Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].N1C=CC=CC=1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].Cl>CN(C)C=O.C(OCC)(=O)C.O>[Cl:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:17](=[O:18])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(O)cc1Cl
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(O)cc1Cl)Oc1ccccc1
Reaction time: 0.5 h

Procedure:
After suspending 4-amino-3-chlorophenol (23.7 g) in N,N-dimethylformamide (100 mL) and adding pyridine (23.4 mL) while cooling on ice, phenyl chloroformate (23.2 ml) was added dropwise below 20° C. Stirring was performed at room temperature for 30 minutes, and then water (400 mL), ethyl acetate (300 mL) and 6N HCl (48 mL) were added, the mixture was stirred and the organic layer was separated. The organic layer was washed twice with 10% brine (200 mL), and dried over magnesium sulfate. The solvent was removed to give 46 g of the title compound as a solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[C:20]3[N:25]=[CH:26][N:27]([CH3:28])[C:19]=3[CH:18]=2)=[CH:13][C:12]=1[C:29]([F:32])([F:31])[F:30].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[C:20]3[N:25]=[CH:26][N:27]([CH3:28])[C:19]=3[CH:18]=2)=[CH:13][C:12]=1[C:29]([F:31])([F:32])[F:30])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCCO)c(C(F)(F)F)c3)cc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
Methanesulphonyl chloride (2.65 g) was added dropwise to a solution of 6-[4-(3-hydroxypropoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (6.7 g) and diisopropylethylamine (9.7 ml) in NMP (40 ml). The mixture was stirred at room temperature for 3 hours. After adding ice (100 g), solid product was collected by filtration, washed with cold ethanol (20 ml) to give 3-[4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy]propyl methanesulfonate (7.4 g).
Reaction SMILES: S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(O)=O)N=1)CC2)=O.[NH2:39][C:40]1[N:44](C(OC(C)(C)C)=O)[N:43]=[C:42]([C:52]2[CH:100]=[CH:99][C:55]([O:56][CH2:57][C:58]#[C:59][C:60]3[S:64][C:63]([N:65]4[CH2:74][CH2:73][C:72]5[C:67](=[C:68]([C:75](=[O:93])[N:76]([C:84]6[S:85][C:86]7[CH:92]=[CH:91][CH:90]=[CH:89][C:87]=7[N:88]=6)C(OC(C)(C)C)=O)[CH:69]=[CH:70][CH:71]=5)[CH2:66]4)=[N:62][C:61]=3[C:94]([O:96]CC)=[O:95])=[CH:54][CH:53]=2)[C:41]=1[C:101]#[N:102]>>[NH2:39][C:40]1[NH:44][N:43]=[C:42]([C:52]2[CH:53]=[CH:54][C:55]([O:56][CH2:57][C:58]#[C:59][C:60]3[S:64][C:63]([N:65]4[CH2:74][CH2:73][C:72]5[C:67](=[C:68]([C:75](=[O:93])[NH:76][C:84]6[S:85][C:86]7[CH:92]=[CH:91][CH:90]=[CH:89][C:87]=7[N:88]=6)[CH:69]=[CH:70][CH:71]=5)[CH2:66]4)=[N:62][C:61]=3[C:94]([OH:96])=[O:95])=[CH:99][CH:100]=2)[C:41]=1[C:101]#[N:102]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(C(=O)OC(C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCOc1ccc(-c2nn(C(=O)OC(C)(C)C)c(N)c2C#N)cc1
Agent: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(-c3ccc(CO)cc3)s1)CC2
Product: N#Cc1c(-c2ccc(OCC#Cc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)n[nH]c1N

Procedure:
The title compound 40 was prepared in a similar manner to the synthesis of compound 34 by substituting compound 34D with compound 40A: 1H NMR (DMSO-d6): δ 8.03 (d, J=7.98 Hz, 1H), 7.60-7.80 (m, 5H), 7.34-7.50 (m, 6H), 7.32-7.49 (m, 6H), 7.12 (d, J=8.9 Hz, 2H), 5.10 (s, 2H), 4.91 (s, 2H), 3.73-3.75 (m, 2H), 3.05-3.07 (m, 2H). MS (ESI(+)): m/z 673 (M+H).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:48])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:41])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:27]=2)=[O:23])=[CH:17][C:16]=1[CH3:40].[CH3:49][C:50]1[S:51][C:52]([CH:56]=O)=[C:53]([CH3:55])[N:54]=1>>[CH3:9][O:10][C:11](=[O:48])/[C:12](/[NH:13][C:14](=[O:41])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH:27]=2)=[O:23])=[CH:17][C:16]=1[CH3:40])=[CH:56]/[C:52]1[S:51][C:50]([CH3:49])=[N:54][C:53]=1[CH3:55]
Reactant: COC(=O)C(NC(=O)c1c(C)cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1C)P(=O)(OC)OC
Reactant: Cc1nc(C)c(C=O)s1
Agent: CN(C)C(=N)N(C)C
Product: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1C
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 51.3 %

