Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:21])[C:12]3[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=3[F:20])[C:6]=2[CH:5]=[CH:4][N:3]1[CH2:22][C:23]1[NH:27][C:26]2[CH:28]=[CH:29][C:30]([C:32](O)=[O:33])=[CH:31][C:25]=2[N:24]=1.[CH3:35][NH2:36].C(O)C>>[CH3:35][NH:36][C:32]([C:30]1[CH:29]=[CH:28][C:26]2[NH:27][C:23]([CH2:22][N:3]3[CH:4]=[CH:5][C:6]4[C:10]([C:11](=[O:21])[C:12]5[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=5[F:20])=[CH:9][NH:8][C:7]=4[C:2]3=[O:1])=[N:24][C:25]=2[CH:31]=1)=[O:33]
Reactant: CN
Reactant: O=C(O)c1ccc2[nH]c(Cn3ccc4c(C(=O)c5c(F)cc(F)cc5F)c[nH]c4c3=O)nc2c1
Solvent: CCO
Product: CNC(=O)c1ccc2[nH]c(Cn3ccc4c(C(=O)c5c(F)cc(F)cc5F)c[nH]c4c3=O)nc2c1

Procedure:
Following the procedure for example 24, the product obtained in Example 26 was treated with methylamine/ethanol instead of ethylamine to give the titled compound. LC/MS: m/z 480(M+H). 1H-NMR (500 MHz, d6-DMSO). δ 2.78 (d, 3H), 5.55 (s, 2H), 7.04 (d, 1H), 7.35 (t, 2H), 7.58-7.62 (m, 2H), 7.75 (dd, 1H), 7.92 (d, 1H), 8.04 (s, 1H), 8.44 (d, 1H), 13.1 (d, 1H).
Reaction SMILES: Cl[CH:2]1[CH:7]([N+:8]([O-:10])=[O:9])[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][C:12]=2[Cl:21])=[CH:5][CH:4]=[N:3]1.[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23].CCN(C(C)C)C(C)C>C(#N)C>[CH:22]([NH:26][CH:2]1[CH:7]([N+:8]([O-:10])=[O:9])[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][C:12]=2[Cl:21])=[CH:5][CH:4]=[N:3]1)([CH2:24][CH3:25])[CH3:23]
Reactant: O=[N+]([O-])C1C(c2ccc(OC(F)F)cc2Cl)=CC=NC1Cl
Reactant: CCC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCC(C)NC1N=CC=C(c2ccc(OC(F)F)cc2Cl)C1[N+](=O)[O-]
Temperature: 25 °C
Yield: 82.3 %

Procedure:
2-Chloro-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridine (0.176 g, 0.53 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of sec butylamine (106 μL, 1.06 mmol) and Hunig's base (184 μL, 1.06 mmol). The reaction was stirred at reflux for 64 h. The solution was cooled to room temperature, extracted with EtOAc/H2O, organic layer was then washed with 1N HCl and made basic with 1N NaOH. The organic layer was washed with brine, dried Na2SO4, filtered and concentrated to yield 0.163 g (83%) of sec-butyl-[4-(chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridin-2-yl]-amine as a yellow oil; MS (AP) 413.0 [(M+H+CH3CN)+, 50].
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2].[CH2:25]([CH2:27][NH2:28])[OH:26]>>[CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH2:23][NH:28][CH2:27][CH2:25][OH:26])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2]
Reactant: NCCO
Reactant: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Product: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(CNCCO)ccc1-2
Yield: 27 %

