Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[Br:27][C:28]1[CH:29]=[C:30]([OH:37])[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[Br:27][C:28]1[CH:29]=[C:30]([CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)[O:37][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Cl
Reactant: O=[N+]([O-])c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (250 mg), 3-bromo-5-nitrophenol (170 mg), potassium carbonate (138 mg), and N-methylpyrrolidone (5 mL) was stirred at 100° C. for 4 hours. To the reactant was added water, followed by extraction with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain 5-(3-bromo-5-nitrophenoxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (336 mg) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][CH3:13])=[CH:7][C:6]=1[CH3:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CCO>[CH3:14][C:6]1[CH:7]=[C:8]([S:12][CH3:13])[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:15]=[C:16]([NH2:18])[S:17][CH:2]=1
Reactant: CSc1cc(C)c(C(=O)CBr)c(C)c1
Reactant: NC(N)=S
Solvent: CCO
Product: CSc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 44.6 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(methylthio)phenyl)ethanone (4.64 g, 17.0 mmol) and thiourea (1.29 g, 17.0 mmol) in 95% EtOH (24.3 mL) was heated at reflux for 120 min. The solution was concentrated and mixed with water (50 mL) and saturated aqueous Na2CO3 (4.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4 (methylthio)phenyl)thiazol-2-amine (1.9 g) as light yellow solids in 45% yield: 1H NMR (500 MHz, CDCl3) δ 6.97 (s, 2 H), 6.26 (s, 1 H), 2.47 (s, 3 H), 2.15 (s, 6 H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[CH:21][CH:22]=3)[N:17]([C:32]3[N:37]=[CH:36][N:35]=[C:34]([NH:38][CH3:39])[CH:33]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:20]2[CH:19]=[C:18]3[C:23]([C:15]([C:11]4[CH:10]=[C:9]([NH:8][C:1](=[O:3])[CH3:2])[CH:14]=[CH:13][CH:12]=4)=[CH:16][N:17]3[C:32]3[CH:33]=[C:34]([NH:38][CH3:39])[N:35]=[CH:36][N:37]=3)=[CH:22][CH:21]=2)=[CH:29][CH:28]=1
Reactant: CC(=O)OC(C)=O
Reactant: CNc1cc(-n2cc(-c3cccc(N)c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNc1cc(-n2cc(-c3cccc(NC(C)=O)c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
Acetic anhydride (20.3 μL, 0.214 mmol) was added to a mixture solution of 6-(3-(3-aminophenyl)-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (30 mg, 0.071 mmol) and pyridine (28.7 μL, 0.355 mmol) in methylene chloride (2 mL) at room temperature. After stirring for 1 hour at room temperature, the reaction solution was added to saturated sodium bicarbonate aqueous solution and then extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (preparative HPLC). The target compound (15 mg) was obtained as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2OC)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccccc2OC)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(2-methoxyphenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 17, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][C:28]=1[C:36]([F:39])([F:38])[F:37]>CN(C)C=O.C(OCC)(=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:1][C:2]2[CH:3]=[C:4]([N:9]([CH3:25])[C:10]3[N:15]=[C:14]4[S:16][C:17]([NH:19][C:20]([CH:22]5[CH2:23][CH2:24]5)=[O:21])=[N:18][C:13]4=[CH:12][CH:11]=3)[CH:5]=[CH:6][C:7]=2[F:8])=[O:35])=[CH:29][C:28]=1[C:36]([F:37])([F:38])[F:39]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccc(F)c(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.1 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.34 mmol) produced in Example 1(x) was dissolved in N,N-dimethylformamide (1.5 mL), 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (89 mg, 0.40 mmol) was added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (140 mg, 72%) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>C(#N)C.CCOC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: ClCCCCCBr
Reactant: Oc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: ClCCCCCOc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-hydroxybenzothiazole (0.2 g, 1.32 mmol) in 10 mL of acetonitrile was added K2CO3 (0.274 g, 1.98 mmol), followed by stirring at 50˜55° C. for 30 min. Then, 1-bromo-5-chloropentane (0.245 g, 1.32 mmol) was added to and reacted with the solution of 2-hydroxybenzothiazole at 80˜90° C. for 3 hours. The reaction was cooled to room temperature, diluted with 10 mL of EtOAc, and washed with distilled water and a saturated NaCl aqueous solution. It was dried over MgSO4 and the solvent was removed by concentration under reduced pressure to afford K23 (0.333 g, 98%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CS(C)=[O:22]>>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]([OH:22])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CS(C)=O
Reactant: CN1CCN=C1C(c1ccccc1)c1ccccn1
Product: CN1CCN=C1C(O)(c1ccccc1)c1ccccn1

