Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH:8]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[OH:9])[CH:7]=1.C1(C)C=CC=CC=1>ClCCl.[O-2].[Mn+4].[O-2]>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:19])=[O:9]
Reactant: Cc1ccc(Br)cc1C(O)c1nc2ccccc2s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(Br)cc1C(=O)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a solution of the above 5-bromo-2-methylphenyl-(benzothiazol-2-yl)methanol (2.60 g) in dichloromethane (30 ml)-toluene (10 ml) was added manganese(IV) oxide (3.42 g), and the mixture was stirred at room temperature for 3 hours. Insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure to give 5-bromo-2-methylphenyl benzothiazol-2-yl ketone (2.45 g) as colorless crystals. APCI-Mass m/Z 332/334 (M+H). (3) The above 5-bromo-2-methylphenyl benzothiazol-2-yl ketone was treated in a manner similar to Reference Example 14-(1) to give 1-(benzothiazol-2-ylmethyl)-5-bromo-2-methylbenzene as oil. APCI-Mass m/Z 318/320 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1.O>CN(C=O)C>[Cl:20][C:21]1[N:22]=[CH:23][N:24]=[C:25]([O:1][C:2]2[CH:3]=[C:4]([CH3:13])[C:5]3[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=3[CH:12]=2)[CH:26]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(O)cc2c1NC(=O)CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2c1NC(=O)CO2
Temperature: 25 °C

Procedure:
0.10 g (0.56 mmol) 7-hydroxy-5-methyl-2H-benzo[b][1.4]oxazin-3(4H)-one and 0.10 g (0.73 mmol) potassium carbonate were placed in 2.0 mL DMF. After 15 min 86 mg (0.56 mmol) 4,6-dichloropyrimidine were added andtmw stirred at RT over the weekend. The reaction mixture was mixed with water, the substance was extracted with ethyl acetate and evaporated down i.vac.
Reaction SMILES: [CH3:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:11]C(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:11][C:2]([CH3:1])([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)C(C)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Product: COC(=O)C(C)(Cl)C(=O)OC
Yield: 99.7 %

Procedure:
In a 10 mL round-bottom flask, a mixture of 1.46 g dimethyl methylmalonate (10 mmol), 1.69 g tetrachloromethane (11 mmol), 0.27 g potassium carbonate (2 mmol), and 63 mg tetra-n-butylammonium fluoride (0.2 mmol) was mixed by a magnetic stirrer at 24° C. for 5 h. The product mixture was filtered, and gas chromatographic analysis of the filtrate showed the presence of 1.8 g of dimethyl α-chloro-α-methylmalonate (99% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH2:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.N1C=CC=CC=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH:28][S:36]([CH3:35])(=[O:38])=[O:37])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethanamine (100 mg, 0.257 mmol) was dissolved in dichloromethane (2.6 mL) and pyridine (0.208 mL, 2.57 mmol) before methanesulfonyl chloride (30 μl, 0.385 mmol) was added and stirred at ambient temperature for 3 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with 1 N HCl (aqueous), washed with 1 N HCl (aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after purification via preparatory LC. MS (ESI) m/z: Calculated: 467.1; Observed: 468.1 (M++H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17](=[O:34])[CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S([O-])(=O)=O.[Ba+2].C1COCC1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.[Pd].C(O)(C)C>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][C:17](=[O:34])[CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)=[CH:21][CH:22]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(C=Cc1ccc(OCc2ccccc2)cc1)C=Cc1ccc(OCc2ccccc2)cc1
Agent: O=[Cr](=O)=O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C(CCc1ccc(OCc2ccccc2)cc1)CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogenation of 24.4 g (54.7 mmol) of 1,5-bis-(4-benzyloxy-phenyl)-penta-1,4-dien-3-one prepared in Example A was effected as described in General Method 3 using 1.0 g 5% Pd over BaSO4 and 1000 mL of THF under hydrogen atmosphere. The product contained both ketone and alcohol. Therefore, the mixture was dissolved in acetone (approximately 500 mL), treated with 10 mL of 8.0N Jones reagent, and stirred overnight at room temperature. Isopropanol was added, and the mixture was filtered through Celite. The filtrate was concentrated to afford the title ketone. 1H NMR (CDCl3) δ 2.67 (m, 4 H), 2.82 (m, 4 H), 5.03 (s, 4 H), 6.88 (d, 4 H), 7.05 (d, 4 H), 7.30-7.43 (m, 10 H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28]>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH:28][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: NCCc1ccccn1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCc3ccccn3)s2)c(C)[nH]c1=O

