Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1>CS(C)=O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:18])([F:20])[F:19])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCC(O)CC2)cc1C(F)(F)F

Procedure:
2.5 g of 4-hydroxypiperidine and 4.7 g of 4-fluoro-2-(trifluromethyl)-benzonitrile were reacted 5 h at 95° C. in DMSO to form 4-(4-hydroxypiperidin-1-yl)-2-(trifluoromethyl)-benzonitrile which, after aqueous work-up and isolation was disolved in 10 ml DMF was reacted at 5° C. with 250 mg of NaH (60% w/w) for 30 min. Then at 0° C., 2 g of 4,6-dichloropyrimidine were added to the mixture, stirred 30 min at room temperature to form 4-{4-[(6-chloropyrimidin-4-yl)oxy]piperidin-1-yl}-2-(trifluoromethyl)-benzonitrile. 115 mg of isolated by aqueous work-up and isolation by column chromatography were reacted with 138 mg of 1-[4-(trifluoromethyl)-phenyl]piperazine in presence of 117 mg of CsCO3, 7 mg of Pd(OAc)2, 21 mg of RuPhos in 2 ml of tert-BuOH at 85° C. over night to provide compound No. 23 after isolation by aqueous workup and column chromatography.
Reaction SMILES: [CH2:1]([C@@:3]1([C:12]([O:14][CH3:15])=[O:13])[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4]1)[CH3:2].[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[C:16]([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C@:3]([CH2:1][CH3:2])([C:12]([O:14][CH3:15])=[O:13])[CH2:7][C:6]=2[CH:8]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: CC[C@@]1(C(=O)OC)Cc2ccccc2O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC[C@@]1(C(=O)OC)Cc2cc(C(C)=O)ccc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl (2S)-2-ethyl-2,3-dihydro-benzofuran-2-carboxylate(3.1 g, 15 mmol) was mixed with acetyl chloride (3.5 g, 45 mmol) and aluminum chloride (6.0 g, 45 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at 25° C. for 1 hr and then poured into 1 N aqueous HCl (100 mL). The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined extracts were washed with brine and concentrated to give essentially pure methyl (2S)-5-acetyl-2-ethyl-2,3-dihydro-benzofuran-2-carboxylate.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][C:20]([C:23]2[S:24][C:25]([CH2:28]O)=[CH:26][N:27]=2)=[CH:19]3)[S:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)(=[O:8])=[O:7])[CH2:3][CH2:2]1.CN(C)C=O.O1CCCC1.S(Cl)([Cl:42])=O>C(OCC)(=O)C.[Cl-].[Na+].O>[Cl:42][CH2:28][C:25]1[S:24][C:23]([C:20]2[NH:21][C:22]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[S:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)(=[O:8])=[O:7])=[N:27][CH:26]=1
Reactant: O=S(=O)(c1cccs1)N(CC1CC1)c1cccc2cc(-c3ncc(CO)s3)[nH]c12
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccs1)N(CC1CC1)c1cccc2cc(-c3ncc(CCl)s3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a mixture of N-(cyclopropylmethyl)-N-{2-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (2.15 g), N,N-dimethylformamide (0.03 mL) and tetrahydrofuran (30 mL) was added thionyl chloride (918 mg), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and saturated brine, and washed with saturated brine. The organic layer was dried over magnesium sulfate and filtrated. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate. The obtained solid was washed with ether-hexane (1:1) to give the title compound (2.05 g, yield 97%) as a pale-yellow solid. melting point 135° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]=[C:13]([Cl:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1)(=[O:7])=[O:6].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:1][CH2:2][CH2:3][NH:4][S:5]([C:8]2[C:9]3[CH:10]=[CH:11][N:12]=[C:13]([Cl:18])[C:14]=3[CH:15]=[CH:16][CH:17]=2)(=[O:6])=[O:7])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(NCCO)c1cccc2c(Cl)nccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCNS(=O)(=O)c2cccc3c(Cl)nccc23)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 74.9 %