Procedure:
Following the procedure for 119, 2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde and ethanolamine were reacted. After aqueous work-up the resulting gum was triturated with DCM/ether/pentane to give a solid that was filtered off and dried to give 131 as an off-white solid (55 mg, 27%). LCMS: RT=5.54 min, [M+H]+=386. 1H NMR δ (ppm) (CDCl3): 8.37 (1 H, s), 8.30 (1 H, d, J=8.11 Hz), 7.13 (1 H, dd, J=8.15, 1.72 Hz), 7.05 (1 H, d, J=1.68 Hz), 5.70-5.63 (1 H, m), 4.41 (2 H, t, J=5.06 Hz), 3.84 (2 H, s), 3.68 (2 H, t, J=5.17 Hz), 3.42 (2 H, t, J=5.07 Hz), 2.85 (2 H, t, J=5.16 Hz), 1.65 (6 H, d, J=6.74 Hz). 2 Exchangeable protons not seen
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([CH3:33])=[C:13]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C@H:23]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:22][CH2:21]4)[N:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCO.[Li+].[OH-]>C1COCC1.O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][C:12]([CH3:33])=[C:13]([CH2:15][CH2:16][O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C@H:23]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][CH2:21]4)[N:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(C(C)C)cc4)sc3C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc(-c2ccc(C(C)C)cc2)nc1CCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of Example 27 (305 mg, 0.657 mmol) in a mixture of THF (8 mL), water (8 mL), and EtOH (4 mL), was added LiOH (63 mg, 2.63 mmol). The reaction mixture was vigorously stirred for 24 h, diluted with water (20 mL), and washed with Et2O (10 mL). The aqueous phase was then acidified to pH ˜1 using 1N HCl, and then extracted with CH2Cl2 (4×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to afford product (189 mg, 66%) as a white solid. (C26H29NO3S): LC-MS, RT 3.95 min, M+H 436.4; 1H NMR (CDCl3): δ 1.25 (s, 3H), 1.28 (s, 3H), 1.70-1.82 (m, 1H), 2.32-2.43 (m, 2H), 2.45 (s, 3H), 2.74-2.98 (m, 4H), 3.18 (t, 2H), 3.47-3.54 (m, 1H), 4.28 (t, 2H), 6.72 (dd, 1H), 6.78 (s, 1H), 7.08 (d, 1H), 7.51 (AB quartet, 4H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[N:16][O:17][CH3:18])[C:12]([NH:14][CH3:15])=[O:13].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:27]([OH:29])=[O:28])=[N:24][C:25]=1Cl.C(O[CH2:34][CH3:35])(=O)C>C1COCC1>[CH3:18][O:17][N:16]=[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][O:3][C:25]1[C:20]([Cl:19])=[CH:21][CH:22]=[C:23]([C:27]([O:29][C:5]([CH2:34][CH3:35])([CH2:10][CH3:9])[CH2:6][CH3:7])=[O:28])[N:24]=1)[C:12]([NH:14][CH3:15])=[O:13]
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Reactant: CCOC(C)=O
Reactant: O=C(O)c1ccc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(CC)OC(=O)c1ccc(Cl)c(OCc2ccccc2C(=NOC)C(=O)NC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60% dispersion in mineral oil, 0.24 g, 6.0 mmol) was added to a solution of 2-hydroxymethyl-α-methyoxyimino-N-methyl-benzeneacetamide (1.11 g, 5.0 mmol) in THF (50 mL). 5,6-Dichloropicolinic acid: 3-ethyl-3-pentyl ester (1.68 g, 5.5 mmol) was dissolved in THF (10 mL) and added slowly via pipet to this mixture. As the mixture was stirred at room temperature under N2 for one hour, the reaction mixture transformed to a dark green solution. The reaction volume was increased to ca. 125 mL with ethyl acetate and washed with water and brine. The organic phase was evaporated in vacuo to provide the crude product which was chromatographed on medium pressure LC using increasing gradient of ethyl acetate in hexane (0-50%). Concentrating chromatographic fractions gave α-(methoxyimino)-N-methyl-2-[[[3-chloro-6-(3-ethyl-3-pentoxycarbonyl)-2-pyridinyl]oxy]methyl]-benzeneacetamide (0.29 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19]Cl)=[CH:7]2.[H-].[Na+].[I:23][C:24]1[C:32]2[C:27](=[N:28][CH:29]=[N:30][C:31]=2[NH2:33])[NH:26][N:25]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][N:26]1[C:27]3=[N:28][CH:29]=[N:30][C:31]([NH2:33])=[C:32]3[C:24]([I:23])=[N:25]1)=[CH:7]2
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: ClCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2Cc1cc2cccc(Cl)c2nc1-c1ccccc1Cl

