)CCC1>[CH:21]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1)([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)c1ccc2ccn(C(C)C)c2c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 1H-indole-6-carboxylate (5.00 g, 28.5 mmol) and cesium carbonate (18.6 g, 57.1 mmol) in DMPU (50 mL) was added 2-iodopropane (3.71 mL, 37.1 mmol). After stirring at 80° C. for 4 h, the solution was cooled to rt, poured onto ether, washed with H2O (three times) and brine, dried with Na2SO4, and concentrated. The crude compound was chromatographed to give the desired product. LCMS (M+1)=218.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([C:7]([O:24][CH2:25][C:26]([CH2:37][OH:38])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(N([P:48]([N:53]([CH:57]([CH3:59])[CH3:58])[CH:54]([CH3:56])[CH3:55])([O-:52])([O-])OCl)C(C)C)(C)C.[CH2:60](O)[CH3:61]>C(OCC)(=O)C.CCCCCC.C(N(CC)CC)C>[CH2:35]([O:34][C:32](=[O:33])[C:26]([CH2:25][O:24][C:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=1)[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH2:37][O:38][P:48]([N:53]([CH:54]([CH3:55])[CH3:56])[CH:57]([CH3:58])[CH3:59])[O:52][CH2:60][CH3:61])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:36]
Reactant: CCO
Reactant: CC(C)N(C(C)C)P([O-])([O-])(OCl)N(C(C)C)C(C)C
Reactant: CCOC(=O)C(CO)(COC(c1ccc(OC)cc1)(c1ccc(OC)cc1)c1ccc(OC)cc1)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(COP(OCC)N(C(C)C)C(C)C)(COC(c1ccc(OC)cc1)(c1ccc(OC)cc1)c1ccc(OC)cc1)C(=O)OCC
Yield: 91 %

Procedure:
Compound 4 was prepared from 1 (553 mg, 1.0 mmol), chloro bis[(N,N,-diisopropyl)amino]phosphite (307 mg, 1.15 mmol), and ethanol (69 mg, 1.5 mmol) as described for 3. Isolation on a silica gel column using gradient from 5:93:2 to 40:58:2 ethyl acetate/hexane/triethylamine gave 4 (662 mg, 91%) as a colorless oil. HR FAB MS: found m/z 727.3486; C39H54NO10P requires 727.3485. 1H NMR (CDCl3) δ 7.40-7.27 (6H, m), 6.92-6.67 (6H, m), 4.37 (1H, dd, J=5.8 and 7.5 Hz), 4.26-4.02 (5H, m), 3.77 (9H, s), 3.68 (2H, s), 3.75-3.39 (2H, m), 3.20 (2H, m), 1.40-1.00 (21H, m). 13C NMR (CDCl3) δ 168.6 (C), 168.4 (C), 158.3 (C), 136.5 (C), 130.0 (CH), 113.0 (CH), 85.6 (C), 63.7 (CH2), 61.6 (CH2), 61.3 (CH2), 60.9 (CH2), 60.0 (CH2), 58.9 (C), 55.2 (CH3), 43.0 (CH), 42.8 (CH), 24.6 (CH3), 24.4 (CH3), 19.1 (CH3), 14.0 (CH3). 31P NMR (CDCl3) δ 145.6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([F:30])=[CH:32][CH:33]=3)[C:15]=2[C:21]#[N:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2C#N)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(NC(=O)c3ccc(F)cc3)c2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 789.1 %

Procedure:
To a solution of 4-(3-Amino-2-cyano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.976 g, 3.23 mmol) and NEt3 (0.9 ml, 6.48 mmol) in THF (40 ml) was added 4-fluoro-benzoyl chloride (0.42 ml, 0.355 mmol). The solution was stirred with a magnetic stirrer at room temperature overnight and the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water (2×30 ml). and brine (30 ml). After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 4-[2-cyano-3-(4-fluoro-benzoylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (1.189 g, 87%). MS: (M+H)+ 425.2.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:19])[N:5]([C:12]([CH:16]([CH3:18])[CH3:17])([CH3:15])[C:13]#[N:14])[C:6]2=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH:27]=[CH2:28]>CC(C)=O>[CH2:28]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:19])[N:5]([C:12]([CH:16]([CH3:17])[CH3:18])([CH3:15])[C:13]#[N:14])[C:6]2=[O:11])[CH:27]=[CH2:26]
