Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:20]=[C:19]([SH:21])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>>[Cl:10][C:11]1[CH:20]=[C:19]([S:21][CH2:1][C@@H:2]([OH:9])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: c1ccc([C@H]2CO2)cc1
Reactant: COC(=O)c1ccc(S)cc1Cl
Product: COC(=O)c1ccc(SC[C@@H](O)c2ccccc2)cc1Cl

Procedure:
119 mg of (S)-styrene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (S)-methyl 2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate. 230 mg of (S)-methyl-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoate was hydrolyzed via Procedure M to give (S)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid. 180 mg of (S)-2-chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid was reacted via Procedure R to give (S)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-2-chloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-phenylethylsulfonyl)benzamide. MS (Q1) 527.0 (M)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:17]1([NH:23][C:24]([NH:16][C:13]2[CH:14]=[CH:15][C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc2oc(-c3ccccc3)nc2c1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To 2-phenylbenzo[d]oxazol-5-amine (75 mg, 0.36 mmol) in dichloromethane (2 mL) at room temperature was added phenyl isocyanate (43 μL, 0.39 mmol). The solution was stirred at room temperature for 16 h. The resulting precipitate was filtered off and washed with dichloromethane to afford 99.9 mg (85%) of the title compound (LCMS RT=6.45 min, MH+ 330.1)
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][NH2:8].[C:9]([C:13]1[CH:22]=[CH:21][C:16]([CH2:17][N:18]=[C:19]=[S:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>ClCCl>[C:9]([C:13]1[CH:22]=[CH:21][C:16]([CH2:17][NH:18][C:19]([NH:8][CH2:7][C:3]2[NH:2][CH:6]=[CH:5][CH:4]=2)=[S:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: NCc1ccc[nH]1
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CNC(=S)NCc2ccc[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
(1H-pyrrol-2-yl)methylamine hydrochloride (60 mg) prepared according to the same procedure as described in Step 2 was dissolved in dichloromethane (2 ml) and to the solution was added 4-t-butylbenzylisothiocyanate (155 mg), followed by stirring at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure and the obtained residue was column-chromatographed (ethyl acetate/hexane=1/3) to yield the compound 17-1 (120 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH3:14])[N:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[C:22]1([CH:28]=[CH:29][CH2:30]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH3:14])[N:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:30][CH:29]=[CH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1
Reactant: Cn1ncc(N2CCNCC2)c(Cl)c1=O
Reactant: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc(N2CCN(CC=Cc3ccccc3)CC2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.3 %

Procedure:
0.75 g (3.3 mmoles) of 4-chloro-2-methyl-5-(1-piperazinyl)-3(2H)-pyridazinone prepared as described hereinafter under the title "Preparation of the starting substances" and 0.91 g (6.6 mmoles) of anhydrous potassium carbonate are suspended in 5 ml of anhydrous dimethyl formamide. Then a solution of 0.5 g (3.3 moles) of 3-phenyl-2-propenyl chloride in 5 ml of anhydrous dimethyl formamide are dropped to the suspension, and the reaction mixture is stirred at room temperature for 24 hours. The dimethyl formamide is evaporated in vacuo, a slight amount of water is added to the residue and the solution thus obtained is extracted with ethyl acetate. The organic phase is dried and evaporated and the residue is crystallized from ethanol. Thus 0.55 g (49%) of the desired compound is obtained. M.p.: 98°-100° C. Its monohydrochloride salt melts at 218°-220° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH2:31][OH:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(O)(=O)C>C(O)C>[CH2:15]([C@:10]1([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4([CH2:31][OH:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[N:7]=2)[C:9]1=[O:17])[CH3:16]
Reactant: Nc1ccc(C2(CO)CCOCC2)cc1
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(C4(CO)CCOCC4)cc3)n2)C1=O
Temperature: 150 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (100 mg) obtained in Step A of Example 8 in ethanol (3.0 mL) were added (4-(4-aminophenyl)tetrahydro-2H-pyran-4-yl)methanol (83 mg) obtained in Step B of Example 152 and acetic acid (25 μL), and the mixture was stirred in a microwave reactor at 150° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (100 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[C:13]([CH3:25])[C:12]=2[C:26](=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:33]N1C(=O)CCC1=O>>[Br:33][CH2:25][C:13]1[C:12]([C:26](=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Product: CCCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Reference Example 5, 4-(3,4-dimethoxyphenyl)-3-hexanoyl-6,7-dimethoxy-2-methylquinoline was brominated with N-bromo-succinimide (NBS) to give 2-bromomethyl-4-(3,4-dimethoxy-phenyl)-3-hexanoyl-6,7-dimethoxyquinoline- This compound was recrystallized from ethyl acetate-hexane to give colorless prisms. mp. 146°-147° C.
Reaction SMILES: [O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([OH:5])=O.[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2>>[O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2)=[O:5]
Reactant: O=C(O)C(=O)N1CCC(Oc2ccccc2)CC1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(Oc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from oxo-(4-phenoxy-piperidin-1-yl)-acetic acid and 5-amino-1,3-dihydro-indol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 78-81° C. (diethyl ether)
Reaction SMILES: CCCCCC.C([Li])CCC.C[CH2:13][O:14]CC.[Si:17]([O:24][CH2:25][C:26]1[C:35]2[C:30](=[C:31]([CH3:36])[CH:32]=[CH:33][CH:34]=2)[C:29]([O:37][CH2:38][O:39][CH3:40])=[CH:28][CH:27]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O>[Si:17]([O:24][CH2:25][C:26]1[C:35]2[C:30](=[C:31]([CH3:36])[CH:32]=[CH:33][CH:34]=2)[C:29]([O:37][CH2:38][O:39][CH3:40])=[C:28]([CH:13]=[O:14])[CH:27]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19]
Reactant: CCOCC
Reactant: COCOc1ccc(CO[Si](C)(C)C(C)(C)C)c2cccc(C)c12
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COCOc1c(C=O)cc(CO[Si](C)(C)C(C)(C)C)c2cccc(C)c12
Reaction time: 1 h

