Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[C:27]([N:32]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[C:33]([C:35]2([C:38]([NH2:40])=[O:39])[CH2:37][CH2:36]2)=[O:34])[CH:28]=[CH:29][C:30]=1[OH:31].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:24][C:25]1[CH:26]=[C:27]([N:32]([C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)[C:33]([C:35]2([C:38]([NH2:40])=[O:39])[CH2:37][CH2:36]2)=[O:34])[CH:28]=[CH:29][C:30]=1[O:31][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Reactant: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(O)c(F)c2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 110 °C
Reaction time: 0.03 h

Procedure:
4-Chloro-6-(methyloxy)-7-{[3-(4-morpholinyl)propyl]oxy}quinoline (60 mg, 0.18 mmol), N1-(3-Fluoro-4-hydroxyphenyl)-N1-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide, Pd(OAc)2 (4 mg, 0.018 mmol), racemic-2-(di-tert-butylphosphino)-1,1′-binaphthyl (14.2 mg, 0.035 mmol), and K3PO4 (57 mg, 0.27 mmol) were added into a vial equipped with a stirring bar and purged with N2. Anisole (400 μL) was added and the open vial was placed under a stream of N2 for ˜2 min. The vial was capped and the mixture was heated to 110° C. for 32 min, at which time the reaction was found to be complete.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][Cl:22])=[CH:16][CH:15]=2)[C:5]([NH2:12])=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:23](O)(=O)[CH:24]([CH3:26])[OH:25]>>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]2[N:12]=[C:23]([CH:24]([OH:25])[CH3:26])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][Cl:22])=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: CC(O)C(=O)O
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1Nc1ccc(CCCl)cc1
Product: CC(O)c1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCCl)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 339, step 3 & Example 1, step 5 from 4-chloro-N2-[4-(2-chloroethyl)phenyl]-5-(trifluoromethyl)-1,2-benzenediamine and lactic acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[C:8]1[S:9][C:10]([CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28]([OH:30])=O)=[C:11](CCCC2C=CC(C)=CC=2)[C:12]=1C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)(Cl)Cl.CCOCC>[O:36]1[CH2:37][CH2:38][N:33]([C:28]([CH2:27][C:26]([CH3:31])([CH3:32])[CH2:25][CH2:24][C:10]2[S:9][CH:8]=[CH:12][CH:11]=2)=[O:30])[CH2:34][CH2:35]1
Reactant: Cc1ccc(CCCc2c(CCC(C)(C)CC(=O)O)sc(C)c2C)cc1
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(C)(CCc1cccs1)CC(=O)N1CCOCC1
Temperature: 50 °C
Yield: 72 %

Procedure:
2 g (0.0157 mol) of oxalyl chloride dissolved in 10 ml of CHCl3 are placed in a 100 ml single-necked flask. After having brought the mixture to 0° C. with an ice bath, 3.9 g (0.0105 mol) of 2,3-dimethyl-4-(3-p-methylphenylpropyl)-5-(4-carboxy-3,3-dimethylbutyl)thiophene (see above, paragraph B of the synthesis of the starting materials) are added. The reaction mixture is then stirred at room temperature and subsequently at 50° C. until the evolution of gas has ceased. The solvent is distilled off at a temperature below 50° C. The acid chloride prepared above dissolved in 60 ml of ether, and 1.82 g (0.021 mol) of morpholine dissolved in 60 ml of ether, are simultaneously poured into a 500 ml three-necked flask while stirring. The morpholinium hydrochloride precipitates instantaneously. After one hour's stirring, the solid is removed by filtration. The filtrate is washed with water, dried over MgSO4, rendered colourless with carbon black and concentrated to dryness. The crude product obtained is purified by chromatography on silica (eluant: CH2Cl2 /CH3COOC2H5 -95/5, then CH2Cl2 /CH3OH-98/2). 3.31 g of 2,3-dimethyl-4-3-p-methylphenylpropyl)-5-(4-morpholinocarbonyl-3,3-dimethylbutyl)thiophene are obtained in the form of a colourless oil, yield: 72%.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:15][C:16]1[CH:17]=[C:18]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=1>CC(O)C>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([C:4]2[O:3][C:2]([NH:15][C:16]3[CH:17]=[C:18]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)=[N:6][CH:5]=2)=[CH:8][CH:9]=1)#[N:12]
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Reactant: N#Cc1ccc(-c2cnc(Cl)o2)cc1
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(C#N)cc3)o2)c1
Temperature: 80 °C