Procedure:
Add 5 g. of 1-methyl-2-(2-pyridylbenzyl)imidazoline and 25 ml. of dimethyl sulfoxide to a solution of potassium t-butylate (prepared from 1.4 g. of potassium and 200 ml. of t-butanol) and stir the resulting solution in a stream of dry air for 30 hrs. Add 2.1 ml. of acetic acid to the resulting mixture and remove the alcohol in vacuo. Shake the residue with 200 ml. of benzene and 50 ml. of cooled 5 sodium carbonate. Separate the benzene phase, water-wash, dry, filter and evaporate in vacuo. Recrystallize the residue from isopropanol acetate to yield 1-methyl-2[α(-2-pyridyl) hydroxybenzyl]imidazoline, m.p. 105°-108° C.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(C(C)C)C(C)C)C.[C:32]([O:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39])(=[O:34])[CH3:33]>C1C=CC=CC=1>[C:32]([O:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38]([N:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:39])(=[O:34])[CH3:33]
Reactant: CCOC(=O)CCCCNc1ccccc1-c1ccccc1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCN(C(=O)c1ccccc1OC(C)=O)c1ccccc1-c1ccccc1
Yield: 73.5 %

Procedure:
15.0 g of ethyl 5-(biphenyl-2-yl)aminovalerate is reacted, analogously to Example 47b), with 6.6 g of ethyldiisopropylamine and 10.0 g of o-acetoxybenzoylchloride in 70 ml of benzene to obtain, as reaction product, 17.0 g (73.4% of theory) of ethyl 5-[o-acetoxy-N-(biphenyl-2-yl)-benzamido]valerate as a viscous non-distillable oil. The saponification of this ester yields 9.1 g (63.2% of theory) of 5-[o-hydroxy-N-(biphenyl-2-yl)benzamido]valeric acid, MP 138° to 139°.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:16][CH2:17][CH2:18][NH:19][CH3:20].C(N(CC)CC)C>O1CCOCC1>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([N:19]([CH2:18][CH2:17][Cl:16])[CH3:20])[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCCCl
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(CCCl)C1CC(=O)N(Cc2ccccc2)C1=O
Temperature: 0 °C

Procedure:
74.8 g (0.4 mol) of N-benzylmaleimide [Arch. Pharm. 308, 489 (1975)] and 52.0 g (0.4 mol) of 2-chloroethyl-methylamine hydrochloride are initially introduced into 400 ml of dioxane and 40.4 g (0.4 mol) of triethylamine are added dropwise at 20° C. The mixture is then boiled under reflux for 5 hours. The batch is subsequently poured into 2 1 of ice-water and extracted with 3 portions of 400 ml of chloroform and the extract is washed with water, dried over sodium sulphate and concentrated on a rotary evaporator. Chromatography of the residue (101.1 g) on silica gel using ethyl acetate:petroleum ether (1:2) gives 56.8 g (51% of theory) of an oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([OH:13])[CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]=[CH:4][N:3]=1.[CH3:14][NH:15][CH3:16].Cl.C(OCC)(=O)C>ClCCl>[ClH:1].[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([OH:13])=[C:6]2[C:11]=1[C:2]([N:15]([CH3:16])[CH3:14])=[N:3][CH:4]=[N:5]2
Reactant: CNC
Reactant: Oc1ccc(Cl)c2c(Cl)ncnc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)c1ncnc2c(O)ccc(Cl)c12
Reaction time: 0.5 h

Procedure:
A solution of 4,5-Dichloro-8-quinazolinol (0.6 g, 2.8 mmol) in dichloromethane is added to a saturated solution of dimethylamine gas in dichloromethane. The reaction mixture is stirred for 30 minutes, re-saturated with dimethylamine gas, stirred for 30 minutes and concentrated in vacuo to obtain a yellow solid. The solid is added to a 2.5% hydrochloric acid/ethyl acetate mixture. The mixture is filtered and the filter cake is washed with water and dried in a vacuum oven to give the title product as a white solid, 0.35 g, mp 232° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(N([CH2:20][CH3:21])CC)C>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C@@H:20]([N:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH3:21])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CNCc1ccccc1
Solvent: CCO
Product: CCOC(=O)C[C@H](C)N(CC(=O)OCC)Cc1ccccc1
Temperature: 0 °C
Yield: 41275.6 %

