Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:10]([CH3:18])=[CH:11][C:12]([F:17])=C([CH:16]=3)C#N)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:19][C:20](=[O:24])[O:21]CC.[ClH:25]>>[ClH:25].[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:10]([CH3:18])=[CH:11][C:12]([F:17])=[C:19]([CH:16]=3)[C:20]([OH:21])=[O:24])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: Cc1cc(F)c(C#N)cc1-n1cnc(C2CC2)c1
Agent: Cl
Product: Cc1cc(F)c(C(=O)O)cc1-n1cnc(C2CC2)c1
Temperature: 100 °C

Procedure:
5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile (11.21 g, 46.50 mmol) was placed in a round bottom flask fitted with a reflux condenser, and suspended in 38% hydrochloric acid (200 mL). The mixture was heated to 100° C. for 4.5 hours, and then cooled to room temperature. Solvent was removed under reduced pressure to give a pink solid, to which was added 100 ml of EA. The solid product was collected by filtration and washed with 3×100 mL EA. To the solid product was added 100 mL 10% methanol in dichloromethane, the mixture stirred, and the filtrate collected. This was repeated with 2 more 100 ml portions of 10% methanol in dichloromethane. The filtrates were combined and solvent was removed under reduced pressure, to provide crude 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methylbenzoic acid hydrochloride. No further purification was carried out (11.13 g, 37.54 mmol). Anal. LC/MS (m/z: 261, M+1)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[N:11]([OH:14])[C:10]1=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][C:18]([O:20][CH2:21][C:22]([O:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:23])=[O:19].C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[N:11]([O:14][CH2:17][C:18]([O:20][CH2:21][C:22]([O:24][CH:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[O:23])=[O:19])[C:10]1=[O:15])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Reactant: CCC(CC)OC(=O)COC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(CC)OC(=O)COC(=O)CON1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
(3S-trans)-3-[(t-Butyloxycarbonyl)amino]-1- hydroxy-4-methyl-2-azetidinone (21.6 g) was dissolved in 250 ml of dimethylformamide. At 0° C. 26.7 g of bromoacetic acid. [(3-pentyloxy)carbonyl]-methyl ester was added, followed by 17 ml of triethylamine. The mixture was stirred overnight, and the dimethylformamide was evaporated in vacuo. The oily residue was dissolved in 300 ml of ethyl acetate, washed with ice-cold NaHCO3 solution and then washed three times with ice water. After drying over MgSO4, the solvent was evaporated in vacuo yielding 35.6 g of the title compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]([OH:12])=O)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:26][C:24]=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][NH:26][C:10](=[O:12])[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=C(O)c1ncccc1[N+](=O)[O-]
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a mixture of 3-nitropicolinic acid (8.7 g, 51.8 mmol, 1.0 eq), methylamine hydrogen chloride (4.2 g, 1.2 eq), EDC (14.9 g, 1.5 eq), HOBt (8.4 g, 1.2 eq) in DMF (30 mL) was added DIEA (54 mL, 6.0 eq). The mixture was stirred at room temperature overnight. The crude was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3 solution. The solvent was removed and the crude was purified by silica gel chromatography (20%˜80% EtOAc/Hex) to obtain the desired product N-methyl-3-nitropicolinamide (3.0 g, isolated yield 32%).
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: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)N[C@H]3CC[C@H](C(=O)O)C3)cnc21
Reactant: CCN(C(C)C)C(C)C
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: [CH3:1][C:2]([O:5][C:6](=[O:25])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[N+:22]([O-])=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])[CH3:3]>C(OCC)(=O)C.[Pd]>[CH3:14][C:11]([O:10][C:8](=[O:9])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[NH2:22])[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:25])([CH3:12])[CH3:13]
Reactant: Cc1ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.3 %

