Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[Cl:12][C:13]1[C:18]2[O:19][C:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][C:21]=3[C:17]=2[CH:16]=[C:15](Br)[CH:14]=1>>[Cl:12][C:13]1[C:18]2[O:19][C:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][C:21]=3[C:17]=2[CH:16]=[C:15]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:14]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccc(Cl)cc4)cc3c2C1
Yield: 48 %

Procedure:
Sodium 4-chlorobenzenesulfinate was coupled with the product of Example 44, step B following the procedure of Example 29, step C. The crude product was purified by flash column chromatography (SiO2, 3:2 hexanes/ethyl acetate) to give tert-butyl 6-chloro-8-(4-chlorophenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (120 mg, 48%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 7.95 (s, 1H), 7.90-7.89 (m, 1H), 7.88-7.87 (m, 1H), 7.82-7.81 (m, 1H), 7.51-7.50 (m, 1H), 7.48-7.47 (m, 1H), 4.56 (s, 2H), 3.84 (t, J=5.4 Hz, 2H), 2.91 (t, J=5.4 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: C(N1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:25])[C:15]4=[CH:14][C:13]=3[CH:12]=2)CC1)(C)C.Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.[H-].[Na+]>>[CH2:7]([O:10][C:11]1[CH:19]=[CH:18][C:17]2[N:16]3[CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:24](=[O:25])[C:15]3=[CH:14][C:13]=2[CH:12]=1)[C:8]1[CH:9]=[CH:13][CH:12]=[CH:11][CH:19]=1
Reactant: BrCC1CC1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: O=C1c2cc3cc(OCc4ccccc4)ccc3n2CCCN1CC1CC1

Procedure:
The title compound was synthesized in analogy to example 17, from 9-benzyloxy-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (example 15, intermediate b)), 1-(bromomethyl)cyclopropane and sodium hydride, to give the compound as a white solid (76%).
Reaction SMILES: [ClH:1].Cl.FC1C=CC(C2C=NC(N3CCNCC3)=NC=2)=CC=1.C(OC([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[N:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=3)=[CH:37][N:36]=2)[CH2:31][CH2:30]1)=O)(C)(C)C>>[ClH:47].[ClH:1].[Cl:48][C:43]1[CH:42]=[C:41]([C:38]2[CH:37]=[N:36][C:35]([N:32]3[CH2:31][CH2:30][NH:29][CH2:34][CH2:33]3)=[N:40][CH:39]=2)[CH:46]=[CH:45][C:44]=1[Cl:47]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1
Agent: Cl
Agent: Fc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Product: Clc1ccc(-c2cnc(N3CCNCC3)nc2)cc1Cl
Yield: 90 %

