Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][CH:10]=1.B(F)(F)F.[CH3:34]COCC>C(OCC)(OCC)OCC>[Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[N:14]=[CH:34][O:16][N:15]=2)=[CH:17][CH:18]=1
Reactant: N=C(NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CCOC(OCC)OCC
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(-c3ncon3)cc2)c(Cl)c1

Procedure:
150 mg of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxy-benzamidine and 15 mg of boron trifluoride ethyl etherate are stirred for 2 hours at 140° C. in 2 ml of triethyl orthoformate. The reaction mixture is concentrated, and the residue is taken up in ethyl acetate and washed with water. Concentration of the organic phase and purification over silica gel yield the title compound (compound 1.14).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]3)[C:8]2=[N:11][S:12]([CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[CH:31]([Mg]Br)=[CH2:32]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]3)[C:8]2([NH:11][S:12]([CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])(=[O:14])=[O:13])[CH:31]=[CH2:32])=[CH:4][CH:3]=1
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CC2(Cc3ccc(Br)cc3C2=NS(=O)(=O)CC[Si](C)(C)C)C1
Solvent: C1CCOC1
Product: C=CC1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of tert-butyl 6′-bromo-1′-(((2-(trimethylsilyl)ethyl)sulfonyl)imino)-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate (0.4031 g, 0.78 mmol) in THF (3 mL) was added vinylmagnesium bromide (1.0 M in THF, 3 mL, 3.0 mmol) at 0° C. under nitrogen. The mixture was allowed to slowly warm to room temperature over 18 h. The reaction mixture was then quenched with saturated NH4Cl, extracted with EtOAc, and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the crude product was directly used in the next step without further purification. LC-MS tR=2.31 min in 3 min chromatography, m/z 543, 545 (MH+), 487, 489 (MH+-56).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:14][C:15]4[N:20](CCC#N)[C:19](=[O:25])[CH2:18][O:17][C:16]=4[N:26]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[C:33]([O:37]C(=O)NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCCCC#N)C(=O)COC=4N=3)=CC=2)CCC1)(C)(C)[CH3:34]>>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:13]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:14][C:15]4[NH:20][C:19](=[O:25])[CH:18]([CH2:34][CH2:33][OH:37])[O:17][C:16]=4[N:26]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCCCC#N)C(=O)CO4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)C(CCO)O4)cc2)CCC1

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(1-(4-cyanobutyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.029 mmol) was reacted to afford the title compound (8.5 mg). 1H NMR (500 MHz, CD3OD): 7.28-7.42 (m, 8H), 7.18 (m, 2H), 5.08 (dd, 1H), 3.84-3.93 (m, 2H), 2.73-2.79 (m, 2H), 2.55-2.61 (m, 2H), 2.25-2.29 (m, 2H), 2.15-2.24 (m, 1H), 1.95-1.97 (m, 1H). LCMS (Method A): RT=3.49 min, M+H+=416.18.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19](=[S:21])[NH2:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(C)(C)C.Br[CH2:24][C:25](=O)[CH2:26][CH3:27].C(OCC)C>CC#N>[CH2:26]([C:25]1[N:20]=[C:19]([C@@H:8]([NH2:7])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[S:21][CH:24]=1)[CH3:27]
Reactant: CCC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=S
Solvent: CC#N
Solvent: CCOCC
Product: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixture of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]-carbamic acid tert-butyl ester, 2, (0.245 g, 0.753 mmol), 1-bromo-2-butanone (0.125 g, 0.828 mmol) in CH3CN (5 mL) is refluxed 3 hours. The reaction mixture is cooled to room temperature and diethyl ether is added to the solution and the precipitate which forms is removed by filtration. The solid is dried under vacuum to afford 0.242 g (90% yield) of the desired product. ESI+MS 278 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].CCCCCC.C([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:22](=[O:24])[CH3:23])[S:5][C:6]=1[CH3:7]
Reactant: Cc1ncsc1C
