Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:41])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1.[N:42]1([CH2:48][CH2:49][OH:50])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:45]3[CH2:46][CH2:47][N:42]([CH2:48][CH2:49][OH:50])[CH2:43][CH2:44]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)(=[O:31])=[O:32])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCCN1CCNCC1
Product: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCO)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-ethanol (Chemical Dynamics) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H43N5O5SCl2 [(M+H)+] 728.2435, observed 728.2431.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][N:15]1[C:19]([Cl:20])=[C:18]([C:21](Cl)=[O:22])[C:17]([Cl:24])=[N:16]1.CC(C)([O-])C.[K+].Cl>C1COCC1.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11](=[C:21]([C:18]2[C:17]([Cl:24])=[N:16][N:15]([CH3:14])[C:19]=2[Cl:20])[OH:22])[C:12]#[N:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(Cl)c(C(O)=C(C#N)c2ccc(C(C)(C)C)cc2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
1.00 g of 4-tert-butylphenylacetonitrile and 1.23 g of 1-methyl-3,5-dichloropyrazole-4-carbonyl chloride were dissolved in 20 ml of THF, and 1.01 g of potassium t-butoxide was added thereto with cooling with ice. After the resulting mixture was stirred overnight at room temperature, water was added thereto, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and dried with sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was dissolved in a mixed solvent of 10 ml of water and 10 ml of dioxane, and 0.38 g of potassium hydroxide was added thereto and heated under reflux for 4 hours. After having been left to be at room temperature, this was acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain 0.64 g of 2-(4-tert-butylphenyl)-3-(1-methyl-3,5-dichloropyrazol-4-yl)-3-hydroxyacrylonitrile from the fraction eluted with n-hexane:ethyl acetate=2:1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([N:16]1[CH2:17][CH:13]([C:9]2([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][CH2:11][CH2:10]2)[CH2:14][C:15]1=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1(C2CNC(=O)C2)CCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A 15.13 g (59.5 mmol) portion of 4-(1-tert-butoxycarbonylaminocyclobutyl)-2-pyrrolidone was dissolved in 30.0 ml of N,N-dimethylformamide, cooled in an ice bath, mixed with 2.62 g (65.44 mmol) of sodium hydride (60% oil suspension) and then stirred at room temperature for 30 minutes. This was mixed with 7.78 ml (65.44 mmol) of benzyl bromide and stirred overnight at room temperature. Since the starting material partially remained, 1.19 g (29.74 mmol) of sodium hydride and 3.54 ml (29.74 mmol) of benzyl bromide were further added and stirred for additional 5 hours at room temperature. After evaporation of the solvent, the resulting residue was mixed with water, extracted with ethyl acetate and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated. Thereafter, the resulting residue was purified by a silica gel column chromatography (silica gel 800 ml, ethyl acetate:hexane=10:1→1:1→2:1) to yield 5.65 g (28%) of the title compound.
Reaction SMILES: [C:1]1([CH:7]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH2:24])[CH2:17][CH2:16]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>>[C:1]1([CH:7]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH:24][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:17][CH2:16]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(NC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(NC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 51.3 %

Procedure:
3.12 g of 4-(diphenylmethylamino)-1-piperidinepropanamine and 1.72 g of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 180° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure. The residue was crystallized by the addition of ethyl ether-hexane (1:3), collected by filtration, washed with hexane and dried to yield 1.83 g of the title compound.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.C(N(CC)CC)C.Cl.[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33]>C(O)C>[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:5]1[N:6]=[CH:1][N:2]=[C:3]2[C:4]=1[N:8]=[CH:9][N:10]2[C@@H:11]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCc1cccc(I)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCc4cccc(I)c4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 85 °C
Yield: 87.5 %

