Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Cl[C:14]1[N:15]=[C:16]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:17]2[S:22][C:21]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[CH:20][C:18]=2[N:19]=1>CN(C=O)C.O>[CH3:31][N:30]([CH3:32])[CH:27]1[CH2:28][CH2:29][N:24]([CH2:23][C:21]2[S:22][C:17]3[C:16]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:15][C:14]([N:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[CH:10]=[C:2]4[CH3:1])=[N:19][C:18]=3[CH:20]=2)[CH2:25][CH2:26]1
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Temperature: 150 °C
Yield: 12.1 %

Procedure:
A solution of 2-methylindole (0.131 g) in DMF (8 mL) was cooled to 0° C. then sodium hydride (0.06 g) added. After 15 min [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.395 g) was added. The reaction vessel was sealed and heated at 150° C. After 1 h the reaction mixture was cooled to room temperature and diluted with water. The resulting precipitate was collected by filtration then purified by chromatography (silica, 0 to 20% of a 49:1 MeOH:NH4OH mixture in dichloromethane) to furnish the title compound (0.059 g, 12%) as a light brown solid. MS m/e 491 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.33-1.57 (m, 2H) 1.74 (d, J=12.43 Hz, 2H) 2.08 (t, J=10.55 Hz, 3H) 2.18 (s, 6H) 2.64 (s, 3H) 2.95 (d, J=11.30 Hz, 2H) 3.74-3.87 (m, 6H) 3.89-4.04 (m, 4H) 6.42 (s, 1H) 6.98-7.20 (m, 2H) 7.37 (s, 1H) 7.43-7.56 (m, 1H) 8.03 (d, J=7.54 Hz, 1H)
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH:24]([OH:26])[CH3:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(=O)(O)[O-]>C(Cl)Cl>[F:29][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([O:26][S:38]([CH3:37])(=[O:40])=[O:39])[CH3:25])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4]
Reactant: CC(O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a stirred solution of 2,2-Difluoro-1-((4S,5R)-4-fluoromethyl-5-{4-[6-(1-hydroxy-ethyl)-pyridin-3-yl]-phenyl}-2,2-dimethyl-oxazolidin-3-yl)-ethanone (2.2 g, 5.39 mmol) in CH2Cl2 (25 mL) is added triethylamine (1.51 mL, 10.78 mmol) and methane sulfonyl chloride (0.527 mL, 6.47 mmol). Reaction mixture is stirred at 0° C. for 30 minutes then diluted using saturated bicarbonate solution and extracted with CH2Cl2 (30 mL) Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combiflash using 45% ethyl acetate in hexane as an eluent to afford the title compound (1.8 g). 1H NMR (400 MHz, DMSO-d6) δ: 1.53 (s, 3H), 1.60 (s, 3H), 1.68 (d, J=6.56 Hz, 3H), 3.21 (s, 3H), 4.54-4.58 (m, 0.5H), 4.66-4.71 (m, 1H), 4.81-4.84 (m, 0.5H), 4.90-4.95 (m, 1H), 5.27 (d, J=3.92 Hz, 1H), 5.79-5.84 (m, 1H), 6.64 (t, J=52.24, 1 H), 7.60-7.63 (m, 3H), 7.81 (d, J=8.2 Hz, 2H), 8.17-8.20 (dd, J1=8.08 Hz, J2=2.24 Hz, 1H), 8.92 (d, J=2.00 Hz, 1H). LC-Ms (m/z): 487.1 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH:10]12[O:15][CH:14]1[CH2:13][CH2:12][CH2:11]2.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:13]2[CH2:12][CH2:11][CH2:10][C@H:14]2[OH:15])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: C1CC2OC2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCC#N
Product: O[C@@H]1CCC[C@H]1Oc1ccc(Br)c(F)c1

