Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14]O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][Br:40])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(Sc2ccccc2CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(OC)cc(Sc2ccccc2CBr)c1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
2-(3,5-Dimethoxyphenylthio)benzyl alcohol (7.9 g) was dissolved in methylene chloride (40 ml), then triphenylphosphine (11.2 g) and carbon tetrabromide (11.2 g) were added thereto, the mixture was stirred at room temperature for ten minutes, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by a silica gel column chromatography (developing solvent; hexane:ethyl acetate=3:1) to give 2-(3,5-dimethoxyphenylthio)-benzyl bromide (9.53 g, yield of 98%).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:33][O:34][NH2:35])[N:27]([CH2:28][C:29]([CH3:32])([OH:31])[CH3:30])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1>CN(C=O)C>[NH2:14][C:15]1[C:24]2[N:25]=[C:26]([CH2:33][O:34][NH:35][C:11]([CH:8]3[CH2:10][CH2:9]3)=[O:12])[N:27]([CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(O)Cn1c(CON)nc2c(N)nc3ccccc3c21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)Cn1c(CONC(=O)C2CC2)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
Triethylamine (0.634 mL, 4.55 mmol) and cyclopropanecarbonyl chloride (0.248 mL, 2.73 mmol) were added to a solution of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (prepared as described in Example 100, 685 mg, 2.27 mmol) in DMF (5 mL). The cloudy mixture was stirred for 2 hours at room temperature, then was partitioned between water (20 mL) and dichloromethane (30 mL). The aqueous layer was extracted with dichloromethane (2×30 mL). The organic layers were combined and allowed to stand overnight at room temperature. Crystals formed and were isolated by filtration, washed with dichloromethane and acetonitrile, and dried in a vacuum oven to provide 442 mg of N-{[4-Amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}cyclopropanecarboxamide as a hydrate, white crystals, mp 209-210° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N(C)C)=O.[Cl:43][C:44]1[CH:45]=[CH:46][C:47]([F:74])=[C:48]([C:50]2[CH:55]=[CH:54][C:53]([CH2:56][N:57]([CH2:68][C@@H:69](O)[C:70]([OH:72])=[O:71])[NH:58][C:59]([C:61]3[O:65][N:64]=[C:63]([O:66][CH3:67])[CH:62]=3)=[O:60])=[CH:52][CH:51]=2)[CH:49]=1.CCN(C(C)C)C(C)C>>[C:70]([C@H:69]([O:8][C:7](=[O:9])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]([CH3:12])[CH3:11])[CH2:68][N:57]([CH2:56][C:53]1[CH:54]=[CH:55][C:50]([C:48]2[CH:49]=[C:44]([Cl:43])[CH:45]=[CH:46][C:47]=2[F:74])=[CH:51][CH:52]=1)[NH:58][C:59]([C:61]1[O:65][N:64]=[C:63]([O:66][CH3:67])[CH:62]=1)=[O:60])([OH:72])=[O:71]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)O[C@H](CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(OC)no1)C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
(S)-2-Methoxycarbonylamino-3-methylbutyric acid (5.7 mg, 32.3 μmol) and HATU (12.3 mg, 32.3 μmol) were stirred in DMA (1.0 mL, 11 mmol) for 15 minutes. (R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (10.0 mg, 21.6 μmol) and DIPEA (11.3 μL, 64.7 μmol) were added, and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was dissolved in AcOH (1.5 mL), filtered, and purification by reverse phase preparative HPLC to yield the title compound (2.7 mg). MS m/z [M+H]+ calc'd for C28H30ClFN4O9, 621.17. found 621.3.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[NH:8][CH:9]([CH3:11])[CH3:10].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl>C1(C)C(C)=CC=CC=1>[Cl:12][C:6]1[C:7]([NH:8][CH:9]([CH3:11])[CH3:10])=[C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:3]=[N:4][CH:5]=1
Reactant: C1CNCCN1
Reactant: CC(C)Nc1c(Cl)cnnc1Cl
Agent: Cl
Solvent: Cc1ccccc1C
Product: CC(C)Nc1c(Cl)cnnc1N1CCNCC1

Procedure:
A mixture of 3,5-dichloro-4-(1-methylethyl)aminopyridazine (PREPARATION 31, 1.77 g) and piperazine (2.96 g) in xylene (18 ml) is refluxed for 40 hr. The mixture is cooled and then treated with concentrated hydrochloric acid (8 ml). After further cooling, a precipitate forms and the organic liquid is separated. The aqueous phase is diluted with an excess of a solution of aqueous sodium hydroxide (10%) and then is extracted with chloroform (3×). The combined organic extracts are washed with water, then saline, dried over sodium sulfate, and concentrated to an oil. The crude product is flash chromatographed on silica gel eluting with methanol. The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.20, 3.04, 3.18, 4.46, 4.73 and 8.50δ; CMR (CDCl3) 24.0, 44.3, 45.9, 50.2, 118.2, 135.8, 148.3 and 155.4δ.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.N1C=CC=CC=1.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>ClCCl>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19]([CH:16]2[CH2:18][CH2:17]2)=[O:20])=[CH:7][N:6]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)C2CC2)cn1
Reaction time: 1 h

Procedure:
5-Amino-2-methoxy pyridine (12.4 g, 0.10 mol) and pyridine (10 ml) were mixed together in dichloromethane (200 ml) in a reaction flask. Cyclopropane carboxylic acid chloride (9.1 ml, 0.10 mol) was added to the reaction mixture over a period of 2 minutes. The reaction was exothermic and the temperature rose to 34° C. The reaction was allowed to stand for one hour at room temperature, after which the reaction mixture was washed with 5% sodium hydroxide (200 ml) and water (100 ml). The resulting organic phase was separated and dried over anhydrous magnesium sulfate. Crystals formed, so the mixture was filtered and washed with 300 ml of acetone and the filtrate evaporated in vacuo to give a solid that was triturated with hexane to yield 16.7 g, after drying. The product was identified by infrared (IR) and nuclear magnetic spectroscopy (NMR) analysis as the title compound, having a melting pont of 130°-131° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[C:18]([O:20][CH3:21])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Br[CH2:32][CH2:33][OH:34]>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([CH2:32][CH2:33][OH:34])[CH2:14][C@@H:13]1[C:18]([O:20][CH3:21])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: COC(=O)[C@H]1CNCC[C@H]1NC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A mixture of methyl(3S,4R)-4-{[(benzyloxy)carbonyl]amino}piperidine-3-carboxylate (WO 2005/066176) (2.29 g, 7.83 mmol), N,N-diisopropylethylamine (2.05 mL, 11.75 mmol and 2-bromoethanol (0.722 mL, 10.18 mmol) in dry acetonitrile (17 mL) was heated in the microwave at 70° C. for 4.5 hours. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate (200 mL) and washed with saturated aqueous sodium hydrogencarbonate solution (100 mL). The aqueous phase was back extracted once with ethyl acetate (100 mL) and the combined organic phases were dried over sodium sulfate. Chromatography on silica gel with dichloromethane/methanol (12:1) gave 2.0 g (76%), mp 73° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]([O:33]CC)=[CH2:32])CCC.[Cl-].[Li+]>C(#N)C.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>[C:31]([C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1)(=[O:33])[CH3:32]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)ccn23)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: CC(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-[3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (0.1 g, 0.27 mmol), tributyl-(1-ethoxy-vinyl)-stannane (0.091 ml, 0.27 mmol, 1 equiv), lithium chloride (0.034 g, 0.81 mmol, 3 equiv) in acetonitrile (4 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.031 g, 27.2 μmol, 0.1 equiv). The reaction mixture was degassed by bubbling through N2, heated in the microwave at 150° C. for 20 min and filtered through a glass microfibre filter. To the filtrate was added 2N HCl (3 ml) and the mixture stirred vigorously for 2 h at room temperature, neutralised with saturated aqueous NaHCO3, extracted with CH2Cl2, the organics combined dried (MgSO4) and the solvent removed in vacuo. The residue was purified by preparative LC-MS to give the desired product as a yellow solid. MS: [M+H]+ 377