Reactant: CC(C)C(C)(C#N)N1C(=O)c2cccc(O)c2C1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc2c1C(=O)N(C(C)(C#N)C(C)C)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-hydroxy-α-isopropyl-α-methyl-1,3-dioxo-2-isoindolineacetonitrile (25.5 g, 0.099 mol), potassium carbonate (75.0 g, 0.543 mol) and acetone is stirred for 4 hours at reflux temperature under a nitrogen atmosphere, cooled to room temperature and treated with allyl bromide (34.1 mL, 0.395 mol). The reaction mixture is stirred overnight at reflux temperature, cooled to room temperature and filtered. The filtrate is concentrated in vacuo, diluted with ether, washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title product as a yellow-orange semi-solid, 26.9 g (91.5% crude yield). The sample is purified by flash chromatography (silica gel, CH2Cl2) to afford a colorless solid, mp 54°-58° C.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](O)=[O:19])[CH:13]=1)=[O:6].CO>C1COCC1>[CH3:3][O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=1)=[O:6]
Reactant: COC(=O)c1ncoc1-c1cccc(C(=O)O)c1
Agent: N#N
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1-c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 5-(3-carboxy-phenyl)-oxazole-4-carboxylic acid methyl ester (500 mg, 2.02 mmol) in THF (14.0 mL) at 0° C. was treated dropwise with a BH3 (10.1 mL of a 1M solution in THF, 10.11 mmol). The resulting mixture was stirred at 0° C. for 4 h. MeOH (14 mL) was then added dropwise. After 30 min, the solvent was removed under reduced pressure. EA (20 mL) was added and the organic phase was washed with 1N NaOH (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (93:7 CH2Cl2-MeOH) gave the title compound as a white solid. TLC: rf (93:7 CH2Cl2-MeOH)=0.32. LC-MS-conditions 02: tR=0.76 min, [M+H]+=234.39.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12](=[O:15])[CH2:13]Br)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C=O)C.[OH-].[K+]>O>[Cl:1][C:2]1[C:3]([N:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:15])[CH3:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1c(Cl)cccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(Nc1ccccc1)c1c(Cl)cccc1C(=O)O
Yield: 66.7 %

Procedure:
A solution of 3-chloro-2-(bromoacetamido) benzoic acid from Example 39 (4.6 g, 15.7 mmol), aniline (3.58 mL, 39.3 mmol) and DMF (45 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (400 mL) and 5% KOH (125 mL) and washed with CH2Cl2 (3×125 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature and filtered. The filter cake was rinsed with cold water (50 mL) and dried under high vacuum at 45° C. to yield 3.19 g (67%) of the title compound as a tan solid; 1H NMR (DMSO-d6) δ 13.1 (broad s, 1H), 9.85 (s, 1H), 7.74 (d, J=7.6, 1H), 7.71 (d, J=8.0, 1H), 7.35 (t, J=7.6, 1H), 7.10 (t, J=7.6, 2H), 6.65-6.58 (m, 3H), 6.1 (broad s, 1H), 3.82 (s, 2H); 13C NMR (DMSO-d6) δ 169.62, 166.77, 148.33, 133.87, 132.70, 131.53, 130.93, 128.90, 128.82, 127.21, 116.59, 112.57, 47.16; MS (LSIMS, m/z) 305 (M+H+).
