Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[C:39]1[CH2:40][CH2:41][N:42]([C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])[CH2:43][CH:44]=1)(=O)=O>COCCOC.C(=O)(O)[O-].[Na+].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:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:17]1[CH:22]=[CH:21][C:20]([C:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[O:46])[CH2:41][CH:40]=2)=[CH:19][CH:18]=1)=[O:32])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(OCc1ccccc1)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2=CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 80 °C
Yield: 80.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (8.0 g, 6.92 mmol) was added to a stirred suspension of N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2,-dioxaborolan-2-yl)benzamide (288 g, 657 mmol; prepared as described in International Patent Publication number WO 03/087057, Method 13, page 60) and benzyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (240 g, 657 mmol; prepared as described in Method 3 below) in 1,2-dimethoxyethane (3000 ml) and saturated aqueous sodium bicarbonate solution (3000 ml). The reaction mixture was heated to 80° C. for 7 h, before being allowed to cool to ambient temperature, with stirring. The reaction mixture was then poured onto water (2000 ml) and extracted with ethyl acetate. The organic extracts were then dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product as a grey solid. This was purified by flash column chromatography on silica, eluting with ethyl acetate/hexane (30:70 v/v) to afford the title compound (279 g, 82%); NMR Spectrum: (DMSO-d6) δ 1.44 (s, 9H), 2.56 (m, 2H), 3.66 (m, 2H), 4.14 (m, 2H), 5.13 (s, 2H), 6.34 (m, 1H), 7.18 (m, 2H), 7.33 (m, 1H), 7.40 (m, 4H), 7.54 (m, 2H), 7.62 (d, 2H), 7.94 (d, 2H), 8.64 (br s, 1H), 9.81 (br s, 1H); Mass Spectrum: MNa+ 550.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CO>[N:22]1([S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: C1COCCN1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Solvent: CO
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(S(=O)(=O)N3CCOCC3)cc2c2cc[nH]c12
Yield: 8.2 %

Procedure:
This compound is prepared according to synthesis 25, from 115 mg (0.30 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 32 μL (0.36 mmol) of morpholine. After trituration in hot methanol, 5 mg (4%) of 8-(morpholine-4-sulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a gray solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([NH:14][C@H:15]2[C@@H:19]3[O:20]C(C)(C)[O:22][C@@H:18]3[C@@H:17]([O:25][CH2:26][CH2:27][OH:28])[CH2:16]2)=[N:5][C:6]([S:10][CH2:11][CH2:12][CH3:13])=[N:7][C:8]=1[Cl:9].[N:29]([O-])=O.[Na+]>O>[Cl:9][C:8]1[C:3]2[N:2]=[N:29][N:14]([C@@H:15]3[CH2:16][C@H:17]([O:25][CH2:26][CH2:27][OH:28])[C@@H:18]([OH:22])[C@H:19]3[OH:20])[C:4]=2[N:5]=[C:6]([S:10][CH2:11][CH2:12][CH3:13])[N:7]=1
Reactant: O=N[O-]
Reactant: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Yield: 80 %

Procedure:
A flask was charged with water (20 mL) and concentrated hydrochloric acid (35%, 1.5 mL). To this, 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol (5 g) was added and the mixture was stirred for clear solution. To this mixture, aqueous sodium nitrite solution (0.86 g in 5 mL) was slowly added at room temperature over a period of 15 minutes and mixture was stirred for about 30 minutes and completion of reaction was monitored by TLC. The solid obtained is isolated by filtration and washed with water (5 mL) and dried under vacuum to afford the title compound in about 80% yield.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4](Br)[C:3]1=[O:9].O.O.O.C([O-])(=O)C.[Na+].[CH2:18]([SH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CO>[CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([S:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:3]1=[O:9]
Reactant: CCCCCCS
Reactant: CN1C(=O)C=C(Br)C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCSC1=CC(=O)N(C)C1=O
Yield: 83 %

