Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[I:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1>CN(C=O)C.ClCCl>[I:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([Cl:3])=[O:15])=[CH:8][CH:7]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (39.53) and DMF (2 drops) were added to a solution of 4-iodophenylacetic acid (26.2 g), in dichloromethane (150 ml). The reaction mixture was stirred at ambient temperature for 18 hours and the solvent removed by evaporation to give 4-iodophenylacetyl chloride as an oil (23 g) which was purified by vacuum distillation; b.p. 118-119° C. (0.35 mmMg)
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.[ClH:19].Br[C:21]1[CH:22]=[CH:23][C:24]2[N:30]([CH2:31][C:32]3[N:33]=[CH:34][NH:35][CH:36]=3)[CH2:29][CH2:28][N:27]([C:37]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)=[O:38])[CH2:26][C:25]=2[CH:49]=1>>[ClH:19].[ClH:19].[NH:35]1[CH:36]=[C:32]([CH2:31][N:30]2[C:24]3[CH:23]=[CH:22][C:21]([C:6]4[S:7][CH:8]=[CH:9][CH:10]=4)=[CH:49][C:25]=3[CH2:26][N:27]([C:37]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)=[O:38])[CH2:28][CH2:29]2)[N:33]=[CH:34]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3cccs3)cc2C1
Yield: 10 %

Procedure:
Example 39 was prepared as a green solid in 10% yield from Compound A of Example 37 and 2-(tributylstannyl)thiophene as described for Compound B of Example 37.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].CN[CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH3:11])[CH2:8][CH2:9][CH2:2][CH2:43][CH3:44])[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCNC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 29.5 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting methyl(pentyl)amine (101 mg, 1.0 mmol) for N-methylethanamine to afford 19.0 mg of the title compound (29.5%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[CH:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[O:10][CH2:9]2)[CH:2]=1.Cl[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.[H-].[Na+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C@H:8]2[C@@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)[CH:15]=3)[O:10][CH2:9]2)[CH:2]=1
Reactant: Oc1ccc2c(c1)C(O)C(Cc1cccnc1)CO2
Reactant: Clc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O[C@H]1c2cc(Oc3ccc4ccccc4n3)ccc2OC[C@H]1Cc1cccnc1
Temperature: 92.5 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
3-(3-Pyridylmethyl)-4,6-chromandiol (5.0 g, 19.4 mmol; EP appln. 312,295) was dissolved in 100 ml dimethylformamide. 2-Chloroquinoline (3.17 g, 19.4 mmol) and then NaH (0.98 g of a 50% dispersion in oil, 20.4 mmol) were added and the mixture stirred at 90-95° C. for 16 hours. The reaction mixture was cooled, quenched into 500 ml H2O, and extracted 4×400 ml ethyl acetate. The organic layers were combined, washed 3×400 ml H2O and 1×400 ml brine, dried (Na2SO4), stripped to an oil (9.47 g) and chromatographed in silica gel gradiently eluted with 4-15% CH3OH in CH2Cl2 to yield 5.07 g of present title product as a white foam; IR (KBr) 3190, 1602, 1492 cm-1 ; MS 384 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14](F)=[CH:13][C:12]=1[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)([O-:10])=[O:9].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH:3]2[CH2:4][NH:5][CH2:6][CH2:7][N:2]2[CH3:1])=[CH:13][C:12]=1[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1nc2ccccc2s1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCNCC1c1ccc([N+](=O)[O-])c(-c2nc3ccccc3s2)c1
Temperature: 90 °C

