Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:27]=[C:26]([CH3:28])[C:5]([C:6]([NH:8][CH2:9][CH2:10][C@H:11]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][CH2:20][C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)[CH2:15][CH2:14]2)[CH3:12])=[O:7])=[C:4]([CH3:29])[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>COCCOC.C(Cl)Cl.C([O-])(O)=O.[Na+].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>[S:23]1[CH:24]=[CH:25][C:21]([CH2:20][NH:19][CH:16]2[CH2:17][CH2:18][N:13]([C@H:11]([CH3:12])[CH2:10][CH2:9][NH:8][C:6]([C:5]3[C:26]([CH3:28])=[CH:27][C:2]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[N:3][C:4]=3[CH3:29])=[O:7])[CH2:14][CH2:15]2)=[CH:22]1
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)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: ClCCl
Solvent: COCCOC
Product: Cc1cc(-c2cccnc2)nc(C)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To an argon-degassed solution of 6-chloro-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (100 mg, 0.23 mmol) and 3-pyridine boronic acid (56 mg, 0.46 mmol) in DME/2 M Na2CO3 (5:2, 3.5 ml) was added Pd(PPh3)4 (15 mg, 0.013 mmol) and the reaction stirred at 90° C. overnight. The mixture was cooled, diluted with CH2Cl2 (25 ml) and saturated aqueous NaHCO3 (25 ml). The aqueous layer was extracted with CH2Cl2 (2×10 ml) and the combined organic extracts were dried (Na2SO4), concentrated and purified by column chromatography on silica gel (CH2Cl2MeOH/NH4OH, 96:4:0 then 88:10:2) to afford 4,6-dimethyl-[2,3′]bipyridinyl-5-carboxylic acid ((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide as a mixture of product and starting amine (˜25%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH3:9][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)=[O:24])[CH2:19][CH2:18]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1>>[CH3:9][C:10]1[C:11]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([N:7]4[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[CH:27][CH:26]=3)=[O:24])[CH2:21][CH2:22]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3)CC2)c(C)c1
Yield: 67.6 %

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one (127 mg) and [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (421 mg) described in Preparation Example 113 and by the reaction and treatment in the same manner as in Example 1, the title compound (276 mg) was obtained.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[NH2:6][CH2:7][C@H:8]([CH3:36])[O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[C:23]([Cl:35])[CH:22]=1)=[N:13][CH:14]=[N:15]2>>[Cl:35][C:23]1[CH:22]=[C:21]([NH:20][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[CH:19][C:10]=3[O:9][C@@H:8]([CH3:36])[CH2:7][NH:6][C:1](=[O:5])[CH2:2][OH:3])[N:15]=[CH:14][N:13]=2)[CH:26]=[CH:25][C:24]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: O=C(O)CO
Reactant: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@@H](CNC(=O)CO)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 47 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 36, preparation of starting materials) to give the title compound in 47% yield; NMR spectrum (DMSO-d6) 1.20 (d, 3H), 3.41 (m, 1H), 3.74 (m, 1H), 3.78 (d, 2H), 4.92 (m, 1H), 5.29 (s, 2H), 5.48 (t, 1H), 7.23 (dd, 2H), 7.31 (d, 1H), 7.35 (m, 1H), 7.58 (m, 2H), 7.70 (t, 1H), 7.87 (td, 1H), 8.13 (d, 1H), 8.17 (t, 1H), 8.47 (s, 1H), 8.58 (d, 1H), 9.98 (s, 1H); Mass Spectrum MH+ 494.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:18]C)=[C:16]([CH3:17])[C:11]=2[O:10][N:9]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([CH3:17])[C:11]=2[O:10][N:9]=1
Reactant: COc1ccc2c(-c3ccccc3F)noc2c1C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1c(O)ccc2c(-c3ccccc3F)noc12