Procedure:
To 5.74 g of N-(2-hydroxyethyl)-1-chloro-5-isoquinolinesulfonamide was successively added 80 ml of pyridine and 7.62 g of p-toluenesulfonylchloride and the mixture was stirred at 15° to 20 ° C. for 24 hours. After completion of the reaction, the mixture was cooled with 200 g of ice water and the mixture was subjected to extraction with 200 ml of dichloromethane twice. The resultant dichloromethane layer was dried over anhydrous magnesium sulfate and the residue was subjected to purification by means of a chromatography column packed with 200 g of silica gel (Wacogel C-200, manufactured by Wako Pure Chemical Industries, Ltd., Japan) using chloroform as an eluent to obtain 6.61 g of N-(2-paratoluenesulfonyloxyethyl)-1-chloro-5-isoquinolinesulfonamide (yield: 75%).
Reaction SMILES: C([N:8]1[CH2:49][CH2:48][CH2:47][C:10]([S:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)(=[O:52])=[O:51])([C:11]([NH:13][C@H:14]([C:40]([O:42]C(C)(C)C)=[O:41])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=3[O:30][CH3:31])=[CH:18][C:17]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:12])[CH2:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>>[C:53]1([S:50]([C:10]2([C:11]([NH:13][C@H:14]([C:40]([OH:42])=[O:41])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([O:30][CH3:31])=[CH:24][CH:25]=[CH:26][C:27]=4[O:28][CH3:29])=[CH:18][C:17]=3[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:12])[CH2:47][CH2:48][CH2:49][NH:8][CH2:9]2)(=[O:52])=[O:51])[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)C2(S(=O)(=O)c3ccccc3)CCCN(C(=O)OC(C)(C)C)C2)C(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)C2(S(=O)(=O)c3ccccc3)CCCNC2)C(=O)O)c(OCc2ccccc2)c1

Procedure:
N-(N-(BOC)-3-phenylsulfonyl-nipecotyl)-4-(2′,6′-dimethoxyphenyl)-2-benzyloxyphenylalanine, tert-butyl ester (74 mg, 0.091 mmol) was treated with TFA according to procedure described in Example 1, Step C to yield N-(3-phenylsulfonyl-nipecotyl)-4-(2′,6′-dimethoxyphenyl)-2-benzyloxyphenylalanine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([Cl:10])=[CH:6][C:7]=1[C:8]#[N:9].[CH3:11][C:12](OC(C)=O)=[O:13].CC(O)=O>O=[Pt]=O>[Cl:10][C:5]1[CH:6]=[C:7]([CH2:8][NH:9][C:12](=[O:13])[CH3:11])[C:2]([Cl:1])=[CH:3][N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cc(Cl)ncc1Cl
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(=O)NCc1cc(Cl)ncc1Cl
Reaction time: 6 h
Yield: 40 %