Procedure:
52 ml of a hexane solution of 1.6M n-butyl lithium was dropped in an absolute ether (110 ml) solution of 19 g of 1-(t-butyldimethylsilyl)oxymethyl-4-methoxymethoxy-5-methylnaphthalene and agitated for 1 hour. After ice cooling, 8.5 ml of N,N-dimethylformamide was dropped in the reaction solution and the ice bath was removed, followed by agitation for 1 hour until room temperature was reached. Iced water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography (2% ethyl acetate/hexane) to obtain 14.1 g of the captioned compound as a brown oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[CH:9][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[CH3:17][Sn:18](Cl)([CH3:20])[CH3:19].O>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([Sn:18]([CH3:20])([CH3:19])[CH3:17])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2occc12
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2oc([Sn](C)(C)C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 111.7 %

Procedure:
To a solution of 4-methoxybenzo(b)furan (2.50 g) in THF (50 ml) was added n-butyllithium (1.54 M hexane solution) (16.5 ml) at −78° C. and the mixture was stirred at the same temperature for 20 min. To this solution was added trimethyltin chloride (5.00 g) and the mixture was further stirred at the same temperature for 1 hr. The reaction mixture was warmed to room temperature and water (200 ml) was added. The mixture was extracted with ethyl acetate, and the obtained organic layer was washed with water and saturated brine and dried over magnesium sulfate. This solution was concentrated under reduced pressure to give the title compound (5.86 g) as pale-yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:7]=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[OH:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=3)[CH:7]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1ccccc1
Product: O=C(Nc1nc2ccc(-c3ccc(O)cc3)cn2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for example 56 but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B5), 150 mg; 0.47 mmol; 1.0 eq.) and 4-hydroxyphenylboronic acid (131 mg; 0.95 mmol; 2.0 eq.) as a white solid (15 mg, 9%). HPLC, Rt: 2.60 min. (purity 97.2%). LC/MS, M+(ESI): 331.1, M−(ESI): 329.1.
Reaction SMILES: [B-](F)(F)(F)F.[N:6]#[O+:7].[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11].N1C=CC=CC=1>C(#N)C>[N:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7]
Reactant: N#[O+]
Reactant: O=C(O)[C@@H]1CCCN1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: O=NN1CCC[C@H]1C(=O)O

