Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]([F:38])([F:37])[CH2:7][NH:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:18]2[N:22]3[N:23]=[CH:24][C:25]([C:27]4[CH:28]=[N:29][N:30]([CH:32]([CH3:36])[C:33](O)=[O:34])[CH:31]=4)=[CH:26][C:21]3=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([NH:4][C:33](=[O:34])[CH:32]([N:30]2[CH:31]=[C:27]([C:25]3[CH:24]=[N:23][N:22]4[C:18]([C:14]5[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:9]([NH:8][CH2:7][C:6]([F:38])([F:37])[F:5])=[O:10])[CH:13]=5)=[CH:19][N:20]=[C:21]4[CH:26]=3)[CH:28]=[N:29]2)[CH3:36])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C(=O)NC1CC1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cyclopropylamine (17 μL, 0.24 mmol) was added to a mixture of 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid (0.16 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (110 mg, 0.24 mmol) in DMF (2.0 mL), followed by triethylamine (45 μL, 0.32 mmol). The reaction mixture was stirred at r.t. for 30 min. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=513.2.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[OH:14][C:15]1[CH:32]=[CH:31][C:18]([O:19][CH:20]([CH3:30])[C:21]([O:28][CH3:29])=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:13])[N:3]=[C:2]([O:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]([CH3:30])[C:21]([O:28][CH3:29])=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:31][CH:32]=1)[CH:11]=[N:10]2
Reactant: Clc1cnc2cc(Cl)c(Cl)cc2n1
Reactant: CCOC(=O)C=C(OC)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2cnc3cc(Cl)c(Cl)cc3n2)cc1

Procedure:
A mixture of 2,6,7-trichloroquinoxaline (0.8 eq, 3.43 ml.), ethyl 4-(4-hydroxyphenoxy)-3-methoxy-2-pentenoate (1.09 g, 1.2 eq), K2CO3 (568 mg) and CH3CN (20 ml) is refluxed overnight and then filtered. The filtrate is concentrated and taken up in CH2Cl2. The CH2Cl2 solution is washed, dried and evaporated to dryness to yield crystalline enol ether, i.e., ethyl 4-[4-(6,7-dichloro-2-quinoxalyloxy)phenoxy]-3-methoxy-2-pentenoate.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].F[C:8]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11].[F:28][C:29]([F:39])([F:38])[O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>CN(C=O)C>[O:19]=[C:15]1[CH:14]=[C:13]([NH:12][C:10](=[O:11])[C:9]2[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:8]=2[O:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][C:29]([F:28])([F:38])[F:39])=[CH:32][CH:33]=2)[CH:18]=[CH:17][NH:16]1
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
Cs2CO3 (651.6 mg, 2 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (60.0 mg, 0.2 mmol) and 4-(trifluoromethoxy)phenol (259.1 μL, 2 mmol) in DMF (1 mL) and the reaction was stirred at 100° C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (79) (25.7 mg, 28%). ESI-MS m/z calc. 458.07. found 459.5 (M+1)+; Retention time: 1.80 minutes (3 minutes run)
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[CH3:20][C:21]1[C:22]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:23][CH:24]=[C:25]([CH:28]=1)[C:26]#[N:27]>>[O:19]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:22]3[C:21]([CH3:20])=[CH:28][C:25]([C:26]#[N:27])=[CH:24][N:23]=3)[CH2:30][CH2:31]2)=[O:16])=[CH:17][CH:18]=1)([CH3:8])[CH3:9]
Reactant: Cc1cc(C#N)cnc1N1CCNCC1
Reactant: CC(C)(c1ccc(C(=O)O)cc1)N1CCCS1(=O)=O
Product: Cc1cc(C#N)cnc1N1CCN(C(=O)c2ccc(C(C)(C)N3CCCS3(=O)=O)cc2)CC1
Yield: 86.5 %

Procedure:
Using 4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1-methylethyl]benzoic acid (100 mg) described in Preparation Example 39 and 5-methyl-6-(piperazin-1-yl)nicotinonitrile (71 mg) described in Preparation Example 103 and by the reaction and treatment in the same manner as in Example 87, the title compound (142 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:18]([O-])=[CH:17][C:16]=2[N:15]=[CH:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:27].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:27])[C:16]=2[N:15]=[CH:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)NCCCCn1cnc2c[n+]([O-])c3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCn1cnc2c(N)nc3ccccc3c21
Reaction time: 0.5 h