Procedure:
A solution of bis(1,1-dimethylethyl)(4-methyl-2-nitrophenyl)propanedioate (D38, 660 mg, 1.88 mmol) in ethyl acetate (25 mL) was treated with 10% Pd/C (0.5 g) and shaken under hydrogen at atmospheric pressure and room temperature for 20 hours. The mixture was filtered through Kieselguhr and the filtrate concentrated under vacuum to afford the title compound as a colourless oil (606 mg, 100%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:4]=1[C:5]([OH:7])=[O:6].[C:15](Cl)(Cl)=[O:16]>O.O1CCCC1>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:3]2[NH:2][C:15](=[O:16])[O:7][C:5](=[O:6])[C:4]=12)([O-:14])=[O:13]
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc([N+](=O)[O-])c2c(=O)o1
Reaction time: 3 h

Procedure:
A solution of 56.5 g of 2-amino-6-nitrobenzoic acid hydrochloride in 200 ml of demineralized water and 200 ml of tetrahydrofuran is cooled to 10° while stirring and treated with phosgene at 10°-30° for 1 hour, a precipitate resulting. The mixture is subsequently diluted with 300 ml of demineralized water and air is conducted through the suspension vigorously for about 3 hours (until the sample is negative for phosgene). The precipitate is filtered off, washed with water and dried in vacuo over phosphorus pentoxide. There is obtained 6-nitroisatoic acid anhydride as beige crystals of m.p. 220°-222° (decomposition).
Reaction SMILES: [CH2:1]([PH:8](=[O:10])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:23]([O:30][C:31]([CH:33]([CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[CH2:34]P(C)(=O)OCC1C=CC=CC=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:1]([P:8]([CH2:34][CH:33]([C:31]([O:30][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:32])[CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:49])(=[O:9])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[PH](O)Cc1ccccc1
Reactant: CP(=O)(CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCC(CP(=O)(O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
Benzylphosphinic acid (2.3 g, 15 mmol) in 150 mL of dry dichloromethane was cooled to 0° C. under a nitrogen atmosphere. Triethylamine (6.5 g, 65 mmol) was added followed by trimethylsilyl chloride (5.8 g, 54 mmol) while the reaction temperature was maintained at 0° C. After 30 minutes dibenzyl 2-methylene-pentanedioate (2) (4.4 g, 13.6 mmol) in 20 mL of dichloromethane was added over 5 minutes. The reaction mixture was allowed to warm to room temperature and stirred overnight. The clear solution was cooled to 0° C. and quenched with 5% hydrochloric acid followed by removal of the organic layer. The organic layer was washed with 5% hydrochloric acid and with brine, dried (MgSO4) and evaporated to give a clear yellow liquid. Purification by flash chromatography and elution with 1:1 hexane/ethyl acetate containing 10% acetic acid yielded 2.0 g (28%) of benzyl[2,4-di(benzyloxycarbonyl)butyl]-phosphinic acid (3, R=CH2Ph, R1=H) as a clear light yellow oil. Rf 0.37 (1:1 Hexane/EtOAc, 10% AcOH).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:8]=1)([O-])=O.[H][H]>C1COCC1.[Pd]>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:7]1[CH:8]=[C:4]([NH2:1])[N:5]=[CH:6]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cn(-c2ccccn2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cn(-c2ccccn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-nitro-imidazol-1-yl)-pyridine (150 mg, 0.79 mmol) in THF (12 ml) was added under inert gas atmosphere 10% Pd/C (28 mg, 0.026 mmol). Upon evacuation, the reaction vessel was charged with hydrogen and the reaction mixture was stirred at ambient temperature overnight. The catalyst was filtered off, the solvent volume was reduced and the amine was used without any further purification as ˜0.2 M THF solution for the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[NH:15][C:16](=[O:18])[CH3:17]>C(O)C.[Pd]>[NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[NH:15][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCCCN
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1cc(N)ccc1OCCCN
Reaction time: 1 h

