Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: O=CC(=O)c1ccccc1
Reactant: CCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: CCc1ccc(C(O)C(=O)c2ccccc2)cc1
Yield: 74 %

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and ethylbenzene (0.49 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 2 hours. The reaction mixture was extracted with ethylacetate, the extract was washed with saturated sodium hydrogen carbonate solution and brine, dried with sodium sulfate anhydrous, and then concentrated to obtain a yellow-colored oil. The oil was crystallized from a petroleum ether/diethylether to obtain 357.1 mg (74.0% yield) of 4'-ethylbenzoin.
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.[C:13]([NH:16][CH:17](Br)[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(=[O:15])[CH3:14]>C1COCC1>[C:13]([NH:16][CH:17]([C:6]1[NH:5][CH:9]=[CH:8][N:7]=1)[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])(=[O:15])[CH3:14]
Reactant: CCOC(OCC)n1ccnc1
Reactant: CC(=O)NC(Br)C(=O)NCc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)NC(C(=O)NCc1ccccc1)c1ncc[nH]1
Temperature: -78 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
The 2-lithio salt solution of 1-diethoxymethylimidazole was added dropwise (15 min) into a cooled (-78° C.) THF solution (130 mL) of 2-acetamido-N-benzyl-2-bromoacetamide (prepared from 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol) and BBr3 (1M in CH2Cl2, 10 mL, 10.0 mmol)). The reaction was stirred at -78° C. (1 h) and then quenched with a saturated aqueous NH4Cl (50 mL) solution. The mixture was stirred at room temperature (30 min), and made basic ("pH" 9.2)by adding aqueous K2CO3. The aqueous mixture was extracted with EtOAc (3×100 mL), and the combined extracts were dried (Na2SO4). The solvents were removed in vacuo and the residue was purified by flash column chromatography on SiO2 gel (2.5% MeOH/CHCl3) to give 0.14 g (7%) of the desired product: mp 228°-230° C. (recrystallized from EtOH); Rf 0.46 (10% MeOH/CHCl3); IR (KBr) 3200 (br), 1610, 1500 (br), 1430, 1350, 740, 680 cm-1 ; 1H NMR (DMSO-d6) δ 1.91 (s, C(O)CH3), 4.29 (d, J=5.6 Hz, CH2), 5.51 (d, J=7.7 Hz, CH), 6.85 (br s, C4H), 7.05 (br s, C5H), 7.18-7.30 (m, 5 PhH), 8.42 (d, J=7.7 Hz, NH), 8.65 (t, J=5.6 Hz, NH), 11.91 (br s, NH); 13C NMR (DMSO-d6) 22.49 (C(O)CH3), 42.21 (CH2), 51.62 (CH), 126.60 (C4'), 126.98 (2C2' or 2C3'), 127.21 (C4), 128.09 (2C2' or 2C3'), 128.32 (C5), 139.05 (C1'), 143.74 (C2), 168.12 (C(O)NH), 169.30 (C(O)CH3) ppm; mass spectrum (FD) 273 (M+ +1, 65), 272 (M+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.Cl[CH2:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(OCC)(=O)C>[CH3:20][N:19]([CH3:21])[C:17](=[O:18])[CH2:16][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])N(CC(=O)N(C)C)CC2
Temperature: 65 °C
Yield: 15.9 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (0.7 g, 3.61 mmol) in THF (100 mL) was added 2-chloro-N,N-dimethylacetamide (1.11 g, 10.8 mmol), and potassium carbonate (2.98 g, 21.6 mmol). After heating at 65° C. for 4 days, the reaction was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was separated, adsorbed onto silica gel, and purified by column chromatography (DCM to 2% MeOH/DCM) to provide N,N-dimethyl-2-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]acetamide (0.16 g, 16%). ESIMS (M+H)+=280.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12]3[N:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH:24]=1.[CH3:25]I.O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:25])[C:12]3[N:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH:24]=1
Reactant: CI
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=Nc1cccnc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1c2ccc(Cl)cc2C(c2ccccc2)=Nc2cccnc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a stirred suspension of 0.25 g (0.01 mole) of sodium hydride (in mineral oil) in 15 ml of anhydrous dimethylformamide was added, portionwise, 3.05 g (0.01 mole) of 8-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The mixture was warmed at about 60° C. for one hr. A solution of 1.42 g (0.01 mole) of methyl iodide in 10 ml of anhydrous dimethylformamide was added dropwise over a 0.5 hr period and the reaction mixture stirred overnight at room temperature after which it was poured into 400 ml of water and stirred for 2 hr. The precipitated solid was recrystallized twice from isopropyl alcohol to give 2.0 g of product, m.p. 153°-6° C. Drying conditions prior to analyses were 1 hr at 82° C./0.1 mm Hg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[OH:16])=[CH:11][C:10]=1[O:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCC>C(Cl)Cl.CCOCC.[O-2].[O-2].[Mn+4]>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:17]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([O:27][CH3:28])[CH:11]=2)=[O:16])[CH:18]=1
