Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:34]2[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=2)[CH2:37]Cl)[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([C:26]3[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1cc(-c2cccc(CN(c3ccc(C)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-methylphenyl)amino]piperidine (581 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)[Cl:15].C([O-])(O)=O.[Na+]>CCO>[Cl:15][CH2:14][CH:16]([OH:18])[CH2:17][N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: ClCC1CO1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OC(CCl)CN1CCN(Cc2ccccc2)CC1
Yield: 75.3 %

Procedure:
1-Benzylpiperazine (8.66 mL, 50 mmol) in EtOH (100 mL) was added dropwise to epichlorohydrin (3.92 mL, 50 mmol) in EtOH (25 mL) with NaHCO3 (4.2 g, 50 mmol) over 30 min at 0° C. under nitrogen. After 16 h the EtOH was removed in vacuo and the crude product eluted through silica gel (5% methanol: methylene chloride) to give pure product (10.12 g, 75.3%) as an amber oil. DCI/MS (M+1) 269. 400 MHz 1H NMR (CDCl3) δ: 7.3 (m, 5H), 4.95 (m, 1H), 4.5 & 4.6 (m, 2H), 3.95 (m, 1H), 3.6 (m, 2H), 3.5 (s, 2H), 2.7 (m, 4H), 2.4 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH2:26][OH:25])[CH:32]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: OCc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(CO)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 6.3 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.05 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(hydroxymethyl)phenylboronic acid (15 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-6-(3-(hydroxymethyl)phenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (1.3 mg, 5%). 1H-NMR (MeOD): 2.05 (t, 1H), 2.21 (t, 1H), 3.07 (s, 3H), 4.50 (s, 1H), 5.81 (d, 1H), 6.94 (d, 1H), 7.11 (s, 1H), 7.19 (d, 1H), 7.30 (m, 4H), 7.41 (m, 4H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:29]=[CH:28][C:7]2[C:8](=[C:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:9]3[C:14]([CH2:15][O:16][C:6]=2[CH:5]=1)=[CH:13][CH:12]=[CH:11][N:10]=3.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:29]1[C:4]([Cl:3])=[CH:5][C:6]2[O:16][CH2:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[C:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:7]=2[CH:28]=1
Reactant: BrBr
Reactant: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3OCc3cccnc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)N1CCC(=C2c3cc(Br)c(Cl)cc3OCc3cccnc32)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
Bromine (0.5 ml, 9.7 mmol) was added to a solution of ethyl 4-(8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)-1-piperidine-carboxylate (1.0 g., 2.6 mmol) in methylene chloride (15 ml) at 20° C. The solution was stirred for 2 hours at 20° C. The reaction mixture was poured onto ice (50 g), basified with 10% NaOH, and extracted with methylene chloride (100 ml). The organic layer was separated, washed with water (20 ml), dried (MgSO4), filtered and evaporated, yielding an oil which was chromatographed on silica gel and eluted with 1:1 ethylacetate/hexanes. The product, ethyl 4-(9-bromo-8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)-1-piperidine-carboxylate (0.8 g., 66% yield) was obtained as a white solid; MS (CI, M+H)=465.
Reaction SMILES: [CH3:1][C@:2]12[CH2:20][CH2:19][C@H:18]3[C@@H:7]([CH:8]=[CH:9][C:10]4[C@:15]3([CH:16]=[O:17])[CH2:14][CH2:13][C:12](=[O:21])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][CH2:3]2.[CH2:22](OCC)C.CCCCCC>O1CCCC1>[CH3:22][C@@H:8]1[CH:9]=[C:10]2[C@:15]([CH:16]=[O:17])([CH2:14][CH2:13][C:12](=[O:21])[CH2:11]2)[C@@H:18]2[C@@H:7]1[C@H:6]1[C@@:2]([CH2:20][CH2:19]2)([CH3:1])[CH2:3][CH2:4][CH2:5]1
Reactant: C[C@@]12CCC[C@H]1[C@@H]1C=CC3=CC(=O)CC[C@]3(C=O)[C@H]1CC2
Reactant: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@@H]1C=C2CC(=O)CC[C@]2(C=O)[C@H]2CC[C@]3(C)CCC[C@H]3[C@H]12

