Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([O:6][C:3]([CH3:7])([CH3:4])[CH3:2])=[O:5]
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CC(=O)OC(C)(C)C
Product: Cc1cc(Cl)nc(Cl)c1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 190.4 %

Procedure:
To a solution of 2,6-dichloro-4-methylnicotinic acid (1.00 g, 4.85 mmol, 1 equiv) in tert-butyl acetate (24 mL) was added 70% perchloric acid (0.88 mL, 14.56 mmol, 3 equiv). After 1 h, reaction was diluted with DCM, washed cautiously with saturated aqueous sodium bicarbonate solution, dried (Na2SO4), and concentrated in vacuo to provide the product (1.21 g, 95%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.15 (s, 1H), 2.37 (d, J=0.5 Hz, 3H), 1.62 (s, 9H); LCMS (ESI, M+1): 262.1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:25][NH:26][C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28]>>[CH3:25][N:26]([C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CN[C@H](C)c1ccccc1
Reactant: O=C(c1ccc(-c2ccc(OCCCCl)cc2)cc1)N1CCCC1
Product: C[C@H](c1ccccc1)N(C)CCCOc1ccc(-c2ccc(C(=O)N3CCCC3)cc2)cc1

Procedure:
The product from Example 11A and N-methyl-N-[(1R)-1-phenylethyl]amine were processed as described in Example 10F to provide the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([O:15]S(C)(=O)=O)[CH2:10]2)=[C:6]([CH2:22][CH2:23][CH3:24])[C:5]=1[OH:25])(=[O:3])[CH3:2].O[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][C:28]=1[Br:38].[H-].[Na+].C1OCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C1COCC1>[C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][C:28]=3[Br:38])[CH2:10]2)=[C:6]([CH2:22][CH2:23][CH3:24])[C:5]=1[OH:25])(=[O:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(O)c(Br)c1
Reactant: CCCc1c(O[C@@H]2CCC[C@H](OS(C)(=O)=O)C2)ccc(C(C)=O)c1O
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCc1c(O[C@H]2CCC[C@H](Oc3ccc(CC(=O)OC)cc3Br)C2)ccc(C(C)=O)c1O

Procedure:
To a solution of the title compound of Step C of this example (500 mg; 1.35 mmole) in toluene (30 ml) and THF (1.5 ml) was added successively 4-hydroxy-3-bromophenylacetic acid, methyl ester (1 g, 4 mmoles), sodium hydride (169 mg; 7 mmoles) and 15-crown-5 (10 mg). The reaction mixture was refluxed for 10 hours under nitrogen. It was then worked-up as in Step B of Example 8 to yield the title compound of this step.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OB(O)c1cccs1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccs4)cc23)CC1
Yield: 54.7 %

Procedure:
Following the general procedure of Example 65, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (100 mg, 0.24 mmols), 2-thienylboronic acid (92 mg, 0.72 mmols), potassium carbonate (197 mg), and Pd(PPh3)4 (28 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (56 mg, 55%)
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:17][C:18](=[O:30])[C@H:19]([CH2:24][C:25]2[N:26]=[CH:27][S:28][CH:29]=2)[CH2:20][C:21](O)=[O:22])[C@@H:9]([OH:16])[C@@H:10]([OH:15])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31]1([CH2:37][NH:38][CH2:39][C:40]2([OH:46])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:37]([N:38]([CH2:39][C:40]1([OH:46])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1)[C:21](=[O:22])[CH2:20][C@@H:19]([CH2:24][C:25]1[N:26]=[CH:27][S:28][CH:29]=1)[C:18]([NH:17][C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C@@H:9]([OH:16])[C@@H:10]([OH:15])[CH2:11][CH:12]([CH3:13])[CH3:14])=[O:30])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](CC(=O)O)Cc1cscn1
Reactant: OC1(CNCc2ccccc2)CCCCC1
Product: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](CC(=O)N(Cc1ccccc1)CC1(O)CCCCC1)Cc1cscn1
Yield: 45.6 %

