Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.Br[CH2:27][C:28](=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][CH2:27][C:28](=[O:30])[CH3:29])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: CC(=O)CBr
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OCC(C)=O
Yield: 63 %

Procedure:
4-Methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl) carbonylthiochroman-1,1-dioxide was used as a starting material (XIH). And, 0.4 g (1.10 mmol) thereof was dissolved in 10 ml of methyl ethyl ketone, and 0.15 g (1.10 mmol) of bromoacetone as a reaction reagent (XII) and 0.30 g (2.20 mmol) of potassium carbonate as a base were added. The resultant mixture was refluxed under heat for 3 hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. Its organic layer was separated, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the resultant oil was purified with flush column chromatography (Wako Gel C-300: hexane/ethyl acetate1:2) to give 0.29 g (yield 63%) of 4-methoxy-5-methyl-6-(5-acetylmethyloxy-1-ethylpyrazol-4-yl) carbonylthiochroman-1,1-dioxide (Compound No. 59) as an end compound which comes under the general formula (XI). Table 20 shows the structures of the starting material (XIH) and the reaction reagent (XII), and the structure and the yield of the end product (XI).
Reaction SMILES: C([O-])(C)(C)C.[K+].[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH3:28])[OH:19])#[N:8].[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[S:39](Cl)(=[O:41])=[O:40])[CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH2:27]([O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:12]1([OH:19])[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:7]#[N:8])[CH:10]=2)[N:14]([S:39]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:38]=2[N:29]=[CH:30][CH:31]=[CH:32]3)(=[O:40])=[O:41])[C:13]1=[O:18])[CH3:28]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccccc1C1(O)C(=O)N(S(=O)(=O)c2cccc3cccnc23)c2ccc(C#N)cc21
Reaction time: 1 h
Yield: 68.3 %

Procedure:
2.3 g (10.6 mMol) of potassium tert-butanolate are added to 5.5 g (18.7 mMol) of the intermediate 1b in 40 ml of DMF at 0° C. The reaction mixture was stirred for 1 h. Then 4.25 g (18.7 mMol) of 8-quinolinesulfonyl chloride were added at 0° C. The reaction solution was stirred at 0° C. for three hours and then at room temperature for 16 h. This reaction solution was poured into aqueous K2CO3 solution, resulting in a precipitate which was isolated. This solid was dissolved in methylene chloride, dried and concentrated in vacuo. The resulting residue was recrystallized from ethanol. 6.2 g of the product were obtained.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: COC(=O)[C@H]1CC[C@H](C#N)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#C[C@H]1CC[C@H](C(=O)O)CC1
Reaction time: 8 h

Procedure:
To a solution of methyl trans-4-cyanocyclohexanecarboxylate (996 mg, 5.96 mmol) in THF (37 mL) was added a solution of 0.5 M lithium hydroxide in water (20 mL). The mixture was stirred overnight then the THF was removed in vacuo and the residual aqueous solution acidified to pH 4. The resulting mixture was extracted with ether (2×30 mL), EtOAc (2×30 mL) and CHCl3 (2×30 mL) then the combined extracts, dried over anhydrous sodium sulfate and concentrated in vacua. This material was taken to the next step without any purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43-1.73 (4 H, m), 2.05-2.22 (4 H, m) and 2.36-2.59 (2 H, m).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:27]3[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=3[Cl:29])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: Brc1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1ccc(Cl)c(-c2ccc(CN3CCNC(Cc4ccccc4)C3)cc2)c1
Temperature: 85 °C
Yield: 59 %

Procedure:
0.1 g of 3-(S)-benzyl-1-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 2,5-dichlorophenyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 6 equiv. of 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated at 85° C. under nitrogen overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.07 g of the title compound. Yield 59% ES MS (+) m/z 411.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([Br:23])[CH:22]=1)[CH:18]=[O:19].[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.S1C=CC=C1[Mg]Br>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:19])[CH:20]=[C:21]([Br:23])[CH:22]=1
Reactant: O=Cc1cc(Br)cc(OCCCCCCCCC2OCCO2)c1
Reactant: Br[Mg]c1ccccc1
Agent: Br[Mg]c1cccs1
Product: OC(c1ccccc1)c1cc(Br)cc(OCCCCCCCCC2OCCO2)c1

