Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]([CH3:23])([CH3:22])[C:19](O)=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:30]1C=CC=CC=1.N1C(F)=NC(F)=NC=1F.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)Cl>[CH:1]1([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]([CH3:23])([CH3:22])[CH2:19][NH2:30])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2C2CCCCCC2)c1
Reactant: c1ccncc1
Agent: Fc1nc(F)nc(F)n1
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(CN)C(c1ccccc1)c1ccc2c(cnn2C2CCCCCC2)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
(c)(d)(e)(f) 3-(1-Cycloheptyl-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (393 mg, 1 mmol) was dissolved in 20 mL DCM and treated with 130 mL pyridine and 127 uL of cyanuric fluoride and stirred overnight. The reaction was extracted from 1 M HCl with EtOAc×3. The combined organic layers were dried over MgSO4, filtered, concentrated, and then taken up in THF (20 mL), cooled to −78° C. and ammonia gas was bubbled in for 1 min. The reaction was allowed to warm to rt. Quantitative conversion to 3-(1-cycloheptyl-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanamide. (M+H)+=390. This compound was dissolved in 15 mL THF and treated with LiAlH4 (4 mL, 4 mmol, 1 M in THF) and stirred for 3 h. The reaction was quenched with EtOAc and then 5 mL 1 M NaOH. After stirring 30 min, the reaction was extracted from brine 4× EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give 3-(1-cycloheptyl-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropan-1-amine. (M+H)+=376. This material was dissolved in 3 mL DCM and treated with 0.2 mL trifluoroacetic anhydride. After 3 h, the reaction was rotovapped down and purified by HPLC to give N-(3-(1-cycloheptyl-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropyl)-2,2,2-trifluoroacetamide (182 mg, 38% for four steps). (M+H)+=472.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1F.CCN(CC)CC>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(Cl)c1
Yield: 63.1 %

Procedure:
To a solution of morpholine (1.1 mL, 12.6 mmol) in DMF (30 mL) were added 2-chloro-1-fluoro-4-nitrobenzene (1.76 g, 10.0 mmol) and Et3N (4.2 mL, 30.1 mmol) with stirring and the mixture was stirred at rt overnight. The mixture was then filtered and the organic phase was poured into 150 mL of DCM, washed with water (150 mL×3) and brine (150 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/DCM (V/V)=10:1) to give the title compound as a yellow solid (1.53 g, 63%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([C:15]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=O)[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[CH3:28][Si:29]([CH3:38])([CH3:37])[CH2:30][CH2:31][O:32][C:33]([NH:35][NH2:36])=[O:34].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:36]([NH:35][C:33]([O:32][CH2:31][CH2:30][Si:29]([CH3:38])([CH3:37])[CH3:28])=[O:34])[C:15]=1[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[O:27])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(=O)c1cccc2ccccc12
Reactant: C[Si](C)(C)CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)n(NC(=O)OCC[Si](C)(C)C)c1-c1cccc2ccccc12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A solution of 2-(Naphthalene-1-carbonyl)4-oxo-4-phenyl-butyric acid ethyl ester (1 g, 2.77 mmol) in toluene (6.5 mL) was treated with Hydrazinecarboxylic acid 2-trimethylsilanyl-ethyl ester (599 mg, 3.34 mmol) and p-toluene sulfonic acid (33 mg). The resulting solution was heated to reflux, with the azeotropic removal of water (Dean Stark trap), under Ar for 6 h, cooled to rt and concentrated in vacuo to afford 2-Naphthalen-1-yl-5-phenyl-1-(2-trimethylsilanyl-ethoxycarbonylamino)-1H-pyrrole-3-carboxylic acid ethyl ester (1.33 g), which was not purified, but used immediately in the next reaction.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[C:10]([F:19])=[C:11]2[C:17]([NH2:18])=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1>N1C=CC=CC=1>[Br:8][C:9]1[C:10]([F:19])=[C:11]2[C:17]([NH:18][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:16][NH:15][C:12]2=[N:13][CH:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
Pivaloyl chloride (0.12 mL, 0.98 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.15 g, 0.65 mmol) in pyridine (5 mL). The reaction was stirred at room temperature for 10 minutes, and then the pyridine was removed. THF (5 mL) and 2N LiOH (3 mL) were added and stirred for 20 minutes. The THF was removed in vacuo, and water (20 mL) was added to the aqueous residue. The solid formed was collected by filtration and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pivalamide (0.128 g, 62% yield) as a solid.
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:15]2[NH:14][C:13](=S)[CH:12]([CH3:17])[N:11]=[C:10]([C:18]3[C:23]([CH2:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:26][CH3:27])[C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].[OH:28][CH2:29][C:30]([NH:32][NH2:33])=O>>[CH2:1]([S:4][C:5]1[C:15]2[N:14]3[C:30]([CH2:29][OH:28])=[N:32][N:33]=[C:13]3[CH:12]([CH3:17])[N:11]=[C:10]([C:18]3[C:19]([CH2:26][CH3:27])=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][CH3:25])[C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: NNC(=O)CO
Reactant: CCCSc1cccc2c1NC(=S)C(C)N=C2c1c(CC)cccc1CC
Product: CCCSc1cccc2c1-n1c(CO)nnc1C(C)N=C2c1c(CC)cccc1CC