Procedure:
1,1,3,3-Tetramethylguanidine (54 μL, 0.425 mmol) was added to a solution of rac.-2-(dimethoxyphosphinyl)-N-[4-[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]amino]carbonyl]-2,6-dimethylbenzoyl]glycine methyl ester (Example 126; 150 mg, 0.25 mmol) in tetrahydrofiran (2 mL) at −40° C. The solution was stirred at −40° C. for 5 min and then 2,4-dimethylthiazol-5-carboxaldehyde (Example 43; 43 mg, 0.3 mmol) was added. The reaction mixture was stirred at −40° C. for 60 min and then allowed to stir at room temperature for 4 h. A second portion of 1,1,3,3-tetramethylguanidine (27 μL, 0.213 mmol) and the reaction was allowed to stir at room temperature for 2 days. The solution was partitioned between pH 6 phosphate buffer and ethyl acetate and the organic layer was dried (MgSO4), filtered and evaporated. The residue was chromatographed (silica gel, ethyl acetate in petroleum ether) to furnish 78 mg of (Z)-2-[[4-[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]amino]carbonyl]-2,6-dimethylbenzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester as a colorless foam (50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH2:39][NH2:40]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:40][CH2:39][CH2:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: NCCc1ccccn1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NCCc1ccccn1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(2-pyridinyl)ethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=551.01 (M+H+); retention time=0.56 minutes.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Cl.[S:20]([O-:24])([OH:23])(=[O:22])=[O:21].C(O)(C)C>C(#N)C>[S:20]([O-:24])([OH:23])(=[O:22])=[O:21].[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N+:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: C1=NCCc2ccccc21
Reactant: ClCc1ccccc1Cl
Agent: O=S(=O)([O-])O
Solvent: CC#N
Solvent: CC(C)O
Product: Clc1ccccc1C[N+]1=Cc2ccccc2CC1

Procedure:
The title compound is prepared analogously to Example A from 3,4-dihydroisoquinoline and 2-chlorobenzyl chloride in acetonitrile. The melting point of the hydrogensulphate is 190°-192° C. (from isopropanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].C(NC(C)C)(C)C.[Li].CN(C)[CH:21]=[O:22].C(O)(=O)C>O1CCCC1.O>[Br:1][C:2]1[C:3]([F:10])=[C:4]([C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)c(F)c1
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(Br)c(F)c1C=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
To a solution of 4-bromo-3-fluoroanisole (10 g, 48.7 mmol, Matrix) in tetrahydrofuran (100 mL) at −78° C. was added lithium diisopropyl amine (32.5 mL, 1.8 M in THF, 58.4 mmol) dropwise during a period of 15 min. The mixture was stirred at −78° C. for another 20 mins. Then N,N-dimethyl-formamide (4.53 mL, 58.4 mmol) was added in one portion. The mixture was stirred at −78° C. for 10 min, then quenched with acetic acid (12 g, 194 mmol) and followed by the addition of water (61 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4) to give 3-bromo-2-fluoro-6-methoxy-benzaldehyde as a yellow solid (Yield: 10 g, 89%)
Reaction SMILES: Br[C:2]1[C:3]([O:32][CH3:33])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:26])[N:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:13]=4[C:12]([C:27]4[S:31][CH:30]=[N:29][CH:28]=4)=[C:9]3[C:10]=2[CH:11]=1.C([Sn](CCCC)(CCCC)[C:39]1[CH:44]=[N:43][CH:42]=[CH:41][N:40]=1)CCC.C(OCC)C>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>[C:22]([N:16]1[C:15](=[O:26])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:32][CH3:33])[C:2]([C:39]5[CH:44]=[N:43][CH:42]=[CH:41][N:40]=5)=[CH:11][C:10]=4[C:9]3=[C:12]([C:27]3[S:31][CH:30]=[N:29][CH:28]=3)[C:13]=2[CH2:21][O:20][CH2:19][CH2:18][CH2:17]1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: COc1cc2c(cc1Br)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1-c1cnccn1)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Yield: 88.1 %

