Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.ClCCl.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH2:22][C@@H:21]([O:23][CH2:24][CH2:25][OH:26])[C@H:20]([O:27][CH2:28][O:29][CH3:30])[CH2:19]2)[N:13]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>O>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH2:22][C@@H:21]([O:23][CH2:24][CH2:25][O:26][S:32]([CH3:31])(=[O:34])=[O:33])[C@H:20]([O:27][CH2:28][O:29][CH3:30])[CH2:19]2)[N:13]=1
Reactant: COCO[C@@H]1CN(c2cccc(Br)n2)C[C@H]1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCO[C@@H]1CN(c2cccc(Br)n2)C[C@H]1OCCOS(C)(=O)=O
Reaction time: 0.25 h

Procedure:
7.9 ml of triethylamine was slowly added to a solution of 70 ml of dichloromethane containing 13.14 g of 2-bromo-6-[(3R,4R)-3-methoxymethyloxy-4-(2-hydroxyethyl)oxypyrrolidine-1-yl]pyridine in an ice bath. Then, 3.2 ml of methanesulfonyl chloride was slowly added thereto, followed by stirring for 15 minutes. Then, the reaction solution was poured into water and extracted twice with dichloromethane. The organic phase was washed with brine and the solvent was removed. The residue was filtered through NH-silica gel, to give 15.66 g of the target compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C@@H:16]1[C@H:11]([CH2:12][CH:13]=[CH:14][CH2:15]1)[CH2:10][CH2:9]3.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:4][C@:3]12[CH2:19][CH2:18][C@H:17]3[C@@H:8]([CH2:9][CH2:10][C@@H:11]4[C@@H:16]3[CH2:15][CH:14]=[CH:13][CH2:12]4)[C@@H:5]1[CH2:6][CH2:7][C:2]2=[O:1]
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC=CC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC=CC[C@@H]43)[C@@H]1CCC2=O
Reaction time: 0.03 h
Yield: 98 %

Procedure:
To a solution of 0.18 g of 17β-hydroxy-5α-estr-2-ene, Compound 5, in 10 ml of acetone cooled to 0°-5° C. is added dropwise Jones reagent until the reaction mixture becomes permanently orange-brown. The reaction mixture is stirred for another 2 min, and then the excess reagent is destroyed by addition of isopropanol. The solvent is evaporated under reduced pressure, and the residue is treated with water (25 ml) and ether (25 ml). The ether phase is separated, and the water is extracted once more with ether (20 ml). The combined ether phase is washed with water, sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent produces 0.175 g of 5α-estr-2-ene-17-one.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][N:26]=[C:25]3[NH:29][CH:30]=[CH:31][C:24]=23)O1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH3:14][N:5]1[C:4]2[CH:3]=[C:2]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[NH:29][CH:30]=[CH:31][C:24]=34)[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:13])[CH3:12]
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Reactant: CC1(C)OB(c2ccnc3[nH]ccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CN1c2cc(-c3ccnc4[nH]ccc34)sc2C(=O)NC1(C)C
Yield: 30 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (183 mg, 0.75 mmol), cesium carbonate (489 mg, 1.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and extracted with 2:1 EtOAc/THF (100 mL×3), and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH). The obtained yellow solid was triturated with EtOAc/hexane, and the precipitate was collected by filtration to afford the title compound (46.9 mg, 30%) as a pale yellow solid:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si](C)(C)C)=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH:24][CH:25]=[O:26])=[CH:7][N:6]=1)=[O:4].[I:27]Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:27])=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH:24][CH:25]=[O:26])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Reactant: ClI
Solvent: ClCCl
Product: COC(=O)c1ncc(CNC=O)nc1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a cold (0° C.) solution of 3-(2-fluoro-4-trimethylsilanyl-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylic acid methyl ester (480 mg, 1.28 mmol) in dichloromethane (13 mL) under N2 was added dropwise a solution of 1M iodine monochloride in dichloromethane (3.0 mL, 3.0 mmol, 2.4 eq), and the mixture was stirred at 0° C. for 1.5 hour. The reaction was quenched by addition of a saturated aqueous solution of sodium thiosulfate (˜3 mL). After stirring for 10 minutes the reaction mixture was poured into ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried (Na2SO4), filtered and evaporated in vacuo to afford the desired product as a yellow solid (548 mg, 99%). LCMS (method C): RT=2.65 min, [M+H]+=431.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[NH:5][C:6]([CH3:30])=[C:7]([C:23]([O:25][CH2:26]CC#N)=[O:24])[CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:9]=1[C:10]([O:12]C)=[O:11].C(Cl)Cl.Cl>CC(C)=O>[CH3:30][C:6]1[NH:5][C:4]([CH3:3])=[C:9]([C:10]([OH:12])=[O:11])[CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1