Procedure:
To ethanol (55 ml) cooled to 0° C. was added acetyl bromide (41 ml, 0.6 mol) dropwise, followed by a solution of (S)-4-methyl-dihydro-furan-2-one (Tetrahedron 1983, 39, 3107; 18.6 g, 0.2 mol) in ethanol (20 ml). The ice bath was removed and the reaction allowed to reach room temperature. After 2 h of stirring the reaction was concentrated, the residue redissolved in dichloromethane, washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated affording (S)-4-bromo-3-methyl-butyric acid ethyl ester (33.6 g, quant). This was redissolved in ethanol (100 ml), cooled to 0° C. and N-benzylglycine ethyl ester (28.2 g, 0.14 mol) and triethylamine (22.4 ml, 0.16 mmol) were added. The reaction was then warmed to 75° C. for 4 d after which time the reaction was concentrated, the residue redissolved in dichloromethane, washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (ethyl acetate/heptane 5:95) afforded the titled product as a light gold oil (20.3 g, 43%). MS (ISP)=322.2 (M+H)+.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[C:13]2[S:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]2.C([O-])(=O)C.[K+].O>C(O)(=O)C>[Br:1][C:23]1[CH:24]=[C:19]([C:11]2[C:12]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:13]=3[C:4]([Br:3])=[C:5]3[C:10]=2[CH:9]=[CH:8][CH:7]=[CH:6]3)[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[C:22]=1[OH:25]
Reactant: BrBr
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c([N+](=O)[O-])c3)c2c1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c([N+](=O)[O-])c3)c2c1C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
A solution of bromine (0.040 mL, 0.756 mmol) in acetic acid (0.5 mL) was added dropwise to a stirred suspension of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (0.20 g, 0.467 mmol), potassium acetate (0.228 g, 2.335 mmol) in acetic acid (4 mL). After 10 min, water was added and the reaction mixture was extracted with ether. Silica gel was added to the ether phase and the solvent was removed. The adsorbate was flashed (gradient: 95:5 to 85:15) to provide the title compound as a yellow solid (0.141 g, 60%): mp 129-130° C.: NMR (DMSO-d6); δ11.30 (s, 1H), 8.22 (d, J=8 Hz, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.67 (quintuplet, J=4 Hz, 1H), 7.51 (d, J=4 Hz, 2H), 2.45 (s, 3H), 1.65 (s, 3H); MS (EI): 2 bromine isotope pattern 505 (40%), 507 (100%), 509 (50%); Anal. Calc. for C20H13Br2NO3S: C, 47.36; H, 2.58; N, 2.76. Found: C, 47.18; H, 2.55; N, 2.63.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C@@H:46]([NH2:48])[CH3:47]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:48][C@H:46]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[Br:39])[CH3:47])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: C[C@H](N)c1ccccc1Br
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4Br)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 30 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and S-(−)-1-(2-bromophenyl)ethylamine (prepared in Example 394B): yield 30%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:14]([N:11]1[CH2:10][CH:9]=[C:8]([CH2:7][CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: c1cc(CCC2CCCO2)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: C1=C(CCC2CCCO2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A solution of 4-(2-[tetrahydrofuran-2-yl]ethyl)pyridine (3.0 g, 16.9 mmol) in anhydrous dimethylformamide (5 ml) was treated with benzyl bromide (2.2 ml, 18.6 mmol) and the mixture was stirred at room temperature for one hour. The reaction was diluted with absolute ethanol (100 ml), treated with sodium borohydride (0.8 g, 21.2 mmol) and stirred at reflux for one hour. The solvent was evaporated in vacuo and the residue partitioned between diethyl ether and water. The organic layer was separated, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed with 3% methanol in dichloromethane as eluant to afford the title compound (3.75 g, 82%) as a colourless oil; δH (DMSO-d6) 1.30-2.08 (8H, m, 4×CH2), 2.45-2.52 (2H, m, tetrahydropyridinyl CH2), 2.52-2.56 (2H, m, CH2), 2.60-2.66 (2H, m, tetrahydropyridinyl CH2), 3.50 (2H, s, PhCH2N), 3.52-3.80 (3H, m, tetrahydrofuranyl CH2 and CH), 5.50-5.55 (1H, m, tetrahydropyridinyl 5-H), and 7.20-7.34 (5H, m, ArH); m/z (CI+, NH3) 272 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][NH:3]1.C(N(CC)CC)C.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:20]([N:3]1[CH2:4][CH:2]1[CH3:1])([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1CN1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CN1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
2-Methyl aziridine is dissolved in CH2Cl2 and triethylamine under argon at 0° C. Benzylchloroformate is added and the contents of the flask are at room temperature overnight. The mixture is poured into 10% citric acid and is extracted with CHCl3. The organic layer is washed with dilute aqueous NaHCO3 and dried over MgSO4. The solution is evaporated to yield N-Cbz-2-methyl aziridine.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14]>>[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14].[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:12][OH:11])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 70 °C
Reaction time: 24 h