Procedure:
The title compound was prepared as described in Example 10 Step 2 with 3-((8-(1,3-dioxolan-2-yl)octyl)oxy)-5-bromobenzaldehyde and phenylmagnesium bromide replacing 3-(8-(1,3-dioxolan-2-yl)octyloxy)benzaldehyde and 2-thienylmagnesium bromide, respectively.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].CCO.Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:15][OH:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: NO
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: N#Cc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
This material was prepared from 4-cyanobenzaldehyde according to Kawase and Kikugawa (J. Chem. Soc., Perkin Trans I 1979, 643). To a solution of 4-cyanobenzaldehyde (1.31 g, 10 mmol) in 1:1 EtOH:pyridine (10 mL) was added hydroxylamine hydrochloride (0.70 g, 10 mmol). The resulting solution was stirred at room temperature for 18 h and was concentrated in vacuo to one-half volume. To this solution was added ice water, causing the product to crystallize from solution. Recrystallization from EtOH--water followed by drying over P2O5 afforded 1.46 g (100%) of the desired oxime; mp: 167.8°-169.4° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[C:13](=S)=[S:14].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[O:5][C:13]([SH:14])=[N:2][CH:3]=2)=[CH:7][CH:8]=1
Reactant: S=C=S
Reactant: NCC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Sc1ncc(-c2ccc(Cl)cc2)o1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 172.9 %

Procedure:
2-amino-1-(4-chlorophenyl)ethanone hydrochloride (0.80 g, 3.88 mmol) and carbon disulfide (0.47 mL, 0.59 g, 7.76 mmol) was suspended in ethanol (10 mL). To this was slowly added a solution of sodium carbonate (0.44 g, 4.08 mmol) in water (4 mL) at ambient temperature. After heating to 80° C. ext. temp. for 18 h the cold mixture was filtered. The filtrate was diluted with acetic acid (40 mL) and stirred for 15 min. at room temperature. Evaporation of the solvents in vacuo gave 1.42 g of a crude 5-(4-chlorophenyl)oxazole-2-thiol which was of ca. 61% purity (HPLC-MS) and used as is in the next step. The crude oxazole-2-thiol compound (1.42 g, max. 3.88 mmol) was suspended in phosphorous oxychloride (5 mL). To this was added dropwise triethyl amine (1.15 mL, 0.84 mg, 8.27 mmol) and the mixture heated to 105° C. ext. temperature for 4 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with aq. sat. bicarbonate (100 mL) and water (50 mL). Drying (sodium sulfate) and concentration in vacuo yielded crude product (615 mg), which was purified by column chromatography (SiO2, 5-40% ethyl acetate in heptanes) to give pure 2-chloro-5-(4-chlorophenyl)oxazole (105 mg, 0.49 mmol, 13%, purity 96% HPLC-MS).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:26]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH3:27].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:29]3[CH:30]=[CH:31][N:32]=[C:28]3[CH2:26][CH3:27])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: CCc1ncc[nH]1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2OC)o1
Temperature: 125 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxylphenoxy)propyl]oxazole (1.00 g), 2-ethylimidazole (960 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (5 ml) was stirred at 120-130° C. for 1 hour. The reaction mixture was poured into water (100 ml), and the resulting precipitate was filtered, air-dried and recrystallized from acetone-isopropyl ether to give 4-(4-chlorophenyl)-2-(2-ethyl-1-imidazolyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole as pale yellow prisms (618 mg, 53%). Melting point 78-79° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH3:23][C:24]([OH:29])([C:27]#[CH:28])[CH2:25][OH:26].CN(C)C=O>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[NH2:1][C:2]1[N:3]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:28]#[C:27][C:24]([OH:29])([CH3:23])[CH2:25][OH:26])[N:5]=2
Reactant: CNC(=O)c1c(N)n(C2CCCC2)c2nc(Cl)ccc2c1=O
Reactant: C#CC(C)(O)CO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(N)n(C2CCCC2)c2nc(C#CC(C)(O)CO)ccc2c1=O
Temperature: 100 °C
Yield: 97.4 %

