Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH3:2][C:3]1[NH:4][CH:5]=[C:6]([C:8](=O)[CH2:9][Br:10])[N:7]=1.C(=O)(O)[O-].[Na+].CC(C)=O.[C:21]([NH:24][C:25]([NH2:27])=[S:26])(=[NH:23])[NH2:22]>O>[BrH:10].[NH:24]([C:25]1[S:26][CH:9]=[C:8]([C:6]2[N:7]=[C:3]([CH3:2])[NH:4][CH:5]=2)[N:27]=1)[C:21]([NH2:23])=[NH:22]
Reactant: Cc1nc(C(=O)CBr)c[nH]1
Reactant: N=C(N)NC(N)=S
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nc(-c2csc(NC(=N)N)n2)c[nH]1
Yield: 79.3 %

Procedure:
2.8 g (9.86 mmol) of 1-(2 -methyl-4-imidazolyl)-2-bromo ethanone hydrobromide was dissolved in 10 ml water. Saturated sodium bicarbonate solution was added to pH 10 and the resultant solid was collected by filtration and washed with 15 ml water. The dried free base was heated at reflux in 50 ml acetone. To the refluxing clear acetone solution was added 1.2 g (9.86 mmol) of amidinothiourea. Solution occurred immediately and within a minute a solid began to form. After 1 hour reflux the slurry was cooled and the solid was collected by filtration and was washed with acetone followed by ether to give 2.37 g (79%) of 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole hydrobromide, mp 158° (dec.); nmr (DMSO-d6) (δ): 7.71 (s shoulder on broad s, 1H); 7.56 (broad s, 4H); 4.32 (s, 1H); 2.51 (s, 3H); calcd. for C8H10N6S.HBr: C, 31.69; H, 3.66; N, 27.72; found: C, 31.46; H, 4.30; N, 27.28.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([Cl:23])=[CH:13][C:12]=1[Cl:24].ClC1C=CC=C(C(OO)=[O:35])C=1.C(OC(=O)C)C.CCCCCC>C(Cl)(Cl)Cl>[F:26][C:2]([F:1])([F:25])[S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([S:17]([CH2:18][C:19]([F:20])([F:21])[F:22])=[O:35])[C:14]([Cl:23])=[CH:13][C:12]=1[Cl:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)CSc1cc(OCCCCCCSC(F)(F)F)c(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: O=S(CC(F)(F)F)c1cc(OCCCCCCSC(F)(F)F)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
In 30 ml of chloroform was dissolved 0.53 g (1.15 mmol) of 6-trifluoromethylthiohexyl-[2,4-dichloro-5-(2,2,2-trifluoroethylthio)phenyl]ether. Thereto was added 0.26 g (1.13 mmol) of 3-chloroperbenzoic acid (purity: about 75%) at 0° C., and the mixture was stirred for 3 hours at room temperature. Then, the solvent was distilled off under reduced pressure, 0.5 ml of triethylamine was added to the residue, and the residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane ethyl acetate=5:1), to obtain 0.41 g (yield: 75%) of an intended product.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:20][NH:21][C:22](=[O:73])[C@@H:23]([NH:26][C:27]([C@H:29]1[NH:47][C:46](=[O:48])[C@H:45]([CH2:49][CH2:50][CH2:51][NH:52]C(OC(C)(C)C)=O)[NH:44][C:43](=[O:60])[C@@H:42]([NH:61]C(OC(C)(C)C)=O)[CH2:41][C:40]2[CH:69]=[C:36]([CH:37]=[CH:38][C:39]=2[OH:70])[C:35]2=[CH:71][C:31](=[C:32]([OH:72])[CH:33]=[CH:34]2)[CH2:30]1)=[O:28])[CH2:24][OH:25])[CH2:9][CH2:10][CH2:11][NH:12]C(OC(C)(C)C)=O)(C)(C)C.[ClH:75]>O1CCOCC1>[ClH:75].[ClH:75].[ClH:75].[ClH:75].[NH2:61][C@H:42]1[CH2:41][C:40]2[CH:69]=[C:36]([CH:37]=[CH:38][C:39]=2[OH:70])[C:35]2=[CH:71][C:31](=[C:32]([OH:72])[CH:33]=[CH:34]2)[CH2:30][C@@H:29]([C:27]([NH:26][C@@H:23]([CH2:24][OH:25])[C:22]([NH:21][CH2:20][C@@H:8]([NH2:7])[CH2:9][CH2:10][CH2:11][NH2:12])=[O:73])=[O:28])[NH:47][C:46](=[O:48])[C@H:45]([CH2:49][CH2:50][CH2:51][NH2:52])[NH:44][C:43]1=[O:60]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@H](CO)NC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)N1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: NCCC[C@H](N)CNC(=O)[C@H](CO)NC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](N)C(=O)N[C@@H](CCCN)C(=O)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
18.4 mg (0.018 mmol) of the compound from Example 179A are dissolved at 0° C. in 1 ml of dioxane. Then 0.26 ml of a 4N hydrogen chloride solution in dioxane are added and the mixture is stirred at RT for 4 h. The mixture is evaporated to dryness in vacuo, and the residue is dried to constant weight under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)N.N(OC(C)(C)C)=O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Cu]>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: c1ccccc1
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: Clc1cccc(-c2ccccc2)c1
Yield: 67.6 %