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[F:14][C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][CH:20]=1>>[F:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: Oc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cccc(F)c2)C1
Yield: 98.1 %

Procedure:
The title compound (D47) (294.6 mg) was prepared according to the experimental procedure described in Description 40 starting from (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (200 mg, 1.068 mmol, available at Aldrich#634786) and 3-Fluorophenol (0.096 ml, 1.068 mmol).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[N:13]([CH3:17])[CH2:14][CH2:15]O>C(Cl)Cl.CN(C=O)C>[Br:12][C:10]1[CH:11]=[C:6]([NH2:5])[C:7]([N:13]([CH2:14][CH2:15][Cl:3])[CH3:17])=[CH:8][CH:9]=1
Reactant: CN(CCO)c1ccc(Br)cc1N
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CCCl)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
Thionyichloride (0.78 g, 6.74 mmol) was added dropwise to a solution of 2-((2-amino-4-bromophenyl)(methyl)amino)ethanol (25C) (1.376 g, 5.62 mmol) in DCM (50 mL) and DMF (10 drops) at 0° C. The mixture was allowed to warm up to rt and stirred for 1 hour. Then, the mixture was heated to 35° C. for 2.5 hours, concentrated, diluted with 1N NaOH, and extracted with DCM. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of PE:EtOAc 100:0-85:15, to provide 0.611 g (41%) of the desired product 4-bromo-N1-(2-chloroethyl)-N1-methylbenzene-1,2-diamine (25D): 1H NMR (300 MHz, CDCl3) δ 6.88-6.79 (3H, m), 4.20 (2H, bs), 3.56 (2H, t), 3.17 (2H, t), 2.67 (3H, s).
Reaction SMILES: Cl.[NH:2]1[CH2:6][C@@H:5]([OH:7])[C@H:4]([OH:8])[CH2:3]1.O.C([O-])([O-])=O.[Na+].[Na+].CS(O[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]([N:32]2[CH2:35][CH:34]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][C:47]([CH2:50][CH3:51])=[CH:46][CH:45]=4)=[C:38]([O:52][CH3:53])[CH:37]=3)[CH2:33]2)=[O:31])[CH:25]=1)(=O)=O>C(O)CC>[OH:8][C@H:4]1[C@H:5]([OH:7])[CH2:6][N:2]([CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([C:30]([N:32]3[CH2:33][CH:34]([C:36]4[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]5[CH:45]=[CH:46][C:47]([CH2:50][CH3:51])=[CH:48][CH:49]=5)=[C:38]([O:52][CH3:53])[CH:37]=4)[CH2:35]3)=[O:31])[CH:25]=2)[CH2:3]1
Reactant: O[C@@H]1CNC[C@H]1O
Reactant: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCOS(C)(=O)=O)ccn4)C3)cc2OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCN5C[C@@H](O)[C@H](O)C5)ccn4)C3)cc2OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a mixed solution of (3R,4R)-pyrrolidine-3,4-diol monohydrochloride (2.1 g) in 1-propanol (60 mL)/water (2.0 mL) was added Na2CO3 (4.0 g). The mixture was stirred at 60° C. for 1 hr. To the mixture was added 2-(2-{3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]azetidine-1-carbonyl}pyridin-4-yloxy)ethyl methanesulfonate (6.7 g) prepared in (1). The reaction mixture was stirred at 100° C. for 10 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: chloroform/methanol=40/1 to 5/1) to give the title compound (4.7 g, 70%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[C:12]1(C)C=CC=C[C:13]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C=C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:12]([C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1)=[CH2:13]
Reactant: CC(=O)Nc1ccc(Br)cn1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=Cc1ccc(NC(C)=O)nc1
Temperature: 85 °C
Yield: 1924.4 %

Procedure:
A solution of of N-(5-bromo-pyridin-2-yl)-acetamide (prepared as described in Preparation One, 4.30 g, 20 mmol) in acetonitrile (15 ml) and triethylamine (5.04 ml) was treated with palladium acetate (45 mg, 0.2 mmol) and tri-o-tolylphosphine (203 mg, 0.66 mmol). The mixture was placed in a pressure reactor under 50 psig of ethylene pressure and heated at 85° C. for 66 hours. The reaction mixture was cooled, vented, and partitioned between phosphate buffer (0.1M, pH 6.6) and ethyl acetate. The aqueous phase was extracted with ethyl acetate twice more. The combined ethyl acetate extracts were washed with additional phosphate buffer, brine and dried over sodium sulfate. The extracts were filtered and evaporated to afford 2.06 g (63%) of the title product as a flaky crystalline residue. Recrystallization from ethyl acetate/cyclohexane gave colorless flakes. mp 120-121° C. 1H NMR (CDCl3): δ=8.55 (br, 1H); 8.24 (d, 1H); 8.15 (d, 1H); 7.76 (d of d, 1H); 6.64 (d of d, 1H); 5.73 (d, 1H); 5.28 (d, 1H); 2.19 (s, 3H). MS (CI): m/z=163 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N+:12]=2[O-:18])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](Br)[CH2:20][CH2:21][CH3:22].O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[C:1]1([CH:7]([S:8]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N+:12]=2[O-:18])(=[O:10])=[O:9])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCBr
Reactant: Cc1cc[n+]([O-])c(S(=O)(=O)Cc2ccccc2)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCCC(c1ccccc1)S(=O)(=O)c1cc(C)cc[n+]1[O-]

Procedure:
To a 100 ml round bottom, 3-necked flask equipped with thermometer, stirrer, were charged 0.5 g (3.2 mmoles) 2-(phenylmethylsulfonyl)-4-methylpyridine 1-oxide, 10 ml CH2Cl2, 0.05 g benzyltriethylammonium chloride and 0.75 ml n-butyl bromide. Said mixture also contained about 5 mg (0.28 mmoles) of water. Immediately, a dark red color formed while the reaction mixture was kept at about 15° while stirring. With time, the color faded, and after 3 hours reaction time, the product (2-(1-phenylpentylsulfonyl)-4-methylpyridine 1-oxide) was isolated, having a melting range of 120°-122° C. The product structure was confirmed by NMR and IR analysis.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH3:9])[C:6](Cl)=[O:7])=[O:4].[CH3:10][C:11]1([CH3:21])[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[C:13]=2[O:12]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]([CH3:9])[C:6](=[O:7])[O:20][C:19]1[C:13]2[O:12][C:11]([CH3:21])([CH3:10])[CH2:15][C:14]=2[CH:16]=[CH:17][CH:18]=1)=[O:4]
Reactant: CN(C(=O)Cl)C(=O)CCl
Reactant: CC1(C)Cc2cccc(O)c2O1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C(=O)CCl)C(=O)Oc1cccc2c1OC(C)(C)C2
Yield: 79.4 %

Procedure:
A mixture of 1.0 g (0.006 m) of N-chloroacetyl-N-methylcarbamoyl chloride and 1.0 g (0.006 m) of 2,3-dihydro-2,2-dimethyl-7-benzofuranol in 15 cc dry toluene was stirred under nitrogen and 0.61 g (0.006 m) of triethylamine was added dropwise over a period of 10 mts. The mixture was stirred for an additional period of 2 hrs., filtered through a bed of celite and then the solvent was stripped off under reduced pressure to yield 1.39 g (yield 77%) of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl N-chloroacetyl-N-methylcarbamate, a light yellow oil. NMR (CDCl3): δ 7.3-6.6 (mn,3H); 4.75(s,2H); 3.40 (s,3H); 3.05 (s,2H) and 1.45 (s,6H). IR (CHCl3): ν1760 and 1725 cm-1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12]O.C(Cl)Cl.[Br:17]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[Br:17][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: OCCc1c[nH]c2ccc(F)cc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Fc1ccc2[nH]cc(CCBr)c2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-(5-Fluoro-1H-indol-3-yl)-ethanol (20.0 g, 112 mmol) was dissolved in abs. CH2Cl2 (250 ml), and tetrabromomethane (56.0 g, 170 mmol) was added at RT. Triphenylphosphine (44.0 g, 165 mmol) was then added in portions at RT, while cooling with water. The solution was stirred at RT for 2.5 h and then concentrated i. vac. The residue was absorbed on to silica gel and divided into two equal portions. The crude product was purified by flash chromatography over 2 columns each with 500 g of silica gel and cyclohexane/ethyl acetate (9:1→4:1). Yield: 25.4 g (93%), red solid
Reaction SMILES: [N:1]([CH:4]([CH3:27])[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:9][CH2:8]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH:24]1([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:16]3[N:17]=[C:13]([C@H:10]4[CH2:11][CH2:12][C@H:7]([O:6][CH2:5][CH:4]([NH2:1])[CH3:27])[CH2:8][CH2:9]4)[O:14][C:15]=3[CH:21]=2)[CH2:26][CH2:25]1
