Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.[CH:15]([N:18]([CH:21]([CH3:23])C)[CH2:19]C)(C)C.[C:24](Cl)(=[O:27])C=C>ClCCl.CNC.O1CCCC1>[CH3:19][N:18]([CH3:15])[CH2:21][CH2:23][C:24]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:6][CH2:7]1)=[O:27]
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CC(=O)Cl
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CCN(C)C)CC2
Temperature: 0 °C
Yield: 67 %

Procedure:
A suspension of 5-(methyloxy)-6-nitro-2,3-dihydro-1 H-indole (1.50 g, 7.73 mmol) and polymer supported diisopropylethylamine (4.1 g, 16 mmol) in dichloromethane (100 mL) was cooled to 0° C. and 2-propenoyl chloride (0.750 mL, 9.3 mmol) was added dropwise. The solution was warmed slowly to room temperature and all solids were observed to dissolve. The mixture was filtered through celite, the celite washed twice with dichloromethane, and the combined filtrates were concentrated under reduced pressure to give a crude residue which was dissolved directly in a 1.0M dimethyl amine solution in tetrahydrofuran (40 mL). The solution was maintained at 60° C. for 12 hours, cooled, taken to a residue under reduced pressure, and purified by chromatography on SiO2 to afford N,N-dimethyl-3-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-3-oxo-1-propanamine (1.52 g, 67% Yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.68 (s, 1 H), 6.91 (s, 1 H), 4.15 (t, J=8.43 Hz, 2 H), 3.91 (s, 3 H), 3.26 (t, J=8.43 Hz, 2 H), 2.81 (t, J=7.33 Hz, 2 H), 2.66 (t, J=7.15 Hz 2 H), 2.27-2.41 (m, 6H). U24644/64/1
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 19.1 %

Procedure:
A mixture of 2-bromophenol (10 g, 57.8 mmol), benzyl bromide (27.5 ml, 0.23 mol) and potassium carbonate (64 g, 0.462 mol) in N,N-dimethylformamide (70 ml) was stirred at room temperature for 72 hours. The suspension was poured into water (500 ml) and extracted with ethyl acetate (2×300 ml). The combined organic fractions were washed with water (300 ml), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (98:2) to give the title compound as a colourless oil (2.9 g). 1H NMR (250 MHz, CDCl3) δ 7.58-7.19 (8H, m), 6.95-6.81 (2H, m), and 5.16 (2H, m).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:15][OH:16])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:17](I)[CH3:18]>O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:15][O:16][CH2:17][CH3:18])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 35.5 %

Procedure:
Sodium hydride (60% purity, 4.6 g) was suspended in tetrahydrofuran (50 mL) and a solution (50 mL) of (R)-1-tert-butoxycarbonyl-2-hydroxymethylpyrrolidine (20 g) in tetrahydrofuran was added dropwise under ice-cooling. After the completion of the dropwise addition, the mixture was stirred with heating at 50° C. for 30 min and ice-cooled. Ethyl iodide (18.7 g) was added to the reaction mixture and the mixture was stirred overnight at room temperature. After the completion of the reaction, the solvent was concentrated and water was added to the obtained residue. The mixture was extracted with chloroform and dried over magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography. The fraction eluted with hexane:ethyl acetate=3:1 was concentrated to give (R)-1-tert-butoxycarbonyl-2-ethoxymethylpyrrolidine (8.1 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH:9]([NH2:11])[CH2:8][CH2:7][C:5]=2[N:6]=1.[S:12]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)([O:15][CH2:16][CH2:17][CH3:18])(=[O:14])=[O:13]>C(O)CC>[CH3:16][CH2:17][CH2:18][NH:11][C@@H:9]1[CH2:10][C:4]2[S:3][C:2]([NH2:1])=[N:6][C:5]=2[CH2:7][CH2:8]1.[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:20][CH:21]=1
Reactant: CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1nc2c(s1)CC(N)CC2
Solvent: CCCO
Product: CCCN[C@H]1CCc2nc(N)sc2C1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A 250 ml, three necked flask was equipped with a magnetic stirrer, a temperature probe, a heating mantle, a claisen joint, a reflux condenser, and a 100 ml addition funnel. The flask was charged with 5 grams of racemic 2,6 diamino-4,5,6,7-tetrahydro-benzothiazole, followed by 80 ml of n-propanol. Under continuous stirring, the mixture was heated to a temperature of 95° C. over 15 minutes generating a clear solution. The addition funnel was charged with a solution of 10.12 grams propyl tosylate and 9.2 ml diisopropylethyleamine in 28 ml n-propanol. This solution was added dropwise to the 250 ml flask with continuous stirring over a period of 2 hours. The reaction was continued with stirring for an additional 6 hours at 95° C., after which the solution was brought to room temperature, and stirring was continued for an additional 6 hours.
Reaction SMILES: [C:1]([CH:3]1[C:6]2=[CH:7][C:8](OC)=[CH:9][CH:10]=[C:5]2[CH2:4]1)#[N:2].[OH-:13].[K+]>C(O)C.O.CCOCC>[NH2:2][CH2:1][CH2:3][CH2:4][O:13][C:6]12[CH:7]=[CH:8][CH:9]=[CH:10][CH:5]1[CH2:4][CH:3]2[CH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:10][CH2:9]1
Reactant: COc1ccc2c(c1)C(C#N)C2
Reactant: [OH-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: NCCCOC12C=CC=CC1CC2CN1CCCCC1
Temperature: 25 °C