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1nc(C)c(C)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Commercially available 4,5-dimethyl-1,3-thiazole (453 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution which was then cooled to −78° C. A hexane solution (1.56 M) (2.8 ml) of n-butyllithium was slowly added over a period of 10 min, and the mixture was stirred at −78° C. for 2 hr. N-Methoxy-N-methylacetamide (454 mg) was dissolved in tetrahydrofuran (2 ml) to prepare a solution which was then slowly added over a period of 10 min, and the mixture was stirred at −78° C. for 2 hr. The cooling bath was removed, an aqueous saturated ammonium chloride solution (10 ml) was added, and the mixture was stirred for 30 min. Further, water (10 ml) was added, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over sodium sulfate. The solvent was removed, and the residue was purified by chromatography on silica gel using hexane/ethyl acetate for development to give the title compound (609 mg, 98%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:30][CH2:31][CH2:32][OH:33])=[N:12][N:13]([CH3:29])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.C[OH:35]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:30][CH2:31][CH2:32][OH:33])=[N:12][N:13]([CH3:29])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:26])[CH2:27][OH:35])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cn1nc(OCCO)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: CO
Product: Cn1nc(OCCO)c(-c2ccc3c(c2)OCO3)c1NS(=O)(=O)c1ccc(C(C)(C)CO)cc1
Reaction time: 48 h

Procedure:
Amycolata autotrophica ATCC35203 maintained on a ¼ strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flasks each containing 50 ml of of MY inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron Shaker with 1″ throw. Two mls of this inoculum was then transferred to each of twenty 300 ml Erlenmeyer flask containing 50 ml of MY production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-[4-(1,3-benzodioxol-5-yl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 17) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 96 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Br:31])[C:27]([Br:30])=[C:28]([Br:29])[C:4]=2[N:3]=1.[C-]#N.[K+]>CCO.CCOC(C)=O>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([Br:31])[C:27]([Br:30])=[C:28]([Br:29])[C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3c(Br)c(Br)c(Br)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3c(Br)c(Br)c(Br)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 0.430 g (0.664 mmol) of the blocked nucleoside (102) and 0.216 g (3.317 mmol) of KCN in 13 mL of 70% EtOH was stirred at room temperature for 6 hr. The reaction mixture was diluted with 75 mL of EtOAc. The EtOAc solution was washed with H2O (50 mL), sat. NaCl solution (50 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (1.9×15 cm, eluted successively with CHCl3, 1%, 2%, 3% MeOH/CHCl3). Evaporation of fractions 43-60 (10 mL per fraction) and recrystallization from MeOH/MeCN gave 0.157 g (2 crops, 44%) of 103 as white crystals. MP: 168°-170° C. MS: (FAB) m/e 518.7947 (28%, MH+ =518.7957). 1H NMR (DMSO-d6): d 8.76 (s, 1,7-H), 5.87 (d, 1, 1 '-H, J1'-2' =8.0 Hz), 5.51 (d, 1,2'-OH, J2'-2'OH =6.0 Hz), 5.42 (t, 1, 5'-OH, J5'-5'OH =4.5 Hz), 5.30 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.37 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.14 (m, 1,3'-H, J3'-4' =2.0 Hz), 4.02 (m, 1,4'-H, J4'-5' =J4'-5" =2.5 Hz), 3.71 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Hz). 13C NMR (DMSO-d6l ): d 142.32 (C2), 140.94 (C3a), 132.50 (C7a), 120.62 (C5), 118.44 (C6), 117.10 (C7), 115.34 (C4), 89.58 (C1'), 86.50 (C4'), 71.93 (C2'), 69.63 (C3'), 60.89 (C5'). Anal. Calcd. for C12 H10Br3ClN2O4 0.3 MeCN: C, 28.36; H, 2.06; N, 6.04. Found: C, 28.25; H, 1.84; N, 5.90. (the Content of 0.3 MeCN was also indicated by 1H NMR.)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([NH:13][C:14]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:15]=3[C:16]([OH:18])=[O:17])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[CH2:26]Cl>>[CH3:26][O:17][C:16](=[O:18])[C:15]1[C:19]([F:24])=[CH:20][C:21]([F:23])=[CH:22][C:14]=1[NH:13][C:11](=[O:12])[CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1
Reactant: O=C(Cc1ccc2c(c1)OCO2)Nc1cc(F)cc(F)c1C(=O)O
