Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]([OH:30])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:16][C:15]=1[NH:31][C:32](=[O:48])[CH2:33][CH:34]1[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:41][C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Ca+2].O>C1C=CC=CC=1>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]([O:30][C:3](=[O:4])[NH2:5])[CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[CH:16][C:15]=1[NH:31][C:32](=[O:48])[CH2:33][CH:34]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=2[O:41][C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(N)=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
64 μl (0.54 mmol) of trichloroacetyl isocyanate, were added to a solution of 272 mg (0.52 mmol) of N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 12) in 6 ml of benzene, and the resulting mixture was stirred for 10 minutes. At the end of this time, a methanolic solution of calcium carbonate was then added, whilst stirring. The reaction mixture was then mixed with water, and the organic phase was separated and dried. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 50 g of silica gel, using a 15:85 by volume mixture of ethyl acetate and methylene chloride as the eluent, to give 135 mg (yield 46%) of the title compound as a foam-like material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][CH2:7][C:6]=2[CH:16]=1.[CH3:17][C:18]1[CH:35]=[CH:34][CH:33]=[CH:32][C:19]=1[C:20]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)=[O:21].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]([C:27]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:20](=[O:21])[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[CH3:17])=[CH:31][CH:30]=3)=[O:28])[CH2:7][C:6]=2[CH:16]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc2c(c1)CNc1ccccc1O2
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cc(Cl)ccc3Oc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a mixture of 0.229 g (1.0 mmol) of 2-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine in 1.0 ml of pyridine under nitrogen is added 0.30 g (1.1 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride. The mixture is stirred at room temperature for 1 hour, heated on a steam bath for 5 minutes and 8 ml of 2N HCl added. The mixture is extracted with ethyl acetate and the extract washed three times with 1 ml of 1N sodium bicarbonate. The organic layer is dried (MgSO4) and the solvent removed. The residue is crystallized from ethyl acetate-hexane to give 0.24 g of crystals., m.p. 207°-208° C. Anal. Calc'd for C28H2N2 O3Cl: C,71.9; H,4.5; N,6.0; Cl,7.6. Found: C,71.6; H,4.6; N,5.9; Cl,7.4.
Reaction SMILES: NC1C=CC(C)=C(N[C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)C=1.ClC1C=C(C2(N)C=C(Cl)N=CN2)C=CC=1F.[CH3:41][C:42]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][C:43]=1[NH2:44].Cl>C(O)CCC.CCOC(C)=O>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[CH:14]=[C:9]([NH:44][C:43]3[CH:45]=[C:46]([N+:49]([O-:51])=[O:50])[CH:47]=[CH:48][C:42]=3[CH3:41])[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: Cc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Agent: Cl
Agent: NC1(c2ccc(F)c(Cl)c2)C=C(Cl)N=CN1
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Temperature: 120 °C

Procedure:
Synthesis of N-(5-Amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)-pyrimidine-4,6-diamine (Int-F) A mixture of 4-(3-chloro-4-fluorophenyl)-6-chloropyrimidin-4-ylamine (IR-4) (1.2 g, 4.6 mmol), 2-methyl-5-nitroaniline (0.85 g, 5.5 mmol) and 1 mL of concentrated HCl in 10 mL of n-butanol was heated at 120° C. for 16 h. With stirring, 5 mL of EtOAc was added to the reaction mixture. The light yellow colored product that precipitated was filtered and dried under vacuum to give N-(3-chloro-4-fluorophenyl)-N′-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine. MS (APCI) (m/z): 374/376 (M+1). A mixture of N-(3-chloro-4-fluorophenyl)-N′-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine (0.55 g, 1.5 mmol) and iron powder (35 mesh, 0.5 g, 5 eq) in 5 mL of HOAc and 2 mL of MeOH was heated at reflux for 2 h. The solvent was removed in vacuo and the dark colored residue was mixed with 150 mL of CH2Cl2 and 15 mL of sat. K2CO3 solution and was stirred at room temperature for 30 min. The organic layer was dried (MgSO4), was concentrated, and was then purified by flash chromatography (silica gel, MeOH/NH4OH/CH2Cl2) to afford 0.115 g of N-(5-amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine as a light colored solid. (Int-F) MS (m/z): 344/346 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH3:15][NH:16][C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20].Cl>O>[CH3:15][NH:16]/[C:17](/[NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=1)=[CH:18]\[N+:19]([O-:21])=[O:20]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CNC(=C[N+](=O)[O-])SC
Agent: Cl
Solvent: O
Product: CN/C(=C\[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 10 °C
Reaction time: 3.5 h
Yield: 90.3 %