Procedure:
In the manner given in Example 11, a solution of 1,3-dihydro-9-propylthio-3-methyl-5-(2,6-diethylphenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butylalchol was refluxed to give 10-propylthio-1-(hydroxymethyl)-4-methyl-6-(2,6-diethylphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](Cl)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2>ClC(Cl)C.C(O)(C)(C)C>[Br:1][C:2]1[S:10][C:9]2[C:8]([NH:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Clc1ncnc2cc(Br)sc12
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Temperature: 25 °C
Yield: 121.7 %

Procedure:
6-Bromo-4-chloro-thieno[3,2-d]pyrimidine (7.73 g, 31 mmol) was dissolved in 50 mL of dichloroethane and 50 mL of t-butyl alcohol, and 5-aminoindole (4.09 g, 31 mmol) were added. The reaction mixture was refluxed for 14 hours, cooled to room temperature, and concentrated in vacuo to afford 13.02 g of (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine. The crude material was used without further purification (83% purity). 1H NMR (400 MHz, DMSO) d 11.1 (s, 1H), 9.62 (s, 1H), 8.38 (s, 1H), 7.63 (s, 1H), 7.49 (s, 1H), 7.35 (m, 2H), 7.10 (d, 1H), 6.40 (s, 1H); LC-MS: 345, 347 (MH+); HPLC RT: 3.77 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:18]1[C:29]([Cl:30])=[CH:28][C:21]2[O:22][C:23]([F:27])([F:26])[CH2:24][O:25][C:20]=2[CH:19]=1>O1CCOCC1.CC#N.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Cl:30][C:29]1[C:18]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:19][C:20]2[O:25][CH2:24][C:23]([F:27])([F:26])[O:22][C:21]=2[CH:28]=1
Reactant: FC1(F)COc2cc(Br)c(Cl)cc2O1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: C1COCCO1
Solvent: CC#N
Product: Nc1ccc(-c2cc3c(cc2Cl)OC(F)(F)CO3)cn1
Temperature: 85 °C
Yield: 8.7 %

Procedure:
2-Aminopyridine-5-boronic acid pinacol ester (62 mg, 0.28 mmol) and 254 (67 mg, 0.23 mmol) were dissolved in 2 mL 1,4-dioxane and 2 mL MeCN. Next 1 ml of 2 M K3PO3 was added and the mixture was bubbled with Ar for 2 min before bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (A-Phos, 14 mg, 0.02 mmol) was added. The reaction was then heated at 85° C. for 2 h. The reaction was cooled and the mixture worked-up with a EtOAc extraction. The resulting crude product was purified by flash column and afforded 255 (6 mg, 9%) as yellow solid.
Reaction SMILES: CC([O-])(C)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>COCCOC.CCOCC.CCCCCCCCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)([O-:24])=[O:23]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: CCCCCCCCCCCC
Solvent: COCCOC
Product: O=[N+]([O-])c1ccccc1N1CCOCC1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 9.6 %

