Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34].[Cl-]>O.ClCCl>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[O:20][S:35]([CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1
Reactant: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(C)CCS3(=O)=O)c1O
Reactant: CCCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)Oc1c(C(=O)c2cc(C)c3c(c2C)C(C)CCS3(=O)=O)cnn1CC
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A 30-ml eggplant type flask was charged with 0.25 g (0.69 mmol) of 4,5,8-trimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide, 5 ml of dichloromethane, 5 ml of water and 0.09 g (0.69 mmol, 1 equivalent) of potassium carbonate, and 0.11 g (0.76 mmol, 1.1 equivalents) of n-propanesulfonyl chloride was dropwise added with stirring at room temperature. 5 mg of benzyltriethylaminonium chloride (BTEAC) was added, and the mixture was allowed to react at the above temperature for 2 hours and then liquid-separated. An aqueous layer was extracted with dichloromethane. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off to give 0.35 g of a crude product, which was recrystalized from ethanol to give 0.31 g (yield 95%) of 4,5,8-trimethyl-6-(1-ethyl-5-n-propanesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 51).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:30])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24]OS(C)(=O)=O)[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[SH:36]>>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][S:36][C:32]3[NH:31][CH:35]=[CH:34][N:33]=3)[N:22]=2)=[O:30])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CCOS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Reactant: Sc1ncc[nH]1
Product: Cc1ccc(NC(=O)Nc2nc(CCSc3ncc[nH]3)cs2)c(C(=O)C2CCCC2)c1
Yield: 49.9 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-{4-[2-(1H-imidazol-2-ylsulfanyl)-ethyl]-thiazol-2-yl}-urea (25 mg, 50%) was prepared from methanesulfonic acid 2-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-ethyl ester (0.05 g, 0.11 mmol) and 1H-imidazol-2-thiol (0.009 g, 0.11 mmol) following the general procedure Z.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[CH:3]=1.[CH3:10][S-:11].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([S:11][CH3:10])[CH:5]=[C:4]([F:9])[CH:3]=1
Reactant: C[S-]
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(F)cc(Br)c1
Temperature: 150 °C

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (5.0 g, 25.9 mmol) in dimethylformamide (40 ml) was added sodiumthiomethylate (1.81 g, 25.9 mmol), and the mixture was heated to 150° C. for 10 min. The reaction mixture was brought to ambient temperature, quenched with saturated aqueous ammonium chloride (100 ml) and extracted with ethylacetate (3×100 ml). The combined organic phases was dried and concentrated in vacuo to receive the pure title compound (3.84 g). MS m/z (rel. intensity, 70 eV) 222 (M+, 100), 220 (M+, 100), 189 (49), 187 (50), 126 (75).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]=2[C:6]=1[OH:20])=[O:4].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([Br:21])[C:8]2[N:11]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:13][C:7]=2[C:6]=1[OH:20])=[O:4]
Reactant: COC(=O)c1ncc2nc(-c3ccccc3)oc2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1O
Yield: 61 %