Procedure:
The 7α-methyl-4-androstene-3,19-diones are produced by alkylating the corresponding 4,6-androstadiene-3,19-dione with dimethyllithium copper in an inert solvent such as diethyl ether, tetrahydrofuran, hexane or mixtures of these at temperatures ranging from -78° C. to 25° C. Tetrahydrofuran is the preferred solvent and temperatures between -5° C. to 10° C. provide optimum results. Quenching the initially formed enolate anion with a weak protonating agent such as a saturated solution of ammonium chloride, oxalic acid or boric acid provides the 7α-methyl-5-androstene-3,19-dione. Quenching the enolate with a strong protonating agent such as hydrochloric acid provides the 7α-methyl-4-androstene-3,19-diones.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]([CH:25]([CH3:26])[CH3:27])[C:29](=[O:36])[C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:28]
Reactant: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1
Reactant: O=C(O)c1ccncc1
Product: CC(C)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(=O)c1ccncc1

Procedure:
2-Chloro-4-(2-{4-[3-(isopropylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-ethyl)-phenol (compound 132) was coupled with isonicotinic acid following procedure D2. LC-MS showed the product had the expected M+H+ of 502. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.9 (d, 2H)) 8.5 (s, 1H) 8.3 (d, 1H) 8.1 (s, 1H) 8.0 (d, 2H) 7.9 (m, 1H) 7.5 (d, 1H) 7.4 (m, 2H) 7.2 (s, 1H) 6.9 (d, 1H) 5.5 (s, br, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 3.1 (m, 1H) 2.9 (m, 2H) 1.2 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[C:20](O)=[O:21])=[CH:5][CH:4]=1.Cl.[NH2:24][CH2:25][C:26]1[CH:40]=[CH:39][C:29]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[O:31])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[C:20]([NH:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[O:31])=[CH:39][CH:40]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: NCc1ccc(C(=O)Nc2ccccn2)cc1
Reactant: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)O)cc1
Agent: Cl
Product: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)NCc2ccc(C(=O)Nc3ccccn3)cc2)cc1
Yield: 71 %

Procedure:
This material was prepared using a method substantially similar to that of Example 5 from 3-(4-methoxyphenyl)-5-phenyl-1H-pyrrole-2-carboxylic acid and 4-(aminomethyl)-N-pyridin-2-ylbenzamide hydrochloride, yielding the title compound. 3-(4-Methoxyphenyl)-5-phenyl-N-{4-[(pyridin-2-ylamino)carbonyl]benzyl}-1H-pyrrole-2-carboxamide: Yield 71%; m.p. 196° C. (dec.); IR 3402, 3239, 1623, 1536, 1432, 1304, 1246 cm−1; 1H-NMR (300 MHz, δ ppm, CDCl3) 9.75 (s, 1H), 8.77 (s, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.29 (d, J=4.8 Hz, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.77 (dt, J=7.0 Hz, J′=1.8 Hz, 1H), 7.57 (d, J=7.2 Hz, 2H), 7.45-7.27 (m, 7H), 7.07 (ddd, J=7.3 Hz, J′=5.0 Hz, J″=0.8 Hz, 1H), 6.90 (d, J=8.7 Hz, 2H), 6.49 (d, J=3.0 Hz, 1H), 6.13 (t, J=5.8 Hz, 1H), 4.52 (d, J=5.9 Hz, 2H), 3.82 (s, 3H); 13C-NMR (75 MHz, δ ppm, CDCl3) 165.7, 161.6, 159.7, 151.9, 148.1, 143.0, 138.8, 134.7, 133.6, 131.6, 430.9, 129.2, 128.3, 127.9, 127.8, 127.7, 125.0, 122.4, 120.1, 114.7, 109.9, 55.6, 43.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH2:22]([NH2:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[CH2:22]([NH:30][S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:13])=[O:12])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCNS(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of 3,4-dimethoxybenzenesulfonyl chloride (0.750 g, 3.17 mmol), triethylamine (1.12 mL, 7.93 mmol) in 10 mL of ethyl acetate, octylamine (0.525 mL, 3.17 mmol) was added dropwise and the resulting solution was stirred overnight. The reaction mixture was filtered and the filtrate was washed 1N HCl (2×), dried with MgSO4, filtered and concentrated in vacuo to afford 0.611 g (78%) of the title compound as a white solid.
Reaction SMILES: [NH:1]([C:3](=[S:6])OC)[NH2:2].[NH:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1.C(OCC)(=O)C>C(O)C>[NH:1]([C:3]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[S:6])[NH2:2]
Reactant: COC(=S)NN
Reactant: OC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: NNC(=S)N1CCC(O)CC1
Temperature: 90 °C

