Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:40]=[CH:41][C:42]=1[Cl:43])[O:26][C:27]1[N:32]=[C:31]2[S:33][C:34]([NH:36][C:37](=[O:39])[CH3:38])=[N:35][C:30]2=[CH:29][CH:28]=1>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[C:37]([NH:36][C:34]1[S:33][C:31]2[C:30]([N:35]=1)=[CH:29][CH:28]=[C:27]([O:26][C:25]1[CH:40]=[CH:41][C:42]([Cl:43])=[C:23]([NH:22][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[C:2]=3[Cl:1])[CH:24]=1)[N:32]=2)(=[O:39])[CH3:38]
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(Cl)c(N)c3)nc2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
2-Chloro-3-(1-cyano-1-methylethyl)benzoic acid (120 mg, 0.537 mmol) produced in Example C61(v) was dissolved in tetrahydrofuran (3.0 mL) and N,N-dimethylformamide (0.01 mL), oxalyl chloride (56.87 μL, 0.672 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, toluene (10 mL) was added to the residue, and the mixture was again concentrated under reduced pressure. The residue was dissolved in N,N-dimethylacetamide (3.0 mL), N-[5-(3-amino-4-chlorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]acetamide (90 mg, 0.269 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (80 mL), the organic layer was washed with aqueous sodium hydrogen carbonate solution (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), further purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0→ethyl acetate/methanol=90/10), and crystallized from diethyl ether to give the title compound (81 mg, 56%) as white crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][N:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:6][CH:7]=1.CCO.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=3)=[N:9][N:8]=2)[CH:7]=1
Reactant: FC(F)(F)c1cccc(C=NNc2ccc(I)cn2)c1
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: FC(F)(F)c1cccc(-c2nnc3ccc(I)cn23)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
To a solution of 5-iodo-2-(2-(3-(trifluoromethyl)benzylidene)hydrazinyl)pyridine (1.60 g, 4.09 mmol) in DCM (10 mL)/EtOH (1 mL), was added PhI(OAc)2 (1.845 g, 5.73 mmol). The mixture was stirred at RT for 5 h, then the solvent was removed in vacuo. The residue was dissolved in DCM and purified on SiO2 column chromatography with 80% 15% MeOH/EA in hexane to afford the title compound (1.21 g, 76% yield) as an off-white solid. MS (ES+, m/z): 390.3 (M++1).
Reaction SMILES: [OH-:1].[Na+].BrBr.[Cl:5][C:6]1[C:11]([Cl:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:7]=1[C:14](=[O:16])C.Cl>O.O1CCOCC1>[Cl:5][C:6]1[C:11]([Cl:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:7]=1[C:14]([OH:16])=[O:1]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1Cl
Reactant: [OH-]
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(Cl)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 90.9 %

Procedure:
Sodium hydroxide (45.42 g, 1.090 mol) was dissolved in water (220 ml), and while cooling with ice, bromine (16.85 ml, 0.327 mol) was dripped therein over a period of 5 minutes. After stirring the reaction solution at 0° C. for 15 minutes, a dioxane (220 ml) solution of 2′,3′,4′-trichloroacetophenone (24.40 g, 0.109 mol) was dripped therein at 0° C. over a period of 30 minutes. After stirring at room temperature for 14 hours, water (350 ml) was added and then washed with dichloromethane (350 ml). The aqueous layer obtained was gradually made acidic with concentrated hydrochloric acid while cooling with ice and the resulting crystals were filtered out. After washing the filtered-out crystals with water, the water was removed by azeotropic distillation with toluene. 22.33 g (91%) of the title compound was thereby obtained as a pale yellow powder.
