Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:22])[NH:15][C:16]([CH3:21])([CH3:20])[CH2:17][C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.C1C(=O)N([Br:31])C(=O)C1.O>C(Cl)Cl>[NH2:1][C:2]1[C:3]([Br:31])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:22])[NH:15][C:16]([CH3:21])([CH3:20])[CH2:17][C:18]=4[N:19]=3)[C:6]=2[CH:23]=1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(N)cc43)sc2C(=O)N1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CC1(C)Cc2nc(N3CCOc4cc(Br)c(N)cc43)sc2C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
To a stirred solution of Example 42 (0.04 g, 0.12 mmol) in DCM (1 mL) was added NBS (0.02 g, 0.12 mmol) and the reaction mixture stirred for 1 h at r.t. Water (2 mL) was added, the layers were separated and the organic fraction was concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (0.006 g, 12%) as a white solid. δH (CDCl3) 7.56 (1H, s), 7.05 (1H, s), 5.30 (1H, s), 4.29-4.23 (2H, m), 4.11-4.05 (2H, m), 2.88 (2H, s), 1.40 (6H, s). LCMS (ES+) 409.2 and 411.2 (1:1 ratio) (M+H)+, RT 3.06 minutes (Method 1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]3[CH:11]=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:9]=3[N:8]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:7]=1.[Si:22]([O:29][C@@H:30]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[CH:37][C:38](Cl)=[N:39][CH:40]=2)[CH2:31]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:17]1([N:8]2[C:6]3[N:7]=[C:2]([NH:1][C:38]4[CH:37]=[CH:36][C:35]([N:32]5[CH2:33][CH2:34][C@@H:30]([O:29][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[CH2:31]5)=[CH:40][N:39]=4)[N:3]=[CH:4][C:5]=3[C:10]3[CH:11]=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:9]2=3)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Cn1c(=O)ccc2c3cnc(N)nc3n(C3CCCC3)c21
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2ccc(Cl)nc2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cn1c(=O)ccc2c3cnc(Nc4ccc(N5CC[C@@H](O[Si](C)(C)C(C)(C)C)C5)cn4)nc3n(C3CCCC3)c21
Temperature: 120 °C
Yield: 49.1 %

Procedure:
A 10 mL reaction vessel was charged with compound 273 (55 mg, 193 μmol), (R)-5-(3-(t-butyldimethylsilyloxy)pyrrolidin-1-yl)-2-chloropyridine (60.3 mg, 193 μmol), tris(dibenzylideneacetone)dipalladium (0) (13 mg, 14 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (17 mg, 29 μmol), and sodium t-butoxide (22 mg, 231 μmol) in 2 mL dry dioxane. The reaction was purged with argon and heated with microwave energy (300 W) for 2 hours at 120° C. The resulting solution was taken up in ethyl acetate (40 mL) and washed with water (30 mL), and brine (30 mL). The organics were dried (MgSO4) and evaporated to give a brown oil. Silica gel chromatography (gradient elution hexanes+2.5% TEA/0-50% ethyl acetate+2.5% TEA) afforded compound 276 as a yellow solid (53 mg, 49%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=1[NH2:17])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10])([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Product: COc1ccc(Nc2ccccc2CC(=O)O)c([N+](=O)[O-])c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-nitro-4-methoxyaniline to yield 2-[(2-nitro-4-methoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:10]2=[O:16])=[C:4]([CH3:17])[CH:3]=1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Cl:29])[CH:25]=2)[N:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.Cl>[Cl:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:28]([O:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([CH:9]3[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:10]3=[O:16])=[C:6]([CH3:8])[CH:7]=1)=[CH:27]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Cc1cc(O)cc(C)c1C1C(=O)CCCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2cnc3ccc(Cl)cc3c2)cc(C)c1C1C(=O)CCCC1=O
Temperature: 140 °C