Procedure:
0.026 mol (6.5 g) of 2-acetylamino-4-nitrophenyl γ-aminopropyl ether in 32 cm3 of absolute ethanol is reduced on a 10% strength Pd/C catalyst under a hydrogen pressure of 20 bars, at 80° C., for one hour. After filtration and after cooling the filtrate with a solid carbon dioxide bath, the expected product precipitates. The product is filtered off and dried in vacuo over P2O5. It melts at 102°-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([Cl:19])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2Oc2ccccc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: ClC1=Nc2cc(Cl)ccc2Oc2ccccc21
Yield: 89.8 %

Procedure:
To a stirred solution of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepin-11-one (0.53 g, 2.15 mmol) in toluene (20 mL) was added phosphorus pentachloride (0.54 g, 2.58 mmol) at room temperature under argon. The resulting mixture was heated at reflux for 4 h and the solvent was removed in vacuo. The residue was redissolved in toluene and reconcentrated. The light yellow solid 8,11-dichlorodibenz[b,f][1,4]oxazepine (0.51 g, quantitative yield) was used directly for the next reaction without further purification.
Reaction SMILES: [O:1]=[C:2]([C@H:25]([CH3:41])[C@@H:26]([O:32][C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34])[C@@H:27]([CH3:31])[CH2:28][CH:29]=[CH2:30])[C:3]([CH3:24])([CH3:23])[C@@H:4]([OH:22])[C@H:5]([CH3:21])[C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7].N1C=CN=C1.[CH2:47]([Si:49](Cl)([CH2:52][CH3:53])[CH2:50][CH3:51])[CH3:48].O>CN(C)C=O>[O:1]=[C:2]([C@H:25]([CH3:41])[C@@H:26]([O:32][C:33]([O:35][CH2:36][C:37]([Cl:39])([Cl:40])[Cl:38])=[O:34])[C@@H:27]([CH3:31])[CH2:28][CH:29]=[CH2:30])[C:3]([CH3:23])([CH3:24])[C@@H:4]([O:22][Si:49]([CH2:52][CH3:53])([CH2:50][CH3:51])[CH2:47][CH3:48])[C@H:5]([CH3:21])[C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O)[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](CC)(CC)CC)[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
A solution of (4S)-3-[(2S,3S,6R,7S,8S)-5-oxo-3-hydroxy-2,4,4,6,8-pentamethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-10-undecenoyl]-4-benzyloxazolidinone (2.6 g), imidazole (0.48 g), and triethylsilyl chloride (0.68 g) in 5 mL of dimethylformamide is stirred for 2 hours at ambient temperature, then poured into water and extracted with ether. The extract is washed with sat. aq. NaCl, dried over MgSO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13](C=O)=[C:14]2[N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[CH:25]2)[CH2:6]1)(=[O:3])[CH3:2]>C(#N)C1C=CC=CC=1.[Pd]>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH:13]=[C:14]2[N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[CH:25]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4cnc5ccccc54)=C(C=O)C[C@@H]32)C1
Agent: [Pd]
Solvent: N#Cc1ccccc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4cnc5ccccc54)=CC[C@@H]32)C1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A solution of 3β-Acetoxy-17-(1H-benzimidazol-1-yl)-16-formylandrosta-5,16-diene (3, 2.04 g, 4.45 mmol) in dry benzonitrile (10 mL) was refluxed in the presence of 10% palladium on activated charcoal (1.02 g, i.e., 50% weight of 3) for 5 h. After cooling to room temperature, the catalyst was removed by filtration through a Celite pad. The filtrate was evaporated, and the residue was purified by FCC [petroleum ether/EtOAc/Et3N (7.5:3:0.5)] gave 1.41 g (73.8%) of pure compound 4: mp 159-160° C.; IR(CHCl3) 3687, 2947, 2854, 2358, 2340, 1725, 1633, 1609, 1557, 1489, 1454, 1373, 1291, 1253, 1195, 1136, 1031, 985, 910, 839, 735, 665, 590, 544, 533, 513, 502, 488 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.02 (s, 3H, 18-CH3), 1.07 (s, 3H, 19-CH3), 2.04 (s, 3H, 3β-OCH3), 4.62 (m, 1H, 3α-H), 5.43 (br s, 1H, 6-H), 5.98 (s, 1H, 16-H), 7.30 (m, 2H, aromatic-Hs), 7.49 (s, 1H, aromatic-H), 7.81 (s, 1H, aromatic-H), and 7.95 (s, 1H, 21-H). HRMS calcd 453.2512 (C28H34O2N2.Na+). found 453.2511.
Reaction SMILES: [O:1]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([NH:20][C:21]([NH2:23])=[O:22])=[C:15]([N+:17]([O-])=O)[CH:16]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.COCCO.[Ni]>[O:1]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([NH:20][C:21]([NH2:23])=[O:22])=[C:15]([CH:16]=1)[NH2:17])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: COCCO
Product: NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1N