Procedure:
A solution of 75 mg of 8e, 150 mg of 2-tributylstannylpyrazine and 16 mg of Pd(PPh3)4 in 2 ml of degassed toluene was heated under N2 atmosphere for 24 hr. The reaction mixture was concentrated and the crude material was chromatographed over silica gel, using a gradient of toluene/acetone. The material isolated was treated with diethyl ether and provided 66 mg of 8g; Mp 235-236° C.; MS-ESI: [M+1] 530.3;
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCCCCC.O1CCOCC1>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]([CH3:16])([CH3:15])[C:4]=3[CH:3]=2)=[CH:20][CH:19]=1
Reactant: CC1(C)c2ccccc2-c2ccc(Br)cc21
Reactant: Nc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CC1(C)c2ccccc2-c2ccc(Nc3ccc(Cl)cc3)cc21
Temperature: 80 °C
Reaction time: 66 h

Procedure:
A 500 ml, 5-neck reaction flask was charged with 2-bromo-9,9-dimethyl-9H-fluorene (25.0 g) (as prepared above), 4-chloroaniline (12.9 g), sodium tert-butoxide (12.3 g), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (rac-BINAP) (0.4 g), tris(dibenzylideneacetone)-dipalladium(0) (Pd2(dba)3) (0.2 g) and 1,4-dioxane (180 ml). This mixture was heated with stirring to 80° C. and held at this temperature for 66 hours, after which time the reaction was deemed complete as indicated by TLC analysis. The reaction mixture was allowed to cool to room temperature and then poured into a beaker containing hexane (1 litre). Residual solids were removed by filtration and the filter cake washed with hexane (300 ml). The combined organic filtrate and washings were concentrated to yield a black/brown oil which was purified by dry flash column chromatography. The title amine was isolated as a red/brown viscous oil. (12.8 g). iii) Preparation of N,N-bis(4-chlorophenyl)-(9,9-dimethyl-9H-fluoren-2-yl)-amine
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][C:15]#[N:16])=[C:4]([C:10]([Cl:13])=[CH:11][CH:12]=1)[C:5](OCC)=[O:6].[BH4-].[Na+]>C(O)C.O.O.O.O.O.O.[Co](Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:4]2[C:3]=1[CH2:14][CH2:15][NH:16][C:5]2=[O:6]
Reactant: CCOC(=O)c1c(Cl)ccc(Cl)c1CC#N
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1NCCc2c(Cl)ccc(Cl)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
Cobalt (II) chloride hexahydrate (166 g, 0.70 mol) was added to a room temperature solution of ethyl 3,6-dichloro-2-(cyanomethyl)benzoate (253d, 90 g, 0.35 mol) in ethanol (1.5 L), and the resulting mixture cooled to 0° C. Sodium borohydride (66.3 g, 1.74 mol) was added in portions. The mixture was stirred at room temperature for 1 hour, and then refluxed overnight. The resulting suspension was filtered and the filtrate concentrated in vacuo. The solids in the filter cake were stirred in ethyl acetate (600 mL), and then filtered again. This procedure was repeated a second time. The combined filtrates were added to the original filtrate residue, and this organic solution washed with water (800 mL) and saturated aqueous sodium chloride solution (800 mL), dried over sodium sulfate, and concentrated in vacuo to give 5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (253e, 29.3 g, 39% yield) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl-].[Al+3].[Cl-].[Cl-].[C:27](Cl)(=[O:29])[CH3:28].Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:18]=[CH:19][C:20]([C:27](=[O:29])[CH3:28])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCOc1ccc(-c2ccccc2)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(C(C)=O)cc2)cc1F

Procedure:
In a reactor were placed 141 g of 3-fluoro-4-octyloxybiphenyl and 400 ml of methylene chloride, to which was gradually added 94 g of anhydrous aluminum chloride at 0° C. or less under stirring and then was added dropwise 56 g of acetylchloride. After completion of dropwise addition, the mixture was stirred for 6 hours while increasing the temperature. The reaction solution was added to dilute hydrochloric acid, and the organic layer was washed with water and dehydrated over Glauber's salt. Subsequently, the solvent was distilled off. The remaining fraction was recrystallized with chloroform, to obtain 3-fluoro-4-octyloxy-4'-acetylbiphenyl.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])=[CH:13][CH:12]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(OS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl-4-hydroxyphenylcarbamate (1.0 g, 4.78 mmol) and triethylamine (0.80 mL, 5.73 mmol) were combined in dichloromethane (50 mL), cooled in an ice bath and treated with methanesulfonyl chloride (0.41 mL, 5.26 mmol). The solution was stirred at ambient temperature for 2 h, then was washed with 1M HCl, dried over sodium sulfate, filtered, and concentrated to give 1.2 g (87%).
Reaction SMILES: [CH:1]12[CH2:13][CH2:12][CH:8]([CH:9]([OH:11])[CH2:10]1)[C:7]1[C:2]2=[CH:3][CH:4]=[CH:5][CH:6]=1.CCOC(C)=O>C(Cl)Cl>[CH:1]12[CH2:13][CH2:12][CH:8]([C:9](=[O:11])[CH2:10]1)[C:7]1[C:2]2=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CC2CCC1c1ccccc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1CC2CCC1c1ccccc12
Yield: 88.5 %