Procedure:
To N-methyl bromomaleimide (100 mg, 0.53 mmol) and sodium acetate trihydrate (70 mg, 0.53 mmol) in methanol (15 mL) was added hexanethiol (74 μL, 0.58 mmol) in methanol (100 mL) dropwise over 1 hour with vigorous stirring. After 5 minutes solvent was removed in vacuo. Purification by column chromatography (gradient elution in 10% ethyl acetate in petroleum ether to 30% ethyl acetate in petroleum ether) afforded the desired compound as a bright yellow solid (99 mg, 0.44 mmol) in 83% yield. δH (600 MHz, CDCl3) 6.03 (s, 1H, H-2), 3.01 (s, 3H, H3-5), 2.89 (t, 2H, J=7.6, 2H, H2-11), 1.76-1.71 (m, 2H, H2-10), 1.46-1.41 (m, 2H, H2-9), 1.33-1.27 (m, 4H, H2-7 and CH2-8), 0.89 (t, 3H, J=6.5, H3-6); δC (125 MHz, CDCl3) 171.47 (C═O), 169.94 (C═O), 151.84 (C3), 117.27 (C2), 31.92 (C11), 31.31 (CH2), 28.64 (CH2), 27.75 (CH2), 24.10 (C5), 24.10 (C7), 14.09 (C6); IR (oil, cm−1) 2727 (w), 1708 (s); MS (FAB+) m/z (relative intensity): 250 ([M+Na], 40), 228 (35), 199 (30), 176 (100); Exact Mass Calcd for [C11H17NO2S]+Na requires m/z 250.0878 Found 250.0880 (FAB+).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[CH:34]=[C:35]([NH:39][C:40]([CH:42]4[CH2:44][CH2:43]4)=[O:41])[CH:36]=[CH:37][CH:38]=3)[CH2:29][CH2:28]2)=[O:9])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1)C1CC1

Procedure:
Example 114 was prepared from triphenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: ESMS m/e: 572.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1C=O.Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.[C:16]([O-:19])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:6][CH:7]=[C:8]([C:16]=1[O:19][CH2:12][CH:13]1[CH2:15][CH2:14]1)[CH:9]=[O:10]
Reactant: BrCC1CC1
Reactant: O=Cc1cccc(O)c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(Br)c1OCC1CC1

Procedure:
300 mg (1.49 mmol) 2-Bromo-3-hydroxy-benzaldehyde, 302 mg (2.24 mmol) (bromomethyl)cyclopropane and 412 mg (2.99 mmol) K2CO3 in 3 mL DMF are stirred at 80° C. over night. Afterwards the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is separated and dried over Na2SO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH:27]1([SH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.O>CC(O)C>[CH:27]1([S:33][C:2]2[O:3][C:4]([C:7]3[N:12]=[C:11]([NH:13][C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=4)[CH:10]=[CH:9][CH:8]=3)=[CH:5][N:6]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: SC1CCCCC1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(Cl)o3)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccnc(Nc2cccc(-c3cnc(SC4CCCCC4)o3)n2)c1
Yield: 70.6 %

Procedure:
A mixture of [6-(2-chloro-oxazol-5-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine (50 mg, 0.174 mmol), K2CO3 (72 mg, 0.523 mmol) and cyclohexanethiol (64 μl, 0.523 mmol) in iPrOH (5 ml) were heated to reflux for 18 h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure to a yellow gum. The gum was taken up in a minimum of DCM and precipitated with n-pentane to afford the title compound as a beige solid (45 mg, 71%). 1H NMR (300 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.10 (s, 1H), 7.56-7.78 (m, 4H), 7.17 (d, J=5.9 Hz, 1H), 6.75 (s, 1H), 3.71 (m, 1H), 2.31 (s, 3H), 2.08 (m, 2H), 1.64 (m, 8H). (ESI+) m/z 367 (M+H)+.
Reaction SMILES: [OH-].[Li+].[CH2:3]([C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=1)[CH2:4][CH2:5][CH3:6].Cl>C1COCC1.O>[CH2:3]([C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc(C(=O)OCC)cs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc(C(=O)O)cs1
Reaction time: 16 h

Procedure:
Lithium hydroxide (5.00 g) was added to a stirred mixture of ethyl 2-butylthiazole-4-carboxylate (example 78, step f) (6.50 g) in THF (80 mL) and water (20 mL). After 16 h, concentrated hydrochloric acid (10 mL) was added and the solution concentrated to ˜40 mL. The reaction mixture was partitioned between ethyl acetate and brine. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and evaporated in vacuo to give the subtitled compound as an off white solid. Yield 4.6 g.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCOCC1.O>[OH:3][CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(C#N)cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)c1ccc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.1 g (0.01 mole) of p-(5-acetyl-2-furyl)benzonitrile and 40 ml of 95% dioxane/water was added portionwise 0.37 g (0.10 mole) of NaBH4 while maintaining the temperature at 15°-20° by means of an ice bath. The reaction was stirred at room temperature for 3 hours and then added to ice/water with a precipitate forming. The precipitate was filtered and dried in vacuum pistol at room temperature to yield 1.6 g (75%), n.p. 79°-82°, of title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1.O.[NH2:15][NH2:16]>C(O)C>[CH3:13][N:11]1[CH:12]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:15][NH2:16])=[CH:7][CH:6]=2)[CH:9]=[N:10]1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cn1cc(-c2ccc(NN)nn2)cn1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a suspension of 3-chloro-6-(1-methyl-1H-pyrazole-4-yl)-pyridazine (21.0 g, 108 mmol) in ethanol (370 mL) was added hydrazine monohydrate (36 mL). The reaction mixture was stirred at reflux for 18 h, then cooled to room temperature. The precipitate was collected via filtration, washed with cold ethanol and dried in vacuo to provide 18 g of [6-(1-methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-hydrazine as a beige solid (87% yield): 1H NMR (DMSO-d6) δ 3.88 (s, 3H), 4.28 (s, 2H), 7.02 (d, 1H), 7.59 (d, 1H), 7.83 (s, 1H), 7.91 (s, 1H), 8.19 (s, 1H); MS (m/z) 191 [M+H+]+.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15]>C1C=CC=CC=1>[O:12]=[C:4]1[N:1]2[N:2]=[C:14]([C:13]([O:17][CH2:18][CH3:19])=[O:16])[CH:15]=[C:3]2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5]1
Reactant: C#CC(=O)OCC
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Solvent: c1ccccc1
Product: CCOC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 25 °C