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (2-pyridin-2-yl)ethylamine as described in Step 5, Example 24 to give the title compound. MS: m/e 404 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[OH:12][C:5]1([CH2:16][N+:13]([O-:15])=[O:14])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1Nc2ccc(I)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 48 h

Procedure:
5-iodoisatin (0.136 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 48 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:54]=[CH:53][C:16]([CH2:17][C:18]4[N:19]([C:31]5[CH:36]=[CH:35][C:34]([N:37]6[S:41](=[O:43])(=[O:42])[N:40]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:39](=[O:52])[CH2:38]6)=[CH:33][CH:32]=5)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=5[Cl:30])[N:22]=4)=[CH:15][CH:14]=3)=[N:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>C(O)(=O)C.O.CCOC(C)=O.[Fe]>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:54]=[CH:53][C:16]([CH2:17][C:18]4[N:19]([C:31]5[CH:36]=[CH:35][C:34]([N:37]6[S:41](=[O:43])(=[O:42])[N:40]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:49])([CH3:50])[CH3:51])[C:39](=[O:52])[CH2:38]6)=[CH:33][CH:32]=5)[CH:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=5[Cl:30])[N:22]=4)=[CH:15][CH:14]=3)=[N:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5=CCCCC5)cn4)cc3)cc2)S1(=O)=O
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5CCCCC5)cn4)cc3)cc2)S1(=O)=O
Temperature: 100 °C

Procedure:
5-{4-[2-[4-(5-Cyclohex-1-enyl-pyridin-2-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (40 mg, 0.05 mmol) was dissolved in 1 mL dry acetic acid, iron powder (−325 mesh, 56 mg, 1 mmol) was added and the mixture was then heated at 100° C. under nitrogen for 2 days. At completion, the reaction mixture was then diluted with water/EtOAc and the leftover iron powder was filtered and washed with EtOAc. The combined organic layer was washed with water, saturated NaHCO3 and brine. The organic layer was then dried over Na2SO4, filtered, and the filtrate was concentrated and purified by silica gel chromatography to afford 5-{4-[2-[4-(5-cyclohexyl-pyridin-2-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: B(F)(F)F.C([NH:12][C@@H:13]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:14](O)[CH2:15][Si](C)(C)C)(OC(C)(C)C)=O.[OH-].[Na+]>CCOCC.C(Cl)Cl>[C:22]1([CH2:21][C@H:13]([NH2:12])[CH:14]=[CH2:15])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(O)C[Si](C)(C)C
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: C=C[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
35.6 ml (0.28 mol) of an approximately 48% solution of boron trifluoride in ether are added at 5° C., over a period of 10 min, to a solution of 18.8 g (0.055 mol) of 3(S)-(Boc-amino)-2(R,S)-hydroxy-4-phenyl-1-trimethylsilyl-butane in 420 ml of methylene chloride. The reaction mixture is then stirred at RT for 16 h, cooled to 10°0 C. and, over a period of 20 min, 276 ml of a 4N sodium hydroxide solution are added. The aqueous phase is removed and extracted twice with 400 ml of methylene chloride each time. The combined organic extracts are washed with brine and dried over sodium sulfate. The title product is further used without additional purification. TLC Rf (C)=0.15; IR (methylene chloride) (cm-1): 3370, 3020, 2920, 1640, 1605.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH:17]3OC(=O)N[CH2:18]3)[CH:14]=2)[NH:9][CH:8]=1)[CH3:4].Cl.NC1C=CC(CC2[O:34][C:33](=[O:35])[NH:32]C2)=CC=1.CN1CCC(C2C3C(=CC=C(CC4COC(=O)N4)C=3)NC=2)CC1.Cl>>[CH3:4][N:3]([CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C@H:17]3[CH2:18][O:35][C:33](=[O:34])[NH:32]3)[CH:14]=2)[NH:9][CH:8]=1)[CH3:2]
Reactant: Nc1ccc(CC2CNC(=O)O2)cc1
Reactant: CN(C)CCc1c[nH]c2ccc(CC3CNC(=O)O3)cc12
Agent: CN1CCC(c2c[nH]c3ccc(CC4COC(=O)N4)cc23)CC1
Agent: Cl
Product: CN(C)CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12