Procedure:
In a manner similar to Example 1, the reaction of 3-chloroaniline (38.3 g, 0.30 mole) with t-butyl nitrite (46.4 g, 0.45 mole) in the presence of copper powder (15.0 g, 0.24 mole) and 4Å molecular sieves (powdered, 15.0 g) in benzene (1650 ml) produced 3-chloro[1,1'-biphenyl] (38.4 g, 67.6% yield, bp 96°/0.15 mm) as an oil. When the experiment was repeated the yield was 65.7%
Reaction SMILES: Cl[CH:2]([CH2:27][CH3:28])[C:3]([NH:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=1[C:16](=[O:26])[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[O:19])=O>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:27]([CH:2]1[C:3]2=[N:5][C:6]3[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=3[C:16]([OH:26])=[C:17]2[C:18](=[N:20][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[O:19]1)[CH3:28]
Reactant: CCC(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCC1OC(=Nc2nccs2)c2c1nc1c(C(F)(F)F)cccc1c2O
Yield: 91.5 %

Procedure:
A solution of 1 g of the product of Step B in 20 ml of tetrahydrofuran and 0.34 g of 4-dimethylamino-pyridine was refluxed for 90 minutes and was evaporated to dryness under reduced pressure. The residue was added to 10 ml of water and was vacuum filtered. The product was dried under reduced pressure at 90° C. to obtain 0.8 g of 1,3-dihydro-3-ethyl-1-[(2-thiazolyl)-imino]-5-trifluoromethyl-furo[3,4-b]quinoline-9-ol melting towards 250°-260° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](=[N:7][OH:8])Cl)[CH3:2].[N:10]1([C:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:23])[CH3:22])[CH2:19][CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1[CH:20]2[CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16][C:15]2([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[O:8][N:7]=1)=[O:9])[CH3:2]
Reactant: CC(=O)N1CC=C(N2CCCC2)CC1
Reactant: CCOC(=O)C(Cl)=NO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=NOC2(N3CCCC3)CCN(C(C)=O)CC12

