Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH2:16]([N:18]([CH2:26][CH3:27])[CH:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[CH3:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:25][CH:22]1[CH2:21][CH2:20][CH:19]([N:18]([CH2:26][CH3:27])[CH2:16][CH3:17])[CH2:24][CH2:23]1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CCN(CC)C1CCC(N)CC1
Product: CCN(CC)C1CCC(Nc2c(C(C)=O)cnc3ccc(Br)cc23)CC1
Yield: 92 %

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (116 mg, 0.408 mmol) was reacted with N1,N1-diethylcyclohexane-1,4-diamine (138 mg, 0.812 mmol) to afford the desired product (157 mg, 51%) as an off-white solid: ESI MS m/z 418 [C21H28BrN3O+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]2[CH:16]([CH2:17][CH2:18][S:19][C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:15][CH2:14][CH2:13][N:12]2[CH:39]=1.[NH:40]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:41]([C:63](O)=[O:64])[CH2:42][S:43][C:44]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1>[CH3:71][C:69]([CH3:72])([O:68][C:66]([NH:40][CH:41]([CH2:42][S:43][C:44]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:63]([N:15]1[CH2:14][CH2:13][N:12]2[CH:39]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:10]=[C:11]2[CH:16]1[CH2:17][CH2:18][S:19][C:20]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:64])=[O:67])[CH3:70]
Reactant: COc1ccccc1-c1cn2c(n1)C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1ccccc1-c1cn2c(n1)C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)N(C(=O)C(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C)CC2
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of the product from Step 13.g. (compound xxi, where R2, R3, R5, R6, and R7 are H, R4 is 2-methoxyphenyl, and n is 1) (1.30 g, 2.45 mmol), Boc-(L)-Cys(Trt)-OH (1.14 g, 2.45 mmol), NMM (270 uL, 2.45 mmol), and HOAt (333 mg, 2.45 mmol) in THF (20 ml) was treated with EDC (470 mg, 2.45 mmol) at room temperature under N2. The reaction was stirred overnight and then concentrated under reduced pressure. Saturated NaHCO3 solution (25 ml) was added and the product was extracted with a 3:2 mixture of hexanes:EtOAc. The extracts were applied to a silica gel column and the product was eluted with 3:2/hexanes:EtOAc. Product fractions were combined and concentrated under reduced pressure to obtain a white foam (2.31 g, 97%) which was used without further purification. Mass spec. 977.6 MH+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[C:18]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[C:4]([O:6]C)=O.[CH3:34][Mg]Br.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[C:4]([C:3]1[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=1[O:12][C:13]1[C:18]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:6])[CH3:34]
Reactant: C[Mg]Br
Reactant: COC(=O)c1c(F)cccc1Oc1ncccc1NC(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1c(F)cccc1Oc1ncccc1NC(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 18 h
Yield: 8.2 %

Procedure:
Methyl 2-fluoro-6-(3-(3-(4-(trifluoromethoxy)phenyl)ureido)pyridin-2-yloxy)benzoate (250 mg, 0.54 mmol) was diluted in THF (10 mL) and cooled to −78° C. Methylmagnesiumbromide (3.0 M in Et2O, 1.07 mL, 3.22 mmol) was added and mixture was warmed to rt and stirred for 18 h. Sodium sulfate decahydrate was added and stirring was continued for 30 min. The solution was filtered over a pad of Celite® and washed using ethyl acetate. The organic phase was evaporated and crude material was purified using preparative HPLC to yield the desired material (20 mg) (M+H)+=450. 1H NMR (400 MHz, Acetone) δ ppm 2.33-2.40 (m, J=1.77 Hz, 3H), 7.07-7.18 (m, 3H), 7.27 (d, J=8.84 Hz, 2H), 7.56 (td, J=8.34, 6.57 Hz, 1H), 7.63-7.70 (m, 3H), 8.20 (s, 1H), 8.67 (dd, J=7.96, 1.64 Hz, 1H), 8.91 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[I-].[K+].CC(C)=O>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)c(O)c1
Yield: 39.4 %

Procedure:
A mixture of 5.52 g (40 mmol) of 3,4-dihydroxybenzaldehyde, 6.09 g (44 mmol) of potassium carbonate, 70 mg of potassium iodide, 110 ml of acetone and 6.84 g (40 mmol) of benzyl bromide was refluxed for 15 hours. Thereafter, the mixture was cooled, the reaction suspension was filtered and the filtrate was evaporated down. Chromatography of the residue over silica gel using 9:1 toluene/ethyl acetate gave 3.6 g of 4-benzyloxy-3-hydroxybenzaldehyde.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O.Cl[C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH:17]=[O:18].[CH3:26][S:27]([C:30]1[N:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>O>[CH3:26][S:27]([C:30]1[N:35]=[CH:34][C:33]([O:36][C:15]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=2[CH:17]=[O:18])=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(O)cn1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C=O)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cesium carbonate (10 g) was added to an N-methylpyrrolidinone (70 ml) solution of 2-chloro-5-nitrobenzaldehyde (5.0 g) and 6-(methylsulfonyl)-3-pyridinol (5 g) obtained in Reference Example 2, and stirred at room temperature for 3 hours. Water was added, then the formed crystal was collected by filtration to obtain the entitled compound as a pale brown solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=O)[CH:13]([CH3:18])[CH2:14][C:15](O)=[O:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:21][NH2:22]>O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]([CH3:18])[CH2:14][C:15](=[O:16])[NH:21][N:22]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(-n2ccnc2)cc1
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccnc2)cc1

