Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C(O)CCC>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: C1COCCN1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CCCCO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCOCC3)n3nccc3n2)cc1
Temperature: 100 °C
Yield: 54 %

Procedure:
N-(7-Chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D) (1.0 equivalent) and morpholine (2.0 equivalent) were dissolved in dry n-butanol (0.1 M) under nitrogen. The mixture was heated to 100° C. for 18 h. Next day, lower temperature to room temperature, and product precipitates. The precipitate was collected by filtration and then washed with diethyl ether to give the titled compound (54%) as a pink solid. Melting point (225.0-229° C.). 1H NMR (400 MHz, MeOD) δ ppm 3.31 (s, 6H) 3.70-3.79 (m, 4H) 3.90-3.98 (m, 4H) 6.35 (d, J=2.27 Hz, 1H) 7.40 (s, 1H) 7.66 (d, J=8.59 Hz, 2H) 7.94 (d, J=8.59 Hz, 2H) 8.01 (d, J=2.27 Hz, 1H). ESI-MS: m/z 382.2 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.O>C(O)(=O)C>[Br:1][C:4]1[CH:5]=[CH:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]=2[CH:3]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)oc1ccccc12
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2oc3ccccc3c2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
Bromine (23.8 g, 0.156 mol) in acetic acid (5 g) is added at 50° C. to a solution of dibenzofuran (25 g, 0.149 mol) in acetic acid (230 g). The mixture is then stirred at 50° C. for 4 hours. The reaction mixture is cooled to room temperature and poured into H2O. The orange solid is washed with Na2S2O3 aq. and H2O. The crude product is then purified by recrystallization from toluene/CH2Cl2, wherein the pure product is obtained as a white solid (13% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[CH:11][C:10]=2[N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1.[C:23](OCC)(=O)C.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([O:19][CH3:23])=[O:18])=[CH:11][C:10]=2[N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(Sc2ccc(C=CC(=O)O)cc2[N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(Sc2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-[4-(4-methylphenylthio)-3-nitrophenyl]acrylic acid (631 mg, MAYB) in a mixture of methanol (12.6 ml), ethyl acetate (6.3 ml) and THF (6.3 ml) was added dropwise to methanol (12.6 ml) beforehand under ice cooling, and then the mixture was added with a solution of thionyl chloride (735 μl, KANTO) in methanol (50 ml) under ice cooling, stirred for 30 minutes, then warmed to room temperature, and further stirred for 15.5 hours. The reaction mixture was poured into aqueous sodium hydrogencarbonate (50 ml) for neutralization, and extracted with ethyl acetate (50 ml), and the organic layer was washed with saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure to obtain the title compound (Intermediate s-1, 659 mg).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: CN(C)CCN
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(NCCN(C)C)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-dimethylamino-ethylamine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 7.81 (br, 1H), 7.78 (d, 1H), 7.01-6.95 (2H), 6.16 (s, 1H), 3.94 (t, 2H), 3.83 (s, 3H), 3.62 (br, 2H), 3.21 (br, 2H), 2.93 (t, 2H) and 2.83 (s, 6H); MS (ESI) (M+H)+ 315.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][C:3]=1[C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12].[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]=[N+:16]=[N-:17])=[CH:4][C:3]=1[C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(CCl)cc1C(Cl)=C(Cl)Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(CN=[N+]=[N-])cc1C(Cl)=C(Cl)Cl
Yield: 89 %

Procedure:
A solution of 4-methyl-3-(trichlorovinyl)benzyl chloride (1.81 g ) and sodium azide (650 mg) in 20 ml of ethanol was heated at reflux for 5 hours. The reaction mixture was concentrated and then chromatographed on silica gel. Elution with 1:1 hexane:methylene chloride afforded 1.65 g of pure azide.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][NH:2][CH2:3][C:4]([O:6][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])=[O:5]
Reactant: OCc1ccccc1
Reactant: CNCC(=O)O
Product: CNCC(=O)OC(=O)c1ccccc1

