Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[OH2:22]>C(O)(=O)C>[F:21][C:15]1[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=1[NH:13][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][NH:3][C:2](=[O:22])[CH:12]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(I)cc1F
Reactant: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Yield: 59 %

Procedure:
Ethyl 6-chloro-4-(2-fluoro-4-iodoanilino)nicotinate (2.03 g, 4.83 mmol) was dissolved in acetic acid (75 mL), to which was added water (25 mL). This solution was heated at reflux for 14 h. The mixture was allowed to cool, then refrigerated, and a cream solid crystallised out. This material was isolated by filtration, washed well with water and hexanes, then dried to afford ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate as a white solid (1.14 g, 59%), m.p. (acetone/MeOH) 262-264° C. 1H NMR [(CD3)2SO, 400 MHz] δ 11.59 (br s, 1H), 9.32 (s, 1H), 8.10 (s, 1H), 7.77 (dd, J=10.1, 1.9 Hz, 1H), 7.61 (ddd, J=8.4, 2.0, 0.8 Hz, 1H), 5.38 (d, J=1.3 Hz, 1H), 7.26-7.33 (m, 1H), 4.27 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H). Anal. Calcd for C14H12FIN2O3: C, 41.8; H, 3.0; N, 7.0. Found: C, 41.9; H, 2.8; N, 7.0.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9](OS(C(F)(F)F)(=O)=O)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[CH2:23]([OH:26])[C:24]#[CH:25]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:25]#[C:24][CH2:23][OH:26])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COc1cc2c(SC)ncnc2cc1OS(=O)(=O)C(F)(F)F
Reactant: C#CCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(SC)ncnc2cc1C#CCO
Yield: 16.6 %

Procedure:
4-(methylthio)-6-methoxy-7-(trifluoromethanesulphonyloxy)quinazoline (1.0 g, 2.82 mmol) in dimethylformamide (30 ml) was reacted with propargyl alcohol (0.51 ml, 8.75 mmol) in the presence of bisdichloro(triphenylphosphine) palladium (100 mg, 0.14 mmol) copper (I) iodide (40 mg) and triethylamine (1.7 ml, 0.0124 mmol) at 90° C. for 2.5 hours under argon. The solvent was evaporated in vacuo, water and hydrochloric acid (2.0 N) were added, and the mixture was extracted with ethyl acetate. Purification by flash chromatography on silica gel, eluting with 7.5% methanol in dichloromethane, yielded 4-(methylthio)-6-methoxy-7-(3-hydroxyprop-1-ynyl)quinazoline (122 mg, 17% yield):
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>O>[C:10]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1CCNCC1
Solvent: O
Product: CC(=O)N1CCC(C(=O)O)CC1
Temperature: 55 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Isonipecotic acid (129.2 g, 1.00 mol) was dissolved in water (390 mL), and acetic anhydride (153.1 g, 1.50 mol) was added dropwise under ice-cooling for about 10 min. (dropwise addition at 15–18° C. for about 10 min.). After stirring at 55±5° C. for 2 hrs., the mixture was allowed to cool to room temperature and stirred under ice-cooling for 1 hr. The precipitated crystals were collected by filtration, washed with cold diisopropyl ether (125 mL×2) and dried under reduced pressure at 40° C. for 8 hrs. to give the title compound (129.1 g, yield 75.4%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[CH2:12][CH3:13].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH3:13])=[O:5]
Reactant: O=C(O)c1ccccc1Br
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
2-Bromobenzoic acid (2.005 g, 9.47 mmol, 1.0 eq.) was combined with iodoethane (1.60 ml, 19.9 mmol, 2.0 eq.)and sodium bicarbonate (1.68 g, 19.9 mmol, 2.0 eq.) in dimethylformamide (10 ml, 1M) and stirred at room temperature for a total of 4 days. The reaction was then diluted with water (20 ml) and extracted with ether:hexane (1:1, 3×20 ml). The combined organic extracts were washed with aqueous 10% sodium hydrogen sulfite (20 ml), water (20 ml), and aqueous saturated sodium chloride (20 ml). Next, the organic extracts were dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on silica gel (50 g) eluting with ether:hexane (1:6) to furnish the title C compound (2.17 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([SH:13])[C:10](O)=[O:11].S(Cl)([Cl:16])=O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([SH:13])[C:10]([Cl:16])=[O:11]
Reactant: O=C(O)C(S)c1cc(Cl)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Product: O=C(Cl)C(S)c1cc(Cl)ccc1Cl
Temperature: 50 °C