Reaction SMILES: [CH2:1]1[O:6][C:4](=[O:5])[NH:3][CH:2]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.[Br:19][CH2:20][C:21](Br)=[O:22].CCOC(C)=O.CCCCCC>C1COCC1.C(OCC)(=O)C>[CH2:7]([C@H:2]1[CH2:1][O:6][C:4](=[O:5])[N:3]1[C:21](=[O:22])[CH2:20][Br:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Br)CBr
Reactant: O=C1NC(Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(CBr)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a solution of S-(−)-4-benzyl-2-oxazolidinone (20.0 g, 112.86 mmol) in THF (200 mL) was added nBuLi (2.5M in hexanes, 47.4 mL, 118.51 mmol) dropwise at −78° C. The solution was stirred at −78° C. for 30 min followed by the addition of bromo acetyl bromide (25.0 g, 10.81 mL, 124.15 mmol). The solution was allowed to warm to 25° C. overnight (19 h). An aliquot was taken and TLC (1:2 EtOAc-hexane) indicated that the reaction was complete. It was diluted with ethyl acetate (200 mL) and the organic layer was washed with saturated aqueous NaHCO3 (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude brown oil (34 g). The crude product was purified by flash chromatography, eluent: 1:4 EtOAc-hexane, to furnish (4S)-4-benzyl-3-(bromoacetyl)-1,3-oxazolidin-2-one as a colorless oil (33.2 g, 98.6%). Mass Spectrum (−ESI): 297 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[CH:43]1([CH2:46][NH:47][CH3:48])[CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:47]([CH2:46][CH:43]1[CH2:45][CH2:44]1)[CH3:48])=[O:25]
Reactant: CNCC1CC1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN(CC1CC1)C(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and cyclopropylmethyl-methylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:19][CH:18]=[C:17]([CH2:20][F:21])[C@@H:7]2[C@H:8]([O:11]C(OCC)C)[O:9][CH:10]=1)=[O:4].Cl.O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:19][CH:18]=[C:17]([CH2:20][F:21])[C@@H:7]2[CH:8]([OH:11])[O:9][CH:10]=1)=[O:4]
Reactant: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC=C(CF)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1=COC(O)[C@H]2C(CF)=CC[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
670 mg of the above (1S,4aS,7aR)-1-[1-(ethoxy)ethoxy]-7-(fluoromethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyrane-4-carboxylic acid methylester were dissolved in tetrahydrofuran followed by addition of 2N aqueous hydrochloric acid and stirring for 2 hours at room temperature. The reaction mixture was neutralized after adding water, and then extracted with ethyl acetate. After washing the organic phase with brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a pale yellow oil from the hexane-ether eluate in the form of (4aS,7aR)-7-(fluoromethyl)-1-hydroxy-1,4a,5,7a-tetrahydrocyclopenta[c]pyrane-4-carboxylic acid methylester (500 mg, yield: 98%). The physicochemical properties of this compound are described below.
Reaction SMILES: [CH2:1]([O:10][C:11](=[O:37])[CH:12]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])=[CH:23][CH:22]=1)[NH:13]C(OC(C)(C)C)=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[BrH:38].C(O)(=O)C>C(OCC)(=O)C>[BrH:38].[CH2:1]([O:10][C:11](=[O:37])[CH:12]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30])=[CH:23][CH:22]=1)[NH2:13])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCC(=O)c1ccccc1)c1ccc(OCC(=O)c2ccccc2)cc1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC(C(=O)OCC(=O)c1ccccc1)c1ccc(OCC(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of N-tert-butoxycarbonyl-2-(4-phenacyloxyphenyl)glycin phenacyl ester (1.0 g.) in ethyl acetate (10 ml.) was added a mixture of hydrobromic acid and acetic acid (2 ml., 4:1 v/v), and then the mixture was stirred for half an hour at ambient temperature. The precipitates were collected by filtration and washed with ethyl acetate to give 2-(4-phenacyloxyphenyl)glycine phenacyl ester hydrobromide (830 mg.), which was recrystallized from a mixture of ethanol, methanol and diethyl ether to give the pure crystals (550 mg.), mp 176° to 177° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH3:7][N:8]([CH3:10])[CH3:9]>>[Cl-:1].[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][N+:8]([CH3:10])([CH3:9])[CH3:7]
Reactant: CN(C)C
Reactant: OCC(O)CCl
Product: C[N+](C)(C)CC(O)CO
Product: [Cl-]
Reaction time: 24 h

Procedure:
To 251 mL of 3-chloro-1,2-dihydroxypropane is added to a round bottom flask equipped with a stir bar, thermometer, and condenser. 837 mL of 25% aqueous trimethylamine is added to the reactor while stirring. The solution is allowed to stir for 16 hours at 15° C. The solution is sparged with nitrogen for six days during which time the pH decreases from about 11 to about 6. The solution is placed under reduced pressure of approximately 25 inches Hg for 24 hours at 65° C. The solution is then placed under reduced pressure of 30 inches of Hg for eight hours at 65° C. 200 mL of isopropanol is added to the solution and the product crystallizes. The product is filtered and placed in a nitrogen dry box for 24 hours and then in a vacuum oven at about 60° C. and at reduced pressure of 26 inches of Hg with a nitrogen sweep for 36 hours. The product is placed in a nitrogen dry box for 24 hours. The product is analyzed for trimethylamine via GC headspace analysis and 3.2 ppm trimethylamine is found. Analysis by HPLC showed 100.0% purity of the 2,3-dihydroxyropyltrimethylammonium chloride. The isolated product has the following structure:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([OH:31])=O)[CH:22]=2)=[N:8][CH:7]=1)=[O:5])C.C(Cl)Cl.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[C:9]([C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29](=[O:31])[N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:22]=1)=[N:8][CH:7]=[C:6]2[C:4]([OH:3])=[O:5]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OCC(=O)O)c2)c2cc(OC)c(OC)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCCC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