Procedure:
Prepared according to the method for the preparation of 5-(4-fluorophenyl)-2-piperazin-1-ylpyrimidine dihydrochloride, from 4-[5-(3,4-dichlorophenyl)-pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (0.93 g), to furnish the title compound as an off-white solid (0.78 g, 90%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.N1C=CC=CC=1.Cl[C:49]([O:51][C:52]1[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=1)=[O:50]>ClCCl>[C:49](=[O:50])([O:51][C:52]1[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=1)[O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C@H:16]([NH:25][C:26]([O:27][C@@H:28]2[C@H:35]3[C@H:31]([O:32][CH2:33][CH2:34]3)[O:30][CH2:29]2)=[O:36])[C@H:15]([OH:37])[CH2:14][N:13]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:38][CH:39]([CH3:41])[CH3:40])=[CH:19][CH:20]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (0.5 g, 0.84 mmol) in dichloromethane (4 mL) at 0° C. was added pyridine (0.16 mL, 0.158 g, 2.0 mmol) and 4-nitrophenyl chloroformate (0.22 g, 1.09 mmol) and the mixture was stirred at ambient temperature for 1 h. Dichloromethane was added and the mixture was washed with 15% citric acid/water (2×), saturated sodium bicarbonate/water, dried (sodium sulfate), evaporated, and purified by chromatography (silica gel, dichloromethane/methanol, 49:1) to provide the title compound as a solid foam (0.5 g, 79% yield). 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.16 (1H, dd), 1.3-1.4 (1H, m), 1.9-2.0 (1H, m), 2.42 (1H, t), 2.65-2.80 (3H, m), 3.0 (2H, dd), 3.3-3.4 (1H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.8 (1H, dt), 5.1 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 7.05 (1H, d), 7.2-7.4 (7H, m), 7.7 (2H, d), 8.35 (2H, d)
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.I[C:14]1[CH:15]=[C:16]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH:17]=[CH:18][C:19]=1[CH3:20]>>[CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[C:12][C:14]3[CH:15]=[C:16]([C:21]4[NH:25][C:24]5[CH:26]=[C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]6)[CH:28]=[CH:29][C:23]=5[N:22]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Reactant: C#Cc1ccc(NC2CC2)nn1
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1ccc(NC2CC2)nn1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole (as prepared in Example 1) in a manner similar to that described for in Example 1. The intermediate compound N-cyclopropyl-6-ethynylpyridazin-3-amine was made as for Example 1 (Step 1 to 3) with the spectra below: 1H NMR (300 MHz, CDCl3) δ: 7.38-7.41 (1H, d, J=9.0 Hz), 6.96-6.99 (1H, d, J=9.0 Hz), 5.99 (1H, s), 3.25-3.27 (1H, m), 2.57 (1H, s), 0.87-0.89 (2H, s), 0.61-0.63 (2H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:5])=[O:4].C[Al](C)C.[Cl:10][C:11]1[CH:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]([C:29]2[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[C:31]([Cl:37])[CH:30]=2)[C:25]([F:28])([F:27])[F:26])[CH:19]=[CH:18][C:12]=1[C:13](OCC)=[O:14]>C(Cl)Cl>[Cl:10][C:11]1[CH:21]=[C:20](/[CH:22]=[CH:23]/[CH:24]([C:29]2[CH:30]=[C:31]([Cl:37])[C:32]([Cl:36])=[C:33]([Cl:35])[CH:34]=2)[C:25]([F:26])([F:27])[F:28])[CH:19]=[CH:18][C:12]=1[C:13]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:14]
Reactant: NCC(N)=O
Reactant: CCOC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl)NCC(F)(F)F
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a stirred solution of glycine amide (0.15 g, 0.58 mmol) in CH2Cl2 (5 mL) was added trimethylaluminum (2 M solution in toluene; 1.45 mL, 2.91 mmol) dropwise, and the reaction mixture was stirred at 28° C. for 30 min A solution of (E)-ethyl 2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoate (0.3 g, 0.58 mmol) in CH2Cl2 (5 mL) was added drop wise to the reaction mixture at 28° C. The reaction mixture was stirred at reflux for 18 h, cooled to 25° C., quenched with 1N HCl solution (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 40% EtOAc in n-hexane) to afford the title compound as yellow solid (0.15 g, 50%): mp 83-85° C.; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 2H), 7.36 (d, J=6.8 Hz, 1H), 7.05 (t, J=5.2 Hz, 1H), 6.70 (t, J=5.2 Hz, 1H), 6.57 (d, J=15.6 Hz, 1H), 6.44 (dd, J=15.6, 8.0 Hz, 1H), 4.23 (d, J=5.6 Hz, 2H), 4.15 (m, 1H), 4.01 (m, 2H); ESIMS m/z 580.72 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]Cl)[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:11][S:12]([O-:14])=[O:13].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][S:12]([CH3:11])(=[O:14])=[O:13])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: ClCc1cc(Br)cnc1Cl
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Cc1cc(Br)cnc1Cl
Temperature: 110 °C
Yield: 94.2 %

Procedure:
A mixture of 5-bromo-2-chloro-3-(chloromethyl)pyridine (124 mg, 0.52 mmol) and sodium methanesulfinate (52 mg, 0.52 mmol) in dioxane (1.4 mL) and water (1.4 mL) was heated to 110° C. in a microwave reactor for 15 min. After cooling to rt, water was added to the reaction mixture which was subsequently extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 5-bromo-2-chloro-3-(methylsulfonylmethyl)pyridine (140 mg, 0.49 mmol, 94% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, 1H), 8.21 (d, 1H), 4.70 (s, 2H), 3.10 (s, 3H); MS (EI) for C7H7BrClNO2S: 284, 286, 288 (Br+Cl isotopes, MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[N:8]=[C:9]2[C:14](=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)[CH:13]=[CH:12][CH:11]=[CH:10]2)=[O:4].[NH:21]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:13]1[C:14]2[C:9](=[N:8][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:21]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)[CH:10]=[CH:11][CH:12]=1
Reactant: C1CNCCNCCNCCN1
Reactant: O=C(CCl)NCc1nc2ccccc2c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CN1CCNCCNCCNCC1)NCc1nc2ccccc2c2ccccc12
Temperature: 25 °C
Yield: 47.1 %