Procedure:
To a mixture of 2-(4-hydroxy-2,6-dimethylphenyl)cyclohexane-1,3-dione (0.200 g, 0.0009 mol), 2,6-dichloroquinoline (0.170 g, 0.0009 mol) and potassium carbonate (0.350 g, 0.0025 mol) is added N,N-dimethylformamide (3 ml), and the mixture is heated at 140° C. for 40 minutes under microwave irradiation. The reaction mixture is then diluted with ethyl acetate (20 ml) and 2M hydrochloric acid (20 ml), and the organic phase is separated, dried over magnesium sulfate and evaporated under reduced pressure. The crude product is purified by preparative reverse phase HPLC to afford 2-[4-(6-chloroquinolin-3-yloxy)-2,6-dimethylphenyl]cyclohexane-1,3-dione as a cream solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:78][CH:79]1[CH2:84][CH2:83][N:82]([CH3:85])[CH2:81][CH2:80]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:78][CH:79]5[CH2:84][CH2:83][N:82]([CH3:85])[CH2:81][CH2:80]5)=[O:27])=[CH:24][C:23]=4[C:31]([F:33])([F:34])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(C(F)(F)F)c2)CC1
Reaction time: 0.17 h
Yield: 43.5 %

Procedure:
To a mixture of 0.075 g (0.155 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 8 mL of dimethylformamide was added 0.0313 g (0.232 mmole) of 1-hydroxybenzotriazole, 0.0880 g (0.232 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.080 g (0.617 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.027 g (0.236 mmole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0392 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-3-trifluoromethyl-benzamide (I-205) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:26][CH2:25][C@:12]34[C:13]5[C:14]6[O:24][C@H:11]3[CH:10]([N:27]3[C:31](=[O:32])[C:30]7=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=[C:29]7[C:28]3=[O:38])[CH2:9][CH2:8][C@@:7]4([OH:39])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][CH2:21][O:22][CH3:23])[CH2:3][CH2:2]1.[C:40](=O)([O-])[O-].[K+].[K+].CI.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[CH2:26][CH2:25][C@:12]34[C:13]5[C:14]6[O:24][C@H:11]3[C@H:10]([N:27]3[C:31](=[O:32])[C:30]7=[C:33]([O:37][CH3:40])[CH:34]=[CH:35][CH:36]=[C:29]7[C:28]3=[O:38])[CH2:9][CH2:8][C@@:7]4([OH:39])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][CH2:21][O:22][CH3:23])[CH2:3][CH2:2]1
Reactant: COCOc1ccc2c3c1O[C@H]1C(N4C(=O)c5cccc(O)c5C4=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCOc1ccc2c3c1O[C@H]1[C@H](N4C(=O)c5cccc(OC)c5C4=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.1 %

Procedure:
In 5 mL of DMF, 119 mg (0.22 mmol) of N-(17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6-yl)-3-hydroxy-phthalimide obtained in Example 102-1 was dissolved, and 93 mg of potassium carbonate and 0.02 mL of methyl iodide were added thereto, followed by stirring the mixture at room temperature for 3.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added to this reaction solution, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain 112 mg of N-(17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6β-yl)-3-methoxy-phthalimide as a crude product.
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:11][CH2:12][CH3:13])[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)[CH3:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[OH-].[Na+]>ClCCCl>[CH2:1]([O:3][C:4]1([O:11][CH2:12][CH3:13])[CH2:9][CH2:8][CH:7]([NH:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1(OCC)CCC(=O)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC1(OCC)CCC(NCc2ccccc2)CC1
Reaction time: 3 h
Yield: 80 %

