Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.Cl[C:55]1[CH:56]=[N:57][C:58]([C:61]#[N:62])=[CH:59][CH:60]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:48]1([NH:47][C:55]2[CH:60]=[CH:59][C:58]([C:61]#[N:62])=[N:57][CH:56]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: N#Cc1ccc(Cl)cn1
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Nc2ccccc2)cn1
Yield: 38.2 %

Procedure:
A mixture of BINAP (0.167 g, 0.00027 mole), palladium acetate (0.06 g, 0.00027 mole) and toluene (10 mL) was degassed with argon for 15 minutes. This mixture was then added to a mixture of aniline (0.5 g, 0.00537 mole), 3-chloro-6-cyanopyridine (0.893 g, 0.00645 mole) and cesium carbonate (3.49 g, 0.01075 mole) in toluene (10 mL). The resulting mixture was heated to reflux for 22 hours. The reaction mixture was then concentrated under reduced pressure and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography using silica gel 60-120 mesh (15% ethyl acetate in hexane) afforded 0.4 g (38%) of 5-phenylamino-pyridine-2-carbonitrile. To a stirred solution of 5-phenylamino-pyridine-2-carbonitrile (0.4 g, 0.00205 mol) in EtOH (15 mL) was added NaOH (0.246 g, 0.0061 mol) and water (10 mL) and the resulting mixture was heated to reflux for 4 hours. The mixture was then concentrated under reduced pressure and the residue was diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.385 g (87%) of 5-phenylamino-pyridine-2-carboxylic acid
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=2)[CH2:4]1.C(N(CC)C(C)C)(C)C.[C:32]1([CH2:38][C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[C:32]1([CH2:38][C:39]([N:3]2[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]3[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=3)[CH2:4]2)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCNC2)cn1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(C(=O)Cc3ccccc3)C2)cn1
Reaction time: 3 h
Yield: 66.4 %

Procedure:
To a stirred suspension of ethyl (2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl}acrylate dihydrochloride (300 mg) in dichloromethane (6 mL) was added N,N-diisopropylethylamine (348 mg) and phenylacetyl chloride (139 mg) in dichloromethane (1 mL) in an ice bath and the resulting mixture was stirred at the same temperature for three hours. The mixture was extracted with chloroform and washed with saturated sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate to afford ethyl (2E)-3-(5-{[(3R)-1-(phenylacetyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate (225 mg) as a pale brown viscous oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:22]=[CH:21][C:6](/[CH:7]=[CH:8]/[C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:4]=1.[N+:23]([C:26]1[CH:39]=[CH:38][C:29]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C=O)C>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]([CH2:2][C:3]2[CH:22]=[CH:21][C:6](/[CH:7]=[CH:8]/[C@@H:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:5][CH:4]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:38][CH:39]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(CNc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CN(Cc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Temperature: 50 °C
Yield: 55.7 %

Procedure:
To a solution of the product of Example 149D (1.09 g, 2.97 mmol) and N-(4-nitrobenzyl)aniline (0.677 g, 2.97 mmol) dissolved in DMF (10 mL) was added potassium carbonate (1.23 g, 8.9 mmol) and the mixture heated at 50° C. for 1 hour. After cooling, the solution had dichloromethane added to it and the mixture extracted with water. The organic extract was then dried, filtered, concentrated and purified by chromatography (silica gel, 0-2% methanol in dichloromethane) to afford 0.85 g (56%) of the title compound. MS (ESI) m/z 514 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([O:13][CH2:12]1)[CH2:4][CH2:5][C:6]1[O:11][CH2:10][CH2:9][CH2:8][CH:7]=1)[CH3:2].Cl.C([O:17]CC)C>O1CCCC1>[CH2:1]([C:3]1([CH2:12][OH:17])[CH2:4][CH2:5][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10][O:11]2)[O:13]1)[CH3:2]
Reactant: CCOCC
Reactant: CCC1(CCC2=CCCCO2)CO1
Agent: Cl
Solvent: C1CCOC1
Product: CCC1(CO)CCC2(CCCCO2)O1
Reaction time: 120 h