Procedure:
4-[4-(1-Imidazolyl)phenyl]-3-methyl-4-oxobutyric acid (75.7 g) was suspended in 145 m of water. After the addition of 17 ml of hydrazine hydrate, the reaction mixture was stirred at reflux temperature for 2 hours. After cooling, the precipitated solid was collected by filtration, washed with water, and dried.
Reaction SMILES: [OH:1][CH:2]([C:7]1[C:8]([CH3:26])=[N:9][C:10]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[N:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4].C(O[C:31]([CH3:34])([CH3:33])[CH3:32])(=O)C.Cl(O)(=O)(=O)=O>>[C:31]([O:1][CH:2]([C:7]1[C:8]([CH3:26])=[N:9][C:10]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[N:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)C(O)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.3 %

Procedure:
To a solution of methyl 2-hydroxy-2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)acetate (0.135 g; 0.380 mmol) in tert-butyl acetate (1.5 mL; 11.23 mmol) under nitrogen atmosphere was added perchloric acid 70% (0.049 mL; 0.570 mmol) and the reaction was stirred at room temperature for 2 days. The reaction was quenched by adding a saturated solution of sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulphate, filtered a,d concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (1-40%) in heptane furnished 0.063 g (40%) of the title compound as a colorless oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[C:11]([C:15]([OH:17])=[O:16])[NH:12]2)=[CH:8][CH:7]=1>C(OC(=O)C)(=O)C>[Cl:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([N+:1]([O-:4])=[O:2])=[C:11]([C:15]([OH:17])=[O:16])[NH:12]2)=[CH:8][CH:7]=1
Reactant: O=C(O)c1cc2ccc(Cl)cc2[nH]1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1[nH]c2cc(Cl)ccc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To an ice-cooled soluton of acetic anhydride (90 ml) and concentrated nitric acid (70%, 10.3 ml) was added 6-chloroindole-2-carboxylic acid (H. W. Ridon and J. C. Tweddle, J. Chem.Soc., 1955, 3499: 18.16 g, 92.84 mmol) portion wise over 20 min. The mixture was stirred for 2 h at 0° C. and the resulting precipitates collected by filtration and washed with a mixture of dichloromethane/hexane (1:1) to give 12.6 g (56%) of the title compound as a yellow solid. 1H-NMR (DMSO-d6) δ: 13.41(1H, br s), 8.04 (1H, d, J=8.8 Hz), 7.62 (1H, d, 1.8 Hz), 7.44 (1H, dd, J=1.8, 8.8 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][CH:22]=[C:23]([CH2:26]Cl)[C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.[Na]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][CH:22]=[C:23]([CH2:26][N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[C:24]=2[Cl:25])=[O:19])=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(Cn2ccnc2)c1Cl