Reactant: COc1cc(C(O)c2cnc3ccccc3c2)ccc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(C(=O)c2cnc3ccccc3c2)ccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 6.2 g of α-[4-(benzyloxy)-3-methoxyphenyl]-3-quinolinemethanol in 200 ml of methylene chloride is treated with 62 g of manganese dioxide and stirred at the reflux temperature 2 hours. After cooling the precipitate is filtered under suction and washed with methylene chloride. The filtrate is evaporated and the oil obtained is dissolved in hot ether, whereupon the solution is treated with a small amount of pentane. The separated crystals are filtered under suction. There is obtained 4-(benzyloxy)-3-methoxyphenyl (3-quinolinyl) ketone in the form of colorless crystals of m.p. 110°-111°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)[N:20]=2)[CH2:14][N:13]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:34][O:35][C:36](=[O:69])[NH:37][CH:38]([C:42]([N:44]1[CH2:48][CH2:47][CH2:46][CH:45]1[C:49]1[NH:50][CH:51]=[C:52]([C:54]2[CH:59]=[CH:58][C:57](B3OC(C)(C)C(C)(C)O3)=[CH:56][CH:55]=2)[N:53]=1)=[O:43])[CH:39]([CH3:41])[CH3:40].C(=O)([O-])[O-].[K+].[K+].C(O)(C(F)(F)F)=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.O.COCCOC>[CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:57]4[CH:58]=[CH:59][C:54]([C:52]5[NH:53][C:49]([CH:45]6[CH2:46][CH2:47][CH2:48][N:44]6[C:42](=[O:43])[CH:38]([NH:37][C:36]([O:35][CH3:34])=[O:69])[CH:39]([CH3:41])[CH3:40])=[N:50][CH:51]=5)=[CH:55][CH:56]=4)=[CH:23][CH:22]=3)=[CH:18][N:17]=2)[CH2:14][N:13]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CN(CC(F)(F)F)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
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: O
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(CC(F)(F)F)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C
Yield: 24.6 %

Procedure:
{1-[4-(4-Bromo-phenyl)-1′-(2,2,2-trifluoro-ethyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (13.0 mg, 0.0244 mmol) was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (12.1 mg, 0.0244 mmol) under an argon atmosphere. Potassium carbonate (6.7 mg, 0.048 mmol) and Pd(PPh3)4 (2.7 mg, 0.0024 mmol) were added, followed by DME (2.0 mL) and water (0.4 mL). The mixture was heated under microwave conditions for 20 minutes at 120° C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product {1-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1′-(2,2,2-trifluoro-ethyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (6.1 mg, 0.006 mmol) as the TFA salt: LCMS-ESI+: calc'd for C41H50F3N9O6: 821.8 (M+). Found: 823.4 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.89-7.82 (m, 10H), 5.39 (dd, J=6.3, 6.3 Hz, 1H), 5.25 (m, 1H), 4.78 (d, J=6.9 Hz, 1H), 4.24 (d, J=7.5 Hz, 1H), 4.10 (m, 1H), 4.00 (d, J=7.5 Hz, 1H), 3.88 (m, 1H), 3.67 (s, 3H), 3.66 (s, 3H), 3.65-3.43 (m, 4H), 2.58 (m, 1H), 2.29-2.01 (m, 5H), 1.03-0.89 (m, 12H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)=[CH:9][C:8]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:30](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:17]1([C:15]2[NH:14][N:13]=[C:12]([N:11]3[C:10]4[CH:9]=[C:8]([NH:20][C@H:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH3:22])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2]=4[N:1]=[CH:30]3)[CH:16]=2)[CH2:19][CH2:18]1
Reactant: CC(=O)O
Reactant: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c(N)c(C(N)=O)c1)c1ccc(F)cc1
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H](Nc1cc(C(N)=O)c2ncn(-c3cc(C4CC4)[nH]n3)c2c1)c1ccc(F)cc1
Yield: 11.1 %

Procedure:
The mixture of (S)-2-amino-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(1-(4-fluorophenyl)ethylamino)benzamide (Method 100, 3.95 g, 10 mmol) and formamidine acetate (2.2 g, 21 mmol) in EtOH (50 ml) was heated at reflux for 36 hours. After cooling, the reaction mixture was treated with saturated sodium bicarbonate solution (30 ml) and EtOAc (80 ml). The organic layer was separated, washed with brine (30 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc-MeOH=30:1) to give the title compound as an off-white solid (0.45 g, 11%). 1H NMR (400 MHz) 12.79 (s, 1H), 9.00 (d, J=2.8 Hz, 1H), 8.42 (s, 1H), 7.67 (d, J=2.8 Hz, 1H), 7.43 (m, 2H), 7.38 (d, J=2.0 Hz, 1H), 7.09 (m, 3H), 6.59 (d, J=6.4 Hz, 1H), 6.16 (d, J=1.6 Hz, 1H), 4.54 (m, 1H), 1.97 (m, 1H), 1.43 (d, J=6.4 Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 404; Found: [M+H]+ 405.