Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)c1cccc(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.7 %

Procedure:
TFA (0.5 mL, 6.490 mmol) was added to a solution of N-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3-fluorobenz amide (9 mg, 0.019 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound as an off-white solid (4 mg). 1H NMR (400 MHz, CD3OD): δ 8.77 (bs, 1H), 7.85 (m, 3H), 7.76 (m, 3H), 7.58 (m, 3H), 7.39-7.35 (m, 1H); ESI-MS [M+H]+: 372.2.
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=O.[Cl-].[CH2:13]([O:20][C:21]1[CH:46]=[CH:45][CH:44]=[CH:43][C:22]=1[CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:13]([O:20][C:21]1[CH:46]=[CH:45][CH:44]=[CH:43][C:22]=1[CH:23]=[CH:3][C:2]([CH3:1])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C=O)=Cc1ccccc1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C=Cc1ccccc1OCc1ccccc1)=Cc1ccccc1
Yield: 90.2 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, 1.32 g of α-methylcinnamaldehyde, 4.47 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) and 1.37 g of 1,8-diazabicyclo[5,4,0]-undec-7-ene were reacted in acetonitrile. The crude product thus obtained was purified as described in the first part of Preparation 3, to give 2.66 g (yield 90%) of 1-(2-benzyloxyphenyl)-3-methyl-4-phenylbutadiene as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26](=[O:43])[C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:42][CH2:41][C:36]4([CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:44]([O-:46])=[O:45])[CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O-:47][C:48]#[N:49].[K+].O>CO>[NH2:49][C:48]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26](=[O:43])[C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH2:34][CH2:35][C:36]4([CH2:37][CH2:38][CH2:39][CH2:40]4)[CH2:41][CH2:42]3)=[CH:31][CH:32]=2)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:44]([O-:46])=[O:45])[CH2:7][S:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:47]
Reactant: NCCCC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC4(CCCC4)CC3)cc2)cc1[N+](=O)[O-]
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=O)NCCCC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC4(CCCC4)CC3)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of Example 287 (60 mg, 0.1 mmol) and potassium cyanate (20 mg, 0.25 mmol) in methanol (1 mL) was stirred at 55° C. for 1.5 hours, cooled to room temperature, treated with water, and extracted with dichloromethane. The combined extracts were washed with saturated sodium bicarbonate, dried (MgSO4), filtered, and concentrated. The concentrate was purified by reverse phase HPLC with 0-100% acetonitrile/water containing 0.1% TFA to provide the desired product. MS (ESI(+)) m/e 709 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.53 (d, 1H), 8.32 (d, 1H), 7.85 (dd, 1H), 7.73 (d, 2H), 7.25-7.10 (m, 6H), 6.93 (d, 2H), 5.90 (s, 1H), 4.10 (m, 1H), 3.34 (m, 6H), 2.91 (t, 2H), 1.75 (m, 1H), 1.59 (m, 4H), 1.42 (m, 8H), 1.34 (m, 4H).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[S:10][C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[CH:12][C:13]=2[CH3:14])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[Cl:27][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[S:10][C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:12][C:13]=1[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}methanol (1.3 g) in toluene (20 mL) was added thionyl chloride (0.4 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (1.3 g, 100%) as an amorphous compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][C:3]1=[O:12]>CO.O>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]1=[O:12]
Reactant: COC(=O)c1ccn(C)c(=O)c1
Solvent: O
Solvent: CO
Product: Cn1ccc(C(=O)O)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
To a stirred solution of methyl 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (1 g, 1.0 eq) in 25 mL MeOH was added a solution of LiOHH2O (755 mg, 3.0 eq) in 5 mL water at rt. The reaction was then stirred at rt for 2 h. Then the solvent was removed in vacuo, and water was added to the residue, followed by addition of 3N HCl (aq) to adjust pH=1˜3. The product was collected by filtration and washed with water to give the product as white solid (540 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.56 (brs, 1H), 7.80 (d, J=7.2 Hz, 1H), 6.83 (d, J=1.6 Hz, 1H), 6.53 (d, J=6.8 Hz, 1.6 Hz, 1H), 3.46 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].BrC[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39]>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[F:39])[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: Fc1ccccc1CCBr
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3F)CC1)O2
Yield: 85.5 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) was alkylated using 1-(2-bromo-ethyl)-2-fluoro-benzene (0.16 ml, 1.5 mmol) as described in Example 56, Step A, giving (E)-3-{1′-[2-(2-fluoro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (181 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:13]([CH3:14])[C:12](=[O:15])[C:9]3([CH2:11][CH2:10]3)[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[CH3:32].C(O)C>Cl.O>[CH:16]1([N:7]2[CH2:8][C:9]3([CH2:11][CH2:10]3)[C:12](=[O:15])[N:13]([CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[CH3:32])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Yield: 41 %

