Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[CH:9][N:10]=2)[N:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH:11][C:19](=[O:21])[CH3:20])=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cnc2ccc(Cl)nn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution 6-chloroimidazo[1,2-b]pyridazin-3-amine and triethylamine (0.8 mL, 6.0 mmol) in DCM (25 mL) was added acetyl chloride dropwise and stirred at rt for overnight. The mixture was concentrated and purified by ISCO column chromatography (10% MeOH/DCM) to give not very pure N-(6-chloroimidazo[1,2-b]pyridazin-3-yl)acetamide (500 mg, 95% yield). 60 mg of non-pure material was further purified by Prep HPLC (neutral) to give pure N-(6-chloroimidazo[1,2-b]pyridazin-3-yl)acetamide. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.01 (d, J=9.35 Hz, 1H), 7.94 (s, 1H), 7.26 (d, J=9.35 Hz, 1H), 2.29 (s, 3H); LRMS (ESI) m/e 210.9 [(M+H)+, calcd for C8H8ClN4O 211.6].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[O:13]>C(#N)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:22])=[O:21])=[O:25])[N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1

Procedure:
To 37 g. of 2-amino-4,6-dimethylpyrimidine in 500 ml of anhydrous acetonitrile was added 67 g of 2-methoxycarbonylbenzenesulfonylisocyanate with stirring at ambient temperatures. The resulting mixture was thereafter stirred for sixteen hours and then filtered to remove the desired product which had precipitated as a white solid, m.p. 198°-202°. It showed infrared absorption peaks at 1750, 1700, 1600 and 1550 cm-1, consistent for the desired compound.
Reaction SMILES: [CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([OH:17])=O)[C:12]=2[CH3:14])[S:7](=[O:19])(=[O:18])[CH2:6][CH2:5]1)[CH3:2].[CH2:20]([N:22]1[C:26]([OH:27])=[CH:25][CH:24]=[N:23]1)[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([C:25]3[CH:24]=[N:23][N:22]([CH2:20][CH3:21])[C:26]=3[OH:27])=[O:17])[C:12]=2[CH3:14])[S:7](=[O:19])(=[O:18])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCSC1CCS(=O)(=O)c2ccc(C(=O)O)c(C)c21
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCSC1CCS(=O)(=O)c2ccc(C(=O)c3cnn(CC)c3O)c(C)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
0.51 Gram (1.7 mmol) of 4-ethylthio-5-methyl-6-carboxythiochroman-1,1-dioxide was dissolved in 5 ml of t-amyl alcohol, and 0.22 g (2.0 mmol, 1.2 eq.) of 1-ethyl-5-hydroxypyrazole and 0.42 g (2.0 mmol, 1.2 eq.) of N,N'-dicyclohexylcarbodiimide were added. The mixture was stirred at room temperature for 3 hours, and then 0.18 g (1.3 mmol) of potassium carbonate was added. The mixture was heated at 80° C. for 8 hours. After the completion of the reaction, the solvent was distilled off. The remaining oil was dissolved in ethyl acetate and product was extracted with a 5 wt % sodium hydrogencarbonate aqueous solution. 2N Hydrochloric acid was added to the resultant aqueous solution to adjust a pH of 1, and the mixture was extracted with ethyl acetate. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 0.5 g (75%) of 4-ethylthio-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8](=O)[NH:9][CH:10]=[CH:11][CH:12]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=c1[nH]cccc1-c1ccccn1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncccc1-c1ccccn1
Temperature: 25 °C

