Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]2[N:16]=[N:17][C:18]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[C:4]2[N:3]=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>CN(C=O)C>[CH2:28]([N:30]([CH2:31][CH3:32])[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]2[N:16]=[N:17][C:18]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[C:4]2[N:3]=1)[CH3:29]
Reactant: CCNCC
Reactant: COc1cc2c(Cl)nc3c(S(=O)(=O)c4ccccc4)nnn3c2cc1OC
Solvent: CN(C)C=O
Product: CCN(CC)c1nc2c(S(=O)(=O)c3ccccc3)nnn2c2cc(OC)c(OC)cc12
Temperature: 40 °C
Yield: 80.4 %

Procedure:
A mixture of 5-chloro-7,8-dimethoxy-3-(phenylsulfonyl)-[1,2,3]triazolo[1,5-a]quinazoline (25 mg, 0.062 mmol) and diethylamine (32 uL, 0.31 mmol) in DMF (2 mL) was heated at 40° C. for 1.5 hrs. After removal of the solvent, the residue was purified by column chromatography on silica gel eluting with 40% ethyl acetate in hexane to yield the desired product (22 mg, 82%). 1H NMR (CDCl3, 600 MHz) δ 8.23 (d, 2H, J=7.2 Hz), 7.93 (s, 1H), 7.55-7.52 (m, 1H), 7.49-7.57 (m, 2H), 7.32 (s, 1H), 4.10 (s, 3H), 3.99 (s, 3H), 3.76 (q, 4H, J=7.2 Hz), 1.46 (t, 6H, J=7.2 Hz); MS (ES+) m/z 442.1 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.[N:10]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19](Br)=[N:20][CH:21]=2)[CH:14]=[CH:13][N:12]=[CH:11]1>>[N:10]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)=[N:20][CH:21]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1cncnc1
Product: c1cn(Cc2ccc(-c3cncnc3)nc2)cn1

Procedure:
Synthesized using pyrimid-5-ylboronic acid (155 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 121 mg, 0.51 mmol, 81%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.23 (s, 2H), 6.93 (t, J=1.3 Hz, 1H), 7.12 (t, J=1.3 Hz, 1H), 7.57 (dd, J=8.2, 2.5 Hz, 1H), 7.67 (s, 1H), 7.74 (dd, J=8.2, 0.9 Hz, 1H), 8.62 (m, 1H), 9.23 (s, 1H), 9.29 (s, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 119.0, 120.5, 130.1, 131.6, 131.8, 136.1, 137.3, 149.2, 152.1, 155.0, 158.8; MS (ESI): m/z=238.10 [M+H]+.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]=[C:7]([NH:15][CH2:16][CH:17]=[CH2:18])[C:8]2[S:13][CH:12]=[C:11](Br)[C:9]=2[N:10]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:22])[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+]>[Cu]>[CH2:1]([NH:4][C:5]1[N:6]=[C:7]([NH:15][CH2:16][CH:17]=[CH2:18])[C:8]2[S:13][CH:12]=[C:11]([NH:22][CH2:19][CH:20]=[CH2:21])[C:9]=2[N:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: C=CCNc1nc(NCC=C)c2scc(Br)c2n1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCNc1nc(NCC=C)c2scc(NCC=C)c2n1
Yield: 72.6 %

Procedure:
120 mg (0.37 mmol) of 2,4-diallylamino-7-bromothieno[3,2-d]pyrimidine, 337 mg (5.9 mmol) of allylamine, 56 mg (0.41 mmol) of potassium carbonate and 1 mg of copper were heated in a sealed tube at 180° C. for 5 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by distilling off excess allylamine under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 81 mg (yield: 72.9%) of the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:44])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38](Cl)=[N:37][N:36]2[C:42]=1[CH3:43])=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH2:25]([O:27][C:28](=[O:44])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:37][N:36]2[C:42]=1[CH3:43])=[O:32])[CH3:26]
Reactant: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2c1C
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1C
Temperature: 95 °C
Reaction time: 15 h
Yield: 35.8 %

Procedure:
1.17 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.891 g of N-(6-chloro-3-methylimidazo[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester were dissolved in 10 ml of 1-methyl-2-pyrrolidone; 0.517 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100° C.) for 15 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (90:10:1). The desired fraction was collected and recrystallized with ethyl acetate-ethyl ether (1:1) to yield 0.629 g of the title compound.
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:10])[NH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]Cl.[H-].[Na+]>CN(C)C=O.O>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][N:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][S:1][C:5]=2[C:6]1=[O:10]
Reactant: CN(C)CCCl
Reactant: O=c1[nH]ccc2ccsc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCn1ccc2ccsc2c1=O
Temperature: 80 °C
Yield: 88.6 %