Procedure:
15 g of 2-amino-7-chloro-1-cyclopentyl-N-methyl-4-oxo-1,4-dihydro[1,8]-naphthyridine-3-carboxamide (53.44 mmol) and 11.11 g of (±)-2-methylbut-3-yne-1,2-diol (83.39 mmol) are introduced successively into a mixture of 267 ml of dimethylformamide and 104 ml of triethylamine in a 500 ml three-necked flask. The reaction mixture is sparged with argon for 15 minutes and then 1.02 g of CuI (5.34 mmol) and 1.87 g of bis(triphenylphosphine) palladium(II)dichloride (2.67 mmol) are successively added. The reaction mixture is heated for 30 minutes at 100° C. and then concentrated under reduced vacuum. The residue is taken up in a chloroform/water mixture and the insoluble material is filtered off. 20 g of a solid are obtained, which is purified by silica chromatography (solid deposit after solubilization in a tetrahydrofuran/methanol mixture and then elution with a dichloromethane/methanol gradient, 99:1 to 80:20) so as to give 7.5 g of expected product in the form of a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][CH2:34][C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]5[CH2:39][CH2:38][N:37]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH2:42][CH2:41]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: COCC(=O)N1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COCC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-acetyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-methoxy-1-piperazin-1-yl-ethanone following General Procedure C.
Reaction SMILES: B(Br)(Br)[Br:2].C[O:6][C:7]1[CH:8]=[C:9]([C:13]2[O:14][C:15]3[C:21]([CH2:22]O)=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH:10]=[CH:11][CH:12]=1>C(Cl)Cl>[Br:2][CH2:22][C:21]1[C:15]2[O:14][C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([OH:6])[CH:8]=3)=[N:17][C:16]=2[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(-c2nc3cccc(CO)c3o2)c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-c2nc3cccc(CBr)c3o2)c1
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of boron tribromide in methylene chloride (1.0 M; 7 ml, 7 mmol) was added dropwise to a suspension of [2-(3-methoxyphenyl)-benzoxazol-7-yl]methanol (457 mg, 1.79 mmol) in methylene chloride (10 ml) at −78° C., and the mixture was stirred at the same temperature for 1 hr. After the removal of the cooling bath, the mixture was stirred at room temperature for 2.5 hrs. The reaction mixture was poured into ice-water (50 ml), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (n-hexane/ethyl acetate=3−1) to give 7-bromomethyl-2-(3-hydroxyphenyl)-benzoxazole (535 mg, 98%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH2:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.FC(F)(F)C(O)=O.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH:31]2[CH2:30][CH2:29][CH:28]([C:25]4[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=4)[CH2:33][CH2:32]2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN)c1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCNC2CCC(c3ccc(O)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethylamine (EXAMPLE 2, Step D, 345 mg) and 4-(4-hydroxyphenyl)cyclohexanone (62 mg) were solvated in 8 mL dry methanol to which ca. 2 g powdered 3 Å molecular sieves were added. The pH of this mixture was adjusted to 6 by the addition of 0.65 mL of a 10% solution of trifluoroacetic acid in methanol and then 90 mg sodium cyanoborohydride was added and the mixture stirred at room temperature. After 20 hours, the mixture was filtered through diatomaceous earth, concentrated in vacuo and purified by flash chromatography on silica gel [(methylene chloride:methanol:, 92:8) then again (chloroform:methanol, 90:10) to separate the diastereomers] to give the title compound (isomer A 40 mg, isomer B 36 mg). m/e=439 (M+H)
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O.O>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C:4](=[CH:3][CH2:2][N:21]2[C:20](=[O:22])[C:19]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]3[C:17]2=[O:27])[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(=CCBr)CC1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=CCN2C(=O)c3ccccc3C2=O)CC1

Procedure:
A solution of 5.775 g (19.900 mM) of tert-butyl 4-(2-bromoethylidene)piperidine-1-carboxylate and 4.05 g (21.9 mM) of potassium phthalimide in 100 ml of N,N-dimethylformamide was stirred at 100° C. for 1 hour. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over anhydrous magnesium sulfate (MgSO4) and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to provide the title compound.
Reaction SMILES: B#B.[CH3:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[C:5](O)=[O:6].O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:3][CH:4]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Br:15])=[CH:13][CH:14]=1)[CH2:5][OH:6]
Reactant: CC(Cc1ccc(Br)cc1)C(=O)O
Agent: B#B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 102 %