Reaction SMILES: [Na].C1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([O-:14])=[O:13].Br[CH:16]1[S:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].C[N:24](C=O)C>>[N:24]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH:16]1[S:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])(=[O:13])=[O:14]
Reactant: O=C1NC(=O)C(Br)S1
Reactant: O=S([O-])c1ccc2ccccc2c1
Reactant: CN(C)C=O
Agent: [Na]
Product: O=C1NC(=O)C(S(=O)(=O)c2ccc3ccccc3n2)S1
Yield: 9 %

Procedure:
30% Aqueous hydrogen peroxide (10.7 mL, 104 mmol) was added dropwise to a stirred solution of 2-quinolinethiol [(II), 8.0 g, 49.6 mmol] in 2.5% aqueous NaOH (229 mL) and ethanol (229 mL). After 1 h the reaction mixture was concentrated to provide a white solid (8.34 g) which contained mainly sodium-2-naphthalenesulfinate (formula IV). A 7.0 g portion of this compound (<32.5 mmol) was added to a solution of 5-bromo-thiazolidine-2,4-dione (6.38 g, 32.5 mmol) in dry DMF (53 mL) and the resultant solution was stirred at room temperature for 4 h. The DMF was removed in vacuo and water (400 mL) was added to the residue. The water phase was extracted with ethyl acetate (2×400 mL) and the combined ethyl acetate phase was dried (brine) and concentrated. The crude product was flash chromatographed (gradient: 98:2 to 97:3 CH2Cl2 : isopropanol) to provide the title compound as a yellow solid (1.1 g, 9%): mp 168°-169° C.; NMR (DMSO, d 6): δ12.9 (broad s, 1H, NH), 8.85 (d, J=8.8 Hz, 1H, ArH), 8.24 (d, J=8.1 Hz, 1H, ARH), 8.16 (d, J=8.7 Hz, 2H, ArH), 8.02 (dd, J=6.9, 8.3 Hz, 1H, ArH), 7.89 (dd, J=6.9, 8.1 Hz, 1H, ArH), 6.95 (s, 1H, CH); MS(EI): 308 (MI, 10%), 265 (8%), 145 (18%), 129 (100%), 128 (75%); Anal. (C12H8N2O4S2): C, H, N.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:25][CH:24]=4)=[N:20]3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)(C)(C)C.C(Cl)Cl.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[N:29]1([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:19]3[N:18]=[CH:17][C:16]4=[CH:15][CH:14]=[C:13]([C:10]5[CH:11]=[CH:12][C:7]([C:6]([OH:35])=[O:5])=[CH:8][CH:9]=5)[N:21]4[N:20]=3)=[CH:24][CH:25]=2)[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-neck round-bottom flask, [A] 4-[2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzoic acid tert-butyl ester (0.34 g, 0.72 mmol), Methylene chloride (10 mL, 200 mmol) and Trifluoroacetic Acid (5.0 mL, 65 mmol) were added and stirred at room temperature overnight. The solvent was removed under vacuum. The resulting solid was washed with DCM to give 4-[2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzoic acid; compound with trifluoro-acetic acid as a yellow solid. LCMS (E/I+) 416.16 (M+H). NMR 1H (DSMO-d6)-9.45 (s, 1H), 9.01 (s, 1H), 8.35 (d, 2H, J=8.40 Hz), 8.07 (d, 2H, J=8.41 Hz), 7.88 (s, 1H), 7.71 (d, 1, J=8.80 Hz), 7.30 (d 1H, J=4.76 Hz), 7.17 (d, 2H, J=8.44 Hz), 6.98 (d, 1H, J=4.80 Hz), 3.83 (t, 4H, J=4.78 Hz), 3.24 (bs, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[C:4](=[O:17])[C:3]=1[CH:18]=O.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[C:4](=[O:17])[C:3]=1[CH:18]=[N:21][OH:22]
Reactant: NO
Reactant: N#Cc1cccc(F)c1-n1ccc(Cl)c(C=O)c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1cccc(F)c1-n1ccc(Cl)c(C=NO)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 2-(4-chloro-3-formyl-2-oxopyridin-1(2H)-yl)-3-fluorobenzonitrile obtained in Step C (2.70 g), hydroxylamine hydrochloride (814 mg), sodium acetate (1.60 g) and methanol (60 mL)/water (15 mL) was stirred at room temperature for 1 hr. The reaction solution was poured into ice water. The resulting solid was collected by filtration, and washed successively with water, 2-propanol and diethyl ether to give the title compound (2.39 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24](O)[CH3:25]>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:24][CH3:25])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)CCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CCc1cccc(O)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 3-(3-hydroxyphenyl)propionic acid (Lancaster, 66.4 g, 0.4 mol) in ethanol (700 mL) was treated with concentrated sulfuric acid (6 mL), heated to reflux for 2 h, and allowed to cool to RT. The mixture was cooled in ice, neutralized with 10% aqueous sodium carbonate and concentrated in vacuo to about 50 mL. Water (˜200 mL) was added and the mixture was extracted three-times with ethyl acetate. The combined ethyl acetate extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield the title compound as an oil (70 g, 90%).