Procedure:
By steps identical to steps (d) to (f) of Synthetic Example 1 and Synthetic Example 2 or steps (d) and (e) of Synthetic Example 1 and Synthetic Example 3 and steps (e) to (h) of Synthetic Example 4, the product from step (a) was converted to (S)-N,N-diemthyl-2-[5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl]ethylamine.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[O:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:5]2[O:6][CH:7]=[C:3]([CH2:2][N:20]3[CH2:25][CH2:24][N:23]([CH2:2][C:3]4[N:4]=[C:5]([C:8]5[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=5)[O:6][CH:7]=4)[CH2:22][CH2:21]3)[N:4]=2)[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: COc1cc(-c2nc(CCl)co2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(-c2nc(CN3CCN(Cc4coc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)co2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)oxazole (124 mg) and piperazine (17 mg) were treated in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[CH2:10][O:11][C:12](=[O:14])[CH3:13].O.CCOCC>CS(C)=O>[C:1]([CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[CH2:10][O:11][C:12](=[O:14])[CH3:13])#[N:2]
Reactant: [C-]#N
Reactant: CC(=O)OCc1ccccc1CCCCl
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)OCc1ccccc1CCCC#N

Procedure:
With exclusion of humidity 12.5 g (0.25 mol) of dry NaCN were heated in 65 ml of anhydrous DMSO to 90° C and at this temperature 44.8 g (0.2 mol) of acetic acid-2-(3-chloropropyl)-benzyl ester were added dropwise. Then the mixture was heated for 50 minutes to 120° C and distributed after cooling between water and ether. The aqueous phase was extracted three times with ether, the organic phase was washed three times with a saturated sodium chloride solution, dried and concentrated under reduced pressure. The product boiled at 128° C/0.2 mm mercury.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1([CH3:19])[CH2:12][C:11](=O)[C:10]2[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:9]=2[O:8]1)[CH3:2].B(F)(F)F.CCOCC.B.C(O)(=O)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1([CH3:19])[CH2:12][CH2:11][C:10]2[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:9]=2[O:8]1)[CH3:2]
Reactant: CCOC(=O)CCC1(C)CC(=O)c2ccc(O)cc2O1
Agent: B
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)CCC1(C)CCc2ccc(O)cc2O1
Reaction time: 0.03 h
Yield: 63.2 %