Procedure:
To 5.5 g of 6-(3-ethyl-(3,4-epoxybutyl))-3,4-dihydro-2H-pyran was added a solution of 2 ml of 10% hydrochloric acid in 25 ml of tetrahydrofuran. The reaction mixture was stirred under nitrogen for five days and then poured into 150 ml of diethyl ether. The resulting solution was washed twice with 50 ml of saturated sodium bicarbonate solution, and dried, and the solvent was removed under high vacuum to yield 6 g of the desired product as a dark brown oil.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:24])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH2:27]([O:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]2[N:41]3[CH:42]=[C:43]([O:46][C@H:47]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[C@@H:50]([NH2:57])[CH2:49][CH2:48]4)[CH:44]=[CH:45][C:40]3=[N:39][N:38]=2)[CH2:33][CH2:32]1)[CH:28]=[CH2:29].CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:27]([O:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]2[N:41]3[CH:42]=[C:43]([O:46][C@H:47]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[C@@H:50]([NH:57][C:5]([NH:6][C:7]5[N:8]([C:16]6[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=6)[N:9]=[C:10]([C:12]([CH3:14])([CH3:15])[CH3:13])[CH:11]=5)=[O:24])[CH2:49][CH2:48]4)[CH:44]=[CH:45][C:40]3=[N:39][N:38]=2)[CH2:33][CH2:32]1)[CH:28]=[CH2:29]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(CO)cc2)n1
Reactant: C=CCOC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C=CCOC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)nn5-c5ccc(CO)cc5)c5ccccc54)cn23)CC1
Yield: 64.9 %

Procedure:
A yellow-brown solution of Intermediate 33a (99.6 mg, 0.237 mmol), Intermediate 57b (90.3 mg, 0.215 mmol) and DIPEA (0.047 mL, 0.269 mmol) in dioxane (3 mL) was stirred at 60° C. for 18 h. The solution was concentrated in vacuo, then the residue suspended in water (5 mL) and extracted with DCM (2×5 mL). The combined organics were passed through a hydrophobic fit and concentrated in vacuo. The residue was purified by FCC, using 2-8% [2M NH3 in MeOH] in DCM, to give the title compound as a pale yellow solid (96.4 mg, 65%). LCMS (Method 3): Rt 3.54 min, m/z 691 [MH+].
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10](COC)[C:11](=[O:18])[C:12]3[CH2:13][CH2:14][CH2:15][NH:16][C:17]=3[C:8]=2[CH:7]=1.[ClH:25]>C(O)C>[ClH:25].[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]2[NH:10][C:11](=[O:18])[C:12]3[CH2:13][CH2:14][CH2:15][NH:16][C:17]=3[C:8]=2[CH:7]=1
Reactant: COCn1c(=O)c2c(c3cc(OCCN(C)C)ccc31)NCCC2
Agent: Cl
Solvent: CCO
Product: CN(C)CCOc1ccc2[nH]c(=O)c3c(c2c1)NCCC3
Temperature: 90 °C
Yield: 84 %