Procedure:
A mixture of 3,6-dichloro-4-cyanopyridine (prepared according to WO 9633975) (3.40 g, 19.65 mmol) and PtO2 (0.40 g) in 1:1 Ac2O/AcOH (60 mL) was shaken in a Parr hydrogenation apparatus at 30 psi H2 for 6 h. The reaction mixture was filtered through a pad a celite and the filtered solids washed with EtOAc. The combined filtrate and washings were concentrated in vacuo and the resulting white solid purified by column chromatography on a 120 g ISCO combi-flash cartridge (silica gel, 20:80 to 100:0 EtOAc/hexane) to afford N-(2,5-Dichloro-pyridin-4-ylmethyl)-acetamide (1.73 g, 40%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:11]3[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][C:10]=3[NH:9][N:8]=2)=[CH:3][CH:2]=1.[ClH:23]>O1CCOCC1>[ClH:23].[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:11]3[CH2:12][NH:13][CH2:14][CH2:15][C:10]=3[NH:9][N:8]=2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccncc3)c2C1
Agent: Cl
Solvent: C1COCCO1
Product: c1cc(-c2n[nH]c3c2CNCC3)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-(pyridin-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (3 g, 10 mmol) in a round-bottom flask was added HCl in dioxane (4 N, 8 ml) and the reaction was stirred at room temperature for overnight. After removal of the solvent, ethyl ether was added and the desired product was obtained by filtration as a light yellow solid (2.2 g). LC-MS found 201 (M+H)
Reaction SMILES: ClC1SC(CO)=C(C2C=CC(Cl)=CC=2)C=1.OC1C=CC(CCC(OCC)=O)=C(F)C=1F.[Cl:32][C:33]1[S:37][C:36]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48]([O:50]CC)=[O:49])=[C:42]([F:53])[C:41]=2[F:54])=[C:35]([C:55]2[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=2)[CH:34]=1>>[Cl:32][C:33]1[S:37][C:36]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48]([OH:50])=[O:49])=[C:42]([F:53])[C:41]=2[F:54])=[C:35]([C:55]2[CH:56]=[CH:57][C:58]([Cl:61])=[CH:59][CH:60]=2)[CH:34]=1
Reactant: CCOC(=O)CCc1ccc(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)c(F)c1F
Agent: CCOC(=O)CCc1ccc(O)c(F)c1F
Agent: OCc1sc(Cl)cc1-c1ccc(Cl)cc1
Product: O=C(O)CCc1ccc(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 197 by coupling of [5-chloro-3-(4-chlorophenyl)thiophen-2-yl]methanol and ethyl 3-(4-hydroxy-2,3-difluorophenyl)propanoate followed by hydrolysis of ethyl 3-(4-((5-chloro-3-(4-chlorophenyl)thiophen-2-yl)methoxy)-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ: 7.36-7.48 (m, 4H), 7.13 (s, 1H), 6.87-6.93 (m, 1H), 6.66-6.67 (m, 1H), 5.07 (s, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.53 (t, J=7.8 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C20H14C12F2O3S, 441.0 (M−H). found 441.0.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14](C(OC(C)(C)C)=O)[C@@H:13]([CH2:23][O:24][C:25]2[C:26]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][NH:14][C@@H:13]([CH2:23][O:24][C:25]2[C:26]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To an ice-cold solution of ethyl 3-(((2R,4R)-4-(benzyloxymethoxy)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)picolinate (845 mg, 1.74 mmol, EXAMPLE 79 Step 3) in dichloromethane (12 mL) was added trifluoroacetic acid, and the mixture was stirred at 0° C. for 1 h. The mixture was warmed to room temperature and stirred for 1 h at this temperature, then the mixture was concentrated in vacuo to afford an oil. The residual oil was purified by NH-gel column chromatography (ethyl acetate only to methanol/ethyl acetate 1:10) to give 200 mg (30%) of the title compound as a pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][NH:5][NH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:8].[OH-].[Na+:25]>O1CCOCC1.CO>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:7]([NH:6][NH:5][CH2:4][C:3]([O-:23])=[O:2])=[O:8])[CH2:10][CH2:11]2)=[CH:21][CH:20]=1.[Na+:25]
Reactant: COC(=O)CNNC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C([O-])CNNC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-(1-(4-chlorobenzyl)-piperazine-4-carboxamido) glycine methyl ester (813 mg, 2.50 mmol) in dioxane-CH3OH (3:1, 12 mL) was treated with 4N aqueous NaOH solution (0.63 mL, 1 equiv.). The mixture was stirred at room temperature for 2 hours. Solvent removal afforded the desired material which was used without further purification (885 mg, 100%).
Reaction SMILES: C=O.F[C:4](F)(F)[C:5]([O-:7])=O.C[NH2+]C1C=CC=CC=1.[CH2:18]1[CH2:28][C:26](=O)C2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1.C(OCC)C>C1COCC1>[CH2:24]=[C:23]1[CH2:22][CH2:21][C:20]2[C:4](=[CH:26][CH:28]=[CH:18][CH:19]=2)[C:5]1=[O:7]
Reactant: O=C1CCCc2ccccc21
Reactant: O=C([O-])C(F)(F)F
Agent: C=O
Agent: C[NH2+]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C1CCc2ccccc2C1=O

Procedure:
To a suspension of paraformaldehyde (46.2 g, 1.54 mol) and N-methylanilinium trifluoroacetate (TAMA, 46.2 g, 1.54 mol) in 340 mL of dry THF was added α-tetralone (50 g, 0.342 mol). The solution was heated at reflux under nitrogen with stirring for 4 h, during which time the paraformaldehyde dissolved. After cooling, diethyl ether (700 mL) was added to the reaction mixture. The solvent was separated from the reaction mixture and washed with 500 mL of saturated sodium bicarbonate. Additional diethyl ether was added to the reaction mixture, separated and used to back extract the aqueous sodium bicarbonate layer. The combined organic layers were dried over magnesium sulfate, and the solution was then concentrated to a volume of approximately 300 mL and filtered through Celite. Complete evaporation of the ether yielded 50 g (90° A) of crude 2-methylene-3,4-dihydronaphthalen-1-one, which was used immediately for the next reaction to prevent polymerization of the product.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[O:13]([CH2:20][CH:21]([OH:29])[CH2:22][N:23]([CH2:25][CH2:26][NH:27][CH3:28])[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[O:13]([CH2:20][CH:21]([OH:29])[CH2:22][N:23]([CH2:25][CH2:26][N:27]([C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8])[CH3:28])[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNCCN(C)CC(O)COc1ccccc1
Reactant: Cc1c(Cl)n(C)c(=O)n(C)c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(N(C)CCN(C)CC(O)COc2ccccc2)n(C)c(=O)n(C)c1=O