Procedure:
4{[1(S)-(Cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxo-3(R)-(4-thiazolylmethyl)-butanoic acid (61 mg, 0.14 mmol, described in example 2, section D) was coupled with 1-{[(phenylmethyl)amino]methyl}cyclohexanol (31 mg, 0.14 mmol, described in example 1, section D) according to the procedure described in example 3 to give the title compound (41 mg, 17%); 1H NMR (400 MHz, DMSO-d6) (2.2:1 mixture of rotamers) δ9.00 and 8.95 (d, J=1.8 Hz, 1H), 7.76 and 7.71 (d, J=8.9 Hz, 1H), 7.36-7.20 (m,4H), 7.15 and 7.10 (d, J=7.2 Hz,2H), 4.77 (broad s,2H), 4.62-4.58 (m,2H), 4.43 and 4.34 (s,1H), 4.13-4.02 (m,1H), 3.17 (d, J=13.8 Hz, 1H), 3.09-2.76 (m,5H), 2.62 (dd, J1 =8.1 Hz, J2 =16.5 Hz, 1H), 2.32 (dd, J1 =5.4 Hz, J2 2 =16.1 Hz, 1H), 1.68-1.25 (m,21H), 1.22-1.03 (m,6H), 0.85 and 0.84 (d, J=6.6 Hz, 3H), 0.73 (t, J=5.4 Hz,3H); FAB mass spectrum , m/z: 642 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:11](=[O:18])[C:10]3[CH:19]=[CH:20][CH:21]=[N:22][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH2:16][CH2:15][N:14]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:13][C:12]=3[C:11](=[O:18])[C:10]3[CH:19]=[CH:20][CH:21]=[N:22][C:9]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c2c(n(-c3cccc(Cl)c3)c3ncccc13)CCNC2
Solvent: CC(C)=O
Product: O=c1c2c(n(-c3cccc(Cl)c3)c3ncccc13)CCN(Cc1ccccc1)C2

Procedure:
React 10-(3-chlorophenyl)-6,7,8,9-tetrahydropyrido[2,3-b][1,6]naphthyridin-5(10H)-one (5 mmol) with benzylbromide (5.8 mmol) in acetone (40 ml) at 25° C. for 3 hours. Evaporate the acetone solvent, and elute the product from silca gel with chloroform to provide the product, 10-(3-chlorophenyl)-6,7,8,9-tetrahydro-7-N-benzyl-pyrido[2,3-b][1,6]naphthyridin-5(10H)-one, m.p. 157°-161° C. after crystallization from CH3CN.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:18])=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:8][N:9]=1)[C:5]#[N:6].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>CS(C)=O.C(OCC)(=O)C>[Cl:18][C:3]1[C:2]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[N:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:4]=1[C:5]#[N:6]
Reactant: Cc1ccccc1N
Reactant: COc1cccc(-c2cnc(Cl)c(Cl)c2C#N)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cnc(Nc3ccccc3C)c(Cl)c2C#N)c1
Temperature: 180 °C

Procedure:
A mixture of 2,3-dichloro-5-(3-methoxyphenyl)isonicotinonitrile (50 mg, 0.179 mmol, from Step 3 of Example 128) and o-toluidine (384 mg, 3.58 mmol) in DMSO (1 mL) was heated to 180° C. under microwave for 1 h. LCMS and HPLC analysis indicated that the reaction was ˜25% complete. The mixture was cooled to room temperature, diluted with ethyl acetate (60 mL), washed with 1 N HCl (5 mL), water (5 mL), brine (5 mL), dried (MgSO4) and concentrated. Purification by reverse phase HPLC (Sunfire S10 30×250 mm column), eluting with 80-100% solvent B (10% methanol-90% water-0.1% TFA) in solvent A (90% methanol-10% water-0.1% TFA), gave 3-chloro-5-(3-methoxyphenyl)-2-(o-tolylamino)isonicotinonitrile as yellow solid, assumed as TFA salt (7 mg, 8% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.13 (1H, s), 7.38-7.54 (2H, m), 7.28-735 (1H, m), 7.15-7.27 (2H, m), 7.07-7.14 (2H, m), 6.97-7.05 (1H, m), 3.87 (3H, s), 2.27 (3H, s); MS (ES+) m/z: 350 (M+H); LC retention time: 3.848 min (analytical HPLC Method A).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([N:12]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[N:14]=[CH:13]2)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])=[S:4].[BH4-].[Na+].[Cl-].[NH4+].O>CO>[OH:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]1([N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[N:14]=[CH:13]1)[C:3](=[S:4])[NH:2][CH3:1]
Reactant: CNC(=S)C1(n2cnc([N+](=O)[O-])c2)CCCCC1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CNC(=S)C1(n2cnc([N+](=O)[O-])c2)CCCCC1O
Yield: 49.6 %