Procedure:
A solution of Pd2(dba)3 [92 mg, 0.1 mmol (4.6 mg, 0.005 mmol, 2 mol % Pd per reaction)], ligand 1 (see FIG. 1) [168 mg, 0.4 mmol (8.4 mg, 0.02 mmol, 4 mol % per reaction)] and NaOt-Bu [40 mg, 0.4 mmol (2 mg, 0.02 mmol, 4 mol % per reaction)] were stirred in 10 mL DME (anhy). After 10 minutes, 0.5 mL of the solution was added via syringe to a test tube containing (under an Argon atmosphere) K3PO4 (148 mg, 0.7 mmol), 2-chloronitrobenzene (79 mg, 0.5 mmol), and morpholine (52 μL, 0.6 mmol). The test tube was capped (with a proper cap-no rubber septa) and heated at 100° C. for 18 hours. The reaction mixture was allowed to cool to r.t., diluted with ether and dodecane was added as an internal standard. The reaction mixture was purified by preparatory TLC (EtOAc/hexanes as the eluent) to yield 10 mg of the desired product (which was used for calibration with the internal standard). The GC yield was calculated to be 38%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH2:15])=[CH:4][CH:3]=1.Cl[CH2:17][C:18]([NH2:20])=[O:19].C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH:15][CH2:17][C:18]([NH2:20])=[O:19])=[CH:6][CH:7]=1
Reactant: NC(=O)CCl
Reactant: NCc1ccccc1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)CNCc1ccccc1-c1ccc(Cl)cc1

Procedure:
A reaction vessel was charged with 7.62 g (30 mmole) of [(4-chlorophenyl)phenyl]methylamine dissolved in 150 ml of absolute ethanol. A mixture of 2.34 g (25 mmole) of chloracetamide and 5.46 g (5 mmole) of sodium bicarbonate was added to the vessel and the resulting suspension was brought to reflux and held at reflux for 2 days. The solution was then cooled, filtered and evaporated under reduced pressure. The residue was dissolved in water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The oily residue was solidified in pentane and crystallized in toluene.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[C:7]3[C:11](=[CH:12][CH:13]=[C:5]2[S:4][CH:3]=1)[NH:10][C:9]1[CH2:14][CH2:15][NH:16][CH2:17][C:8]3=1.[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22]Cl>CN(C)C=O>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][N:16]1[CH2:15][CH2:14][C:9]2[NH:10][C:11]3[C:7]([C:8]=2[CH2:17]1)=[C:6]1[C:2]([CH3:1])=[CH:3][S:4][C:5]1=[CH:13][CH:12]=3
Reactant: Cc1csc2ccc3[nH]c4c(c3c12)CNCC4
Reactant: CN(C)CCCCl
Solvent: CN(C)C=O
Product: Cc1csc2ccc3[nH]c4c(c3c12)CN(CCCN(C)C)CC4