Reactant: CC(CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(N)CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-[trans-4-(2-azidopropoxy)cyclohexyl]-6-(cyclopropylmethoxy)-1,3-benzoxazole (249 mg) and triphenylphosphine (353 mg) in THF (4 mL)/water (2 mL) was stirred at 60° C. overnight. The reaction mixture was allowed to cool to room temperature, and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate/methanol) to give the title compound (172 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9](O)=[O:10])=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([Cl:26])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H]([C@H](C(=O)Cl)c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
19.5 g (73.13 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 860 ml of dichloromethane, and 0.5 ml of DMF was added. At from −5° C. to −10° C. (ice/acetone cooling bath), 73 ml (146.26 mmol) of a 2 M solution of oxalyl chloride in dichloromethane were then slowly added dropwise, and the mixture was stirred at this temperature for 1 h. After the reaction had gone to completion, the reaction solution was evaporated under reduced pressure and the residue obtained was taken up in 200 ml dichloromethane and then once more concentrated to dryness. This gave 20.1 g (70.5 mmol, 96% of theory) of the title compound as a colourless oil. Without further purification and without further spectroscopic characterization, the product obtained in this manner was used for subsequent reactions.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9](S(C)(=O)=O)[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1)(=[O:4])=[O:3].C(O)C.CN.FC1C=C(C=CC=1F)CO[C:41]1N=C(NC)C(C2C=CC(Cl)=CC=2)=C(C2C=CC(Cl)=CC=2Cl)[N:42]=1>C(#N)C>[CH3:1][S:2]([C:5]1[N:10]=[C:9]([CH2:41][NH2:42])[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Reactant: CNc1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CN
Solvent: CC#N
Solvent: CCO
Product: CS(=O)(=O)c1nc(CN)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reaction time: 1 h

Procedure:
To a round bottom flask fitted with a magnetic stirrer bar and rubber septum was added 2,4-bis(methylsulfonyl)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]-pyrimidine (Reference Example 5, Step A, 50 mg, 0.1 mmol), and 1 mL each of ethanol and acetonitrile. The mixture was cooled to 0° and methylamine (2 eq., 400 μL, 1M in THF) was added via syringe. The mixture was stirred for 1 h, the solvents removed under reduced pressure and the product chromatographed (77/23 hexanes/ethyl acetate) to give two products: a higher Rf product (unidentified) and 2-(3,4-difluorobenzyloxy)-4-(N-methylamino)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine as the lower Rf product. HPLC/MS: m/e=442 (M+−1); Rt=3.58 min. 1H-NMR 500 MHz (CDCl3): δ 3.13 (d, J=5 Hz, 3H), 3.37 (s, 3H), 7.07 (d, J=8 Hz 1H), 7.10 (d, J=8 Hz, 2H), 7.18 (d, J=8 Hz, 1H), 7.38-7.40 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:10]=[C:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.C([Li])CCC.CN(C)[CH:23]=[O:24]>C1COCC1>[C:11]1(=[CH:10][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[CH:23]=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc(Br)cc1C=C1CCCC1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1C=C1CCCC1
Temperature: 25 °C

Procedure:
4-bromo-2-cyclopentylidenemethylanisole (738 mg, 2.5 mmol) in THF (20 ml) was cooled to -78° C. while stirring under nitrogen. n-Butyllithium (1 ml, 2.5M in Hexane, 2.5 mmol) was added dropwise over 1 minute. N,N-Dimethylformamide (0.5 ml) was added rapidly. The ice bath was removed an the reaction was warmed to room temperature. The reaction was diluted with ethyl acetate (100 ml) and was washed with water (50 ml) and brine (50 ml). The organic was dried over MgSO4, filtered and concentrated. The product was purified via flash chromatography. The yield of the title compound (440 mg, 1.8 mmol) was 72%.