Procedure:
3-(2-fluorophenyl)-6-methoxy-7-methyl-1,2-benzisoxazole (16.1 g) is heated at 200° C. for two hours with 64 g of pyridine hydrochloride. The melt is poured into H2O and extracted with ethyl acetate. After washing with 5% HCl the ethyl acetate is dried and evaporated to give 3-(2-fluorophenyl)-6-hydroxy-7-methyl-1,2-benzisoxazole, mp 216°-219° C.
Reaction SMILES: C[CH2:2][N:3](C(C)C)C(C)C.[CH3:10][Si:11]([CH3:38])([CH3:37])[CH2:12][CH2:13][O:14][CH2:15][N:16]1[C:20]2=[N:21][CH:22]=[C:23]([NH:25][C:26](=[O:36])[NH:27][C@H:28]3[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=O)[CH2:29]3)[N:24]=[C:19]2[CH:18]=[CH:17]1.Cl.CN.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:2][NH:3][C:33]([C@H:30]1[CH2:31][CH2:32][C@H:28]([NH:27][C:26]([NH:25][C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][N:16]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:38])([CH3:10])[CH3:37])[C:20]3=[N:21][CH:22]=2)=[O:36])[CH2:29]1)=[O:35]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)N[C@H]3CC[C@H](C(=O)O)C3)cnc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)[C@H]1CC[C@H](NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 126.1 %

Procedure:
DIPEA (0.02 mL, 0.11 mmol) was added at RT to a mixture of (1S,3S)-3-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-ureido}cyclopentanecarboxylic acid (0.075 g, 0.179 mmol), methylamine hydrochloride (0.024 g, 0.355 mmol), and EDCI (0.051 g, 0.266 mmol) in 1 mL of DCM. The resulting mixture was stirred at RT for 16 hours before being partitioned between H2O and DCM. The aqueous layer was back extracted twice with DCM. The combined organic layers were dried (Na2SO4), filtered, and evaporated. The residue was purified by SiO2 flash chromatography (DCM/MeOH 0 to 10% MeOH) to give 0.06 g of (1S,3S)-3-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-ureido}-cyclopentanecarboxylic acid methylamide (76% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.CON(C)[C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)=[O:13]>C1COCC1>[F:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)=[O:13]
Reactant: Fc1cccc(Br)c1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(F)c2)C1
Temperature: 55 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A solution of 1-bromo-3-fluoro-benzene (57.7 g, 0.33 mol) in anhydrous THF (480 mL) was added dropwise to Mg (10.6 g, 0.44 mol) at rt under nitrogen. The mixture was stirred at 50-60° C. for 1 hr. The resulting Grignard reagent was used for the next step. The Grignard reagent was added dropwise to a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (60 g, 0.22 mol) in anhydrous THF (600 mL) at −78° C. under nitrogen. After addition, the mixture was allowed to stir at rt for 1.5 hr. The mixture was quenched with saturated NH4Cl solution (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(3-fluorobenzoyl)piperidine-1-carboxylate (67.5 g, 100%), which was used immediately in the next step without purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(C2=CCC3(CC2)OCCO3)nc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(C2CCC3(CC2)OCCO3)nc1
Reaction time: 3 h

Procedure:
Palladium hydroxide on carbon (1 g, 20 wt % Pd) was added to a solution of Example 93A (2.66 g, 9.66 mmol) in methanol (40 mL) and ethyl acetate (10 mL). The mixture was placed under vacuum and filled with hydrogen (balloon) and allowed to stir for 3 hours before it was filtered through a pad of Celite using methanol to rinse. The solvent was evaporated and the product was dissolved in dichloromethane and dried over Na2SO4. After filtration and concentration, the title compound was isolated as a slightly yellow solid and used in the following step without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([Si:7]([CH3:48])([CH3:47])[O:8][C:9]([C:12]#[C:13][CH:14]([OH:46])[C@H:15]([C:17]1[C@:34]2([CH3:35])[C@H:20]([C:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24]([CH2:25][C@@H:26]([O:36][Si:37]([CH3:45])([CH3:44])[C:38]([CH3:43])([CH3:42])[CH:39]([CH3:41])[CH3:40])[CH2:27][CH2:28]2)=[CH:23][CH:22]=3)[CH2:19][CH:18]=1)[CH3:16])([CH3:11])[CH3:10])([CH3:6])[CH3:5].[C:49]1([N:55]=[C:56]=[S:57])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C1COCC1.N1C=CN=C1>[CH3:3][C:4]([Si:7]([CH3:47])([CH3:48])[O:8][C:9]([C:12]#[C:13][CH:14]([O:46][C:56](=[S:57])[NH:55][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C@H:15]([C:17]1[C@:34]2([CH3:35])[C@H:20]([C:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24]([CH2:25][C@@H:26]([O:36][Si:37]([CH3:44])([CH3:45])[C:38]([CH3:43])([CH3:42])[CH:39]([CH3:40])[CH3:41])[CH2:27][CH2:28]2)=[CH:23][CH:22]=3)[CH2:19][CH:18]=1)[CH3:16])([CH3:10])[CH3:11])([CH3:6])[CH3:5]
Reactant: CC(C)C(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]2CC[C@]2(C)C([C@H](C)C(O)C#CC(C)(C)O[Si](C)(C)C(C)(C)C)=CC[C@@H]32)C1
Reactant: S=C=Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)C(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]2CC[C@]2(C)C([C@H](C)C(C#CC(C)(C)O[Si](C)(C)C(C)(C)C)OC(=S)Nc4ccccc4)=CC[C@@H]32)C1
Reaction time: 1 h
Yield: 111.3 %