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:36]=[CH:35][N:16]3[C:17](=[O:34])[C:18]([CH:32]=O)=[C:19]([N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH2:22]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].FC(F)(F)COP([CH2:51][C:52]([O:54][CH3:55])=[O:53])(=O)OCC(F)(F)F.N12CCCN=C1CCCCC2>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([NH:10][C:11]([C:13]2[CH:36]=[CH:35][N:16]3[C:17](=[O:34])[C:18](/[CH:32]=[CH:51]/[C:52]([O:54][CH3:55])=[O:53])=[C:19]([N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([N:29]([CH3:30])[CH3:31])=[O:28])[CH2:22]4)[N:20]=[C:15]3[CH:14]=2)=[O:12])[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)C1CCCN(c2nc3cc(C(=O)Nc4nc(C(C)(C)C)cs4)ccn3c(=O)c2C=O)C1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1c(N2CCCC(C(=O)N(C)C)C2)nc2cc(C(=O)Nc3nc(C(C)(C)C)cs3)ccn2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
The N8-[4-(tert-butyl)-1,3-thiazol-2-yl]-2-{3-[(dimethylamino)carbonyl]-piperidino}-3-formyl-4-oxo-4 H-pyrido[1,2-a]pyrimidine-8-carboxamide (84.2 mg, 0.18 mmol) obtained in (B) was dissolved in tetrahydrofuran (10 ml), added with lithium chloride (45.3 mg, 1.07 mmol), and added dropwise with bis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl)phosphonate (112.9 μl, 0.53 mmol) and 1,8-diazabicyclo-[5,4,0]undec-7-ene (73.4 μl, 0.53 mmol). After the reaction solution was stirred at room temperature for 2 hours, the solvent was evaporated, and the residue was purified by preparative TLC (chloroform:methanol=20:1, v/v) to obtain the title compound (63.7 mg, 68.2%) as a mixture of orange oil and solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g of 4-(4-bromophenyl)piperidin-4-ol is placed in 20 ml of dichloromethane. 0.65 ml of triethylamine and then 0.33 ml of methanesulphonyl chloride are added. The reaction mixture is stirred at ambient temperature for 2 h. It is washed with water and then with a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and then evaporated under reduced pressure. The crude product obtained is chromatographed on silica gel, elution being carried out with a dichloromethane/methanol (99/1) solvent mixture. 1.1 g of 4-(4-bromophenyl)-1-(methanesulphonyl)piperidin-4-ol are obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1[CH3:29].O>C(O)CCC>[CH3:29][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:19]=1[NH:18][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: Clc1nc(-c2ccccc2)c2ccccc2n1
Solvent: CCCCO
Solvent: O
Product: COC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)c(C)c1
Temperature: 160 °C
Yield: 79.6 %

Procedure:
A mixture of 2-chloro-4-phenylquinazoline (200 mg, 0.83 mmol) and methyl 4-amino-3-methylbenzoate (137 mg, 0.83 mmol) in n-butanol was heated to 160° C. for 1 h and then cooled to rt. Water (10 mL) was added and the product collected by filtration to give the methyl 3-methyl-4-(4-phenylquinazolin-2-ylamino)benzoate (244 mg, 79%), which was dissolved in a 1:1 mixture of water and methanol (10 mL) containing sodium hydroxide (100 mg, 2.5 mmol). The mixture was heated to 60° C. overnight. Ethyl acetate (100 mL) was added and the phases were separated. The aqueous layer was acidified with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator to give 3-methyl-4-(4-phenylquinazolin-2-ylamino)benzoic acid (188 mg, 80%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH2:13][OH:14])[CH:2]=1.[C:15]([O:19][C:20](=[O:22])[O-:21])([CH3:18])([CH3:17])[CH3:16]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].[Pd].C(O)(C)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][CH2:13][OH:14])[CH:2]=1.[C:15]([O:19][C:20](=[O:21])[O-:22])([CH3:18])([CH3:17])[CH3:16]
Reactant: OCC#Cc1cnc2ccccc2c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)(C)OC(=O)[O-]
Solvent: CC(C)O
Product: OCC=Cc1cnc2ccccc2c1

Procedure:
To a 250 mL single-necked round-bottom flask was charged the 3-(3-quinolyl)-2-propyn-1-ol t-butyl carbonate (1.52 g, 5.37 mmol), isopropanol (30 mL) and 5% palladium on calcium carbonate poisoned with lead (Lindlar's catalyst, 75 mg, 0.049 equiv). The suspension was stirred (rapidly) magnetically and the atmosphere above the solution was purged with hydrogen. A balloon of hydrogen gas was then placed over the reaction stirring mixture and the reaction was allowed to stir for 16 hours at room temperature. The reaction mixture was then filtered through a 0.45μ filter disk and rinsed with 10 mL of isopropanol. The combined filtrates were concentrated under reduced pressure and the residue (1.55 g) was taken up in 9 mL of heptane/acetone (8:1) and eluted through a plug of silica gel (1.5 g) with 8:1:0.01 heptane/acetone/triethylamine. The desired fractions were combined and concentrated under reduced pressure to provide 3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate: 1.1 g, 71.9%