Procedure:
A suspension of 56.89 g (202 mmol) of the N-methyl-1-(4-nitroimidazol-1-yl)-2-oxocyclohexanecarbothioamide prepared in the Example 16 in 640 ml of methanol was cooled with ice. 2.68 g (70.8 mmol) of sodium borohydride was added to the resulting suspension in portions in 3 minutes in such a way that the bulk temperature did not exceed 10° C. The obtained mixture was stirred under cooling with ice for 30 minutes, followed by the addition of a saturated aqueous solution of ammonium chloride and water in this order. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt and dried over anhydrous magnesium sulfate. The resulting organic phase was analyzed by silica gel thin-layer chromatography [developer: benzene/ethyl acetate (1:2)], by which it was ascertained that the product of this stage was composed of a lowly polar diastereomer (L form. Rf: 0.41) and a highly polar diastereomer (M form. RF: 0.29) at a ratio of 2:1. The organic phase was concentrated. In the course of this concentration, a crystal began to precipitate. The crystal thus formed was recovered by filtration. Thus, 28.48 g of the title compound was obtained in the form of a diastereomer as a pale-yellow crystal (yield: 50%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17]S(C)(=O)=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH-].[Na+]>C(O)(=O)C>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1ccc(N2CCN(S(C)(=O)=O)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 106.8 %

Procedure:
Methanesulfonic acid 4-(4-methanesulfonylpiperazin-1-yl)phenyl ester (3.2 g, 9.5 mmol) is placed in 29 ml of a 1N aqueous solution of sodium hydroxide. The reaction medium is stirred at reflux for 48 h. Acetic acid is added at ambient temperature to pH 4. The precipitate formed is filter-dried and washed with water and then dried over P2O5. 2.6 g of expected 4-(4-methanesulfonylpiperazin-1-yl)phenol are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[N:11]=[CH:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:20]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)=[CH:19][N:18]=2)=[N:14][CH:15]=1)#[N:9]>ClCCl>[CH3:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([C:20]2[C:21]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][C:17]([NH:16][C:13]3[N:14]=[CH:15][C:10]([C:8]#[N:9])=[N:11][CH:12]=3)=[N:18][CH:19]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(-c2cnc(Nc3cnc(C#N)cn3)cc2NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cnc(Nc3cnc(C#N)cn3)cc2NC2CCNCC2)cc1
Reaction time: 1 h
Yield: 62.5 %

Procedure:
Trifluoroacetic acid (0.1 μL, 1.298 μmol) was added to tert-butyl 4-(2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)piperidine-1-carboxylate (4 mg, 7.97 μmol) dissolved in dichloromethane (0.45 mL) and the mixture was stirred for 1 hr. The mixture was concentrated and purified by ion exchange on (solute SCX II acidic resin (1 g), eluting with MeOH then 2M NH3-MeOH. The basic fractions were combined and concentrated. Preparative thin layer chromatography, eluting with 10% MeOH/1% NH3/89% dichloromethane) gave 5-(5-(4-methoxyphenyl)-4-(piperidin-4-ylamino)pyridin-2-ylamino)pyrazine-2-carbonitrile (2 mg, 4.98 μmol, 62.5% yield) as a yellow powder.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]([C:42]([F:45])([F:44])[F:43])([C:38]([F:41])([F:40])[F:39])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[C:23]([CH3:36])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:37])(C)(C)C.[CH2:48]([O:50][C:51](=[O:60])[CH2:52][C:53]1[CH:54]=[N:55][C:56](Br)=[N:57][CH:58]=1)[CH3:49].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH2:48]([O:50][C:51](=[O:60])[CH2:52][C:53]1[CH:54]=[N:55][C:56]([C:24]2[CH:25]=[CH:26][C:21]([C:16]([CH2:19][CH3:20])([C:13]3[CH:14]=[CH:15][C:10](/[CH:9]=[CH:8]/[C:7]([OH:6])([C:42]([F:44])([F:45])[F:43])[C:38]([F:41])([F:40])[F:39])=[C:11]([CH3:37])[CH:12]=3)[CH2:17][CH3:18])=[CH:22][C:23]=2[CH3:36])=[N:57][CH:58]=1)[CH3:49]
Reactant: CCOC(=O)Cc1cnc(Br)nc1
Reactant: CCC(CC)(c1ccc(/C=C/C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cc1cnc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c3)cc2C)nc1
Temperature: 95.5 °C
Reaction time: 10 h
Yield: 40.8 %