Procedure:
94.8 g of 2,5-dichlorophenylthioglycolic acid are added to 103.2 g of thionyl chloride. 0.24 g of N-methylpyrrolidone is added, and the mixture is heated at 50° C. for 2 hours and is then cooled down to 0° C. At this temperature the 2,5-dichlorophenylthioglycoloyl chloride formed is then added dropwise in the course of 1 hour to a suspension of 160 g of thionyl chloride and 77.2 g of anhydrous aluminum chloride. The suspension is stirred at 0°-5° C. for 1 hour and is then poured onto a mixture of 1,200 g of ice and 800 ml of water, the resulting mixture is stirred at 80° C. for 1 hour and is then filtered with suction, and the filter cake is washed until neutral and dried in vacuo at 50° C. This gives 88.4 g of 94.5% pure 4,7-dichloro-3-oxythionaphthene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:12]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cncc(Br)c1
Yield: 49.2 %

Procedure:
A solution of 9 g (40 mmol) of ethyl 5-bromonicotinate in 25 ml of methanol is added dropwise, at room temperature, to a suspension of 14.8 g (400 mmol) of sodium borohydride in 75 ml of methanol. After addition, the reaction medium is refluxed for 2 hours. The reaction medium is evaporated to dryness, taken up in aqueous sodium hydroxide solution to pH 9, and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated under vacuum. 3.7 g (50%) of (5-bromopyrid-3-yl)methanol are obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:20]1[N:21]=[CH:22][N:23]=[C:24]2[C:31]=1[C:30]1[CH2:29][CH2:28][CH2:27][C:26]=1[S:25]2>C1COCC1>[CH3:16][N:8]([CH:5]1[CH2:6][CH2:7][CH:2]([O:1][C:20]2[N:21]=[CH:22][N:23]=[C:24]3[C:31]=2[C:30]2[CH2:29][CH2:28][CH2:27][C:26]=2[S:25]3)[CH2:3][CH2:4]1)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(O)CC1
Reactant: Clc1ncnc2sc3c(c12)CCC3
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.3 %

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl N-(4-hydroxycyclohexyl)-N-methylcarbamate (447 mg, 1.95 mmol, 1.30 equiv) in anhydrous THF (30 mL), then sodium hydride (300 mg, 7.50 mmol, 5.00 equiv, 60% dispersion in mineral oil) was added and stirring for 20 min at room temperature under nitrogen. Then 12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (316 mg, 1.50 mmol, 1.00 equiv) was added and stirred for 6 h at ambient temperature. The reaction mixture was quenched with NH4Cl (sat.) at 0° C., diluted with brine, extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by a silica gel column with EA/PE (1:10-1:4) to provide tert-butyl N-methyl-N-(4-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yloxy]cyclohexyl)carbamate (450 mg, 74%) as a white solid. MS: (ES, m/z): 404 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[C:9]([NH:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNc1ccccc1
Solvent: CCOCC
Product: O=C(NNc1ccccc1)c1ccccc1
Temperature: 5 °C

Procedure:
A four neck flask (2 liters) equipped with a thermometer and a stirrer was charged with 216 g (2.0 mol) of phenylhydrazine and 1.5 liter of ether and cooled down to 5° C. Dropwise added thereto was 56.2 g (0.4 mol) of benzoyl chloride in 2 hours while stirring, and then the solution was heated to room temperature (20° C.) to continue stirring for 12 hours. Crystal was filtered off and washed sufficiently with deionized water and then dried under reduced pressure to obtain slightly brown crystal.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH2:10]2)[CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C=O)C>[C:33]([O:32][C:30](=[O:31])[CH2:29][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]2([CH2:8][CH2:9][N:4]([CH2:3][C:2]([F:1])([F:18])[F:19])[CH2:5][CH2:6]2)[CH2:10]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: FC(F)(F)CN1CCC2(CC1)CNc1ccccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CC2(CCN(CC(F)(F)F)CC2)c2ccccc21