Procedure:
Following the procedure described in Example 7 above, MeNHCH2COOH is esterified with benzyl alcohol to provide MeNHCH2COOBz (22).
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:41])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1)=[O:29]>ClCCl>[N:1]1[N:10]2[C:4]([CH2:5][N:6]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:41])=[N:36][CH:35]=3)=[O:38])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
To a chilled (0° C.) solution of 0.37 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine and 836 microliters of triethylamine in 5 ml of dichloromethane is added 0.761 g of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride. The mixture is stirred at room temperature under argon for 5 hours. An additional 420 microliters of triethylamine and 0.38 g of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride is added and the mixture stirred 16 hours. The mixture is diluted with 60 ml of dichloromethane and washed with 25 ml each of H2O, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered (twice) through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated to give a yellow glass (0.68 g) which is crystallized from ethyl acetate to give 0.38 g of white crystals, m.p. 250°-260° C.; mass spectrum (FABL) 442.4 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].N1C=CC=CC=1.CCOCC.[C:28]([N:32]=[N:33][C:34]([C:41]#[N:42])([CH3:40])[CH2:35][CH2:36][C:37](Cl)=[O:38])([CH3:31])([CH3:30])[CH3:29]>O>[C:28]([N:32]=[N:33][C:34]([C:41]#[N:42])([CH3:40])[CH2:35][CH2:36][C:37]([O:16][C:14]1[CH:13]=[CH:12][C:3]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[C:2]([OH:1])[CH:15]=1)=[O:38])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)N=NC(C)(C#N)CCC(=O)Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)N=NC(C)(C#N)CCC(=O)Oc1ccc(C(=O)c2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 4.7 g. (.022 m) of 2,4-dihydroxybenzo- phenone and 2.5 ml. of pyridine in 35 ml. of ether in a 4 neck 100 ml. round bottom flask containing a thermometer, condenser and magnetic stirring bar was added 4.0 g. (.0218 m) of 4-t-butylazo-4-cyanovaleryl chloride dropwise with cooling so the temperature did not rise above 25° C. After completion of the addition the reaction mixture was stirred 1/2 hour at room temperature and then diluted with 100 ml. of water. The ether layer was separated, washed consecutively with 5% HCl, water, and 10% NaHCO3 solution and saturated sodium chloride solution. The ether was evaporated off and the residue dissolved in methylene chloride, dried over anhydrous sodium sulfate, filtered and the methylene chloride stripped off under reduced pressure. The product weighted 8.8 g. (99% yield) and was a viscous syrup. The infrared spectrum was in agreement with the structure of the desired product.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])C>C(O)C.O>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]([OH:19])=[O:5]
Reactant: CCOC(=O)c1ccccc1OCCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCCCOc1ccccc1C(=O)O
Temperature: 50 °C
Reaction time: 7 h

Procedure:
1N sodium hydroxide solution (11.1 ml) is added to a solution of 2-(3-methoxypropoxy)-benzoic acid ethyl ester (2.4 g) in ethanol (20 ml) and water (10 ml), and the reaction mixture is stirred at 50° C. for 7 hours. The mixture is concentrated and the acidified aqueous phase is extracted with dichloremethane (3×40 ml). The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 2-(3-Methoxypropoxy)-benzoic acid, Rf (hexane-ethyl acetate-glacial acetic acid 1:2:0.1)=0.43, is obtained in the form of a yellowish oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:18])=[N:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:18])=[N:14][N:15]2[CH2:10][C:9](=[O:8])[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1n[nH]c2cc(OCc3ccccc3)ccc12
Solvent: CN(C)C=O
Product: CC(=O)Cn1nc(C)c2ccc(OCc3ccccc3)cc21