Procedure:
Degassed N,N-dimethylformamide (0.32 mL) was added to 2-[4-(1-{4-[(E)-3-(t-butyl-dimethyl-silanyloxy)-4,4,4-trifluoro-3-trifluoromethyl-1-butenyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 77-(1); 35.8 mg, 0.0523 mmol), 2-bromopyrimidine-5-acetic acid ethyl ester (Example 43-(3); 37.3 mg, 0.152 mmol), tetrakis(triphenylphosphine)palladium (0) (29.8 mg, 0.0258 mmol) and potassium phosphate (48.7 mg, 0.229 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 91 to 100° C. for 10 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=4/1) to give the title compound (13 mg, 41%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=3)=[C:12]([CH2:25][OH:26])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[NH2:59][C:60]([CH3:64])([CH3:63])[CH2:61][OH:62]>C1COCC1.CO.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:59][C:60]([CH3:64])([CH3:63])[CH2:61][OH:62])=[O:21])=[CH:18][N:17]=3)=[C:12]([CH2:25][OH:26])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)NC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.58 mmol) in THF (6 mL) were added 1-hydroxybenzotriazole hydrate (86.3 mg, 0.55 mmol), N-ethyldiisopropylamine (241 μL, 1.38 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (108 mg, 0.55 mmol) and 2-amino-2-methyl-1-propanol (50.7 mg, 0.55 mmol). The reaction mixture was stirred overnight at room temperature. Chromatography (silica, dichloromethane:methanol=0:100 to 95:5) afforded the title compound (120 mg, 50%) as a colourless oil. MS: m/e=434.4 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]1[S:11](=[O:13])(=[O:12])[O:10][CH2:9][CH2:8][O:7][S:4]1(=[O:6])=[O:5].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24](Cl)=[O:25]>C(COC)OC>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]([CH:3]1[S:4](=[O:5])(=[O:6])[O:7][CH2:8][CH2:9][O:10][S:11]1(=[O:13])=[O:12])=[O:25]
Reactant: O=S1(=O)CS(=O)(=O)OCCO1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(c1ccc2ccccc2c1)C1S(=O)(=O)OCCOS1(=O)=O
Reaction time: 0.75 h
Yield: 84.5 %

Procedure:
To a suspension of 3 g NaH in 50 mL of glyme was added 1.0 g of ethylene methanedisulfonate. To this solution was added 1.1 g of 2-naphthoyl chloride and the H2 evolved was measured. The theoretical amount of H2 evolved in about 45 min. The solvent was then removed from the solution on a rotary evaporator. The residue was taken up in 50 mL of water and washed with CH2Cl2. The water solution was acidified and an oil separated which was then extracted with CH2Cl2 which was dried over MgSO4, and evaporated to leave 1.65 g (93%) of crude product. Subsequent crystallization from CH2Cl2-cyclohexane gave 1.49 g (84%) ethylene 2-naphthoylmethanedisulfonate, m.p. 150-158° C. (95-4).
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH2:19]([NH2:22])[CH2:20][NH2:21]>C(O)(=O)C>[NH2:21][CH2:20][CH2:19][NH:22][CH:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)C(=O)COc1ccc(C(C)=O)cc1
Reactant: NCCN
Solvent: CC(=O)O
Product: CCN(CC)C(=O)COc1ccc(C(C)NCCN)cc1