Procedure:
A solution of 17.9 g (0.118 mol) of 2-chlorohydroxyiminoacetic acid ethyl ester in 20 mL of DCM was added to a solution of 16.3 g (84 mmol) of 1-(4-pyrrolidin-1-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (A) in 150 mL of DCM. On so doing, the solution warmed up and turned red. After cooling to 0° C. (ice bath), 16.4 g (0.118 mol) of triethylamine were slowly added dropwise with stirring. The mixture was stirred for 12 h at RT and then washed, firstly with 10% (weight percent) citric acid solution in water, and then with sat. aq. common salt solution. After removal of the solvent under a vacuum, the residue was purified by column chromatography (SiO2, EtOAc/EtOH 9:1). 18.5 g (71% of theoretical) of the desired product 5-acetyl-7a-pyrrolidin-1-yl-3a,4,5,6,7,7a-hexahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid ethyl ester (B) were obtained in the form of a brown oil.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH:12]=[O:13])[CH:3]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH2:12][OH:13])[CH:3]=1
Reactant: O=Cc1cc(F)c2c(c1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: OCc1cc(F)c2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
8-fluoro-2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (0.87 g: 4.8 mmol) was dissolved in ethanol (20 ml) and sodium borohydride (0.45 g; 11.95 mmol) was added at 0° C. The reaction mixture was stirred at rt for 2 h and poured into ice-water. The pH was adjusted to 5 by adding glacial acetic acid in portions and the aqueous mixture was extracted with ethyl acetate (80 ml). The organic phase was washed with water (30 ml), brine (30 ml), dried over sodium sulfate and concentrated under vacuum to give (8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methanol (0.84 g; 95% yield) as a yellow oil. 1H NMR (400 MHz, CD3OD) δ 6.66 (dd, 1H), 6.64 (br. s, 1H), 4.44 (s, 2H), 4.26 (s, 4H)
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:29][Si](C)(C)C>CC(CC)=O>[ClH:29].[CH3:28][N:2]([CH3:1])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:4][CH2:5][CH:6]([CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccn2)CCC(CC(=O)NCCCc2ccccc2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
The less polar diastereoisomer of 2-(4-dimethylamino-4-pyridin-2-ylcyclohexyl)-N-(3-phenylpropyl)acetamide (400 mg, 1.05 mmol) was dissolved in ethyl methyl ketone (10 ml), and chlorotrimethylsilane (0.2 ml, 1.58 mmol) was added. After a reaction time of 2 h, the hydrochloride was obtained as a beige-coloured solid in a yield of 94% (411 mg) with an m.p. of 218-220° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.[NH:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].Cl.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:13]([C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH3:14])[CH3:20]
Reactant: O=C(O)CCCc1ccncc1
Reactant: CCOC(=O)CNC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CN(C)C(=O)CCCc1ccncc1
Reaction time: 8 h

Procedure:
4-(4-Pyridyl)butanoic acid 10-5 (100 mg, 1.8 mmol), H-Sar-OEt·HCl (300 mg, 2.0 mmol), BOP (965 mg, 2.2 mmol) and NMM (700 μL, 6.4 mmol) were combined in 9 mL DMF. After stirring overnight the mixture was diluted with EtOAc, washed with water (4×), sat. NaHCO3, and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 80% to 100% EtOAc/hexane) provided 6-1 as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C([Cl:16])(=O)C.P(Cl)(Cl)(Cl)(Cl)Cl>CCOCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([Cl:16])=[O:12]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(Cl)c1cc2ccccc2[nH]1
Yield: 73.3 %

Procedure:
To a mixture of 1H-Indole-2-carboxylic acid (2.50 g, 15.5 mmol) and acetyl chloride (31 mL, 0.43 mol) in Et2O (31.5 mL) was added phosphorus pentachloride (3.55 g, 17.1 mmol) in portions, and the mixture was then heated under reflux for 1.5 hours. The cooled reaction mixture was concentrated under reduced pressure, and the crude product obtained thus was recrystallized from heptanes to give 1H-indole-2-carbonyl chloride (2.04 g, 73%) as yellow needles.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].ClC1C(OC)=CC=C(Cl)C=1N[C:27](=O)[N:28](C)[C:29]1[CH:34]=[C:33](NC2C=CC(N3CCN(C)CC3)=CC=2)[N:32]=[CH:31][N:30]=1>>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:33]3[CH:34]=[C:29]([NH:28][CH3:27])[N:30]=[CH:31][N:32]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Reactant: COc1ccc(Cl)c(NC(=O)N(C)c2cc(Nc3ccc(N4CCN(C)CC4)cc3)ncn2)c1Cl
Product: CCN1CCN(c2ccc(Nc3cc(NC)ncn3)cc2)CC1