Procedure:
To a stirred solution of 1.5 g of racemic-3,4-dihydro-7-hydroxy-2-methyl-4-oxo-2H-1-benzopyran-2-propanoic acid ethyl ester in 8 ml of dry tetrahydrofuran, with ice bath cooling, was added 1.4 ml of boron trifluoride etherate, over a period of 2 minutes. The mixture was stirred at 0°-5° C. for 5 minutes whereupon 5.4 ml of 1M borane in tetrahydrofuran was added. Stirring was continued at 0°-5° C. for 2.5 hours then the mixture was decomposed by the addition of glacial acetic acid. Solvents were removed in vacuo then the residue was dissolved in methylene chloride. The solution was washed with sodium bicarbonate solution and brine, then dried, filtered and concentrated under reduced pressure. The residual orange oil (1.4 g) was chromatographed on 50 g of silica gel. Elution with 4:1 hexane-ethyl acetate afforded 0.9 g (63.1%) of racemic-3,4-dihydro-7-hydroxy-2-methyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a colorless oil.
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.[CH3:32][CH:33]1[CH2:38][C:37](=O)[CH2:36][CH2:35][N:34]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.[Cl-].[Na+].O>[C:28]([CH2:27][C:23]1([N:21]2[CH:22]=[C:18]([C:17]3[C:12]4[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:19]=[N:20]2)[CH2:24][N:25]([CH:37]2[CH2:36][CH2:35][N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:33]([CH3:32])[CH2:38]2)[CH2:26]1)#[N:29]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1CC(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (2.6 g, 6.3 mmol) and tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (1.3 g, 6.3 mmol) in THF (30 mL) were added N,N-diisopropylethylamine (4.4 mL, 25 mmol) and sodium triacetoxyborohydride (2.2 g, 10 mmol). The mixture was stirred at room temperature overnight. After addition of 20 mL of brine, the solution was extracted with EtOAc. The extract was dried over anhydrous Na2SO4 and filtered. After removing the solvent, the residue was purified by combiflash chromatography eluting with 30-80% EtOAc in hexanes to give 2.6 g (81%) of the desired product tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-methylpiperidine-1-carboxylate. LC-MS: 607.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:22])[CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1.C(N(CC)CC)C.[C:30]1([CH2:36][C:37]([Cl:39])=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl.CCOCC>O1CCOCC1.CO>[ClH:39].[OH:22][CH:3]([CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1)[CH2:2][NH:1][C:37](=[O:38])[CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NCC(O)CNc1cc(-c2ccccc2)nc2ccccc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(Cc1ccccc1)NCC(O)CNc1cc(-c2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.2 %

Procedure:
To a room temperature solution of (RS)-1-amino-3-(2-phenyl-quinolin-4-ylamino)-propan-2-ol (0.293 g, 1 mmol) and triethylamine (0.42 ml,3 mmol) in dioxane (6 ml) was added a solution of phenylacetylchloride (0.198 ml, 1.5 mmol) in dioxane (1 ml). After stirring for 3 hours at room temperature, the reaction mixture was quenched with H2O and 1N NaOH. The aqueous phase was extracted with CH2Cl2 (5×10 ml). The combined organic phases were dried over Na2SO4, concentrated and chromatographed over silica gel (CH2Cl2—MeOH, 19:1 then 9:1) to provide a yellow oil which was dissolved in MeOH. HCl-Et2O was added to provide (RS)-N-[2-hydroxy-3-(2-phenyl-quinolin-4-ylamino)-propyl]-2-phenyl-acetamide hydrochloride (0.113 g, 25%) as a light yellow foam, MS: m/e=412.3 (M+H+).
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[SH:16].[CH3:17]O>>[CH3:17][O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:7]([Br:6])=[C:8]([SH:16])[CH:9]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)c(S)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)c(S)c1