Reactant: ClCCl
Product: COC(=O)c1c(F)cc(F)cc1NC(=O)Cc1ccc2c(c1)OCO2
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a 0-5° C. cooled suspension of 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-4,6-difluoro-benzoic acid (0.50 g, 1.49 mmol) in dichloromethane (20 mL) was added 2 M (trimethylsilyl)diazomethane diethyl ether solution (0.82 mL, 1.64 mmol). The mixture was stirred at room temperature for 1 h, then the solvent was evaporated, to provide the title compound (0.52 g, 98% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]1[C:9]2([CH:13]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][NH:11][CH2:10]2)[CH2:8][CH2:7]1.C(N(CC)CC)C>C1COCC1>[CH3:1][S:2]([N:11]1[CH2:12][CH:13]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[C:9]2([CH2:8][CH2:7][CH2:6]2)[CH2:10]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CNCC12CCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CN(S(C)(=O)=O)CC12CCC2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (0.073 ml, 0.939 mmol) was added dropwise to a stirred solution of (+/−)-tert-butyl 6-azaspiro[3.4]octan-8-ylcarbamate (0.177 g, 0.783 mmol) in and triethylamine (0.436 ml, 3.13 mmol) in THF (9.78 mL) @ 0° C. under N2. Stirring @ 0° C. was continued for 1.5 hr. +/−MS after 1 hr 15 min looked the same as for 40 min, mostly desired product with a trace of sm. Additional methanesulfonyl chloride (0.073 ml, 0.939 mmol) was added and stirring was continued for 50 minutes. +/−MS after 40 m indicated that the reaction had proceeded essentially to completion and no starting material was detected by mass spectrum analysis (m/e 303.4, M−H for desired product). The volatile solvents were removed under vacuum. Ethyl acetate and water were added, the organic layer was washed twice with water, followed by washing with brine, and the organic layer was separated, dried (Na2SO4), and concentrated under vacuum to yield 0.231 g of the crude product as a yellow viscous semi-solid. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 4 g column), eluting with 100 mL of 1:1 hexane:EtOAc yielded 0.197 g of the title compoud as a white solid. +/−MS: m/e 303.4 (M−H). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.61 (br. s., 1H), 4.10 (br. s., 1H), 3.49 (dd, J=10.6, 5.3 Hz, 1H), 3.43-3.36 (m, 2H), 3.29 (dd, J=10.6, 3.1 Hz, 1H), 2.84 (s, 3H), 2.18-2.08 (m, 1H), 2.05-1.86 (m, 5H), 1.47 (s, 9H).
Reaction SMILES: [CH2:1]([CH:4]1[NH:8][S:7](=[O:10])(=[O:9])[NH:6][C:5]1=[O:11])[CH2:2][CH3:3].[C:12]1([CH2:18]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CN(C=O)C>[C:12]1([CH2:18][N:6]2[C:5](=[O:11])[CH:4]([CH2:1][CH2:2][CH3:3])[NH:8][S:7]2(=[O:9])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCC1NS(=O)(=O)NC1=O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Yield: 35.4 %

Procedure:
A mixture of 4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (20.74 g, 0.117 mol), phenylmethyl bromide (22.09 g, 0.129 mol), and tetrabutylammonium bromide (3.77 g, 0.012 mol) in toluene (400 ml) and DMF (50 ml) was refluxed for 40 hours, cooled, and poured over ice/water. The crude product was purified by flash chromatography to afford 11.1 g of 2-phenylmethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VII: R1 =propyl; R2 =R3 =H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][CH2:6][CH2:7][O:8][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC(=O)OCCO
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCOC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A 500 ml round-bottom flask was initially charged with 51.1 g of hydroxyethyl acrylate in 100 ml of pyridine/toluene (1:1, v/v) together with 0.05 g of 2,6-di-tert-butyl-4-methylphenol at 0° C. and 65.0 g of benzoyl chloride were slowly added dropwise. The mixture was stirred at room temperature until the hydroxyethyl acrylate content had fallen below 0.1%. Thereafter, the mixture was poured onto 0.5 l of ice-water and acidified with 1 N aqueous hydrochloric acid. The aqueous phase was extracted three times with 0.5 l each time of tert-butyl methyl ether. The organic phase was washed with 10% sodium hydrogencarbonate solution, dried over sodium sulfate and filtered. Another 0.05 g of 2,6-di-tert-butyl-4-methylphenol was added and the organic solvents were distilled off. The product was obtained as a colorless oil.