Procedure:
4.7 g. 4-Chloro-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione and 6.0 g. 1-phenoxy-3-(2-methylaminoethyl-N-methylamino)-propan-2-ol (b.p. 138°-142° C./0.01 mm.Hg; obtained from phenyl glycidyl ether and N,N'-dimethylethylenediamine) are stirred for 72 hours at 80° C. in 10 ml. pyridine. The reaction mixture is then dissolved in methylene chloride, washed with water, dried and chromatographed on silica gel using, as elution agent, methylene chloride-methanol (20:1 v/v). By evaporation of the pure fractions, there are obtained 3.0 g. (31% of theory) of the desired product in the form of an almost colorless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].[CH3:36][O:37]CCN>>[OH:35][CH:7]1[CH:8]([OH:34])[CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:14]=3[N:13]=[N:12]2)[CH2:10][CH:6]1[C:4]([NH:3][CH2:1][CH2:2][O:37][CH3:36])=[O:5]
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Reactant: COCCN
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCCOC)C(O)C3O)c2n1

Procedure:
The title compound was prepared according to the method of example 1, step d), using the product of example 1, step c) and 2-methoxyethylamine, followed by deprotection according to the method of example 1, step e).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][Br:27])=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)cnn1CCc1ccc(CO)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(OCc2ccccc2)cnn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 240 mg (0.71 mmol) 5-benzyloxy-2-[2-(4-hydroxymethyl-phenyl)-ethyl]-2H-pyridazin-3-one (example 21.1a) in 2.0 mL of DCM is added at 0° C. 134 μL (1.43 mmol) phosphorus tribromide. The mixture is stirred 4 h at RT, cooled to 0° C. and aqueous saturated NaHCO3-solution is added until pH >7. The layers are separated, the aqueous phase is extracted with DCM and the combined organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:32][O:33][CH2:34][P:35]([O:40][CH2:41][CH3:42])([O:37][CH2:38][CH3:39])=[O:36])[CH2:10][O:11][N:12]1[CH:20]=[N:19][C:18]2[C:13]1=[N:14][CH:15]=[N:16][C:17]=2[N:21]1C(=O)C2=CC=CC=C2C1=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CNN>ClCCl>[Si:1]([O:8][CH:9]([CH2:32][O:33][CH2:34][P:35]([O:40][CH2:41][CH3:42])([O:37][CH2:38][CH3:39])=[O:36])[CH2:10][O:11][N:12]1[CH:20]=[N:19][C:18]2[C:13]1=[N:14][CH:15]=[N:16][C:17]=2[NH2:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(COCC(COn1cnc2c(N3C(=O)c4ccccc4C3=O)ncnc21)O[Si](C)(C)C(C)(C)C)OCC
Agent: CNN
Solvent: ClCCl
Product: CCOP(=O)(COCC(COn1cnc2c(N)ncnc21)O[Si](C)(C)C(C)(C)C)OCC
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 61.3 %

Procedure:
A solution of 9-[2-(t-butyldimethylsilyloxy)-3-(diethoxyphosphorylmethoxy)propoxy]-6-phthalimidopurine (0.99 g, 1.6 mmol) in dichloromethane (10 ml) was cooled to 0° C., treated with methylhydrazine (0.lml, 1.76 mmol) and stirred at 20° C. for 1.5 h. The reaction mixture was filtered and evaporated in vacuo and the residue dissolved in ether. The ether was filtered, evaporated in vacuo and the residue chromatographed twice on silica, eluting firstly with chloroform-methanol 20:1 and then with chloroform, to give 9-[2-(t -butyldimethylsilyloxy)-3-(diethoxyphosphorylmethoxy)propoxy]adenine (480mg, 61%) as a clear oil. νmax (film) 3350, 1650, 1600 and 1590 cm-1 ; δH (CDCl3) 0.07 (6H, S, CH3SiCH3), 0.88 (9H, S, (CH3)3CSi), 1.34 (6H, t, J6.8 Hz, 2×CH3CH2), 3.75 (2H, d, J5.2 Hz, CH2OCH2P), 3.87 (2H, d, J8.2 Hz, CH2P), 4.17 (4H, m, 2×CH3CH2), 4.22 (1H, m, CHOSi), 4.42 (1H, m, CH2ON), 4.53 (1H, m, CH2ON), 5.71 (2H, br.s, D2O exchangeable, NH2), 7.99 (1H, s, H-2/H-8), 8.36 (1H, s, H-2/H-8). Found: C, 45.57; H, 7.40; N, I3.65%; [M-H]+ 488.0297. C19H36N5O6PSi.0.7H2O requires C, 45.44; H, 7.50; N, 13.94%; [M-H]+ 488.0294.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH:9][NH2:10])[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:4]=1)[CH3:2].[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)=O>C(O)C>[CH2:1]([C:3]1[N:8]=[C:7]([NH:9][N:10]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[CH3:19])[CH:6]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[N:4]=1)[CH3:2]
Reactant: CC(=O)c1ccc(N(C)C)cc1
Reactant: CCc1nc(NN)cc(-c2ccccc2OC)n1
Solvent: CCO
Product: CCc1nc(NN=C(C)c2ccc(N(C)C)cc2)cc(-c2ccccc2OC)n1
Yield: 12.5 %