Procedure:
In a manner similar to that described in Paragraph A above, N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.30 g, 0.64 mmol) reacted with sodium imidazole (0.17 g, 1.9 mmol) in DMF (10 mL) to afford N-(4-chlorophenyl)-2-[((3-chloro-4-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide. Purification by HPLC on a C18 Dynamax column with acetonitrile in water gradient with 0.1% trifluoroacetic acid afforded two products: The earlier eluting material afforded N-(4-chlorophenyl)-2-[((3-chloro-4-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, trifluoroacetic acid salt as a cream-colored solid; NMR (DMSO-d6/TFA) 11.1 (s, 1), 10.8 (s, 1), 9.2 (s, 1), 8.3 (d, 1), 8.1 (s, 1), 7.9 (d, 1), 7.7 (m, 5), 7.4 (d, 2), 5.4 (s, 2) ppm. The later eluting material afforded N-(4-chlorophenyl)-2-[((3-chloro-4-(hydroxymethyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a white solid; NMR (DMSO-d6/TFA) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 5.4 (br, 1), 4.4 (s, 2) ppm.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O[C:8]1[C:11](=O)[C:10](=[O:13])[C:9]=1[OH:14].C(N(CC)CC)C.Br.[Br:23][CH2:24][CH2:25][CH2:26][NH2:27].CO>C1(C)C=CC=CC=1>[CH3:3][C:2]([CH3:5])([CH3:4])[CH2:1][O:6][C:11]1[C:10](=[O:13])[C:9](=[O:14])[C:8]=1[NH:27][CH2:26][CH2:25][CH2:24][Br:23]
Reactant: NCCCBr
Reactant: CC(C)(C)CO
Reactant: O=c1c(O)c(O)c1=O
Agent: Br
Solvent: CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)COc1c(NCCCBr)c(=O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of neopentyl alcohol (600 g, 6.82 moles) and toluene (1200 mL) was refluxed in suspension with 1,2-dihydroxy-1-cyclobutene-3,4-dione (230 g, 2.02 moles). Water was collected from the stirred mixture with a Dean-Stark separator. After water collection had stopped (ca. 11.5 hours) a clear, orange, homogeneous solution resulted. Reflux was continued and toluene (700 mL) was collected over an additional 1.5 hours. The solution was removed from reflux at this point and cooled to room temperature. Triethylamine (255 g, 2.50 moles) was added in a single portion to the stirred, room temperature solution. To this was added over 0.5 hour, a solution of bromopropylamine hydrobromide in absolute methanol (438 g, 2.0 moles of amine salt in 600 mL methanol). After addition was complete, the solution was stirred for an additional 0.5 hour. The mixture was concentrated at reduced pressure (45° C.) to a total volume of about 1500 mL. Water (2000 mL) was added and the solution was again concentrated at reduced pressure until about 1500 mL of distillate had been removed. The thick solution was filtered to isolate a white solid. The solid was recrystallized from 800 mL of warm isopropanol with gradual cooling to room temperature and -5° C. The product was collected by filtration, washed with two separate 500 mL portions of 1:1 hexane:isopropanol and dried at 45° C., aspirator pressure to a constant weight. The title compound was obtained as a white to very pale yellow powder, m.p. 111°-113° C., yield 528.4 g (86%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][C:11]([F:16])([F:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:17]>>[Cl-:17].[F:15][C:11]1([F:16])[CH2:12][CH2:13][CH2:14][NH2+:8][CH2:9][CH2:10]1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(F)(F)CC1
Product: FC1(F)CCC[NH2+]CC1
Product: [Cl-]
Reaction time: 8 h

Procedure:
To 830 mg (3.53 mmol) of 4,4-Difluoro-perhydro-azepine-1-carboxylic acid tert-butyl ester was added 5 mL of 2 M aq. HCl and stirring was continued overnight at room temperature. The reaction mixture was freeze dried and used for the next step without further purification
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[O:11][CH2:10][CH:9]1[C:16](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:34][C:35]1[CH:39]=[C:38]([Br:40])[S:37][C:36]=1[C:41]([NH2:43])=[O:42]>O1CCCC1.O>[Br:40][C:38]1[S:37][C:36]2[C:41](=[O:42])[NH:43][C:16]([CH:9]3[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:12]([CH3:14])([CH3:15])[O:11][CH2:10]3)=[N:34][C:35]=2[CH:39]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OCC1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C)(C)OCC1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 60 °C
Yield: 55.2 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-6,6-dimethylmorpholine-3-carboxylic acid (1.00 g) and triethylamine (1.08 mL) in tetrahydrofuran (20 mL) was added, while stirring under ice-cooling, 2-methylpropyl chlorocarbonate (0.50 mL). After stirring at room temperature for 30 min, a solution of 3-amino-5-bromothiophene-2-carboxamide (568 mg) produced in Example 1, step D, in tetrahydrofuran (3 mL) was added. The reaction system was stirred with heating at 60° C. for 3 hr. Water was poured into the reaction system, and the mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue were added 2M aqueous sodium hydroxide solution (7.7 mL) and ethanol (20 mL), and the mixture was stirred with heating at 80° C. for 5 hr. Brine was poured into the reaction system, the mixture was extracted with 3:1 ethyl acetate/tetrahydrofuran mixture, and the extract was washed with brine, and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate) to give the title compound (630 mg) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH3:27]S(O)(=O)=O>C(Cl)Cl>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:27])=[O:23])[CH2:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)O
Reactant: O=C(O)C1CC=C(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CC=C(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Yield: 71 %

Procedure:
A solution of 70.0 g (0.22 mol) of 4-(2-phenyl-1H-indol-3-yl)-3-cyclohexene-1-carboxylic acid (Example 1), 35.2 g (1.1 mol) of methanol, 350 mL of methylene dichloride, and 0.5 mL of methanesulfonic acid was heated under reflux for 21 h. The reaction mixture was cooled, washed with water, dried over sodium sulfate, concentrated in vacuo, and crystallized from ethyl acetate:hexane to give 51.8 g (71%) of methyl 4-(2-phenyl-1H-indol-3-yl)-3-cyclohexene-1-carboxylate in two crops: m.p. 175°-177° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH2:32]([NH2:35])[CH2:33][NH2:34]>C1COCC1.C(OC(C)=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:34][CH2:33][CH2:32][NH2:35])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NCCN
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 89.6 %

