Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([O:33][CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:34][O:33][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[C:17]=23)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Reactant: CN1CCNCC1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCN4CCN(C)CC4)c23)ccc1OCc1ccccn1
Yield: 59 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[3-methoxy-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate and N-methylpiperazine to give the title compound in 59% yield; NMR Spectrum: 2.10 (s, 3H), 2.52 (hidden by DMSO, 8H), 2.78 (t, 2H), 3.81 (s, 3H), 4.42 (t, 2H), 5.16 (s, 2H), 7.01 (d, 1H), 7.20 (dd, 1H), 7.36 (t+d, 2H), 7.54 (d, 1H), 7.84 (td, 1H), 8.26 (s, 1H), 8.36 (s, 1H), 8.58 (d, 1H); Mass Spectrum: 491 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:31])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:14]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:13]=1)=[O:10])(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:31])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:14]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:13]=1)=[O:10]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(C2CCCC2)c(C#Cc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)C(=O)Nc1ccc(C2CCCC2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-cyclopentyl-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate E2e (18 mg, 0.04 mmol) and DCM:TFA (9:1, 2 ml) is stirred at RT for 90 minutes. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 13 mg (94%). HPLC-MS: M+H=334; tR=2.09 min (*Method—1).
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:11][C:10]2[C:9](=[O:12])[N:8]([CH3:13])[C:7]3=[N:14][C@@H:15]4[CH2:19][CH2:18][CH2:17][C@@H:16]4[N:6]3[C:5]=2[N:4]=1.[CH3:20]I>>[CH3:2][C:3]1[N:11]([CH3:20])[C:10]2[C:9](=[O:12])[N:8]([CH3:13])[C:7]3=[N:14][C@@H:15]4[CH2:19][CH2:18][CH2:17][C@@H:16]4[N:6]3[C:5]=2[N:4]=1
Reactant: CI
Reactant: Cc1nc2c([nH]1)C(=O)N(C)C1=N[C@@H]3CCC[C@@H]3N12
Agent: Cl
Product: Cc1nc2c(n1C)C(=O)N(C)C1=N[C@@H]3CCC[C@@H]3N12

Procedure:
By using cis-5,6a,7,8,9,9a-hexahydro-2,5dimethylcyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one hydrochloride, and methyl iodide instead of 4-chlorobenzyl chloride in accordance with Example 21, the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:12])[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:33]([CH3:34])=[C:32]([C:35](Cl)=[O:36])[CH:31]=[N:30]2)=[CH:25][CH:24]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:12][C:35]([C:32]2[CH:31]=[N:30][N:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[C:33]=2[CH3:34])=[O:36])[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: CCCC(N)c1cncc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1cncc(Br)c1
Reaction time: 15 h
Yield: 75.4 %

Procedure:
A solution of 1-(5-bromo-pyridin-3-yl)-butylamine (470 mg, 2.0 mmol), diisopropylethylamine (0.82 mL, 4.7 mmol) and DMAP (19 mg, 0.16 mmol) in CH2Cl2 (20 mL) is treated with 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl chloride (400 mg, 1.6 mmol) and stirred for 15 hours. The reaction mixture is then diluted with CH2Cl2 (50 mL), washed with saturated aqueous ammonium chloride (2×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluted with 20 to 50% EtOAc/hexanes) to provide 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [1-(5-bromo-pyridin-3-yl)-butyl]amide as a colorless foam-solid (540 mg, 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12](Br)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24][S:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12]([C:29]3[CH:30]=[CH:31][C:26]([S:25][CH3:24])=[CH:27][CH:28]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)(O)CCOc1c(Br)cnn(-c2ccc(F)c(F)c2)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CSc1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCCC(C)(C)O)cc1
Yield: 64.5 %