Procedure:
To a solution of thieno[2,3-c]pyridin-7(6H)one (2.92 g, 19.3 mmol) in dry dimethylformamide (20 ml) under a nitrogen atmosphere was added 2-(dimethylamino)ethyl chloride hydrochloride (3.15 g, 21.8 mmol). This mixture was warmed to 80° C. and sodium hydride in mineral oil (60%, 2.6 g, 65 mmol) was added carefully and rapidly. After 1.5 hours additional 2-(dimethylamino)ethyl chloride hydrochloride (1.45 g, 10 mmol) was added. After two hours the reaction mixture was cooled and diluted with water. The crude product was extracted into chloroform and then into dilute hydrochloric acid. The acidic solution was made basic with sodium hydroxide and the product extracted into diethyl ether. This was dried over anhydrous sodium sulfate, filtered and evaporated to give an oily product (3.8 g, 89% yield) which contained less than 10% of the by-product resulting from O-alkylation.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O1CCCC1>[CH3:23][S:24]([O:1][CH2:2][CH:3]([NH:5][C:6]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])[CH3:4])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.6 %

Procedure:
In tetrahydrofuran (400 ml) were dissolved 46.5 g (222 mmol) of benzyl (2-hydroxy-1-methylethyl)carbamate and 26.96 g (266 mmol) of triethylamine, and a solution of 27.96 g (244 mmol) of methanesulfonyl chloride in tetrahydrofuran was slowly dropped thereinto at 0° C. After the resulting mixture was stirred at room temperature for 5 hours, the triethylamine hydrochloride precipitated was filtered under reduced pressure and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and water was added thereto, followed by three runs of extraction with ethyl acetate. The extract solution was washed with saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off and the crude crystals thus obtained were washed twice with a solvent (hexane:ethyl acetate=4:1) to obtain 49.5 g (yield 78%) of 2-(benzyloxycarbonylamino)propyl methanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[NH:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:50]([CH2:57][CH2:58][NH:59][C:60](=[O:62])[CH3:61])=[CH:49]1.[H-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:60]([NH:59][CH2:58][CH2:57][C:50]1[C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:48]([CH2:32][CH2:31][O:30][CH:18]2[CH:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]4[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=4[O:2][CH3:1])=[CH:16][CH:15]=3)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]2)[CH:49]=1)(=[O:62])[CH3:61]
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCn2cc(CCNC(C)=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of 0.20 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.067 g of N-[2-(1H-indol-3-yl)ethyl]acetamide in 7 ml of N,N-dimethylformamide is admixed at 0° C. with 0.024 g of sodium hydride dispersion (60%) and stirred at room temperature over 20 hours. The reaction mixture is poured onto saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.35 (EtOAc); Rt=5.69.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:24])([C:7]3[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:25].CN(C)C=O>C(O)C.[Pd]>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:24])([C:7]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:25]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(C=Cc4ccccc4)cc3CC[C@@H]12
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(CCc4ccccc4)cc3CC[C@@H]12

Procedure:
A 150 mg portion of the product of Example 279 was hydrogenated on a Parr apparatus at 40 p.s.i. in 50 mL of ethanol containing 5 mL of dimethylformamide and 20 mg of 10% palladium/carbon catalyst. When the starting material had been consumed, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel, eluting with 90% ethyl acetate/hexane to obtain a product which was recrystallized from ethyl acetate/hexane to produce the desired product. m.p. 109°-111°.
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][S:14][C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH:9]=[CH:10][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][S:14][C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccccc1SCCc1cccc(OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccccc1SCCc1cccc(O)c1
Reaction time: 8 h
Yield: 77.3 %

Procedure:
Methyl 2-{[2-(3-tert-butoxyphenyl)ethyl]thio}benzoate (402 mg, 1.167 mmol) was dissolved in DCM (3 ml). Trifluoroacetic acid (3 ml) was added. The mixture was stirred overnight and then evaporated to dryness. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using ethyl acetate/heptane (2.5:97.5, then 5:95, then 10:90 and then 25:75) as eluant gave 260 mg the desired product, yield 77%. 1H NMR (500 MHz, CDCl3): δ 2.94 (t, 2H), 3.17 (t, 2H), 3.95 (s, 3H), 6.18 (s, 1H) 6.77-6.83 (m, 3H), 7.18 (t, 2H), 7.34 (d, 1H), 7.44 (t, 1H) and 7.99 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OC)=[O:23])[N:4]=1)#[N:2].[NH2:26][CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:26][CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:23])[N:4]=1)#[N:2]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3cccc(F)c3)ccc2c1O
Reactant: CCOC(=O)C(C)(C)CN
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cccc(F)c3)ccc2c1O