Procedure:
The title compound of Example 48 [8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one] (0.89 g, 0.002 mol) in dry THF, stirring at 23°, under Ar, was treated with ethylenediamine (668 uL, 0.01 mol). The color became orange. LC MS showed no starting material after 5 min. Reaction was stripped to dryness; the residue taken up in EtOAc-H2O. The layers were separated and the aq phase adjusted to pH 10.5 with 10% NaOH. Aq phase was extracted twice with EtOAc; combined organic layers were dried (Na2SO4), then evaporated to give 0.762 g (89%) of the title compound as a glass. LC MS (m/e)=426 (MH+). Rt=1.52 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[C:11]([F:27])[CH:10]=1)#[N:2].[CH3:28][C:29]1[NH:30][C:31]([NH:34][CH:35]2[CH2:40][CH2:39][S:38][CH2:37][CH2:36]2)=[N:32][N:33]=1>>[F:27][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:17](=[O:18])[N:34]([CH:35]2[CH2:36][CH2:37][S:38][CH2:39][CH2:40]2)[C:31]2[N:32]([N:33]=[C:29]([CH3:28])[N:30]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: Cc1nnc(NC2CCSCC2)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCSCC2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 53.4 %

Procedure:
A mixture of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (1.5 g) and 5-methyl-N-(tetrahydro-2H-thiopyran-4-yl)-4H-1,2,4-triazol-3-amine (0.4 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.54 g, 27%).
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18](C1C(OC)=CC=C2C=1C=CN2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]
Reactant: COc1c(Br)ccc2cc[nH]c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1c(OC)ccc2[nH]ccc12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2cc[nH]c2c1OC

Procedure:
3-(7-Methoxy-1H-indol-6-yl)-3-phenyl-acrylic acid ethyl ester CXXXVIII was prepared from 6-bromo-7-methoxy-1H-indole using the procedure described above for preparation of 3-(5-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester XLVIII (Example 12).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH3:14][CH:15]([CH3:17])[O-:16].[Na+].[Na]>C(O)(C)C>[CH:15]([O:16][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1)([CH3:17])[CH3:14]
Reactant: CC(C)[O-]
Reactant: Clc1ccc(N2CCNCC2)nn1
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)Oc1ccc(N2CCNCC2)nn1

Procedure:
3-Chloro-6-piperazinopyridazine (4.0 g) [J. Med. Chem., 5, 541 (1963)] and sodium isopropoxide, prepared by addition of sodium (0.7 g) to dry isopropanol (70 ml), were heated in a bomb at 130°-140° C. for 10 hours. The solvent was evaporated in vacuo, the residue taken up in methylene chloride (300 ml) and the resulting solution washed with water (2×50 ml). The organic extract was dried (Na2SO4) and evaporated in vacuo to give 3-isopropoxy-6-piperazinopyridazine (3.3 g). A sample in ethyl acetate, was converted to the maleate salt by treatment with maleic acid in ethyl acetate. The resulting solid was re-crystallized from ethanol, m.p. 144°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:17])(=[O:16])[NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:19](Cl)=[O:20]>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:17])(=[O:16])[NH:12][CH:13]2[CH2:14][CH2:15]2)=[CH:7][C:3]=1[C:4]([N:6]=[C:19]=[O:20])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Yield: 91.4 %

Procedure:
To a solution of 2-chloro-5-(N-cyclopropylsulfamoyl)benzamide (1.50 g, 5.46 mmol) in EDC (20 mL) was added oxalyl chloride (0.59 mL, 6.55 mmol). The reaction mass was refluxed for 1-2 h. Excess of solvent was removed under vacuum to afford 1.5 g of desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=4)[CH:20]=3)[CH2:14][CH2:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:49]2[CH:56]=[CH:55][CH:54]=[CH:53][C:50]=2[CH2:51][Cl:52])[CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46]>>[ClH:52].[ClH:52].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=4)[CH:20]=3)[CH2:16][CH2:17]2)[CH2:51][C:50]2[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=2[C:41]2[CH:42]=[C:43]([O:47][CH3:48])[C:44]([O:45][CH3:46])=[C:39]([O:38][CH3:37])[CH:40]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(-c2ccccc2CCl)cc(OC)c1OC
Reactant: COc1cc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc(OC)c1
Product: COc1cc(OC)cc(N(Cc2ccccc2-c2cc(OC)c(OC)c(OC)c2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)c1
Product: Cl

Procedure:
4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 2-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. A free base obtained was converted to a dihydrochloroide to give the title compound as yellow powder.