Procedure:
A solution of [2-Ethyl-6-(2-methoxy-phenyl)-pyrimidin-4-yl]-hydrazine (100 mg, 0.41 mmol) and 4-dimethylaminoacetophenone (67 mg, 0.41 mmol) in ethanol (1.0 mL) was heated in the microwave (CEM Discover, 150 C, QuickTest method) for 6 hours. An initial purification by Si gel chromatography (2:1 hexanes:ethyl acetate) was followed by a crystallization from ethyl acetate:hexanes to yield 20 mg (13%) of the title compound as a yellow solid. HPLC Purity: 97%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]2[S:13][CH:14]=[C:15]([CH3:16])[C:11]=2[C:10](=[O:17])[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]1=[O:27])=[O:5])[CH3:2].S(Cl)([Cl:31])(=O)=O>ClC(Cl)(Cl)Cl.CCCCCC>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]2[S:13][C:14]([Cl:31])=[C:15]([CH3:16])[C:11]=2[C:10](=[O:17])[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]1=[O:27])=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(C)csc21
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(C)c(Cl)sc21
Yield: 65 %

Procedure:
A 0.427 g quantity of 1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (compound IV-5) synthesized in Reference Example 6 and 0.162 g of sulfuryl chloride were dissolved in 30 ml of anhydrous tetrachloromethane, and the mixture was allowed to react at 50° to 70° C. for 6 hours. The residue obtained by concentration of the reaction mixture was subjected to silica gel column chromatography using a 2:1 mixture of chroloform and n-hexane as an eluent to afford 0.30 g of 1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-6-chloro-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione having m.p. of 141° to 145° C. in a yield of 65%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:16][C:17]([N:19]([CH2:21][CH:22](OC)OC)[CH3:20])=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[ClH:27]>O>[CH3:20][N:19]1[CH:21]=[CH:22][N:16]([C:4]2[CH:3]=[CH:2][C:7]([O:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[C:13]([Cl:27])[CH:14]=3)=[CH:6][CH:5]=2)[C:17]1=[O:18]
Reactant: Cl
Reactant: COC(CN(C)C(=O)Nc1ccc(Oc2ccc(C)cc2)c(Cl)c1)OC
Solvent: O
Product: Cc1ccc(Oc2ccc(-n3ccn(C)c3=O)cc2)cc1Cl

Procedure:
N-[3-chloro-4-[(4-methylphenoxy)]phenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea (0.02 mole), water (30 ml) and concentrated hydrochloric acid (3 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. The mixture is refluxed for a period of about 30 minutes and then cooled and extracted with ethyl acetate. The extract is washed with dilute aqueous sodium bicarbonate, with two portions of water and is then dried. The ethyl acetate is removed by mild warming under reduced pressure to yield the desired product 1-methyl-3-[4-[3-chloro-4-methylphenoxy]phenyl]-4-imidazolin-2-one.
Reaction SMILES: C1C2C3C=CC=CC=3C=CC=2[NH2+:3]C=1.[NH:14]1[C:23]2[C:18](=[CH:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[CH:22]=2)[CH2:17][CH2:16][CH2:15]1>>[N:14]1([NH2:3])[C:23]2[C:18](=[CH:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: C1=Cc2c(ccc3ccccc23)[NH2+]1
Reactant: c1ccc2cc3c(cc2c1)CCCN3
Product: NN1CCCc2cc3ccccc3cc21

Procedure:
In a similar manner, benzo[e]indolium derivatives can be prepared from 1,2,3,4-tetrahydrobenzo[g]quinoline or a suitable derivative to provide 3,4-dihydrobenzo[g]quinolin-1(2H)-amine or the corresponding derivative, Intermediate C, illustrated in Scheme 5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:28]=[C:29]([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[CH:28]=2)=[S:37])=[CH:18][CH:17]=1
Reactant: Cc1cccc(C(=O)N=C=S)c1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 95%).