Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:11]([F:27])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH3:28].C(O)(C)C>>[NH2:28][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:11]([F:27])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cc(F)c(Oc2cc(Cl)ncn2)cc1F)OCc1ccccc1
Reactant: N
Solvent: CC(C)O
Product: Nc1cc(Oc2cc(F)c(NC(=O)OCc3ccccc3)cc2F)ncn1
Temperature: 120 °C
Yield: 15 %

Procedure:
A mixture of benzyl [4-(4-chloropyrimidin-6-yloxy)-2,5-difluorophenyl]carbamate (3.92 g) and 2M ammonia-isopropanol (50 ml) was heated at 120° C. for 2 days in a sealed tube. The reaction mixture was allowed to cool to room temperature, then concentrated under reduced pressure. The resultant residue was partitioned between ethyl acetate and a 10% aqueous solution of potassium bisulfate. The organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2). Fractions containing the target compound were concentrated under reduced pressure and the residue was dried under reduced pressure to provide the titled compound as pale yellow crystals (561 mg, 15%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8](N)[C:9]=1[C:10](O)=O)([O-:3])=[O:2].[CH3:14][C:15]([CH3:21])=[C:16]1C=[CH:19][CH:18]=[CH:17]1.C(ON=O)(C)(C)C>C(COC)OC>[C:15](=[C:16]1[CH:10]2[C:9]3[C:8]([CH:17]1[CH:18]=[CH:19]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N+:1]([O-:3])=[O:2])([CH3:21])[CH3:14]
Reactant: CC(C)=C1C=CC=C1
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Agent: CC(C)(C)ON=O
Solvent: COCCOC
Product: CC(C)=C1C2C=CC1c1c2cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
A solution containing 6-nitroanthranilic acid (3) (19.65 g, 0.108 mol) and commercially available 6,6-dimethylfulvene (4) (17.2 g, 0.162 mol) in dimethoxyethane (DME, 125 mL) was added dropwise over 50 min to a stirred, 70° C. solution of tert-butylnitrite (90%, 17.3 g, 0.151 mol) in DME (350 mL). The mixture was stirred for 1 h and was cooled to room temperature. The reaction mixture was evaporated to yield a crude thick black oil which was directly subjected to silica gel chromatography eluting with ethyl acetate in petroleum ether (0-5% gradient) to afford 10 g of the crude product as a yellow oil, which partially crystallized on standing. Recrystallization from heptane gave the title compound (6.5 g, 26.5%) as a pale yellow solid: 1H NMR (300 MHz, DMSO) δ 7.70 (d, 1H), 7.42 (d, 1H), 7.09-7.01 (m, 1H), 7.00-6.92 (m, 2H), 5.33 (bs, 1H), 4.45 (bs, 1H), 1.55 (s, 6H); EIMS m/z 227.
Reaction SMILES: [C:1]1(=[O:14])[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)Cl.[Br:21]Br>C(Cl)(Cl)Cl.II>[Br:21][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:1](=[O:14])[CH2:2]1
Reactant: O=C1CCCCCCCCCCCN1
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClC(Cl)Cl
Product: O=C1CC(Br)CCCCCCCCCN1
Yield: 45.9 %

Procedure:
19.7 g of laurolactam in 100 ml of chloroform were cooled to 0° C. 20.8 g of phosphorus pentachloride were added portionwise over a period of 40 minutes while keeping the temperature below 5° C. There was then added 0.2 g of iodine, followed by 16.0 g (0.2 mol) of bromine over a period of 20 minutes. The mixture was heated under reflux for 4 hours, cooled, evaporated and poured on to ice. The product was taken up in chloroform, washed with sodium hydrogen sulfate solution, dried over anhydrous magnesium sulfate and evaporated. Crystallization from chloroform/ n-hexane yielded 12.65 g (46%) of 3-bromolaurolactam of melting point 155°-157° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([OH:11])[C:6]([Cl:10])=[CH:7][C:8]=1[F:9].[CH2:12](Br)[C:13]#[CH:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:10][C:6]1[C:5]([O:11][CH2:14][C:13]#[CH:12])=[CH:4][C:3]([NH2:2])=[C:8]([F:9])[CH:7]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: C#CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cc(N)c(F)cc1Cl