Procedure:
A mixture of 6-chloropurine riboside (Aldrich Chemical Co., 100 mg, 0.35 mmol), triethylamine (0.146 ml, 1.05 mmol), and 3-iodobenzylamine hydrochloride (103 mg, 0.38 mmol) in ethanol (2 ml) was heated for 18 h at 85° C. in a sealed bottle. After the reaction mixture was concentrated to dryness, the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 10:1) to yield N6 -(3-iodobenzyl)-9-[β-D-ribofuranosyl]-adenine (148 mg, 88%) as a colorless solid: m.p. 172° C.; 1H NMR (DMSO-d6) d 3.54 (m, 1H, H-5'a), 3.67 (m, 1H, H-5'b), 3.96 (d, J=3.3 Hz, 1H, H-4'), 4.14 (m, 1H, H-3'), 4.60 (m, 1H, H-2'), 4.66 (br s, 2H, CH2), 5.16 (d, J=4.4 Hz, 1H, exchangeable with D2O, 3'-OH), 5.34 (br s, 1H, exchangeable with D2O, 5'-OH), 5.43 (d, J=6.1 Hz, 1H, exchangeable with D2O, 2'-OH), 5.89 (d, J=6.0 Hz, 1H, H-1'), 7.11 (pseudo t, J=8.0 and 7.8 Hz, 1H, H-5"), 7.36 (d, J=7.6 Hz, 1H, H-4" or -6"), 7.58 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.72 (s, 1H, H-2"), 8.21 (s, 1H, H-2 or 8), 8.40 (s, 1H, H-2 or 8), 8.48 (br s, 1H, exchangeable with D2O, N6H,).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:19][CH3:20])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:21][CH2:22][C:23]1[C:24](=[O:33])[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:19][CH3:20])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:21][CH2:22][C:23]1[C:24](=[O:33])[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[CH:29]([CH3:30])[CH3:31])=[O:9]
Reactant: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Reactant: CCN(c1cc(Br)cc(C(=O)O)c1C)C1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCN(c1cc(Br)cc(C(=O)NCc2c(C(C)C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reaction time: 8 h
Yield: 68.4 %

Procedure:
5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoic acid (2.0 g, 0.0058 mol) was dissolved in DMSO (20 mL) and 3-(aminomethyl)-4-isopropyl-6-methylpyridin-2(1H)-one (2.1 g, 11.7 mmol) and triethyl amine (0.585 g, 5.8 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PyBOP (4.5 g, 8.7 mmol) was added to it and stirring was continued for overnight. After completion of the reaction, the reaction mixture was poured into ice, extracted with 10% MeOH/DCM. Combined organic layers were dried, concentrated to obtain crude; which then purified by solvent washings to afford the title compound (2.0 g, 68.9%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].CS(O[CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Reactant: COCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCCCCn1c(-c2ccccc2)nc(Cl)c1C=O
Temperature: 90 °C
Reaction time: 7 h
Yield: 99.1 %

Procedure:
To a solution of 4-chloro-2-phenyl-1H-imidazole-5-carbaldehyde (500 mg) and 4-methoxybutyl methanesulfonate (660 mg) in N,N-dimethylacetamide (10 ml) was added cesium carbonate (2.4 g); and the mixture was stirred at 90° C. for 7 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-3:7) was concentrated under reduced pressure to give the object product (702 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].O1CCCC1.Cl[C:24]1[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.[H-].[Na+]>CCOCC>[Cl:30][C:29]1[C:24]([O:1][CH2:2][C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[CH:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[CH:9]=2)[O:6][CH3:7])=[N:25][CH:26]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:28]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(c1cc(C)no1)c1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(c1cc(C)no1)c1ccccc1COc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a mixture of 0.21 g (0.9 mmol) of 5-(2-hydroxymethyl-α-methoxybenzyl)-3-methylisoxazole, 3 ml of tetrahydrofuran and 0.29 g (1.35 mmol) of 2,3-dichloro-5-trifluoromethylpyridine was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at room temperature for 2 hours. After completion of the reaction, 100 ml of ether was added and washed with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[2-(3-chloro-5-trifluoromethyl-2-pyridyloxymethyl)-α-methoxybenzyl]-3-methylisoxazole (0.32 g, 86.1%) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:21][CH2:22][OH:23].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-{5-Methyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-oxazol-4-yl}-ethanol (0.264 g, 0.85 mmol) and triethylamine (0.154 mL, 1.1 mmol) in CH2Cl2 (4 mL) at 0° C. is added methanesulfonyl chloride (0.077 mL, 1.0 mmol). The mixture is warmed to room temperature and stirred for 2 h. The mixture is concentrated to provide methanesulfonic acid 2-{5-methyl-2-[4-(pyridin-2-ylmethoxy)-phenyl]-oxazol-4-yl}-ethyl ester, which is used without purification. MS (m/e): 389 (M+1)
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][N:6]([CH3:10])[CH2:7][CH2:8][OH:9]>>[N:6]([CH2:7][CH2:8][O:9][CH2:3][CH2:2][C:1]#[N:4])([CH3:10])[CH3:5]
Reactant: CN(C)CCO
Reactant: C=CC#N
Product: CN(C)CCOCCC#N