Procedure:
A suspension of 7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester (3.57 g, 13.2 mmol; example 1d), N-bromosuccinimide (2.47 g, 13.9 mmol), and benzoyl peroxide (320 mg, 1.32 mmol) in 43 mL of benzene was heated at reflux temperature for 5 hours. The reaction mixture was washed successively with saturated sodium bicarbonate, brine, saturated ammonium chloride solution, and brine. The organic solution was dried, filtered, and concentrated. The residue was purified by flash chromatography eluting from silica gel with a gradient of 0-25% methanol in methylene chloride to give 2.81 g of the title compound as a light yellow solid. MS: (+) m/z 348.9, 350.9 (M+1, 79Br/81Br).
Reaction SMILES: [B-](F)(F)(F)F.N#[O+].[NH2:8][C:9]1[C:14]([F:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19](N)=[CH:18][CH:17]=2)[N:12]=[C:11]([C:23]([O:25][CH3:26])=[O:24])[C:10]=1[CH:27]=[CH2:28].[I-:29].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O.CC#N>[NH2:8][C:9]1[C:14]([F:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([I:29])=[CH:18][CH:17]=2)[N:12]=[C:11]([C:23]([O:25][CH3:26])=[O:24])[C:10]=1[CH:27]=[CH2:28]
Reactant: [I-]
Reactant: C=Cc1c(C(=O)OC)nc(-c2ccc(N)cc2)c(F)c1N
Agent: F[B-](F)(F)F
Agent: N#[O+]
Agent: O=S([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: C=Cc1c(C(=O)OC)nc(-c2ccc(I)cc2)c(F)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a 0° C. suspension of nitrosyl tetrafluoroborate (0.041 g, 0.348 mmol) in CH2Cl2 (1 mL) was added a solution of methyl 4-amino-6-(4-aminophenyl)-5-fluoro-3-vinylpicolinate (0.1 g, 0.348 mmol) in a 1:1 mixture of CH2Cl2 and CH3CN (4 mL). The reaction mixture was stirred at 0° C. for 30 min, then a solution of sodium iodide (0.261 g, 1.740 mmol) dissolved in a minimum of water was added and the reaction was stirred at 20° C. for 30 min. The mixture was then poured into a 10% aqueous solution of sodium sulfite and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, hexanes/EtOAc gradient) followed by preparative reverse phase HPLC (water/acetonitrile gradient) to afford the title compound as a white solid (32 mg, 0.080 mmol, 23.09%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[N:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[Cl:16][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:23]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:24])=[CH:13][CH:14]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Oc1ccc(Oc2c(Cl)cncc2Cl)cc1
Product: O=C(Oc1ccc(Oc2c(Cl)cncc2Cl)cc1)N1CCOCC1

Procedure:
The title compound was prepared from 4-(3,5-dichloro-pyridin-4-yloxy)-phenol and morpholine-4-carbonyl chloride. The crude product was purified by preparative HPLC (66%, white crystals. HPLC-MS m/z=368.9 (M+1), Rt: 4.0 min.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])([CH3:17])[CH3:16]>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[O:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:15]([CH3:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: CC(C)c1ccccc1O
Product: CC(C)c1ccccc1Oc1nnc(N)nc1-c1ccccc1
Yield: 4.1 %

Procedure:
5-Phenyl-6-[2-(propan-2-yl)phenoxy]-1,2,4-triazin-3-amine (20 mg, 7%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 2-isopropyl phenol (0.43 g, 3.18 mmol) according to the general procedure of Example 3.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][C@@H:7]([OH:9])[C@H:6]([CH3:10])[CH2:5][CH2:4]1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([C:19]([NH2:21])=[O:20])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>O>[Cl:11][C:12]1[N:17]=[C:16]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@@H:6]([CH3:10])[C@H:7]([OH:9])[CH2:8]2)[C:15]([C:19]([NH2:21])=[O:20])=[CH:14][N:13]=1
Reactant: NC(=O)c1cnc(Cl)nc1Cl
Reactant: C[C@@H]1CC[C@@H](N)C[C@H]1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@H](Nc2nc(Cl)ncc2C(N)=O)C[C@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a reactor was added (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (16.0 kg), 2,4-dichloropyrimidine-5-carboxamide (19.0 kg), K2CO3 (14.9 kg) and THF (160 L) at 25° C. The batch was cooled to 0° C., and water (160 L) was added. The batch was stirred for an additional 1 h at 0° C., warmed to 25° C. and held for 16 h. Water (288 L) was added to the batch while keeping the batch at 25° C., and the batch was cooled to 15° C. and agitated for an additional 4 hs. The batch was filtered, rinsed twice with water (2×80 L), and dried in a vacuum oven at 40° C. with nitrogen bleed for 24 h to give 2-chloro-4-{[(1R,3R,4R)-3-hydroxy-4-methylcyclohexyl]amino}pyrimidine-5-carboxamide as white powder (23.3 kg, 86% yield). 1H NMR (DMSO-d6) δ 0.93 (d, J=5.7 Hz, 3H), 0.97-1.29 (m, 4H), 1.63-1.68 (m, 1H), 1.75-1.88 (m, 1H), 2.09-2.13 (m, 1H), 3.00-3.08 (m, 1H), 3.80-3.95 (m, 1H), 4.65 (d, J=5.1 Hz, 1H), 7.69 (br. s., 1H), 8.20 (br. s., 1H), 8.53 (s, 1H), 9.22 (d, J=7.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][CH2:28][C:29](=[O:31])[CH2:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1.CO[CH:34](OC)[N:35]([CH3:37])[CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH2:27][CH2:28][C:29](=[O:31])/[C:30](=[CH:34]\[N:35]([CH3:37])[CH3:36])/[C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=1
Reactant: Cc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCC(=O)C5)cc2Cl)n1
Reactant: COC(OC)N(C)C
Product: Cc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCC(=O)/C5=C\N(C)C)cc2Cl)n1