Procedure:
A solution of the chloro 9 (20.0 mg, 70.2 μmol) in anhydrous CHCl3 (5 mL) was added to a solution of cyclen (48.4 mg, 0.281 mmol) and triethylamine (11.7 μL, 84.2 μmol) in anhydrous CHCl3 (15 mL) under N2 (g). The reaction mixture was heated to reflux under N2 (g) for 23 hours. The reaction mixture was then allowed to cool to room temperature and washed with NaOH (aq) (1.0 M, 3×5 mL) and H2O (3×5 mL). The organic phase was dried over MgSO4, and concentrated under reduced pressure yielding product 10 as a colorless oil (13.9 mg, 47.1%). This procedure follows closely that developed by Gunnlaugsson and coworkers. (Massue et al. Tetrahedron Lett., 2007, 48, 8052-8055).
Reaction SMILES: [Cl:1][C:2](=[C:8]([Cl:10])[Cl:9])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]=1[NH:20][C:21](=[O:24])[O:22][CH3:23]>O1CCCC1.N12CCN(CC1)CC2>[Cl:1][C:2](=[C:8]([Cl:10])[Cl:9])[C:3]([NH:5][C:6]([N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[NH:20][C:21](=[O:24])[O:22][CH3:23])=[O:7])=[O:4]
Reactant: O=C=NC(=O)C(Cl)=C(Cl)Cl
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: COC(=O)Nc1nc2ccccc2n1C(=O)NC(=O)C(Cl)=C(Cl)Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.9 %

Procedure:
13.5 g of trichloroacryloyl-isocyanate were added dropwise to 10 g of methyl 2-benzimidazolyl-carbamate and 0.1 g of 1,4-diazabicyclo (2,2,2) octane in 160 ml of tetrahydrofuran and the mixture was stirred for 17 hours at room temperature and was vacuum filtered. The crystals obtained were washed with petroleum ether and dried under reduced pressure to obtain 18.2 g of methyl 1-trichloroacryloylcarbamoyl-2-benzimidazolyl-carbamate as a solid melting at 231°C.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[Cl:23])[C:10](=[O:11])[C:5]2=[N:4][N:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:23][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:9]1[CH2:8][CH2:7][N:6]2[C:2]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)=[N:3][N:4]=[C:5]2[C:10]1=[O:11]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1c2nnc(Br)n2CCN1Cc1cccc(C(F)(F)F)c1Cl
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: [Na+]
Solvent: C1COCCO1
Product: O=C1c2nnc(-c3ccc(F)cc3)n2CCN1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 100 °C
Yield: 46.1 %