Procedure:
A solution of methyl hydrazinecarbothioate (1.0 g, 8.2 mmol) and piperidin-4-ol (1.24 g, 12.3 mmol) in ethanol (7 mL) was refluxed with heating at 90° C. for 2 days. After addition of ethyl acetate, the reaction solution was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the crude desired product. The crude product was used directly for the next reaction.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([CH2:16][CH3:17])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[CH2:16]([C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:19])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([OH:18])[CH:14]=1)[CH3:17]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(CC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of (4-ethyl-1,6-dihydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.19 g, 0.70 mmol) in THF (8 mL) and H2O (2 mL) was added LiOH (0.178 g) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated in vacuo and the residue purified by preparative HPLC to give (4-ethyl-1,6-dihydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid (0.080 g, 50%). 1H NMR (400 MHz, DMSO-d6δ 9.26 (s, 1H), 6.87 (s, 1H), 6.69 (s, 1H), 5.40 (m, 1H), 2.92 (m, 1H), 2.55 (m, 2H), 2.00 (m, 1H), 1.16 (m, 3H). MS (ESI) m/z: 235 [M−1]−. HPLC purity: 92.64% (220 nm), 95.63% (Maxplot).
Reaction SMILES: C([CH:3]([C:22]([OH:24])=[O:23])[N:4]([C:12](OCC1C=CC=CC=1)=O)[CH2:5][P:6]([CH2:10][CH3:11])([CH2:8][CH3:9])=[S:7])C.Br.[CH3:26]COCC>C(O)(=O)C>[CH2:12]([N:4]([CH2:5][P:6]([CH2:10][CH3:11])([CH2:8][CH3:9])=[S:7])[CH2:3][C:22]([OH:24])=[O:23])[CH3:26]
Reactant: CCOCC
Reactant: CCC(C(=O)O)N(CP(=S)(CC)CC)C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC(=O)O)CP(=S)(CC)CC
Reaction time: 1 h

Procedure:
Ethyl N-carbobenzoxy-N-(diethylthiophosphinylmethyl)glycine (1 g., 0.0024 mole) was dissolved in 5 ml. of 30% hydrogen bromide in glacial acetic acid at 0° C. The mixture was stirred for one hour. Ether was added and the oily precipitate was isolated by decanting the ether layer. The oil was washed with ether twice, then suspended in benzene and treated with propylene oxide. The solution was concentrated in vacuo to yield ethyl N-(diethylthiophosphinylmethyl)glycine (0.15 g., 0.0005 mole) as an oil, ND25 =1.4960.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[CH:13][C:12]=2[Cl:19])=[CH:5][C:4]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)=[O:22].[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1.N1C=CC=CC=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([CH2:17][NH:18][S:34]([CH:31]3[CH2:33][CH2:32]3)(=[O:36])=[O:35])[CH:14]=[CH:13][C:12]=2[Cl:19])=[CH:5][C:4]=1[C:21]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([Br:30])=[CH:28][CH:29]=1)=[O:22]
Reactant: COc1ccc(NC(=O)c2cc(CN)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2cc(CNS(=O)(=O)C3CC3)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
A mixture of 52.5 mg N-[4-methoxy-3-(4-bromophenyl)aminocarbonyl-phenyl]-2-chloro-5-aminomethyl-benzamide (0.10 mmol), 16.8 mg cyclopropylsulphonic acid chloride (0.12 mmol), 1.0 mL pyridine and 4.0 mL acetonitrile was stirred overnight, concentrated, dissolved in 3 mL DMF and purified by prep. HPLC.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[Cl:13].[Cl-].[NH4+]>O1CCCC1>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:1])=[CH:7][C:6]=1[Cl:13]
Reactant: O=Cc1ccc(Br)c(Cl)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
A solution of methylmagnesium bromide (4.8 mL, 3M, 14.4 mmol) was added dropwise to the solution of 4-bromo-3-chlorobenzaldehyde (1.52 g, 7.0 mmol) in tetrahydrofuran at −40° C. Then the mixture was stirred at 25° C. for 3 hrs. Saturated ammonium chloride solution (10 mL) was added to the mixture. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=1:1) to give 1-(4-bromo-3-chlorophenyl)ethanol as a white solid (1.32 g, 81%). 1H NMR (300 MHz, d6-DMSO): 7.69 (d, J=8.1, 1H), δ 7.53 (d, J=0.9, 1H), 7.19 (dd, J1=8.1, 1H J2=0.9, 1H), 5.38 (d, J=3.6, 1H), δ 4.70 (m, 1H), 1.30 (d, J=6.6, 3H).
Reaction SMILES: C([N:8]1[CH2:11][CH:10]([O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]3[N:19]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[N:20]=[CH:21][C:14]=23)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH:8]1[CH2:9][CH:10]([O:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]3[N:19]([C:22]4[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=4)[N:20]=[CH:21][C:14]=23)[CH2:11]1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CN(Cc5ccccc5)C4)ncnc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CNC4)ncnc32)cc1
Yield: 318.5 %

