Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])O[C:5](=[O:8])[C:6]=1[CH3:7].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[CH2:20][NH2:21].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[CH2:20][N:21]1[C:5](=[O:8])[C:6]([CH3:7])=[C:2]([Br:1])[C:3]1=[O:9]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CC1=C(Br)C(=O)OC1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)C(C)=C(Br)C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
3-bromo-4-methyl-2,5-furandione (prepared as described in Org. and Bimolecular chemistry, pag 1782, 2004; 4.8 g, 25.1 mmol) and {[2,4-bis(methyloxy)phenyl]methyl}amine (3.78 mL, 25.1 mmol) were dissolved in acetic acid (100 mL) and the mixture was stirred at 100° C. overnight. Solvent was then concentrated under reduced pressure, additional acetic acid (100 mL) was added followed by sodium acetate (1.443 g, 17.59 mmol) and the mixture was refluxed for further 3 hours. Solvent was eliminated under reduced pressure and the residue was partitioned between DCM and water. Organic phase was washed with water, dried and solvent was eliminated under reduced pressure providing a crude that was purified by flash chromatography (eluent: Cy to Cy/AcOEt 7:3) affording 1-{[2,4-bis(methyloxy)phenyl]methyl}-3-bromo-4-methyl-1H-pyrrole-2,5-dione (8.55 g, 25.1 mmol, 100% yield) as a light yellow solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=5)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)[CH:7]=[CH:6][C:5]=12.[Cl:26]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:26][C:3]1[N:4]2[CH:9]=[C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=5)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5nccn5c4)n3n2)cn1
Solvent: ClCCl
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Cl)n5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
3-Imidazo[1,2-a]pyridin-6-ylmethyl-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 10, 33.6 mg, 0102 mmol) was dissolved in DCM (1 mL) with N-chlorosuccinimide (15 mg, 0.112 mmol). The RM was stirred at rt for 22 h. The solvent was removed. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and the acetonitrile was removed. The aqueous solution was basified with 5% NaHCO3 solution and it was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4, filtered and concentrated to afford the white title compound (tR 0.7 min (conditions 2), MH+=364).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[CH2:4].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([O-])=O.C(=O)([O-])[O-].[K+].[K+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CCO.C1COCC1.O.ClCCl.C1(C)C=CC=CC=1.C(#N)C>[CH3:5][C:3](=[CH2:4])[CH2:2][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH2:6]
Reactant: C=C(C)CCl
Reactant: O=[N+]([O-])c1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: C=C(C)COc1ccccc1N
Reaction time: 2 h

Procedure:
A mixture of 3-chloro-2-methyl-1-propene (5.43 g, 60 mmol), 2-nitrophenol (5.56 g, 40 mmol), potassium carbonate (11.05 g, 80 mmol), tetrabutylammonium hydrogen sulfate (0.271 g, 0.89 mmol) and acetonitrile (120 ml) was heated under reflux for 16 h. The mixture was portioned between toluene and aqueous potassium carbonate (5%), and the organic phase was dried and concentrated. The residue and sodium dithionite (13.9 g, 80 mmol) in EtOH-THF-H2O (2:1:1, 100 ml) was heated under reflux for 3 h and left over the weekend in the fridge. Then, additional sodium dithionite (7 g, 40 mmol) was added and the mixture was boiled for 2 h. The reaction mixture was portioned between dichloromethane and aqueous potassium carbonate (10%) and the organic layer was dried (Na2SO4). Concentrated of the solution gave the subtitle compound.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].[C:5]([O-:8])([O-])=O.[K+].[K+].Cl.[Cl:12]C[C:14]1[CH:15]=[CH:16][C:17]2[N:21]=[C:20]3[S:22][C:23]([C:25]([N:27]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH3:28])=[O:26])=[CH:24][N:19]3[C:18]=2[CH:35]=1>CN(C=O)C>[ClH:12].[CH:29]1([N:27]([CH3:28])[C:25]([C:23]2[S:22][C:20]3=[N:21][C:17]4[CH:16]=[CH:15][C:14]([CH2:5][OH:8])=[CH:35][C:18]=4[N:19]3[CH:24]=2)=[O:26])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CN(C(=O)c1cn2c(nc3ccc(CCl)cc32)s1)C1CCCCC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cn2c(nc3ccc(CO)cc32)s1)C1CCCCC1