Procedure:
A mixture of 4-(2-chlorooxazol-5-yl)benzonitrile 2 (0.20 g, 0.98 mmol) and commercially available N-(3-aminophenyl)methanesulfonamide 6 (0.182 g, 0.98 mmol) in 2-propanol (20 mL) was heated to 80° C. for 18 h with stirring. Upon cooling, a white solid precipitated out which was filtered off, washed with 2-propanol, and dried. This was then triturated with ether and filtered to yield the title product, a white solid, as the hydrochloride salt of 7 (0.14 g, 40%). Free amine containing filtrate was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide 7 (0.151 g, 44% yield) as pale yellow solid. MS (ES) m/z 355 (M+H+).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:12]([OH:14])=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:15](O)[CH3:16]>>[ClH:1].[CH2:15]([O:13][C:12](=[O:14])[C@H:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:2])[CH3:16]
Reactant: CCO
Reactant: N[C@@H](CCc1ccccc1)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@@H](N)CCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Hydrogen chloride gas is bubbled through a solution of (L)-homophenylalanine (5.13 g, 28.7 mmol) in 100 mL of ethanol for 5 minutes. The mixture is stirred at room temperature for 16 hours. The mixture is concentrated in vacuo to yield L-homophenylalanine ethyl ester hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:23])[C:5]2=1.Cl.[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29]Cl)[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([O:23][CH2:26][CH2:25][N:27]([CH2:31][CH3:32])[CH2:28][CH3:29])[C:5]2=1
Reactant: CCN(CC)CCCl
Reactant: Oc1cccc2c1c1cc(Cl)ccc1n2Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1c1cc(Cl)ccc1n2Cc1ccc(F)cc1
Yield: 73.2 %

Procedure:
6-Chloro-9-(4-fluorobenzyl)-9H-carbazol-4-ol (0.0619 g, 0.19 mmol), 2-diethylaminoethylchloride hydrochloride (0.0494 g, 0.29 mmol), potassium carbonate (0.0750 g, 0.54 mmol), sodium iodide (0.0021 g, 0.014 mmol) and DMF (1 mL) are heated at 85° C. for 4 h. After the mixture had cooled, it is partitioned between water and ether. The aqueous layer is also extracted with ethyl acetate several times. The combined organic layers are dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (75 mL) using methanol/dichloromethane (1/99 to 2/98 to 4/96) to give 0.0591 g (73%) of the title compound; mp 99-99.5° C.; MS (ESI+) for C25H26ClFN2O m/z 425.2 (M+H)+; IR (drift) 2972, 1588, 1507, 1467, 1454, 1342, 1270, 1221, 1151, 1123, 817, 799, 778, 740, 714 cm−1; 1H NMR (CDCl3) δ1.15, 2.75, 3.12, 4.33, 5.44, 6.71, 6.93, 7.04, 7.20, 7.34, 8.33. Anal. Calcd for C25H26ClFN2O: C, 70.66; H, 6.17; N, 6.59. Found: C, 70.23; H, 6.05; N, 6.61.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([N:13]([CH3:37])[C:14]([N:16]([CH3:36])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[ClH:40].CC(O)C>>[ClH:40].[ClH:40].[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([N:13]([CH3:37])[C:14]([N:16]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)[CH2:20][NH:19][CH2:18]2)[CH3:36])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(F)cn1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CC(C)O
Product: CN(C(=O)N(C)[C@@H]1CNC[C@H]1c1ccc(F)cn1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of the compound (2.5 g) obtained in Example 190 and 2N hydrogen chloride/2-propanol (25 mL) was stirred at 45 to 55° C. for 4 hr, concentrated under reduced pressure and recrystallized from ethanol/IPE to give the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH:16](=[N:15][NH:14][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNc1ccc(Oc2ccccc2)cc1
Reactant: O=Cc1ccccc1
Solvent: CO
Product: C(=NNc1ccc(Oc2ccccc2)cc1)c1ccccc1