Procedure:
The title compound is prepared as described in Example 144A but using 4-(4-ethylpiperazin-1-yl)-aniline (1 g, 4.88 mmol) and (6-chloro-pyrimidin-4-yl)-methyl-amine (Example 1) (771 1.81 g, 12.68 mmol, 1.3 eq.). Purification of the residue by silica gel column chromatography (DCM/MeOH, 93:7) followed by trituration in diethyl ether affords the title compound as a white solid: ESI-MS: 313.2 [MH]+; tR=1.10 min (gradient J); TLC: Rf=0.21 (DCM/MeOH, 93:7).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:20])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CC(C)=O>[CH2:29]([O:20][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:16]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc2cc(-c3ccccc3)cc(O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(-c2ccccc2)cc2ccc([N+](=O)[O-])cc12

Procedure:
A mixture of 125 g of 3-phenyl-7-nitro-1-naphthol prepared in step (2), 65 g of anhydrous potassium carbonate, 95 g of allyl bromide and 1200 ml of acetone was refluxed for 4 hours with good stirring. After cooling, the mineral salts were removed by filration and the residual organic solution was evaporated to dryness under reduced pressure. The crystals thus formed were washed with petroleum ether, filtered and dried at 80° C. under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.S(Cl)([Cl:15])(=O)=O>>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH:8]=[N:7][CH:6]=1
Reactant: Fc1ccc2cnccc2c1
Reactant: O=S(=O)(Cl)Cl
Product: Fc1ccc2cncc(Cl)c2c1
Temperature: 25 °C

Procedure:
A solution of 1.5 g 6-fluoro-isoquinoline (5) in 4.5 ml sulfuryl chloride was heated to 60° C. in a microwave reactor (CEM Discovery) for 8 h. After cooling to room temperature the mixture was poured on ice and extracted three times with CHCl3. After drying over Na2SO4 the solvent was distilled off and the crude product was purified by flash chromatography to yield 930 mg of 9. Rt=1.37 min (Method #1). Detected mass: 182.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH2:25](I)[CH2:26][CH3:27]>>[CH2:25]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:7][C:6]1[CH:19]=[CH:20][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=1)[CH2:26][CH3:27]
Reactant: O=c1nc(Nc2ccc(C(F)(F)F)cc2)sc2ncccc12
Reactant: CCCI
Agent: [H-]
Agent: [Li+]
Product: CCCn1c(=Nc2ccc(C(F)(F)F)cc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 646 mg of 2-(4-trifluoromethylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 18 mg of lithium hydride and 0.19 ml of propyl iodide were used. As a result, 546 mg of 3-propyl-2-[(4-trifluoromethylphenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][N:12]3[CH:21]=2)[CH:6]=[CH:7][CH:8]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][N:12]3[CH:21]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cn3ccc4ccccc4c3n2)c1
Agent: Br
Solvent: CC(=O)O
Product: Oc1cccc(-c2cn3ccc4ccccc4c3n2)c1