Procedure:
1-Cyano-5-methoxybenzocyclobutene (29 g) is stirred with saturated KOH in ethanol (180 ml) for about 12 hours under nitrogen at RT. Water (60 ml) is added to the reaction mixture which is refluxed for about 3 hours. The mixture is cooled to RT, diluted with water, washed with ether and the aqueous layer acidified forming an oil. The oil is dissolved in ether and the ethereal solution washed, dried over Na2SO4, filtered and evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH:12][C@H:13]1[CH2:32][N:17]2[C:18]3[C:23]([C:24]([CH2:25][C:26]([O:28]CCC)=[O:27])=[C:16]2[CH2:15][CH2:14]1)=[CH:22][CH:21]=[CH:20][CH:19]=3>>[CH3:11][N:12]([C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@H:13]1[CH2:32][N:17]2[C:18]3[C:23]([C:24]([CH2:25][C:26]([OH:28])=[O:27])=[C:16]2[CH2:15][CH2:14]1)=[CH:22][CH:21]=[CH:20][CH:19]=3
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(Cl)Cc1ccccc1
Product: CN(C(=O)Cc1ccccc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from phenylacetyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 377.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH:5]([CH3:16])[C:4]=2[CH:3]=1.[OH-].[K+].O.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>CS(C)=O.ClCCl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]3[C:29](=[O:30])[C:28]4[C:27](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]3=[O:35])([CH3:16])[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CC1c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CC1(CCCCN2C(=O)c3ccccc3C2=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.3 %

Procedure:
2,7-dibromo-9-methyl-9H-fluorene (10.0 g, 29.58 mmol) was dissolved in 50 mL DMSO under nitrogen. To mixture was added KOH (2.01 g, 35.79 mmol), water (1.5 mL), N-(4-bromobutyl)phthalimide (9.93 g, 35.2 mmol), and stirred reaction at room temperature for 2.0 hours, then at 50° C. for 3.0 hours. The reaction was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with brine (2×), and water. Removal of solvent yield a solid, which was purified by column chromatography (7:3, hexanes:EtOAc) to yield white solids (3.08 g, 20%). 1H NMR (500 MHz, CDCl3): δ=7.81-7.83 (m, 2H), 7.68-7.71 (m, 2H), 7.48-7.51 (m, 4H), 7.41-7.44 (dd, 2H), 3.46-3.49 (t, 2H), 2.00-2.04 (p, 2H), 1.47-1.49 (m, 2H), 1.45 (s, 3H), 0.65-0.68 (m, 2H).
Reaction SMILES: C(Cl)Cl.C(Cl)(Cl)Cl.[CH3:8][C@:9]12[CH2:19][CH2:18][C@@H:17]3[CH2:20][C@:14]1([O:15][C:16]3([CH3:22])[CH3:21])[CH:13]=[CH:12][CH2:11][CH2:10]2.ClC1C=CC=C(C(OO)=[O:31])C=1>C1C=CC=CC=1>[CH3:8][C@:9]12[CH2:19][CH2:18][C@@H:17]3[CH2:20][C@@:14]1([O:15][C:16]3([CH3:22])[CH3:21])[C@H:13]1[O:31][CH:12]1[CH2:11][CH2:10]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)O[C@@]23C=CCC[C@@]2(C)CC[C@@H]1C3
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)O[C@@]23C[C@H]1CC[C@]2(C)CCC1O[C@@H]13

