Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CCOCC>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:20]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
To a solution of phenol (1.88 g, 20.0 mmol) in DMF (40 mL) is added potassium carbonate (3.03 g, 22.0 mmol) and ethyl bromoacetate (2.34 mL, 21.0 mmol), and the mixture is stirred at 70° C. for 18 h. The mixture is cooled to RT, Et2O is added, and the mixture is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is vacuum distilled to give 3.39 g of the product 430.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1.[CH:20]1([CH2:23][NH:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][N:24]([CH2:25][CH2:26][O:27][CH3:28])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][N:15]=[CH:14]4)=[O:9])[CH:3]=2)[CH2:22][CH2:21]1
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1
Reactant: COCCNCC1CC1
Product: COCCN(CC1CC1)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (1H-indazol-5-yl)-amide (Intermediate 16) and N-(cyclopropylmethyl)-2-methoxyethanamine, the title compound was obtained as a beige solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[CH:23])[CH:17]=1)#[CH:15]>>[C:14]([C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=2)[CH:19]=[CH:20][CH:21]=1)#[CH:15]
Reactant: COC(=O)CCc1ccc(I)cc1
Reactant: C#Cc1cccc(C#C)c1
Product: C#Cc1cccc(C#Cc2ccc(CCC(=O)OC)cc2)c1

Procedure:
The title compound was prepared from methyl 3-(4-iodophenyl)propanoate (120 mg, 0.41 mmol) and 1,3-diethynylbenzene (0.06 mL, 0.45 mmol) according to the general procedure IC, with the exception that the reaction was performed at room temperature, to give 52 mg (43%) of an yellow-brown gummy oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:3). Rf: 0.41 (EtOAc:hexanes, 1:2); 1HNMR (CDCl3) δ 7.65 (s, 1H), 7.49-7.42 (m, 4H), 6.31-7.29 (m, 1H), 7.19-7.17 (m, 2H), 3.67 (s, 3H), 3.09 (s, 1H), 2.99-2.93 (t, 2H, J=7.8 Hz), 2.66-2.61 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 173.0, 141.1, 135.0, 131.8, 131.7, 128.4, 123.7, 122.4, 120.8, 90.0, 88.0, 82.8, 77.7, 51.6, 35.3, 30.8; EI-MS m/z 288 (M+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A solution of 2-bromo-1-(4-fluorophenyl)ethanone (5.00 g, 23.0 mmol) and potassium thiocyanate (2.24 g, 23.0 mmol) in ethanol (50 ml) was stirred at 80° C. for 3 hours. After cooling to room temperature, water (60 ml) was poured into the reaction solution, and a crystal was separated by filtration, which was washed with 50% aqueous ethanol solution to give the desired product (3.71 g, 82.5%) as a solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11](=[O:35])[CH2:12][C@@H:13]([NH:15][C@@H:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:20]=1[F:34])[CH2:17][CH3:18])[CH3:14])(C)(C)C.Cl.C(OCC)C>C(OCC)(=O)C>[NH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:35])[CH2:12][C@H:13]([NH:15][C@@H:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:20]=1[F:34])[CH2:17][CH3:18])[CH3:14]
Reactant: CC[C@@H](N[C@@H](C)CC(=O)NCCNC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC[C@@H](N[C@H](C)CC(=O)NCCN)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Reaction time: 0.33 h

Procedure:
To (2-{(S)-3-[(R)-1-(3-benzoyl-4-chloro-2-fluoro-phenyl)-propylamino]-butyrylamino}-ethyl)-carbamic acid tert-butyl ester (13 mg, 0.025 mmol) residue was added hydrogen chloride in ethyl acetate (2N, 2 ml). The mixture was stood at room temperature for 20 minutes, diethyl ether was added to precipitate solids. These were isolated by filtration and dried in a vacuum oven to furnish the desired material as a white solid