Procedure:
To a cooled suspension of 28.2 g of nitrosyl tetrafluoroborate in 300 ml of dry acetonitrile there is added, with vigorous stirring, over the course of 10 minutes, 18.4 g of L-proline, followed by a solution of 19 g of pyridine in 50 ml of acetonitrile during 15 minutes. The stirring is continued for an hour and the reaction mixture is then concentrated to dryness under reduced pressure. The residue is extracted with 3×200 ml of ethyl acetate, the ethyl acetate extracts are combined, washed twice with saturated sodium chloride solution that has been made slightly acidic with concentrated hydrochloric acid. The ethyl acetate solution is dried over anhydrous sodium sulfate, filtered and concentrated to dryness at room temperature under reduced pressure. The product, N-nitroso-L-proline melts at 108°-109° (dec.) after crystallization from a mixture of ether and petroleum ether (30°-60°).
Reaction SMILES: [BH4-].[Na+].[Br:3]/[CH:4]=[CH:5]/[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(O)C>[Br:3]/[CH:4]=[CH:5]/[CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(=O)/C=C/Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)/C=C/Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled mixture of 20 g. of sodium borohydride in 800 ml. of anhydrous ethanol is added 160 g. of crude 1-bromo-trans-1-octen-3-one (Example 992) over a period of 0.5 hour. The mixture is stirred for 2 hours with ice cooling and is then partitioned between ice water and benzene. The organic phase is washed with water and saturated brine, dried (Na2SO4), and evaporated to an oil. Distillation gives the product as an oil, b.p. 66°-68° C. (0.025 torr.).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:25]=1)[C:20]([OH:22])=O>CCCCCCC.CCOC(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1cc(Cl)cc(OC(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(OC(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-chloro-5-(trifluoromethoxy)benzoic acid (CAS RN 158580-93-9) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Yellow solid (31%). MS (ESI): m/z=421.09 [M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:15]=O.Cl.[NH2:18]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:15]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:13][C:14]=2[CH:1]=1)#[N:18]
Reactant: NO
Reactant: O=Cc1ccc2c(c1)Sc1ccccc1O2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc2c(c1)Sc1ccccc1O2
Reaction time: 1 h

Procedure:
The crude phenoxathiin-2-aldehyde was dissolved in acetic acid (150 ml) and boiled with hydroxylamine hydrochloride (2.76 g) and sodium acetate (3.24 g) for 1.5 hr. Acetic anhydride (150 ml) was added, and the mixture boiled under reflux for 3 hr., cooled and filtered. The filtrate was poured into water and stirred for 1 hour to decompose the acetic anhydride, then extracted with chloroform, washed with water and sodium bicarbonate solution, dried, and evaporated to give crude 2-cyanophenoxathiin as an oil which solidified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]=O>>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1/[CH:19]=[C:6]1/[C:7](=[O:11])[C:8]2[C:4]([CH2:5]/1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2
Reactant: O=Cc1ccncc1Br
Reactant: O=C1CCc2cc(Cl)ccc21
Product: O=C1/C(=C/c2ccncc2Br)Cc2cc(Cl)ccc21

Procedure:
The title compound 94 is prepared according to the procedure reported in Example 35.3 with 5-chloro-1-indanone (0.83 g, 5 mmol) and 3-bromo-4-pyridinecarboxaldehyde (0.93 g, 5 mmol) as reactants. White solid. (Yield 0.44 g, 26%).
Reaction SMILES: [Cl-].[NH2:2][N+:3]1[CH:7]=[C:6]([CH2:8][Cl:9])[N:5]([NH2:10])[C:4]=1[CH3:11].[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)(=O)C>[Cl-:9].[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:2][N+:3]2[CH:7]=[C:6]([CH2:8][Cl:9])[N:5]([N:10]=[CH:18][C:17]3[CH:20]=[CH:21][C:14]([N:13]([CH3:22])[CH3:12])=[CH:15][CH:16]=3)[C:4]=2[CH3:11])=[CH:16][CH:15]=1
Reactant: Cc1n(N)c(CCl)c[n+]1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: Cc1n(N=Cc2ccc(N(C)C)cc2)c(CCl)c[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 36 h