Procedure:
15.87 g (44.52 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-1H-imidazo[4,5-c]quinoline-5-oxide was dissolved in 400 ml of methylene chloride and 200 ml of concentrated aqueous ammonia (29%) was added thereto under ice-cooling. A solution of p-toluenesulfonyl chloride (9.34 g, 48.98 mmol) in 50 ml of methylene was further added thereto and the mixture was stirred for 30 minutes, then rasing up to room temperature stirred for 2 hours. After the reaction solution was separated, the organic phase was washed with brine and dried (Na2SO4). The solvent was distilled off and the residue was triturated with chloroform, then collected by filtration to obtain 7.10 g (19.97 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-1H-imidazo[4,5-c]-quinoline-4-amine shown below as a faint yellowish white solid. ##STR55## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3440, 3380, 3110, 2980, 1710, 1650, 1530, 1260, 1160, 760.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:26])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]([CH3:24])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:25]=1.[Se](=O)=[O:28]>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:26])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]=[O:28])=[C:17]([CH3:24])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:25]=1
Reactant: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: Cc1c(C=O)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a 200 mL round bottom flask equipped with a stir bar was added 2-(2,6-dichloro-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (2.4 g, 6.2 mmol), selenium dioxide (2.0 g, 18 mmol) and dioxane (150 mL). The flask was fitted with a condenser and heated to reflux for 4.5 h. The reaction was then removed from heat and allowed to cool to room temperature. The slightly opaque solution was filtered through celite and washed with dichloromethane:methanol (9:1). The solution was concentrated and the resulting residue triturated with dichloromethane to produce 2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (1.8 g, 72%) as a brownish yellow solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6+TFA) δ 10.65 (s, 1H), 10.24 (s, 1H), 7.96 (d, 1H, J=8.6 Hz), 7.78 (d, 1H, J=8.6 Hz), 7.70 (d, 2H, J=7.8 Hz), 7.49 (d, 2H, J=7.8 Hz), 4.15 (s, 3H), 2.70 (s, 3H); ESMS (m/z): found, 401.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:27][CH:26]=1)(=[O:30])=[O:29])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCOc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 124 mg of 4-butoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.98 (t, 3H, J=7.6 Hz), 1.45 (m, 2H), 1.72 (m, 2H), 3.79 (t, 2H, J=6.6 Hz), 6.66 (d, 2H, J=8.8 Hz), 7.31 (d, 1H, J=2.8 Hz), 7.35-7.42 (m, 4H), 7.47 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.53-7.60 (m, 3H), 7.75 (d, 1H, J=8.8 Hz), 9.62 (s, 1H). MS: m/z 444.9 (M++1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:48]([N:43]1[CH2:44][CH2:45][CH:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41][CH2:42]1)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccccc2)CC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 58 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and benzoyl chloride as starting materials in 58% yield. LCMS for C32H32ClN6O2 (M+H)+: m/z=567.2.
Reaction SMILES: Cl.CO[C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[N:25]([CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[C:26]=[S:27]>ClCCl>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH2:7][CH:5]2[NH:6][C:26](=[S:27])[N:25]([CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[C:4]2=[O:17])=[CH:9]1
Reactant: S=C=NCCN1CCOCC1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(Cc2c[nH]c3ccccc23)NC(=S)N1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.5 %

Procedure:
To a solution of L-tryptophan methyl ester hydrochloride (0.250 mg, 0.001 mol.) in dichloromethane (10 mL) was added triethyl amine (3.0 eq.) followed by 4-(2-isothiocyanato-ethyl)-morpholine (0.190 gm, 0.0011 mol.). The reaction mixture was stirred at room temperature for 24 hr, and then concentrated. The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane to give 893-17 (292 mg, 83%): mp 167-169° C., 1H NMR (500 MHz, CDCl3): 2.45-2.51 (m, 6H), 3.02-3.07 (dd, J=9.5 and 15.0 Hz, 1H), 3.46-3.50 (dd, J=4.0 and 15.0 Hz, 1H), 3.65 (m, 4H) 3.89 (d, J=7.0 Hz, 2H), 4.35-4.38 (m, 1H), 6.38 (s, 1H), 7.12 (d, J=2.5 Hz, 1H), 7.16-7.19 (m, 1H), 7.23-7.25 (dd, J=1.5 and 8.0 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[C:11]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.O1CCCC1.Cl>C(OCC)(=O)C>[OH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[N:12]=[C:11]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCOC2CCCCO2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCO)CC1
Yield: 79.5 %