Procedure:
244 g of acrylonitrile are added dropwise to 356.5 g of 2-dimethylaminoethanol and 5 ml of Triton B in the course of 15 minutes. In the course of the ensuing exothermic reaction the mixture warms from room temperature to 75° C. While adding a further 5 ml of Triton B, the mixture is heated for 8 hours to 95° C. and then distilled. Yield: 451.4 g (79.4%) of analytically pure product (analysis by gas chromatography); b.p. 102° C./8 torr.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[C:6]([S:13][CH3:14])[N:5]([NH2:15])[CH:4]([CH3:16])[N:3]=1.[CH3:17][O-:18].[Na+]>>[CH3:17][O:18][C:2]1[C:7]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[C:6]([S:13][CH3:14])[N:5]([NH2:15])[CH:4]([CH3:16])[N:3]=1
Reactant: C[O-]
Reactant: CSC1=C(C2=NCCN2)C(Cl)=NC(C)N1N
Agent: [Na+]
Product: COC1=NC(C)N(N)C(SC)=C1C1=NCCN1
Reaction time: 4 h

Procedure:
3 g 4-chloro-2-methyl-6-methylthio-5-(2-imidazolin-2-yl)-aminopyrimidine (Example 2) are mixed with 60 ml 15% methanolic sodium methylate solution and boiled for 4 hours under reflux. Then about 40 ml methanol are distilled off. The solution is mixed with water and cooled until it crystallizes. 1.5 g of 4-methoxy-2-methyl-6-methylthio-5-(2-imidazolin-2-yl)-aminopyrimidine is obtained, (Melting point 267° C.) after recrystallization from nitromethane.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[O:12][CH2:11][CH2:10][O:5]1
Reactant: OCCO
Reactant: O=Cc1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccccc1C1OCCO1
Reaction time: 4 h

Procedure:
To a solution of 50.0 g of 2-bromobenzaldehyde in 50 ml of toluene was added ;b 25.0 ml of ethylene glycol plus 500 mg of p-toluenesulfonic acid. The mixture was heated at reflux with a Dean Stark Trap for 18 hours. Then an additional 10 ml of ethylene glycol was added to the mixture and reflux was continued for 4 hours longer. The solvent was evaporated in vacuo and the residue was dissolved in ether. The organic solution was washed with 5% sodium bicarbonate, dried over magnesium sulfate and filtered. The filtrate was evaporated to an oil which was distilled through a Kugelrohr apparatus. The fraction boiling at 130° C., 0.1 mm was collected giving 60.3 g of 2-(2-bromophenyl)-1,3-dioxolane.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[S-2:15].[K+].[K+].[Cl:18][CH2:19][CH2:20][CH:21]1[CH2:27][N:26]([CH3:28])[C:25](=O)[C:24]2[CH:30]=[CH:31][C:32]3[C:37]([C:23]=2[O:22]1)=[CH:36][CH:35]=[CH:34][CH:33]=3>C1(C)C=CC=CC=1>[Cl:18][CH2:19][CH2:20][CH:21]1[CH2:27][N:26]([CH3:28])[C:25](=[S:15])[C:24]2[CH:30]=[CH:31][C:32]3[C:37]([C:23]=2[O:22]1)=[CH:36][CH:35]=[CH:34][CH:33]=3
Reactant: CN1CC(CCCl)Oc2c(ccc3ccccc23)C1=O
Reactant: [S-2]
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2c(ccc3ccccc23)C1=S
Yield: 84.1 %

Procedure:
A mixture of 9.55 g of phosphorus pentasulfide and 9.5 g of potassium sulfide were ground together and added to a solution of 20.2 g (0.07 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylnaphth[2,1-f][1,4]oxazepin-5(4H)-one in 200 ml of dry toluene. The mixture was stirred and heated at reflux for 7 hr. The hot reaction mixture was filtered and the product crystallized from the cooled filtrate. Recrystallization from chloroform gave 18 g (84%) of yellow crystals, m.p. 167°-170° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][C:10]=1[C:19]1[NH:24][C:23](=[O:25])[N:22]2[C:26]([CH3:32])=[N:27][C:28]([CH2:29][CH2:30][CH3:31])=[C:21]2[N:20]=1)[CH3:7]>ClCCl>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:17])=[O:16])=[CH:11][C:10]=1[C:19]1[NH:24][C:23](=[O:25])[N:22]2[C:26]([CH3:32])=[N:27][C:28]([CH2:29][CH2:30][CH3:31])=[C:21]2[N:20]=1)[CH3:7]
Reactant: COCCN
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)NCCOC)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
55 mg (0.73 mmol) of 2-methoxyethylamine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5) and stirring up with diethyl ether, 64 mg (57%) of 4-ethoxy-N-(2-methoxy-ethyl)-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonamide are obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH3:14][NH:15][CH3:16]>CN(C)C=O>[CH3:14][N:15]([CH3:16])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc([N+](=O)[O-])cc1