Procedure:
A 5.9 g portion of 3-(2-pyridinyl)-2(1H)-pyridinone in 100 ml of phosphorus oxychloride was heated on a steam bath for 18 hours, then concentrated under vacuum. The residue was stirred with crushed ice and chloroform and adjusted to pH 7 with 10N sodium hydroxide. The organic layer was separated, dried, filtered through a short pad of hydrous magnesium silicate and the filtrate concentrated under vacuum to an oil. This oil was heated with hexane, filtered while hot and the filtrate cooled to room temperature, giving 3.5 g of 2'-chloro-2,3'-bipyridine as white needles, mp 50° C.
Reaction SMILES: [Na+].[Na+].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10]2.O.O.O.C([O-])(=O)C.[Na+].[N+](C1C(S(O)(=O)=O)=C(C=CC=1)C([O:43][C:44](=O)[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([N+:51]([O-:53])=[O:52])[C:46]=1[S:54]([OH:57])(=[O:56])=[O:55])=O)([O-])=O>O>[N+:51]([C:47]1[C:46]([S:54]([OH:57])(=[O:55])=[O:56])=[C:45]([CH:50]=[CH:49][CH:48]=1)[C:44]([NH:4][C:5]1[CH:6]=[C:7]([S:23]([OH:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:10]2)=[O:43])([O-:53])=[O:52]
Reactant: O=C(OC(=O)c1cccc([N+](=O)[O-])c1S(=O)(=O)O)c1cccc([N+](=O)[O-])c1S(=O)(=O)O
Reactant: Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12)c1cccc([N+](=O)[O-])c1S(=O)(=O)O

Procedure:
A 6.6 g portion of 8-amino-1,3,6-naphthalenetrisulfonic acid trisodium salt and 2.92 g of sodium acetate trihydrate are dissolved in 180 ml of water at 2° C. A 4.0 g portion of 3-nitrosulfobenzoic anhydride is added with stirring. A 400 ml portion of water is added and the mixture is allowed to stand 21/2 hours, filtered and the filtrate is cooled, acidified with 2-3 ml of hydrochloric acid and diluted with ethanol. The pink solid is collected by filtration, washed with 85% ethanol, ether and dried giving 2.5 g of 8-(3-nitro-2-sulfobenzamido)-1,3,6-naphthalene trisulfonic acid, tetrasodium salt.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)([CH3:3])[CH3:2].Cl.[O:13]1[C:18]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:16]2[CH2:17][C:18]3([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[O:13][CH2:14][CH2:15]2)=[O:11])[N:8]=1)([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: CC(C)c1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 2-isopropylthiazole-4-carboxylic acid (1 g) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (1.71 g) in DMF (30 mL) was cooled in an ice bath and treated with triethylamine (2.442 mL) followed by HATU (2.89 g). The ice bath was removed and the mixture was stirred at 20° C. for 1 hour. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 70% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 2 g.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([NH:11][OH:12])=[NH:10])=[CH:7][C:6]=1CC)[CH:2]=[CH2:3].[Cl:18]C1C=C(C=C(C)C=1O)C=O>>[CH2:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([C:9]([NH:11][OH:12])=[NH:10])=[CH:7][C:6]=1[Cl:18])[CH:2]=[CH2:3]
Reactant: C=CCOc1c(C)cc(C(=N)NO)cc1CC
Reactant: Cc1cc(C=O)cc(Cl)c1O
Product: C=CCOc1c(C)cc(C(=N)NO)cc1Cl

Procedure:
The title compound is prepared in analogy to 4-allyloxy-3-ethyl-N-hydroxy-5-methyl-benzamidine starting from commercially available 3-chloro-4-hydroxy-5-methyl-benzaldehyde; LC-MS: tR=0.69 min, [M+1]+=241.10.
Reaction SMILES: [NH:1]1CCC(C(N)=O)CC1.[CH:10]([C:12]1[CH:45]=[CH:44][C:15]([C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([O:28][C:29](=[O:43])[NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:24][CH2:23]2)=[O:17])=[CH:14][CH:13]=1)=[O:11].[O-]S([O-])(=O)=O.[Na+].[Na+].CC(O)=O>CC(O)C>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([O:28][C:29](=[O:43])[NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:24][CH2:23]2)=[O:17])=[CH:44][CH:45]=1)(=[O:11])[NH2:1]
Reactant: NC(=O)C1CCNCC1
Reactant: O=Cc1ccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: NC(=O)c1ccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 30 °C