Procedure:
A solution of the product from Step B (2.3 g, 9.7 mmol) in DMF (10 ml) was treated by the sequence described for Example 1, Step B to give a residue, which was used in the next step without further purification: MS (ES) m/z 295 (M+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:23])[CH2:13][CH2:14][NH:15][S:16]([CH2:19][CH2:20][CH2:21][CH3:22])(=[O:18])=[O:17].[H-].[Na+]>>[CH3:11][N:12]([CH3:23])[CH2:13][CH2:14][N:15]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[S:16]([CH2:19][CH2:20][CH2:21][CH3:22])(=[O:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCCS(=O)(=O)NCCN(C)C
Agent: [H-]
Agent: [Na+]
Product: CCCCS(=O)(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 1-fluoro-4nitro-benzene, N-(2-dimethylamino-ethyl)-butanesulphonamide and sodium hydride as base
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10]B(O)O.C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[Br:8][C:7]1[C:2]([CH3:10])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Br)c(Br)c1
Reactant: CB(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ncc(Cl)cc1Br
Temperature: 50 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
2,3-Dibromo-5-chloropyridine (1.3 g, 4.70 mmol), methylboronic acid (0.30 g, 5.01 mmol), bis(triphenylphosphine)palladium(II) chloride (0.50 g, 0.70 mmol) and dioxane (10 mL) were added. K2CO3 (2 M aq. solution, 7.0 mL, 14.0 mmol) was added and the reaction was put under N2 (g) atmosphere. The reaction was heated to reflux for 5 h. The reaction was stirred at 50° C. overnight and then heated to reflux for additionally 1 h. Methylboronic acid (0.14 g, 2.35 mmol) was added and the reaction was refluxed for 4 h and the allowed to cool down to r.t. The mixture was filtered through a silica plug. EtOAc and water were added and the phases were separated. The organic phase was washed two more times with water. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (12 g SiO2, O-20% MeOH containing 0.1 M NH3 in DCM). The fractions containing pure product were pooled and concentrated, yielding the title compound (123 mg, 13% yield): 1H NMR (DMSO-d6) δ ppm 2.56 (s, 3 H), 8.29 (d, 1 H), 8.52 (d, 1 H); MS (CI) m/z 206 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH2:7]([OH:14])[C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9]>>[C@@H:2]1([O:9][C@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[CH2:7][OH:14])[O:1][C@H:3]([CH2:5][OH:6])[C@@H:2]([OH:1])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: OCC(O)CO
Reactant: OC[C@@H](O)[C@@H](O)CO
Product: OC[C@@H](O)[C@H](CO)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
In addition to glycerol (2.0 mol) and erythritol (0.14 mol) given in Table 3 above, 2-O-β-D-glucosyl-D-erythritol (0.74 mol) and 2,4-bis-hydroxymethyl-5-O-β-D-glucosyl-1,3-dioxane (0.35 mol) were obtained as the controlled Smith-degradation products of mannoglucan. Furthermore, acetolysis of mannoglucan gave 3-O-α-D-mannosyl-D-glucose and cellobiose, and partial acid hydrolysis of mannoglucan (0.33N sulfuric acid, 100° C., 7 hrs.) yielded 6-O-α-D-mannosyl-D-glucose and cellobiose.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:49])[CH2:11][NH:12][C:13]2[CH2:17][N:16](S(C(F)(F)F)(=O)=O)[C:15](=[O:25])[C:14]=2[C:26]2[N:30](C(OC(C)(C)C)=O)[C:29]3[CH:38]=[C:39]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[CH:40]=[C:41]([CH3:42])[C:28]=3[N:27]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].ClC1C=C([C@H](O)CNC2CNC(=O)C=2C2NC3C=C(N4CCOCC4)C=C(C)C=3N=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:49])[CH2:11][NH:12][C:13]2[CH2:17][NH:16][C:15](=[O:25])[C:14]=2[C:26]2[NH:30][C:29]3[CH:38]=[C:39]([N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)[CH:40]=[C:41]([CH3:42])[C:28]=3[N:27]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(O)CNC2=C(c3nc4c(C)cc(N5CCOCC5)cc4n3C(=O)OC(C)(C)C)C(=O)N(S(=O)(=O)C(F)(F)F)C2)cc1Cl
Agent: Cc1cc(N2CCOCC2)cc2[nH]c(C3=C(NC[C@@H](O)c4cccc(Cl)c4)CNC3=O)nc12
Product: COc1ccc(C(O)CNC2=C(c3nc4c(C)cc(N5CCOCC5)cc4[nH]3)C(=O)NC2)cc1Cl
Yield: 60.2 %