Procedure:
10 g of 1-methyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole, dissolved in 200 ml of dimethylformamide at 90° C., are heated to 90° with a solution of 12 ml of 3-dimethylaminopropyl chloride in 50 ml of dimethylformamide for 3 hours. The reaction mixture is filtered, the filtrate is evaporated and the residue is taken up in chloroform. After washing with water and drying, the organic phase is concentrated, the residue is chromatographed on SiO2 with chloroform/methanol/NH4OH (7:3:0:1) and the product is recrystallised from isopropanol. Melting point: 184° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>O1CCOCC1>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCN3)c2n1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCCN3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
The crude aqueous solution containing approx 45 mg 2-(butyloxy)-8-(methyloxy)-9-[2-(2-piperidinyl)ethyl]-9H-purin-6-amine (45 mg, 0.129 mmol) was treated with a solution of HCl in 1,4-dioxane (0.807 mL, 3.23 mmol, 4 molar solution). This was stirred at ambient temperature in a capped vial overnight to give a pale solution. A further 1 ml of 4 molar HCl solution in 1,4-dioxane was added and stirring continued over the weekend. The yellow reaction solution was evaporated to dryness under N2 in a blow down unit. The residue was purified by MDAP (Method A), appropriate fractions were evaporated under N2 in a blow down unit to give the title compound as a white solid (23.3 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14](C4C=CC=CC=4)[C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:24]1[C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]2[C:33]([O:35][C:36](=[O:37])[C:26]=2[CH:25]=1)=O>>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[N:1]1[C:33](=[O:35])[C:27]2[C:26](=[CH:25][CH:24]=[C:29]([C:30]([OH:32])=[O:31])[CH:28]=2)[C:36]1=[O:37]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Cc1ccc(-c2nc3c(-c4ccccc4)cccc3o2)cc1N
Product: Cc1ccc(-c2nc3cc(-c4ccccc4)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methylphenyl)-4-phenylbenzoxazole (167 mg, 0.9 mmol) and 1,2,4-benzenetricarboxylic anhydride (250 mg, 0.9 mmol) the title compound was obtained, 340 mg (82%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.34(d, 2H), 8.26(dd, 1H), 8.13(d, 1H), 8.05(d, 1H), 7.85(d, 1H), 7.73(m, 4H), 7.50(t, 1H), 7.39(t, 1H), 2.28(s, 3H). MS 473 m/z (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[Mg].Cl[CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1>O1CCCC1>[F:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)([OH:16])[C:4]=2[CH:3]=1
Reactant: O=c1c2ccccc2sc2ccc(F)cc12
Reactant: CN1CCC(Cl)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3ccccc3Sc3ccc(F)cc32)CC1

Procedure:
Similarly, 2-fluoro-9-thioxanthone (5.0 g.) is reacted with the Grignard reagent derived from 1.06 g. of magnesium turnings and 5.85 g. of 4-chloro-N-methylpiperidine in tetrahydrofuran as described above to give the corresponding 2-fluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 189°-190° C. The latter is dehydrated by the same procedure to obtain 4-(2-fluoro-9-thioxanthenylidene)-1-methylpiperidine as the maleate salt, m.p. 175°-179° C.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=3)[C:9](=[O:17])[C:8]2=[O:18])=[CH:4][CH:3]=1.[N+:21]([CH3:24])([O-:23])=[O:22]>O>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=3)[C:9]([OH:17])([CH2:24][N+:21]([O-:23])=[O:22])[C:8]2=[O:18])=[CH:4][CH:3]=1
Reactant: O=C1C(=O)N(Cc2ccc(Br)cc2)c2ccc(Cl)cc21
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1N(Cc2ccc(Br)cc2)c2ccc(Cl)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 24 h

Procedure:
1-(4-bromobenzyl)-5-chloroindoline-2,3-dione (0.175 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 24 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15](O)=[O:16])[N:14]=1.[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29]1[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][N:30]=1>>[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29]1[N:30]=[CH:31][C:32]([NH:35][C:15]([C:13]2[N:14]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][C:2]([F:22])([F:1])[F:23])[O:11][C:12]=2[C:18]([F:20])([F:21])[F:19])=[O:16])=[CH:33][N:34]=1
Reactant: COCCN(C)c1ncc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2OC(F)(F)F)oc1C(F)(F)F
Product: COCCN(C)c1ncc(NC(=O)c2nc(-c3ccccc3OC(F)(F)F)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was prepared from 2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd for C20H17F6N5O4 (m/e) 505. obsd 506 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][S:22](N1CCOC1=O)(=[O:24])=[O:23])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:31][C@@H:32]1[CH2:47][C:46]2=[CH:48][CH:49]=[C:43]([CH:44]=[CH:45]2)[O:42][CH2:41][CH2:40][CH2:39][CH2:38][O:37][CH2:36][C@H:35]([CH:50]([CH3:52])[CH3:51])[NH:34][C:33]1=[O:53].O1CCNC1>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][S:22](=[O:23])(=[O:24])[NH:31][C@@H:32]1[CH2:47][C:46]2=[CH:45][CH:44]=[C:43]([CH:49]=[CH:48]2)[O:42][CH2:41][CH2:40][CH2:39][CH2:38][O:37][CH2:36][C@H:35]([CH:50]([CH3:51])[CH3:52])[NH:34][C:33]1=[O:53])[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](N)C(=O)N1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NS(=O)(=O)N1CCOC1=O)C(=O)OC(C)(C)C
Agent: C1COCN1
Solvent: CC#N
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NS(=O)(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Reaction time: 24 h
Yield: 14.6 %