Procedure:
Methyl 1-cyano-7-(3-fluorophenoxy)-4-hydroxyisoquinoline-3-carboxylate (18 mg, 0.05 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (31 mg, 0.21 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 22 mg. MS: (−) m/z 450.30 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)(=[O:7])=[O:6].Cl.CCN(CC)CC.[C:27](Cl)(=[O:29])[CH3:28]>C(Cl)Cl>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:27](=[O:29])[CH3:28])[CH2:10][CH2:9]1)(=[O:6])=[O:7]
Reactant: NC1CCN(S(=O)(=O)Cc2ccccc2Br)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(S(=O)(=O)Cc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a mixture of 1-(2-bromobenzylsulfonyl)piperidin-4-amine.HCl (200 mg, 0.54 mmol) and Et3N (164 mg, 1.62 mmol) in dry DCM (20 mL) was added acetyl chloride (85 mg, 1.1 mmol) drop-wise at rt. The reaction mixture was stirred at rt for 2 hours before concentrating to dryness and purifying the residue by HPLC to give the title compound (180 mg, 89%). MS (ESI): mass calcd. for C14H19BrN2O3S, 374.03; m/z found, 374.8 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)=[O:3].[F:12][C:13]1[CH:14]=[C:15]([C:20]2([O:30][CH3:31])[CH2:24][CH2:23][N:22]([CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:21]2)[CH:16]=[C:17](F)[CH:18]=1>>[C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:17]2[CH:16]=[C:15]([C:20]3([O:30][CH3:31])[CH2:24][CH2:23][N:22]([CH2:25][C:26]([F:27])([F:28])[F:29])[CH2:21]3)[CH:14]=[C:13]([F:12])[CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:1]
Reactant: COC1(c2cc(F)cc(F)c2)CCN(CC(F)(F)F)C1
Reactant: CC(=O)Nc1ccc(S)cc1
Product: COC1(c2cc(F)cc(Sc3ccc(NC(C)=O)cc3)c2)CCN(CC(F)(F)F)C1
Yield: 54 %

Procedure:
Using an analogous procedure to that described in Example 6, 4-mercaptoacetanilide was reacted with 3-(3,5-difluorophenyl)-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine to give 3-[3-(4-acetamidophenylthio)-5-fluorophenyl]-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine in 54% yield, m.p. 127°-129° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][O:24][C:25]([CH2:27]P(OC)(OC)=O)=[O:26]>>[CH3:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[CH:27][C:25]([O:24][CH3:23])=[O:26])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1sc(COc2ccc(C=O)cc2)nc1-c1ccccc1
Reactant: COC(=O)CP(=O)(OC)OC
Product: COC(=O)C=Cc1ccc(OCc2nc(-c3ccccc3)c(C)s2)cc1