Procedure:
In Scheme III, compound of formula (5) is reduced by metallic hydride complex, preferably LiAlH4, to form compound of formula (Ic-1) in organic solvent such as diethylether, tetrahydrofuran, 1,2-dimethoxyethane, or any other solvent that does not interfere with the reaction at room temperature. Oxidation of compound of formula (Ic-1) by CrO3/pyridine, pyridinum chlorochromate (PCC) or Jones reagent, preferably PCC, produces compound of formula (Ic-2) and the reaction is generally conducted in organic solvent such as methylene chloride, chloroform, benzene or any other solvent that does not interfere with the reaction at room temperature or heated. (1S,6S,9R)6,10,10-trimethyl-11-oxatricyclo[7.2.1.01,6]dodec-2-ene (formula 8) is oxidized by organic peracid, preferably meta-chloroperbenzoic acid, to form (1S,2S,6R,9R)6,10,10-trimethyl-2,3-epoxy-11-oxatricyclo[7.2.1.01,6]dodecane (formula 9) and the reaction is conducted in organic solvent such as diethylether, methylene chloride, chloroform, benzene or any other solvent that does not interfere with the reaction at room temperature or cooled. The thus produced compound (9) is reduced by metallic hydride complex, preferably LiAlH4 to form (1S,3S,6R,9R)6,10,10-trimethyl-11-oxatricyclo[7.2.1.01,6]dodecan-3-one (formula 10) and the reaction is conducted in organic solvent such as diethylether, tetrahydrofuran, 1,2-dimethoxyethane or any other solvent that does not interfere with the reaction at room temperature or cooled with ice bath. Compound of formula (10) is oxidized by CrO3/pyridine, PCC, or Jones reagent, preferably PCC to form (1S,6R,9R)6,10,10-trimethyl-11-oxatricyclo[7.2.1.01,6]dodecan-3-one (formula 11 ) and the reaction is conducted in organic solvent such as methylene chloride, chloroform, benzene or any other solvent that does not interfere with the reaction at room temperature or heated. Compound (11) is reacted with organometallic reagent such as Grignard reagent or organolithium reagent to form compound of formula (Ic-3) and the reaction is conducted in organic solvent such as diethylether, tetrahydrofuran or any other solvent that does not interfere with the reaction at room temperature or cooled with ice bath. Compound of formula (10) react with phosphorous trihalide in the presence of triphenylphosphine to form (1S,3R,6R,9R)6,10,10-trimethyl-3-halo-11-oxatricyclo[7.2.1.01,6]dodecane and the reaction is conducted in anhydrous diethylether and cooled with ice bath or ice-salt mixture.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][C:14]1[C:18]([S:19](Cl)(=[O:21])=[O:20])=[C:17]([CH3:23])[O:16][N:15]=1>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[S:19]([C:18]1[C:14]([CH3:13])=[N:15][O:16][C:17]=1[CH3:23])(=[O:21])=[O:20]
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: CNCCC#Cc1ccccn1
Product: Cc1noc(C)c1S(=O)(=O)N(C)CCC#Cc1ccccn1
Yield: 17.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 3,5-dimethylisoxazole-4-sulfonyl chloride (79 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 17 mg of N,3,5-trimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)isoxazole-4-sulfonamide as a brown oil (Yield: 17%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.[Cl:21][C:22]1[CH:43]=[CH:42][C:25]([CH2:26][N:27]2[C:32](=[O:33])[C:31]([C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([F:41])[CH:35]=3)=[CH:30][N:29]=[CH:28]2)=[CH:24][CH:23]=1.CC(C)([O-])C.[K+].C1COCC1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:27]2[C:32](=[O:33])[C:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[N:8]([CH2:7][C:6]6[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=6)[N:9]=[C:10]([CH3:18])[C:11]=45)=[C:36]([F:41])[CH:35]=3)=[CH:30][N:29]=[CH:28]2)=[CH:42][CH:43]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Reactant: O=c1c(-c2ccc(O)c(F)c2)cncn1Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(-c5cncn(Cc6ccc(Cl)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 137.1 %

Procedure:
To a 10 mL round bottom flask was added 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (13.0 mg, 0.0454 mmol), prepared according to the procedure of Example 43, Step E, 3-(4-chlorobenzyl)-5-(3-fluoro-4-hydroxyphenyl)pyrimidin-4(3H)-one (10 mg, 0.0302 mmol) prepared according to the procedure of Example 43, Step D and dissolved in DMF (0.5 mL). A 1M solution of potassium t-butoxide in THF (0.0454 mL, 0.0454 mmol) and potassium carbonate (6.27 mg, 0.0454 mmol) were both added and the resulting mixture was stirred at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and the crude mixture was partitioned between water (10 mL) and ethyl acetate (15 mL). The organic layer washed with brine, dried over sodium sulfate and evaporated to afford 24.1 mg of brown oil. The crude product was purified by silica gel chromatography (Biotage 12M), loading with chloroform and eluting with 1.5% MeOH in CHCl3 to afford the desired product as an off-white solid (5 mg, 28%). LRMS (APCI pos) m/e 583.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH3:25][O-:26].[Na+]>CO>[CH3:25][O:26][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccccc1OC1CCN(c2ccc(Cl)nn2)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Reaction time: 4 h