Procedure:
A solution of 48 g (0.30 mole) of 3-diazooxindole and 38.7 g (0.39 mol) of ethyl propiolate in 2 l. of benzene is refluxed overnight. The reaction mixture is cooled to room temperature and the crude product filtered, wt.=60 g. Crystallization from absolute ethanol gives 54 g, m.p. 242°-244° (Sl. d.).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49](C1C=CC=CC=1CS(Cl)(=O)=O)#[N:50]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=1[C:49]#[N:50])(=[O:41])=[O:40])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: N#Cc1ccccc1CS(=O)(=O)Cl
Product: N#Cc1ccccc1CS(=O)(=O)NCCc1c(CCOc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 72 %

Procedure:
The title compound was prepared from 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (Step 6, Example 1) and (2-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7 as a white solid in 72% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[NH:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:6]1=2)=[O:4].Cl.[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:21][CH:20]=1)=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[C:6]2[C:7](=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:8][CH2:9][N:10]1[CH2:17][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])=[CH:23][CH:24]=1)=[O:4]
Reactant: CC(=O)N[C@@H](C)c1ccc(C=O)cc1
Reactant: COC(=O)C1NCCc2cc(O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1c2ccc(O)cc2CCN1Cc1ccc([C@H](C)NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 200 mg (0.821 mmol) 7-hydroxy-1,2,3,4-tetrahydro-3-isoquinoline-4-carboxylic acid methyl ester hydrochloride and 157 mg (0.821 mmol) (S)—N-(1-(4-formylphenyl) ethyl) acetamide (example III) in 5 mL THF are added 141 μL (2.46 mmol) AcOH and the mixture is stirred at r.t. for 10 min. After that time, the resulting mixture is cooled to 0° C., 261 mg (1.23 mmol) sodium triacetoxyborohydride are added and the reaction mixture is stirred at r.t. for 2 h. After that time, the reaction is quenched by addition of 500 μL water and purified by HPLC (ACN/H2O/NH3).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[CH3:15].CCCCCC.C([Li])CCC.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>O1CCCC1>[CH2:13]([O:12][CH2:11][CH2:10][O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([B:27]([OH:32])[OH:28])=[C:3]([CH3:15])[CH:4]=1)[CH3:14]
Reactant: CCOCCOc1cc(C)c(Br)c(C)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOCCOc1cc(C)c(B(O)O)c(C)c1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
To a solution of 2-bromo-5-(2-ethoxyethoxy)-1,3-dimethylbenzene (10.0 g, 36.6 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium hexane solution (1.6 M, 25.1 mL, 40.2 mmol) at −78° C. with stirring. The reaction mixture was stirred at the same temperature for 30 min. and triisopropyl borate (10.5 mL, 45.5 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 3 hrs. 5 N Hydrochloric acid (20 mL) was added to the reaction mixture and the mixture was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane/diethyl ether and dried to give the title compound (5.9 g, yield 68%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[C:6]([Cl:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][NH:18][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:6]([Cl:17])[CH:5]=1)[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(Oc2c(Cl)cc(N)cc2Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CNc1cc(Cl)c(Oc2ccc(OC)cc2)c(Cl)c1
Temperature: 0 °C
Yield: 76 %