Procedure:
The compound (40 mg, 0.120 mmol) prepared in step 7 was dissolved in ethanol (3 ml), added with 12 N hydrochloric acid (2 ml). The resulting mixture was refluxed for 12 hours at 90° C. Once the reaction was completed, the mixture was concentrated under reduced pressure and the residue was washed ethyl acetate to obtain the title compound (36 mg, yield: 84%, yellow solid).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[C:12]3[CH:13]=[C:14](I)[CH:15]=[C:16]4[C:21]=3[N:20]([CH:22]=2)[N:19]([CH3:23])[CH2:18][CH2:17]4)=[O:9])=[CH:4][CH:3]=1.[CH2:28]([OH:31])[C:29]#[CH:30].C(NCC)C>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[C:12]3[CH:13]=[C:14]([C:30]#[C:29][CH2:28][OH:31])[CH:15]=[C:16]4[C:21]=3[N:20]([CH:22]=2)[N:19]([CH3:23])[CH2:18][CH2:17]4)=[O:9])=[CH:4][CH:3]=1
Reactant: CN1CCc2cc(I)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Reactant: C#CCO
Solvent: CCNCC
Product: CN1CCc2cc(C#CCO)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
A dry flask is charged with N-(4-chlorobenzyl)-5-iodo-1-methyl-7-oxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide (Preparation 40, 0.100 g), cuprous iodide (0.012 g), dichlorobistriphenylphosphine palladium (0.0072 g), propargyl alcohol (0.022 g), and diethylamine (4 mL). The reaction mixture is stirred at room temperature for 5 h and concentrated at reduced pressure. The residue is chromatographed, using 20 g of silica gel packed and eluted with EtOAc/CH2Cl2 (1/1), to obtain the title compound in 74% yield as a tan colored solid. Physical characteristics: M.p. 165-167° C.; 1H NMR (DMSO-d6) δ10.21, 8.67, 8.13, 7.74, 7.38, 5.41, 4.55, 4.35, 3.49, 3.12, 2.85; 13C NMR (DMSO-d6) δ173.69, 162.80, 144.92, 137.79, 133.56, 132.88, 130.54, 128.44, 127.97, 127.49, 126.10, 124.99, 117.98, 109.97, 90.12, 81.73, 48.60, 47.63, 43.24, 40.64, 17.64; MS (ESI+) m/z 422 (M+H)+; HRMS (FAB) m/z 422.1282 (C23H20ClN3O3+H); TLC (silica gel GF): Rf=0.22 acetone/chloroform (1/4).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>C1COCC1.CN(C=O)C>[CH2:26]([NH:28][C:29](=[O:30])[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:27]
Reactant: O=C(Nc1ccc(-c2ccc(CO)cc2)cc1)[C@H]1CN2CCC1CC2
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)OCc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
35 mg (0.10 mmol) of (3R)-N-[4′-(hydroxymethyl)-1,1′-biphenyl-4-yl]-1-azabicyclo-[2.2.2]octane-3-carboxamide are dissolved in 1 ml of a 1:1 THF/DMF mixture. 17 mg (0.21 mmol) of ethyl isocyanate are added, and the mixture is stirred at 60° C. overnight. The solvent is removed under reduced pressure, and the crude product is purified by preparative HPLC. 24 mg (55% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=2)[C:11]([F:22])=[CH:10][C:9]=1[F:23])([CH3:4])([CH3:3])[CH3:2].[S-:25][C:26]#[N:27].[K+].BrBr>C(O)(=O)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:16]=[C:17]3[S:25][C:26]([NH2:27])=[N:21][C:18]3=[CH:19][CH:20]=2)[C:11]([F:22])=[CH:10][C:9]=1[F:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)cn2)c(F)cc1F
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of tert-butyl{5[(5-aminopyridin-2-yl)oxy]-2,4-difluorophenyl}carbamate (8.70 g, 25.8 mmol) and potassium thiocyanate (9.72 g, 100 mmol) in acetic acid (100 mL) was added dropwise bromine (6.39 g, 40 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. The yellow insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution (400 mL), and the mixture was extracted with ethyl acetate (300 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (9.00 g, 88%) as a pale-yellow amorphous.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[C:13](B(O)O)=[CH:12][CH:11]=[CH:10][N:9]=1.Br[C:18]1[CH:31]=[C:30]2[C:21]([O:22][C:23]3[C:24]([F:43])=[CH:25][C:26]([O:41][CH3:42])=[CH:27][C:28]=3[C:29]32[C:35]2=[N:36][CH2:37][CH2:38][CH2:39][N:34]2[C:33]([NH2:40])=[N:32]3)=[CH:20][CH:19]=1>O1CCOCC1.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:43][C:24]1[C:23]2[O:22][C:21]3[C:30](=[CH:31][C:18]([C:13]4[C:8]([F:7])=[N:9][CH:10]=[CH:11][CH:12]=4)=[CH:19][CH:20]=3)[C:29]3([C:35]4=[N:36][CH2:37][CH2:38][CH2:39][N:34]4[C:33]([NH2:40])=[N:32]3)[C:28]=2[CH:27]=[C:26]([O:41][CH3:42])[CH:25]=1
Reactant: OB(O)c1cccnc1F
Reactant: COc1cc(F)c2c(c1)C1(N=C(N)N3CCCN=C31)c1cc(Br)ccc1O2
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(F)c2c(c1)C1(N=C(N)N3CCCN=C31)c1cc(-c3cccnc3F)ccc1O2
Temperature: 100 °C
Yield: 19.3 %