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:17]4[N:18]([CH:31]=[CH:32][N:33]=4)[CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)[N:21]=3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:70]([C:74]1[CH:79]=[CH:78][C:77]([NH2:80])=[CH:76][CH:75]=1)([CH3:73])([CH3:72])[CH3:71]>CN(C=O)C>[C:70]([C:74]1[CH:75]=[CH:76][C:77]([NH:80][C:25](=[O:27])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([C:20]3[N:21]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[O:8])=[CH:10][CH:11]=4)[C:17]4[N:18]([CH:31]=[CH:32][N:33]=4)[CH:19]=3)[CH:23]=2)=[CH:78][CH:79]=1)([CH3:73])([CH3:71])[CH3:72]
Reactant: O=C(O)c1cccc(-c2cn3ccnc3c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)c1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(NC(=O)c2cccc(-c3cn4ccnc4c(Nc4ccc(C(=O)N5CCOCC5)cc4)n3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{8-[4-(Morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzoic acid (9) (0.23 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate reagent (0.23 mmol) and N,N′-diisopropylethylamine (0.77 mmol) is stirred under N2 for 15 min. in 1 mL DMF. 4-tert-Butyl-phenylamine (0.37 mmol) is added and the reaction stirred at rt for 8 hrs. The reaction is partitioned between ethyl acetate (15 mL) and water (15 mL) and the ethyl acetate layer washed with water (2×15 mL) and brine (1×15 mL). The organic layer is dried over sodium sulfate and the solvent removed in vacuo. The resulting crude oil is dissolved in 1 ml CH2Cl2 and clean yellow solid is precipitated by slow addition of diethyl ether, yielding the final product, (10) N-(4-tert-Butyl-phenyl)-3-{8-[4-(morpholine-4-carbonyl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH2:13](Br)[CH:14]=[CH2:15]>[OH-].[K+]>[CH2:15]([O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)[CH:14]=[CH2:13]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Product: C=CCOc1ccc2cc(Br)ccc2c1

Procedure:
In reaction D, 6-bromo-2-naphthol and allylbromide, represented by the graphic formulae VIII and XIII, respectively, are refluxed together in ethanoic potassium hydroxide to produce 2-allyloxy-6-bromonaphthalene of graphic formula XIV. 2-Allyloxy-6-bromonaphthalene undergoes a Claisen rearrangement under high temperatures followed by acid catalyzed ring closure to produce 7-bromo-1,2-dihydro-2-methylnaphtho[2,1-b]furan of graphic formula XV. See Organic Reaction Vol. II, 1944, pages 1 to 48. The conversion of 7-bromo-1,2-dihydro-2-methylnaphtho[2,1-b]furan to 7-hydroxy-1,2-dihydro-2-methylnaphtho[2,1-b]furan represented by graphic formuale XVI is accomplished thru a series of steps described in Organic Synthesis Vol.49 pages 90-93, 1972. Other substituted 7-hydroxy-1,2-dihydronaphtho[2,1-b]furans may be synthesized by replacing allylbromide (XIII) with another reactant such as 3-bromo-2-methyl-propene. Coupling the resulting 7-hydroxy-1,2-dihydronaphtho[2,1-b]furan with the appropriate propargyl alcohol would result in compounds represented by graphic formula IB having formula IIB as group A. ##STR8##
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[O:16][CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:44]=[CH:43][C:22]([O:23][CH2:24][CH2:25][N:26]([CH2:30][CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[C:27]([NH2:29])=[O:28])=[CH:21][CH:20]=1)#[N:18].C(Cl)Cl>C(#N)C>[CH2:1]([N:8]1[CH2:15][CH:14]2[O:16][CH:10]([CH2:11][N:12]([CH2:31][CH2:30][N:26]([CH2:25][CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:44][CH:43]=3)[C:27]([NH2:29])=[O:28])[CH2:13]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC3CNCC(C2)O3)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCN(CCOc2ccc(C#N)cc2)C(N)=O)cc1
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1ccc(OCCN(CCN2CC3CN(Cc4ccccc4)CC(C2)O3)C(N)=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
