Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=[C:5]2[N:6]=1>CO.[H][H].[Pt]=O>[OH:1][C:2]1[NH:3][C:4]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Oc1nc2cccccc-2n1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: Oc1nc2c([nH]1)CCCCC2
Yield: 87.6 %

Procedure:
A solution of 2-Hydroxy-cycloheptimidazole (16.0 g) in methanol was stirred vigorously with platinum oxide (0.2 g) in the hydrogen stream. An off-white suspended solution obtained after 16 hrs, was refluxed and filtered. The insoluble material was extracted again with hot methanol (200 ml) and filtered. The combined filtrate was concentrated in reduced pressure. Obtained yellow powder was washed with ethanol (50 ml) and filtered. 14.6 g of the desired compound was obtained. m.p. 272° C./dec.
Reaction SMILES: [N:1]1[C:8](Cl)=NC(Cl)=NC=1Cl.[OH-].[Na+].[CH3:12][C:13]([CH3:15])=O>>[C:8](#[N:1])[C:12]1[C:12](=[CH:13][CH:15]=[CH:15][CH:13]=1)[C:8]#[N:1]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1ccccc1C#N
Reaction time: 2 h

Procedure:
A solution of intermediate D (32.7 g) in acetone (500 ml) was added to cyanuric chloride (18.5 g) in acetone (150 ml) at 0° C. and stirred at this temperature for 2 hours, maintaining the pH at 6 with 0.5M sodium hydroxide solution. The precipitated solid was filtered off, washed with ice cold water (2×250 ml) and dried to give the damp product (65.2 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=[CH:9]2>C(O)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([N+:1]([O-:4])=[O:2])=[C:11]([O:16][CH3:17])[CH:10]=[CH:9]2
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2cc(Br)ccc2c1
Solvent: CC(=O)O
Product: COc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Temperature: 50 °C
Yield: 90 %

Procedure:
10 ml of 98% strength nitric acid dissolved in 70 ml of acetic acid were added dropwise to 50 g (0.21 mol) of 6-bromo-2-methoxynaphthalene dissolved in 350 ml of acetic acid at room temperature. The mixture was heated to 50° C. and, after the product had crystallized, cooled. The precipitate was filtered off with suction to yield 53.1 g (90%) of the product. Melting point 156°-157° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[N+:20]([O-])=O)[O:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[N:11][CH:12]=1)=[CH2:2].O1CCCC1.CO.C(OCC)(=O)C>[C].[Pd].CCCCCC>[CH2:1]([C:3]1[CH:4]=[C:5]([O:6][C:7]2[CH:12]=[N:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:17]=[CH:18][C:19]=1[NH2:20])[CH3:2]
Reactant: C=Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)ccc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.7 %

Procedure:
A mixture of 5-(3-ethenyl-4-nitrophenoxy)-2-(methylsulfonyl)pyridine (5.0 g), 10% palladium carbon (1.0 g, containing water (50%)), tetrahydrofuran (100 mL), and methanol (50 mL) was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 3 days. The catalyst was filtered off, and the obtained filtrate was concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=25:75 to 60:40, volume ratio) to give the title compound (4.05 g, yield 89%) as a pale-yellow oil.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([OH:7])=[O:6].CCN(C(C)C)C(C)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18]([N:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([OH:7])=[O:6])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
(S)-Azetidine-2-carboxylic acid (250.4 mg, 2.5 mmol) was dissolved in DMF (15 mL) and distilled water (6 mL). The solution was cooled to 0° C., and DIEA (645 μL, 3.7 mmol) was added followed by benzyl chloroformate (530 μL, 3.7 mmol). The reaction was stirred at 0° C. and allowed to warm to ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]#[N:9])=[CH:5][N:6]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)Cl>[C:16]([NH:1][C:2]1[S:3][C:4]([S:7][C:8]#[N:9])=[CH:5][N:6]=1)(=[O:18])[CH3:17]
Reactant: N#CSc1cnc(N)s1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ncc(SC#N)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.3 %