Procedure:
33.7 g of 5-phenoxysulfonyl-2-ureidonitrobenzene in 250 ml of methanol and 250 ml of 2-methoxyethanol are hydrogenated under normal pressure with a catalytic amount of Raney nickel. After uptake of hydrogen is complete, the catalyst is filtered off with suction, washed with dimethylformamide and the solution is evaporated under reduced pressure, induced to crystallize with methanol, and the crystals are filtered off with suction and washed with methanol, melting point 180° C., decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:13]=[N:14][C:15](Cl)=[N:16][CH:17]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>C(O)CCC.O>[Br:11][C:12]1[CH:13]=[N:14][C:15]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)=[N:16][CH:17]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Nc1ccc(CCO)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCc1ccc(Nc2ncc(Br)cn2)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-aminophenyl)ethanol (0.72 mol), 5-bromo-2-chloropyrimidine 4 (0.72 mol), sodium iodide (0.72 mol), and diisopropylethylamine (1.45 mol) in n-butanol (400 mL) is heated at reflux for 16 h. The reaction is cooled to rt and the mixture is diluted with water. The light yellow solid that precipitates is filtered to give 2-(4-(5-bromopyrimidin-2-ylamino)phenyl)ethanol 18. 1H NMR (300 MHz, d6-DMSO) δ 9.72 (s, 1H), 8.52 (s, 2H), 7.55 (m, 2H), 7.09 (d, 2H), 4.64 (m, 1H), 3.52 (m, 2H), 2.65 (m, 2H). MS (m/z) (M+1)+: 294.1, 296.1.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][NH:5][C:4](=[O:14])[CH:3]=1.CS(C1C=CNC(=O)C=1)(=O)=O.[CH2:26]([C:29]1[CH:30]=[N:31][C:32]([N:35]2[CH2:40][CH2:39][CH:38](CS([O-])(=O)=O)[CH2:37][CH2:36]2)=[N:33][CH:34]=1)[CH2:27][CH3:28].CS(OC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O>>[C:8]1([C:7]2[C:2]([O:1][CH:38]3[CH2:39][CH2:40][N:35]([C:32]4[N:31]=[CH:30][C:29]([CH2:26][CH2:27][CH3:28])=[CH:34][N:33]=4)[CH2:36][CH2:37]3)=[CH:3][C:4](=[O:14])[NH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCc1cnc(N2CCC(CS(=O)(=O)[O-])CC2)nc1
Reactant: O=c1cc(O)c(-c2ccccc2)c[nH]1
Agent: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: CS(=O)(=O)c1cc[nH]c(=O)c1
Product: CCCc1cnc(N2CCC(Oc3cc(=O)[nH]cc3-c3ccccc3)CC2)nc1

Procedure:
The compound in Step C was prepared according to the procedures described in Example 1 substituting 4-hydroxy-5-phenylpyridin-2(1H)-one for 4-hydroxy-1-(4-(methylsulfonyl)pyridine-2(1H)-one and 1-(5-propylpyrimidin-2-yl)piperidin-4-ylmethanesulfonate for tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate in Step D. MS (ESI) 391 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[C:12]1([CH:18](Br)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:19][CH:18]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(Br)c1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: CC(c1ccccc1)n1cc(C=O)c2ccccc21