Procedure:
The title compound was prepared following the method described for example 98 step 4, utilizing 4-({3-chloro-4-[(6-methylpyridin-2-yl)methoxy]phenyl}amino)-5,8-dihydro[1]benzothieno[2,3-d]pyrimidin-7(6H)-one (435 mg, 1.0 mmol) and dimethylformamide-dimethylacetal (230 mg, 1.9 mmol). The desired product was collected as a yellow solid (302 mg, 62%). 1H-NMR (DMSO-d6) (major rotomer) δ 8.26 (s, 1H), 8.18 (s, 1H), 7.75 (d, 1H), 7.72 (d, 1H), 7.51 (dd, 1H), 7.34 (d, 1H), 7.21 (d, 1H), 7.18 (d, 1H), 7.07 (s, 1H), 5.21 (s, 2H), 3.27 (t, 2H), 3.12 (s, 3H), 3.09 (s, 3H), 2.57 (t. 2H); LCMS RT=2.38 min; [M+H]+=506.1.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[CH:19]=[C:18](Cl)[N:17]=[N:16][C:15]=4[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[CH:19]=[C:18]([C:29]5[CH:30]=[N:25][CH:26]=[N:27][CH:28]=5)[N:17]=[N:16][C:15]=4[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CN1CCc2cc(Cl)nnc2C1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(CN1CCc2cc(-c3cncnc3)nnc2C1)N1CCN(C2CCC2)CC1
Temperature: 80 °C

Procedure:
A mixture of 7-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-3-chloro-5,6,7,8-tetrahydropyrido-[3,4-c]pyridazine (22 mg, 0.06 mmol), 5-pyrimidineboronic acid (12 mg, 0.09 mmol), Pd(PPh)4 (5.5 mg) and Na2CO3 (28 mg, 0.18 mmol) in DME (3 mL) and water (1 mL) is heated overnight at 80° C. Water is added and the mixture is extracted with DCM. The combined organic layers are dried (MgSO4) and solvent is removed in vacuo to give the crude product, which is purified by PTLC (4% TEA in EA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 9.40 (2H, s), 9.36 (1H, s), 7.64 (1H, s), 4.18 (2H, s), 3.84 (4H, m), 3.48 (2H, s), 3.84˜3.16 (4H, m), 2.56-2.64 (1H, m), 2.04-2.20 (4H, m), 1.60-1.98 (6H, m); MS (+VE) m/z 394.2 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=3[N:10]=[C:4]2[CH:3]=1.[F:22][C:23]([F:40])([F:39])[C:24]1[N:29]=[CH:28][C:27]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=2)=[CH:26][CH:25]=1>>[O:38]=[C:34]1[CH:33]=[C:32]([O:31][CH2:30][C:27]2[CH:28]=[N:29][C:24]([C:23]([F:40])([F:22])[F:39])=[CH:25][CH:26]=2)[CH:37]=[CH:36][N:35]1[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=3[N:10]=[C:4]2[CH:3]=1
Reactant: O=c1cc(OCc2ccc(C(F)(F)F)nc2)cc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3cc(Br)ccn3c2C1
Product: CC(C)(C)OC(=O)N1CCc2nc3cc(-n4ccc(OCc5ccc(C(F)(F)F)nc5)cc4=O)ccn3c2C1
Yield: 38.6 %