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].Cl.[NH2:28]O.Cl>CO.CO.O.O>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:28][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](CCC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1CCC(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
A solution of cis-methyl 2-(3,3-dimethylbutyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.78 g, 5.22 mmol) in MeOH (3.9 mL) was added to a solution of NaOH (288 mg, 7.2 mmol) in MeOH/H2O (4.4 mL/0.3 mL) at −30° C. After 10 min was added hydroxylamine hydrochloride (726 mg, 10.45 mmol) and NaOH (418 mg, 10.45 mmol) in MeOH (5.2 mL) and H2O (5.2 mL). Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (7.7 mL) at 80° C. and heated at 80° C. for 1 h. Concentration of the organic solvent and extraction with DCM (×2), drying using a phase separator and evaporation gave an orange oil. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 30-60% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,3-dimethylbutyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (717 mg, 44%) was isolated. 1H NMR (400 MHz, cdcl3) δ 0.79 (s, 9H), 1.01-1.19 (m, 2H), 1.23-1.48 (m, 2H), 1.83-1.96 (m, 2H), 1.98-2.11 (m, 2H), 2.94-3.04 (m, 1H), 3.09-3.19 (m, 1H), 3.70 (s, 3H), 3.91-4.06 (m, 2H), 5.71 (d, 1H). MS m/z 311 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][O:21][CH3:22])[C:15]2=[O:23])=[CH:9][N:8]=1)[CH3:3].[Cl:24][C:25]1[S:29][C:28]([O:30][CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Cl:24][C:25]1[S:29][C:28]([O:30][CH2:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][C:10]3[CH:9]=[N:8][C:7]([NH:6][CH2:5][CH2:4][N:2]([CH3:1])[CH3:3])=[N:12][CH:11]=3)[C:15](=[O:23])[C@@H:16]2[CH2:20][O:21][CH3:22])=[O:33])=[CH:27][CH:26]=1
Reactant: COC[C@@H]1NCCN(Cc2cnc(NCCN(C)C)nc2)C1=O
Reactant: O=C(O)COc1ccc(Cl)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC[C@H]1C(=O)N(Cc2cnc(NCCN(C)C)nc2)CCN1C(=O)COc1ccc(Cl)s1
Reaction time: 12 h

Procedure:
The title compound can be prepared by placing 1-[(2-{[N,N-dimethylaminoethyl]-amino}-pyrimidin-5-yl)-methyl]-3-(S)-methoxymethyl-piperazine-2-one, (5-chloro-thiophen-2-yloxy)-acetic acid, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate and triethylamine in DMF and stirring 8-16 h. The mixture is evaporated and is diluted with ethyl acetate. The organic phase is washed with water, 2 N HCl, 1 N NaOH and brine, is dried (MgSO4) and is evaporated. The residue is purified by flash chromatography (silica gel, 4:1 ethyl acetate/hexanes) to provide the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH:11]([CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)C>CCOCC>[OH:9][CH2:10][CH:11]([CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)CCCc1cc(OC)c(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cc(CCCC(CO)CCCc2ccccc2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 2.00 mL, 2.00 mmol) was added dropwise to a solution of ethyl-2-(3-phenylpropyl)-5-(3,4,5-trimethoxyphenyl)pentanoate (1.39 g, 3.36 mmol) in ether (30 mL) at 0° C. After 30 min., a second aliquot of lithium aluminum hydride (1.0 M in tetrahydrofuran, 1.00 mL, 1.00 mmol) was added and the resulting solution was stirred for 30 minutes. Rochelles salt (1 M, 40 mL) was added and the mixture was stirred vigorously for 1.5 h. The aqueous layer was extracted with ether and the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified silica gel chromatography, eluting with 50% ethyl acetate/hexanes, to yield 4-hydroxymethyl-7-phenyl-1-(3,4,5-trimethoxyphenyl)heptane (1.23 g, 98%). 1H NMR (300 MHz, CDCl3): δ 1.36 (m, 5 H), 1.60 (m, 5 H), 2.56 (t, 2 H, J=7.7), 2.63 (t, 2 H, J=7.7), 3.58 (d, 2 H, J=5.3), 3.84 (s, 3 H), 3.86 (s, 6 H), 6.40 (s, 2 H), 7.25 (m, 5 H).