Procedure:
4-[2-(3-Chloro-4-methoxy-phenyl)-2-hydroxy-ethylamino]-3-(1-tert-butyloxycarbonyl-4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-1-trifluoromethanesulfonyl-1,5-dihydro-pyrrol-2-one (0.017 g, 0.023 mmol) was reacted according to the procedure used to synthesize (S)-4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-3-(4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl)-1,5-dihydro-pyrrol-2-one and afforded the title material (0.0069 g, 59%) as a white solid. HPLC: 91% (220 nm), LCMS (+ESI, M+H+) m/z 498, HRMS calcd for C25H28N5O4Cl=497.1830, found: 497.1815; IR ν (cm−1): 3386, 1636, 1558; 1H NMR (400 MHz, methanol-d4) δ (ppm): 2.48 (3H, s), 3.11 (4H, br dd), 3.49 (1H, dd, J=13.9 and 6.8 Hz), 3.57 (1H, dd, J=13.9 and 4.3 Hz), 3.85–3.87 (7H, m), 4.14 (2H, 2d JAB=18.1 Hz), 4.85–4.88 (1H, m), 6.75 (1H, s), 6.92 (1H, s), 7.02 (1H, d, J=8.4 Hz), 7.33 (1H, dd, J=8.4 and 1.8 Hz), 7.47 (1H, d, J=1.8 Hz).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][Si:6]([CH3:11])([O:9][CH3:10])[O:7][CH3:8].[CH:12]([N:15]=[C:16]=[N:17][CH:18]([CH3:20])[CH3:19])([CH3:14])[CH3:13].N=C=N>>[CH:12]([N:15]=[C:16]([NH:17][CH:18]([CH3:20])[CH3:19])[N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][Si:6]([CH3:11])([O:9][CH3:10])[O:7][CH3:8])([CH3:14])[CH3:13]
Reactant: CC(C)N=C=NC(C)C
Reactant: CNCCC[Si](C)(OC)OC
Agent: N=C=N
Product: CO[Si](C)(CCCN(C)C(=NC(C)C)NC(C)C)OC
Reaction time: 2 h

Procedure:
A mixture of 27 g of N-methyl-(3-(methyldimethoxysilyl)propyl)amine (0.152 mol, 20% excess) and of 16 g of diisopropylcarbodiimide (0.127 mol) was heated for 8 h at 100° C. (carbodiimide conversion of 98%). The final colorless mixture was devolatilized at 100° C. under 2 mbar for 2 h to give 39.3 g of a colorless, low-viscosity liquid corresponding to the expected guanidine, containing 2 wt % of the initial amine.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([NH:7][N:8](C(OCC1C=CC=CC=1)=O)[CH3:9])=[O:6])[CH3:3].Cl>CO.[Pd]>[CH3:1][C:2]([CH3:20])([O:4][C:5]([NH:7][NH:8][CH3:9])=[O:6])[CH3:3]
Reactant: CN(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNNC(=O)OC(C)(C)C
Yield: 71.6 %

Procedure:
A solution of 1-[(1,1-dimethylethoxy)carbonyl]-2-[(phenylmethoxy)carbonyl]-2-methylhydrazine (15.0 g, 53. mmole) in 100 ml of methanol containing 4.9 ml of concentrated hydrochloric acid was hydrogenated at 1 atm in the presence of 3.0 g of 10% palladium-on-charcoal catalyst for 1 hour. The catalyst was filtered and the solvents were removed in vacuo. The residue was dissolved in water, the pH adjusted to 8.0 with sodium hydroxide and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated to give 5.6 g of the title compound as a colorless solid, m.p. 50° C.
Reaction SMILES: [CH2:1]([C:3](C#N)([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([C:3]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:10][CH2:11]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(C#N)(CC)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: Br[Mg]c1ccccc1
Product: CCC(CC)(c1ccccc1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Yield: 62 %