Procedure:
A solution of 1′-(2,2,2-trifluoroethyl)-1,2-dihydrospiro[indole-3,4′-piperidine] from Step A (64.0 mg, 0.237 mmol), potassium carbonate (49.0 mg, 0.355 mmol), potassium iodide (59.0 mg, 0.355 mmol), and tert-butyl bromoacetate (0.042 mL, 0.284 mmol) in DMF (2 mL) was stirred at 50° C. for 1 h. The reaction mixture was quenched with H2O. The aqueous layer was extracted with CH2Cl2 (3×20 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=385 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.Br[CH2:24][C:25]1([CH3:30])[O:29][CH2:28][CH2:27][O:26]1.[OH-].[Na+]>CN(C=O)C>[C:11]1([C:10]2[C:3]3[C:2]([NH:1][CH2:24][C:25]4([CH3:30])[O:29][CH2:28][CH2:27][O:26]4)=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(CBr)OCCO1
Reactant: Nc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1(CNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)OCCO1
Temperature: 120 °C
Yield: 13.7 %

Procedure:
A stirred mixture of 4-amino-5,6-diphenylfuro[2,3-d]pyrimidine (50 mg, 0.17 mmol), 2-bromomethyl-2-methyl-[1,3]dioxolane (prepared according to Visweswariah et al., Synthesis, 1982, 4, 309-310) (38 mg, 0.21 mmol) and sodium hydroxide granules (21 mg, 0.53 mmol) in DMF (1 mL) was heated in a microwave at 120° C. for 5 minutes. The resulting mixture was filtered and purified by preparative HPLC to give a beige solid (9 mg). 1H NMR (CDCl3): 8.39 (1H, s), 7.52-7.41 (7H, m), 7.23-7.18 (3H, m), 5.05 (1H, br s), 3.77-3.63 (4H, m), 3.50 (2H, m), 1.19 (3H, s). LC/MS: 388 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C@@H:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:14][S:13]2)=[C:7]([CH3:25])[CH:6]=1)=[O:4].[Li+].[OH-]>CO.O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[N:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C@@H:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:14][S:13]2)=[C:7]([CH3:25])[CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(N=C2SC[C@H](CC(C)C)N2CC(C)C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)O)ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of (4S)-2-(4-methoxycarbonyl-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine (prepared in a manner analogous to that described in Method D2a; 0.035 g, 0.097 mmol) in a mixture of MeOH (1.5 mL) and H2O (1.5 mL) was added LiOH (0.016 g, 0.39 mmol). The resulting mixture was stirred for 2 d at room temp., then was concentrated under reduced pressure. The residue was adjusted to pH 1 with a 1% HCl solution, then extracted with EtOAc (4×10 mL). The combined organic layers were sequentially washed with H2O (15 mL), a saturated NaCl solution (15 mL), and dried (Na2SO4). Concentration under reduced pressure gave (4S)-2-(4-carboxy-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine (0.034 g, 100%): TLC (40% EtOAc/hex) Rf 0.08. This material was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)[CH:18]=1)[NH2:15].O1CCOCC1.CS(O)(=O)=O>C(OCC)(=O)C>[F:10][C:5]1[C:6]([O:8][CH3:9])=[N:7][C:2]([NH:15][C:14]2[CH:16]=[C:17]([B:19]3[O:23][C:22]([CH3:24])([CH3:25])[C:21]([CH3:27])([CH3:26])[O:20]3)[CH:18]=[C:12]([CH3:11])[CH:13]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1nc(Cl)ncc1F
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1nc(Nc2cc(C)cc(B3OC(C)(C)C(C)(C)O3)c2)ncc1F
Temperature: 100 °C

Procedure:
To a flask containing 2-chloro-5-fluoro-4-methoxypyrimidine (0.32 g, 1.97 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.40 g, 1.72 mmol) were added dioxane (17 mL) and methanesulfonic acid (0.13 mL, 1.97 mmol). The reaction was heated at 100° C. overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield 5-fluoro-4-methoxy-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine. MS ESI calc'd for C18H24BFN3O3 [M+H]+ 360. found 360. 1H NMR (500 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.27 (d, J=3.2, 1H), 8.00 (s, 1H), 7.57 (s, 1H), 7.07 (s, 1H), 4.01 (s, 3H), 2.25 (s, 3H), 1.26 (s, 12H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([CH2:27][CH:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:38][CH3:39])[CH2:29]1)=O.CCCCCC>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:25][CH2:27][CH:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:38][CH3:39])[CH2:29]1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cccc2c1CCC(CC=O)C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1cccc2c1CCC(CC=C(Br)Br)C2
Reaction time: 0.17 h