Procedure:
2-(3-Methoxyphenyl)imidazo[2,1-a]isoquinoline (11 g.) is refluxed for four hours in a mixture of 100 ml. of acetic acid and 100 ml. of 48 percent hydrobromic acid. The reaction mixture is evaporated to dryness and the residue is taken up with 200 ml. of water and 20 ml. of 30 percent sodium hydroxide. After filtration, the filtered solution is extracted with dichloromethane and the aqueous phase is neutralized with dilute hydrochloric acid. The resulting solid precipitate is collected by filtration and crystallized from dichloromethane. Yield 9 g. of the title product which melts at 201°-2° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH:12][NH2:13])=[C:7]([Cl:14])[N:6]=1)=[O:4].[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[C:18](Cl)[N:17]=1>C(O)CC(C)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH:12][NH:13][C:18]2[N:17]=[C:16]([NH2:15])[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=2)=[C:7]([Cl:14])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)c(NN)nc1N
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)CCO
Product: COC(=O)c1nc(Cl)c(NNc2nc(N)c3cc(OC)c(OC)cc3n2)nc1N
Temperature: 120 °C
Reaction time: 12 h
Yield: 96.2 %

Procedure:
Compound (51) (5 mmol) was added to a solution of 4-amino-2-chloro-6,7-dimethoxy quinazoline (0.96 g, 4 mmol) in isoamyl alcohol (10 mL) at 25° C. The mixture was then stirred at 120° C. for 12 h. After cooling to room temperature, the desired product was filtered and rinsed with acetone to give 1.62 g (96%) of the title compound: TLC (Rf =0.30; 10% CH3OH/CH2Cl2); 1H NMR (DMSO) δ 11.90 (br, 1H), 10.30 (br, 1H), 9.80 (br, 1H), 9.00 (br, 1H), 8.80 (br, 1H), 7.80 (s, 1H), 7.69 (d, 1H, J=2.0), 7.41 (s, 1H), 7.19 (s, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.76 (s, 3H); HRMS (FAB) m/z 421.1152 (M+H)+ (C16H18N8O4Cl requires 421.1110); Anal. (C16H18N8O4Cl·1/4CH3OH) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:26][C@@H:27]([OH:31])[C:28]([OH:30])=[O:29])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.[C:33](=[O:41])([O:37][CH:38]([CH3:40])[CH3:39])[O:34][CH2:35]Cl.[Na+].[I-].N1C=CC=CC=1>CN(C=O)C.O>[CH:38]([O:37][C:33]([O:34][CH2:35][O:29][C:28](=[O:30])[C@H:27]([OH:31])[CH2:26][N:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:32])=[CH:13][CH:12]=1)[NH:16][C:17]([C:19]1[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=1)=[O:18])=[O:41])([CH3:40])[CH3:39]
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Reactant: CC(C)OC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCOC(=O)OC(C)C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
A mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 430 mmol), chloromethyl isopropyl carbonate (132 mg, 860 mmol), NaI (129 mg, 860 μmol) and pyridine (136 mg, 1.7 mmol) in DMF (5.0 mL) was stirred at 25° C. overnight. The mixture was then poured into water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=1:1) to yield the title compound as a colorless liquid (10 mg). LC-MS: 580 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.28 (d, J=6 Hz, 6H), 3.37-3.39 (m, 2H), 3.98 (s, 3H), 4.22-4.24 (m, 2H), 4.38-4.40 (m, 1H), 5.78-5.91 (m, 2H), 6.54 (s, 1H), 7.22-7.18 (t, J=9 Hz, 1H), 7.34-7.36 (m, 1H), 7.46-7.55 (m, 5H).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)=[O:5]>C(N)(C)C>[CH:16]([NH:19][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)=[O:5])([CH3:17])[CH3:15]
Reactant: CC(C)c1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)cc1
Solvent: CC(C)N
Product: CC(C)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(C(C)C)cc1
Temperature: 65 °C

Procedure:
A mixture of 300 mg (0.95 mmol) of the compound obtained in step B in 15 ml isopropylamine is heated to 65° C. for 10 h in a sealed tube. The excess of amine is stripped off i.v. Extraction of the residue with ethyl acetate/water gives a quantitative yield of the product in form of a yellow resin, which is used without purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCCC1>[OH:9][CH2:8][C:4]1[CH:3]=[C:2]([NH:1][C:17](=[O:19])[CH3:18])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(CO)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(CO)c1
Temperature: 0 °C
Yield: 74.1 %