Procedure:
tert-Butyl 7-bromo-3,4-dihydropyrido[4′,3′:4,5]imidazo[1,2-a]pyridine-2(1H)-carboxylate (175 mg, 0.498 mmol) and 4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (134 mg, 0.498 mmol) were reacted according to Example 18 (step g) to provide the title compound (104 mg, 44%) as a yellow solid: ESI MS m/z 542 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])N.N([O-])=[O:19].[Na+]>O>[Cl:6][C:7]1[CH:8]=[C:9]([OH:19])[CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15]
Reactant: Nc1ccc(C(F)(F)F)c(Cl)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a sulfuric acid (14 ml) —H2O (14 ml) solution of 3-chloro-4-(trifluoromethyl)aniline (1.96 g, 10 mmol) was added a H2O (10 mL) solution of sodium nitrite (828 mg,12 mmol) at 0 ° C. The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was poured into 10 M sulfuric acid (50 mL). The stirred mixture was refluxed at 110 ° C. for 2 hours. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with ethyl acetate The organic layer was then washed with brine, dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a ethyl acetate/hexane=⅓ to furnish 945 mg (48% yield) of the title compound as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23][CH2:24]O)=[CH:21][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:19]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:24][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)Cn1ccc2ccc(OCCc3cc(-c4ccc(C(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with 2-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-ethanol in the presence of di-tert-butyl azodicarboxylate and triphenylphosphine to give (6-{2-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-ethoxy}-indol-1-yl)-acetic acid ethyl ester as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-])=[C:4]2[CH2:9][CH2:10][C@@H:11]([CH3:12])[C:3]=12.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:16][CH:9]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[C@H:11]([CH3:12])[CH2:10]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1CCc2c1c(Cl)nc[n+]2[O-]
Product: CC(=O)OC1C[C@@H](C)c2c(Cl)ncnc21
Yield: 70 %

Procedure:
A solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide (1.45 g, 7.85 mmol) in acetic anhydride (20 mL) was heated to 110° C. for 2 hours. After cooling, excess solvent was removed under vacuum. The residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (3:1) to give (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (1.25 g, 70%). 1H NMR (CDCl3, 400 MHz) δ 8.92 (m, 1H), 6.30-6.03 (m, 1H), 3.60-3.30 (m, 1H), 2.84 (m, 1H), 2.40-2.20 (m, 1H), 2.15 (d, J=6 Hz, 2H), 1.75 (m, 2H), 1.47 (d, J=6.8, 2H), 1.38 (d, J=7.2, 1H). MS (APCI+) [M+H] +227.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[CH:26](/B(O)O)=[CH:27]\[CH3:28].CCO>C1(C)C=CC=CC=1.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>[F:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:8]([C:7]1[C:2](/[CH:26]=[CH:27]/[CH3:28])=[N:3][C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:5][C:6]=1[CH3:19])=[O:9]
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Reactant: C/C=C/B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: C/C=C/c1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 110 °C
Yield: 72.7 %

Procedure:
To a solution of 400 mg (1.1 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide in toluene (15 ml) were added 140 mg (1.7 mmol) (E)-prop-1-enylboronic acid, 1.1 g (3.3 mmol) CsCO3 and EtOH (1.5 ml). After degassing with argon for 15 min 370 mg (0.32 mmol) Pd(PPh3)4 were added and the RM was heated to 110° C. for 5 h. Subsequently the RM was filtered through celite and the filtrate was concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:1) provided 300 mg (0.8 mmol, 74%) (E)-N-(3-fluorobenzyl)-4-methyl-6-morpholino-2-(prop-1-enyl)-pyridine-3-carboxylic acid amide (example 9). [M+H]+ 370.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.OS(O)(=O)=O.O.[C:18](=O)([O-])[O-].[Na+].[Na+]>CO.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:18])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(Br)cnc1N
Yield: 73.9 %

Procedure:
A slurry of 2-amino-5-bromopyridine-3-carboxylic acid (7 g, 32.2 mmol) in methanol (150 mL) and H2SO4 (7 mmol) was heated to reflux for 48 h. The reaction mixture was concentrated to ca. 40 mL. Water (100 mmol) was added to the residual oil, and the mixture neutralized with sodium carbonate. Ethyl acetate (400 mL) was added and the organic layer was washed with saturated aqueous sodium chloride then dried (Na2SO4) and concentrated to give the title compound (5.5 g, 73.9% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](=[O:9])[N:4]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:3]=1[CH3:21].[NH2:22][CH2:23][C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:4]1[C:3]([CH3:21])=[C:2]([Cl:1])[N:7]=[C:6]([NH:22][CH2:23][C@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:5]1=[O:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN
Product: Cc1c(Cl)nc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)c(=O)n1CC(=O)OCc1ccccc1
Yield: 80 %