Procedure:
Sodium hydride (60% dispersion, 6.55 g, 164 mmol) was suspended in 200 mL of THF followed by the addition of 446 mg (6.55 mmol) imidazole at 5° C. To this gray suspension, a solution of crude 93 g (131 mmol) (3β)-25-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[[dimethyl(1,1,2-trimethylpropyl)silyl]oxy]cholesta-5,7,16-trien-23-yn-22-ol in 700 mL of THF was added dropwise at 8°-10° C. over 30 min. The resulting dark brown suspension was stirred at the same temperature for 1 h. Then, a solution of 17.3 mL (144 mmol) phenyl isothiocyanate in 200 mL of THF was added, and the mixture was stirred at 10° C. for 1 h. The reaction was quenched by the dropwise addition of 500 mL of 10% aqueous NaHCO3 followed by 70 g of celite. After stirring for 10 minutes, the solid was filtered and washed with 500 ml of ethyl acetate. The aqueous layer was extracted twice with 500 ml each of ethyl acetate. The combined organic layers were washed successively with 10% aqueous NaHCO3 and brine, dried over MgSO4, and concentrated to dryness. Some polar, colored impurities were removed by dissolving 132 g of the residue in 200 mL of 3% ethyl acetate in hexane and filtering it through a plug of 120 g of silica gel. The plug was washed with 1 L of 3% ethyl acetate in hexane. The eluate was collected and concentrated to dryness to give 117 g (overweight) of crude phenylcarbamothioic acid O-[(3β)-25-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[[dimethyl(1,1,2-trimethylpropyl)silyl]oxy]cholesta-5,7,16-trien-23-yn-22-yl] ester as an orange oil. This crude material was used for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.Cl.O.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:17]1[CH2:18][CH2:19][NH:14][CH2:15][CH2:16]1
Reactant: O=C1CCNCC1
Reactant: COc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: O
Product: COc1ccc2[nH]cc(C3CCNCC3)c2c1

Procedure:
This compound was prepared following the procedure described in Example 1 (parts A and B) starting with 5 g (33.9 mmol) of 5-methoxyindol and 13.2 g (86.2 mmol) of 4-piperidone monohydrate hydrochloride. After the usual work-up 6.5 g (83% of yield) of the desired product were obtained.
Reaction SMILES: OO.C([C@@H]1COC(=O)N1[C:16](=[O:34])[C@@H:17]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])C1C=CC=CC=1.C[O:36]C1C=C(OC)C=CC=1C=O.[O-]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:22]([O:21][C:20]([NH:19][CH2:18][C@H:17]([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:16]([OH:34])=[O:36])=[O:26])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 93.8 %

Procedure:
35% H2O2 (0.240 mL, 2.91 mmol) was added to a solution of LiO—H2O (0.0978 g, 2.33 mmol) in 2:1 THF:H2O (33 mL). The reaction mixture was stirred at room temperature for 35 minutes and then cooled to 0° C. A solution containing a mixture of tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropylcarbamate (0.535 g, 1.17 mmol) and 2,4-dimethoxybenzaldehyde (0.194 g, 1.17 mmol) in THF (7 mL) was added dropwise by addition funnel. The reaction mixture was placed in an ice bath to slowly warm the reaction mixture and it was stirred overnight. The reaction mixture was then cooled to 0° C., and 1M Na2SO3 (7 mL) was added to the mixture. The mixture was stirred for 5 minutes and then warmed to room temperature while being stirred for 20 minutes. The reaction mixture was then transferred to a separatory funnel and washed with ether (3×). The aqueous layer was acidified with KHSO4(s), and the mixture was extracted with DCM (2×). The combined extracts were dried (Na2SO4), filtered, and concentrated to give (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (0.329 g, 94.2% yield) as a white residue. LC/MS (APCI+) m/z 200 [M−BOC+H]+.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=1[OH:20])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:8][S:9]([C:12]1[C:13]([OH:20])=[C:14]([NH:19][C:30]([NH:29][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=2[Cl:21])=[O:31])[CH:15]=[CH:16][C:17]=1[Cl:18])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O)Nc1cccc(Cl)c1Cl
Yield: 11.7 %