Procedure:
Conc. H2SO4 (6.25 mL) was added dropwise to a refluxing solution of Example 1b and its dimer (3 g) in dry MeOH (60 mL). The reaction mixture was refluxed for 15 h, concentrated and treated with ice to obtain a mixture of the desired ester and that of its dimer, which was filtered, washed with water and dried. Purification was effected using flash chromatography (silica gel, EtOAc/PE60-80° C.) to obtain the title compound and its dimer ester (2.8 g) which was in turn converted into the title compound as given below: Triphenylphosphine (1.5 g, 5.71 mmol) was added to a solution of the dimer ester in MeOH/H2O (15 mL 4:1, v/v) and allowed to stir overnight at room temperature. The reaction mixture was concentrated, treated with water and extracted with ethyl acetate. The ethyl acetate layer was concentrated and the crude obtained was purified using flash chromatography as above to obtain more of the title compound. Yield: 2.0 g, (72%); mp: 81° C.; 1H NMR (CDCl3): δ 3.90 (s, 3H, OCH3), 4.0 (s, 1H, SH), 7.05-7.25 (m, 3H, Ar); MS: m/e (EI+) 247 (M+).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].[CH3:17][CH:18](O)[CH3:19]>>[CH:18]([O:15][C:5]1[CH:6]=[CH:7][C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])=[CH:9][C:4]=1[C:3]([OH:2])=[O:16])([CH3:19])[CH3:17]
Reactant: CC(C)O
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Product: CNS(=O)(=O)c1ccc(OC(C)C)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example B13(d-e) from 2-Hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 2-Propanol. MS (m/e): 272.2 ([M−H]−, 100%)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:26])[CH2:24]Br)=[CH:19][CH:18]=1.O>CC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:24][C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:26]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C(=O)COc2ccccc2Br)cc1

Procedure:
44.3 g of potassium carbonate were added to a mixture of 34 ml of 2-bromo phenol, 150 ml of acetone and 75 g of 4'-methoxy-2-bromo acetophenone in 150 ml of acetone. The mixture was refluxed for 16 hours and the solution was poured into water. The aqueous phase was extracted with ethyl acetate, dried, filtered and brought to dryness to obtain 101 g of the desired product melting at 104° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:37]([CH2:38][CH3:39])=[CH:36][N:35]=[C:34]([CH3:40])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:38]([C:37]1[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:41])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:18])([F:20])[F:19])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)=[CH:33][C:34]([CH3:40])=[N:35][CH:36]=1)[CH3:39]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)ncc3CC)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)ncc3CC)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(5-ethyl-2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M135) (0.30 g, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (220 mg, 92%).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].C([O:13][C:14]1[CH:19]=[CH:18][C:17]([S+:20]([C:27]2[CH:32]=[CH:31][C:30]([O:33]C(C)(C)C)=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)(C)(C)C.FC(F)(F)S(O)(=O)=O>CO>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[OH:13][C:14]1[CH:19]=[CH:18][C:17]([S+:20]([C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)Oc1ccc([S+](c2ccccc2)c2ccc(OC(C)(C)C)cc2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Product: Oc1ccc([S+](c2ccccc2)c2ccc(O)cc2)cc1
Yield: 94 %

Procedure:
A solution of 55.7 g (0.1 mol) of bis(p-tert-butoxyphenyl)phenylsulfonium trifluoromethanesulfonate and 1.5 g (0.01 mol) of trifluoromethanesulfonic acid in 500 g of methanol was heated at 60° to 70° C. for 7 hours with stirring. The reaction mixture was evaporated in vacuo. The residual oil was washed two times with 100 g of diethyl ether. The amount of this crude product was 42 g (94% yield). Without further purification, the crude product was used in subsequent reaction.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:6]=1[C:7](O)=[O:8])([O:3][CH3:4])=[O:2].B.CSC>C1COCC1>[CH3:4][O:3][C:1](=[O:2])[C:5]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:6]=1[CH2:7][OH:8]
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1C(=O)O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)c(Cl)cc1CO
Temperature: 25 °C
Yield: 16.8 %

Procedure:
To a solution of the product of Step A (1.06 g, 4.28 mmol) in 5 mL of THF at 0° C. was added borane-methyl sulfide (6.42 mL of 2M solution in THF, 12.84 mmol, 3.0 eq). The reaction was allowed to warm to room temperature. After 16 hours the reaction was cooled to 0° C. and quenched with methanol. The volatiles were removed in vacuo and the oil flash chromatographed with 2:1 hexane/ethyl acetate to yield the titled compound (169 mg, 17%). Approximately 80% of the starting material was also recovered.