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (50 g) and N-methyl-1-(methylthio)-2-nitroetheneamine (40 g) in water (235 ml) was stirred and heated at 45°-50° C. The solution was stirred further for 3-4 hrs. It was acidified with hydrochloric acid and extracted with chloroform. The solution was basified with potassium carbonate and ranitidine base was separated. The water, if any, was removed by azeotropic distillation under reduced pressure at 40°-45° C. using isopropanol. The resultant solution was cooled to 10° C. and n-hexane (500 ml) was added. Ranitidine base was filtered off and dried under vacuum to give the crude product (66.2 g), m.p. 68°-70° C.; purity=99.4% (HPLC); IR(KBr): 3280, 3200, 2820, 2774, 1620, 1580, 1440, 1370, 1258, 1130, 1020, 990, 820, 790, 760, 680 and 600 cm-1 ; δH (CDCl3):2.23 [6H,s, --N(CH3)2 ], 2.75(2H, t, --SCH2CH2), 2.85(3H,br d, CH3NH--), 3.3 (2H,2t, --CH2NH--), 3.4(2H,s, >NCH2), 3.7 (2H,s, CH2 bridge linking), 6.0-6.2 (2H,AB,furan) and 6.5 (,1H,s,=CHNO2).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:17])[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[C:8]([Cl:15])[C:7]=2[Cl:16].O.[C:19]([OH:22])(=[O:21])[CH3:20]>C([O-])(=O)C.[Ag+]>[C:19]([O:22][CH2:2][CH2:3][C:4]1[C:5](=[O:17])[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[C:8]([Cl:15])[C:7]=2[Cl:16])(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCCl)=C2
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCOC(C)=O)=C2
Temperature: 105 °C

Procedure:
2-(2-Chloroethyl)-6,7-dichloro-5-methoxy-1H-inden-1-one (18.4 g, 0.0619 mole) and silver acetate (22.7 g, 0.1362 mole) were suspended in acetic acid (225 ml) and water (2 ml) and the mixture stirred and heated at 105° C. for 9 hours and at ambient temperature for 16 hours. The mixture was filtered and the residue on the funnel washed with ethyl acetate. The combined filtrate were evaporated in vacuo and the residue suspended in water. The mixture was extracted first with 10% tetrahydofuran in ether, then with methylene chloride and finally with ethyl acetate. The combined organic extracts were washed with water, then with brine. After drying over MgSO4 the combined organic extracts were evaporated in vacuo. The residue was treated with warm ethyl acetate (10 ml) and tetrahydrofuran (10 ml) and then cooled. The solid that formed was removed by filtration with an equal mixture of ethyl acetate and hexane and dried to give 2-(acetoxyethyl)-6,7-dichloro-5-methoxy-1H-inden-1-one, 8.1 g, m.p. 134°-136° C.
Reaction SMILES: [S:1]1[C:5]2=[C:6]3[C:10](=[CH:11][CH:12]=[C:4]2[N:3]=[CH:2]1)[NH:9][C:8](=[O:13])[CH2:7]3.[C:14]([O:17][CH:18](OCC)OCC)(=O)[CH3:15]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[CH2:14]([O:17][CH:18]=[C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]3[N:3]=[CH:2][S:1][C:5]3=2)[NH:9][C:8]1=[O:13])[CH3:15]
Reactant: O=C1Cc2c(ccc3ncsc23)N1
Reactant: CCOC(OCC)OC(C)=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: CCOC=C1C(=O)Nc2ccc3ncsc3c21