Procedure:
A solution of N-benzyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (54 mg, 0.17 mmol) and 2,3-dichlorophenylisocyanate (34 μL, 0.26 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (60/40, v/v), gave the desired product (10 mg, 12%). EI-MS (m/z) 498.2, 500.1, 502.1 (M−).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:18]1[C@H:20]2[C:21](=[O:42])[CH:22]=[C:23]3[C@:39]([CH3:40])([C@@H:19]12)[C@@H:38]1[C@H:26]([C@H:27]2[C@:35]([CH3:41])([CH2:36][CH2:37]1)[C@@H:30]([C@H:31]([CH3:34])[CH2:32][OH:33])[CH2:29][CH2:28]2)[CH:25]=[CH:24]3.C1C=CC=CC=1>CCOCC>[O:18]1[C@H:20]2[C:21](=[O:42])[CH:22]=[C:23]3[C@:39]([CH3:40])([C@@H:19]12)[C@@H:38]1[C@H:26]([C@H:27]2[C@:35]([CH3:41])([CH2:36][CH2:37]1)[C@@H:30]([C@H:31]([CH3:34])[CH2:32][O:33][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH2:29][CH2:28]2)[CH:25]=[CH:24]3
Reactant: C1=COCCC1
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: C[C@H](COC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 65 %

Procedure:
1.8 ml. of 3,4-dihydro-2H-pyran and 20 mg of anhydrous p-toluenesulphonic acid were added to a solution of 2.45 g of (20S)-1α,2α-epoxy-21-hydroxy-20-methyl-pregna-4,6-dien-3-one in 125 ml. of absolute benzene. After standing at room temperature for 1 hour, the solution was diluted with ether, washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and concentrated in a water-jet vacuum. The residue was chromatographed on 30 g of silica gel using hexane/ether (4:1) for the elution, there being obtained 2.0 g (65%) of (20S)-1α,2α-epoxy-20-methyl-21-tetrahydropyranyloxy-pregna-4,6-dien-3-one. After recrystallisation from hexane, the product melted at 101°-102° C. and was shown by thin-layer chromatography, mixed melting point and IR spectrum to be identical with the compound prepared as described in Example 7.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:23][C:22]2[C:21]3[C:16](=[C:17]([Cl:24])[CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:14]=2[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>[Pd].C(O)C>[CH2:29]([O:28][C:26]([CH2:25][N:15]1[C:14]2[CH2:13][CH2:12][CH:11]([C:9]([OH:10])=[O:8])[CH2:23][C:22]=2[C:21]2[C:16]1=[C:17]([Cl:24])[CH:18]=[CH:19][CH:20]=2)=[O:27])[CH3:30]
Reactant: CCOC(=O)Cn1c2c(c3cccc(Cl)c31)CC(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cn1c2c(c3cccc(Cl)c31)CC(C(=O)O)CC2
Reaction time: 1 h

Procedure:
A mixture of 8-chloro-9-ethoxycarbonylmethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid benzyl ester (2.5 g, 5.9 mmol) and 10% palladium on activated charcoal (480 mg) in ethanol (200 ml) is stirred under a hydrogen atmosphere for 1 h. The catalyst is filtered off and washed with ethanol. The filtrate is concentrated to dryness to deliver Intermediate 1.3. tR (LC-5) 0.96 min; ESI-MS (positive ion): m/z 336.23 [M+H]+ (calcd 335.79 for C17H18NO4C1). 1H-NMR (DMSO-d6): 1.18 (t, J=7.0 Hz, 3H); 1.85 (m, 1H); 2.19 (m, 1H); 2.66 (m, 4H); 2.90 (m, 1H); 4.14 (q, J=7.0 Hz, 2H); 5.17 (s, 2H); 6.96 (t, J=7.6 Hz, 1H); 7.04 (d, J=7.3 Hz, 1H); 7.38 (d, J=7.6 Hz, 1H); 12.3 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-hydroxybenzoic acid (15.0 g) in methanol (150 mL) was added dropwise thionyl chloride (10.1 mL) under ice-cooling. The reaction solution was stirred at 70° C. overnight under argon atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (14.2 g).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][N:2]=1.Br[CH2:13][CH2:14][OH:15]>>[OH:15][CH2:14][CH2:13][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[N:2]1
Reactant: O=c1[nH]nnc2ccccc12
Reactant: OCCBr
Product: O=c1c2ccccc2nnn1CCO