Procedure:
Isonipecotamide (15.4, 120 mmol, 2.0 eq.) and IPA (200 mL) were added to the solution of biphenyl-2-yl-carbamic acid 1-{2-[(4-formylbenzoyl)methylamino]ethyl}piperidin-4-yl ester from the previous step. Liquid (200 mL) was distilled off and additional IPA (400 mL) was added under reduced pressure at 60° C. Liquid (400 mL) was distilled off over a period of 1.5 hours and additional IPA (600 mL) was added. Liquid (100 mL) was distilled off and the remaining solution was cooled to 30° C. to yield a hazy white mixture, which was then added to Na2SO4 (18 g). The flask was rinsed with IPA (100 mL) and added to the solution. The resulting mixture was cooled to room temperature and AcOH (20 mL, 360 mmol, 6.0 eq.) was added. The mixture was cooled to 18° C. with an ice bath and NaHB(OAc)3 (38.2 g, 180 mmol, 3.0 eq.) was added over 5 minutes. The mixture was allowed to warm up to 25° C. and was maintained at that temperature for 2 hours. Solvent was removed under reduced pressure, and the remaining material was used directly in the next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[C:17]2[C:8]([O:9][C:10]3[CH:11]=C(C(O)=O)[CH:13]=[CH:14][C:15]=3[C:16]2=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C([O:30]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCC)C.[CH:52]([N:55]([CH:58]([CH3:60])C)[CH2:56][CH3:57])([CH3:54])C>CN(C=O)C.O>[CH2:58]([N:55]([CH2:56][CH3:57])[C:52]([C:54]1[CH:13]=[CH:14][C:15]2[C:16](=[O:19])[C:17]3[C:8]([O:9][C:10]=2[CH:11]=1)=[CH:7][CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:18]=3)=[O:30])[CH3:60]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)Nc1ccc2oc3cc(C(=O)O)ccc3c(=O)c2c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)c1ccc2c(=O)c3cc(NC(C)=O)ccc3oc2c1
Reaction time: 3 h

Procedure:
Compound 6f (2 g, 6.7 mmol) in 35 mL of DMF was treated with HATU (2.5 g, 6.7 mmol), diethylamine (0.2 mL, 8.7 mmol), and diisopropylethylamine (4.75 mL, 26.8 mmol). After stirring for 3 h the reaction was poured into water and the solid was collected to give the product, compound 7f. The filtrate was extracted with diethyl ether/THF (1:1). The combined organic phases were washed with water, brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and combined with the above solid to give 1.5 g total of compound 7f. MS m/z=353 (M+1).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([I:3])=[CH:17][CH:16]=2)=[CH:10][CH:11]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(Cc2ccc(I)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a 25 mL vial which contained a suspension of NaH (60% in mineral oil, 60 mg, 1.5 mmol) in DMF (10 mL) was the product from step 3 (310 mg, 1 mmol) at 0° C. The mixture was allowed to warm to rt and stir at rt for 30 min then cooled to 0° C. To this reaction mixture was added (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (355 mg, 1 mmol) at 0° C. The resulting mixture was allowed warm to rt and stir at rt for 30 min and then was heated to 90° C. and stirred at 90° C. for 16 h. After cooling to rt, the mixture was poured onto 200 mL ice-water solution and this solution was allowed to stir at 0° C. for 30 min. The solid which formed was filtered out, dried through air to afford the title product (290 mg, 59%); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.79-2.08 (m, 4H), 3.26-3.46 (m, 2H), 3.70-3.93 (m, 1H), 3.85 (s, 2H), 4.02-4.19 (m, 2H), 6.82-6.88 (m, 2H), 6.91 (d, J=7.6 Hz, 2H), 7.04 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H):
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([N:7]=[C:8]=[O:9])[CH:3]=1.C([OH:13])C=C.[CH:14]1[CH:19]=CC=C[CH:15]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:8](=[O:13])[O:9][CH2:15][CH:14]=[CH2:19])[CH:3]=1
Reactant: Cc1cc(N=C=O)no1
Reactant: C=CCO
Reactant: c1ccccc1
Product: C=CCOC(=O)Nc1cc(C)on1