Procedure:
To a solution of 3-bromo-7-(2-chloro-3-(trifluoromethyl)benzyl)-6,7-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8(5H)-one (100 mg, 0.24 mmol) and 4-fluorophenylboronic acid (40 mg, 0.27 mmol) in dioxane (0.6 mL) was added 1M Na2CO3 (0.6 mL). The flask was purged with nitrogen for 10 minutes and Pd(PPh3)4 (14 mg, 0.012 mmol) was added at once. The flask was purged with nitrogen for an additional 5 minutes and then heated at 100° C. for 18 h. After cooling to rt, brine was added, and the mixture was extracted with EtOAc (×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to give a brown solid. Purification by chromatography (SiO2; hexanes—100% EtOAc) afforded the desired product as a white solid (47 mg, 45%). MS (ESI): mass calcd. for C19H13ClF4N4O, 424.1; m/z found, 425.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 7.91-7.73 (m, 4H), 7.59-7.54 (m, 1H), 7.49-7.43 (m, 2H), 4.89 (s, 2H), 4.56-4.42 (m, 2H), 3.92-3.84 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6].Cl[C:14]1[N:23]=[C:22]([NH2:24])[C:21]2[C:16](=[CH:17][C:18]([O:27][CH3:28])=[C:19]([O:25][CH3:26])[CH:20]=2)[N:15]=1>>[NH2:24][C:22]1[C:21]2[C:16](=[CH:17][C:18]([O:27][CH3:28])=[C:19]([O:25][CH3:26])[CH:20]=2)[N:15]=[C:14]([N:10]2[CH2:9][CH2:8][N:7]([C:5](=[O:6])[CH2:4][CH2:3][O:2][CH3:1])[CH2:12][CH2:11]2)[N:23]=1
Reactant: COCCC(=O)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Product: COCCC(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 1-(3-methoxypropionyl) piperazine (6.4 g) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (8.9 g) in 100 ml of isoamylalchohol is refluxed with stirring for 6 hours. The reaction mixture is cooled at room temperature for 12 hours. The crystallized product is separated and wet recrystallized by dissolving in warm methanol, with the subsequent addition of ether to the beginning of turbidity. The yield is 13.4 g of the title compound in the form of a hydrochloride monohydrate, which melts at 268°-272° C. with decomposition. Another crystallization from a methanol-ether mixture yields the analytically pure product melting at 273°-278° C. with decomposition.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][Si:33]([C:36]#[CH:37])([CH3:35])[CH3:34]>C(#N)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([C:37]#[C:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[CH:11]=3)[C:6](=[O:24])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(Br)ccc2c1=O
Reactant: C#C[Si](C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(C#C[Si](C)(C)C)ccc2c1=O
Temperature: 0 °C

Procedure:
To a solution of 25.4 g ethyl 7-bromo-1,4-dihydro-1-(4-fluorophenyl)-4-oxo-3-quinolinecarboxylate in 975 ml acetonitrile at 40°-50° C. was added 1.4 g cuprous iodide and 325 ml triethylamine. The air in the reaction was replaced by argon, and 1.4 g bis-triphenylphosphine palladium dichloride and 15.5 ml trimethylsilylacetylene were added. The reaction mixture was heated at reflux for one hour, then chilled to 0° C, and the product was collected to give 23.4 g ethyl 1,4-dihydro-1-(4-fluoro- phenyl)-4-oxo-7-(trimethylsilylethynyl)-3-quinolinecarboxylate. A sample of the compound was further purified by recrystallization from DMF to give a colorless solid, m.p. 247°-249° C. The corresponding carboxylic acid, obtained by hydrolysis of the ester with ethanolic hydrogen chloride, was obtained as a light-tan powder, m.p. 289° C. (decompn.).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][C:5](OC2C=CC([N+]([O-])=O)=CC=2)=[N:4][S:3]1(=[O:21])=[O:20].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([NH2:32])[CH3:31]>ClCCl.C(N(CC)C(C)C)(C)C>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([NH:32][C:5]1[O:6][C:7]([CH3:8])([CH3:9])[C:2]([CH3:1])([CH3:22])[S:3](=[O:20])(=[O:21])[N:4]=1)[CH3:31]
Reactant: CC1(C)OC(Oc2ccc([N+](=O)[O-])cc2)=NS(=O)(=O)C1(C)C
Reactant: C[C@H](N)c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC1=NS(=O)(=O)C(C)(C)C(C)(C)O1)c1ccccc1F
Yield: 97 %