Procedure:
3-(2-hydroxyethyl)-1,2,3-benzotriazin-4(3H)one was prepared according to the general procedure outlined in example 1, step 1. Starting from 1,2,3-benzotriazin-4(3H)one (1.5 g, 10 mmol) and 2-bromoethanol (1.68 mL, 20 mmol), 1.20 g (63%); off white solid; m.p. 114° C., MS: 191.9 (M+H)+
Reaction SMILES: [Cl: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)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]3)[C:4]=2[CH:3]=1.[ClH:28].[CH3:29][N:30]([CH3:42])[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.[OH-].[Na+]>CS(C)=O.O>[ClH:1].[ClH:28].[ClH:1].[Cl: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)[N:5]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:41][C:38]4[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][CH2:31][N:30]([CH3:29])[CH3:42])=[CH:40][CH:39]=4)[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: CN(C)CCCOc1ccc(O)cc1
Reactant: ClCCN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCCOc1ccc(OCCN2CCN(CCCN3c4ccccc4Sc4ccc(Cl)cc43)CC2)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
A solution of 1-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-4-(2-chloroethyl)piperazine (4.22 g) and 4-(3-dimethylaminopropoxy)phenol hydrochloride, (2.3 g) in dimethylsulfoxide (100 ml) was stirred under nitrogen and warmed to 55° C. Then a solution of sodium hydroxide (0.8 g) in water (3 ml) was added and the reaction was stirred at 55°-65° for 2 hours. The usual work-up furnished the crude salt, which was crystallized from methanol-ethyl acetate to give 1.5 g of 3-[[4-[2-[4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]-1-piperazinyl]ethoxy]phenyl]oxy] -N,N-dimethylpropanamine trihydrochloride, mp 228°-230°.
Reaction SMILES: ClCC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13]Cl)[C:6]=1Br.[Li]CCCC.C(O)(=O)C.[OH-].[Na+]>C1COCC1>[OH:4][C:5]1[C:6]2[CH2:13][CH2:12][O:11][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: ClCCOc1cccc(OCCCl)c1Br
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Oc1cccc2c1CCO2
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 98.7 %

Procedure:
The product of Step 2 (39.25 g) was dissolved in THF (0.5 L) and cooled to −78° C. nBuLi (2.5M in hexanes, 300 mL) was then added dropwise over 30 minutes and the reaction stirred at −70° C. for an additional 45 minutes. The solution was then warmed to 0° C. over 10 minutes and stirred at this temperature for 1 hour. Glacial acetic acid (16 mL) was added followed by 1N NaOH (160 mL) and the layers allowed to separate. The organics were extracted with 1N NaOH (2×80 mL) and the combined aqueous fractions were then washed with TBME (160 mL). TBME (240 mL) was then added and the aqueous layer acidified with 6N HCl. The aqueous layer was re-extracted with TBME (240 mL), and the combined organics stirred over activated charcoal (5 g) for 15 minutes, filtered through Celite, and concentrated in vacuo. The crude product was crystallized from toluene and heptane to yield the title compound (16.8 g, 99%).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12](Cl)[CH:11]=[C:10]([CH3:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([OH:19])([CH3:18])[CH3:17].[H-].[Na+]>C1COCC1>[NH:1]([C:8]1[N:9]=[C:10]([CH3:15])[CH:11]=[C:12]([O:19][CH:16]([CH3:18])[CH3:17])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)O
Reactant: Cc1cc(Cl)nc(Nc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OC(C)C)nc(Nc2ccccc2)n1
Yield: 64.1 %

Procedure:
In the same manner as in Example 3, 3.1 g of 2-anilino-4-chloro-6-methylpyrimidine, 1.9 g of isopropyl alcohol and 0.7 g of NaH were added to 50 ml of THF and allowed to react at room temperature for 4 hours to obtain 2.2 g of 2-anilino-4-methyl-6-isopropoxypyrimidine (yield 65%). nD20 1.5931.