Procedure:
0.31 g (0.0030 mol) of N-methylpiperazine was added to the mixture of 0.41 g (0.015 mol) of 2-(2′-nitro-5′-fluorophenyl)benzothiazole and 0.32 g (0.0023 mol) of K2CO3 in 5 ml of dimethyl sulfoxide. The reaction was stirred magnetically and heated at 90° C., the progression thereof being verified by TLC.
Reaction SMILES: NC1C=C(S(C2C=CC=CC=2)(=O)=O)C=CC=1S(N)(=O)=O.C(N=C=S)(C)C.[NH2:27][C:28]1[CH:33]=[C:32]([S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:31]=[CH:30][C:29]=1[S:43]([NH:46][C:47]([NH:49][CH:50]([CH3:52])[CH3:51])=S)(=[O:45])=[O:44].C(Cl)(Cl)=O>>[CH:50]([NH:49][C:47]1[NH:27][C:28]2[CH:33]=[C:32]([S:34]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)(=[O:35])=[O:36])[CH:31]=[CH:30][C:29]=2[S:43](=[O:44])(=[O:45])[N:46]=1)([CH3:52])[CH3:51]
Reactant: CC(C)NC(=S)NS(=O)(=O)c1ccc(S(=O)(=O)c2ccccc2)cc1N
Agent: CC(C)N=C=S
Agent: Nc1cc(S(=O)(=O)c2ccccc2)ccc1S(N)(=O)=O
Agent: O=C(Cl)Cl
Product: CC(C)NC1=NS(=O)(=O)c2ccc(S(=O)(=O)c3ccccc3)cc2N1

Procedure:
Starting from 2-amino-4-(benzenesulfonyl)benzenesulfonamide and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amino-4-(benzenesulfonyl)benzenesulfonyl)-N′-isopropylthiourea was prepared; m.p. 178-180° C. Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound, m.p. 308-310° C.
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[N:26]1([C:32]2[N:33]=[CH:34][C:35]([C:44]([OH:46])=O)=[N:36][C:37]=2[O:38][CH2:39][C:40]([F:43])([F:42])[F:41])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[CH3:47][O:48][C:49](=[O:56])[C@H:50]([CH2:52][CH:53]([CH3:55])[CH3:54])[NH2:51]>>[CH3:47][O:48][C:49](=[O:56])[C@@H:50]([NH:51][C:44]([C:35]1[CH:34]=[N:33][C:32]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[C:37]([O:38][CH2:39][C:40]([F:41])([F:42])[F:43])[N:36]=1)=[O:46])[CH2:52][CH:53]([CH3:55])[CH3:54]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1cnc(N2CCOCC2)c(OCC(F)(F)F)n1
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1cnc(N2CCOCC2)c(OCC(F)(F)F)n1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 5-morpholin-4-yl-6-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid and (S)-leucine methyl ester (commercially available). m/z (ES+): 435.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[O-:12][CH2:13][CH3:14].[Na+].Cl>C(O)C>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH3:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncc(C(=O)O)cc1Br
Reaction time: 1 h
Yield: 56.9 %

Procedure:
A slurry of 5-bromo-6-chloronicotinic acid (240 mg, 1.0 mmol) and sodium ethoxide (138 mg, 2.0 mmol) in anhydrous ethanol (2 mL) was heated under microwave conditions at 100° C. for 15 min; an additional portion of sodium ethoxide (79 mg, 1.0 mmol) was added and heating was continued for 1 hr. After cooling the reaction mixture was adjusted to a pH of 4 with 1 N aqueous hydrochloric acid, the resulting solids collected and dried in vacuo to afford 5-bromo-6-ethoxynicotinic acid (140 mg). 1H NMR (400 MHz, DMSO-d6) d ppm 1.33 (t, J=7.02 Hz, 3H) 4.43 (q, J=7.09 Hz, 2H) 8.32 (d, J=2.15 Hz, 1H) 8.64 (d, J=1.95 Hz, 1H) 13.28 (br. s., 1H); m/z=248.2 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:19]=[CH:18][C:17]2[NH:16][C:15]3[CH:14]=[C:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[C:12]4[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:11]=4[C:10]=3[C:9]=2[CH:8]=1)(=O)=O.[CH2:34]([Sn](CC)(CC)CC)[CH3:35].[SnH4]>>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:13]1[C:12]2[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:11]=2[C:10]2[C:9]3[CH:8]=[C:7]([CH:34]=[CH2:35])[CH:19]=[CH:18][C:17]=3[NH:16][C:15]=2[CH:14]=1
Reactant: CC[Sn](CC)(CC)CC
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1[nH]c3ccc(OS(=O)(=O)C(F)(F)F)cc3c21
Agent: [SnH4]
Product: C=Cc1ccc2[nH]c3cc(-c4ccccc4Cl)c4c(c3c2c1)C(=O)NC4=O