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[Br:1][C:2]1[C:3]([N:24]([CH2:25][CH2:26][OH:27])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CNCCO
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and 2-methylamino-ethanol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.57 min, UPLC-MS (Condition 3) tR=1.11 min, m/z=434.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:16]=[N:17][C:18]([CH2:21][OH:22])=[CH:19][CH:20]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:16]=[N:17][C:18]([CH:21]=[O:22])=[CH:19][CH:20]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(CO)nc2)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C=O)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A solution of [4-(6-hydroxymethyl-pyridin-3-yloxy)-phenyl]-carbamic acid t-butyl ester (0.25 g, 0.8 mmol) in DCM (3.0 ml) was treated with activated MnO2 (0.42 g, 4.8 mmol) and the suspension was stirred at RT for 2 h. The reaction suspension was filtered and the filtrate was concentrated in vacuo to provide [4-(6-formyl-pyridin-3-yloxy)-phenyl]-carbamic acid t-butyl ester (0.24 g, 95% yield). MS (ESI) m/z: 315.0 (M+H+).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21]O>S(=O)(=O)(O)O>[CH3:21][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid (500 mg, 1.89 mmol) in methanol (15 mL) was treated slowly with concentrated sulfuric acid (3 drops). The resulting reaction mixture was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid methyl ester (377 mg, 72%) as a white solid: mp 63-66° C.; EI-HRMS m/e calcd for C16H22O4S (M+) 310.1239, found 310.1230.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[N:4]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[OH-].[K+].Cl.O>CO>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[N:4]([C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1
Reactant: COC(=O)c1cc2c(cn1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c(cn1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
To a suspension of methyl 3-bromo-1-trityl-1H-pyrazolo[4,3-c]pyridine-6-carboxylate (6.0 g, 12.04 mmol) in MeOH (60 mL), 1N KOH (42.1 mL, 42.1 mmol) was added. The reaction mixture was heated to 50° C. for 1 h. After cooling down to room temperature, 1N HCl was added to pH=4. The product 8a was collected by filtration and washed with H2O (5.3 g, 10.95 mmol, 91%). MS ESI calc'd. for C26H19BrN3O2 [M+H]+ 484, found 484.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH2:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>C(#N)C>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH2:10][CH2:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: BrCCCCCCBr
Reactant: Oc1ccc(C2=NCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: BrCCCCCCOc1ccc(C2=NCCO2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 114 %

Procedure:
A stirring suspension of 163 g (1.0 mole) of 4,5-dihydro-2-(4-hydroxyphenyl)oxazole and 276 g (2.0 mole) milled potassium carbonate in 750 ml acetonitrile was heated to reflux in a 5 liter round-bottomed flask. A total of 457.5 ml (3.0 mole) of 1,6-dibromohexane was added all at once and reflux continued for 1 hour. The reaction mixture was filtered and the cake of inorganic salts washed with 100 ml of acetonitrile. The filtrate was evaporated on a rotary evaporator (bath temperature <40° C.) and the resulting residue slurried in 1.6 liters of hexane and chilled to 0° C. The resulting white solid was filtered and washed with 500 ml cold hexane. The recovery was 263 g (80%) of white solid. A total of 535 g of crude product was slurried in 1.1 liter of refluxing tert-butyl methyl ether. The mixture was allowed to cool to 30° C. and filtered with suction. The filtrate was cooled to 0° C. and the product crystallized. The solid was filtered off and dried to yield 372 g (70% recovery) of 2-[4(6-bromohexyloxy)phenyl]4,5-dihydro-oxazole, m.p. 79°-81° C. The crude product can also be recrystallized from acetonitrile. This removes excess dibromohexane and most of an undesired byproduct formed by reaction of 1 mole of dibromohexane with 2 moles of 4,5-dihydro-2-(4-hydroxyphenyl)oxazole, namely 1,6-bis[4-(4,5-dihydro-2-oxazolyl)phenoxy]hexane, m.p. 174°-175° C. when isolated and purified.