Procedure:
The product from Example 471C (12.79 g, 32.86 mmol) was coupled to 4-(methyl-thio)phenylboronic acid (6.07 g, 36.15 mmol) with K2CO3 (10 g, 72.3 mmol) and PdCl2(PPh3)2 (1.15 g, 1.64 mmol) in ethanol (200 mL) at 60–65° C. for 40–70 minutes to provide the title intermediate (yield: 9.16 g, 64.5%).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([N:15]([C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[CH2:16][CH2:17][NH2:18])[CH3:14].[BH4-].[Na+].O>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:18][CH2:17][CH2:16][N:15]([CH2:13][CH3:14])[C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CCN(CCN)c1cccc(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CCNCc1ccc(C(C)(C)C)cc1)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
1.62 g (10 mmol) of 4-tert-butyl benzaldehyde and 1.78 g (10 mmol) of N*1*-ethyl-N*1* -m-tolyl-ethane-1,2-diamine were dissolved in 20 ml methanol and the solution was stirred for 2 h at rt. 567 mg (15 mmol) of sodium borohydride were added in portions under nitrogen. The reaction mixture was stirred at rt over night. Water was added and the solvent was evaporated. The reaction mixture was extracted with diethyl ether and the organic layer was washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave the 3.08 g (95%) product as a light yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.33 (d, 2H), 7.24 (d, 2H), 7.09 (dd, 1H), 6.51 (m, 3H), 3.78 (s, 2H), 3.42 (t, 2H), 3.34 (q, 2H), 2.85 (t, 2H), 2.29 (s, 3H), 1.31 (s, 9H), 1.11 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([OH:10])=[C:2]([NH:1][S:18]([CH3:17])(=[O:20])=[O:19])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(O)c(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
10 g of 2-amino-4-methoxyphenol was dissolved in 100 ml of methylene chloride. 17 ml of pyridine was added thereto and the mixture was cooled to 5° C. Then, 9.1 g of methanesulfonyl chloride was added dropwise in 10 minutes and stirring gas conducted for 1 hour at 5°-10° C. The solvent was removed by distillation under reduced pressure. To the residue were added 100 ml of ethyl acetate and 50 ml of water. The mixture was adjusted to pH 2 with 4N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from isopropyl alcohol to obtain 14.4 g (yield: 92%) of 4-methoxy-2-methylsulfonylaminophenol having a melting point of 135°-136° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: CC(=O)c1cc(Br)cs1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)cs1

Procedure:
1-(4-(4-(Trifluoromethyl)phenyl)thien-2-yl)ethanone is prepared from (4-bromothien-2-yl)ethanone and 4-trifluoromethylphenylboronic acid according to general procedure A.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.CO.[N+](=[CH:17][Si](C)(C)C)=[N-]>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:17])=[O:11])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)CCc1ccc(I)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-(4-iodophenyl)propanoic acid (commercially available) in toluene and methanol (9:1, 0.2 M) 0° C. was added (diazomethyl)trimethylsilane (1 N solution in Et2O, 2 eq). After stirring at room temperature overnight the reaction mixture was concentrated under vacuum and the resulting crude residue was purified by chromatography (silica gel, 20-50% EtOAc in hexanes) to afford methyl 3-(4-iodophenyl)propanoate.
Reaction SMILES: C(OC(N[C@@H](C([N:16]([CH2:46][CH:47]([CH3:49])[CH3:48])[NH:17][C:18](=[O:45])[C@@H:19]([CH:24]([C:34](=[O:44])NOCC1C=CC=CC=1)[CH2:25][CH2:26][CH2:27]C1C=CC=CC=1)[CH2:20][CH:21]([CH3:23])[CH3:22])=O)C)=O)C1C=CC=CC=1.[C:50]([O:54]C(C([C@@H](CC(C)C)C(O)=O)CC=C)=O)([CH3:53])([CH3:52])[CH3:51]>>[C:50]([O:54][C:34]([CH:24]([C@@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:18]([NH:17][NH:16][CH2:46][CH:47]([CH3:48])[CH3:49])=[O:45])[CH2:25][CH:26]=[CH2:27])=[O:44])([CH3:53])([CH3:52])[CH3:51]
Reactant: C=CCC(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)O
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1)C(CCCc1ccccc1)C(=O)NOCc1ccccc1
Product: C=CCC(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)NNCC(C)C