Procedure:
4-Bromo-3-fluorophenol (8.00 g, 41.9 mmol) and 6-oxabicyclo[3.1.0]hexane (8.25 mL, 95.2 mmol) were combined in butyronitrile (5.0 mL) and treated with sodium carbonate (4.04 g, 38.1 mmol). The reaction was subjected to microwave irradiation for 2 hours at 175° C., then filtered through Celite®. The filter cake was washed with ethyl acetate, then dichloromethane, and the combined filtrates were concentrated under reduced pressure to provide product as a dark brown oil. This material was used without additional purification. Yield: 11.59 g, >41.9 mmol, assumed quantitative. 1H NMR (400 MHz, CDCl3) δ 1.61-1.89 (m, 5H), 2.02-2.24 (m, 2H), 4.30 (m, 1H), 4.46 (m, 1H), 6.63 (ddd, J=8.9, 2.8, 1.1 Hz, 1H), 6.73 (dd, J=10.5, 2.8 Hz, 1H), 7.40 (dd, J=8.9, 8.0 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[C:11]3[N:16]=[N:17][N:18]([CH3:19])[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].CS(O[CH2:29][C@H:30]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:31]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.C(OCC)(=O)C>[CH3:19][N:18]1[C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([O:1][CH2:29][C@H:30]4[CH2:34][CH2:33][N:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=5)[CH2:31]4)=[C:3]([C:20]([F:23])([F:22])[F:21])[CH:4]=3)[N:13]=[C:12]([C:14]#[N:15])[C:11]=2[N:16]=[N:17]1
Reactant: CS(=O)(=O)OC[C@H]1CCN(c2ccccn2)C1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(O)c(C(F)(F)F)c3)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OC[C@H]4CCN(c5ccccn5)C4)c(C(F)(F)F)c3)cc21

Procedure:
6-(4-Hydroxy-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (0.313 mmol, 0.1 g), (S)-(1-(pyridin-2-yl)pyrrolidin-3-yl)methyl methanesulfonate (0.376 mmol, 0.096 g), cesium carbonate (0.470 mmol, 0.153 g) and tetrabutylammonium idodide (0.157 mmol, 0.058 g) were stirred in DMF (1 ml) at 50° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water and dried over Na2SO4. The resulting residue was triturated with ether and filtered. The solid was sonicated in methanol, filtered and dried to afford (S)-1-methyl-6-(4-((1-(pyridin-2-yl)pyrrolidin-3-yl)methoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile. (0.032 g)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]([OH:16])[CH:15]=1)[C:12](=[O:17])[C:11]1[C:6](=[CH:7][CH:8]=[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]3=1)[O:5]2.[CH2:22]1[S:24][CH:23]1[CH2:25]Cl>CC(C)=O>[OH:16][C:14]1[CH:15]=[C:2]([O:1][CH2:25][CH:23]2[CH2:22][S:24]2)[CH:3]=[C:4]2[C:13]=1[C:12](=[O:17])[C:11]1[C:6](=[CH:7][CH:8]=[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]3=1)[O:5]2
Reactant: ClCC1CS1
Reactant: O=c1c2c(O)cc(O)cc2oc2ccc3ccccc3c12
Solvent: CC(C)=O
Product: O=c1c2c(O)cc(OCC3CS3)cc2oc2ccc3ccccc3c12
Temperature: 57.5 °C
Yield: 43.3 %

Procedure:
9,11-dihydroxy-12H-benzo[a]xanthen-12-one (0.1 g, 0.18 mmol) prepared in Step 1 of Examples 14 and 15, CS2CO3 (0.36 g, 0.54 mmol), and anhydrous acetone (13 mL) were charged to a dry round-bottom flask, and epithiochlorohydrin (0.2 g, 1.08 mmol) dissolved in anhydrous acetone (2 mL) was added thereto with stirring. The reaction mixture was stirred with reflux overnight at a temperature of 55 to 60° C. under a nitrogen atmosphere. Solid of the reaction mixture was filtered, removed and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:3 (v/v)) to give a yellow solid compound 11-hydroxy-9-(thiiran-2-ylmethoxy)-12H-benzo[a]xanthen-12-one (27.3 mg, 21.7%) and a yellow solid compound 9,11-bis(thiiran-2-ylmethoxy)-12H-benzo[a]xanthen-12-one (31.2 mg, 20.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C1([O:24][C:25](=O)[NH:26][CH2:27][CH:28]2[CH2:33][CH2:32][C:31]([N:40]([CH3:42])[CH3:41])([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)C=CC=CC=1>O1CCOCC1>[CH3:41][N:40]([CH3:42])[C:31]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:32][CH2:33][CH:28]([CH2:27][NH:26][C:25]([N:15]2[CH2:16][CH2:17][CH:12]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:8][CH:7]=3)[CH2:13][CH2:14]2)=[O:24])[CH2:29][CH2:30]1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Reactant: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Solvent: C1COCCO1
Product: COc1ccc2[nH]cc(C3CCN(C(=O)NCC4CCC(c5ccccc5)(N(C)C)CC4)CC3)c2c1
Yield: 30.1 %

