Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)CCC.C1(C)C=CC=CC=1>CCOCC.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:13]([C:11]1[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=[C:2]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CC(C)(C)c1cc(Br)cc2c1OCC2(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)c1cc(-c2cccs2)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 281 %

Procedure:
A mixture of 5-bromo-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]furan (2.26 g, 8.0 mmol), 2-(tributylstannyl)thiophene (3.05 mL, 9.6 mmol), tetrakis(triphenylphosphine)palladium (0.92 g, 0.8 mmol), and 40 mL of toluene is heated under argon at reflux of 2 h. The reaction mixture is cooled to room temperature, diluted with ether, washed with 10% aqueous ammonium hydroxide solution and with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 6.44 g of a dark oil. Purification by flash column chromatography on silica gel (0.5% ethyl acetate-hexane) yields about 0.98 g (45%) of the title compound initially as a colorless oil, which solidifies upon standing; mp 61-63° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)[CH:23]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Brc1cccc(N2CCOCC2)c1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(N5CCOCC5)c4)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-morpholin-4-yl-phenyl)-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 4-(3-bromo-phenyl)-morpholine (126.0 mg, 0.5202 mmol) in a manner analogous to Step 2d and was isolated as a yellow solid (0.022 g, 14%). MP=234-236° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (dd, J=6.6, 1.1 Hz, 1H), 8.26-8.22 (m, 2H), 8.10-8.05 (m, 2H), 7.66 (dd, J=7.3, 1.1 Hz, 1H), 7.36 (t, J=2.2 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.05-6.98 (m, 2H), 6.85 (s, 1H), 6.59 (dd, J=8.3, 1.9 Hz, 1H), 3.91-3.87 (m, 4H), 3.24-3.20 (m, 4H), 3.10 (s, 3H). MS=450 (MH)+.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH:2]12.Cl[C:11]1[N:12]=[CH:13][C:14]([C:17]([NH:19][C:20]2[NH:21][N:22]=[C:23]([CH2:25][CH2:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)[CH:24]=2)=[O:18])=[N:15][CH:16]=1>CS(C)=O>[CH2:1]1[CH:2]2[CH2:9][CH2:8][CH2:7][N:3]2[CH2:4][CH2:5][N:6]1[C:11]1[N:12]=[CH:13][C:14]([C:17]([NH:19][C:20]2[NH:21][N:22]=[C:23]([CH2:25][CH2:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)[CH:24]=2)=[O:18])=[N:15][CH:16]=1
Reactant: C1CC2CNCCN2C1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN5CCCC5C4)cn3)[nH]n2)cc(OC)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
1,2,3,4,6,7,8,8a-Octahydropyrrolo[1,2-a]pyrazine (429 mg, 3.40 mmol) was added in one portion to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (659 mg, 1.70 mmol) in anhydrous dimethylsulfoxide (1.70 ml) at 25° C. The resulting solution was stirred at 100° C. for 18 h. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% TFA) and MeCN as eluents. The material was then put through basic HPLC to obtain the free base. Fractions containing the desired compound were evaporated to dryness to afford the title compound (438 mg, 54%) as a cream solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:25]C(=O)C1C=CC=CC=1)=[N:16][CH2:17][CH2:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>Cl>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:16][CH2:17][CH2:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)=[NH:25]
Reactant: O=C(NC(=NCCCc1c[nH]cn1)NCCSCc1nc2ccccc2[nH]1)c1ccccc1
Agent: Cl
Product: N=C(NCCCc1c[nH]cn1)NCCSCc1nc2ccccc2[nH]1