Procedure:
In an analogous manner to that described in Example 1, part (i), but using 2(R)-[1(RS)-(tert-butoxycarbonyl)-3-butenyl]-4-methylvaleric acid in place of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid there was obtained 2(R)-[1(RS)-(tert-butoxycarbonyl)-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([N:29]2[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]2)[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([N:29]3[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]3)[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: OC1CCN(c2cccc(Br)n2)C1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(N4CCC(O)C4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (200 mg, 0.64 mmol) and 1-(6-bromopyridin-2-yl)pyrrolidin-3-ol (132 mg, 0.54 mmol) as the starting materials.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2cc(F)cc(Br)c2)cc1C
Product: Cc1cc(Oc2cc(F)cc(Oc3ccc(Cl)cc3Oc3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-chloro-2-phenoxy-phenol as in Example 18 to afford 0.118 g (22%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C28H22O5ClF 492, found 493 and 495 (M+1 and M+3).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[C:35]1([OH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[F:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:23]=2[O:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(F)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: Oc1ccccc1
Product: Cc1cc(Oc2cc(F)cc(Oc3ccc(C(F)(F)F)cc3Oc3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepare by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with phenol as in Example 45 to afford 0.080 g (28%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H22O5F4 526, found 527 (M+1, 100%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[CH2:7][C:6]2[C:8]([CH3:20])=[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.Br[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][CH3:31])[CH:24]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([N:17]2[CH2:16][CH2:15][N:14]([C:9]3[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]4[O:4][C:3]([CH3:21])([CH3:2])[CH2:7][C:6]=4[C:8]=3[CH3:20])[CH2:19][CH2:18]2)=[CH:24][C:25]=1[O:30][CH3:31]
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: COc1cc(Br)ccc1F
Agent: Cl
Product: COc1cc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)ccc1F
Yield: 53.2 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine hydrochloric acid salt (311 mg, 1.00 mmol) synthesized in Reference example 147 and 4-bromo-1-fluoro-2-methoxybenzene (308 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 212 mg (yield 53%). Melting point was 152 to 155° C. (hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16].[C:20]([Mg]Br)#[C:21][CH3:22]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:17]1[CH2:18][CH2:19]1)([C:20]#[C:21][CH3:22])[OH:16]
Reactant: Nc1ccc(-c2cccc(Cl)c2)cc1C(=O)C1CC1
Reactant: CC#C[Mg]Br
Product: CC#CC(O)(c1cc(-c2cccc(Cl)c2)ccc1N)C1CC1

Procedure:
1-(4-Amino-3′-chloro-biphenyl-3-yl)-1-cyclopropyl-1-propynyl-methanol was prepared from (4-amino-3′-chloro-biphenyl-3-yl)-cyclopropyl-methanone and propynylmagnesium bromide according to Example 41.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][NH:7][C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[CH2:13]([N:31]=[C:32]=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:13]([NH:31][C:32]([N:7]1[C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:8]1)=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CC1(C)CNC(=O)CC(C)(C)N1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)N1CC(C)(C)NC(C)(C)CC1=O

Procedure:
Using the same procedure as described in Example 4, 17 parts of 2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one and 32 parts of n-octadecyl isocyanate were reacted together and afforded 4-n-octadecylcarbamoyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one as a colourless solid which was recrystallised from petroleum ether (of boiling range 60° to 80°C) and had a melting point of 56.5°-58°C. This material gave the following elemental analysis by weight:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[CH:6]2.FC(F)(F)C(O)=O.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(ccn2C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CCN2C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 5-methoxy-1-methylindole (182 mg, 1.13 mmol) in 2.3 mL of acetic acid was added trifluoroacetic acid (1.1 mL). After the reaction mixture was added sodium cyanoborohydride (142 mg, 2.26 mmol) at 0° C., the reaction mixture was stirred at the same temperature for 2 h. After the reaction mixture was basified by 50% sodium hydroxide aqueous solution, the solution was extracted with diethyl ether (20 mL) twice. The combined extracts were washed with brine (5 mL), and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain 5-methoxy-1-methylindoline (131 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[S:15]([NH2:25])(=[O:24])([C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)=[O:16]>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[S:9]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([S:15](=[O:24])(=[O:16])[NH2:25])=[CH:18][CH:19]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(/C=C/S(=O)(=O)Cl)cc1
Product: COc1ccc(/C=C/S(=O)(=O)Nc2ccc(S(N)(=O)=O)cc2)cc1
Yield: 46.2 %

Procedure:
A solution of (E)-4-methoxystyrylsulfonyl chloride (10 mmol) and sulfanilamide (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 181-183° C., was obtained in 46.2% yield.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:13]=[CH:14][C:15]([C:30]([F:33])([F:32])[F:31])([OH:29])[CH2:16][C:17]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([CH3:19])[CH3:18])[N:4]=1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:13][CH2:14][C:15]([C:30]([F:31])([F:32])[F:33])([OH:29])[CH2:16][C:17]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([CH3:19])[CH3:18])[N:4]=1)[CH3:2]
Reactant: CCc1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1ccc2c(NCC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Reaction time: 2 h