Reaction SMILES: [F:1][C:2]([F:25])([C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:3][CH2:4][Si:5]([CH3:8])([CH3:7])Cl.[C:26]([Mg]Br)#[CH:27]>C1COCC1>[F:1][C:2]([F:25])([C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:3][CH2:4][Si:5]([C:26]#[CH:27])([CH3:8])[CH3:7]
Reactant: C[Si](C)(Cl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#C[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Yield: 95.9 %

Procedure:
In an oven-dried 250-mL round bottom flask, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyldimethylchlorosilane (9.67 g, 21.9 mmol) was dissolved in 20 mL anhydrous THF. Ethynylmagnesium bromide (50 mL, 25 mmol, 0.5 M in THF) was added and the mixture was heated to 60° C. for 12 hr. After allowing the mixture to cool to room temperature, the reaction was quenched by the dropwise addition of water, followed by the addition of dilute sulfuric acid to dissolve the magnesium salts. The organic layer was separated, washed with water (3×20 mL) and brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product was purified by chromatography on silica gel using hexane as an eluant. Removal of solvent yielded 9.0 g (21 mmol, 96%) of the product as a colorless liquid. Analysis of the colorless product provided the following data: 1H-NMR (200 MHz, CDCl3) δ=2.4 (s, 1H), 2.1 (m, 2H), 0.8 (m, 2H), 0.2 (s, 6H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][C:20]3=[O:28])[CH2:16][CH2:17][C@H:10]2[CH2:9]1)(OC(C)(C)C)=O.[ClH:29]>C(Cl)(Cl)Cl.C(OCC)C>[ClH:29].[ClH:29].[CH2:9]1[NH:8][CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][C:20]3=[O:28])[CH2:16][CH2:17][C@@H:10]12
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](CN3C(=O)Cc4ccccc43)CC[C@H]2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C1Cc2ccccc2N1C[C@@H]1CC[C@H]2CNCCN2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 0.53 g (1.38 mmol) of 1-[(7R,9aS)-2-BOC-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazin-7-ylmethyl]-1,3-dihydro-indol-2-one in 10 mL of chloroform was treated with excess HCl(g) in ethyl ether and stirred at room temperature for 1 h. The solvent was evaporated to give 0.49 g (100%) of 1-[(7R,9aS)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazin-7-ylmethyl]-1,3-dihydro-indol-2-one dihydrochloride.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[S:3]([C:6]1[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=1)(=[O:5])=[O:4].[CH3:15][C:16]([CH3:26])([CH:20]1[O:24][CH:23]([CH3:25])[CH2:22][O:21]1)[CH2:17][NH:18][CH3:19]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:14])[S:3]([C:6]1[S:10][C:9]([NH:11][C:12]([N:18]([CH2:17][C:16]([CH3:15])([CH3:26])[CH:20]2[O:24][CH:23]([CH3:25])[CH2:22][O:21]2)[CH3:19])=[O:13])=[N:8][N:7]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1nnc(N=C=O)s1
Reactant: CNCC(C)(C)C1OCC(C)O1
Solvent: CCOC(C)=O
Product: CC1COC(C(C)(C)CN(C)C(=O)Nc2nnc(S(=O)(=O)N(C)C)s2)O1

Procedure:
5-(N,N-Dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl isocynate dimer (6 grams) N-[2,2-dimethyl-2-(4-methyl-1,3-dioxolan-2-yl)ethyl]methylamine (6 grams) and ethyl acetate (20 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer. The reaction mixture is heated on a steam bath for a period of about 2 hours. Solvent is then stripped off using a rotary evaporator to yield the desired product N-[5-(N,N-dimethylaminosulfonyl)-1,3,4-thiadiazol-2-yl]-N'-[2,2-dimethyl-2-(4-methyl-1,3-dioxolan-2-yl)ethyl]-N'-methylurea as the residue.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][NH2:12].C(N(CC)CC)C.Cl[C:21]([O:23][CH3:24])=[O:22]>C1COCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][NH:12][C:21](=[O:22])[O:23][CH3:24]