Procedure:
Compound (616) was prepared from (615) prepared as described in example 479 (using the procedure described in example 309, with tetraethyl tin as the stannane to give a yellow oil. 1H NMR δ [(CD3)2SO] 11.71 (s, 1H), 11.48 (br, 1H), 8.23 (s, 1H), 8.78, (s, 1H), 7.99 (s, 1H), 7.62–7.43 (m, 5H), 7.2–7.1 (m, 1H), 6.10 (d, J=17.6 Hz, 1H), 5.46 (d, J=11.3 Hz, 1H). EIMS found: M+=372.0661. C22H13ClN2O2 requires 372.0666.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@H:13]1[C@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][C:15](=[O:24])[CH2:14]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[CH:12]([C@H:13]1[C@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][C:15](=[O:24])[CH2:14]1)=[O:11]
Reactant: O=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C[C@@H]1CC(=O)C[C@H]1c1ccccc1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxalyl chloride (0.352 mL, 0.512 g, 4.03 mmol) in methylene chloride (8 mL) at −70° C. was added dropwise DMSO (0.573 mL, 0.630 g, 8.06 mmol). After 10 min, a solution of (+)-trans-3-hydroxymethyl-4-phenylcyclopentan-1-one from Example 11, Step F (0.153 g, 0.807 mmol) in methylene chloride (1 mL) was added dropwise. The reaction mixture was stirred at −70° C. for 45 min and then diisopropylethylamine (2.1 mL, 1.6 g, 4.48 mmol) was added. The reaction mixture was allowed to warm to rt for 10 min and then diluted with methylene chloride, poured into water, and extracted three times with methylene chloride. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude title compound (0.15 g) was used directly in Step B.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:15][CH2:16][CH3:17])=O.C>N1C=CC=CC=1.CCOCC>[CH2:16]([O:15][C:13]1[O:5][C:4](=[O:6])[C:3]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1)[CH3:17]
Reactant: CCOC(=O)Cl
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOc1nc2cccc(C)c2c(=O)o1
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 2-amino-6-methyl benzoic acid (25g., 0.165 mol) in dry pyridine (125 ml) at room temperature under anhydrous conditions was added ethyl chloroformate (47.33 ml, 3 equiv.) in a dropwise manner over 15 minutes. After stirring for 2 hours, the excess pyridine was removed under reduced pressure at a bath temperature of 40° C., and the residue was stirred vigorously in ice-cold water (250 ml) for 15 minutes. The pale yellow powder was collected by filtration, washed with water (100 ml) and air-dried to give the crude product (30.4g). The crude product was treated with active charcoal (2g) in ether (200ml) to afford a white solid after removal of solvent. Recrystallization from EtOAc/pet. ether gave 2-ethoxy-5-methyl-4H-3,1-benzoxazin-4-one (28.1g, 83%) as colorless crystals; m.p. 104°-105° C.; analysis for C11H11NO3 : C, 64.38; H, 5.40; N, 6.83. Found: C, 64.21; H, 5.43; N, 6.80.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(F)c1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1c(F)cccc1C=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of 3-fluoro-2-hydroxybenzaldehyde (5.328 g, 38.02 mmol) and potassium carbonate (7.88 g, 57.03 mmol) in acetone (60 mL) was added dimethyl sulphate (3.96 mL, 41.83 mmol). The resulting suspension was stirred at 60° C. for 2 h before being allowed to cool and then concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL) and water (50 mL). The organic phase was washed with saturated sodium bicarbonate (50 mL) with the resulting organic phase being dried (MgSO4) and the solvent evaporated in vacuo to give a pale yellow oil (6.262 g, 38.02 mmol, 100%). δH (300 MHz, CDCl3) 10.40 (1H, s, CHO), 7.60 (1H, d, Ar), 7.30 (1H), m, Ar), 7.10 (1H, m, Ar), 4.10 (3H, s, OCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2.[OH:26]O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]2)=[O:26]
Reactant: O=C1CCc2cc(OCCCCSc3cc(Cl)ccc3Cl)ccc2N1
Reactant: OO
Solvent: CC(=O)O
Product: O=C1CCc2cc(OCCCCS(=O)c3cc(Cl)ccc3Cl)ccc2N1
Temperature: 25 °C