The above 1-(3-carboxymethoxybenzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (88.5 mg, 0.19 mmol) was suspended in 8 ml of methylene chloride containing 10 equivalent of pyrrolidine, 2.0 equivalent of HBTU and 3.0 equivalent of triethylamine. The mixture was stirred at room temperature overnight and then evaporated to remove solvents. The residue was extracted with ethyl acetate and water. The organic layer was dried and solvents were evaporated. The residue was dissolved in 4 ml of methanol and aqueous lithium hydroxide was added (0.5N, 1 ml). The mixture was stirred overnight until all starting material disappeared. The reaction was loaded to a preparative HPLC for purification to give 6,7-Dimethoxy-1-[3-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzoyl]-isoquinoline-4-carboxylic acid as a fluffy solid (29 mg, 33%). ES-MS calcd for C25H24N2O7 (m/e) 464.5, obsd 465.4 (M+H).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:20]CCl>>[ClH:20].[NH:10]1[CH2:11][CH2:12][CH:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCOCC2)CC1
Reactant: ClCCl
Product: C1CC(N2CCOCC2)CCN1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride was bubbled through an ice-cooled solution of tert-butyl 4-(4-morpholinyl)-1-piperidinecarboxylate (J.O.C. 1990; 55(8); 2552) (6.5 g, 24 mmol) in dichloromethane (100 ml), and the solution then stirred at 0° C. for 2 hours. The reaction was degassed under nitrogen, allowed to warm to room temperature, and evaporated under reduced pressure to afford the title compound as a white solid, 5.91 g.
Reaction SMILES: Cl[CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].[NH3:12]>C1(C)C=CC=CC=1>[NH2:12][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11]
Reactant: N
Reactant: CCCC1CC(=O)N(CCl)C1
Solvent: Cc1ccccc1
Product: CCCC1CC(=O)N(CN)C1
Temperature: 25 °C

Procedure:
A solution of 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (41.34 g, 0.235 mol) in toluene (350 ml) is added dropwise at −78° C. to liquid ammonia (300 ml). At the end of the addition, the temperature is raised slowly to room temperature, and ammonia of the crude mixture is allowed to distill at room temperature overnight. Filtration of the reaction mixture and subsequent evaporation lead to 55 g of the crude 1-(aminomethyl)-4-propylpyrrolidin-2-one x76 which is used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:14][C:15]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][NH:35][CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][N:35]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:22][CH2:23]1.[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CNCC4)CC2)c(F)c1
Reactant: CN(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CN(C(=O)N(C)C)CC4)CC2)c(F)c1
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (4.9 mg, 0.046 mmol) was added to a solution of 2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (12.1 mg, 0.023 mmol) and triethylamine (10 μL, 0.069 mmol) in DCM (230 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (12.1 mg, 88%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.27-1.32 (m, 6H), 1.89-1.99 (m, 2H), 2.06-2.15 (m, 2H), 2.81 (s, 2H), 2.91 (s, 6H), 3.00-3.09 (m, 2H), 3.39-3.46 (m, 2H), 3.55 (t, J=5.8 Hz, 2H), 3.75 (s, 3H), 4.13 (quin, J=6.4 Hz, 1H), 4.30 (s, 2H), 4.34-4.40 (m, 1H), 6.67 (ddd, J=8.9, 3.0, 1.5 Hz, 1H), 6.74 (dd, J=12.8, 2.9 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 487.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][NH:6][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:2].CN1C=CN=C1.[C:33](Cl)(=[O:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].C(N(CCCC)CCCC)CCC>[Ti](Cl)(Cl)(Cl)Cl.O.ClC1C=CC=CC=1>[C:7]([NH:6][CH:5]([C:33](=[O:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:4]([O:3][CH2:1][CH3:2])=[O:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCC(=O)OCC
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: Clc1ccccc1
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: CCCCCCCCCCCCCCCCCC(=O)NC(C(=O)CCCCCCCCCCCCCCC)C(=O)OCC
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
A chlorobenzene solution (33.0 ml) of N-octadecanoylglycine ethyl ester (2.00 g, 5.41 mmol) and N-methylimidazole (533 mg, 6.49 mmol) was cooled to −10° C., and palmitoyl chloride (1.49 g, 5.41 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 45 minutes at the same temperature, titanium tetrachloride (3.60 g, 18.94 mmol) and tributylamine (4.01 g, 21.64 mmol) were added thereto. The resulting mixture was stirred for 1.5 hours at −10° C. After water (25 ml) was added thereto and the mixture was heated to room temperature, the organic layer was separated. It was confirmed by comparative analysis with sample product using HPLC that the organic layer contained 2.52 g of the title compound (yield: 77%).