Procedure:
To a mixture of 2-amino-5-thiocyanatothiazole (15.7 g, 0.1 mol) and pyridine (12 g, 0.15 mol) in methylene chloride (100 mL) was added acetic anhydride (1.2 g, 0.12 mol) at rt. The mixture was stirred at rt for 6 h. The mixture was concentrated to dryness and to the residue MeOH (50 mL) was added. The precipitates were collected and washed with water. The solid was dried and recrystallized from MeOH to afford 2-acetylamino-5-thiocyanatothiazole (15.2 g, 76%) as a solid, mp 212° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccc2nc(C3CCCCC3)ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: c1ccc2c(c1)CCC(C1CCCCC1)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
A solution of 2-cyclohexylquinoline (2.66 g, 12.61 mmol) in glacial acetic acid (25 ml) was treated with sodium cyanoborohydride (2.38 g, 37.82 mmol) and stirred at room temperature for 4 h and then 40° C. for 18 h. The mixture was then treated with 2 M sodium hydroxide (200 ml), stirred for 30 min and extracted into ethyl acetate (3×100 ml). The combined organic layers were then washed with water (3×100 ml), dried with sodium sulfate, evaporated under reduced pressure and the residue purified by flash chromatography eluting with 0-3% (v/v) ethyl acetate in isohexane to afford 2-cyclohexyl-1,2,3,4-tetrahydroquinoline as a yellow oil (1.61 g, 7.49 mmol).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-].[Na+].[K+].[Br-]>CO>[OH:10][C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:2](=[O:3])[CH:1]=[CH:17][C:16]1[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)c1cccc(O)c1
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C=CC(=O)c2cccc(O)c2)cc1

Procedure:
3-Hydroxy acetophenone, 2 (6.8 g, 50 mmol), 4-methoxy benzaldehyde, 4 (6.0 mL, 50 mmol) and 50% aqueous sodium hydroxide (50 mL) in methanol (110 mL) were reacted as in 7 to yield 8. Yield 12.5 g (98%); mp 93-94° C.; MS (FAB) 255 (M++1); IR (KBr) 3366, 1649; 1H NMR (200 MHz, CDCl3) δ 7.80 (d, J=15.6 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.55 (d, J=2.3 Hz, 1H), 7.38 (d, J=15.6 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.04 (d, J=7.9 Hz, 1H), 6.92 (d, J=8.6 Hz, 2H), 3.85 (s, 3H).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][C:12]([C:15](O)=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH2:30]>>[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH:30][C:15]([C:12]1[S:11][C:10]([NH:9][C:8]([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])=[N:14][CH:13]=1)=[O:16]
Reactant: COC(=O)CN
Reactant: O=C(O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: Cl
Product: COC(=O)CNC(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 75 %

Procedure:
Prepared in 75% yield as described in general procedure (K) using 2-(3,3-dicyclohexylureido)-thiazole-5-carboxylic acid and glycine methyl ester hydrochloride.
Reaction SMILES: CC[O-].[Na+].[C:5]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:6][C:7]([O-])=[O:8].[CH3:14][O:15][CH2:16][CH2:17][N:18]1[C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:22]=2[C:21](=O)[O:20]C1=O.Cl>>[CH2:12]([O:11][C:5]([C:6]1[C:7](=[O:8])[N:18]([CH2:17][CH2:16][O:15][CH3:14])[C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:22]=2[C:21]=1[OH:20])=[O:10])[CH3:13]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COCCn1c(=O)oc(=O)c2cnc(-c3ccccc3)nc21
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)c1c(O)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O