Procedure:
NaN3 (0.20 g) and K2CO3 (0.78 g) were added to DMF (5 ml) solution of 6-chloromethyl-N-cyclohexyl-N-methylthiazolo[3,2-a]benzoimidazole-2-carboxamide hydrochloride (0.15 g) produced from the compound of Example 63 in the same manner as described in Example 75, and the mixture was stirred at 80° C. for 15 hours, mixed with a catalytically effective amount of Bu4NI and stirred at 80° C. for 8 hours and then at 120° C. for 15 hours. After cooling, the reaction solution was poured into water and extracted with EtOAc. After drying with MgSO4, the solvent was evaporated to obtain the title compound (0.14 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=1>CN(C)C(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:12])([F:13])[F:3])[CH:6]=2)[N:16]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cccc(Oc2cccc(Cl)n2)c1
Temperature: 90 °C

Procedure:
17.45 g (690 mmol) of sodium hydride (95 percent) was suspended in 420 ml of N,N-dimethylacetamide. 106.7 g (658 mmol) of 3-(trifluoromethyl)phenol was added dropwise over 2 hours at 15° C. The resultant phenate solution was added dropwise over 2.5 hours, under nitrogen, to a solution of 162.4 g (1.097 mol) of 2,6-dichloropyridine in 330 ml of N,N-dimethylacetamide, heated to 90° C. After a further 3 hours of reaction time, the mixture was cooled to room temperature, the precipitate of sodium chloride was filtered off and the filtrate was concentrated. The residue was taken up with toluene and 0.1 N hydrochloric acid, and the organic phase was washed with saturated sodium chloride solution and concentrated. The oily residue (ca. 200 g) was distilled under a vacuum. The yield of the title compound was 151.5 g (84 percent) of a colorless oil, content (GC) 99.8 percent. Other data concerning the title compound was:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16]C)=[O:15])=[C:12]([CH3:18])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:19])[C:3]=1[F:20].[OH-].[Na+].Cl>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:18])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:19])[C:3]=1[F:20]
Reactant: COC(=O)c1c(-c2ccc(Br)c(F)c2F)ccnc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nccc(-c2ccc(Br)c(F)c2F)c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
To a solution of methyl 4-(4-bromo-2,3-difluorophenyl)-2-methylnicotinate (800 mg, 2.34 mmol) in MeOH (10 mL) was added NaOH (935 mg, 23.38 mmol) in Water (10 mL). The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was evaporated under reduced pressure and the residue obtained was adjusted to pH ˜3 by adding 1.5N HCl solution. The product was extracted with dichloromethane and the layers were separated. The organic phase was dried over Na2SO4, and concentrated under reduced pressure to afford 4-(4-bromo-2,3-difluorophenyl)-2-methylnicotinic acid (700 mg, 2.133 mmol, 91% crude yield) as an off-white solid which was carried on without further purification. LC/MS (ESI) m/e 330.0 [(M+2H)+, calcd for C13H10BrF2NO2 330.1]; LC/MS retention time (method C): tR=1.34 min.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.[NH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(CCCN)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(CCCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Yield: 16 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (80 mg, 0.25 mmol) and 5-Amino-2,2-dimethyl-pentanoic acid HCl salt (136 mg, 0.75 mmol) in 0.5 M NaOMe/MeOH (2.5 mL, 5 mmol) was microwaved at 120° C. for 2.5 h. Reaction mixture was diluted with water (100 mL) and acidified by 1 N HCl to pH=3-4. It was extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography, eluting with 10-100% EtOAc/hexanes to provide the title compound 17 mg (0.04 mmol) in 16% yield. LC-MS ESI−: 431.94 (M−1)−.
Reaction SMILES: C(S)C.[Cl-].[Al+3].[Cl-].[Cl-].[CH:8]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21]C)[C:17](=[O:23])[CH2:16][CH2:15][CH2:14]2)([CH3:10])[CH3:9]>ClCCl>[OH:21][C:20]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][CH2:16][C:17]2=[O:23])=[CH:12][C:11]=1[CH:8]([CH3:10])[CH3:9]
Reactant: COc1cc2c(cc1C(C)C)CCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CC(C)c1cc2c(cc1O)C(=O)CCC2
Reaction time: 0.08 h
Yield: 59.4 %