Procedure:
A suspension of 5.55 gm (0.014 mol) of 6-[4-(2,5-dichlorophenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril in 40 ml of glacial acetic acid was admixed with 1.19 ml of an aqueous 40.06% solution of hydrogen peroxide (0.014 mol) dissolved in 1.5 ml of glacial acetic acid, and the mixture was stirred at room temperature. The suspension cleared, and an almost clear solution was obtained. After 70 hours white crystals separated out, which were suction-filtered off and recrystallized from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:21]Br>C(Cl)Cl.C(O)(=O)C>[Br:21][C:11]1[S:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:12]=1
Reactant: BrBr
Reactant: CSc1ccc(-c2sccc2-c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CSc1ccc(-c2sc(Br)cc2-c2ccc(F)cc2)cc1
Reaction time: 1.5 h

Procedure:
A solution of 3-(4-fluorophenyl)-2-(4-methylthiophenyl)thiophene (15 g, 50 mmole) in methylene chloride (150 ml) was diluted with 150 ml of acetic acid and cooled to about 5°. A 1M solution of bromine in acetic acid (55 ml, 1.1 equiv.) was then added dropwise. The reaction mixture was stirred at 0° for 1.5 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution washed with saturated aqueous sodium bicarbonate and brine, dried, and concentrated in vacuo. Recrystallization from ethanol gave the title compound (15.4 g), m.p. 113°-116°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([S:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:31][CH2:30][CH2:29][CH2:28][S:27][C:24]1[CH:25]=[CH:26][CH:21]=[CH:22][C:23]=1[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1
Reactant: CCCCSc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCSc1ccccc1-c1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
In toluene/ethanol/water (10/1/1.2 ml) was dissolved methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (730 mg), and to the solution were added 4-(butylthio)phenyl borate (780 mg) and potassium carbonate (620 mg). The mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (127 mg), and the mixture was stirred at 90° C. for 16 hours, cooled to room temperature, extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give methyl 7-[(4-butylthio)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (680 mg).
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:21])[NH:16]3)[CH:8]=[CH:9][CH:10]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[OH2:21].[C:22]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:21])[NH:16]3)[CH:8]=[CH:9][CH:10]=1)(=[O:24])[CH3:23]
Reactant: Nc1cccc(-c2nccc3[nH]c(=O)ccc23)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2nccc3[nH]c(=O)ccc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture containing 6.57 g of 5-(3-aminophenyl)-1,6-naphthyridin-2(1H)-one dihydrochloride monohydrate and 63 ml of pyridine was added dropwise over a period of 5 minutes 4.8 ml of acetic anhydride. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator to dryness. The residue was slurried with water; and, the solid was collected, washed with water and dried in a vacuum oven at 90° C. to yield 5.4 g of 5-(3-acetylaminophenyl)-1,6-naphthyridin-2(1H)-one monohydrate, m.p. 258°-262° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[CH:7]=1>C(O)(=O)C.CO.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]2[N:6]([C:8]([CH:11]([CH3:12])[CH3:13])=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(C)c1nnc2c([N+](=O)[O-])cc(Br)cn12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1nnc2c(N)cc(Br)cn12