Procedure:
Combine tert-butyl 4-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (6.88 g, 14.84 mmol), tetrahydrofuran (136 mL) and 1 N aqueous hydrochloric acid (25 mL). Stir the reaction at room temperature overnight. Dilute with ethyl acetate and wash with saturated aqueous sodium chloride and saturated aqueous sodium bicarbonate. Extract the combined aqueous layers with 9:1 dichloromethane:isopropyl alcohol. Dry the combined organic layers over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to 50% ethyl acetate in hexanes to ethyl acetate to 10% methanol in ethyl acetate to 10% methanol in dichloromethane, to give the title compound as a white solid (4.48 g, 79%). MS (ES) m/z=380 [M]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:15][CH3:16])[S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:17])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1.CO>CN(C=O)C>[CH2:15]([C:13]1[S:14][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:17][CH2:25][CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[NH:29][CH:28]=4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:16]
Reactant: CCc1nc2c(N)nc3cc(O)ccc3c2s1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3cc(OCCc4c[nH]c5ccccc45)ccc3c2s1
Temperature: 60 °C

Procedure:
A scintillation vial was charged with 4-amino-2-ethylthiazolo[4,5-c]quinolin-7-ol (1.0 eq., 1.0 mmol) and anhydrous DMF (2 mL). The mixture was warmed until a solution was obtained. An additional amount of DMF (1 mL) was added. To this stirred orange solution was added cesium carbonate (3.0 eq., 3.0 mmol) and a solution of 3-(2-bromoethyl)indole (1.0 eq., 1.0 mmol) dissolved in DMF (2 mL). Additional DMF (1 mL) was used to rinse the vial. The vial was capped and heated to 60° C. overnight. The reaction was monitored by HPLC. The reaction was quenched by adding the reaction mixture drop-wise to water (60 ml) with stirring. A precipitate formed. The solid was collected by vacuum filtration. The solid was then dissolved in methanol and adsorbed onto silica gel (6 g) for purification by HPFC (0-15% CMA in chloroform, 1440 mL). Pure fractions were combined and concentrated; the resulting solid was recrystallized from methanol to provide a peach colored crystalline solid, mp 218-220° C. MS (APCI) m/z 389 (M+H)+. Anal. calcd for C22H20N4OS.0.8 CH3OH: C, 66.13; H, 5.65; N, 13.53. Found: C, 66.43; H, 5.03; N, 13.90.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.F>>[OH:11][C:5]1[CH:10]=[CH:9][C:8]([C:2]([NH2:3])=[S:1])=[CH:7][CH:6]=1
Reactant: Oc1ccccc1
Reactant: N#C[S-]
Agent: F
Agent: [K+]
Product: NC(=S)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 85 %

Procedure:
At a temperature and in the manner as described in Example 1, 69 g of potassium thiocyanate (0.7 mol) and 52 g of phenol (0.55 mol) are stirred with 0.5 l of 98% hydrofluoric acid, and subsequently, the mixture is stirred for 3 days at room temperature. 0.3 l of hydrofluoric acid are then distilled off at normal pressure and a bath temperature of up to 60° C, the remainder is cooled and the residue is stirred with ice and water. The crude product precipitated is suction-filtered and may be purified by dissolving in dilute soda solution at room temperature, clarifying the solution and subsequent precipitation of the product with mineral acid or by recrystallization from water. The 4-hydroxy-thiobenzamide so obtained has a melting point of 192° - 193° C. The yield is 85% of the theoretical yield, relative to the phenol used.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[O:19][C:18]([N:20]3[CH:26]4[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]4)[CH2:22][CH2:21]3)=[N:17][C:14]2=[N:15][CH:16]=1>>[C:1]1([C:11]2[CH:12]=[C:13]3[O:19][C:18]([N:20]4[CH:26]5[CH2:25][CH2:24][N:23]([CH2:28][CH2:27]5)[CH2:22][CH2:21]4)=[N:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1cnc2nc(N3CCN4CCC3CC4)oc2c1
Reactant: OB(O)c1ccccc1
Product: c1ccc(-c2cnc3nc(N4CCN5CCC4CC5)oc3c2)cc1
Yield: 27 %

Procedure:
The title compound was prepared according to the procedure detailed in Example 44 using phenyl boronic acid and 4-(6-bromo-oxazolo[4,5-b]pyridin-2-yl)1,4-diaza-bicyclo[3.2.2]nonane (prepared in Example 47) in 27% yield: 1H NMR (CDCl3, 400 MHz) δ 8.48 (d, 1H, J=2.1 Hz), 7.62 (d, 1H, J=2.1 Hz), 7.57-7.55 (m, 2H), 7.47-7.43 (m, 2H), 7.40-7.34 (m, 1H), 4.62 (br s, 1H), 4.00 (t, 2H, J=5.8 Hz), 3.20-3.15 (m, 4H), 3.08-3.01 (m, 2H), 2.19-2.08 (m, 2H), 1.90-1.81 (m, 2H); MS (Cl) m/z 321.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25]Cl)[CH:12]=3)=[CH:10][C:3]=12.[I-:37].[Na+]>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][I:37])[CH:12]=3)=[CH:10][C:3]=12
Reactant: [I-]
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCCl)c2cc1OC
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCI)c2cc1OC
Yield: 110.4 %