Procedure:
This compound is obtained according to the process described in Tet. Lett. 5595-5598, 1990. To 270 mmol of 4,4-diethoxycyclohexanone in 700 ml of stirred anhydrous 1,2-dichloroethane, at room temperature and under a nitrogen atmosphere, are added 270 mmol of benzylamine in 50 ml of 1,2-dichloroethane, 270 mmol of acetic acid and then 80 g of sodium triacetoxyborohydride. After stirring for 3 hours, 11 of saturated sodium hydrogen carbonate solution is poured onto the reaction medium. The pH is brought to 8 using 1N sodium hydroxide. The organic phase is recovered, dried and evaporated. The expected product is then obtained after purification of the residual oil by chromatography on a column of silica, using a dichloromethane/methanol/aqueous ammonia (95/5/0.5) mixture as eluent.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].B(F)(F)F.[CH3:39][CH2:40][O:41]CC>C(O)CO>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4([C:29]([CH3:31])([CH3:30])[CH3:32])[O:41][CH2:40][CH2:39][O:33]4)=[C:22]([CH3:34])[CH:21]=3)([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOCC
Reactant: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)ccc2s1
Agent: FB(F)F
Solvent: OCCO
Product: CCOC(=O)c1cc2cc(C(CC)(CC)c3ccc(OCC4(C(C)(C)C)OCCO4)c(C)c3)ccc2s1
Temperature: 90 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
A solution of 5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carboxylic acid ethyl ester (170 mg, 0.354 mmol)) in ethylene glycol (3.0 mL) is treated with BF3-Et2O (2.0 mL). The mixture is stirred at 90° C. for 6 h, cooled to RT, and quenched with water (50 mL). The mixture is extracted with EtOAc (2×20 mL), and the organic layer is concentrated and purified using silica gel column chromatography (10% EtOAc/Hex) to afford the product as an oil (94 mg, 51%).
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:50]=[C:49]([CH3:51])[O:48][N:47]=3)[C:41]2=[O:52])[S:33][C:34]=1[C:35]([O:37]CC)=[O:36]>>[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:50]=[C:49]([CH3:51])[O:48][N:47]=3)[C:41]2=[O:52])[S:33][C:34]=1[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3cc(C)on3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1cc(CN2CCN(c3nc(C)c(C(=O)O)s3)C2=O)no1
Yield: 85 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 4-methyl-2-(3-((5-methylisoxazol-3-yl)methyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 85% yield: MS (ES+) m/z 323.1 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](Cl)=[O:11].[CH3:13][CH2:14][CH2:15][CH:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH2:15]([CH:16]([NH:20][C:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:11])[CH2:17][CH2:18][CH3:19])[CH2:14][CH3:13]
Reactant: CCCC(N)CCC
Reactant: O=C(Cl)c1cc2ccccc2o1
Product: CCCC(CCC)NC(=O)c1cc2ccccc2o1
Yield: 73 %

Procedure:
Prepared in a similar manner to example 1 using benzofuran-2-carbonyl chloride and heptan-4-amine. Yield: 73%. 1H NMR (500 MHz, CDCl3): δ 0.93 (t, 6H, J=7.2 Hz), 1.41 (m, 8H), 3.01 (s, 3H), 4.18 (m, 1H), 6.29 (d, 1H, J=9.94 Hz), 7.20 (d, 1H, J=8.62 Hz), 7.37 (m, 2H), 7.44 (s, 1H). MS (M+H, 260)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([OH:10])[CH:3]=1.[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: BrC1CCCC1
Reactant: CSc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(Br)cc1OC1CCCC1
Temperature: 60 °C