Procedure:
Prepared according to Procedure I using 8-chloro-3-(chloromethyl)-2-(2-chlorophenyl)quinoline (0.235 g, 0.73 mmol), NaH (0.047 g 60% in oil, 1.17 mmol, 1.6 eq) and 3-iodo-1H-pyrazolo{3,4-d}pyrimidin-4-amine (0.209 g, 0.8 mmol, 1.1 eq) in DMF. 1-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained after purification as a white solid [PI3KδIC50=14 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (1 H, s), 8.09 (1 H, dd, J=8.6, 1.2 Hz), 7.98-8.05 (2 H, m), 7.66 (1 H, t), 7.48 (1 H, dd, J=8.2, 0.8 Hz), 7.36 (1 H, dt, J=7.8, 1.6 Hz), 7.25 (1 H, dt, J=7.4, 1.2 Hz), 7.13 (1 H, dd, J=7.4, 1.6 Hz), 5.53 (2 H, s) Mass Spectrum (ESI) m/e=547.0 and 549.0 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:8][CH2:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:4].[Cl:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=1[C:34]1[CH:38]=[C:37]([CH2:39]O)[O:36][N:35]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:8][CH2:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:39][C:37]2[O:36][N:35]=[C:34]([C:27]3[C:28]([F:33])=[CH:29][CH:30]=[C:31]([F:32])[C:26]=3[Cl:25])[CH:38]=2)=[CH:13][CH:12]=1)=[O:4]
Reactant: COC(=O)C1=C(c2ccc(O)cc2)CCN(C(=O)OC(C)(C)C)C1
Reactant: OCc1cc(-c2c(F)ccc(F)c2Cl)no1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)cc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
To a sol. of compound B2 (10.0 g, 30 mmol) and [3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-yl]-methanol (8.84 g, 30 mmol) in toluene (60 mL) were added ADDP (15.1 g, 60 mmol) and PBu3 (90%, 30.0 mL; 108 mmol). The mixture was stirred for 2 h at 80° C., and was allowed to cool to rt. The solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:4→EtOAc) yielded the title compound (8.64 g, 51%). LC-MS: tR=1.15 min; ES+: 561.25.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[NH:14][CH2:13][C@@H:12]1[CH3:18].C=O.[BH3-][C:22]#N.[Na+].C(O)(=O)C>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[N:14]([CH3:22])[CH2:13][C@@H:12]1[CH3:18]
Reactant: [BH3-]C#N
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1C
Temperature: 0 °C
Yield: 100 %

Procedure:
Racemic-1-(2-Fluoro-4-nitrophenyl)-trans-2,5-dimethylpiperazine (5.71 g, 24.3 mmol) and formalin (24 mL) are dissolved in 70 mL of acetonitrile. The solution is cooled to 0° C. and 2.44 g of NaBH3CN (38.8 mmol) is added in small portions. Acetic acid (2 mL) is added until no further effervescence is observed. The crude reaction mixture is then filtered through a thick plug of silica gel that is rinsed with 10% MeOH in CH2Cl2. Concentration in vacuo gives a yellow solid that is further purified by addition of ethyl acetate and filtration. Concentration in vacuo of the filtrate gave 6.1 g of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,4,5-trimethylpiperazine as an off-white solid (24.3 mmol, 100%). 1H NMR (300 MHz, CDCl3) δ 1.04 (d, J=4.9 Hz, 1H), 1.07 (d, J=5.2 Hz, 1H), 2.20 (dd, J=11.5, 8.8 Hz, 1H), 2.32 (s, 3H), 2.41-2.50 (m, 1H), 2.65 (dd, J=11.6, 8.9 Hz, 1H), 2.90 (dd, J=11.5, 3.3 Hz, 1H), 3.25 (dd, J=11.8, 3.0 Hz, 1H), 3.44-3.53 (m, 1H), 7.10 (t, J=8.5 Hz, 1H), 7.90 (dd, J=11.5, 2.7 Hz, 1H), 7.95-8.00 (m, 1H). LCMS-ESI (m/z): calcd for C13HBFN3O2, 267.14; [M+H]+ found, 268.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[K+].[Br-].Br[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1>C(#N)C>[Br-:10].[CH2:11]([C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]([CH3:22])[C:32]=1[N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[NH:5][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCCCCCCCBr
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCCc1c(-[n+]2c[nH]c(Cl)c2Cl)c(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromooctane (1.55 mL, 9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 2-bromomethylnaphthalene (1.98 g, 9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, resulting in a yellow/white precipitate.
Reaction SMILES: C[Mg]Cl.[CH:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([CH3:11])[CH:5]=1.C1(C)C=CC=CC=1.[CH2:19]=[O:20]>O1CCCC1.CN1CCCN(C)C1=O>[OH:10][C:9]1[CH:8]=[CH:7][C:6]([CH3:11])=[CH:5][C:4]=1[CH:19]=[O:20]
Reactant: C=O
Reactant: Cc1ccc(O)cc1
Agent: C[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CN1CCCN(C)C1=O
Product: Cc1ccc(O)c(C=O)c1
Reaction time: 2 h
Yield: 18 %