Procedure:
50 ml. of NaOEt (0.5 g. Na -0.021 mole) was added to 3.4 g. (0.021 mole) of ethyl malonate and stirred 10 minutes, then evaporated to dryness. DMF was added until a solution was achieved and then 3.2 g. (0.011 mole) of 1-(2-methoxyethyl)-7-phenyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione was added and this mixture refluxed 2 hours. The chilled reaction was poured into dilute HCl and the ensuing precipitate filtered off and rinsed with water. Recrystallization from ethyl acetate gave 3.5 g. of the title product--m.p. 178°-179° C.
Reaction SMILES: [NH:1]([C:8](=[O:32])[CH:9]([C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:21][CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]([C:8](=[O:32])[CH:9]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:30][CH:31]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of tert-butyl 4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoate, prepared in the previous step, in CH2Cl2 (200 mL) at room temperature was added trifluoroacetic acid (50 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated. The crude acid was dissolved in CH2Cl2, filtered, and precipitated with hexanes. The solid was collected by filtration, washed with hexanes, and dried under high vacuum to yield 4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoic acid (7.58 g, 71% from dimethyl [4-(tert-butoxycarbonyl)phenyl]malonate) as an off white solid: 1H NMR (600 MHz, DMSO-d6) δ 12.94 (s br, 1H), 10.26 (s br, 2H), 7.94 (d, J=8.2 Hz, 2H), 7.58 (d, J=7.6 Hz, 4H), 7.54 (d, J=8.2 Hz, 2H), 7.30 (t, J=7.6 Hz, 41-1), 7.05 (t, J=7.3 Hz, 2H), 4.97 (s, 1H); ESIMS calcd 375.1 (M++H), found 375.1 (M++H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[C:5]([C:21]#[N:22])=[CH:4][N:3]=1.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:23]1([NH:29][C:2]2[C:7]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:13][CH:12]=4)[S:10][C:6]=3[C:5]([C:21]#[N:22])=[CH:4][N:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)c1ccc(-c2cc3c(Cl)ncc(C#N)c3s2)cc1
Reactant: NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cc3c(NC4CCCCC4)ncc(C#N)c3s2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a solution of 4-chloro-7-cyano-2-(4′-t-butylphenyl)-thieno[3,2-c]pyridine (0.05 g, 0.153 mmol) in DMF was added cyclohexylamine (0.017 g, 0.168 mmol) and potassium carbonate (0.023 g, 0.168 mmol). The resulting mixture was stirred under nitrogen at 80° C. for 2 h. After this time the mixture was partitioned between ethyl acetate (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL), and the organic layer washed with water and brine, then dried over magnesium sulphate and concentrated under reduced pressure. Purification by silica gel chromatography (eluent 20% ethyl acetate in hexane) afforded 0.042 g of 102. 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.63 (d, 2H), 7.50 (d, 2H), 7.38 (s, 1H), 5.14 (bs, 1H), 4.20 (bs, 1H), 2.18 (m, 2H), 1.80 (m, 4H), 1.6–1.12 (m, 13H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=1[O:34][CH3:35].O.Cl>CCO>[Br:1][C:2]1[C:3]([N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([NH:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=2[O:34][CH3:35])=[N:6][CH:7]=1
Reactant: CNC(=O)C(C)(C)CN(c1nc(Cl)ncc1Br)C1CCCC1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNC(=O)C(C)(C)CN(c1nc(Nc2ccc(C(=O)OC)cc2OC)ncc1Br)C1CCCC1
Temperature: 90 °C
Yield: 23 %

Procedure:
3-[(5-bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-N,2,2-trimethyl-propanamide (266 mg, 0.6825 mmol) and methyl 4-amino-3-methoxy-benzoate (185.5 mg, 1.024 mmol) were dissolved in EtOH (2 mL) and Water (8 mL) and treated with HCl (134.5 μL of 37% w/v, 1.365 mmol). Heat at 90° C. overnight. Cool to ambient temperature and remove solvent in vacuo. The reaction mixture was diluted with EtOAc/NaHCO3 and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filter and concentrated. The crude residue was purified by column chromatography (0 to 100% EtOAc/Petrol) to give the sub-title compound as a beige oil (84 mg, 23%); NMR (400.0 MHz, DMSO) d 0.97 (s, 6H), 1.44-1.69 (m, 8H), 2.45 (d; J=4.4 Hz, 3H), 3.58 (br s, 2H), 3.84 (s, 3H), 3.96 (s, 3H), 4.11 (quin, 1H), 7.32-7.34 (m, 1H), 7.52 (d, J=1.8 Hz, 1H), 7.61 (d, 1H), 8.07 (s, 1H), 8.38 (s, 1H) and 8.43 (d, J=8.5 Hz, 1H); MS ES(+) 536.0, ES (−) 534.1.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([CH:22]2[O:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][CH2:23]2)=[O:21])[CH2:15][CH2:14]1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.Cl>CO.[OH-].[Na+]>[C:1]([NH:9][C:10]([NH:12][CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH:20]([CH:22]2[O:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][CH2:23]2)[OH:21])[CH2:17][CH2:18]1)=[O:11])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCN(CC(=O)C2COc3ccccc3O2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(NC(=O)c1ccccc1)NC1CCN(CC(O)C2COc3ccccc3O2)CC1
Temperature: 25 °C