Procedure:
3,5-Dichloro-4-(4-methoxy-phenoxy)-phenylamine (10.2 g, 0.03 mol), ethyl bromoacetate (5.39 g, 0.03 mol) and diisopropylethylamine (5.1 g, 0.03 mol) in 50 mL of DMF were stirred at 120° C. for 18 h. The reaction mixture was poured in to ice-water. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel, (hexane:ethyl acetate 90:10) to afford pure [3,5-Dichloro-4-(4-methoxy-phenoxy)-phenylamino]-acetic acid ethyl ester.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1.C(=O)([O-])O.[Na+]>C(O)C.O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=2)[CH:14]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Brc1ccc2nc(-c3ccccc3)cn2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
1.99 g of 2-bromo-1-phenylethanone, 1.73 g of 2-amino-5-bromopyridine and 1 g of sodium hydrogen carbonate in a mixture of 20 ml of ethanol and 5 ml of water are placed in a round-bottomed flask. The mixture is heated at 80° C. for 4 h and left to cool and 40 ml of water are added. The mixture is stirred for 15 min and the precipitate is then recovered by filtration; it is washed with water and then with diisopropyl ether and dried in a desiccator. 1.8 g of compound are obtained. Mp=192-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[N:12]1([CH2:17][CH2:18][OH:19])[CH:16]=[CH:15][N:14]=[CH:13]1.N1C=CN=C1.[C:25]1(=[O:30])[O:29]CCO1>C(#N)C.C(N(CC)CC)C>[C:25]([OH:29])(=[O:30])/[CH:7]=[CH:3]\[C:4]([OH:19])=[O:5].[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:19][CH2:18][CH2:17][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[O:5]
Reactant: O=C1OCCO1
Reactant: OCCn1ccnc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)/C=C\C(=O)O
Product: O=C(OCCn1ccnc1)c1ccc(Cl)cc1Cl
Reaction time: 1.5 h

Procedure:
11 g (0.05 mol) of 2,4-dichlorobenzoyl chloride were added dropwise to a mixture of 5.5 g (0.05 mol) of 1H-imidazole -1-ethanol [prepared from imidazole and ethylene carbonate by the process of British patent No. 939,681], 20 ml of triethylamine and 150 ml of acetonitrile. The reaction mixture was kept at about 80° C. for another 1.5 hours and then the solvent was evaporated. The residue was dissolved in a mixture of ethyl acetate and diethyl ether and was then extracted with water and subsequently with dilute hydrochloric acid. The acidic aqueous layer was made alkaline after which the base was taken up in ethyl acetate. The organic layer was extracted three times with water, dried and partly concentrated by evaporation. The residue was acidified with maleic acid and the 2-(1H-imidazol-1-yl)-ethyl 2,4-dichlorobenzoate (Z)-2-butenedioate (1:1) obtained was crystallized from a mixture of 2-propanol, acetone and diethyl ether to obtain the product with a melting point of 116-117° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[N:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:31]=[CH:32][CH:33]=2)O1.CN(C)C(=O)C>C(OCC)(=O)C.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>[CH3:11][C:9]1[N:8]=[CH:7][N:6]2[C:2]([C:32]3[CH:31]=[C:30]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:29]=[CH:28][CH:33]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: Cc1cc2ncc(Br)n2cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cc2ncc(-c3cccc(-c4ccccc4C#N)c3)n2cn1
Temperature: 80 °C
Yield: 49 %

Procedure:
A stirred mixture of 3-bromo-7-methylimidazo[1,2-c]pyrimidine (0.1013 g, 0.478 mmol), dried potassium phosphate (0.2027 g, 0.955 mmol) and a 0.5 M solution of 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-2-carbonitrile in N,N-dimethylacetamide (1.91 ml, 0.955 mmol) was degassed by evacuation and refilling with nitrogen three times. Tetrakis(triphenylphosphine)palladium(0) (28.7 mg, 0.0248 mmol) was then added and the mixture was degassed with two more evacuation-refilling cycles before heating at 80° C. under nitrogen for 45 h, adding more dried potassium phosphate (0.0503 g, 0.237 mmol), a 0.5 M solution of 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile in N,N-dimethylacetamide (0.48 ml, 0.240 mmol) and tetrakis(triphenylphosphine)palladium(0) (8.0 mg, 0.0069 mmol) after 21 h with degassing. The mixture was diluted with ethyl acetate and filtered through glass fibre filter paper, washing solid with more ethyl acetate. The combined filtrates were washed with saturated aqueous NaCl (15 ml), and the aqueous layer was further extracted with ethyl acetate (2×25 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, EtOAc) to give 72.8 mg (49%) of the title compound as a yellow-brown solid: mp 119° C. (softens) (CH2Cl2-EtOAc-isohexane); 1H NMR (400 MHz, CDCl3) δ 2.57 (3H, s), 7.36 (1H, s), 7.51 (1H, td, J 7.6, 1.2 Hz), 7.57-7.72 (6H, m), 7.78 (1H, fine m), 7.82 (1H, dd, J 7.5, 1.4 Hz), 9.34 (1H, s); MS (ES+) m/z 311 [M+H]+; Anal. Found: C, 71.93; H, 4.68; N, 16.35%. Required for C20H14N4.1.4H2O: C, 71.58; H, 5.05; N, 16.70.