3-Benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane (0.18 g, 0.82 mmol; see WO 01/28992) and toluene-4-sulfonic acid 2-{1-[2-(4-cyanophenoxy)ethyl]-ureido}ethyl ester (0.50 g, 1.24 mmol; see Preparation D above) were mixed in dry acetonitrile (15 mL) and stirred at 60° C. overnight. DCM (10 mL) was added, together with 0.5 g of PS—NCO (polymer-supported isocyanate). The mixture was stirred for 2 h, then filtered and evaporated. The crude product was put on a SCX-II (cation exchanger)-plug, which plug was then eluted with DCM:MeOH (NH3-saturated), 80:20. The product was further purified on a Horizon prep. column (40 g, A: DCM(1% MeOH), B: DCM/MeOH(NH3-sat.), 80:20. Gradient 0-30% B over 1080 mL). The product was then further purified by prep. HPLC and finally extracted with DCM/Na2CO3 (aq.) to give 193 mg (51.9%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:5]2[CH:13]=[C:14]([C:16]([O:18]CC)=O)[N:15]=[C:4]2[CH:3]=1.O.[NH2:22][NH2:23]>CCO>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:5]2[CH:13]=[C:14]([C:16]([NH:22][NH2:23])=[O:18])[N:15]=[C:4]2[CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cn2c(-n3cccn3)cc(Br)cc2n1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cn2c(-n3cccn3)cc(Br)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of ethyl 7-bromo-5-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylate (3.96 g, 11.8 mmol) in EtOH (100 mL) was added hydrazine hydrate (5.91 mL, 0.118 mmol) and the mixture stirred overnight at rt. After 3 days, the reaction was almost complete by LCMS so stirring was maintained for 1 more night. The mixture was diluted with EtOH (50 mL), filtered and the solids washed with EtOH (2×50 mL), EtOAc (2×50 mL) and heptane (50 mL) before being air dried. The yield was 3.56 g (94%) LCMS MS: 321.01, 322.98 [M+H]+.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][O:12][CH2:13][C:14]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH3:26])([CH3:16])[CH3:15]>ClCCl>[CH3:11][O:12][CH2:13][C:14]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:3]=[O:4])=[C:18]1[CH3:26])([CH3:16])[CH3:15]
Reactant: COCC(C)(C)n1c(C)cc2ccccc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COCC(C)(C)n1c(C)c(C=O)c2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
To a solution of 2 ml anhydrous N,N-dimethylformamide dissolved in 80 ml anhydrous dichloromethane was added phosphoryl trichloride (5 g, 32.6 mmol) at 0° C. The resultant reaction mixture was allowed to stirred at 0° C. for 3 hours. 1-(1-methoxy-2-methylpropan-2-yl)-2-methyl-1H-indole (800 mg, 3.7 mmol) was added dropwise at 0° C. Then the resulting reaction mixture was allowed to stir for 1 hour at 0° C., and then warmed to the ambient temperature. The reaction mixture was allowed to stir for 24 hours at room temperature. The reaction mixture was quenched with saturated sodium acetate. The pH was adjusted to around 8 by progressively adding 2N sodium hydroxide below 0° C., extracted with dichloromethane (100 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 10:1→5:1→2:1) to give 1-(1-methoxy-2-methylpropan-2-yl)-2-methyl-1H-indole-3-carbaldehyde (510 mg, 57%) as a light yellow oil. LCMS (M+H) m/z: calcd. 245.14. found 245.9.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:17]4[CH:18]=[C:19]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[N:20]5[C:25]=4[C:24]([NH2:26])=[N:23][CH:22]=[N:21]5)[CH:13]=[CH:14]3)=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:34][C:35](N(C)C)=[O:36]>>[C:35]([N:30]1[CH2:29][CH2:28][CH:27]([C:19]2[N:20]3[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]3)=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:16]=4)[CH:18]=2)[CH2:32][CH2:31]1)(=[O:36])[CH3:34]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(CC5CCCCC5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Product: CC(=O)N1CCC(c2cc(-c3ccc4cn(CC5CCCCC5)nc4c3)c3c(N)ncnn23)CC1
Yield: 16 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-[2-(cyclohexylmethyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting methane sulfonyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 11 mg (16%) of the desired product was isolated. 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1 H) 7.79-7.84 (m, 2 H) 7.65 (s, 1 H) 7.23 (d, 1 H) 6.63 (s, 1 H) 4.29 (d, 2 H) 3.85 (d, 2 H) 3.35-3.40 (m, 1 H) 2.94 (td, 2 H) 2.88 (s, 3 H) 1.58-2.24 (m, 10 H) 1.07-1.30 (m, 5 H). LC-MS [M+H]+=508.3, RT=2.86 min.