Reactant: COc1cc(Cl)c(Cl)c(CN)c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NCc1cc(OC)cc(Cl)c1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A stirred solution of 54.0 grams (0.262 mole) of 2,3-dichloro-5-methoxy-phenylmethylamine and 27.0 grams (0.267 mole) of triethylamine in 1000 mL of THF was cooled below 5° C., and 24.8 grams (0.262 mole) of methyl chloroformate was added dropwise at a rate to maintain the reaction mixture temperature below 5° C. Upon completion of addition, the reaction mixture was stirred at about 5° C. for one hour, then it was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time thin layer chromatographic (TLC) analysis of the reaction mixture indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to a residue, which was then shaken with ethyl acetate and water. The aqueous layer was washed with ethyl acetate, and the wash was combined with the original organic layer. The combination was then washed with one portion of water and one portion of an aqueous saturated sodium chloride solution. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding 66.0 grams (95.3% yield) of the subject compound, mp 90°-91° C. (99% pure by gas chromatographic (GC) analysis). The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH3:23])[N:14]=2)[CH3:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:24]I.[H-].[Na+]>CN(C=O)C>[CH3:23][C:15]1[N:14]=[C:13]([N:11]([C:8]2[CH:9]=[CH:10][C:5]([N:4]([CH3:24])[C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH3:12])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: CI
Reactant: CC(=O)Nc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 600 %

Procedure:
To a solution of (4-acetamido-phenyl)-(2-methyl-quinazolin-4-yl)-methylamine (231 mg, 0.075 mmol) in 5 mL of DMF was added methyl iodide (0.9 g, 6.3 mmol) and the mixture was cooled to 0° C. Sodium hydride (60% oil suspension, 75 mg, 1.9 mmol) was added, and the mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched by adding 50 uL of water, diluted with 25 mL of ethyl acetate, washed with water (25 mL×3) and saturated NaCl. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by chromatography (90% ethyl acetate/hexanes) to give the title compound (143 mg, 0.45 mmol, 59%). 1H NMR (CDCl3): 7.19 (d, J=8.1, 1H), 7.54 (ddd, J=8.4, 6.6, 1.8, 1H), 7.16 (s, broad, 4H), 6.97-7.09 (m, 2H), 3.66 (s, 3H), 3.28 (s, 3H), 2.76 (s, 3H), 1.92 (s, 3H).
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].ON1C2C=CC=CC=2N=N1.[OH:60][CH2:61][C@@H:62]([C@@H:64]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[OH:67])[OH:65])[NH2:63].C(N=C=NC(C)C)(C)C.Cl>C(Cl)(Cl)Cl>[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:63][C@H:62]([C@@H:64]([C@@H:66]([CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[OH:67])[OH:65])[CH2:61][OH:60])=[O:49])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
A mixture of 27-oleoyloxyheptacosanoic acid (2 g, 2.9 mmoles), chloroform (76 ml), dried 1-hydroxybenzotriazole (1.28 g, 10.9 mmoles), phytosphingosine (1.23 g, 3.9 mmoles) and N,N'-diisopropylcarbodiimide (0.88 ml, 5.64 mmoles) was stirred under nitrogen for 24 hours at room temperature. After adding 50 ml of a 1N hydrochloric acid solution and stirring the organic layer was filtrated, washed with brine and concentrated. The title product (2.07 g) was obtained by crystallization from hot isopropanol (50 ml).