Procedure:
Using the procedure of Example 1, Step A and employing 50.0 g (252.45 mmol) of 3-amino-6-chloro-4-fluorophenol hydrochloride, 80% propargyl bromide (60.07 g, 504.9 mmol), and potassium carbonate (69.8 g, 504.9 mmol) in acetonitrile (200 mL), the title compound was obtained as a yellow solid (16.2 g), m.p. 62°-64° C. IR (nujol, era-1), NH2 (3298.0), triple bond (2117.6). 1H NMR was consistent with the structure.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)CC>[CH2:19]([NH:26][CH2:15][CH:14]([OH:16])[CH2:13][O:12][C:11]1[CH:17]=[CH:18][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:9][CH:10]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CC1
Reactant: NCc1ccccc1
Solvent: CCCO
Product: OC(CNCc1ccccc1)COc1ccc(CCOCC2CC2)cc1
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
1-[4-(2-Cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane (10 g) and benzylamine (13 g) were stirred under reflux, in n-propanol (100 ml) for 20 hours. The mixture was cooled and evaporated under reduced pressure to give a residue. This was stirred under petroleum ether (60°-80°) for 30 minutes; the solvent was decanted and the residue triturated with further petroleum ether. A white solid was obtained, collected by filtration and recrystallised from acetonitrile to afford N-benzyl-3-[4-(2-(cyclopropylmethoxy)ethyl)phenoxy]-2-hydroxypropylamine (8.8 g), m.p. 75°-6° C.
Reaction SMILES: [OH:1][CH:2]1[CH:8]([NH:9][C:10]([C@@H:12]([NH:17][C:18]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:23]=3[CH:24]=2)=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:7][CH:6]([CH3:31])[CH2:5][N:4]([S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)(=[O:34])=[O:33])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:15][CH:14]([CH3:16])[CH2:13][C@H:12]([NH:17][C:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:23]=2[CH:24]=1)=[O:19])[C:10](=[O:11])[NH:9][C@H:8]1[CH2:7][C@H:6]([CH3:31])[CH2:5][N:4]([S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)(=[O:34])=[O:33])[CH2:3][C:2]1=[O:1]
Reactant: COc1ccc2oc(C(=O)N[C@@H](CC(C)C)C(=O)NC3CC(C)CN(S(=O)(=O)c4ccccn4)CC3O)cc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc2oc(C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]3C[C@H](C)CN(S(=O)(=O)c4ccccn4)CC3=O)cc2c1
Yield: 83 %

Procedure:
To a solution of 5-methoxy-benzofuran-2-carboxylic acid {(S)-1-[3-hydroxy-6-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide (110 mg, 0.19 mmol) in 5 ml CH2Cl2, was added Dess-Martin reagent (122 mg, 0.29 mmol) at RT. The solution was stirred for 2 h when 50 ml CH2Cl2 was added and then washed with 10% NaHCO3 and brine. Purification by column chromatograghy (50% ethyl acetate in hexane) gave the title compound (90 mg, 82% yield). 1H-NMR (400 Hz, CDCl3): d (ppm): 8.69(d, 1H), 7.94(m, 2H), 7.39-7.24(m, 3H), 7.02(m, 4H), 5.26(m, 1H), 4.69(m, 2H), 3.84(m, 4H), 3.00(m, 1H), 2.05(m, 1H), 1.73(m, 2H), 1.61(m, 4H), 1.18(d, 3H), 0.97(d,6H);). The diastereomers were separated by HPLC. Diastereomer 1: MS (M+H+): 571.2; Diastereomer 2: MS (M+H+): 571.2
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:18]=[C:17]([CH3:19])[O:16][N:15]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>C1COCC1>[CH3:13][C:14]1[CH:18]=[C:17]([CH2:19][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][Br:20])[O:16][N:15]=1
Reactant: BrCCCCCCBr
Reactant: Cc1cc(C)on1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(CCCCCCCBr)on1
Temperature: -70 °C