Procedure:
A mixture of 0.0515 g (0.000168 mole) of 2-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VII-53), 0.0283 g (0.000183 mole) of 4-amino-3-methylbenzoic acid, 1 mL of ethanol, 4 mL of water and 4 drops of hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the precipitate which formed was collected by filtration to give 0.029 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methylbenzoic acid (I-60) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=3)[CH2:12][CH2:11]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CN2CCCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
The resulting 1-(3,3-diphenylpropyl )homopiperazine was dissolved in 3 mL of acetonitrile followed by adding 213 mg of 4-nitrobenzyl bromide and 144 mg of potassium carbonate. The mixture was stirred at 70° C. for 14 hours and allowed to cool to room temperature and the solvent was removed under reduced pressure. 20 mL of aqueous 2N sodium hydroxide was added and the mixture was extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate) to obtain 255 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure; and the residue was dried to obtain the hydrochloride salt of the titled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C(O)CCC>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCCO
Solvent: CCCCO
Product: Cc1ccc(NCCCO)c([N+](=O)[O-])c1
Yield: 33 %

Procedure:
A mixture of 171 parts of 1-chloro-4-methyl-2-nitrobenzene, 150 parts of 3-amino-1-propanol and 400 parts of butanol is stirred and refluxed for 30 hours. The reaction mixture is evaporated and the residue is poured onto water. The product is extracted with methylbenzene. The extract is washed with water and with a hydrochloric acid solution 2N, dried, filtered and evaporated. The residue is purified by columnchromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 70 parts (33%) of 3-[(4-methyl-2-nitrophenyl)amino]-1-propanol as a residue.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:17]=1N)=[O:12])[CH3:9].[ClH:25]>C(#N)C.[Cu]Cl>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:17]=1[Cl:25])=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cnn(C2CCCCC2)c1N
Reactant: Cl
Agent: Cl[Cu]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)c1cnn(C2CCCCC2)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 42 %

Procedure:
Copper(I) chloride (2.500 g, 25.25 mmol) was suspended in 7.0 mL cold (ice/acetone bath) anhydrous acetonitrile. t-Butyl nitrite (5.75 mL, 90%, 43.56 mmol) was added, followed by a suspension of 5-amino-1-cyclohexyl-1H-pyrazole-4-carboxylic acid ethyl ester (4.408 g, 18.58 mmol) in 27.0 mL acetonitrile. The mixture was stirred at room temperature for 45 minutes and then at 70° C. for 1.25 hour. The mixture was cooled to room temperature, slowly added to 6N HCl (17.5 mL) and then extracted with methylene chloride. The organic phase was washed sequentially with water and brine. The aqueous phases were back extracted with a second portion of methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The crude residue was chromatographed by flash chromatography eluting with a gradient of 10-50% ethyl acetate/hexanes to give 5-chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.98 g; 42%). Mass spectrum: m/z: 257.3 (M+H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:29]([F:32])([F:31])[F:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:33][NH2:34]>>[CH3:33][NH:34][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([C:29]([F:32])([F:31])[F:30])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4cccc(C)c4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3cccc(C)c3)c2O1