Procedure:
By using 2-(4-acetylphenoxy)-N,N-diethylacetamide (250 mg), ethylenediamine (400 μl) and acetic acid (700 μl) as starting materials, the title compound (52.9 mg) was obtained in the same manner as that of Reference Example 64, (1).
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>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>[CH2:1]([N:3]([C:6]1[CH:11]=[CH:10][C:9]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To an oven dried flask fitted with a magnetic stir bar and condenser, Pd(PPh3)4 (207 mg, 0.18 mmol) and cuprous iodide (115 mg, 0.6 mmol) was added and the system was evacuated and back flushed with N2. Dry THF (25 mL) was added, subsequently N,N-diethyl-(4-iodophenyl)amine (1 g, 3.6 mmol in 3 mL THF) and dry degassed diisopropylethylamine (2.5 mL, 14.5 mmol) stirred for 10 min. Trimethylsilylacetylene (0.85 mL, 6 mmol) was added and the mixture was stirred at room temperature for 4 h and then at 80° C. for 30 min. The reaction mixture was cooled to room temperature, poured into ice water and stirred at rt for 1 h. The mixture was extracted with ethyl acetate (50×3), the combined organic layer was washed with saturated ammonium chloride solution and was dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation and the crude product was purified by silica gel column chromatography using hexane/EAC (0-5%) as eluent. Yield: 0.54 g. (61%). IR (neat) 2958, 2857, 2145, 1605, 1515, 1468, 1401 cm−1; 1H NMR (400 MHz, CDCl3) 7.37 (d, J=8.8 Hz, 2H), 6.57 (d, J=8.8 Hz, 2H), 3.37 (q, 7.2 Hz, 4H), 1.19 (t, 6.8 Hz, 6H), 0.32 (s, 9H); 13CNMR (100 MHz, CDCl3) δ 147.41, 133.14, 110.81, 108.66, 106.77, 90.43, 44.09, 12.35.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:25]1[O:27][CH2:26]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]3[CH2:25][CH2:26][O:27][C:7]3([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: C1CO1
Reactant: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C1CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 15 g. (51.9 mmole) of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 150 ml. of dry benzene, 9 g. (67.7 mmole) of aluminum chloride was added and stirring was continued 15 minutes. The reaction mixture was cooled in an ice bath and 8.8 g. (0.2 mole) of ethylene oxide was added dropwise. After 18 hours of stirring at room temperature, the reaction mixture was heated to 40° for 1 hour and then cooled to room temperature and treated with 5 g. (37.6 mmole) of aluminum chloride, followed by 4.4 g. (0.1 mole) of ethylene oxide. The reaction mixture was heated 4 hours at 45° -50° and then evaporated to dryness. Methylene chloride, ice and ammonium hydroxide were added and the solid removed by filtration. The filtrate was separated and the organic phase reduced to dryness in vacuo. The residue was dissolved in dilute hydrochloric acid and the pH of the solution adjusted to 5 with ammonium hydroxide. The acidic solution was washed with ether, made basic and extracted with methylene chloride. The organic phase was washed with brine, dried and evaporated to dryness. Recrystallization from methylene chloride-hexane gave the above-titled product as colorless rods, m.p. 183° -184°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:21]1[CH2:22][CH2:23][CH2:24][C:19]([OH:25])([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:20]1)=[O:5]
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1ccccc1Br
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccccc3Br)C2)c1

Procedure:
The compound of Example 20 was prepared according to the general preparation protocol A from 2-bromobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].Cl.[CH:15]([N:18]([CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]Cl)([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:20][CH2:19][N:18]([CH:22]([CH3:24])[CH3:23])[CH:15]([CH3:17])[CH3:16])[C:8](=[O:11])[C:7]2=[O:12]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: Cc1cc(Br)c2c(c1)C(=O)C(=O)N2
Agent: Cl
Product: Cc1cc(Br)c2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Yield: 13.1 %

Procedure:
By using the 7-bromo-5-methylisatin and 2-diisopropylaminoethyl chloride hydrochloride, a method analogous to that described in Reference Example 1 was carried out to obtain 7-bromo-1-(2-diisopropylaminoethyl)-5-methylisatin having a melting point of 94°-97° C. (yield: 13.1%).