Procedure:
Potassium carbonate (1M aq. Solution) (1.391 mL, 1.391 mmol), 2-fluoropyridin-3-ylboronic acid (98 mg, 0.696 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phospine)dichloropalladium(II) (0.34 mmol) and 7′-bromo-4′-fluoro-2′-methoxy-3,4-dihydro-2H-spiro[imidazo[1,5-a]pyrimidine-8,9′-xanthen]-6-amine (150 mg, 0.348 mmol) were combined in dioxane (3 mL), capped under argon, and heated at 100° C. for 2 hours. The solution was concentrated, and the product was purified from the crude concentrate via silica gel column chromatography (RediSep 12 g column) using 0-100% 90/10/1 (DCM/MeOH/ammonia) in DCM to afford 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-methoxy-3,4-dihydro-2H-spiro[imidazo[1,5-a]pyrimidine-8,9′-xanthen]-6-amine (30 nig, 0.067 mmol). MS m/z=449.2 [M+H].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1F.[O:18]1[C:22]2([CH2:26][CH2:25][NH:24][CH2:23]2)[O:21][CH2:20][CH2:19]1.C(OCC)(=O)C>C(#N)C.O>[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[N:24]1[CH2:25][CH2:26][C:22]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:23]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1CC2(CN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCC3(C2)OCCO3)c(F)c1
Temperature: 75 °C

Procedure:
Potassium carbonate (6.9 g) was added to a mixture of 3,4-difluoronitrobenzene (8.0 g) and 1,4-dioxa-7-aza-spiro[4.4]nonane (12.9 g) in acetonitrile (34.6 mL) and the reaction mixture was heated for 2 h at 75° C. Ethyl acetate and water were added to the reaction mixture. The aqueous phase was extracted several times with ethyl acetate. The organic phases were combined, dried over sodium sulfate and the solvent was removed in vacuum. In this way the product was obtained with molecular weight 268.24 (C12H13FN2O4); MS (ESI): 269 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH2:32].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:32][CH2:31][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: COc1ccccc1CCN
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CCNc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 140 °C
Yield: 16.2 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (500 mg, 1.64 mmol), 2-[2-(methyloxy)phenyl]ethanamine (500 mg, 3.31 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 4 hours at 140° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC (gradient: 10% CH3CN/H2O to 30% CH3CN/H2O) to afford the title compound (100 mg) as a yellow solid. LC-MS (ES) m/z=376 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 2.81-2.84 (m, 2H), 3.52 (m, 2H), 3.74 (s, 3H), 5.37 (s, 2H), 6.01 (s, 2H), 6.28 (s, 1H), 6.76-6.86 (m, 4H), 7.22 (t, J=8.4 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: [CH:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[NH2:20]>>[CH3:16][O:17][C:18](=[O:23])[C:19]([NH:20][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:12]=1)=[O:15])([CH3:22])[CH3:21]
Reactant: O=C(O)c1cccc(C2CCCCC2)n1
Reactant: COC(=O)C(C)(C)N
Product: COC(=O)C(C)(C)NC(=O)c1cccc(C2CCCCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclohexyl-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (LC/MS): 305.1 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[S:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)(O)[O-].[K+].C(=O)=O>C(O)C.O>[CH2:19]([O:18][C:16]([C:15]1[S:10][C:9]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:13][CH:12]=2)=[N:11][C:21]=1[CH3:23])=[O:17])[CH3:20]
Reactant: CC(C)(C)c1ccc(C(N)=S)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])O
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(C(C)(C)C)cc2)nc1C
Temperature: 25 °C
Yield: 87.3 %

Procedure:
The solution of 3.87 g (20 mmol) of 4-tert-butyl-thiobenzamide and 3.45 g (21 mmol) of ethyl 2-chloro-acetoacetate in 15 ml of ethanol was heated at reflux for 3 hours. Afterwards, the reaction mixture was cooled to ambient temperature and a solution of 3 g of potassium bicarbonate in 15 ml of water was added and the mixture was stirred until the gas evolution (CO2) had ceased. The compound was then extracted with 3 portions of 50 ml of tert-butyl methyl ether, the combined organic phases were washed with water, then with brine, dried over anhydrous sodium sulfate and finally evaporated. 5.3 g of 2-(4-tert-butyl-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (87.4% of theory) were obtained as pale yellow viscous oil.
Reaction SMILES: [BH4-].[Li+].[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](OCC)=[O:15])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[H][H].O>O1CCCC1>[C:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][OH:15])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: [H][H]
Reactant: CCOC(=O)C(OC1CCN(C(C)=O)CC1)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(OC(CO)c2ccccc2)CC1
Yield: 98.4 %