Procedure:
A suspension of 0.760 g of 4-chloro-2-[1-(2-chloroethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 0.315 g of sodium iodide in 70 ml of 2-butanone is brought to reflux for approximately 24 hours. The reaction mixture is evaporated to dryness under reduced pressure (13 kPa), taken up with 50 ml of water, and extracted with three times 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). 0.98 g of 4-chloro-2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a yellow oil, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][Li].[C:3]1([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]=[CH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-].[NH4+]>C(OCC)C.O.[Cu]Br>[CH3:1][CH:10]1[CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:14][CH2:13][C:12](=[O:15])[CH2:11]1
Reactant: [Li]C
Reactant: O=C1C=CC(c2ccccc2)CC1
Agent: [Cu]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CC1CC(=O)CCC1c1ccccc1
Temperature: -20 °C
Yield: 37.4 %

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 2.9 grams (0.020 mole) of copper(I) bromide in 10 mL of diethyl ether was cooled to -20° C., and 50 mL (0.070 mole) of 1.4M methyllithium in diethyl ether was added slowly. Upon completion of addition, a solution of 4.6 grams (0.027 mole) of 4-phenyl-2-cyclohexenone in 5 mL of diethyl ether was added dropwise at a rate to maintain the reaction mixture temperature below -20° C. Upon completion of addition, a solution of 4.2 grams (0.080 mole) of ammonium chloride in 20 mL of water was added. Upon completion of addition, the reaction mixture was stirred as it warmed to ambient temperature. The reaction mixture was then diluted with 200 mL of diethyl ether and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished commencing with 10% diethyl ether in petroleum ether and finishing with 15% diethyl ether in petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.9 grams of 3-methyl-4-phenylcyclohexanone as a liquid. The NMR spectrum was consistent with the proposed structure, and it indicated that the product was predominantly the trans isomer. The reaction-was repeated on a larger scale. The 3-methyl-4-phenylcyclohexanone isolated from the larger reaction was a solid, mp 71.5°-72.5° C. The NMR spectrum of a sample from the larger reaction was also consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(Cl)cc3)c2c1O
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)c1nc(-c2ccccc2)c2snc(-c3ccc(Cl)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-Bromo-3-(4-chloro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and phenylboronic acid: MS (m/z) 411.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(=O)O[CH2:15][CH2:14][O:13]1>>[OH:13][CH2:14][CH2:15][O:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OCCO1
Reactant: Nc1nc2c(O)cccc2o1
Product: Nc1nc2c(OCCO)cccc2o1
Yield: 46 %

Procedure:
The title compound was prepared according to the procedure of Example 91, Step 1, starting from 4-hydroxy-2-amino-1,3-benzoxazol* (0,97 g, 6.5 mmol) and ethylene carbonate (0.63 g, 7.1 mmol). Solid; yield 46%; mp 124-126° C. Anal. (C9H10N2O3) C, H, N.
Reaction SMILES: C(N[C:6]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:22][N:21]=[CH:20][CH:19]=1)(=[O:11])=[O:10])=[O:7])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[O:22]1[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:9]([N:8]=[C:6]=[O:7])(=[O:11])=[O:10])=[CH:19][CH:20]=[N:21]1
Reactant: CCCCNC(=O)NS(=O)(=O)c1ccccc1-c1ccno1
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1ccccc1-c1ccno1
Temperature: 25 °C

Procedure:
A suspension of 6 g of N-(butylaminocarbonyl)-2-(isoxazol-5-yl)benzenesulfonamide, prepared in Example 6, in 50 ml of xylene containing 0.2 g of DABCO was heated at 130°-135° C. while 1.6 ml of phosgene was added portionwise at a rate to maintain a reflux temperature of 130°-135° C. The mixture was refluxed for an additional 2 hours, cooled under nitrogen to room temperature, filtered, and the filtrate was concentrated to dryness in vacuo. A sample of the crude oily product displayed a characteristic sulfonyl isocyanate band in the IR at 2200 cm-1.