Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH:14]1([CH2:17][S:18][C:19]([CH3:23])([CH3:22])[CH:20]=O)[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][S:18][C:19]([CH3:23])([CH3:22])[CH2:20][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][CH2:9][C:10]([SH:13])([CH3:11])[CH3:12])[CH2:16][CH2:15]1
Reactant: CC(C)(C=O)SCC1CC1
Reactant: CC(C)(S)CNc1ccccc1N
Product: CC(C)(S)CNc1ccccc1NCC(C)(C)SCC1CC1
Yield: 85 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (0.43 g, 2.19×10-3 mol) and 0.82 g (5.19×10-3 mol, 237 M %) 2-cyclopropylmethylthio-2-methylpropanal were reacted by the method of Example 2 to yield 0.63 g (85%) of 1-(2-cyclopropylmethylthio-2-methylpropylamino)-2-(2-mercapto-2-methylpropylamino)benzene as an oily product after purification by filtration through flash silica in a 350 ml sintered glass funnel, eluting with 200 ml portions of 2×100% hexane, 3×90% hexane/ether, 2×80% hexane/ether.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]=[C:28]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc(-c5ccccc5)nc5ccccc45)cc3CC[C@@H]12
Yield: 63.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 4-chloro-2-phenylquinazoline (111 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80-100% ethyl acetate/hexanes eluent gradient) to give 112 mg (63%) of the title compound as an off white solid. mp 185°-193°. FDMS: m/e=465. α[D]589 =+49.59 (c=0.57, chloroform).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:20][CH:19]([CH3:21])[CH2:18][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=[C:4]1[CH2:3][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(C)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Reactant: C1COCCN1
Agent: Cl
Product: CC(C)Cn1c(CN2CCOCC2)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Yield: 68 %

Procedure:
2-Chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (Example 10, prepared from 2.0 g of the corresponding alcohol) was added to morpholine (5 mL). The mixture was refluxed for 4 hr. The resulting solution was cooled to room temperature. A solid precipitated. The solid was filtered from the mixture and slurried in aqueous sodium bicarbonate solution. The product was filtered from the mixture, washed with water, and dried to yield 1.7 g (68.0%) of solid, which was recrystallized from ethanol to give a pure product m.p. 228-234° C. Analysis: Calculated: C, 67.2; H, 7.4; N, 20.6. Found: C, 67.3; H, 7.9; N, 20.6.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:27]2[CH2:29][CH2:28]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=3)=[N:16][CH:17]=2)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH:30][NH:31][C:32](=N)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:27]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:30][N:31]=[C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=3)=[N:16][CH:17]=2)=[O:11])[CH2:28][CH2:29]1
Reactant: N=C(NO)c1ccccc1
Reactant: CCOc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cn1
Product: CCOc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(c4nc(-c5ccccc5)no4)CC3)cn2)cn1

Procedure:
The title compound is prepared from 2-(6-ethoxy-pyridin-3-yl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide and N-hydroxy-benzamidine following a procedure analogous to that described in Example 6. LC (method 3): tR=2.20 min; Mass spectrum (ESI+): m/z=512 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.Cl>CCOC(C)=O.O1CCOCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: COc1ccc2ncnc(Cl)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2c1

Procedure:
To 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (275 mg, 1 mmol) was added 4-chloro-6-methoxyquinazoline (194 mg, 1 mmol) according to the procedure described in Example 1B Step 1. The resulting compound was dissolved in EtOAc and 4N HCl in dioxane was added. The mixture was sonicated, stirred and concentrated in vacuo to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxyquinazolin-4-yloxy)phenyl)urea as the mono-hydrochloride (299 mg, 0.64 mmol, 64%). 1H NMR (300 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.20 (s, 1H), 8.65 (s, 1H), 7.95 (d, 1H), 7.75-7.60 (m, 3H), 7.42 (t, 1H), 7.29 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 3.98 (s, 3H), 1.29 (s, 9H); LC-MS (ESI) m/z 434 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[C:6]([O:17][CH2:18][CH2:19][CH3:20])[CH:5]=[C:4]([CH3:21])[N:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[C:6]([O:17][CH2:18][CH2:19][CH3:20])[CH:5]=[C:4]([CH3:21])[N+:3]=1[O-:30]
Reactant: CCCOc1cc(C)nc(C)c1C(=O)Nc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCOc1cc(C)[n+]([O-])c(C)c1C(=O)Nc1ccccc1
Yield: 91.2 %