Procedure:
0.985 g (5 mmol) of 1,3-diamino-4-(chloromethyl)-2-methylimidazolium chloride and 7.45 g (50 mmol) of 4-dimethylaminobenzaldehyde are dissolved in 250 ml of glacial acetic acid. The solution is left to stand at room temperature for 36 hours and evaporated. The residue is placed on a column loaded with 150 g of silica gel (particle size 0.063-0.2 mm) and the product is eluted with chloroform/methanol (9:1). The eluate is evaporated and the product is crystallized from ethanol/ether. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-4-(chloromethyl)-2-methylimidazolium chloride of melting point 188° (dec.)
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:8]2[CH2:9][C:10]3[S:14][C:13]([SH:15])=[N:12][C:11]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1)C.[C:21]1([CH:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][CH2:29][CH2:30]I)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH:27]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:29][CH2:30][S:15][C:13]2[S:14][C:10]3[CH2:9][C:8]4[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:20])=[CH:19][CH:18]=[CH:17][C:16]=4[C:11]=3[N:12]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ICCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1Cc1sc(SCCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 44 %

Procedure:
Using ethyl[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and 4,4-diphenylbutyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 44%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[I:14]Cl>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:4][C:3]=1[I:14]
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Reactant: ClI
Solvent: CC#N
Product: CNS(=O)(=O)Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
To a suspension of 1.06 g (5.31 mmol, 1.0 equiv.) of 4-amino-N-methylbenzenemethanesulfonamide in 20 mL of acetonitrile was added 0.862 g (5.31 mmol, 1.0 equiv.) of iodine monochloride. The reaction was stirred for 15 minutes at room temperature. The mixture was partitioned between 25 mL of ethyl acetate and 15 mL of 20% aqueous sodium thiosulfate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield an oil. The oil was filtered through a plug of silica gel using 40% ethyl acetate in hexane to yield 1.13 g (65%) of 4-amino-3-iodo-N-methylbenzenemethanesulfonamide.
Reaction SMILES: COC[O:4][CH2:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.CO.Cl.[OH-].[Na+]>O>[OH:4][CH2:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1
Reactant: COCOCCc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=Cc1ccc(CCO)cc1
Temperature: 60 °C
Reaction time: 17.5 h
Yield: 99.6 %

Procedure:
Next, a mixture of 4-(2-methoxymethoxyethyl)benzaldehyde (8.2 g, 42.1 mmol), methanol (160 mL), water (6 mL) and concentrated hydrochloric acid (4 mL) was stirred at 60° C. for 17.5 hours. After cooling to room temperature, the reaction mixture was neutralized with aqueous sodium hydroxide and evaporated under reduced pressure to remove methanol. The residue was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After concentration, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10 to 50:50) to give 4-(2-hydroxyethyl)benzaldehyde (6.3 g).
Reaction SMILES: [C:1]([Si:5]([O:18][CH2:19][C@@H:20]([N:22]=[C:23]=[O:24])[CH3:21])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[N:31]=[C:30](Cl)[C:29]([CH:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH3:34])=[CH:28][N:27]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[C:1]([Si:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:18][CH2:19][C@@H:20]([N:22]1[C:28]2=[N:27][C:26]([Cl:25])=[N:31][CH:30]=[C:29]2[CH:33]([CH3:34])[N:35]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:23]1=[O:24])[CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(NC(C)c2cnc(Cl)nc2Cl)cc1
Reactant: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N=C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)N([C@@H](C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3nc(Cl)ncc3C2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-tert-Butyl-2-isocyanato-propoxy-diphenylsilane (generated in situ from 0.440 g, 1.20 mmol, of (S)-(+)-3-(tert-butyl-diphenyl-silanyloxy)-2-methylpropionic acid) (from Example 13b supra) in hot toluene (2 mL; 120° C.) was treated with a solution of (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-(4-methoxy-phenyl)-amine (0.35 g; 1.10 mmol) (from Example 1d supra) in toluene (2 mL). The resulting solution was kept at 120° C. for 30 minutes, then cooled to room temperature and concentrated. The residue was dissolved in anhydrous tetrahydrofuran (4 mL) and cooled in an ice-brine bath. Potassium tert-butoxide (1.0 M in tetrahydrofuran; 1.2 mL; 1.20 mmol) (Aldrich) was added dropwise and stirring continued in the cold for 15 minutes. The mixture was filtered through a bed of silica gel and eluted with ethyl acetate. Further purification with flash chromatography (Biotage 40 M; 25:75 ethyl acetate-hexanes) gave 1-[2-(tert-butyl-diphenyl-silanyloxy)-1-(S)-methyl-ethyl]-7-chloro-3-(4-methoxy-phenyl)-4-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a mixture of diastereomers. (Yield 0.31 g; 46%). No separation of diastereomers was seen at this time.