Procedure:
Methylmagnesium chloride solution in tetrahydrofuran (100 mL, 3.0M, 300 mmol) at room temperature was treated dropwise over 30 minutes with a solution of 32.3 g (300 mmol) of p-cresol in 30 mL of tetrahydrofuran. An additional 70 mL of tetrahydrofuran was added to moderate the exothermic reaction. The mixture was aged at room temperature for 2 hours then treated with 400 mL of toluene, 41mg of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 23 g of paraformaldehyde. The reaction mixture was heated at reflux for 18 hours, then cooled and washed with 200 mL of 2N aqueous hydrochloric acid and 200 mL of water. The organic layer was removed, filtered through Celite, dried over magnesium sulfate, filtered and solvents removed under vacuum. Crystallization of the crude residue from cold hexanes gave 7.4 g (54 mmol, 18%) of the product. The mother liquors were further purified by column chromatography on silica gel, eluting with methylene chloride, to give an additional 17.5 g (128 mmol, 43%) of the product. 1H NMR (200 MHz,CDCl3): 2.33 (s,3H), 6.89 (d,10 Hz,1H), 7.33 (m,2H), 9.83 (s,1H), 10.80 (s,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[CH2:29][OH:30])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19]C)(=[O:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(S(Cl)(=O)=O)CCCC.N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[CH2:29][OH:30])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH2:19])(=[O:17])=[O:18])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1CO)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCCCS(=O)(=O)Cl
Agent: N
Product: C[C@H](CCCS(N)(=O)=O)N(c1cc(Cl)ccc1CO)S(=O)(=O)c1ccc(Cl)cc1
Yield: 60 %

Procedure:
4-chloro-N-[5-chloro-2-(hydroxymethyl)phenyl]-N-[4-(aminosulfonyl)-1(R)-methylbutyl]-benzenesulfonamide was prepared analogous to 4-chloro-N-[5-chloro-2-(hydroxymethyl)phenyl]-N-[4-[(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[5-chloro-2-(acetoxymethyl)phenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with ammonia.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O:9]=[P:10](Cl)([Cl:12])[Cl:11].P(Cl)([Cl:17])([O-])=O>CCOCC>[P:10]([Cl:12])([Cl:11])([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([Cl:17])[CH:4]=1)=[O:9]
Reactant: Oc1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=P([O-])(Cl)Cl
Solvent: CCOCC
Product: O=P(Cl)(Cl)Oc1ccc(Cl)c(Cl)c1

Procedure:
3,4-Dichloro-phenyl dichlorophosphate was prepared as described in Example 2 from p-chlorophenol (3.79 g, 0.023 mol), POCl3 (2.17 mL, 0.023 mol) and TEA (3.25 mL, 0.023 mol) and dry Et2O (25 mL).The dichlorophosphate 11c was obtained as a yellow clear oil (2.93 g, 0.0105 mol, 45%) and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13]([CH:15]=[C:16](OCC)[NH:17][CH3:18])#[N:14]>>[C:13]([CH:15]=[C:16]([NH:17][CH3:18])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:14]
Reactant: CCOC(=CC#N)NC
Reactant: NCCCCc1ncccc1Cl
Product: CNC(=CC#N)NCCCCc1ncccc1Cl
Reaction time: 5 h

Procedure:
3-Chloro-2-(4-aminobutyl)pyridine is added to a solution of 1-cyano-2-ethoxy-2-methylaminoethylene and stirred at 100° for 5 hours. Chromatographic purification of the reaction mixture yields the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[C:14]=1[Cl:25].[CH3:26][Al](C)C.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1.C1(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)C=CC=CC=1>[Cl:25][C:14]1[C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=1[CH2:12][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][C:9]([NH2:11])=[N:10][C:2]=2[CH3:26]
Reactant: C[Al](C)C
Reactant: COc1cc(Cn2cnc3c(Cl)nc(N)nc32)c(Cl)c(OC)c1OC
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(Cn2cnc3c(C)nc(N)nc32)c(Cl)c(OC)c1OC
Temperature: 25 °C