Procedure:
20 ml of ethanethiol was added to 100 ml of a suspension of 28 g of aluminium chloride in dichloromethane cooled with ice. The obtained mixture was stirred for 5 minutes, followed by the slowly, dropwise addition thereto of 50 ml of a solution of 15.3 g of 6-isopropyl-7-methoxy-1-tetralone in dichloromethane. After the completion of the dropwise addition, the obtained mixture was stirred for 3 hours at room temperature and poured onto ice-water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt successively, dried over anhydrous magnesium sulfate, and distilled to remove the solvent. The obtained solid residue was washed with n-hexane to give 8.5 g of the title compound as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].CN1CCOCC1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([NH:6][S:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=1)(=[O:35])=[O:34])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(OC)cc1
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a suspension of D-tryptophan methyl ester hydrochloride (4 mmol) in 40 mL of methylene chloride, magnetically stirred and cooled in an ice bath, under a nitrogen atmosphere, is added 8 mmol of NMM and 4 mmol of 4-methoxybenzene sulfonyl chloride. The mixture is allowed to come to ambient temperature overnight. It is diluted with ethyl acetate and washed twice with aqueous 10% HCl, then successively with water, 1M sodium bicarbonate, and brine. The organic solution is dried over sodium sulfate and concentrated to afford 1.05 g (65%) of a white solid, m.p. 120°-122° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][CH2:13][CH2:12][CH2:11]2.[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([CH2:24]O)=[CH:19][N:18]=1>>[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([CH2:24][C:8]2[CH:9]=[C:10]3[C:15](=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)[NH:14][CH2:13][CH2:12][CH2:11]3)=[CH:19][N:18]=1
Reactant: Nc1ncc(CO)c(N)n1
Reactant: COCCOc1cccc2c1NCCC2
Product: COCCOc1cc(Cc2cnc(N)nc2N)cc2c1NCCC2

Procedure:
The procedure of Example 1 was used to react 1,2,3,4-tetrahydro-8-methoxyethoxyquinoline (3.11 g) with 2,4-diamino-5-hydroxymethylpyrimidine, and 2,4-diamino-5-(1,2,3,4-tetrahydro-8-(2-methoxyethoxy)-6-quinolylmethyl)pyrimidine was isolated and purified as in this example. The free base was recrystallized from absolute ethanol; m.p. 149°-151° C. NMR (Me2SO-d6) δ 1.76 (m, 2, CH2), 2.61 (tr, 2, CH2), 3.22 (m, 2, CH2), 3.31 (s, 3, OMe), 3.39 (s, 2, bridge CH2), 3.65 (m, 2, CH2CH2O), 3.97 (m, 2, OCH2CH2), 4.60 (br. s., 1, NH), 5.60 and 5.90 (2 br s, 4, (NH2)2), 6.36 (d, 1, J=1-2, Ar), 6.53 (d, 1, J=1- 2, Ar), 7.45 (s, 1, pyrimidine-6-H). Anal. Calcd. for C17H23N5O2 : C, 61.99; H, 7.04; N, 21.26. Found: C, 61.82; H, 7.06; N, 21.25.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[N+:15]([C:3]1[CH:4]=[C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O-:17])=[O:16]
Reactant: C1CNCCN1
Reactant: O=C1CCC(c2ccc(Cl)c([N+](=O)[O-])c2)=NN1
Product: O=C1CCC(c2ccc(N3CCNCC3)c([N+](=O)[O-])c2)=NN1