Procedure:
A solution of 3-chloro-6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridazine (150 mg, 0.42 mmol) in MeOH (1 mL) and NaOMe (2.5 mL, 0.87 mmol, 25-30% in MeOH) was heated at 80° C. After 4 h, solvent was evaporated and the mixture was diluted with water (3 mL), extracted with EtOAc (3×2 mL) and dried over Na2SO4. Evaporation of the solvent followed by purification Combiflash chromatography (SiO2, eluant 30-40% EtOAc/hexanes) afforded the desired product. 1H NMR (500 MHz, acetone-d6): δ 1.87-1.95 (m, 2H), 2.07-2.14 (m, 2H), 3.58-3.64 (m, 2H), 3.78-3.86 (m, 2H), 3.97 (s, 3H), 4.90-5.00 (m, 1H), 6.94 (d, 1H), 7.08-7.12 (m, 1H), 7.35 (t, 2H), 7.59-7.65 (m, 2H). MS (+ESI) m/z 354 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C@@H:9]([C:17](=[O:23])[NH:18][CH2:19][CH2:20][CH2:21][OH:22])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl.CN(C)C1C=CN=CC=1>[C:32]([O:22][CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:23])[C@H:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:24])[CH3:8])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)NCCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.2 %

Procedure:
A solution of N-((1R)-1-(3-hydroxypropylcarbamoyl)-2-phenylethyl)-N-methyl-carbamic acid tert-butylester (965 mg, 2.86 mmol) in dichloromethane (10 mL) was cooled to 0° C. 4-(dimethylamino)pyridine (35 mg, 0.29 mmol), triethylamine (0.60 mL, 4.29 mmol), and acetic acid anhydride (0.32 mL, 3.43 mmol) were added. The reaction mixture was stirred for 5 hours, while it was warming slowly to room temperature. The reaction mixture was diluted with dichloromethane (100 mL) and washed with 10% sodium hydrogensulfate solution. The aqueous phase was extracted with dichloromethane (2×50 mL). The organic phases were combined and washed with saturated sodium hydrogen carbonate solution. They were dried over magnesium sulfate. The solvent was removed in vacuo, and the crude product was purified by flash chromatography on silica (90 g) with ethyl acetate/dichloromethane (1:3 to 1:1) to give 890 mg of 3-((2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-phenylpropionylamino)propyl acetate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([OH:25])[C@H:16]([NH:19][C:20](=[O:24])[CH:21]([Cl:23])[Cl:22])[CH2:17][F:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl.O>[C:33]([NH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C@@H:15]([OH:25])[C@H:16]([NH:19][C:20](=[O:24])[CH:21]([Cl:23])[Cl:22])[CH2:17][F:18])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)(=[O:35])[CH3:34]
Reactant: NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.2 %