Procedure:
A suspension of 6-chloro-9-(2-chloro-3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine, see example 97) (0.2 mmol) and tetrakis(triphenylphosphino)-palladium (0.02 mmol) in dry THF (3 mL) was treated with trimethylaluminum (2M in toluene, 0.45 mmol) under nitrogen and heated to reflux for 3 h. The reaction mixture was cooled to r.t., diluted with toluene (5 mL) and quenched with methanol (0.5 mL) followed by ammonium chloride (1 mmol). The mixture was heated to reflux for 2 h and filtered, while hot, on Celite. See J. Med. Chem. 1999, 42, 2064–2086. TLC (100% EtOAc) Rf was 0.2. HPLC Rt: 4.800 min.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH2:8]Cl)(=[O:3])[CH3:2].[CH:11]([O-:13])=[O:12].[Na+].O>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:11]([O:13][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])=[O:12]
Reactant: O=C[O-]
Reactant: CC(=O)OCC=C(C)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC=C(C)COC=O
Temperature: 40 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
4-Acetoxy-2-methyl-1-chloro-2-butene (8.13 g, 50 mmol) was dissolved in dimethylformamide (25 ml) and placed in a 100 ml four neck flask. To this were added sodium formate powder (6.80 g, 100 mmol, 2 equivalents) and tetra n-butylammonium bromide (0.81 g, 2.5mmol, 5 mol %). The mixture was stirred at 40° C. for 24 hours under heating. After completion of the reaction, the reaction mixture was poured into ice-cooled water (about 30 ml)and extracted with ether (50 ml) three times. The extracted ether layer was dried over anhydrous sodium sulfate. Evaporation of the ether followed by purification by silica gel column chromatography (ethyl acetate-hexane (=1:3)) gave 4-acetoxy-2-methyl-2-buten-1-ol formate (8.18 g, 47.5 mmol; Yield: 95.0%).
Reaction SMILES: [BrH:1].C(O)(=O)C.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14](=O)[CH2:15][S:16][C:17]#[N:18].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[Cl:6])[N:18]=1
Reactant: Br
Reactant: N#CSCC(=O)c1ccc(Cl)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(-c2csc(Br)n2)c(Cl)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A 25% hydrogen bromide/acetic acid (60 ml) solution was added to a solution of 2-(2,4-dichlorophenyl)-2-oxoethyl thiocyanate (5.97 g, 24.3 mmol) in acetic acid (60 ml), and the mixture was stirred at 130° C. for 2 hours. Water (120 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 6.89 g (92.0%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:36][CH3:37])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:19]>C(O)C.N1CCCCC1>[CH2:36]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:29][C:28]=1[CH3:35])=[O:26])[CH3:37]
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.9 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide as a yellow solid (74.4 mg, 61%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:13](=O)[O:12][C:10](=O)[C:9]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:8]12.CSC1[NH:22][CH2:23][CH2:24][N:25]=1.[OH-].[K+]>O1CCOCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:8]2[C:9](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:10](=[O:12])[N:22]2[CH2:23][CH2:24][N:25]=[C:13]12
Reactant: O=c1oc(=O)n(Cc2cccs2)c2ccccc12
Reactant: CSC1=NCCN1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1c2ccccc2N(Cc2cccs2)C2=NCCN12

Procedure:
A mixture of 20 g. of N-(2-thienylmethyl)isatoic anhydride, 9 g. of 2-methylmercapto-imidazoline and 1 pellet of potassium hydroxide in about 300 ml. of dioxane is heated at reflux for 5 hours, the solvent then evaporated off and the residue dissolved in methylene chloride. After washing twice with water the solution is extracted 3 times with 1N. hydrochloric solution. Heating on a steam bath avoids precipitation and after filtering hot through celite, sodium bicarbonate solution is added and the resulting precipitate is recovered by filtering, washed with water, dissolved in methylene chloride and the methylene chloride exchanged for diethyl ether. The resulting precipitate is recovered by filtering, washed with diethyl ether and dried under reduced pressure at 40°C. to obtain 10-(2-thienylmethyl)-2,3-dihydro-imidazo[2,1-b]quinazolin-5(10H)-one, m.p. 124°-127°C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[Cl:10])[NH2:6].N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21].CCCCCC>ClCCl>[Cl:10][C:9]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:4][C:3]=1[C:2]([F:1])([F:11])[F:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccccc1
Reaction time: 1.5 h
Yield: 89.2 %

Procedure:
3-trifluoromethyl-4-chloroaniline (25 g, 0.1278 mol) and pyridine (26 ml, 0.3195 mol) were dissolved in dichloromethane (250 ml). The reaction mass was cooled to 0° C. to −5° C. and a solution of phenyl chloroformate (22 ml, 0.1661 mol) in dichloromethane (100 ml) was added drop wise maintaining the temperature of the reaction mass below 0° C. The reaction mass was stirred at 0° C. to 5° C. for 1-2 hours and quenched with water (200 ml) below 10° C. The organic phase was separated and washed with water followed by 1N HCl. It was then dried over sodium sulfate and concentrated to obtain solid. This solid was agitated with hexane (350 ml) at ambient temperature for 2-3 hours and filtered. The obtained product was vacuum dried at 50° C. to give phenyl 4-chloro-3-(trifluoromethyl)phenylcarbamate (36 g) as white solid.