Procedure:
According to the method described for Reference Example 22, 4-(5-methyl-4-phenyl-2-thiazolylmethoxy)benzaldehyde was allowed to react with trimethyl phosphonoacetate to give methyl 4-(5-methyl-4-phenyl-2-thiazolylmethoxy)cinnamate. Recrystallization from ethyl acetate--hexane gave colorless prisms, m.p.142°-143° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[Na+]>C(#N)C>[C:18]([O:21][CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1)(=[O:20])[CH3:19]
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cc(COC(C)=O)nc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (1.62 g, 5.17 mmol, from Step A) was dissolved in acetonitrile (15 mL) and sodium acetate (2.8 g, 34 mmol) was added. The mixture was heated to 80° C. for 4 hours, then stood at room temperature overnight. Acetonitrile was removed in vacuo. The residue was partitioned between water and ethyl acetate and the aqueous layer was extracted with two further portions of ethyl acetate. The combined extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-60% ethyl acetate/hexane afforded purified product. Yield: 0.95 g (63%); LC-MS: 293.0 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.15 (s, 1H), 5.36 (s, 2H), 4.53 (q, 2H), 2.25 (s, 3H), 1.46 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24](I)[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:29]([OH:32])[C:30]#[CH:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:31]#[C:30][CH2:29][OH:32])[CH:25]=[CH:26][C:17]=4[C:16]=3[N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C#CCO
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(I)cc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C#CCO)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method O, 2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-30) and prop-2-yn-1-ol were converted to I-52 (38%): HRMS Calcd. for C23H20N4O4: 417.1562, Found 417.1551.
Reaction SMILES: [CH3:1][C:2]#[N:3].C([Li])CCC.Br[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=1>C1COCC1>[Br:16][C:12]1[N:11]=[C:10]([CH2:1][C:2]#[N:3])[CH:15]=[CH:14][CH:13]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCc1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of MeCN (14.29 mL, 274 mmol) in THF (300 mL) at −78° C. was added n-butyllithium (2.5 Min hexanes, 100 mL, 251 mmol). After stirring for 30 minutes at −78° C., 2,6-dibromopyridine (18.0 g, 76 mmol) in THF (100 mL) was added. The reaction was stirred at −78° C. for 45 minutes, warmed to room temperature over 45 minutes, and quenched with water. The mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica, 0-40% ethyl acetate/hexanes) afforded the title compound as a yellow solid. LRMS (APCI) calcd for C7H6BrN2 [M+H]+ 197, found 197.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([O:15][CH3:16])[C:13]([C:17]#[N:18])=[C:12]([C:19]#[N:20])[CH:11]=2)=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:1][C:11]1[C:12]([C:19]#[N:20])=[C:13]([C:17]#[N:18])[N:14]([O:15][CH3:16])[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: COn1c(-c2ccc(Cl)cc2)cc(C#N)c1C#N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COn1c(C#N)c(C#N)c(Br)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
Bromine (0.341 g, 0.00213 mol) is added to a stirred mixture of 5-(p-chlorophenyl)-1-methoxypyrrole-2,3-dicarbonitrile (0.5 g, 0.00193 mol) and sodium acetate (0.318 g, 0.00388 mol) in acetic acid. The reaction mixture is heated at 95°-100° C. overnight, cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined ethyl acetate extracts are washed sequentially with water, saturated sodium bicarbonate solution, aqueous sodium metabisulfite solution, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a solid that is crystallized from ethyl acetate/hexanes to give the title compound as a yellow solid (0.406 g, 62%), mp 166.5°-167° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:9]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=2)=[O:11])=[CH:15][CH:14]=1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: Nc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc(F)cc1)c1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
4-Nitropyrazole-3-carboxylic acid (10 g; 63.66 mmol) was added to a stirred solution of 4-fluoroaniline (6.7 ml; 70 mmol), EDC (14.6 g; 76.4 mmol), and HOBt (10.3 g; 76.4 mmol) in DMF (25 ml), then stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure and the residue triturated with ethyl acetate/saturated brine solution. The resultant yellow solid was collected by filtration, washed with 2M hydrochloric acid, then dried under vacuum to give 15.5 g of the title compound. (LC/MS: Rt 2.92 [M+H]+ 250.89).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18]C(O)=[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[O:22])[CH:15]=1.Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:5]2[O:4][C:2](=[O:3])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[C:21](=[O:22])[C:16]=2[CH:15]=1
Reactant: COc1cccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 12 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 12 (1.42 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0°. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 24.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1N.[Na+].[Br-:11].Br.N([O-])=O.[Na+]>O>[Br:11][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[Cl:1]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: [Br-]
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cccc(Br)c1Cl
Temperature: 37.5 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
32.7 g 2,3-Dichloroaniline (0.20 mole) is added to a mixture of 21.4 g of NaBr (0.20 mole, 1.0 equivalent), 110.0 g of 48% aqueous HBr (0.66 mole, 3.3 equivalents) and 70 ml water at 30-45° C. The mixture is stirred for 15 minutes at 30-45° C. and then heated to 60° C. Then 2.9 g Cu(I)Br (0.02 mole, 0.10 equivalent) is added and the mixture is stirred for 15 minutes at 60° C. After this, an aqueous solution of NaNO2 (40% solution in water, 37.6 g, 0.22 mole, 1.1 equivalents) is added via subsurface feeding over a period of 2 hours at 60-65° C. The reaction mixture is stirred for 30 minutes at 60-65° C. The organic phase containing the reaction product is separated from the aqueous phase and is cooled to ambient temperature, leading to solidification of the reaction product. The remaining liquid is discarded and the crude product is washed two times with 10 ml water and dried under vacuum. 44.0 g (89% of theory) of 1-bromo-2,3-dichlorobenzene is obtained in the form of a light brown solid (purity: 91%). For further characterisation, the crude product was purified by vacuum distillation (130° C./20 mmHg). 38.0 g (84% of theory) of pure 1-bromo-2,3-dichlorobenzene is obtained in the form of white crystals.