Procedure:
The same procedures used in Example 1 were repeated except for using 870 mg of indole-3-carbaldehyde and α-phenylethyl bromide in place of the benzyl bromide used in Example 1 to give 1.42 g of 1-(α-methylbenzyl)indole-3-carbaldehyde as an orange-colored oily substance. The yield thereof was found to be 95%.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:18]=[N:19][C:20]([CH2:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([C:30]([O:32]C)=[O:31])[CH2:26][CH2:25]4)=[N:21][CH:22]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[F:34][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:22]=[N:21][C:20]([CH2:23][C@H:24]4[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]4)=[N:19][CH:18]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1
Reactant: COC(=O)[C@H]1CC[C@H](Cc2ncc(-c3cc(C)cc(Nc4nccc(C(F)F)n4)c3)cn2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnc(C[C@H]3CC[C@H](C(=O)O)CC3)nc2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl trans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]methyl}cyclohexanecarboxylate (60 mg, 0.13 mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (16 mg, 0.39 mmol) and then the reaction mixture was stirred at 60° C. for 8 hours. After cooling to room temperature, water was added to the mixture and the pH was adjusted to pH 2 by the addition of aqueous 1M HCl. The mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate/petroleum ether) to give trans-4-{[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]methyl}cyclohexanecarboxylic acid. MS ESI calc'd for C24H26F2N5O2 [M+H]+ 454. found 454. 1H NMR: (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.95 (s, 2H), 8.72 (s, 1H), 8.00 (s, 1H), 7.59 (s, 1H), 7.50 (s, 1H), 7.22 (s, 1H), 7.08 (s, 1H), 6.88 (t, J=54.4 Hz, 1H), 3.14-3.13 (m, 1H), 2.79-2.77 (m, 2H), 2.35 (s, 3H), 2.07-2.04 (m, 1H), 1.87-1.84 (m, 2H), 1.66 (s, 1H), 1.30-1.21 (m, 3H), 1.07-1.03 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[CH2:22]([O:42][C:43]1[C:49]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:48][C:46]([NH2:47])=[CH:45][C:44]=1[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:47][C:46]2[CH:45]=[C:44]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:43]([O:42][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:49]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH:48]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Reactant: CCCCCCCCCCCCCCCCCCCCOc1c(-c2ccccc2)cc(N)cc1-c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCOc1c(-c2ccccc2)cc(N=C(C)c2cccc(C(C)=Nc3c(C)cc(C)cc3C)n2)cc1-c1ccccc1
Reaction time: 24 h

Procedure:
2-[1-(2,4,6-trimethylphenylimino)ethyl]-6-acetyl pyridine (3 g, 10.7 mmol), prepared according to the method disclosed in WO02/28805, and 4-eicosanoxy-3,5-diphenylaniline (5.8 g, 10.7 mmol) were dissolved in 200 ml of toluene. To this solution, 4 Å molecular sieves were added. After standing for 1 day the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from cold ethanol. The product, D, was isolated as a yellow treacle (6.5 g, 8.1 mmol, 76%) after drying at 60° C. in vacuo.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1.Cl>O1CCOCC1>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([N:15]2[CH2:14][CH2:13][C:5]3[C:4](=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:2])=[CH:17][CH:18]=1)([CH3:23])([CH3:25])[CH3:24]
Reactant: COC(=O)c1c(CCNc2ccc(C(C)(C)C)cc2)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2CCc3cccc([N+](=O)[O-])c3C2=O)cc1

Procedure:
A solution of the amine (Step C, 0.41 g, 1.2 mmol), conc. HCl (0.1 mL), and dioxane (4 mL) was heated in a microwave at 200° C. for 5 min. The mixture was concentrated in vacuo to give the crude compound as a red oil. Purification by silica flash chromatography (0-25% EtOAc:hexane) gave the desired compound as a yellow oil. MS m/e 325 (M+H)+. Calc'd for C19H20N2O3-324.37.