Procedure:
Then a mixture of 1.42 g (5 m mol) of 2,6-dimethyl-N-phenyl-4-propoxy-3-pyridinecarboxamide obtained thus, 2.16 g (10 m mol) of a commercially available m-chloroperbenzoic acid (80% purity) and 40 ml of chloroform was stirred for 8 hours at room temperature. The reaction mixture was discharged to a separation funnel and after the addition of the 10% aqueous sodium hydrogen sulfite solution, was shaken. The separated oil phase was washed with aqueous saturated sodium hydrogen carbonate solution and then with aqueous saturated sodium chloride solution. It was then dehydrated over anhydrous magnesium sulfate and filtered. After the filtrate was concentrated, the residue was crystallized from a mixture of ethyl acetate and hexane to obtain 1.37 g of the title compound
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:15]=1[C:16]([O:18][CH3:19])=[O:17])=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].ClCCl>>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:15]=1[C:16]([O:18][CH3:19])=[O:17].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(O)cccc1OCCCCN

Procedure:
Methyl 2-{4-[(tert-butoxycarbonyl)amino]butoxy}-6-hydroxybenzoate (410 mg, 1.2 mmol) was treated with trifluoroacetic acid/dichloromethane (6 mL, 1:1/v:v) at ambient temperature for 3 hours, concentrated under reduced pressure and evaporated with acetonitrile twice to provide the titled amine as its trifluoroacetic acid salt (450 mg).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C@@H:11]1[C@:19]2([CH3:20])[C@H:14]([C@@H:15]([OH:21])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1)[CH3:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[C:1]([O:7][CH2:8][C@H:9]([C@@H:11]1[C@:19]2([CH3:20])[C@H:14]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1)[CH3:10])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: C[C@H](COC(=O)C(C)(C)C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](COC(=O)C(C)(C)C)[C@H]1CC[C@H]2C(=O)CCC[C@]12C
Temperature: 0 °C
Yield: 91.8 %

Procedure:
The compound of Example 1C (1.1 g, 3.7 mmol) was dissolved in 5 mL of dichloromethane and cooled to 0° C.; 4.1 g of pyridinium dichromate was added, followed by 30 mg of pyridinium p-toluenesulfonate. The resultant mixture was stirred for 8 hours at 0° C.; an additional 1.8 g of pyridinium dichromate and 20 mg of pyridinium p-toluenesulfonate were added, and the mixture was allowed to warm to ambient temperature overnight. The mixture was diluted with ether and filtered through a pad of diatomaceous earth with an ether wash. The filtrate was washed with 1 N aqueous HCl, and then filtered through a plug of silica gel. The crude product was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 10% to 15% ethyl acetate in hexanes to furnish the titled compound (1.0 g, 94%).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([CH2:22][C:23]([O:25]C)=[O:24])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:5]1>C1COCC1.Cl>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:5]1
Reactant: COC(=O)Cc1ccc2nc(-c3cn(C)c4ccccc34)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cc(-c2nc3ccc(CC(=O)O)cc3o2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
After addition of 0.25N NaOH (3.75 mL, 0.93 mmol) to a solution of methyl 2-(1-methyl-3-indolyl)-6-benzoxazolylacetate (200 mg, 0.62 mmol) in THF (6.5 mL), the mixture was stirred at room temperature for 2 hours. Under ice cooling, the reaction mixture was poured in 1N HCl (10 mL). The crystals thus precipitated were collected by filtration, washed with water and dried under reduced pressure, whereby 2-(1-methyl-3-indolyl)-6-benzoxazolylacetic acid (189 mg, 99%) was obtained as a colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:30])[CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[CH:6][CH:5]=1.[CH3:32][C:33]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=2)[CH:39]=[C:38]([CH3:48])[C:34]=1[C:35](O)=[O:36]>>[C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:10]([CH:20]1[CH2:21][CH2:22][N:23]([CH:26]([CH3:30])[CH2:27][CH2:28][NH:29][C:35](=[O:36])[C:34]2[C:38]([CH3:48])=[CH:39][C:40]([C:42]3[CH:43]=[CH:44][N:45]=[CH:46][CH:47]=3)=[CH:41][C:33]=2[CH3:32])[CH2:24][CH2:25]1)[C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:31])=[CH:9][CH:8]=1)#[N:19]
Reactant: COC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCN)CC2)cc1
Reactant: Cc1cc(-c2ccncc2)cc(C)c1C(=O)O
Product: Cc1cc(-c2ccncc2)cc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1

Procedure:
Using general procedure E with 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 107) (100 mg, 0.24 mmol) and 2,6-dimethyl-4-pyridin-4-yl-benzoic acid (59 mg, 0.26 mmol) followed by general procedure K with the resulting ester afforded 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-4-pyridin-4-yl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid as a white solid (92 mg, 58% over 2 steps).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5](C(OC)=O)([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:3]1C(OC)=O.[Cl-].[Na+].O>CN(C=O)C>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1
Reactant: COC(=O)C1CC(C(=O)OC)(C(=O)OC)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CCC(=O)CC1