Procedure:
Streptomyces olivaceus, strain NRRL B-3583, is cultivated in a nutrient medium containing 0.7% xylose, 0.3% dextrose, 0.5% beef extract, 0.25% yeast extract, 1.0% peptone, 0.5% NaCl, 0.05% MgSO4. 7H2O and 0.024% CoCl2. 6H2O. The fermentation is allowed to proceed at 28° C. for 24 hours. A 2% (weight per volume) solution of a cationic polyelectrolyte is added to the fermentation broth in amounts equivalent to 0.05% (weight per volume) of the dry flocculant. The broth is briefly agitated to promote aggregation of the cells. Agitation is then stopped and sedimentation of the flocculated cells is allowed to proceed. The cell aggregates are harvested in a manner analogous to that described in Example 1. The flocculated cells are dried at 60° C. for 24 hours before subjecting the dried cell mass to gentle mechanical crushing action to reduce to particle sizes suitable for column operation. The crushed cell material is poured into a jacketed column partially filled with a 1.0 M glucose solution. The packed column is heated to 70° C. and a 1.0 M glucose solution containing 0.04 M MgCl2. 6H2O adjusted to pH 8 is passed through the column to give conversion of glucose to fructose.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:14](Br)=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[C:30]1([Sn](CCCC)(CCCC)CCCC)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C.CCOC(C)=O.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>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(-c1ccc(F)cc1)n2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc2c(c1O)c(-c1ccccc1)c(-c1ccc(F)cc1)n2-c1ccccc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of 3-bromo-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (180 mg, 0.395 mmol), phenyltributlytin (149 μL, 0.454 mmol), and Pd(PPh3)2Cl2 (14 mg, 0.020 mmol) in DMF (2 mL) was stirred at 130° C. overnight. Then the mixture was diluted with EtOAc, washed with water and saturated NaCl aqueous solution respectively; the EtOAc phase was dried over anhydrous sodium sulfate, concentrated, the residue was purified by column and prep TLC to give a white solid, the desired title compound (59 mg). The title compound, ESI MS (m/z): 453 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:6])[C:4]#[N:5].[CH3:7][NH:8][CH3:9]>C1COCC1>[OH:1][CH2:2][CH:3]([CH2:6][N:8]([CH3:9])[CH3:7])[C:4]#[N:5]
Reactant: C=C(C#N)CO
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(C#N)CO
Temperature: 45 °C

Procedure:
2-hydroxymethyl-acrylonitrile (37 mmol, 3.1 g, prepared as per procedure described by Csuk et al. in Tetrahedron, 1996, 52, 9759-9776) was treated with dimethylamine (25 mL of a 2M solution in THF) and the reaction was heated in a sealed vessel at 45° C. for 14 h. The reaction was cooled to room temperature and all the volatiles were removed by concentration under vacuum. The crude 2-hydroxymethyl-3-dimethylaminopropionitrile thus obtained was dissolved in dry THF (50-60 mL) and this solution was added dropwise to a cold (−78° C.) suspension of LAH (6 g) in THF (300 mL). The reaction was gradually warmed to room temperature and stirred for an additional 12 h at room temperature. The reaction was then cooled in an ice bath and very carefully quenched by the sequential addition of H2O (6 mL), 4M NaOH (6 mL) and H2O (18 mL). The white slurry thus obtained was filtered through celite and the filter bed was washed with additional CH2Cl2. The entire filtrate was then concentrated under vacuum to provide crude amine 23.