Procedure:
1-Benzoyl-3-[1-(2-[1,4-benzodioxan-2-yl]-2-oxoethyl)piperid-4-yl]-urea (7.21 g, 0.017 mol) was suspended in methanol (80 cm3) and was stirred at room temperature. Sodium borohydride (1.0 g, 0.026 mol) in 2N sodium hydroxide (10 cm3) was added dropwise to the stirring solution and then left to stir for a further hour. Water was added and the solid filtered off and dried (5.41 g, 75%). A. T.L.C. of a small portion of the solid was run in freshly prepared toluene: ethanol: 0.880 ammonia (90:10:1 by volume) on a silica plate and was found to contain two components having RF values of about 0.30 and 0.34. The solid was recrystallised from n-butyl acetate (9 times) to give the component (1.19 g) with the lower RF value. This was suspended in a small amount of methanol and ethanolic HCl added until the solution was just acidic. The hydrochloride of the title compound (0.96 g, 74%) was collected.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11]>C(#N)C>[C:10]([NH:14][C:6]1[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)N
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CC#N
Product: CC(C)(C)Nc1nc(Cl)ncc1F
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To 20 ml of acetonitrile were added 6.4 g of 2,4-dichloro-5-fluoropyrimidine and 7.0 g of t-butylamine, then the mixture was stirred at 50° C. for 20 minutes. The solution was concentrated under reduced pressure, and separated by adding 40 ml of distilled water and 70 ml of chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated pale yellow crystals were dispersed in diisopropylether and collected by filtration to obtain 4.1 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[C:7](=O)([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[O:8]C(C)C>C(O)(C)C>[CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7](=[O:8])[O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH3:3]
Reactant: CC(C)OC(=O)OCCN(C)C
Reactant: CN(C)CCO
Solvent: CC(C)O
Product: CN(C)CCOC(=O)OCCN(C)C