Reaction SMILES: Cl.[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH2:12])[CH2:9]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[C:24]([CH3:31])[CH:23]=1>C(O)C>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][C:24]=1[CH3:31])=[O:30])[CH2:9]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: COc1ccc(N=C=O)c(C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(NC(=O)NC2C3CC4CC(C3)CC2C4)c(C)c1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A mixture of 2.5 g (13.3 mmol) of 2-adamantylamine hydrochloride, 1.84 ml (13.3 mmol) of triethylamine in 50 ml of ethanol was heated under reflux. Then 1.94 ml (13.3 mmol) of 4-methoxy-2-methylphenylisocyanate was added and the mixture was stirred under reflux for 2 h. After cooling at room temperature the precipitate was filtered, washed with ethanol and dried under vacuum to give 4.2 g (61%) a white solid.
Reaction SMILES: Cl.[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH2:22])[S:19][CH:20]=1.C(N(CC)CC)C.[CH3:30][O:31][C:32](Cl)=[O:33]>O1CCOCC1>[CH:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([CH2:21][NH:22][C:32](=[O:33])[O:31][CH3:30])[S:19][CH:20]=1
Reactant: NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)NCc1nc(-c2ccc3c(c2)Nc2ccccc2S3)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
The compound of Example 362 (0.622 g; 2.0 mmol) is dissolved in dioxane (100 ml) cooled down to 0° C. Triethylamine is added, then, dropwise, methylchloroformate (2.5 mmol). The reaction medium is then stirred for 3 hours at ambient temperature before being poured into ice-cold water and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated under vacuum. The expected product is purified on a silica column (eluent: 10% acetone in dichloromethane). The pure fractions are combined and the solvents are evaporated off in order to produce an off-white solid with a yield of 46.0%. Melting point: 151-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>ClCCl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1c(F)cccc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
2-(2-chloro-6-fluorophenyl)ethanol (500 mg, 2.87 mmol), was dissolved in dichloromethane (20 mL), and triethylamine (870 mg, 8.61 mmol) was added to the reaction mixture. The solution was cooled to 0° C. and methanesulfonyl chloride (492 mg, 4.31 mmol) was added slowly. After the addition was complete, the reaction was stirred at 0° C. for 15 min and at room temperature for 4 hours. Water was slowly added and the solution was extracted with dichloromethane. The organic layer was washed with brine, and dried over sodium sulfate and concentrated in vacuo to give the residue 2-chloro-6-fluorophenethyl methanesulfonate (52) as a clear oil.
Reaction SMILES: [N:1]1([C:7]([C:9]2([C:15]3[CH:31]=[CH:30][C:18]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:17][CH:16]=3)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[C:34](O)(=O)C>C(Cl)Cl>[CH3:34][N:4]1[CH2:3][CH2:2][N:1]([C:7]([C:9]2([C:15]3[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:30][CH:31]=3)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[O:8])[CH2:6][CH2:5]1
Reactant: CC(=O)O
Reactant: O=C(N1CCNCC1)C1(c2ccc(OCCCN3CCCOCC3)cc2)CCOCC1
Agent: C=O
Solvent: ClCCl
Product: CN1CCN(C(=O)C2(c3ccc(OCCCN4CCCOCC4)cc3)CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
4-(3-{4-[4-(piperazin-1-ylcarbonyl)tetrahydro-2H-pyran-4-yl]phenoxy}propyl)-1,4-oxazepane (45 mg, 0.1 mmol) was dissolved in DCM (3 ml), to which was added formaldehyde (37% w/w in H2O, 12 mg, 0.12 mmol) and acetic acid (8 mg, 0.12 mmol) and was stirred at room temperature for 30 minutes before adding STAB (25 mg, 0.12 mmol). The solution was allowed to stir for a further 45 minutes before washing the solution with saturated sodium bicarbonate (10 ml), followed by brine (10 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the title compound as a white solid (25 mg, 56%). 1H NMR (400 MHz, d6-DMSO) δ 1.76-2.13 (m, 11H), 2.55-2.78 (m, 6H), 3.16-3.39 (m, 8H), 3.50-3.62 (m, 4H), 3.63 (m, 2H), 3.72 (M, 2H), 3.99 (t, 2H), 6.92 (d, 2H), 7.12 (d, 2H). LRMS ESI+ m/z 446 [MH]+.