Procedure:
In each case 5-methoxy-3-piperidine-4-yl-1H-indole (169.3 mg, 0.735 mmole) in dioxane (4.5 ml) and the diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester (259.0 mg, 0.735 mmole) were dissolved in two microwave reaction vessels. The reaction mixture was treated with microwave radiation as follows: experiment 1 (150° C., 52 minutes) and experiment 2 (200° C., 2 minutes). In each experiment the reaction mixture was worked up by distilling off the solvent in vacuo. The respective residue contained, apart from phenol, also the two diastereomers of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (30 g and 40 g). Methanol/EE (1:1, ca. 600 ml) was used as eluent. The non-polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide [experiment 1 (116 mg, m.p. 106°-107° C., 32%) and experiment 2 (89 mg, m.p. 110°-112° C., 25%)], and the polar diastereoisomer of 4-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide [experiment 1 (108 mg, m.p. 98°-100° C., 30%) and experiment 2 (92 mg, m.p. 92°-97° C., 26%)] were thereby obtained in pure form.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:17][C:18]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH2:20].Cl>CC(O)CCC>[ClH:1].[F:17][C:18]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH:20][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: COCCOc1ccc2c(Cl)cnnc2c1
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CCCC(C)O
Product: COCCOc1ccc2c(Nc3cc(O)c(C)cc3F)cnnc2c1
Yield: 83.8 %

Procedure:
A solution of 4-chloro-7-(2-methoxyethoxy)cinnoline (156 mg, 0.65 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (111 mg, 0.78 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (8 ml) and 5M isopropanolic hydrogen chloride (1 ml) was heated at 120° C. for 2.5 hours. The solid was filtered off washed with isopropanol and then ether and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)cinnoline hydrochloride (207 mg, 84%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].[OH:10][C:11]([CH3:19])([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][SH:13].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH:5]([C:6]([OH:8])=[O:7])[S:13][CH2:12][C:11]([OH:10])([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCC(C)(O)CS
Reactant: COC(=O)/C=C\C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCC(C)(O)CSC(CC(=O)OC)C(=O)O
Reaction time: 3 h

Procedure:
A mixture of 2.6 g of maleic acid monomethyl ester, 3.2 g of 2-hydroxy-2-methylheptane-1-thiol, 0.5 ml of pyridine and 120 ml of methylene chloride is stirred for 3 hours at 30°. After the usual working up, 6-hydroxy-3-hydroxycarbonyl-6-methyl-4-thiaundecanoic acid methyl ester is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24](F)[N:23]=4)=[CH:20][N:21]=3)[N:18]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=[O:31])C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]4[N:23]=[C:24]([OH:31])[CH:25]=[CH:26][CH:27]=4)=[CH:20][N:21]=3)[N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc([C@H]2CCCN2c2ccc3ncc(-c4cccc(F)n4)n3n2)c1
Reactant: CC(=O)O
Solvent: ClCCl
Product: Oc1cccc(-c2cnc3ccc(N4CCC[C@@H]4c4cccc(F)c4)nn23)n1
Temperature: 120 °C