Procedure:
To a 250-mi round bottom flask was added a stir bar, 6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one (4.0 g, 0.021 mol), 40 mL of glacial acetic and diethoxymethyl acetate (17.0 g, 0.105 moles). The flask was fitted with a reflux condensor and charged with nitrogen. The reaction was heated to reflux for 8 h. The flask was cooled, the stir bar was removed and the reaction was concentrated to a wet solid. The solid was triturated with a solution of ether and ethanol. The mixture was filtered, and the solid was washed with an ethanol-ether solution and was dried under vacuum to yield the title compound: 1H NMR (DMSO-d6):δ 10.5 (s, 1H), 9.1 (s, 1H), 7.8 (d, 1H), 7.7 (s, 1H), 7.0 (d, 1H), 4.5 (q, 2H), 1.4 (t, 3H); APCI-MS m/z 245 (M-H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[OH:11])=[O:5].C(N(CC)CC)C.CS(O[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:12])[C:10]=1[O:11][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])=[O:5]
Reactant: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1O
Reactant: CS(=O)(=O)OCc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1ncc(C(=O)c2ccc(Cl)cc2Cl)c1OCc1ccccc1Cl
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a mixture of 1.33 g (0.0049 mol) of 4-(2,4-dichlorobenzoyl)-1-methyl-5-hydroxypyrazole, 0.54 g (0.0054 mol) of triethylamine and 30 ml of toluene was added 1.3 g (0.0059 mol) of o-chlorobenzyl methanesulfonate. Then, the reaction mixture was refluxed with stirring for 2 hours. After cooling, the reaction mixture was washed with 20 ml of water three times, and the organic layer was separated. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure and was subjected to a column chromatography (silica gel, eluent; ethyl acetate:benzene=1:9) to obtain 1.5 g of the title compound (yield: 77%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na][Na].[C:11]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][CH2:17][C:18]([NH:20][C:21]#[N:22])=[O:19])#[N:12]>CN(C)C=O>[C:21]([N:20]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]([N:13]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]#[N:12])=[O:23])#[N:22]
Reactant: N#CNC(=O)CCCC(=O)NC#N
Reactant: BrCc1ccccc1
Agent: [Na][Na]
Solvent: CN(C)C=O
Product: N#CN(Cc1ccccc1)C(=O)CCCC(=O)N(C#N)Cc1ccccc1

Procedure:
359.2 g (2.0 mols+5% excess) of benzyl bromide are added dropwise to a suspension of 224.1 g (1.0 mol) of the disodium salt of glutaric acid bis-(N-cyanamide) and 1 liter of dimethylformamide at 20°-27° C. in the course of 40 minutes, the components are reacted at 68°-78° C. for 3 hours and 50 minutes and the mixture is then filtered with suction. The filtrate is concentrated on a rotary evaporator at 100° C. in vacuo and the residue is recrystallised from 800 ml of toluene. 253.7 g (70.4% of theory) of a colourless, crystalline product which has a melting point of 97.5°-100.4° C. are obtained.
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([CH3:5])[CH2:3][OH:4].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([C@:2]([NH:1][CH2:18][C:17]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=2[O:15][CH3:14])([CH3:5])[CH2:3][OH:4])[CH:11]=1
Reactant: C[C@](N)(CO)c1cc(Br)ccc1F
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CN[C@@](C)(CO)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of (R)-2-amino-2-(5-bromo-2-fluorophenyl)propan-1-ol (9.2 g, 37.1 mmol, Eq: 1.00) in 1,2-dichloroethane (145 ml) was added at 23° C. 2,4-dimethoxybenzaldehyde (6.16 g, 37.1 mmol, Eq: 1) followed by sodium triacetoxyborohydride (15.7 g, 74.2 mmol, Eq: 2.0). The reaction mixture was stirred at 23° C. overnight. The reaction mixture was extracted with sat NaHCO3/CH2Cl2 twice. The combined organic layers were dried over Na2SO4, filtered off and evaporated totally. The residue was purified by silica gel chromatography with 0-50% EtOAc in heptane to give the (R)-2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propan-1-ol (14.1 g, 35.4 mmol, 95.5% yield) as a light brown oil. Mass (calculated) C18H21BrFNO3 [398.27]; (found) [M+H]+=398.0, 400.0.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([NH2:10])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1)=[O:3].[C:15]([OH:19])(=[O:18])[CH:16]=[CH2:17]>C(O)(=O)C>[C:2]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([O:11][CH3:12])=[CH:8][C:9]=1[NH:10][CH2:17][CH2:16][C:15]([OH:19])=[O:18])(=[O:3])[CH3:1]
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: C=CC(=O)O
Solvent: CC(=O)O
Product: COc1cc(NCCC(=O)O)c(C(C)=O)cc1OC
Temperature: 90 °C
Yield: 84.2 %