Procedure:
The title compound was prepared (0.026 g, 67%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(3-methylphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.050 g, 0.11 mmol) and methylamine (0.12 g, 3.9 mmol). mp 228-230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([NH:6][NH:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=O.O=S(Cl)[Cl:24]>>[Cl:24][C:4]([C:3]1[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=1[Cl:1])=[N:6][NH:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)NNC(=O)c2ccccc2Cl)cc1
Reactant: O=S(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NN=C(Cl)c2ccccc2Cl)cc1
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
Into a 500 mL round bottom flask was placed 2-chloro-N′-tosylbenzohydrazide (10 g, 30.79 mmol). To this was added SOCl2 (36.6 g, 307.56 mmol). The resulting solution was allowed to react, with stirring, for 1.5 hours while the temperature was maintained at 75° C. in a bath of oil. To the mixture was added 2-chloro-N′-tosylbenzohydrazide (10 g, 30.79 mmol), while cooling to a temperature of 60° C. The resulting solution was allowed to react, with stirring, for an additional 2 hours while the temperature was maintained at 75° C. in a bath of oil. The reaction mixture was then quenched by the adding 100 mL of n-hexane. A filtration was performed. The filter cake was washed with n-hexane. The solid was dried in an oven under reduced pressure. This resulted in 19.6 g (74%) of N′-(chloro(2-chlorophenyl)methylene)-4-methylbenzenesulfonohydrazide as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14])([O-])=O.O.O.[Sn](Cl)[Cl:22].Cl>C(O)C>[ClH:22].[CH:15]1[C:12]2[C:13]([NH2:14])=[N:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[NH:10][C:11]=2[CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccccc1Nc1ccccc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC1=Nc2ccccc2Nc2ccccc21
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Combine 2-(2-Nitro-phenylamino)-benzonitrile (6.14 g, 25.66 mmol), tin(II) chloride dihydrate (17.37 g, 76.99 mmol), 5N HCl (105 ml), and ethanol (65.0 ml). Stir the mixture at reflux for 24 hours then cool it to ambient temperature and chill it in the refrigerator for 2 hours. Remove the ethanol under vacuum and chill in the refrigerator again. Filter off the resulting precipitate by vacuum filtration and dry it in a vacuum oven to give 6.31 g (100%) of a yellow solid: mass spectrum (ion spray): m/z=210.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][C:6]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)Br>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][CH:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1
Reactant: Brc1cccc(CC(Br)(Cc2cccc(Br)c2)Cc2cccc(Br)c2)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: Brc1cccc(CC(Cc2cccc(Br)c2)Cc2cccc(Br)c2)c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A suspension of 150.5 g (250 mmol) of tris(3-bromobenzyl)bromomethane and 163.5 g (2.5 mol) of zinc dust in 2000 ml of glacial acetic acid was stirred at 50° C. for 6 h. After cooling, the reaction mixture was filtered through silica gel (care: the filter residue is pyrophoric!). The filtrate was freed from glacial acetic acid under reduced pressure, and the residue was taken up in 1000 ml of dichloromethane. After the dichloromethane phase had been washed with water (2×500 ml), dried over sodium sulfate/sodium hydrogencarbonate and evaporated, the residue was freed from final traces of water by taking up in 500 ml of toluene and removal of the toluene by azeotropic distillation. The yield, with a purity of about 97%, was 122.9 g (235 mmol), corresponding to 94.0% of theory.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](OC)=[O:21])[CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:21][CH2:20][C:17]1[CH:18]=[C:19]2[C:14]([CH:13]=[CH:12][N:11]2[S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc2ccn(S(=O)(=O)c3ccc(C)cc3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(CO)cc32)cc1
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
A solution of methyl 1-(4-methylphenylsulfonyl)indole-6-carboxylate (28.0 g) in tetrahydrofuran (250 ml) was added dropwise to a slurry of lithium aluminum hydride (4.5 g) in tetrahydrofuran (300 ml) at 0°. After stirring at 0° for 15 minutes, the excess lithium aluminum hydride was quenched with a saturated solution of sodium sulfate and the resultant white precipitate was removed by filtration. The filtrate was dried (MgSO4) and evaporated to give 6-hydroxymethyl-1-(4-methylphenylsulfonyl)indole (21.5 g, 84%) as an ivory solid; partial NMR (80 MHz, CDCl3): 2.33(s, 3H, ArCH3), 4.77(d, 2H, OCH2), 6.62(dd, 1H, H3 -indole), 7.97(m, 1H, H7 -indole).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:13]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:13]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:12][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])=[CH:23][CH:24]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: COC(=O)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(F)ccc1OCc1ccc(C(C)(C)C)cc1