Procedure:
0.65 g (1.4 mmol) of N-[2-[(benzimidazol-2-yl) methylthio]ethyl]-N'-benzoyl-N"-[3-(imidazol-4-yl)propyl]-guanidine are heated under reflux in 45 ml of 18% hydrochloric acid for 6 hours and worked up by a method analogous to that of Example 109.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([N:22]=[C:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([NH:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1N=C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1NC(C)C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A solution of N-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine (7.69 g, 19.8 mmol) in 50 mL of methanol was cooled to 0° C. The solution was treated with sodium borohydride (1.12 g, 29.7 mmol) over 10 min. The reaction was allowed to slowly come to ambient temperature. After 2 h, the reaction was quenched with 15 mL of saturated NH4Cl solution and concentrated under reduced pressure to yield a tan solid residue. The solid was dissolved in 100 mL of CHCl3 and 25 mL of saturated K2CO3 solution then separated. The organic portion was washed with water (25 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated to yield a brown oil. The oil was purified by chromatography (SiO2, 98:2 CHCl3:MeOH) to yield 6.63 g of N-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine as a tan foam.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:11]>C1C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH2:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N
Solvent: c1ccccc1
Product: NC(=O)Cc1ccccc1

Procedure:
Dissolved 15 g (0.1 mol) of phenylacetyl chloride in 100 ml of benzene. While stirring on a magnetic stirrer, introduced ammonia gas into the benzene solution at 20°-30° C. After reaction, the solid was collected by filtration, washed with water, and dried. The filtrate was washed in a separators funnel with water, and dehydrated with anhydrous magnesium sulfate. The solution was evaporated to dryness in a rotary evaporator. The residue together with the solid above obtained was purified by column chromatography employing silica gel-chloroform system, and recrystallization with chloroform to yield white crystal as compound 3-1. Yield, 11 g (80%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18](CC2C=CC(OC)=CC=2)[CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])=[O:34])=[C:4]([F:44])[CH:3]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])=[O:34])=[C:4]([F:44])[CH:3]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)ccc3F)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)ccc3F)c(F)cc2Cl)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea (314 mg, 0.505 mmol) and anisole (273 mg, 2.52 mmol) was treated with TFA (3.0 mL, 51.9 mmol) and stirred at RT for 2.5 h. The mixture was concentrated to near-dryness, treated with EtOAc and satd. NaHCO3 and the resulting solid collected via filtration and dried to afford 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea (233 mg, 92% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.24 (m, 2H), 8.40 (s, 1H), 8.17 (d, J=8.7 Hz, 1H), 7.97 (m, 1H), 7.73 (s, 1H), 7.54 (d, J=11.0 Hz, 1H), 7.27 (m, 1H), 7.02 (m, 1H), 6.80 (m, 1H), 6.23 (s, 1H), 4.12 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz, 3H), 1.19 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 502.2 [M+H]+.
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][NH:11][C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][Cl:29].O>CN(C=O)C>[C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])[C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCCBr
Reactant: O=C(c1ccccc1)n1c(=O)[nH]cc(I)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCCCl)c1=O
Yield: 95 %

Procedure:
3-Benzoyl-5-iodo-1H-pyrimidine-2,4-dione (Prep36, 2.5 g, 7.3 mmol), K2CO3 (1 g, 7.3 mmol) and 1-bromo-4-chloro-butane (2.10 mL, 18 mmol) were suspended in dry DMF (10 mL). After stirring the reaction at room temperature overnight, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated; the crude was purified by flash chromatography with petroleum ether-ethyl acetate (7-3) to give the title compound as a white solid (3 g, 98% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O
Yield: 73 %

Procedure:
A mixture of 3.88 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.4 ml of ethyl bromoacetate and 4.0 g of anhydrous potassium carbonate in 50 ml of anhydrous acetone was stirred at reflux for 6 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was purified by chromatography on silica gel. Elution with 20% ethyl acetate-toluene gave 4.13 g, mp 51°-52°, (73% yield) of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[O:35]1[CH2:40][CH2:39][CH:38]([C:41](Cl)=[O:42])[CH2:37][CH2:36]1>C1COCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH3:24])[C:41]([CH:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)=[O:42])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C(Cl)C1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)C1CCOCC1)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
[1-(4-Methylamino-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.13 g, 0.35 mmol) was dissolved in THF (5 ml). To this was added diisopropylethylamine (0.18 ml, 0.7 mmol) in one portion followed by the drop wise addition of tetrahydro-2H-pyran-4-carbonyl chloride (0.06 ml, 0.38 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was concentrated, diluted with DCM (200 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.17 g, 98% yield) as a white powder which was taken on without further purification. Tr=1.89 min m/z (ES+) (M+Na+) 504.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([O:19][CH3:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[Br:18][C:15]1[CH:16]=[CH:17][C:10]2[O:9][C:8]([C:6]([OH:7])=[O:5])=[C:12]([CH3:13])[C:11]=2[C:14]=1[O:19][CH3:20]
Reactant: COc1c(Br)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(Br)ccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 10 h
Yield: 76.7 %