Procedure:
10.0 g (39.4 mmol) of 6-(4-chloro-3-nitro-phenyl)-4,5-dihydro-3(2H)-pyridazinone are boiled under reflux with 10.2 g (118.2 mmol) of piperazine for 5 hours.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1)[CH3:2].[CH3:10][O:11]C(Cl)Cl.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:4][C:5]([CH2:8][CH3:9])=[CH:6][C:7]=1[CH:10]=[O:11])[CH3:2]
Reactant: CCc1ccc(CC)s1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: CCc1cc(C=O)c(CC)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.7 %

Procedure:
Titanium tetrachloride (8.0 cm3, 70 mmol) was added slowly under nitrogen to a stirred solution of 2,5-diethylthiophene (6.0 g, 43 mmol) in dichloromethane (25 ml) at 0° C. After 10 min, 1,1-dichloromethyl methyl ether (5.0 g, 43 mmol) was added dropwise causing a vigorous reaction and the evolution of hydrogen chloride. The dark mixture was stirred at 0° C. for 30 min followed by 1 h at 20° C. and then poured onto ice water (100 ml). The organic phase was separated, the aqueous solution was extracted with dichloromethane (3×20ml) and the combined organic extracts were wahsed with 10% aqueous sodium hydroxide (2×50 ml) and dried. Removal of the solvent gave a brown oil which was distilled at reduced pressure to yield 2,5-diethyl-3-thiophenecarboxaldehyde (4.1 g, 57%) as a colourless oil which darkened rapidly, b.p. 72° C. at 0.3 mmHg (Found M+ 168.0620. C9H12SO requires M, 168.0609) which showed νmax (film) 1195m, 1387m, 1457m, 1676s, 2875m, 2933m and 2970s cm-1 ; δH (CCl4) 1.28 (3H, t, J 8 Hz) 1.32 (3H, t, J 8 Hz), 2.75 (2H, q, J 8 Hz), 3.13 (2H, q, J 8 Hz), 6.93 (1H, s), 9.85 (1H, s); m/z 168 (M+), 153 (M+ -CH3), 139 (M+ -C2H5).
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[Cl:41][C:42]1[C:47]([S:48](Cl)(=[O:50])=[O:49])=[CH:46][CH:45]=[CH:44][N:43]=1>O1CCCC1.O>[Cl:41][C:42]1[C:47]([S:48]([N:22]2[C:23]([C:24]3[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=3)=[C:19]([F:18])[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21]2)(=[O:50])=[O:49])=[CH:46][CH:45]=[CH:44][N:43]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccnc2Cl)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 39 mg) in tetrahydrofuran (6 mL) were added dropwise 15-crown-5 (0.19 mL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (243 mg) in tetrahydrofuran (1 mL) and 2-chloropyridine-3-sulfonyl chloride (239 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:7) to give the title compound as a pale-yellow oil (yield 340 mg, 91%).
Reaction SMILES: C1(C)C=CC(S(O)=O)=CC=1.C([N:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])C=C.C(=O)([O-])O.[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([NH:14][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C=CCN(CCCCC)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)O)cc1
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCCCCNc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
p-Toluenesulfinic acid (188 ml, 1.20 mmol) was added at room temperature to a solution of N-allyl-N-pentylphenylamine(221 mg, 1.08 mmol) and tetrakis(triphenylphosphine)palladium(87.8 mg, 75.9 μmol) in dichloromethane(11 ml). The reaction mixture was stirred at room temperature for 60 minutes and saturated aqueous sodium hydrogen carbonate(6.8 ml) was added. After stirred for 5 minutes, the mixture was extracted with ether(80 ml). The extract was dried on magnesium sulfate, filterd and concentrated in vacuum. The residue was chromatographed on silica gel to give N-pentylphenylamine(164 mg) in 93% yield as a colorless oil.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:8][C:9]([C:11]1[C:15]([NH:16][C:17]([C:19]2[C:24]([NH:25][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:23][CH:22]=[C:21]([CH:32]3[CH2:34][CH2:33]3)[N:20]=2)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=1)=O>>[CH:1]1([NH:6][C:9]([C:11]2[C:15]([NH:16][C:17]([C:19]3[C:24]([NH:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)=[CH:23][CH:22]=[C:21]([CH:32]4[CH2:34][CH2:33]4)[N:20]=3)=[O:18])=[CH:14][N:13]([CH3:35])[N:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: NC1CCCC1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)NC2CCCC2)n1
Yield: 19 %