Procedure:
A mixture of 2-amino-4,5-dimethoxyacetophenone (910 g, 4.66 mol), acrylic acid (730 ml., 10.67 mol), and acetic acid (2100 ml) was heated at 90° C. for 2 hours. Following treatment with Darco and hot filtration, the product was precipitated by the addition of water (2475 ml) over a 1 hour period. The reaction mixture was cooled and the product was filtered and washed with cold distilled water (4×90 ml) and cold methanol (1×600 ml). Drying under vacuum at 60° C. gave 1049 g (84%) of the product as a yellow powder, mp 149.5°-151.5° C. NMR (CDCl3) δ 2.50 (s, 3H, ArCOCH3), 2.73 (t, 2H, CH2 --CO2H), 3.57 (t, 2H, N--CH2), 3.82 (s, 3H, CH3OAr), 3.93 (s, 3H, CH3OAr), 6.18 (s, 1H, ArH), 7.13 (s, 1H, ArH), 10.05 (broad s, 2H, NH, COOH).
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: C1CCNC1
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCCC4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-Dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexyl methyl)-amide and pyrrolidine. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (t, J=6.01 Hz, 1H), 7.80 (d, J=9.22 Hz, 1H), 7.47-7.54 (m, 2H), 6.96 (d, J=9.21 Hz, 1H), 4.16 (s, 1H), 3.51-3.53 (m, 4H), 3.26-3.28 (m, 2H), 1.97-1.98 (m, 4H), 1.71-1.73 (m, 1H), 1.45-1.61 (m, 6H), 1.00-1.07 (m, 1H), 0.83-0.84 (m, 3H), 0.73-0.79 (m, 1H). m/z: 402.2 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(OCc2ccccc2)c1
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 2-(3-hydroxyphenyl)acetate (3 g, 16.6 mmol) in DMF (25 ml) was added potassium carbonate (2.99 g, 21.6 mmol) at room temperature followed by drop wise addition of benzyl bromide (3.13 g, 18.3 mmol). The reaction mixture was stirred for 16 hours and taken in ethyl acetate, washed with water (2×) and brine. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH:9]([Cl:13])[C:10](Cl)=[O:11].[Cl:14][C:15]([Cl:22])([Cl:21])[CH:16]1[NH:20][CH2:19][CH2:18][S:17]1>CCOCC>[Cl:14][C:15]([Cl:22])([Cl:21])[CH:16]1[N:20]([C:10](=[O:11])[CH:9]([Cl:13])[Cl:8])[CH2:19][CH2:18][S:17]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: ClC(Cl)(Cl)C1NCCS1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(C(Cl)Cl)N1CCSC1C(Cl)(Cl)Cl
Yield: 83.5 %

Procedure:
40 g of triethylamine (0.4 mole), then 43 g of dichloroacetyl chloride (0.3 mole) are added successively, while maintaining the temperature of the reaction mixture at about 0° C. to 41 g of 2-trichloromethyl-1,3-thiazolidine (0.2 mole), dissolved in 300 ml of ether. After the removal of the triethylamine hydrochloride formed in the reaction and washing the organic phase with water, the organic layer is concentrated by stripping part of the ether. By crystallization and filtration, 53 g (yield 82%) of 2-trichloromethyl-3-dichloroacetyl-1,3-thiazolidine of melting point 124° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[CH2:16]1[C:19]2([CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH2:18][O:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:21]2[CH2:22][CH2:23][CH2:24][C:19]3([CH2:16][O:17][CH2:18]3)[CH2:20]2)=[O:15])=[CH:4][N:3]=1
Reactant: C1CNCC2(C1)COC2
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCCC4(COC4)C3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 2-oxa-6-azaspiro[3.5]nonane by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].Br[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[CH:18]/[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:34])[CH:22]=2)=[CH:13][CH:12]=1>C(N(CC)CC)C.C1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:41][C:38]1[CH:37]=[CH:36][C:35](/[C:17](/[C:14]2[CH:13]=[CH:12][C:11]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:16][CH:15]=2)=[CH:18]\[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:34])[CH:22]=2)=[CH:40][CH:39]=1
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)C(C)c1ccc(OC/C=C(\c2ccc(Cl)cc2)c2ccc(Br)cc2)cc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)c1ccc(OC/C=C(\c2ccc(Cl)cc2)c2ccc(C#CCN3CCOCC3)cc2)cc1C