Procedure:
wherein the 2-(N,N-dimethylamino)ethanol reacts with the isopropyl 2-dimethylaminoethyl carbonate formed in step ii) to form bis[2-(N,N-dimethylamino)ethyl]carbonate and isopropanol,
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH2:31][CH:32]=C)=[C:20]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:35].[Na+].C(OCC)(=O)C.[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH2:31][CH2:32][OH:35])=[C:20]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCc1c(OCc2ccccc2)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: O=[Os](=O)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc(OCc4ccccc4)c(CCO)c3O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.9 g (8.4 mmole) of [(2R)-8-allyl-7-(benzyloxy)-2,3-dihydro-1,4-bezodioxin-2-yl]methyl 4-methylbenzenesulfonate in 300 mL of tetrahydrofuran was added 1.8 mL (0.30 mmole) of 4% aqueous osmium tetroxide. The solution was stirred at room temperature under nitrogen for 30 minutes, then a solution of 9.0 g (40 mmole) of sodium periodate in 75 mL of water was added dropwise over a 30 10 minute period. The mixture was allowed to stir at room temperature under nitrogen for 15 hours. Ethyl acetate (400 mL) was then added and the solution was washed twice with 300 mL portions of water and with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum to 2.8 g of a colorless oil. The oil was redissolved in 100 mL of methylene chloride, 3.0 g (12 mmole) of tetra-n-butylammonium borohydride added and the mixture stirred at room temperature for 15 hours. The excess reducing agent was then destroyed by the cautious addition of 200 mL of 1 N aqueous HCl, the organic phase removed in a separatory funnel, and the aqueous back-extracted with 100 mL of methylene chloride. The combined organic phases were washed with 250 mL of saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with first methylene chloride, then 2% methanol in methylene chloride, to give 2.3 g of the (R)-enantiomer of the title compound as a colorless oil. 1H-NMR (CDCl3): doublet 7.8 δ (2H); multiplet 7.4 δ (5H); doublet 7.37 δ (2H); doublet 6.65 δ (1H); doublet 6.45 δ (1H); singlet 5.0 δ (2H); multiplet 4.43 δ (1H); multiplet 4.2 δ (3H); doublet of doublets 4.0 δ (1H); triplet 3.73 δ (2H), triplet 2.9 δ (2H); singlet 2.43 δ (3H); broad singlet 1.65 δ (1H).
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[CH:17]=O.[NH4+].[OH-]>CS(C)=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2]>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:16]=1[C:17]1[NH:12][C:7]2[CH:6]=[C:5]([C:4]([OH:3])=[O:13])[CH:10]=[CH:9][C:8]=2[N:11]=1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [NH4+]
Solvent: CS(C)=O
Product: O=C(O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,4-diamino-benzoic acid ethyl ester (0.9 g) and 2,6-dichlorobenzaldehyde (1.2 g) in DMSO (20 mL) was added Sc(OTf)3 (0.1 g) and Cu(OTf)2 (0.07 g). The mixture was stirred in an open flask at ambient temperature overnight, before it was poured into aqueous NH4OH. Resulting precipitate was collected by filtration and the wet solid was dissolved in MeOH (20 mL). To it was added 1N NaOH (12 mL) and the mixture was heated to reflux overnight, when it was cooled to ambient temperature, diluted by water, and washed with ether. The aqueous phase was then carefully acidified to pH 3-4 and resulting precipitate was filtered and air dried to give crude 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid as tan solid: 1H NMR (400 MHz, CD3OD) 8.4 (br s, 1H), 8.0 (d, 1H), 7.7 (s, 1H), 7.6 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([OH:9])=O)([O-:3])=[O:2].S(Cl)(Cl)=O.[F:20][C:21]([F:29])([F:28])[C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([NH:27][C:24]1[S:25][CH:26]=[C:22]([C:21]([F:29])([F:28])[F:20])[N:23]=1)=[O:9])([O-:3])=[O:2]
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1nc(C(F)(F)F)cs1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
A mixture of 3,4-dinitrobenzoic acid (1.78 g, 8.4 mmol) and thionyl chloride was stirred for 2 h at reflux. The mixture was concentrated i.vac., toluene and 4-trifluoromethyl-thiazol-2-ylamine (1.49 g, 8.4 mmol) were added and the mixture was stirred at 120° C. for 3 days. Then the mixture was filtered and dried i.vac.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].C(=O)([O-])[O-].[Na+].[Na+].[C:26]1([C:32]#[CH:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>[Cl-].[Na+].O.[Cu]I.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.O1CCOCC1>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:33]#[C:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:15][CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1[nH]c(-c2ccc(Br)cc2)cc1C(N)=O
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)Nc1[nH]c(-c2ccc(C#Cc3ccccc3)cc2)cc1C(N)=O
Temperature: 95 °C
Reaction time: 5 h
Yield: 57 %

Procedure:
2-Aminocarbonylamino-5-(4-bromophenyl)pyrrole-3-carboxamide (Compound No. 1-1, 100 mg, 0.31 mmol), sodium carbonate (69 mg, 0.65 mmol), copper(I) iodide (12 mg, 0.063 mmol), phenylacetylene (68 μL 0.62 mmol) and tetrakis(triphenylphosphine)palladium(0) (38 mg, 0.033 mmol) in mixed solvent (8 mL), which consists of water and 1,4-dioxane (1:3), were stirred at 95° C. for 5 hours. The brine (5 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL), and then the organic layer was dried over magnesium sulfate. The layer was filtered with celite and the solvent was removed under reduced pressure. The obtained solid was washed with ethyl acetate (2 mL), and dried under reduced pressure to give the target compound (61 mg) as a pale yellow solid (Yield 57%).