Procedure:
Lithium borohydride (3.24 g.) was added portionwise to a solution of α-(N-acetyl-4-piperidinoxy) phenylacetic acid, ethyl ester (11.2 g.) in dry tetrahydrofuran (200 ml.). When the hydrogen evolution had subsided the reaction mixture was heated under reflux for 4 hours. Water was added to the cooled solution, the solvent evaporated in vacuo, then the residue taken up in chloroform (200 ml.) and washed with dilute hydrochloric acid, water and brine. The chloroform extract was dried (MgSO4) and the solvent evaporated in vacuo. Thin layer chromatography analysis of the product indicated that reduction was incomplete, therefore the product in tetrahydrofuran (100 ml.) was treated with a further quantity of lithium borohydride (3.24 g.) and heated under reflux for 4 hours. The reaction mixture was treated as above to give N-acetyl-4-(2-hydroxy-1-phenyl-ethoxy) piperidine (9.5 g.) as an oil which solidified on standing. A sample crystallized from ether and had an m.p. of 92°-94° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([F:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=1[F:17])(=O)=O.[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1>O1CCCC1>[F:13][C:12]1[CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=[C:8]([F:17])[C:7]=1[N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1
Temperature: 70 °C
Reaction time: 56 h
Yield: 63.6 %

Procedure:
2,6-Difluoro-4-nitrophenyl trifluoromethanesulfonate (992 mg, 3.23 mmol) is dissolved in dry tetrahydrofuran (15 mL) and then treated dropwise with thiomorpholine (0.487 mL, 4.85 mmol). The reaction is then heated to reflux (70° C.) under nitrogen for 16 hours. The reaction is then allowed to cool to room temperature, stirring over the weekend (56 hours) under nitrogen. At this time, the reaction is found to be complete by thin layer chromatography. The reaction mixture is concentrated under reduced pressure to yield a yellow solid and then absorbed onto silica gel (25 g). The material is then chromatographed on more silica gel (75 g, packed with hexane), eluting with 5% ethyl acetate/hexane to give 535 mg (64%) of the title compound as a solid, mp: 104-105° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>C(O)C>[CH2:9]([N:11]([CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1)[CH3:10]
Reactant: Clc1ccc(I)cn1
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)c1ccc(I)cn1
Temperature: 120 °C
Reaction time: 24 h
Yield: 39.9 %

Procedure:
To a suspension of 2-chloro-5-iodopyridine (1.0 g, 4.18 mmol) in ethanol (8 ml) was added dropwise diethylamine (0.43 ml, 4.18 mmol). After stirring at 120° C. for 1 day, the mixture was stirred at 150° C. for 6.5 days (2 equivalents of diethylamine was added twice during the reaction). The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give N,N-diethyl-5-iodopyridin-2-amine (460 mg, yield 40%).
Reaction SMILES: C([N:5]1[C:9](=O)[N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[S:6]1)CCC.N#C[Br:16]>ClCCl>[Br:16][C:9]1[N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[S:6][N:5]=1
Reactant: CCCCn1sc2nccn2c1=O
Reactant: N#CBr
Solvent: ClCCl
Product: Brc1nsc2nccn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
To a cooled solution of 2-butylimidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-one (4.78 g, 0.0242 mole) in 25 mL dichloromethane, cyanogen bromide (5.13 g, 0.0482 mole) was added in one portion and the mixture was stirred for 16 h at room temperature. The precipitate was filtered, slurried in 10 mL of methanol and subsequently washed with dichloromethane to give 4.45 g (90%) of 3-bromoimidazo[1,2-d]-1,2,4-thiadiazole as a colourless powder: mp 220° C. (dec); MS m/z 205, 203 (M+). Anal. Calcd for C4H2N3SBr · 1/2 H2O: C, 22.55; H, 1.42; N, 19.72; O, 3.75; S, 15.02; Br, 37.50. Found: C, 22.79; H, 1.41; N, 19.42; O, 2.67; S, 14.61; Br, 38.20.