Procedure:
To a solution of carbon tetrabromide (19.5 g) in methylene chloride (50 ml) was added triphenylphosphine (30.8 g) at 0° C., and the mixture was stirred for 10 min. To the mixture was added a solution of 2-formylmethyl-5-methoxy1,2,3,4-tetrahydronaphthalene (4.09 g; the compound prepared by method described in the specification of the Japanese Patent Application No. 3-130467) in methylene chloride (25 ml) at 0° C. The mixture was stirred for 30 min at 0° C. To the mixture was gradually added n-hexane, and filtrated to remove triphenylphosphineoxide. The filtrate was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=24:1) to give the title compound (6.42 g) having the following physical data.
Reaction SMILES: [I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][NH2:14])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:15](C(CC)(CC)C([O-])([O-])[O-])[CH3:16]>OS(O)(=O)=O>[I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:12][C:15]([CH3:16])=[N:14][N:13]=3)=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NNC(=O)c1ccn2c(I)cnc2c1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Product: Cc1nnc(-c2ccn3c(I)cnc3c2)o1
Temperature: 80 °C

Procedure:
3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid hydrazide (0.18 g, 0.59 mmol) was treated with triethylorthoacetate (3 ml) and concentrated H2SO4 (1 drop). The mixture was heated at 80° C. o/n, allowed to cool, solid was filtered off and washed with EtOH and dried to afford 0.165 g of product. MS: [M+H]+ 327
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.BrBr>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(Cl)cc2)=NN1
Agent: BrBr
Solvent: CC(=O)O
Product: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A 47.5 g. portion of 6-(p-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone (prepared as in Example 1 of U.S. Pat. No. 3,689,652) is dissolved in 250 ml. of glacial acetic acid at 65°-70° C. with stirring. Then a solution of 14 ml. (42 g.) of bromine liquid in 50 ml. of acetic acid is added portionwise during a 20 minute period. The reaction mixture is stirred at 65° C. for 3 hours and is cooled to 4° C. The precipitate is collected and washed with 100 ml. of ethyl acetate. The solid is suspended in 500 ml. of water, 25 ml. of concentrated ammonium hydroxide is added and the mixture is stirred at room temperature overnight. The precipitate is collected, washed with 500 ml. of water and dried at 60° C. to afford 6-(p-chlorophenyl)-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][O:4][C:5]1[C:10]([O:11][CH:12]([F:14])[F:13])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:15]=[CH:16]/[C:17]1[N:18]=[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]2[C:25]=1[C:26]([OH:28])=O.[CH:31]1([C:34]2[N:35]=[C:36]([NH2:39])[S:37][CH:38]=2)[CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH3:1][C:2]([CH3:29])([CH3:30])[CH2:3][O:4][C:5]1[C:10]([O:11][CH:12]([F:13])[F:14])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:15]=[CH:16]/[C:17]1[N:18]=[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]2[C:25]=1[C:26]([NH:39][C:36]1[S:37][CH:38]=[C:34]([CH:31]2[CH2:33][CH2:32]2)[N:35]=1)=[O:28]
Reactant: Nc1nc(C2CC2)cs1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3ccccn3c2C(=O)O)cccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3ccccn3c2C(=O)Nc2nc(C3CC3)cs2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 13 (100 mg, 0.240 mmol) with 4-cyclopropyl-1,3-thiazol-2-amine (37 mg, 0.264 mmol) in the presence of EDCI hydrochloride (91 mg, 0.480 mmol) and DMAP (27 mg, 0.240 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 35 mg of the product as an off-white solid; 1H NMR (300 MHz, CDCl3) δ 0.79-0.85 (m, 2H), 1.05 (s, 9H), 1.20-1.26 (m, 2H), 1.95-2.01 (m, 1H), 3.58 (d, J=5.4 Hz, 2H), 6.60-6.71 (m, 1H), 6.90-6.98 (m, 1H), 7.10-7.27 (m, 3H), 7.38-7.46 (m, 1H), 7.50-7.56 (m, 2H), 7.63-7.70 (m, 1H), 7.92 (d, J=15.6 Hz, 1H), 7.99 (d, J=15.0 Hz, 1H), 13.03 (br s, 1H); APCI-MS (m/z) 539.45 (MH)+.
Reaction SMILES: [Mg].CI.[CH2:4]([O:11][C:12]1[CH:21]=[CH:20]C(C(OC)=O)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+].C[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[CH2:4]([O:11][C:12]1[CH:21]=[CH:20][C:27]([C:26]([OH:25])([CH3:29])[CH3:28])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: COC(C)(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
Under argon 6.63 g of magnesium (273 mmol) was suspended in 15 mL of tert-butyl methyl ether. A solution of 38.68 g of methyl iodide (273 mmol) in 145 mL of tert-butyl methyl ether was added during 45 minutes under stirring while maintaining the temperature at 40° C. Then stirring was continued at 40° C. for 1.5 hours and then the mixture was cooled to room temperature. A solution of 30.0 g of methyl 4-benzyloxybenzoate (124 mmol) in 120 mL of tetrahydrofuran was then added during 1 hour. The temperature was kept at 20° C. After complete addition, the reaction mixture was heated to 42° C. and stirred 3 hours at this temperature. After cooling to room temperature, the reaction mixture was poured into a mixture of 300 mL of 10% aqueous ammonium chloride and 100 g of ice and extracted with ethyl acetate. The organic phases were washed with water and saturated aqueous sodium bicarbonate, combined, dried and evaporated to give the crude product as an oil which partially crystallised. The product was dissolved at 25° C. in diethyl ether. When crystals started to separate the solution was cooled to 18° C. After 30 minutes hexane was added. The suspension was then stirred for 1 hour at 5° C. The crystalline 2-(4-benzyloxy-phenyl)-propan-2-ol was collected on a filter and washed with hexane.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[CH2:9][CH2:8]2.CC1C=CC(N=[CH:23][C:24]2[C:25]([NH2:33])=[CH:26][C:27]3[O:31][CH2:30][O:29][C:28]=3[CH:32]=2)=CC=1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]2[C:10]3=[N:33][C:25]4[CH:26]=[C:27]5[O:31][CH2:30][O:29][C:28]5=[CH:32][C:24]=4[CH:23]=[C:9]3[CH2:8][C:7]=2[CH:6]=1
Reactant: COCOc1ccc2c(c1)CCC2=O
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Product: COCOc1ccc2c(c1)Cc1cc3cc4c(cc3nc1-2)OCO4
Yield: 15.8 %