Procedure:
Diborane (192 ml of a 1.0 M solution in THF) was added dropwise over 25 minutes to a solution of 2-methyl-3-(4-bromophenyl)propanoic acid (38.9 g) in THF (240 ml) at 0° C. The reaction mixture was stirred for 45 minutes at 0° C. and then allowed to warm to ambient temperature over 2 hours. Water (120 ml) was added followed by solid potassium carbonate (144 g) and then more water (80 ml). The reaction mixture was extracted with diethyl ether (3×250 ml), the combined organic layers were dried (MgSO4) and the solvent was evaporated to give 2-methyl-3-(4-bromophenyl)propanol as a yellow oil (37.4 g), mass spectrum (+ve CI): 248 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: COc1cccc(Br)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(Br)cccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a mixture of 2-bromo-6-methoxybenzoic acid (40 g, 0.176 mol) in DMF (300 mL) was added K2CO3 (24.8 g, 0.176 mol) and CH3I (37 g, 0.264 mol). The mixture was stirred at RT overnight. The reaction was quenched with 1M HCl aq and the mixture was extracted with EtOAc (3×300 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound (41 g, 99%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31](=[O:36])C(Cl)(Cl)Cl)=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1.O>O1CCOCC1>[C:9]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:10]=[CH:11][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:1][CH2:2][C:3]4[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=4)=[O:36])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:13][CH:14]=1
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NCc1cccnc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3)cc1)C2
Yield: 10.6 %

Procedure:
A solution of 0.216 g (0.002 mol) of 3-aminomethylpyridine and 0.508 g (0.001 mol) of 1-[10-(1,1′-biphenyl-4-ylcarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-2,2,2-trichloroethanone of Step B in 25 mL of 1,4-dioxane was heated overnight under reflux with stirring. The cooled reaction mixture was poured into 200 mL of water. The solid was collected and dried to provide the title compound (0.053 g).
Reaction SMILES: CS(O[CH:6](C)[C:7]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=1)(OC)OC)(=O)=O.[C:23](=[O:26])(O)[O-:24].[Na+].CO>O>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:7]([CH3:6])[C:23]([OH:24])=[O:26])=[CH:17][CH:16]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: O=C([O-])O
Reactant: COC(OC)(c1ccc(CC(C)C)cc1)C(C)OS(C)(=O)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 72.3 %

Procedure:
A mixture of 17 g of 1-(4-isobutylphenyl)-1,1-dimethoxyprop-2-yl methanesulfonate from Example 21, 16.5 g of sodium bicarbonate, 170 ml of methanol and 135 ml of water is heated to 67°-70° C. and held at reflux for 23 hours. Then the methanol is distilled from the reaction mixture and the aqueous phase remaining is extracted with 150 ml of methylene chloride. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with 150 ml of methylene chloride. The organic phase is dried over magnesium sulfate, and the solvent evaporated to yield 7.67 g of 2-(4-isobutylphenyl)propionic acid (melting point: 73°-75° C.).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=N[CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1.Br[C:25]1C=CC=CC=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:25][CH:18]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])=[N:3]1
Reactant: Brc1ccccc1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2ccccc2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (example 16) in accordance with the general method of example 20 using Bromobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=308.4 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@@H:5]([NH2:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9][CH:8]=1.[Br:28][C:29]1[CH:30]=[CH:31][C:32]([NH2:38])=[C:33]([CH:37]=1)[C:34](O)=[O:35]>>[CH3:2][O:3][C:4](=[O:27])[C@@H:5]([NH:26][C:34](=[O:35])[C:33]1[CH:37]=[C:29]([Br:28])[CH:30]=[CH:31][C:32]=1[NH2:38])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2Oc2ccccc2)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Br)ccc1N
Yield: 80 %

Procedure:
(S)-(2-Amino-5-bromo-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (1.53 g, 80%) was prepared from (2S)-Amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester HCl salt (1.0 g, 2.6 mmol, 5-bromo-2-amino-benzoic acid (0.5 g, 2.9 mmol) as described in general procedure A.