Procedure:
200 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 111 mg of (S)-1-(2-fluorophenyl)ethylamine were dissolved in 1 ml of dichloromethane and 0.10 ml of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction solution was diluted with 50 ml of dichloromethane, washed three times with 30 ml of 10% aqueous ammonia solution, three times with 30 ml of 1 N aqueous hydrochloric acid and with 30 ml of saturated aqueous sodium hydrogencarbonate solution, dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (194 mg) with a molecular weight of 328.4 g/mol (C15H21FN2O3S); MS (ESI): m/e=329 (M+H+).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C@@:8]12[C:24](=O)[CH2:23][CH2:22][C@H:21]1[C@H:20]1[C@@H:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=3[CH2:18][CH2:19]1)[CH2:10][CH2:9]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH2:1]=[C:24]1[CH2:23][CH2:22][C@H:9]2[C@H:10]3[C@H:11]([CH2:20][CH2:21][C@:8]12[CH3:7])[C:12]1[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=1[CH2:18][CH2:19]3
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (100.03 g, 0.28001 mol) and potassium t-butoxide (31.42 g, 0.2800 mol) in anh. dimethylsulfoxide (DMSO, 320 mL) under argon was stirred in an oil bath (68°-81° C.) 1 h, after which estrone (15.14 g, 55.99 mmol) in anh. DMSO (320 mL) was added via syringe. See FIG. 17. Stirring was continued 1 h and the reaction allowed to cool. The mixture was poured into 800 mL of ice-1N hydrochloric acid and then extracted three times with 400 mL aliquots of ether. The combined organic extracts were washed with 350 mL of saturated sodium bicarbonate+400 mL of brine, dried over sodium sulfate, and flash filtered through a 58 mm high×84 mm dia. column of silica gel (200-40 mesh). Product continued eluting with additional ether. Concentration of appropriate fractions under reduced pressure and three-fold recrystallization from aqueous ethanol gave very fine white needles (11.47 g, 42.73 mmol, 76%), m.p. 134°-136° C., homogeneous to TLC (20% ethyl acetate/hexanes on silica gel, Rf 0.45). (NA-1994A-242B)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)(=[O:28])=[O:27])=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cc(N)ccc2Br)CC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: CN1CCN(c2cc(NS(=O)(=O)c3ccc4ccccc4c3)ccc2Br)CC1

Procedure:
The title compound (E120) was prepared from 4-bromo-3-(4-methylpiperazin-1-yl)benzenamine (EP 0533267A, intermediate 61) (600 mg, 2.23 mmol) and naphthalene-2-sulfonyl chloride (504 mg, 2.23 mmol) using the method of Example 1 (939 mg, 92%) MH+=460/462.
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:15][N:16]=1)=[CH:8]2.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][C:18]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:20])=[CH:15][N:16]=1)=[CH:8]2)[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:23]
Reactant: C1COCCN1
Reactant: CN(c1cccc2cc(-c3ncc(CC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(-c3ncc(CC(=O)N4CCOCC4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a mixture of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)acetic acid (0.38 g), morpholine (0.16 g), 1H-1,2,3-benzotriazol-1-ol (0.18 g) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide-hydrochloride (0.26 g) at 0° C., and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. A solution of the obtained crystals in tetrahydrofuran was treated with activated carbon and concentrated to give the title compound (0.37 g, yield 83%) as colorless crystals. The crystals were recrystallized from ethyl acetate. melting point 199-200° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:13](=[O:16])[N:12]4[N:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=[C:11]4[NH:10][C:9]=3[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH2:34]([O:33][C:31]([CH2:30][CH2:29][CH2:28][N:10]1[C:9]2[C:8](=[O:26])[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:15][C:14]=2[C:13](=[O:16])[N:12]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=[C:11]12)=[O:32])[CH3:35]
Reactant: O=C1c2[nH]c3cc(-c4ccccc4)nn3c(=O)c2CN1C1CCCCC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCCn1c2c(c(=O)n3nc(-c4ccccc4)cc13)CN(C1CCCCC1)C2=O
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of 100 g (2.87) mmole) of 6-cyclohexyl-4,7-dihydro-2-phenyl-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-dione (see preparation 1), 0.82 ml. (5.7 mmoles), of ethyl 4-bromobutyrate and 0.41 g., 3.0 mmole of potassium carbonate in 11 ml. of -dimethyl-sulfoxide (DMSO) was stirred at 50° C. for 16.5 hours. Then 35 ml. of water was added and the mixture was suction filtered. The collected solid was washed with more water and air dried. The crude solid was recrystallized from 95% ethanol (100 ml), reflux cooled to room temperature, affording 1.11 g (84% yield) of the titled compound as very fine white needles, m.p. 195°-196° C. 1H NMR (CDCl3, δ) 8.06 (d, 2H, phenyl-H (ortho), 7.45 (m, 3H, phenyl-H), 6.70 (s, 1H, pyrazole-H, 4.74 (t, 2H, J=Hz, 4-NCH 2), 4.37 (s, 2H, lactam CH2), 4.16 (q, 2H, J=7 Hz, OCH2), 4.15 (m, 1H, 6-NCH), 2.49 (t, 2H, CH2CO2C2H5), 2.23 (m, 2H, CH2), 1.15-1.95 (m, 10H, cyclohexyl CH2), 1.26 (t, 3H, J"7 Hz, CH3.