Procedure:
A 55 g (0.2 mole) portion of trimethyl 4-oxocyclohexane-1,1,3-tricarboxylate is dissolved in 240 ml DMF and to this is added 26 g (0.445 mole) of sodium chloride and 16 ml (0.89 mole) of water, under nitrogen. This mixture is heated to reflux and maintained for 48 hours, under nitrogen. The reaction is then stripped to dryness under reduced pressure, the residue added to water and the crude product extracted into dichloromethane (3×100 ml). The combined extracts are dried over MgSO4 and stripped to dryness, giving a yellow oil. This crude product is vacuum-distilled to obtain methyl 4-oxocyclohexane-1-carboxylate (b.p. 82°-108° C. at 1.0 mm Hg) which is used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([S:8]([N:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][C:26]3[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=3)=[O:24])[CH2:16][CH2:15]2)[CH2:12][CH3:13])(=[O:10])=[O:9])[CH:7]=1>CO.[Pd]>[CH3:32][C:30]1[CH:31]=[C:26]([NH:25][C:23](=[O:24])[NH:22][CH2:21][CH2:20][N:17]2[CH2:18][CH2:19][CH:14]([N:11]([CH2:12][CH3:13])[S:8]([C:6]3[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=3[O:34][CH3:35])(=[O:10])=[O:9])[CH2:15][CH2:16]2)[CH:27]=[C:28]([CH3:33])[N:29]=1
Reactant: CCN(C1CCN(CCNC(=O)Nc2cc(C)nc(C)c2)CC1)S(=O)(=O)c1cc(Br)ccc1OC
Agent: [Pd]
Solvent: CO
Product: CCN(C1CCN(CCNC(=O)Nc2cc(C)nc(C)c2)CC1)S(=O)(=O)c1ccccc1OC
Reaction time: 15 h

Procedure:
A suspension of 5-bromo-N-(1-{2-[3-(2,6-dimethyl-pyridin-4-yl)-ureido]-ethyl}-piperidin-4-yl)-N-ethyl-2-methoxy-benzenesulfonamide (Example 99, 30 mg, 0.05 mmol) and Pd—C (10%, 20 mg) in MeOH (10 mL) is stirred under hydrogen atmosphere for 15 h. The catalyst is filtered off and the reaction mixture evaporated to provide the title compound.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[NH:8]2.[CH2:14]([OH:19])[CH:15]([OH:18])[CH2:16]Cl>C(O)C>[OH:18][CH:15]([CH2:14][OH:19])[CH2:16][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[NH:8]2
Reactant: OCC(O)CCl
Reactant: O=C1CCc2c(O)cccc2N1
Agent: [Na]
Solvent: CCO
Product: O=C1CCc2c(cccc2OCC(O)CO)N1
Yield: 29.6 %

Procedure:
0.23 g of sodium metal was dissolved in 40 ml of ethanol, and 1.63 g of 5-hydroxy-3,4-dihydrocarbostyril and 1.1 g of glycerol α-monochlorohydrin were added to the resulting solution followed by refluxing the mixture for 6 hours. After allowing the mixture to cool, the precipitated crystals were filtered, and the filtrate was concentrated to dryness. The residue thus obtained was extracted with 100 ml of chloroform, and the extract was washed with a 5% aqueous sodium hydroxide solution and then water and then dried over anhydrous sodium sulfate. The chloroform was then removed by distillation and the resulting residue was recrystallized from ethanol to give 0.7 g of 5-(2,3-dihyroxy)propoxy-3,4-dihydrocarbostyril as a colorless amorphous solid having a melting point of 173° - 175° C.
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:11]=[CH:12]/[C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([N+:26]([O-])=O)[CH:14]=2)[CH:8]=[CH:9][CH:10]=1>[Fe].C(O)(=O)C>[NH2:26][C:15]1[CH:14]=[C:13](/[CH:12]=[CH:11]/[C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:25]=[CH:24][C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Temperature: 25 °C

Procedure:
0.70 g of iron powder was added to a suspension of 7.5 mL of methanol and 7.5 mL of acetic acid containing 1.5 g of tert-butyl 4-((E)-2-(3-methoxyphenyl)vinyl)-2-nitrobenzoate, and the resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure. A saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the obtained residue and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=4:1] to obtain 0.44 g of tert-butyl 2-amino-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:14])([CH3:13])[NH:9][CH2:10]2)=[CH:5][C:4]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:13])([CH3:14])[N:9]([C:31]([C:30]3[CH:34]=[C:35]([O:39][CH3:40])[C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=3)=[O:32])[CH2:10]2)=[CH:5][C:4]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19]
Reactant: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)NC2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)N(C(=O)c1cc(OC)c(OC)c(OC)c1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.8 %