Procedure:
To a solution of diisopropylamine (8.4 ml, 0.06 mol) in THF, was added, at -5° C., and under nitrogen, n-butyllithium (1.6M in Hexane, 37.5 ml, 0.06 mole). After the addition was complete, the solution was cooled to -70° C. and 3,5-dimethylisoxazole (5.82 g, 0.06 mol) in THF (20 ml) was added dropwise. The mixture was stirred for an additional hour at -70° C., then added, via nitrogen purge, to a solution of 1,6-dibromohexane (58.56 g, 0.24 mol) in THF (40 ml), and chilled to -70° C. with stirring. The mixture was allowed to gradually warm to room temperature and then stirred overnight. After quenching with saturated solution of ammonium chloride (30 ml), the mixture was extracted with isopropylacetate (250 ml) and the extract was washed with distilled water and dried. Removal of the solvent and excess 1,6-dibromohexane gave an oil which was purified by c.c. (EtAcO/Hexane; 1:4).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[CH2:18]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:18][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1nc2ccccn2c1C#Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1nc2ccccn2c1C#Cc1ccccc1
Yield: 97.2 %

Procedure:
0.238 g (0.949 mmol) of (3-(phenyl-ethynyl)imidazo[1,2-a]pyridin-2-yl) methanol were dissolved in 5 ml of dichloromethane with magnetic stirring and then 0.346 ml (4.75 mmol) of thionyl chloride were added. The mixture was stirred at r.t. for 2 h before being concentrated in vacuo. The residue was taken up into 20 ml of a mixture consisting of ethyl acetate and of a saturated NaHCO3 aqueous solution (1/1, v/v). After separation, the aqueous phase was extracted with 10 ml of ethyl acetate. The combined organic phases were washed with 10 ml of a saturated NaCl aqueous solution and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. 0.246 g (yield=96%) of 2-(chloromethyl)-3-(phenyl ethynyl)imidazo[1,2-a]pyridine were obtained as a brown solid. LC-MS: m/z=267 (MH+); UV purity at 254 nm=98%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([OH:11])=[N:5][NH:6]2.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:24][C@@H:25]1[C@@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C@H:29]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@@H:28]([CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[O:27][C@@H:26]1Br)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>C(#N)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:11][C@@H:26]1[O:27][C@H:28]([CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:29]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:35])[CH3:36])[C@H:25]1[O:24][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[N:5][NH:6]2
Reactant: Oc1n[nH]c2cccc(Br)c12
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(Br)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C