Procedure:
A stirred solution of 4-bromo-2-hydroxythioanisole (15.9 g) and cyclopentyl bromide (16.05 g) in dry dimethylformamide (170 mL) is treated with anhydrous potassium carbonate (14.7 g) and the mixture is heated at 60° C. for 1 day. After cooling, the solution is diluted with water (250 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts are dried over magnesium sulfate and concentrated. The residue is subjected to flash chromatography, eluting with a mixture of ethyl acetate and pentane (5:95 v/v), to give 4-bromo-2-cyclopentyloxy-1-(methylthio)benzene, in the form of an oil (17.2 g). [NMR (DMSO): 7.14-7.03(m,3H),4.93(m,1 H), 2.33(s,3H),2.0-1.53(m,8H)].
Reaction SMILES: Cl[C:2]1[C:3]([C@@H:13]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[Cl:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:27][CH3:26])[C:3]([C@@H:13]([N:15]1[C:16](=[O:25])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]1=[O:24])[CH3:14])=[N:4]2
Reactant: CSc1ccccc1B(O)O
Reactant: C[C@@H](c1nc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1ccccc1-c1nc2c(Cl)cccc2nc1[C@H](C)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
A 5 L three-necked round-bottomed flask equipped with a mechanical stirrer, a condenser, a nitrogen gas inlet and a temperature probe was charged with DMF (2.16 L), (S)-2-(1-(3,5-dichloroquinoxalin-2-yl)ethyl)isoindoline-1,3-dione (273 g, 733 mmol) and 2-(methylthio)phenylboronic acid (136 g, 807 mmol). To the mixture, was added potassium carbonate (203 g, 147 mmol) and [1,1-bis(di-phenylphosphino)ferrocene]palladium(ii) chloride, complex with DCM (29.9 g, 36.7 mmol). The mixture was vacuum purged with N2 (2×), and heated to 100° C. The reaction was monitored by LC-MS, and deemed complete after 4 h. The reaction was cooled to rt (21° C.), and then divided into two batches. Each batch was partitioned between EtOAc (1.08 L) and water (1.35 L) in a 4 L separatory funnel. After phase separation, the organic layer was washed with brine (2×500 mL) and concentrated to afford the crude product. The combined batches of crude material were loaded on silica gel and purified by flash chromatography (ISCO/RediSep™) (hexane:EtOAc=10:0 to 6:4) to provide the product as a light brown solid 320 g with 98% LC purity and 95% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:30][CH3:31])=[C:8]([S:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:15]([Br:29])[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:32]COC(C)=O>CCO.CC(O)=O.[Fe]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:30][CH3:31])=[C:8]([S:10]([C:13]2[CH:14]=[C:15]([Br:29])[C:16]3[N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:32]=[N:19][C:17]=3[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c(Nc3ccccc3)c([N+](=O)[O-])c2)c(SC)s1
Reactant: CCOC(C)=O
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3c(c2)ncn3-c2ccccc2)c(SC)s1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Iron powder (110 mg, 2 mmol) was added to a solution of 4-(3-bromo-5-nitro-4-phenylamino-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (Example 318: step d) in EtOH (4 mL) and 50% aqueous AcOH (1 mL). The reaction was stirred for 30 min at 60° C. during which a new lower spot became evident by TLC analysis. EtOAc (10 mL) was added and the mixture was filtered through a 0.22 μm polypropylene syringe filter. Additional EtOAc (30 mL) was added and the solution was extracted with aq NaHCO3 (3×10 mL) and brine (20 mL). The solution was dried and concentrated in vacuo. One-half of the residue (26 mg) was suspended in formic acid (3 mL) and was heated at 95° C. for 4 h. The formic acid was removed in vacuo and the residue was purified by chromatography to yield the product (23 mg). 1H-NMR (CDCl3): δ 8.56 (d, 1H, J=1.6 Hz), 8.13 (s, 1H), 8.07 (d, 1H, J=1.6 Hz), 8.04 (s, 1H), 7.55 (m, 3H, 7.41 (m, 2H), 3.87 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:28])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:36][C:35](=O)[CH:34]=[C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=2)[O:32]1>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:28][C:35](=[O:36])[CH2:34][C:33](=[O:32])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:47])[F:46])[CH:39]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C(F)(F)F)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1NC(=O)CC(=O)c1cccc(C(F)(F)F)c1
Yield: 67.6 %