Procedure:
A suspension of (4-phenoxyphenyl)hydrazine (J. Org. Chem. 1956, 395; 1.5 g) in methanol (10 mL) was mixed with benzaldehyde (0.76 mL) and heated to reflux. The crystals which separated out on cooling were filtered off with suction. The product with the molecular weight of 288.35 (C19H16N2O); MS (ESI): 289 ([M+H]+), was obtained in this way.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:35])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)(=[O:28])=[O:27])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:49](OC(=O)C)([F:51])[F:50]>O>[CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:49]([F:51])[F:50])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)(=[O:28])=[O:27])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of {2-ethyl-8-fluoro-3-[4-(morpholine-4-sulfonyl)benzyl]-4-oxo-1,4-dihydroquinolin-5-yloxy}acetic acid methyl ester (0.14 g), N,N-dimethylformamide (3.0 mL), potassium carbonate (0.12 g) and acetic acid chlorodifluoromethyl ester (0.15 mL) was stirred at 80° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1:1 by volume) gave title compound, 0.092 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([F:13])([F:12])[F:11].[H-].[Na+].[CH3:29][S:30]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)(=[O:32])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:26][CH2:37][C:36]2[CH:35]=[CH:34][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:40][CH:39]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:24])[C:10]([F:11])([F:13])[F:12]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [H-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(c1ccc(OCc2ccc(S(C)(=O)=O)cc2)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a suspension of 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinolin-3-yl-propyl)-phenol (Example 179, 75 mg) in N,N-dimethylacetamide (1 ml) was added NaH (60% dispersion in mineral oil, 9 mg) at 0° C. The mixture was stirred at 0° C. for 1 h and at room temperature for 1 h. 4-Methylsulfonylbenzyl bromide (54 mg) was added and the mixture was stirred at room temperature for 3 h. Cesium carbonate (32 mg) was added and the mixture was stirred for 2 days at room temperature and for 5 h at 50° C. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was washed with brine and dried (MgSO4). The product was purified by chromatography (SiO2, cyclohexane=>cyclohexane/EtOAc 1:1) to give the title compound (69 mg) as a light yellow solid. MS (m/e)=550.3 [M+H+].
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:23][C:24]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:25]=1[NH2:26]>ClCCl>[C:1]1([CH2:7][C:8]([NH:26][C:25]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:24]=2[OH:23])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1cc(Cl)ccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1cc(Cl)ccc1O
Reaction time: 1 h

Procedure:
Phenylacetic acid (20 g, 0.15 mol) in dichloromethane (120 ml) was treated with 1,1′-carbonyl diimidazole (25 g, 0.15 mol). After 1 hour, a solution of 2-hydroxy-5-chloroaniline in dichloromethane was added. The mixture was stirred overnight and processed in the usual manner to give 31.2 g of the title compound as a crystalline solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:20]3[N:19]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[NH:17][C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:11])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH:47]=O)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]3[C:20]4[N:19]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[NH:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)=[O:11])[CH2:4][CH2:3]2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CC(C)(C)c1nc2c(C(=O)NCC3CCNCC3)cccc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CN2CCC(CNC(=O)c3cccc4[nH]c(C(C)(C)C)nc34)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a suspension of the bis HCl salt of 2-tert-butyl-1H-benzoimidazole-4-carboxylic acid (piperidin-4-ylmethyl)amide (4.28 g, 11.06 mmol) in dichloromethane (55 mL) at room temperature was added N,N-diisopropylethylamine (1.71 g, 2.31 mL), 1-(tert-butoxycarbonyl)piperidine-4-carboxaldehyde (2.58 g, 12.17 mmol) and sodium triacetoxyborohydride (3.28 g, 15.48 mmol) sequentially. The resulting mixture was stirred at room temperature for 2 h then extracted with 1M aqueous hydrochloric acid. The combined aqueous layers were basified to pH 12 with sodium hydroxide pellets, then extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The resulting residue was dried under high vacuum to give a light brownish foam (4.9 g, 9.6 mmol, 87%) which was used without further purification. (m/z): [M+H]+ calcd for C29H45N5O3 512.35, found: 512.4.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1.Cl[Cu]>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:20]2[CH:21]=[CH:22][C:23]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:24][CH:25]=2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Nc1ccc(I)cc1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 110 °C

Procedure:
To a solution of 4-trifluoromethoxy-phenol (0.7 mL, 5.4 mmol) in NMP (6 mL) was added Cs2CO3 (1.76 g, 5.4 mmol). The slurry was degassed for 2 min and added N-(4-iodo-phenyl)-methanesulfonamide (0.80 g, 2.7 mmol) from Example 33, Step A, 2,2,6,6-tetramethylheptane-3,5-dione (0.056 mL, 0.27 mmol) and CuCl (0.134 g, 1.35 mmol) subsequently. The reaction mixture was heated to 110° C. under N2 overnight. The reaction was brought to the usual work-up and the crude material was purified by chromatography (20% EtOAc/hexanes). MS (EI) 348 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[F:10].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Br:9])=[C:6]([F:8])[C:7]=1[N+:11]([O-:13])=[O:12]
Reactant: Fc1cc(Br)c(F)cc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(F)c(Br)cc(F)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1,4-Dibromo-2,5-difluorobenzene (100 g, 0.37 mol) is dissolved in concentrated sulfuric acid (200 g) and treated with fuming nitric acid (56 g, 0.44 mol, HNO3 content >90%) by drop-wise addition at an internal temperature that is maintained between 50–60° C. After the addition is complete, the mixture is cooled to room temperature and stirred for 12 hours, then poured into ice-water (1000 mL). The suspension is extracted with EtOAc (3×500 mL). The combined organic extracts are dried (MgSO4) and concentrated by rotary evaporator to give 2,5-dibromo-3,6-difluoronitrobenzene as an oily yellow solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[CH:11]=[N:12][OH:13].[Cl:14]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:13][N:12]=[C:11]([Cl:14])[C@H:2]1[CH2:3][O:4][C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:1]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=C[C@H]1COC2(CCCCC2)O1
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (9.08 g, 49 mmol) in DMF (50 mL) was added 1-chloropyrrolidine-2,5-dione (7.20 g, 53.9 mmol) and the reaction stirred overnight at ambient temperature. The reaction was poured into water (500 mL) extracted with ether. The organics were washed with brine and dried over magnesium sulfate. The material was concentrated in vacuo to yield (R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (10.4 g, 47 mmol, 96.6%).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH2:8][OH:9])=[O:7].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.O>COCCOC.CCOCC>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][O:9][CH2:8][C:6]([O:5][CH2:4][CH3:3])=[O:7]
Reactant: BrCCCCBr
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)COCCCCBr