Procedure:
In step 16-1, a suspension of (R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazine (16 g, 42 mmol) in acetic acid (150 mL) was heated overnight at 120° C. (approx. 20 hours). The suspension turned clear after heating. The mixture was concentrated under vacuum to give a brown oil. The oil was dissolved in CH2Cl2 (750 mL) and washed with saturated NaHCO3 (300 mL×3), brine (300 mL×2). The organic layer was separated, dried over (Na2SO4) and concentrated to give 15.5 g of the crude (R)-6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-ol (16-1) which was used in the next step without further purification. LC/MS: 376.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1.[NH2:13][CH2:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])[CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CC(O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]([NH:9][CH:10]=[O:11])=[C:6]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])[N:20]=2)[N:7]=1
Reactant: NCc1cccc(N2CCCC2=O)n1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)c(NC=O)c(NCc2cccc(N3CCCC3=O)n2)n1
Yield: 54.1 %

Procedure:
A mixture of N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (3.61 g, 17.43 mmol) and 1-(6-aminomethylpyridin-2-yl)pyrrolidin-2-one (containing triphenylphosphine oxide) (10.00 g, ca. 50 mmol) and triethylamine (4.86 mL, 34.86 mmol) in propan-2-ol (100 mL) was heated at reflux for 18 h, cooled and the resulting precipitate filtered to give the title compound (3.41 g) as an off-white solid; NMR δH (400 MHz, d6-DMSO) 9.21 (1H, s), 8.20 (1H, d, J 1 Hz), 8.12 (1H, d, J 8.5 Hz), 7.73 (1H, t, J 7.5 Hz), 7.38 (1H, t, J 6 Hz), 7.02 (1H, d, J 7.5 Hz), 6.45 (2H, br s), 4.53 (2H, d, J 6.0 Hz), 4.00-3.95 (2H, m), 2.57 (2H, t, 18.0 Hz) and 2.08-2.00 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[CH3:26]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[C:18]([CH3:26])[CH:19]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1cc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)ccc1F

Procedure:
The title compound, MS: m/e=326.4 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-fluoro-3-methyl-benzene boronic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][S:6][C:7]1[C:11]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[N:10][S:9][N:8]=1)[CH3:2].S(=O)(=O)(O)[OH:20].B1([O-])OO1.O.O.O.O.[Na+]>CO>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][S:6]([C:7]1[C:11]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[N:10][S:9][N:8]=1)=[O:20])[CH3:18]
Reactant: O=S(=O)(O)O
Reactant: CCN(CC)CCSc1nsnc1-n1ccnc1
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CO
Solvent: O
Product: CCN(CC)CCS(=O)c1nsnc1-n1ccnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A cold (0° C.) solution of the compound of Example 10 in methanol istreated slowly with excess 30% sulfuric acid an then sodium perborate tetrahydrate (10 equivalents) is added. The mixture is stirred at 0° C. for 2 hrs and then at ambient temperature for 2 hrs. The methanol is removed in vacuo and the residue basified with 50% sodium hydroxide and filtered. The filter cake is washed with methylene chloride and the aqueous filtrate extracted with the methylene chloride washings. The combined extract is washed with water, dried, and concentrated to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:13]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[CH:8]([NH2:10])[CH3:9].CCN(C(C)C)C(C)C.Cl[C:34]1[N:39]=[C:38]([NH:40][C:41]2[CH:45]=[C:44]([CH:46]3[CH2:48][CH2:47]3)[NH:43][N:42]=2)[CH:37]=[CH:36][N:35]=1>CC(C(O)C(C)C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:13]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[CH:8]([NH:10][C:34]1[N:39]=[C:38]([NH:40][C:41]2[CH:45]=[C:44]([CH:46]3[CH2:48][CH2:47]3)[NH:43][N:42]=2)[CH:37]=[CH:36][N:35]=1)[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)N)c(Cl)cc32)cc1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: CC(C)C(O)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)Nc4nccc(Nc5cc(C6CC6)[nH]n5)n4)c(Cl)cc32)cc1
Temperature: 140 °C
Yield: 142.2 %