Procedure:
A solution of 387 mg (0.858 mmol) of tert-butyl(S)-6-tert-butoxycarbonylamino-2-(2-oxooxazolidine-3-sulfonylamino)hexanoate and 250 mg (0.780 mmol) of (9S,12R)-12-amino-9-isopropyl-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-11-one (compound 1-1E) in 15 ml of acetonitrile was stirred at 80° C. After 1 day (d), the same amount of the oxazolidine was again added, and the mixture was stirred for 1 d. The reaction mixture was then concentrated and the residue was purified by prep. HPLC. Product-containing fractions were combined, the acetonitrile was evaporated off, made slightly alkaline with sat. NaHCO3 solution and extracted several times with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated. 78 mg of the title compound were obtained.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.C(=O)(O)[O-].[Na+]>Br>[NH:12]1[CH:13]=[CH:14][C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])=[N:11]1
Reactant: COc1ccccc1Nc1cc[nH]n1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccccc1Nc1cc[nH]n1

Procedure:
The product of step (b) (4.6 g) was dissolved in 48% aqueous HBr (100 ml) and refluxed for 8 hours. The mixture was poured onto water (750 ml), neutralised with solid sodium bicarbonate, extracted with ethyl acetate, washed with brine and evaporated to give the title compound as a white crystalline solid, 0.49 g, mp 163°-4° (from ethyl acetate/cyclohexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:19][CH:20]([CH3:30])[CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:18])=[CH:13][C:12]=2[CH2:31][CH:32]=[CH2:33])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:19][C@H:20]([CH3:30])[CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:18])=[CH:13][C:12]=2[CH2:31][CH2:32][CH3:33])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C=CCc1cc(C(=O)NC(C)CCCc2cccnc2)ccc1-c1ccc(OC)c(OC)c1
Agent: [Pd]
Product: CCCc1cc(C(=O)N[C@H](C)CCCc2cccnc2)ccc1-c1ccc(OC)c(OC)c1
Yield: 94.6 %

Procedure:
A solution of 282 mg of 3',4'-Dimethoxy-2-(2-propenyl)-N-[1-methyl-4-(3-pyridinyl)butyl][1,1'-biphenyl]-4-carb oxamide was hydrogenated over 40 mg of 10% palladium on carbon to give 268 mg of (R)-3',4'-Dimethoxy-2-propyl-N-[1-methyl-4-(3-Pyridinyl)butyl][1,1'-biphenyl]-4-carboxamide as a foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([CH2:17][O:18][CH3:19])[CH:16]=1)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH3:20][N:21](C)C=O>C(OCC)C.[C-]#N.[Zn+2].[C-]#N.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>[Si:7]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:16]=[C:15]([CH2:17][O:18][CH3:19])[CH:14]=1)[C:20]#[N:21])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CN(C)C=O
Reactant: COCc1cc(Br)cc(CO[Si](C)(C)C(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: COCc1cc(C#N)cc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 80 °C
Yield: 79 %

Procedure:
To a solution of (3-bromo-5-methoxymethyl-benzyloxy)-tert-butyl-dimethylsilane (2.1 g, 6.081 mmol) in dimethylformamide (10 mL) at room temperature was added zinc cyanide (428.4 mg, 3.649 mmol). The reaction mixture was degassed by passing argon through for 2 h before tetrakis(triphenylphosphine)palladium (422 mg, 0.365 mmol) was added. The reaction mixture was heated at 80° C. under argon for 8 h. The reaction mixture was taken up in diethyl ether and washed with ammonium hydroxide, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 5-10% ethyl acetate in hexanes yielded 3-(tert-butyl-dimethylsilanyloxymethyl)-5-methoxymethyl-benzonitrile (1.402 g, 79%).