Procedure:
Using the procedure of Example 1, 5-methoxymethoxyindan-1-one (327 mg, 1.7 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (432 mg, 1.7 mmol) to yields 8-methoxymethoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (86.3 mg, 15% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:17][CH2:16][CH2:15][C@H:14]3[N:9]2[C:10](=[O:18])[CH2:11][CH:12]=[CH:13]3)=[CH:4][CH:3]=1>[Pt]=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:17][CH2:16][CH2:15][C@H:14]3[N:9]2[C:10](=[O:18])[CH2:11][CH2:12][CH2:13]3)=[CH:4][CH:3]=1
Reactant: O=C1CC=C[C@H]2CCC[C@@H](c3ccc(Cl)cc3)N12
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@H]2CCC[C@@H](c3ccc(Cl)cc3)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
Platinum oxide (95 mg) was added to a methanol solution (50 mL) of (6S,9aR)-6-(4-chlorophenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (1.09 g). The resulting reaction solution was stirred under hydrogen atmosphere at room temperature for 1 hr and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: heptane-ethyl acetate system) to give 877 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[C:7](=O)([O:13]C(C)(C)C)[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][C@@H:2]([NH:1][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH3:6]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CC[C@H](N)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-aminobutan-1-ol (1 eq) in THF (0.26 M) at 0° C. was added di-tert-butyl carbonate (1 eq) and triethylamine (1 eq). The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated en vaccuo; and the residue was diluted in ethyl acetate. The organic solution was washed with water (2×), brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The material was carried onto the next step without further purification.