Procedure:
This was prepared according to the procedure described in Example 1 using 1-ethyl-1-[4-(2-oxo-2,3-dihydro-1H-1,3-benzimidazol-1-yl)piperidino]-propyl cyanide and phenylmagnesium bromide. Yield was 62%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@H:11]2[CH3:16])=[O:9])=[CH:4][CH:3]=1.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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]>[Br:24][C:22]1[CH:23]=[C:18]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][C@H:11]3[CH3:16])=[O:9])=[CH:6][N:7]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: C[C@@H]1COCCN1C(=O)c1ccc(N)nc1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 132a (332 mg, 1.5 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (H-001) (480 mg, 1.8 mmol), and cesium carbonate (978 mg, 3.0 mmol). After bubbling nitrogen through the suspension for 3 minutes, Xantphos (87 mg, 0.15 mmol) and tris(dibenzylideneacetone)dipalladium(0) (69 mg, 0.075 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and heated at reflux for 2.5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×50 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (2:1 to 1:2) to afford 132b (430 mg, 70%) as a yellow solid. MS-ESI: [M+H]+ 407.3
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:10][C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:3][C:2]=1[C:35]1[CH:36]=[CH:37][S:33][CH:34]=1
Reactant: OB(O)c1ccsc1
Reactant: COc1ccc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cc1-c1ccsc1
Temperature: 25 °C

Procedure:
To a stirred solution of tert-butyl 4-[4-(3-iodo-4-methoxyphenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (82.1 mg, 0.15 mmol), 3-thienylboronic acid (28.8 mg, 0.225 mmol) and potassium carbonate (41.5 mg, 0.3 mmol) in dioxane/water (4:1) (1.0 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), complex with dichloromethane (1:1) (12 mg, 0.015 mmol). The resulting mixture was bubbled N2 for 5 min and then heated at reflux for 16 h. After cooled to rt, the solvents were removed under reduced pressure. The residue was dissolved in DMF (2 mL). The DMF solution was filtered and purified by HPLC to give the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ=1.43 (s, 9H), 3.56 (m, 2H), 3.82 (s, 3H), 4.03 (m, 2H), 6.38 (s, br, 1H), 6.73 (s, 1H), 7.09 (d, J=9.2 Hz, 1H), 7.45 (dd, J=0.8, 5.2 Hz, 1H), 7.60 (dd, J=2.8, 4.8 Hz, 1H), 7.76 (m, 1H), 7.80 (dd, J=2.8, 8.8 Hz, 1H), 7.94 (d, J=2.8 Hz, 1H), 8.22 (s, 1H), 9.26 (s, 1H), 11.90 (s, 1H). MS (ES+): m/z 504.05 [MH+]. HPLC: tR=3.22 min (ZQ2000, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl.[NH2:25][C@H:26]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:28][CH2:29][CH3:30].F[B-](F)(F)F.CN([CH+]N(C)C)C.CN1CCOCC1>ClCCl>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:25][C@H:26]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Reactant: CCCC[C@H](N)C(=O)OC
Agent: CN(C)[CH+]N(C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCC[C@H](NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12)C(=O)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
500 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (Example 6A; 1.57 mmol, 1 equivalent) were initially charged in 10 ml of anhydrous dichloromethane, and 313 mg of methyl L-norleucinate hydrochloride (1.73 mmol, 1.1 equivalents), 554 mg of benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU; 1.73 mmol, 1.1 equivalents) and 0.864 ml of 4-methylmorpholine (7.85 mmol, 5 equivalents) were added in succession. The reaction mixture was stirred at room temperature for 4 h. The mixture was then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, with water and finally with saturated aqueous sodium chloride solution, dried and concentrated. The residue obtained was chromatographed on a 100 g silica gel cartridge (Biotage Isolera; cyclohexane/ethyl acetate gradient as mobile phase). This gave 644 mg of the target compound (91% of theory).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:4]=1[NH:10][S:11]([NH2:14])(=[O:13])=[O:12])#[N:2].[CH3:15][C:16]([CH3:21])=[CH:17]B(O)O>>[C:1]([C:3]1[CH:8]=[C:7]([CH:15]=[C:16]([CH3:21])[CH3:17])[CH:6]=[CH:5][C:4]=1[NH:10][S:11]([NH2:14])(=[O:13])=[O:12])#[N:2]
Reactant: N#Cc1cc(Br)ccc1NS(N)(=O)=O
Reactant: CC(C)=CB(O)O
Product: CC(C)=Cc1ccc(NS(N)(=O)=O)c(C#N)c1

Procedure:
Prepared as in Example 77a from N-(2-cyano-4-bromophenyl)sulfamide (Example 83b) and 2-methylprop-1-enylboronic acid.