Procedure:
To a stirred solution of crude N-{(1S,2R)-2-[4-(6-Aminomethyl-pyridin-3-yl)-phenyl]-1-fluoromethyl-2-hydroxy-ethyl}-2,2-dichloro-acetamide (30 mg, 0.077 mmol) in CH2Cl2 (2 mL) is added triethyl amine (8 mg, 0.078 mmol) and acetic anhydride (20 mg, 0.198) and the reaction mixture was stirred at room temperature for 6 h. Diluted with water and extracted with CH2Cl2 dried over sodium sulphate and solvent is evaporated in vacuo to give crude, which is purified by silica gel prep TLC using the mobile phase 10% methanol in CH2Cl2 to afford title compound (5 mg): 1H-NMR (400 MHz, DMSO-d6) 6: (s, 3H), 4.30-4.34 (m, 1H), 4.45 (d, J=5.96 Hz, 2H), 4.48-4.51 (m, 1H), 4.55-4.58 (m, 1H), 5.00 (d, 1H), 5.95 (d, 1H), 6.12 (s, 1H), 6.99 (bs, 1H), 7.34-7.36 (m, 1H), 7.47-7.50 (m, 2H), 7.62-7.67 (m, 2H), 7.96 (dd, J1=8.2 Hz, J2=2.4 Hz, 1H), 8.76 (d, J=2.2 Hz, 1H). LC-Ms (m/z): [M+H]=428.10.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:22])([CH3:21])[CH3:20])[C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1)=O.[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)=[O:27])[CH3:24]>CN1C(=O)CCC1.O>[CH2:23]([O:25][C:26]([CH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:4]2[N:9]=[C:8]([C:10]3[N:14]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:22])([CH3:21])[CH3:20])[C:13]4=[N:12][CH:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]
Reactant: CS(=O)c1nccc(-c2cnc3c(C(C)(C)O)cccn23)n1
Reactant: CCOC(=O)C1CCC(N)CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C1CCC(Nc2nccc(-c3cnc4c(C(C)(C)O)cccn34)n2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
A mixture of 2-[3-(2-methylsulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyridin-8-yl]-propan-2-ol (0.19 g), 4-amino-cyclohexanecarboxylic acid ethyl ester (0.31 g) in NMP (2 mL) was stirred at 100° C. for 3 h. The reaction mixture was cooled to RT, and diluted with water. The resulting solid was filtered and dried, then purified by ISCO using 100% DCM to 10% MeOH/DCM. Fractions were collected, concentrated, and titurated with EtOAc/hexane. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide 4-{4-[8-(1-hydroxy-1-methyl-ethyl)-imidazo[1,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester (0.215 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.O1CCCC1.C[Mg]Br.[O:18]1[CH2:23][CH2:22][CH:21]([C:24](OC)=[O:25])[CH2:20][CH2:19]1>C1(C)C=CC=CC=1.ClCCl>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:8][C:24]([CH:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)=[O:25])[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)C1CCOCC1
Reactant: Cc1c(N)cncc1Br
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1c(Br)cncc1NC(=O)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25.9 %

Procedure:
To a solution of 5-bromo-4-methylpyridin-3-amine (128.9 mg, 0.6892 mmol) in tetrahydrofuran (4.0 mL, 49 mmol) at 0° C. was added 1.4 M of methylmagnesium bromide in toluene (0.55 mL). After stirring at 0° C. for 10 minutes, methyl tetrahydro-2H-pyran-4-carboxylate (92.00 g, 638.1 mmol) was added. The reaction mixture was stirred overnight while warming to room temperature. The reaction mixture was poured into dichloromethane, washed with saturated aqueous NaHCO3, dried over MgSO4, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-10% methanol in dichloromethane) to yield 53.5 mg (26%) of N-(5-bromo-4-methylpyridin-3-yl)tetrahydro-2H-pyran-4-carboxamide. LCMS (ESI): M+H=299.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:29]=[C:9]2[CH:10]=[C:11]([NH:14][C:15]([C:17]3[N:18]([CH3:28])[N:19]=[CH:20][C:21]=3[C:22]([N:24]3[CH2:27][CH2:26][CH2:25]3)=[O:23])=[O:16])[CH:12]=[CH:13][N:8]2[N:7]=1)=[O:5])C.O.[OH-].[Li+].Cl>CO.O.O1CCCC1>[N:24]1([C:22]([C:21]2[CH:20]=[N:19][N:18]([CH3:28])[C:17]=2[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:8]3[N:7]=[C:6]([C:4]([OH:5])=[O:3])[N:29]=[C:9]3[CH:10]=2)=[O:16])=[O:23])[CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(C(=O)O)nc2c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 126.6 %

Procedure:
A mixture of ethyl 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (example 33, step d) (658 mg, 1.66 mmol) and lithium hydroxide hydrate (139 mg, 3.31 mmol) in methanol (20 ml) and water (5 ml) and tetrahydrofuran (10 ml) was stirred for 6 hours at 60° C. (soluble when heated). The mixture was neutralized using hydrochloric acid 2N (1.655 ml, 3.31 mmol) and the mixture was evaporated affording 7-{[4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carbonyl]-amino}-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (776 mg, 77.4%) as a light brown solid which was used in the following reactions. A mixture of 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (120 mg, 244 μmol), dimethylamine hydrochloride (99.4 mg, 1.22 mmol), propylphosphonic anhydride (50% in ethyl acetate, 359 μl, 609 μmol) and diisopropylethylamine (298 μl, 1.71 mmol) in tetrahydrofuran (7 ml) was stirred for 20 hours at 25° C. The solvent was evaporated, the residue was triturated with sodium bicarbonate solution, the precipitated solid was filtered off, washed with water and dried. The material was applied on silicagel and purified by flash chromatography over a 5 g silicagel column using dichloromethane/methanol 5% as eluent affording 7-{[4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carbonyl]-amino}-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid dimethylamide (39 mg, 40.4%) as an off-white foam. MS: m/z=397.1 (M+H+)