Procedure:
A mixture of 4-bromo-1H-indazol-3-ol (1.27 g), potassium carbonate (1.65 g) and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (which can be prepared in a manner described in literature, for example, Liebigs Ann. Chem. 1982, pp. 41-48; J. Org. Chem. 1996, vol. 61, pp. 9541-9545) (4.15 g) in acetonitrile (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1-2/1) to give the title compound (2.04 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:29])[CH2:9]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34]C(O)=O.[BH3-]C#N.[Na+]>CO.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]4[CH2:28][CH2:27][N:26]([CH3:34])[CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:29])[CH2:9]2)=[C:4]([C:30]([F:33])([F:31])[F:32])[CH:3]=1
Reactant: CC(=O)O
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a solution of (2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-piperidin-4-ylphenyl)sulfonyl]piperazine (81 mg, 0.155 mmol) in MeOH (2 mL) was added (CHO)n 27 mg, 0.93 mmol), HOAc (13.7 μL, 0.23 mmol) and NaBH3CN (6 mg, 0.093 mmol). The reaction mixture was stirred at room temperature overnight then 50° C. till disappearance of starting material. The reaction was diluted with DCM and quenched with aq. NaHCO3. The organic layer was separated and dried over Na2SO4 and purified on SiO2 gel column eluted with hexanes/EtOAc to give the desired product as a sticky oil (65 mg, 84%). It was redissolved in Et2O and acidified with 1N HCl in Et2O and triturated with hexanes/Et2O to give the titled compound as a white solid. HRMS: calcd for C24H29F4N3O2S+H+, 500.19893. found (ESI-FTMS, [M+H]1+), 500.19765.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:20])=[C:10]([CH:19]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[Cl-].[NH4+].Cl>O1CCCC1.CCOCC>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:20])=[C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH:1]=[CH2:2])[OH:12])[CH:19]=1
Reactant: C=C[Mg]Cl
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(O)(c1ccccc1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
225 ml of a filtered solution of 2.5 M/liter of vinyl magnesium chloride in tetrahydrofuran were added dropwise with stirring at -10° C. to a mixture of 58 g of 5-chloro-2-hydroxy-benzophenone and 900 ml of anhydrous ether and the mixture was stirred at room temperature for 16 hours and was refluxed for 3 hours. The mixture was iced and 600 ml of aqueous 10% ammonium chloride solution and 50 ml of concentrated hydrochloric acid were added thereto dropwise. The decanted organic phase was washed twice with 100 ml of water, was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The oil residue was chromatographed over silica gel and was eluted with methylene chloride to obtain 34.4 g of 5-chloro-2-hydroxy-α-phenyl-α-ethenyl-benzene-methanol.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNCc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A solution of 4′-bromomethylbiphenyl-2-carboxylic acid t-butyl ester made as described in Preparation 2 (7.2 g, 20.8 mmol), N-(2-aminoethyl) (t-butoxy)carboxamide (10 g, 62.4 mmol), and potassium carbonate (4.3 g, 31.2 mmol) in THF (40 mL) was stirred at room temperature overnight. The mixture was concentrated then extracted with EtOAc (3×150 mL) and water (80 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford crude intermediate (3a) (98.4% yield), which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)C.[NH2:23][NH2:24]>CO>[NH:23]([C:4](=[O:3])[CH2:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)[NH2:24]
Reactant: CCOC(=O)Cc1nc2ccc(C(=O)OC(C)(C)C)cc2s1
Reactant: NN
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc2nc(CC(=O)NN)sc2c1
Reaction time: 16 h
Yield: 86.8 %