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:37][N:38]([CH3:43])[CH:39]1[CH2:42][NH:41][CH2:40]1.C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:41]4[CH2:42][CH:39]([N:38]([CH3:43])[CH3:37])[CH2:40]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)C1CNC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CC(N(C)C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (30.0 mg, 0.058 mmol) and 3-(dimethylamino)azetidine dihydrochloride (30.2 mg. 0.174 mmol) in 1,4-dioxane (1 mL) was added triethylamine (58.8 mg, 81.0 μL, 0.581 mmol). The reaction mixture was heated at 50° C. for 1 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C30H35ClN5O3S (M+H+): 580.2; Found: 580.1 (M+H+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18](Cl)=[C:13]3[C:12]([Br:20])=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CCN(C(C)C)C(C)C>CC(O)C>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:18]2[N:17]=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[N:11]=[C:12]([Br:20])[C:13]=23)[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=S(=O)(c1ccccc1)n1nc(Br)c2c(Cl)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2c(Br)nn3S(=O)(=O)c2ccccc2)CC1
Temperature: -10 °C
Yield: 67.7 %

Procedure:
A solution of 1-Benzenesulfonyl-3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.8 g, 4.8 mmol), Boc-piperazine (1.4 g, 7.2 mmol) and DIPEA (2.1 mL, 12 mmol) in IPA (40 mL) was stirred and heated at reflux overnight. The reaction mixture was cooled to −10° C., the solids isolated by vacuum filtration, rinsed with cold IPA and dried further on high vacuum line to give 4-(1-Benzenesulfonyl-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.7 g, 67%) as a white powder. LCMS (APCI+) m/z 523 and 525 [M+H]+; Rt: 3.57 min. 1H NMR (CDCl3, 400 MHz) δ 8.53 (1H, s), 8.23 (2H, d, J 8.5 Hz), 7.65 (1H, t, J 6.9 Hz), 7.54 (2H, t, J 7.8 Hz), 3.82-3.79 (4H, m), 3.60-3.57 (4H, m), 1.48 (9H, s.)
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[O-:12][S:13]([O-:15])=[O:14].[Na+].[Na+].O>CCO>[CH3:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[S:13]([OH:15])(=[O:14])=[O:12]
Reactant: O=S([O-])[O-]
Reactant: Cc1cccc([N+](=O)[O-])c1F
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccc([N+](=O)[O-])c1S(=O)(=O)O
Yield: 205.9 %

Procedure:
In a similar fashion using route 39 general procedure 95, 2-fluoro-3-nitrotoluene (2.5 g 16.1 mmol) in EtOH (60 ml) and Na2SO3 (4.61 g, 36.58 mmol) in EtOH: water (40 ml: 50 ml) at 70° C. for 16 h gave the title compound (7.2 g) which was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:29]5[CH:30]=[N:31][C:32]([NH2:39])=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:40][CH3:41])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42].O1CCOCC1>C(Cl)Cl>[CH3:41][O:40][C:16]1[CH:17]=[C:18]([C:21]2[S:25][C:24]3=[N:26][CH:27]=[C:28]([C:29]4[CH:34]=[C:33]([C:35]([F:37])([F:36])[F:38])[C:32]([NH2:39])=[N:31][CH:30]=4)[N:23]3[N:22]=2)[CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1.[ClH:42]
Reactant: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)ccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{4-[5-(6-Amino-5-trifluoromethyl-pyridin-3-yl) -imidazo[2,1-b][1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (23 mg; 0.039 mmol; 1 eq) was suspended in anhydrous DCM (3 ml) and 4M HCl in 1,4-dioxane (0.097 ml, 0.39 mmol, 10 eq) was added. The reaction mixture was stirred at RT overnight. The solvents were removed and the residue was co-evaporated with DCM (×3). The residue was triturated in CH3CN and filtered to give the desired product as HCl salt (19 mg, 92%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=3.25 min, [M+H]+ m/z 491.2; 1H NMR (300 MHz, DMSO) δ 9.10 (s, 2H), 8.88 (s, 1H), 8.49 (d, J=1.6 Hz, 1H), 7.87 (s, 1H), 7.53 (m, 2H), 7.31 (d, J=9.1 Hz, 1H), 4.76 (s, 1H), 3.91 (s, 3H), 3.17 (m, 2H), 3.09 (m, 2H), 2.12 (m, 2H), 1.90 (m, 2H).