Procedure:
To a suspension of 5-methyl-3-isoxazolyl isocyanate (1.71 g) in benzene (46 ml), allyl alcohol (0.88 g) is added, and the resultant mixture is refluxed for 3 hours. After cooling, the reaction mixture is evaporated to remove the solvent, whereby allyl N-(5-methyl-3-isoxazolyl)carbamate (2.38 g) is obtained. This substance is recrystallized from cyclohexane to give crystals melting at 76.5° to 77.5° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)(C)(C)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22]O)=[O:21]>CCO>[CH:13]1[CH:12]=[N+:11]([O-:21])[CH:10]=[C:9]([CH2:8][NH2:7])[CH:14]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([OH:22])=[O:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCc1cccnc1
Solvent: CCO
Product: NCc1ccc[n+]([O-])c1
Product: O=C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To pyridin-3-ylmethyl-carbamic acid tert-butyl ester (3.89 g, 18.7 mmol) dissolved in EtOH (50 mL), was added 3-chloroperoxybenzoic acid (4.7 g, 27.4 mmol). After 4 hours the volatiles were removed in vacuo and the crude was redissolved in CH2Cl2 (25 mL). To this solution was added TFA (25 mL) and the reaction was stirred at 25° C. for 2 h then the volatiles were removed in vacuo. The crude was redissolved in CH2Cl2 and evaporated. This procedure was done twice more. (1-Oxy-pyridin-3-yl)-methylamine was obtained with contamination of 3-chlorobenzoic acid, but carried further without any additional purification (2.74 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][CH2:12][OH:13])=[N:7][C:6]=2[CH:14]=1.[CH:15]([C:17]([CH3:19])=[O:18])=[CH2:16].[OH-].[Na+].CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]([CH2:16][CH2:15][C:17](=[O:18])[CH3:19])[CH2:11][CH2:12][O:13][S:30]([CH3:29])(=[O:32])=[O:31])=[N:7][C:6]=2[CH:14]=1
Reactant: OCCNc1nc2cc(Cl)ccc2o1
Reactant: CS(=O)(=O)Cl
Reactant: C=CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)CCN(CCOS(C)(=O)=O)c1nc2cc(Cl)ccc2o1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a 1000 mL 3-neck round bottom flask equipped with a septum, thermocouple, inert gas inlet and magnetic stir bar was charged 3-3 (25.2 g, 119 mmol). To this flask was added 126 mL DMF, 12.2 mL methyl vinyl ketone (148 mmol) and 0.119 mL 10M NaOH (1.19 mmol). The reaction was then aged for 6 hours, at which time conversion was judged to be complete by HPLC. The solution was diluted with 252 mL iPAc and cooled to 0° C., then 23.1 mL Et3N (166 mmol) followed by dropwise addition of 12.0 mL methanesulfonyl chloride (154 mmol) over 45 minutes, maintaining internal temperature less than 10° C. After a further 30 minutes, conversion was judged to be complete by HPLC. The solution was washed with 3×63 mL 5 w/w % aqueous NaHCO3 solution, then 66 mL water. After cutting the aqueous layer, the organics were reduced to approximately two volumes or 50 mL iPAc. The organics were then agitated by an overhead stirrer during slow addition of 151 mL n-Heptane over 4 hours. Over this time a crystalline white precipitate developed, and was allowed to stir overnight. At this time there was a thick slurry, which was filtered and washed with 2×50 mL 90:10 n-Heptane:IPAc, and after drying with a nitrogen stream over the filter pad, 3-4 was obtained as a white crystalline solid (34.6 g., 96 mmol). 1H NMR (500 MHz, CDCl3): δ=7.29 (s, 1H), 7.16 (d, J=8.2 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 4.46 (s, 2H), 3.92 (s, 2H), 3.81 (t, J=5.9 Hz, 2H), 2.98-2.92 (m, 5H), 2.16 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]2[CH2:23][CH2:22][N:21](C(OCC)=O)[CH2:20][CH2:19]2)[C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Br>C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCC(N(C(=O)Cc2ccccc2)c2ccc(Cl)cc2)CC1
Agent: Br
Solvent: CC(=O)O
Product: Cl
Product: O=C(Cc1ccccc1)N(c1ccc(Cl)cc1)C1CCNCC1