Procedure:
600 mg (1.3 mmol) of 1-(2-ethylquinolin-5-ylimino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol in 5.0 ml of methanol is mixed at 0° C. with 197 mg (5.2 mmol) of sodium borohydride. After 2 hours at room temperature, water is added, and methanol is removed in a vacuum. The aqueous phase is extracted with dichloromethane, the combined organic phases are dried on sodium sulfate, and the solvent is removed in a vacuum. After purification on silica gel with hexane-ethyl acetate (0-100%), 400 mg (66% of theory) of the product is obtained.
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C([Sn](CCCC)(CCCC)[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)CCC.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:2]1[S:3][C:4]([C:21]2[S:20][CH:19]=[CH:23][CH:22]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1cc(Br)sc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(-c2cccs2)sc1-c1cccs1
Temperature: 100 °C
Yield: 85 %

Procedure:
The synthesis of 3T-ET is carried by first synthesizing ethyl 2-(2,5-dibromothiophen-3-yl)acetate using known methods and is performed as follows. Ethyl 2-(2,5-dibromothiophen-3-yl)acetate (6.4 g, 10 mmol) and 2-(tributylstannyl)thiophene (15 g, 20 mmol) are added to a 30 mL dry DMF solution of dichlorobis-(triphenylphosphine)palladium (1.3 g, 1.5 mmol). After three freeze thaw cycles, the mixture is heated at 100° C. for 48 hours. The mixture is cooled to room temperature and poured into a beaker containing 150 mL of water and subsequently extracted with CH2Cl2. The extracted CH2Cl2 mixture is dried with Na2SO4. After filtering and evaporation of solvent, the crude product is purified by chromatography on silica gel using toluene as eluent. The final product is obtained in 85% yield as pale yellow oil. The characterization of the compound is consistent with that published in the literature.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][NH:13][CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:18](C)=O.[Na+]>CO.C(Cl)Cl.C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:15][CH2:14][N:13]([CH3:18])[CH2:12][C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCNC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCc2c(n(C)c3cc(Br)ccc23)C1
Reaction time: 1 h
Yield: 88 %

Procedure:
7-Bromo-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.24 g, 4.68 mmol) was dissolved in a mixture of MeOH (20 mL) and CH2Cl2 (5 mL) and formaldehyde (0.56 mL, 37% aqueous solution) was added. After stirring for 1 h, NaBH(OAc)3 (1.98 g, 9.34 mmol) was added and the mixture stirred for a further 10 minutes. The mixture was diluted with methylene chloride (50 mL), washed with saturated Na2CO3 solution, concentrated and purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) to provide the title compound (1.15 g, 88%) as a white powder: 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J=1.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.16 (dd, J=8.3, 1.7 Hz, 1H), 3.61 (s, 2H), 3.55 (s, 3H), 2.86-2.76 (m, 4H), 2.56 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]([C:14]1[S:18][C:17]([S:19]([OH:22])(=[O:21])=[O:20])=[C:16]([CH3:23])[CH:15]=1)([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH3:13])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>CC(=O)CC>[CH3:34][C:33]([CH3:36])([CH3:35])[C:32](=[O:37])[CH2:31][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:3]([C:14]2[S:18][C:17]([S:19]([OH:22])(=[O:21])=[O:20])=[C:16]([CH3:23])[CH:15]=2)([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][C:8]=1[CH3:13]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1cc(C)c(S(=O)(=O)O)s1
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)O)s1
Yield: 108.2 %

Procedure:
To a solution of 5-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-thiophene-2-sulfonic acid dimethylaminemethyleneamide (5.1 g, 12.48 mmol) in 2-butanone (50 ml) is added potassium carbonate (2.59 g, 18.72 mmol), and chloropinacolone (3.28 ml, 24.91 mmol). The reaction is refluxed overnight, filtered, and concentrated. The residue is partitioned between EtOAc (400 ml) and 0.2N HCl (100 ml). The organic layer is washed with brine (100 ml), MgSO4 dried, concentrated, and chromatographed (120 g SiO2, 50% EtOAc/Hex) to yield the title compound (6.11 g, 97%).