Procedure:
4-(1-Benzyl-azetidin-3-yloxy)-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (0.01 mmol, 46 mg) was dissolved in a mixture of ethyl acetate (5 mL) and methanol (5 mL). Palladium catalyst (30 mg, 65% by wt) was added to the reaction. The mixture was exposed to hydrogen gas for 60. minutes at room temperature and atmospheric pressure. The mixture was passed through celite to remove palladium catalyst. Removal of organic solvents in vacuo and purification by flash chromatography provided 4-(azetidin-3-yloxy)-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine as a white solid (11 mg, 5%). 1H NMR (400MHz, MeOH-d4) δ (ppm): 8.45 (m, 2H); 8.37 (d, 2H); 8.05 (d, 2H); 4.54 (m, 1H); 4.35 (dd, 2H); 3.69 (m, 2H); 3.09 (s, 3H). LCMS (ESI), m/z 346.2 (M+H+, 100%).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C@:10]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[C@@H:9]1[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:19][C:15]1[C:14]([F:20])=[C:13]([C@H:11]2[CH2:12][N:8]([CH2:7][C:6]([OH:36])=[O:5])[C@@H:9]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C@@:10]2([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])[C:21]#[N:22])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)C[C@@H]1N(CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N(CC(=O)O)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
To a solution of rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid tert-butyl ester (2.1 g, 3.9 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 24 h. The mixture was concentrated, and water was added. The “pH” of the mixture was adjusted to 6-7 by saturated aqueous NaHCO3 solution, then extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried over MgSO4, then concentrated to give rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid as a off-white solid (1.6 g, 85%). HRMS (ES+) m/z Calcd for C24H24Cl2F2N2O2+H [(M+H): 481.1256; Found: 481.1254.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:13])[C:10](O)=[O:11])=[CH:6][CH:5]=[C:4]([Cl:14])[N:3]=1.CN(C)C=O.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:13])[C:10]([Cl:22])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:14])[N:3]=1
Reactant: CC(Oc1ccc(Cl)nc1Cl)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Cl)nc1Cl)C(=O)Cl