Procedure:
According to the general method described in step 5 of example 27, reaction of cyclopentylamine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (19%) as amorphous yellow solid.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([NH2:15])=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.C1(C)C=CC=CC=1.[N:27]1([CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN(C=O)C>[OH:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][N:27]1[CH2:32][CH2:31][N:30]([C:2]2[C:8]3[CH:9]=[CH:10][C:11]([C:13]([NH2:15])=[O:14])=[CH:12][C:7]=3[S:6][C:5]3[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=3[N:3]=2)[CH2:29][CH2:28]1
Reactant: NC(=O)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Reactant: OCCOCCN1CCNCC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2c(c1)Sc1ccccc1N=C2N1CCN(CCOCCO)CC1
Temperature: 110 °C

Procedure:
To a solution of 11-chloro-dibenzo[b,f][1,4]thiazepine-3-carboxylic acid amide, prepared as described in the previous step, (0.40 g) in DMF (1.5 mL) and toluene (1.5 mL) was added 2-(2-piperazin-1-yl-ethoxy)-ethanol (0.50 g, 2.9 mmol). The solution was heated in a 110° C. oil bath under nitrogen for 5 hours, concentrated, and purified (silica gel, 2-5% methanol-dichloromethane containing ammonia eluent) to give the title compound as an off white solid. LC-MS: m/z 427 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[N:24]=[N:25][C:26]=3[CH:27]([CH3:29])[CH3:28])=[CH:16][C:15]=2[CH3:38])[CH3:12])[CH:6]=1)C.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[N:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][N:11]([CH3:12])[C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([OH:39])=[O:3])=[C:15]([CH3:38])[CH:16]=2)=[C:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[N:24]1
Reactant: CCOC(=O)c1cccc(N(C)Cc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1CN(C)c1cccc(C(=O)O)c1
Temperature: 70 °C

Procedure:
To a solution of 3-({4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzyl}-methyl-amino)-benzoic acid ethyl ester (20 mg, 0.035 mmol) in THF (4.0 mL) and methanol (4.0 mL) is added 5 M NaOH (0.5 mL). The reaction mixture is heated to 70° C. for two hours and cooled to room temperature. A solution of 5 M HCl (0.5 mL) is added. The reaction mixture is concentrated and triturated with methanol and then water is added to precipitate the product. The title compound (10 mg, 53%) is collected by vacuum filtration as a white solid. LC-MS: 537.3 (M−1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:11]([O:15][C:16](=[O:17])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:22]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCc1cccc(O)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1cccc(Oc2ncccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 93.7 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (4.76 g, 30 mmols), N-tert-butoxycarbonyl-3-hydroxyphenethylamine (7.11 g, 30 mmols), potassium carbonate (4.14 g, 30 mmols) and N,N-dimethylformamide (50 ml) was stirred at 100° C. for 12 hours. The reaction mixture was cooled, then poured into water, and then extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give an yellow oil of tert-butyl[2-[3-(3-nitro-2-pyridyloxy)phenyl]ethyl]carbamate (10.1 g, 92.5%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC1C[S:46](=[O:49])(=[O:48])[CH2:45]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH:14]3[CH2:45][S:46](=[O:49])(=[O:48])[CH2:15]3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S1(=O)CC(Br)C1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(C3CS(=O)(=O)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-bromo-thietane 1,1-dioxide and isolated as white solid. MS (m/e): 387.3 (MH+).