Procedure:
To a solution of (3-aminophenyl)methanol (1.87 g, 14.7 mmol) in tetrahydrofuran (10 mL) was added triethylamine (7 mL, 73.5 mmol). The reaction was cooled down to 0° C., acetic anhydride (1.5 mL, 16 mmol) was added dropwise. The reaction was warmed to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The ethyl acetate layer was dried over MgSO4, concentrated, trituated with CH2Cl2 to yield N-(3-(hydroxymethyl)phenyl)acetamide as a yellow solid (1.8 g, 74%). HPLC retention time (Method C)=1.03 min. LC/MS (ESI) (M+H)+=166.
Reaction SMILES: [OH-].[K+].CS(C)=O.[F:7][C:8]1[C:9]([O:18][CH3:19])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[NH2:17].Cl[CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]>O>[NH2:17][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([F:7])[C:9]=2[O:18][CH3:19])[N:13]([CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[N:12]=1
Reactant: COc1c(F)ccc2[nH]nc(N)c12
Reactant: N#Cc1cccc(CCl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1c(F)ccc2c1c(N)nn2Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 48 %

Procedure:
Finely ground potassium hydroxide (6.59 g, 118 mmol, 2.5 equiv.) was treated with DMSO (100 mL). To this was added 5-fluoro-4-(methyloxy)-1H-indazol-3-amine (for a preparations see Intermediate 56) (8.5 g, 47 mmol) and the mixture stirred at room temperature for 50 minutes. To the red coloured mixture was added 3-chloromethyl benzonitrile (8.9 g, 59 mmol, 1.25 equiv.) in one portion. A small exotherm of −5° C. was observed. The mixture was allowed to stir at room temperature for 25 minutes before pouring into water (600 mL) and extracting with chloroform (400 mL). The aqueous was re-extracted with chloroform (2×400 mL). The organic extracts were combined, washed with water (3×500 mL), dried over MgSO4, filtered and evaporated to give the crude product. This was dry loaded onto silica and chromatographed eluting with 20% petrol up to 70% EtOAc-petrol. The material came off impure so was re-chromatographed on a suction column. The impure material was loaded in DCM and eluted with DCM up to 30% EtOAc-DCM to give the title compound (8.25 g, 48%) as an off-white solid. LCMS (System A) RT=0.96 min, ES+ve m/z 297 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10](/C(/C)=C\SC)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.C(S(O)(=O)=O)(F)(F)F>O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS/C=C(/C)n1c(=O)n(Cc2ccccc2)c2ccccc21
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: O=c1[nH]c2ccccc2n1Cc1ccccc1
Reaction time: 3 h
Yield: 47.4 %

Procedure:
35 mg of 1-benzyl-3-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-1,3-dihydro-2H-benzimidazol-2-one 1 (0.113 mmol) prepared as described in example 2 were solubilised in a solution of MeOH/H2O 1:1 (2 mL). Then, CF3SO3H (2 mL) was added and the solution refluxed under magnetic stirring. After 3 h, H2O was added (5 mL) and the solution was extracted 3×10 mL of CH2Cl2. The resulting solid was finally chromatographed on silica gel (CH2Cl2/AcOEt 8:2) to yield 1-benzyl-1,3-dihydro-2H-benzimidazol-2-one 2 as a white powder (12 mg, 48%). Mp 194° C. (Iitt. G. Vernin, H. Domlog, C. Siv, J. Metzger, J. Heterocyclic Chem., 18, 85 (1981): 198° C.); Rf=0.23 (CH2Cl2/AcOEt 8:2); 1H NMR (200 MHz, CDCl3) δ=5.11 (2H, s, CH2), 6.84-7.35 (9H, m, Ar), 10.08 (1H, brs, NH).