Procedure:
To 220 mg of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 3 mL of TFA/dichloromethane (1:1) and the solution was stirred at room temperature for 10 h. When the reaction was done, the solvents were removed by vacuum and the residue was triturated with hexane/dichloromethane. Filtration of the suspension gave 141 mg (77% yield) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.COC[O:11][CH2:12][CH2:13][CH:14]1[O:18][C:17]2=[N:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][N:16]2[CH2:15]1>C(Cl)Cl>[OH:11][CH2:12][CH2:13][CH:14]1[O:18][C:17]2=[N:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][N:16]2[CH2:15]1
Reactant: COCOCCC1Cn2cc([N+](=O)[O-])nc2O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cn2c(n1)OC(CCO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
Trifluoroacetic acid (2 ml) was added to a solution of 2-(2-methoxymethoxyethyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 25 (0.2 g, 0.822 mmol) in methylene chloride (10 ml) followed by stirring at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1), and crystallized from methanol-diisopropyl ether to afford 2-(2-hydroxyethyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (0.11 g, yield 65%) as a light yellow powder.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][N:6]([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[N:21]#[C:22]Br>C1COCC1.CCOC(C)=O>[CH2:13]([N:6]([CH2:5][C@@H:2]1[CH2:3][O:4][C:22]([NH2:21])=[N:1]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: CCN(C[C@@H](N)CO)c1ccccc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(C[C@@H]1COC(N)=N1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.5 %

Procedure:
To a stirred solution of (R)-2-amino-3-(ethyl-phenyl-amino)-propan-1-ol (235 mg) at r.t. in THF (10 ml) under an argon atmosphere were added potassium carbonate (334 mg) and a solution of cyanogen bromide (256 mg) in THF (5 ml). Stirring at r.t. was continued for 18 h. The mixture (off-white suspension) was diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (Isolute® SPE flash NH2 column, aminopropyl-functionalized silica; gradient:CH2Cl2->CH2Cl2/MeOH 9:1) to provide (R)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine (142 mg, 54%) as off-white solid. MS (ISP): 220.1 ([M+H]+)
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16])[CH:2]=[CH2:3].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CC#N>[CH2:1]([C:4]1[C:13]([O:14][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16])[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCc1c(O)cc(C(=O)OC)cc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: C=CCc1c(OCc2ccccc2)cc(C(=O)OC)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.6 %

Procedure:
To a mixture of dimethyl 4-allyl-5-hydroxyisophthalate (376b) (5.05 g, 20.18 mmol) and Cs2CO3 (13 g, 40.1 mmol) in CH3CN (30 mL) was added benzyl bromide (3.6 mL, 30.27 mmol). The mixture was stirred at room temperature for 14 hours. The solution was treated with water, and extracted with EtOAc (2×). The organic layer was dried over sodium sulfate, filtered and evaporated to provide the desired product as white solid (6.5 g, 98% yield). The crude product was used without purification. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.85 (t, J=6.78 Hz, 2 H) 3.89-3.93 (m, 3 H) 3.93 (s, 3 H) 4.93-4.99 (m, 1 H) 4.99-5.07 (m, 1 H) 5.16 (s, 2 H) 5.87-6.11 (m, 1 H) 7.30-7.38 (m, 1 H) 7.39-7.55 (m, 4 H) 7.74 (d, J=1.51 Hz, 1 H) 8.12 (d, J=1.70 Hz, 1 H); MS (ESI, pos):341.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([CH:51]4[CH2:56][CH2:55][CH2:54][CH:53]([C:57]([O:59][CH3:60])=[O:58])[CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[Cl:61][C:62]1[CH:63]=[C:64]([CH:68]=[CH:69][CH:70]=1)[C:65](Cl)=[O:66]>>[Cl:61][C:62]1[CH:63]=[C:64]([CH:68]=[CH:69][CH:70]=1)[C:65]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([CH:51]4[CH2:56][CH2:55][CH2:54][CH:53]([C:57]([O:59][CH3:60])=[O:58])[CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:66]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)C1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(NC(=O)c5cccc(Cl)c5)cc4)cc3C2=O)C1
Yield: 87 %