Procedure:
Under nitrogen atmosphere, 4-propargylmorpholine (550 mg, 4.4 mmol) bis(triphenylphosphine)palladium(II) dichloride (40 mg, 0.057 mmol) and copper(II) acetate (7 mg, 0.038 mmol) were added to a degassed solution of the above ester (280 mg, 0.55 mmol) in triethylamine (30 mL). The reaction mixture was refluxed for 8 h, diluted with benzene (100 mL), filtered and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, chloroform/methanol 9:1) yielding ethyl (Z)-[4-[3-(4-chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]propionate.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: BrBr
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CC(=O)O
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Reaction time: 0.33 h

Procedure:
To a solution of 80.0 g (0.452 mol) of 2,6-diisopropylaniline in 2000 cm3 of glacial acetic acid, 23.3 ml (72.3 g, 0.452 mol) of bromine were added dropwise, while vigorously stirring, over 20 minutes. This mixture was stirred additionally for 2 hours at 40° C. The white precipitate that formed was filtered off, washed with 100 ml of acetic acid, and dried in air. The resulting white solid was added to a solution of 150 g of potassium hydroxide in 600 ml of water. This mixture was stirred for 30 minutes. The product was extracted with 3×100 ml of methyl-tert-butyl ether. The combined organic fractions were washed with Na2SO4 and evaporated to dryness. Fractional distillation gave a yellowish oil, b.p. 112-115° C./1 mm Hg. Yield 48.8 g (42%).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25]([BH3-])#N.[Na+]>C(O)=O.O1CCCC1>[CH3:25][N:8]1[CH2:9][C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:2](=[O:1])[N:7]12
Reactant: [BH3-]C#N
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2ncc3ccsc3c12
Agent: [Na+]
Solvent: O=CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CN2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.34 g of methyl 7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]pyridazine-10-carboxylate in 10 ml of formic acid are treated dropwise under argon at 25°-30° with 0.31 g of sodium cyanoborohydride in 2 ml of tetrahydro-furan. The mixture is left to stir at room temperature for 24 hours. The solution is poured into 50 ml of ice-water. The yellowish crystals are removed by filtration and washed with water. After drying in vacuo, recrystallization is carried out from ethyl acetate. There is obtained methyl 4,5-dihydro-5-methyl-7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno-[2,3-d]pyridazine-10-carboxylate of m.p. 180°-181°.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:11](=S)=[S:12].[OH-].[K+]>O.C(O)C>[SH:12][C:11]1[O:8][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:9][N:10]=1
Reactant: NNC(=O)c1cccnc1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Sc1nnc(-c2cccnc2)o1

Procedure:
13.7 g (0.1 mol) of nicotinic acid hydrazide and 8 g (0.105 mol) of carbon disulfide are added dropwise to a solution of 56 g (0.1 mol) of potassium hydroxide in 20 g of water and 350 ml of 95% ethanol. The reaction mixture is refluxed for 3 hours, then the solvent is evaporated off under vacuum and the residue is dried under a high vacuum. The dry residue is stirred in 75 ml of water, filtered, and the filtrate is neutralised with 1N hydrochloric acid. The precipitated product is isolated by filtration, washed in succession with acetone and hexane and vacuum dried, affording 9.9 g (55% of theory) of the title compound with a melting point of 237° C.