Procedure:
Sodium hydride (9.0 g., 0.375 mole) is suspended in 1,2-dimethoxyethane. The mixture is stirred and cooled in an ice bath while ethyl glycollate (39.0 g., 0.375 mole) is added dropwise during one hour. 1,4-Dibromobutane (108 g., 0.5 mole) is added all at once to the resulting thick suspension. The mixture is warmed gently to initiate a strongly exothermic reaction; then the mixture is heated 3 hours on the steam bath. The mixture is poured into cold water. The heavy oil layer is taken up in ether, washed with three portions of water, and dried over sodium sulfate.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl.Cl>C(O)(C)C>[NH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc(F)cc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(C)O
Product: Nc1cccc(NC(=O)c2ccc(F)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
4-Fluoro-N-(3-nitro-phenyl)-benzamide (10.0 g, 36.2 mmol) (Example I5) was dissolved in isopropanol (150 ml) and tin chloride (24.7 g, 130.3 mmol) was added. The mixture was cooled to 0° C. and a solution of concentrated hydrochloric acid (20 ml) was added slowly. The reaction mixture was stirred at 80° C. for 2 hours. Then ⅓ of the total volume of isopropanol was evaporated. Water (200 ml) was added to the concentrated mixture and a solution of aqueous sodium hydroxide (4N) was added to adjust the pH to 7-8. The phases were separated and the aqueous phase was extracted three times with ethyl acetate (200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to give N-(3-amino-phenyl)-4-fluoro-benzamide (5 g, 60% yield). 1H-NMR (CDCl3, 400 MHz): 7.93 (m, 2H), 7.27 (t, 2H), 7.01 (m, 1H), 6.89 (t, 1H), 6.78 (d, 1H), 5.01 (s, 2H) ppm.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([O:14][CH3:15])(=[O:13])[CH2:11][SH:12].CC(C)([O-])C.[K+]>CN(C=O)C>[CH3:15][O:14][C:10]([C:11]1[S:12][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]=1[NH2:5])=[O:13]
Reactant: COC(=O)CS
Reactant: N#Cc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccccc2c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 2-fluorobenzonitrile (9.0 g, 74.3 mmol) and methyl thioglycolate (13.3 mL, 148.6 mmol) in DMF (50 mL) at 0° C. was added potassium tert-butoxide portionwise (16.7 g. 149 mmol) over 15 min with vigorous stirring. The orange solution was warmed to rt and stirred for 1 h before being poured into 700 mL of vigorously stirring ice water. The precipitate was filtered and air-dried to give a pale yellow solid (13.6 g, 88%) that was used without purification. 1H NMR (CD3OD): 8.16-8.12 (m, 1H), 7.85-7.82 (m, 1H), 7.54-7.49 (m, 1H), 7.43-7.38 (m, 1H), 7.19 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24](C5C=CC=CC=5)N(C)[C:26]=4[CH3:27])=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37].CS([O:42][CH2:43][CH2:44][CH2:45][N:46]1[CH2:52][CH:51]([OH:53])[C:48]2([CH2:50][CH2:49]2)[CH2:47]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:53][CH:51]1[C:48]2([CH2:50][CH2:49]2)[CH2:47][N:46]([CH2:45][CH2:44][CH2:43][O:42][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]([C:2]5[CH:11]=[CH:10][CH:5]=[CH:4][CH:3]=5)[C:20]([C:22]5([C:23]([NH2:24])=[O:35])[CH2:27][CH2:26]5)=[O:21])=[N:17][CH:18]=4)=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:36][CH3:37])[CH2:52]1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)nc3)ccnc2cc1O
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)nc3)ccnc2cc1OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 120.3 %

Procedure:
To a solution of N-(5-(7-hydroxy-6-methoxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.640 mmol) in DMA (4 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (239 mg, 0.960 mmol) and Cs2CO3 (416 mg, 1.280 mmol). The reaction was then stirred at rt for 48 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (5 mL) and CHCl3 (25 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1 (v/v/v)EtOAc/CH3OH/Et3N) to afford the desired compound as a pale yellow solid (240 mg, 60%).