Procedure:
To a solution of 5.6 g of tricyclo[6.2.2.02,7]dodeca-2,4,6-trien-9-ol in 30 mL of DCM were added 110 mL of a 15% DMP solution in DCM. After stirring overnight 300 mL of EtOAc/Hept (1:1) were added, the obtained suspension was filtered over a pad of celite and the filtrated was concentrated in vacuo. The residue was treated again with EtOAc/Hept (1:1) and filtered over celite. This procedure was repeated twice to obtain 4.9 g of the desired compound as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[O:25][N:24]=[C:23]([CH3:26])[CH:22]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[O:25][N:24]=[C:23]([CH3:26])[CH:22]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1cc(NC(=O)CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)on1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(NC(=O)CN2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(N(C)C)cc5)nc34)CC2)on1
Temperature: 70 °C
Reaction time: 4.5 h

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(3-methylisoxazol-5-yl)acetamide (0.036 g, 0.09 mmol) and ethanol (4 ml) was added 4-dimethylaminobenzaldehyde (0.018 g, 0.11 mmol) followed by a freshly prepared 1M aqueous solution of Na2S2O4 (0.36 ml, 0.36 mmol). The reaction mixture was stirred at 70° C. for 4.5 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was triturated with water (4 ml); the brown precipitate was collected by filtration, washed with water (3×2 ml), ethanol (3×2 ml) and diethyl ether (2×5 ml). This solid was absorbed on silica gel, and the free-running powder was placed on a 10 g isolute silica column which was eluted with ethyl acetate/dichloromethane (v/v; 1:1), and 4% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid after trituration with diethyl ether (0.007 g, 16%). 1H-NMR (500 MHz, DMSO-d6) 2.19 (s, 3H, isoxazole CH3), 2.73 (s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.31 (s, 2H, NCH2CO), 3.71 (s, 4H, piperazine N(CH2)2), 6.18 (s, 1H, isoxazole C—H), 6.82 (d, J=8.9 Hz, 2H) and 8.01 (d, J=8.9 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4NMe2), 8.03 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.45 (br s, 1H, CONH), 13.15 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:19])=[C:15]([CH:18]=1)[CH:16]=O>>[O:1]1[C:5]([CH2:16][C:15]2[CH:18]=[C:11]([Br:10])[CH:12]=[CH:13][C:14]=2[Cl:19])=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2occc2c1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: Clc1ccc(Br)cc1Cc1cc2ccccc2o1

Procedure:
Benzo[b]furan and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:40]1[CH2:46][CH2:45][CH2:44][C@H:41]1[CH2:42][OH:43]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:40]1[CH2:46][CH2:45][CH2:44][C@H:41]1[CH:42]=[O:43])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: OC[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C=O
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 22.3 g of N-benzyloxycarbonylalanine. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 g of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated until dryness whereby a semi-solid substance was obtained. This substance was recrystallized from isopropyl alcohol to obtain a white solid substance which was then dissolved in 470 ml of THF. To this solution was added 7.4 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed with 100 ml of 1-M Na2CO3 solution, dehydrated over anhydrous Na2SO4 and evaporated until dryness. To the resultant oily substance were added 32.4 g of WSCD.HCl and 180 ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Subsequently, 6 ml of a DMSO solution of 2-M anhydrous H3PO4 was added and the whole was stirred for further 2 hours. The reaction was stopped with 360 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 250 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 250 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 350 ml, unreacted materials were removed twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 2.9 g (9.9%).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:15])[N:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)[C:6]=1[CH3:7].[CH3:16]I>>[I:1][C:2]1[N:3]=[C:4]([CH3:15])[N:5]([C:8]2[CH:13]=[CH:12][N:11]([CH3:16])[C:10](=[O:14])[CH:9]=2)[C:6]=1[CH3:7]
Reactant: Cc1nc(I)c(C)n1-c1cc[nH]c(=O)c1
Reactant: CI
Product: Cc1nc(I)c(C)n1-c1ccn(C)c(=O)c1

Procedure:
The title compound, white solid, MS: m/e=330.1 (M+H+), was prepared in accordance with the general method of example 3 from 4-(4-iodo-2,5-dimethyl-imidazol-1-yl)-1H-pyridin-2-one and methyl iodide.
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:29]([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCCC1C=CN=CC=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]([CH2:14][CH2:15][C:38]3[CH:37]=[CH:29][N:36]=[CH:40][CH:39]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Br
Agent: BrCCc1ccncc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3ccncc3)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 4-(2-bromoethyl)pyridine hydrobromide and isolated as brown solid. MS(m/e): 388.3 (MH+).