Procedure:
A mixture of 10 parts of ethyl 4-[N-(4-chlorophenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylate and 125 parts of glacial acetic acid, previously saturated with gaseous hydrogen bromide, is heated for 9h.45 at 62° C., while stirring. The reaction mixture is cooled and glacial acetic acid is evaporated in vacuo. The semi-solid residue is taken up in 150 parts of water, alkalized with a concentrated sodium hydroxide solution and the product is extracted with trichloromethane. The extract is dried over sodium sulfate and evaporated. The oily residue is triturated in 56 parts of 1,1'-oxybisethane and the solid crude free base is filtered off. It is converted into the hydrochloride salt in the conventional manner in 1,1'-oxybisethane and 2-propanone, yielding 4 parts of N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide hydrochloride; mp. 206.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:44])(=O)=O)=CC=1>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:20]([F:44])=[C:19]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[CH:17][N:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc(N3CCc4cc(S(C)(=O)=O)ccc43)c2F)CC1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
4a (43 mg, 0.09 mmol) was dissolved in 1 mL of DCE with N-fluorobenzenesulfonimide (62 mg, 0.2 mmol). The mixture was stirred for 2 days at 75° C. then the solvent was evaporated under vacuum. The crude material was dissolved in 20% of DCM in methanol and purified by preparative HPLC to give 13-1; LCMS 493.1 (MH+), tR=5.21 (Method 5). EC50: 382 nM.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]=[C:13]([NH2:19])[N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C[C:21]1[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][NH:23][N:22]=1.[C:35]([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([C:15]1[CH:16]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:25]4[CH:21]=[N:22][N:23]([CH3:35])[CH:24]=4)[CH:3]=3)[NH:8][CH:9]=2)[N:12]=[C:13]([NH2:19])[N:14]=1)[CH3:18]
Reactant: CCc1cc(-c2c[nH]c3ncc(Br)cc23)nc(N)n1
Reactant: O=C([O-])[O-]
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(-c2c[nH]c3ncc(-c4cnn(C)c4)cc23)nc(N)n1
Temperature: 120 °C

Procedure:
A suspension of 50 mg (0.157 mmol) of 4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-ethylpyrimidin-2-ylamine, 56 mg (0.282 mmol) of methylpyrazole-4-boronic acid pinacol ester, 9 mg (0.008 mmol) of tetrakis(triphenylphosphine)palladium(0) and 0.45 ml of a 2M Na2CO3 solution (0.900 mmol) in 0.6 ml of DMF is heated for 30 min at 120° C. in the microwave. The reaction mixture is filtered, the filter cake is washed with MeOH, and the filtrate is evaporated in vacuo. The residue is purified by preparative HPLC, giving 4-ethyl-6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-2-ylamine as a colourless solid, ESI 320.
Reaction SMILES: [C:1]([CH:3]([O:33][CH3:34])[CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([N:24](C)[C:25](=O)OC(C)(C)C)[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)#[N:2].Cl>ClCCl>[CH3:34][O:33][C@@H:3]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:19][CH2:20][CH:21]([NH:24][CH3:25])[CH2:22][CH2:23]4)[C:7]=3[C:6]1=2)[C:1]#[N:2].[CH3:34][O:33][C@H:3]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:19][CH2:20][CH:21]([NH:24][CH3:25])[CH2:22][CH2:23]4)[C:7]=3[C:6]1=2)[C:1]#[N:2]
Reactant: COC(C#N)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Agent: Cl
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](C#N)OC)CC4)CC1
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](C#N)OC)CC4)CC1
Reaction time: 4 h

Procedure:
Into a 50-mL round-bottom flask, a solution of tert-butyl N-(4-[[(3R)-3-(2-cyano-2-methoxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (100 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (10 mL) was added hydrochloric acid (12 M, 0.5 mL) in a water/ice bath and stirred for 4 h. After completion and concentration in vacuo, the residue was neutralised with saturated aqueous sodium bicarbonate, extracted with 3×50 mL of DCM. The combined organic layers were concentrated under vacuum and the crude product (80 mg) was purified by preparative HPLC under the following conditions: (SHIMADZU): column: Xbridge Prep C18 5 um, 19*150 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 56.0% in 15 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the corresponding (2S)-2-methoxy-3-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanenitrile (12.5 mg) as a off-white semi-solid and (2R)-2-methoxy-3-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanenitrile (3.5 mg) as a light yellow semi-solid, respectively.