Procedure:
Prepared from [2-amino-4-(6-benzyloxy-pyridin-3-yl)-phenyl]-carbamic acid tert.-butyl ester (Example G30) (203 mg, 0.52 mmol) and 2,2-dimethyl-6-(3-trifluoromethyl-phenyl)-[1,3]dioxin-4-one (Example J5) (150 mg, 0.55 mmol) according to the general procedure K. Obtained as an off-white solid (213 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.C(Cl)Cl>CO>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[C:7]1[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: COc1ccccc1C=O
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ccccc1-2
Solvent: ClCCl
Solvent: CO
Product: COc1ccccc1C=C1c2ccccc2-c2ccc([N+](=O)[O-])cc21
Temperature: 72 °C
Reaction time: 6 h

Procedure:
To a solution of 2-nitrofluorene (1.05 g, 5 mmol) and 2-methoxybenzaldehyde (0.816 g, 6 mmol) in 20 mL of methanol was added KF—Al2O3 (0.75 g, 4.5 mmol). The resulting mixture was stirred at 72° C. After 6 hrs, TLC indicated that the starting material was gone. 40 mL of CH2Cl2 was added into the reaction mixture. The insoluble solid was filtrated, and the filtrate was concentrated under vacuum to give a yellow solid, which was recrystallized from alcohol and CH2Cl2 to give 1.2 g of CYD-1-70 as a yellow solid. 1H-NMR (600 MHz, CDCl3) δ 8.84 (s, 0.36H), 8.26 (m, 1.65H), 8.10 (m, 3.05H), 8.02 (s, 0.57H), 7.55 (m, 4H), 7.24 (m, 1.24H), 7.10 (m, 0.91H), 3.84 (s, 3H)
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1.[NH2:14][C:15]1[S:16][C:17]([C:23]2[C:28]([F:29])=[CH:27][C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:25][C:24]=2[F:34])=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21]>>[CH3:1][NH:2][C:3](=[O:13])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:14][C:15]2[S:16][C:17]([C:23]3[C:24]([F:34])=[CH:25][C:26]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:27][C:28]=3[F:29])=[CH:18][C:19]=2[C:20]([NH2:22])=[O:21])[N:7]=1
Reactant: CNC(=O)OCc1cccc(Br)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CNC(=O)OCc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using (6-bromopyridin-2-yl)methyl methylcarbamate (149 mg, 0.61 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (200 mg, 0.64 mmol) as the starting materials.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([CH:11]1[O:16][C:15](=[O:17])[CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:32][CH2:31]4)=[C:26]([F:41])[C:25]=3[F:42])=[C:20]([F:43])[C:19]=2[F:44])[CH2:13][CH2:12]1)[CH2:9][CH3:10].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C(O)=O>[CH2:8]([CH:11]1[O:16][CH:15]([OH:17])[CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:32][CH2:31]4)=[C:26]([F:41])[C:25]=3[F:42])=[C:20]([F:43])[C:19]=2[F:44])[CH2:13][CH2:12]1)[CH2:9][CH3:10]
Reactant: CCCCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4=O)c(F)c3F)c(F)c2F)CO1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CCCCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4O)c(F)c3F)c(F)c2F)CO1
Reaction time: 3 h
Yield: 99.6 %

Procedure:
Toluene (10 ml) was added to 6-propyl-3-(2,2′,3,3′-tetrafluoro-4′-(6-pentyltetrahydro-2H-pyran-3-yl)biphenyl-4-yl)tetrahydro-2H-pyran-2-one (20) (1.2 g) prepared in the first step. A diisobutylaluminum hydride-toluene solution (0.99 M; 3.49 ml) was added dropwise at −50° C. or lower, and the stirring was continued for 3 hours. The reaction mixture was poured into a 10% aqueous solution of formic acid (15 ml) to give two layers. The water layer was extracted with toluene (10 ml) twice, and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to leave 6-propyl-3-(2,2′,3,3′-tetrafluoro-4′-(6-pentyltetrahydro-2H-pyran-3-yl)biphenyl-4-yl)tetrahydro-2H-pyran-2-ol (21) (1.2 g) in 98% yield.