Procedure:
The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preperation 17) and tert-butyl (2R)-2-(aminomethyl)-1-pyrrolidinecarboxylate [see preparation 52]. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (10:90) changing to (80:20) in 10% increments to afford the title compound as a clear oil, (80%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11].OC1C=C(C)OC(=O)C=1.ClC(OCCC)=O.[Br:32]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>II.C(Cl)(Cl)Cl>[Br:32][C:7]1[C:2]([OH:1])=[C:3]([C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])[C:4](=[O:9])[O:5][C:6]=1[CH3:8]
Reactant: BrBr
Reactant: CCCOC(=O)c1c(O)cc(C)oc1=O
Agent: CCCOC(=O)Cl
Agent: Cc1cc(O)cc(=O)o1
Agent: II
Solvent: ClC(Cl)Cl
Product: CCCOC(=O)c1c(O)c(Br)c(C)oc1=O
Temperature: 5 °C
Reaction time: 168 h
Yield: 40.8 %

Procedure:
A chloroform (100 ml) solution of 4-hydroxy-6-methyl-3-propoxycarbonyl-2-pyrone (6.0 g, 28.3 mmol), synthesized from 4-hydroxy-6-methyl-2-pyrone and propyl chloroformate, was ice cooled, and a chloroform (100 ml) solution of bromine (4.0 ml, 78 mmol) and iodine (140 mg, 0.55 mmol) slowly added dropwise. After stirring for 7 days at 5° C., an aqueous sodium thiosulphate solution was added and separation performed. After drying and concentrating, crystallization was performed from ethanol and there was obtained the bromo-derivative, 5-bromo-4-hydroxy-6-methyl-3-propoxycarbonyl-2-pyrone (3.36 g, 41%), as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[C:14]([O:18][C:19]([N:21]1[CH2:24][CH:23]([CH2:25]OS(C)(=O)=O)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:24][CH:23]([CH2:25][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[CH:8][C:9]2=[O:13])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Reactant: COc1ccc2ncc(=O)[nH]c2c1
Product: COc1ccc2ncc(=O)n(CC3CN(C(=O)OC(C)(C)C)C3)c2c1
Yield: 35.7 %

Procedure:
Using the procedure of Example 2, step 2.i, but starting from 7-methoxy-2(1H)-quinoxalinone (1.00 g; prepared according to WO 2006/134378) and 3-[[(methylsulfonyl)oxy]methyl]-1-azetidinecarboxylic acid tert-butyl ester (1.65 g; prepared according to WO 02/066470), the second eluting compound was isolated as a yellow oil (700 mg, 35% yield).
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:22][O:21]3)=[CH:16][C:15]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(#N)C>O>[C:1]([C:5]([N:7]1[C:8]([NH2:9])=[CH:13][CH:12]=[CH:11][CH:10]1[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:21])[CH2:22][N:38]2[CH2:39][CH2:40][N:35]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][CH2:37]2)=[CH:16][C:15]=1[O:23][CH:24]([CH3:25])[CH3:26])=[O:6])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)Oc1cc(C2CO2)ccc1-c1cccc(NC(=O)C(C)(C)C)n1
Reactant: c1ccc(CCN2CCNCC2)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)Oc1cc(C(O)CN2CCN(CCc3ccccc3)CC2)ccc1C1C=CC=C(N)N1C(=O)C(C)(C)C
Temperature: 80 °C
Yield: 61.1 %

Procedure:
To a 25 mL round-bottomed flask equipped with condenser and N2 inlet were added 300 mg (0.847 mmol) N-t-butylcarbonyl-6-(2-isopropoxy-4-oxiranylphenyl)-pyridin-2-ylamine, 193 mg (1.017 mmol) N-phenethylpiperazine, 9 mL acetonitrile, and 0.85 mL water. The reaction was heated to 80° C. for 20 hours, cooled, and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride/ammonium hydroxide as eluant to afford 283 mg (62%) of an off-white foam.