Procedure:
4.44 g (26 mmol) of methyl 5-fluoro-2-hydroxybenzoate [CAS 391-92-4], 5.25 g 28.7 mmol) of 4-tert-butylbenzyl chloride [CAS 19692-45-6], 18.0 g (130 mmol) of potassium carbonate and 6.5 g (39.2 mmol) of potassium iodide are dissolved in 25 ml of acetone and stirred under reflux for 12 h. The solvent is distilled out in vacuo, and the residue is taken up in ethyl acetate and washed once with 10% strength sodium hydroxide solution and three times with 1 N hydrochloric acid. The solution is dried over sodium sulfate, filtered, washed with ethyl acetate and concentrated. 8.36 g (26 mmol, 100% of theory) of the title compound are isolated.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([O:22]C2CCCCO2)=[CH:7][CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[CH:11]=[C:10]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O1CCOCC1.Cl>>[F:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([OH:22])=[CH:7][CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[CH:11]=[C:10]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1cc(-c2ccccc2)c2ccc(OC3CCCCO3)c(OCCF)c2o1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1cc(-c2ccccc2)c2ccc(O)c(OCCF)c2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 8-(2-fluoroethoxy)-4-phenyl-7-(tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one was added 1.5 mL of a 4 M HCl dioxane solution. The mixture was stirred at rt for 30 min under Ar atmosphere and concentrated. The crude product was purified with chromatography (hexane/EtOAc) to afford 8-(2-fluoroethoxy)-7-hydroxy-4-phenyl-2H-chromen-2-one (AD-C-004S-WZ01055) as a white solid (24 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 7.57-7.54 (m, 3H), 7.52-7.49 (m, 2H), 7.08 (dd, J=8.8, 1.2 Hz, 1H), 6.87 (dd, J=8.8, 1.2 Hz, 1 H), 6.11 (d, J=1.2 Hz, 1H), 4.86 (m, 1H), 4.74 (m, 1H), 4.50 (m, 1H), 4.43 (m, 1H); MS (ESI) m/z 301 (M+H+), 323 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)n2)c1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)c1

Procedure:
The title compound was prepared from 6′-bromo-4-methyl-6-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl (example E.96) (0.393 g, 1.0 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.283 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.500 g, 95%). MS (ISP) 526.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)[CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1ccc(CNCC(=O)Nc2cc(Cl)cc(Cl)c2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(CNCCNc2cc(Cl)cc(Cl)c2)cc1OC

Procedure:
In a manner similar to Preparation 2, react N-(3,5-dichlorophenyl)-2-[[(3,4-dimethoxyphenyl)methyl]amino]acetamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:19][C:20]1[C:21]([N:30]2[CH2:33][CH:32]([NH2:34])[CH2:31]2)=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>CN(C=O)C.CCOC(C)=O>[Cl:19][C:20]1[C:21]([N:30]2[CH2:31][CH:32]([NH:34][C:2]3[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:33]2)=[N:22][CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=1
Reactant: NC1CN(c2ncc(C(F)(F)F)cc2Cl)C1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(NC2CN(c3ncc(C(F)(F)F)cc3Cl)C2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 84796.1 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (150 mg, 0.525 mmol) was dissolved in dry DMF (1 mL) under nitrogen atmosphere. 1-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]azetidin-3-amine (133 mg, 0.530 mmol) was added followed by TEA (53 mg, 0.525 mmol) and the reaction mixture was heated in a microwave reactor for at 120° C. for 20 mins. The mixture was diluted with EtOAc, washed with saturate aqueous NaHCO3, dried with Na2SO4, filtered and evaporated. The crude product was purified on a Biotage Horizon HPFC system using Heptane and EtOAc as eluant affording the title compound (223 g, 84.0%). 1H NMR (500 MHz, CDCl3): δ 1.60 (d, 6H), 4.01-4.06 (m, 3H), 4.10-4.15 (m, 2H), 4.40-4.48 (m, 1H), 5.62 (bs, 1H), 7.51 (s, 5H), 7.59 (s, 1H), 8.25 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 20.38, 44.61, 48.06, 59.87, 109.52, 115.56, 117.98 (q, JC-F=33.6 Hz), 124.42, 124.75, 129.29, 130.48, 131.49, 134.49, 135.16, 143.70, 156.92, 158.26; Mass Spectrum: M+H+ 501.1.