Procedure:
23.6 g (0.1 mole) of 2-[(2,6-dichloro-3-pyridyl)oxy]-propionic acid, 150 ml of chloroform and 1.5 ml of dimethylformamide are heated with stirring to 55°, and in the course of 1 hour a solution of 18 g (0.15 mole) of thionyl chloride in 40 ml of chloroform is added dropwise. The reaction mixture is subsequently refluxed for 16 hours and is afterwards concentrated in vacuo. The product obtained is used directly for further reactions.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.B(O)(O)[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1>>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:21][CH:22]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: Cc1ccc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, white solid (74 mg, 94%), MS (ISP) m/z=316.5 [(M+H)+], mp 240.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 0.325 mmol).
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][CH2:11][CH2:12][NH2:13].CS[C:19]([N:33]([CH3:42])[N:34]=CC1C=CC=CC=1)=[N:20][C:21](=O)[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].Cl.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CC(C)=O>[CH3:42][N:33]1[C:19]([NH:13][CH2:12][CH2:11][CH2:10][O:9][C:8]2[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=2)[CH:2]=[O:3])=[N:20][C:21]([CH2:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[N:34]1
Reactant: CSC(=NC(=O)CS(=O)(=O)c1ccccc1)N(C)N=Cc1ccccc1
Reactant: NCCCOc1cccc(C2OCCO2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: Cn1nc(CS(=O)(=O)c2ccccc2)nc1NCCCOc1cccc(C=O)c1
Yield: 70.5 %

Procedure:
A mixture of 3-[3-(1,3-dioxolan-2-yl)phenoxy]propanamine (2.3 g) and methyl-1-methyl-2-(phenylmethylene)-N-[2-(phenylsulphonyl)acetyl]hydrazine carboximidothioate (4.0 g) was heated at 60° under water pump vacuum for 3 h. The reaction mixture was dissolved in toluene (100 ml), 5N hydrochloric acid (100 ml) and acetone (50 ml) and stirred at room temperature for 18 h. The aqueous layer was basified to pH 9 with potassium carbonate and extracted with ethyl acetate. The organic extract was evaporated to give the title compound as an amber gum (3.0 g) T.l.c. Methanol; Rf 0.8.
Reaction SMILES: [H-].[Na+].[CH:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:13]=2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:8][CH:7]=1)=O.CI.CN(C)[CH:36]=[O:37]>>[CH:36]([CH2:3][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:13]=2[C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[CH:10][CH:11]=1)=[O:37]
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(NC=O)cc2)s1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(NCC=O)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%; 40 mg) was added to an ice-cooled solution of ethyl 5-[4-(formylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylate (0.35 g) in N,N-dimethylformamide (10 ml). The mixture was stirred at ambient temperature for 30 minutes, and to the resulting mixture was added methyl iodide (0.23 g) at 5° C. The mixture was stirred at ambient temperature for 1.5 hours and poured into ice-water. The precipitates were collected, washed with water, and dried in vacuo to give ethyl 5-[4-(N-formylmethylamino)phenyl]-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylate (0.34 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:31][CH3:32])=[CH:5][C:6]2[N:12](CC)[C:11](=[O:15])[CH:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH2:23])[N:9]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:7]=2[CH:30]=1.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:31][CH3:32])=[CH:5][C:6]2[NH:12][C:11](=[O:15])[CH:10]([C:16]3[CH:17]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][NH:23][C:39](=[O:41])[CH3:40])[N:9]=[C:8]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:7]=2[CH:30]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCN1C(=O)C(Cc2ccccc2N)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(c1ccccc1)=NC(c1ccccc1CNC(C)=O)C(=O)N2
Reaction time: 24 h
Yield: 70 %

Procedure:
To a solution of 40 mg (0.09 mmol) of 7,8-dimethoxy-1-ethyl-3-(2-aminobenzyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one IIca, add 18.4 mg (0.23 mmol) of pyridine in 4 ml of CH2Cl2, 11.5 mg (0.11 mmol) of acetic anhydride dropwise. Stir for 24 hours. Evaporate to dryness and purify by silica chromatography (AcOEt then AcOEt 5/CH2Cl2 4/EtOH 1). Yield: 70%. M: 144–145° C. 1H-NMR (CDCl3, 300 MHz): d 0.89–0.96 (m, 3H, CH3), 2.01 (s, 1H, COCH3), 3.36–3.45 (m, 2H, CHCH2), 3.61 (s, 3H, OCH3), 3.73–3.84 (m, 2H, CHCH2+1HNCH2), 3.91 (s, 3H, OCH3), 6.60 (s, 1H Ar), 7.07–7.61 (m, 10H Ar). Mass: (M+H)+=472.23.