Procedure:
A mixture of 1-(6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (180 mg, 0.51 mmol), DIPEA (133 mg, 1.03 mmol), and 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (97 mg, 0.41 mmol) in 2,4-dimethyl-3-pentanol (0.5 mL) was heated at 140° C. for 18 h. The reaction mixture was concentrated under reduced pressure to afford a crude 320 mg (41%) of N2-(1-(6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as brown solid, which was used in the next step without further purification. MS (ESI): m/z=549.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[F:15][C:16]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[F:15][C:16]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: Nc1ccc(F)cc1F
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(F)cc1F

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2,4-difluoroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].ClC(OCC)=O.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([NH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:9])(=[O:3])[CH3:2]
Reactant: NCCN1CCOCC1
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)SCC(CC(C)C)C(=O)NCCN1CCOCC1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 51.6 %

Procedure:
2-[(Acetylthio)methyl]-4-methylpentanoic acid (2.0 g) is dissolved in 40 ml of tetrahydrofuran (THF) and 1.0 g of triethylamine. This solution is cooled to -5° C. and ethyl chloroformate in 5 ml of THF is added dropwise. The reaction mixture is stirred at -5° C. for 20 minutes and then N-(2-aminoethyl)morpholine [1.3 g] in 20 ml of THF is added dropwise. It is stirred at 20° C. for 4 hours and stored at 0° C. for about 16 hours. Triethylamine hydrochloride is filtered off and the filtrate is concentrated in vacuo. This residue is dissolved in ether and washed once with aqueous NaHCO3 and twice with water. The ether is dried with MgSO4, filtered and concentrated in vacuo to yield 1.6 g of material. This is purified by dissolving 0.6 g in 2 ml of ether and placing it on top of a pad of alumina (activity II 10 g). The column is washed through with 250 ml of ether which is concentrated in vacuo. Product crystallizes and is washed with 1:5 ether-pentane. The remainder of the crude is seeded with a small crystal and then washed with 1:5 ether-pentane. Total yield is 1.0 g of the title compound, melting point 54°-59° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.Br.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[N:31]1[CH:32]=[CH:33][C:28]([C:26]2[CH2:25][O:21][C:20](=[O:22])[C:19]=2[C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:18][CH:17]=2)=[CH:29][CH:30]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 15.2 %

Procedure:
To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (3.0 g, 0.01 mol) in acetonitrile (40 mL) were added TEA (1.3 mL, 0.01 mol) and 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (2.86 g, 0.01 mol) at RT under an inert atmosphere. The reaction mixture was stirred for 1 h and then cooled to 0° C. DBU (46.6 g, 0.03 mol) was then added and the reaction mixture was stirred for 2 h at 0° C. and quenched with HCl (1 N). The aqueous layer was basified with a NaHCO3 solution and extracted with DCM (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 25% EtOAc in hexanes to afford 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (600 mg, 15%) as a solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])[S:6][CH:7]=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31].CN(C)C=O.[H-].[Na+]>O>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][CH2:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[N:4]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCc1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1OCc1csc(CCc2nc(-c3ccccc3)oc2C)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.5 %

Procedure:
To a mixture of 4-[2-(4-chloromethyl-2-thiazolyl)ethyl]-5-methyl-2-phenyloxazole (0.64 g), methyl 2-(2-hydroxyphenyl)acetate (0.30 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.09 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water, 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetate as a colorless oil (0.49 g, 60%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[O:21][CH3:22]>N1C=CC=CC=1>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:16][C:15]=1[O:21][CH3:22]
Reactant: COc1cc(N)ccc1Cl
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccc(Cl)c(OC)c1

Procedure:
Prepared according to Procedure A using diethyl 2-methylmalonate (4.91 mL, 28.6 mmol), pyridine (3.1 mL) and 4-chloro-3-methoxyaniline (3.00 g, 19.04 mmol). The reaction mixture was heated for 5 days. The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(4-chloro-3-methoxyphenylamino)-2-methyl-3-oxopropanoate. Mass Spectrum (ESI) m/e=286.1 (M+1).