Procedure:
To a solution of 225 (300 mg, 0.83 mmol) in DCM (5 ml) was added TEA (0.23 ml, 1.65 mmol) and 3,4,5-trimethoxybenzoyl chloride (228 ml, 0.99 mmol). The reaction mixture was stirred at rt for 12 h. Water (10 ml) was added and the aqueous layer was extracted with DCM (3×30 ml). The combined organic phases were washed with sat. aq. NaHCO3 (10 ml) and brine (10 ml), dried (MgSO4) and concentrated in vacuo. Purification (flashmaster: 20 g, gradient elution 100% hex to 100% EtOAc over 25 min) afforded the title compound (240 mg, 52%) as a colourless oil. 1H NMR (270 MHz; CDCl3) 1.04 (18H, d, J=6.7 Hz, 6×CH3CH), 1.14-1.24 (3H, m, 3×CH), 1.55 (6H, s, 2×CH3), 2.74 (2H, s, CH2), 3.80 (3H, s, OCH3), 3.85 (6H, s, 2×OCH3), 3.86 (3H, s, OCH3), 4.19 (2H, s, CH2), 6.53 (1H, s, CH), 6.56 (2H, s, 2×CH), 6.71 (1H, s, CH). LC/MS (ES+) tr=0.2.23 min, m/z 580.24 (M++Na). HRMS (ES+) calcd for C31H47NO6Si (M++H) 558.3245, found 558.3237.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.Br.[Br:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Br.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[BrH:14].[N:1]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: BrCCNCCBr
Reactant: Nc1ccc2[nH]c(=O)ccc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc2cc(N3CCNCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
A mixture of 25 g of 6-aminocarbostyril, 50 g of bis(β-bromoethyl)amine hydrobromide and DMF was stirred at 80°-90° C. for 3 hours. After cooling to room temperature, 8.2 g of Na2CO3 was added to the mixture and stirred at 80°-90° C. for 4 hours. After cooling to room temperature, crystals which precipitated were collected by filtration, washed with ethanol and dried to give 22 g of 6-(1-piperazinyl)carbostyril hydrobromide, m.p. above 300° C., pale yellow rhombic crystals (water-ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[C:14]([OH:21])[CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[NH:10])=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[C:14]([O:21][CH3:22])[CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[NH:10])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N=C(Nc1ccc(Cl)cc1)c1ccc2cccc(O)c2n1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc2ccc(C(=N)Nc3ccc(Cl)cc3)nc12
Yield: 45.7 %

Procedure:
A mixture of 0.10 g (0.33 mmol) of N-(4-chloro-phenyl)-8-hydroxy -quinoline-2-carboxamidine, 0.137 g (1 mmol) of K2CO3 and 0.021 g (0.33 mmol) of iodomethane in 3.5 mL of DMF was heated under microwave (100 W, 5 min). It was diluted with 20 mL of NaHCO3, extracted with three 10 mL portions of ether. The combined organic extracts were washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC eluting with 20% ethyl acetate in hexanes to give 0.047 g of N-(4-chloro-phenyl)-8-methoxy -quinoline-2-carboxamidine.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[N:7][CH:8]=1.[I-:18].[K+]>CC(C)=O.C(Cl)Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:5]2[CH:6]=[N:7][CH:8]=[C:3]([CH2:2][I:18])[CH:4]=2)=[O:10])=[CH:12][CH:13]=1
Reactant: [I-]
Reactant: O=C(c1ccc(F)cc1)c1cncc(CCl)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1cncc(CI)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (5-chloromethyl-pyridin-3-yl)-(4-fluoro-phenyl)-methanone (1J) (220 mg, 0.88 mmol) in 5 mL of acetone at room temperature is added potassium iodide (590 mg, 3.6 mmol). After being stirred at room temperature for 3 hours, the reaction mixture is diluted with 50 mL of CH2Cl2 and washed with 5 mL of water. After concentration, the residue is dissolved in 15 mL of CH2Cl2 and washed with 2 mL of saturated sodium hyposulfite. After being dried, the solution was concentrate to give a 80/20 mixture (by 1H NMR) of (4-fluoro-phenyl)-(5-iodomethyl-pyridin-3-yl)-methanone (1F) and the starting chloride (1J) as light yellow solid that is used without further purification for next step reaction. MS (ESI) m/e 342 (M+H+).