Procedure:
The compound of example 546 was prepared analogous to compound of example 97 by reaction of compound of example 543 with 3-chloro benzoyl chloride.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.COC(=O)C(O)C(C)C.[C:35]([O:39][C:40](=[O:44])[C@H:41](O)[CH3:42])([CH3:38])([CH3:37])[CH3:36].CO>C(OCC)(=O)C>[C:35]([O:39][C:40](=[O:44])[C@@H:41]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH3:42])([CH3:38])([CH3:37])[CH3:36]
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Agent: COC(=O)C(O)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)OC(C)(C)C

Procedure:
Following the procedure of Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol and 2-hydroxy-3-methyl-butyric acid methyl ester and (R)-2-hydroxy-propionic acid tert-butyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give (S)-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid tert-butyl ester as a yellow oil contaminated with triphenylphosphine oxide. LCMS: RT=3.86 min, [M+H]+=480
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27](O)[CH2:28][OH:29]>C1(C)C=CC=CC=1>[CH2:9]([C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:29][CH2:28][CH2:27][O:15]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC(=O)c1ccc(C)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCC1(c2ccc(C)cc2)OCCO1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
A mixture of 1-(4-methylphenyl)-1-heptanone (200 mg, 0.980 mmol), p-toluenesulfonic acid (17 mg, 0.098 mmol) and ethylene glycol (0.16 mL, 2.9 mmol) in dry toluene (10 mL) was heated at reflux with a Dean-Stark apparatus under nitrogen for 24 h. The mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was taken up in ether (20 mL) and the solution was washed with saturated sodium carbonate solution (2×10 mL) and brine (1×10 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with dichloromethane/hexane (1:2) afforded 2-hexyl-2-(4-methylphenyl)-1,3-dioxolane (19) as a tan-coloured oil (162 mg, 67%). 1H nmr (200 Mz, CDCl3) 0.80-0.92 (m, 3H, CH2CH3), 1.18-1.40 [m, 8H, (CH2)4], 1.84-1.89 (m, 2H, CCH2), 2.34 (s, 3H, ArCH3), 3.73-3.81 (m, 2H, OCH2), 3.94-4.02 (m, 2H, OCH2), 7.13 (d, J=8.2 Hz, 2H, 2×ArH), 7.32 (d, J=8.2 Hz, 2H, 2×ArH).
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:37]([NH:39][NH2:40])=[O:38])[CH2:23][CH2:22][N:21]([C:24](=[O:36])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[C:26]=4[F:35])[CH2:20][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42]>O1CCCC1>[C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][C:18]3([C:37]4[O:38][C:41](=[O:42])[NH:40][N:39]=4)[CH2:19][CH2:20][N:21]([C:24](=[O:36])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[C:26]=4[F:35])[CH2:22][CH2:23]3)[CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nccc1Nc1cccc(CC2(C(=O)NN)CCN(C(=O)c3cccc(C(F)(F)F)c3F)CC2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)n1nccc1Nc1cccc(CC2(c3n[nH]c(=O)o3)CCN(C(=O)c3cccc(C(F)(F)F)c3F)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 68.5 mg of 4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)-1-(2-fluoro-3-(trifluoromethyl)benzoyl)piperidine-4-carbohydrazide in 5 ml of tetrahydrofuran was added 23.7 mg of 1,1′-carbonyldiimidazole at room temperature. The reaction mixture was stirred at room temperature overnight, and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1 to ethyl acetate) to give the title compound as a colorless oil.