Procedure:
To a solution of Compound 188b (480 mg, 1.5 mmol) in methanol (15 mL) was added anhydrous hydrazine (0.19 mL, 6.0 mmol) and the mixture stirred for 16 h. The resulting precipitate was filtered, washed with three volumes of methanol and dried in vacuo to afford Compound 188c (400 mg, 87%) as white powder. LCMS=1.64 min using analytical method (B), 308.0 (M+H). 1H NMR (400 MHz, CD3OD) δ 8.59 (d, J=1.1 Hz, 1H), 8.08 (dd, J=8.6, 1.8 Hz, 1H), 8.02-7.97 (m, 1H), 1.63 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH:13]=1
Reactant: CC(C)OC(=O)CBr
Reactant: COc1cc(CNc2c(F)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a solution of 4-fluoro-3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]-2-methyl-phenol (390 mg, 1.1 mmol, 1.0 eq) in DMF (6 mL) was added Cs2CO3 (538 mg, 1.65 mmol, 1.5 eq). The reaction was stirred 30 min, then isopropyl 2-bromoacetate (239 mg, 1.32 mmol, 1.2 eq) was added at room temperature. The reaction mixture was stirred at room temperature for a further 1 h, then water was added and the aqueous layer was extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude product was purified by column chromatography (petroleum ether:EtOAc, 1:0, 100:1, to 20:1) to give the title compound as a colorless oil (400 mg, 80%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C@H:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([N+:25]([O-:27])=[O:26])[CH:19]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>ClCCl>[Br:8][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C@@H:10]([CH3:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][C:20]=1[N+:25]([O-:27])=[O:26]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCC[C@H](C)Oc1ccc(C)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: CCCCCC[C@H](C)Oc1ccc(CBr)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
A suspension of 6.1 g (34.4 mmol) of NBS and 4 g of silica gel in 125 ml of dry dichloromethane was stirred under argon for 30 min. Then a solution of 4.56 g (17.2 mmol) of (S)-4-(1-methylheptyloxy)-2-nitro-toluene in 150 ml of dichloromethane was added via syringe. The reaction mixture was stirred at room temperature for 72 h. The resulting suspension was filtered through a short silica gel pad and the pad was washed several times with dichloromethane. The solvent was evaporated and the crude product extracted with a mixture of hexanes/ethyl acetate [95/5]. The suspension was filtered, the solvent removed and the residue was purified by flash chromatography using hexanes as eluent, affording 4.6 g (78%) of (S)-α-Bromo-4-(1-methylheptyloxy)-2-nitrotoluene (Compound 35, Scheme VI, R1 =(S)--OCH(CH3)C6H13) as a yellow liquid; Rf [hexanes/ethyl acetate 98/2]: 0.26; 1H NMR (300 MHz, CDCl3): δ 0.86(t, 3 H, J=6.7 Hz), 1.18-1.48(m, 8 H), 1.30(d, 3 H, J=6.1 Hz), 1.58(m 1 H), 1.70(m, 1 H), 4.40(m, 1 H), 4.77(s, 2 H), 7.06(dd. 1 H, J=2.7 Hz, J=8.5 Hz), 7.40(d, 1 H, J=8.5 Hz), 7.50(d, 1 H, J=2.7 Hz); 13C NMR (300 MHz, CDCl3): δ 13.98, 19.36, 22.50, 25.28, 29.10, 29.25, 31.67, 36.12, 75.00, 111.93, 121.08, 124.14, 133.61, 148.69, 158.92; IR (CHCl3): 3020, 2930, 2850, 1625, 1525, 1500, 1350, 1320, 1250, 1100, 975, 850, 825 cm-1 ; Mass spectrum, m/z(rel.intensity): 345(M+ +1 1.38), 343(M+ -1 1.35), 264(37), 152(100), 112(28), 71(59), 57(93), 55 (38), 43(93), 41(70).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17](Cl)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:25][CH3:26])[CH:13]=1)=[O:11])[CH3:8]>C(N(CC)CC)C>[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:18]([F:23])[CH:19]=2)[N:14]([CH2:25][CH3:26])[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cn(CC)c2cc(Cl)c(F)cc2c1=O
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CC)c2cc(N3CCNCC3)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 71.3 %

Procedure:
A mixture of 18 ml of triethylamine, 10.3 g of anhydrous piperazine, and 8.9 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester was refluxed with stirring for 20 hrs. The reaction mixture was concentrated under reduced pressure, 30 ml of chloroform was added to the residue, and cooled at 0° C. to give crystals. The crystals were filtered to recover 2 g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. The above filtrated solution was extracted with diluted hydrochloric acid, the hydrochloric acid layer was neutralized with diluted sodium hydroxide solution, and the neutralized solution was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, the chloroform was evaporated under reduced pressure. The residue was treated by the same procedure in Example 1 to give 7.4 g (71% yield) of 1-ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. mp: 178°- 180° C.
Reaction SMILES: [NH2:1][C:2]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].[C:20](=O)(OC(Cl)(Cl)Cl)[O:21]C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:18]([F:19])[CH:17]=[CH:16][CH:15]=3)[NH:1][C:20]2=[O:21])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1cccc(F)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2c(F)cccc2c1=O
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-fluorobenzamide (5.70 g, 17.6 mmol) in THF (100 mL) was treated with bis(trichloromethyl) carbonate (triphosgene) (6.28 g, 21.2 mmol) at room temperature and stirred for 15 min. The mixture was diluted with EtOAc, carefully treated with saturated aqueous NaHCO3 and stirred at room temperature until gas evolution stopped. The separated organic phase was washed sequentially with saturated aqueous NaHCO3, water and brine, and was dried and concentrated. The residue was triturated with ether to provide 3-(3-bromo-2-methylphenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione as an off-white solid (6.00 g, 97% yield). Mass spectrum m/z 349, 351 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.59 (d, J=17.6 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.70 (dd, J=7.8, 1.2 Hz, 1H), 7.54-7.43 (m, 1H), 7.28-7.21 (m, 2H), 7.21-7.17 (m, 1H), 2.28 (s, 3H).