Procedure:
Compound B was prepared by heating A, 6-bromo-3-isopropyl-8-nitro-[1,2,4]triazolo[4,3-a]pyridine, prepared as described in Example 9A, Step 1, (0.777 mmole) in acetic acid (6 mL) in the presence of Zinc dust (3.89 mmole) at 60 C for 1 hour. The reaction mixture was then diluted with methanol and filtered to celite. The filtrate was concentrated down and the residue was then filtered through silica gel with first ethyl acetate and then with 1:4 mixture of methanol and dichloromethane. The filtrate was evaporated in vacuo to yield B, 6-bromo-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-8-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][O:17][CH:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20].C(N(CC)CC)C>CC(C)=O>[CH3:16][O:17][CH:18]([CH2:22][CH3:23])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: CCC(OC)C(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCC(OC)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Temperature: 0 °C
Yield: 62.3 %

Procedure:
20.3 g (0.1 mole) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred with 18.1 g (0.12 mole) of 2-methoxybutyryl chloride and 10.1 g (0.1 mole) of triethylamine in 200 ml of absolute acetone for 3 hours at room temperature. 100 g of ice were added, the crystals were filtered off under suction and recrystallized from dimethylformamide/water, and the resulting product was dried at 50° C. under greatly reduced pressure. 18.9 g (63%) of 6-[p-(2-methoxybutyrylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained. Mp.: 151°-152° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21](OCC)=[O:22])[N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[N:27]1([CH2:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:31][CH2:30][CH2:29][CH2:28]1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]([N:38]3[CH2:37][CH2:36][N:35]([CH2:34][CH2:33][CH2:32][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)[CH2:40][CH2:39]3)=[O:22])[N:17]=2)(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CCOC(=O)c1noc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)n1
Reactant: C1CCN(CCCN2CCNCC2)C1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N3CCN(CCCN4CCCC4)CC3)no2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using ethyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,2,4-oxadiazole-3-carboxylate (27 mg, 0.07 mmol), 1-[3-(pyrrolidin-1-yl)propyl]piperazine (40 mg, 0.20 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (2 mL). A portion of the crude product was purified using prep method D.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[N:11][CH:10]=[CH:9]3)[CH:3]=[N:2]1.CS(O[CH2:21][CH2:22][C@@H:23]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C@H:23]([NH:32][C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:22][CH2:21][N:1]2[CH:5]=[C:4]([C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][CH:15]=3)[CH:12]=[N:11][CH:10]=[CH:9]4)[CH:3]=[N:2]2)=[CH:30][CH:29]=1
Reactant: c1cc2cc(-c3cn[nH]c3)ccc2cn1
Reactant: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)Cc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCn1cc(-c2ccc3cnccc3c2)cn1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.4 %

Procedure:
A mixture of 6-(1H-pyrazol-4-yl)isoquinoline (130 mg, 0.67 mmol), (S)-3-(tert-butoxycarbonylamino)-4-(4-chlorophenyl)butyl methanesulfonate (327 mg, 0.87 mmol) (prepared as shown in Scheme 15), and cesium carbonate (434 mg, 1.33 mmol) in DMF (5 mL) was stirred at room temperature for 24 hours. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (acetone/hexanes=0-40%) to provide the product as a tan solid (324 mg, 100%). LCMS (API-ES) m/z: 477 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[CH2:7](O)[CH:8]=[CH:9][CH2:10][OH:11].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:2]([CH:3]1[O:11][CH2:10][CH:9]=[CH:8][CH2:7][O:4]1)([CH3:6])([CH3:5])[CH3:1]
Reactant: OCC=CCO
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)C1OCC=CCO1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A mixture of 430 g (5 moles) of 2,2-dimethylpropanal, 3 g of p-toluenesulfonic acid and 440 g (5 moles) of but-2-ene-1,4-diol in 1000 ml of toluene was refluxed, and the water of reaction formed was removed in the course of 3 hours (h). The mixture was then left to cool to room temperature, 10 ml of a 25% strength sodium hydroxide solution were added to the solution, the mixture was washed neutral with a little water and the toluene was distilled off under reduced pressure at from 50° to 60° C. The residue obtained was distilled under 0.1 mbar to give 702 g of 2-tert-butyl-4,7-dihydro-1,3-dioxepin of boiling point 80° C./32 mbar.