Procedure:
4.9 g (20 mmol) of 4-(2-bromoethyloxy)-nitrobenzene and 2.7 g (60 mmol) of dimethylamine in 50 ml of dimethylformamide are heated to 100° C. for 24 hours in a bomb tube. After removal of the solvent in vacuo the residue is taken up in water and extracted with dichloromethane. The organic phase is dried and concentrated by evaporation.
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[SH:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:5][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:12][CH2:13][CH2:14][OH:15])[CH:8]=[CH:7][CH:6]=1
Reactant: OCCS
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cccc(SCCO)c1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
3-Chloro-2-nitro-aniline (1.12 g, 6.5 mmol), 2-mercaptoethanol (0.60 ml, 8.6 mmol), and potassium carbonate (0.99 g, 7.1 mmol) were combined in dry DMF (15 ml) and stirred at 130° C. for 4 h. The solution was allowed to cool and was concentrated in vacuo. Purification by silica gel chromatography (70% EtOAc/hexanes) gave 1.29 g (93%) of 2-(3-amino-2-nitro-phenylsulfanyl)-ethanol as a bright red solid. 1H NMR (300 MHz, DMSO-d6) δ 7.20 (t, 1H, J=8.1 Hz), 6.80 (s, 2H), 6.73 (dd, 1H, J=8.4, 0.9 Hz), 6.63 (dd, 1H, J=7.8, 1.2 Hz), 4.92 (t, 1H, J=6.0 Hz), 3.58 (q, 2H, J=6.0 Hz), 2.98 (t, 2H, J=6.0 Hz). 2-(2,3-Diamino-phenylsulfanyl)-ethanol. 2-(3-Amino-2-nitro-phenylsulfanyl)-ethanol (1.02 g, 4.8 mmol) was reduced by hydrogenation using 45 psi of H2 with 109%0 Pd—C, (180 mg) in EtOAc (25 mL) for 6 h. After filtering through Celite, solvent was removed in vacuo. Purification by silica gel chromatography (EtOAc) gave 762 mg (87%) of 2-(2,3-diamino-phenylsulfanyl)-ethanol as a faintly yellow solid. 1H NMR (300 MHz, CDCl3) δ 6.98 (dd, 1H, J=7.5, 10.5 Hz), 6.60-6.72 (m, 2H), 3.65 (t, 2H, J=5.7 Hz), 3.55 (br s, 5H), 2.91 (t, 2H, J=5.7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[F:11][CH2:12][CH:13](O)[CH2:14][F:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:13]([CH2:14][F:15])[CH2:12][F:11])[CH:7]=1
Reactant: OC(CF)CF
Reactant: COc1ccc(Br)cc1O
Product: COc1ccc(Br)cc1OC(CF)CF
Yield: 56.9 %

Procedure:
The title compound was prepared by the method outlined for Preparative Example 63 using 5-bromo-2-methoxy-phenol (765 uL, 9.87 mmol) and 1,3-difluoro-2-propanol (765 uL, 9.87 mmol) to afford titled compound as a colorless solid (1.58 g, 55%). 1H NMR (DMSO-d6) 7.28 (d, J=2.4, 1H), 7.14 (dd, J=8.8, 2.4, 1H), 6.97 (d, J=8.8, 1H), 4.55-4.35 (m, 5H), 3.75 (s, 3H). LC/MS (Method B) 3.50 min, [M+1]+ 281/283.
Reaction SMILES: Br[C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>C(#N)C.[F-].[K+].O>[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:24]2[CH:2]=[CH:3][C:4]3[C:8]4[CH:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=4[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]=3[N:23]=2)=[CH:29][CH:28]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Br)cnc21
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2ccc(-c3ccc(CO)cc3)nc21
Temperature: 140 °C
Yield: 172.5 %

Procedure:
A mixture of 3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (700 mg, 0.87 mmol), 4-hydroxymethylbenzeneboronic acid (400 mg, 1.32 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (52.5 mg, 0.064 mmol) in acetonitrile (21 mL) and 2N aqueous potassium fluoride solution (21 mL) was divided equally across two 25 mL microwave vials. Each vial was degassed with nitrogen for 10 minutes before the mixtures were heated under microwave irradiation at 140° C. for 30 minutes. The reaction mixtures were allowed to cool to ambient temperature, combined and diluted with water (50 mL). The precipitate was collected by filtration, washed with water (50 mL) and left to air dry. The resultant grey solid was purified by flash column chromatography (silica, 40 g column, ISCO, 0-100% ethyl acetate in cyclohexane). The isolated solid was then triturated with hot t-BME to afford the title compound as a light grey solid (646 mg, 26%). LCMS (Method B): RT=4.11 min, M+H+=431.