Procedure:
Next, a solution of NaOH (41.3 mL of 35% NaOH in 375 mL H2O) was slowly added to a solution of 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(2-cyano)ethoxycarbonyl-1,4-dihydropyridine (80 g, 0.21 mol) in acetone (240 mL). Then, CH2Cl2 (500 mL) was added and 12N HCl (41.3 mL) slowly introduced. The resulting precipitate was filtered and recrystallized from dimethylformamide/H2O (175 mL DMF, 72 mL H2O) to yield 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (mp=242° C.).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[CH:20][CH:19]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[O-:34]S([O-])(=O)=O.[Mg+2].[O-][Mn](=O)(=O)=O.[K+]>C(O)(C)(C)C.O>[O:34]=[C:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[CH2:7][N:6]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][CH:19]=2)=[O:17])[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2
Reactant: O=S(=O)([O-])[O-]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3C(=O)c3ccccc32)cc1
Temperature: 65 °C
Yield: 107.6 %

Procedure:
A mixture of 1.08 g of N-[4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2-methylbenzamide in 50 ml of t-butanol is heated, 2 ml of water is added followed by 1.18 g of MgSO4, and 2.6 g of KMnO4. An additional 0.84 g of KMnO4 in 25 ml of water is added followed by heating at 65° C. for 18 hours. The reaction mixture is filtered and the filtrate evaporated in vacuo to give 1.2 g of a residue which is purified by column chromatography on silica gel by elution with ethyl acetate and 9:1 ethyl acetate-methanol to give 160 mg of the desired product as a solid, m.p. 115°-119° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[CH:18]=[CH:17]2)[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1.NC1CCN(CCN2C3C(=CC=CC=3)C=CC2=O)CC1>O1CCOCC1>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[CH:18]=[CH:17]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2ccc(=O)c3ccccc32)CC1
Agent: Cl
Agent: NC1CCN(CCn2c(=O)ccc3ccccc32)CC1
Solvent: C1COCCO1
Product: NC1CCN(CCn2ccc(=O)c3ccccc32)CC1
Yield: 51.4 %

Procedure:
tert-Butyl{1-[2-(4-oxoquinolin-1(4H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 166, 480 mg crude, 1.29 mmol) was reacted with 4M HCl/dioxane in dioxane as described for Intermediate 163 to give 180 mg (51%) of the crude product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][OH:14])[CH2:7][CH2:6]2.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])[CH2:7][CH2:6]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)CCC(CO)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCC(COS(=O)(=O)c1ccc(C)cc1)C2
Yield: 80.9 %

Procedure:
(RS)-(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-methanol (939 mg, 4.88 mmol), p-toluenesulfonyl chloride (934 mg, 4.9 mmol), triethylamine (1.12 ml, 7.88 mmol) and N,N-dimethyl aminopyridine (10 mg) in CH2Cl2 (10 ml) was stirred together at ambient temperature for 24 hr. Acidification with 1N HCl (pH 1-2), extraction of the aqueous phase with CH2Cl2 (2×20 ml), drying (Na2SO4) filtration and evaporation afforded the crude product which wag chomatographed over SiO2 (Merck 230-400 mesh) eluting with EtOAc-n-Hexane (1:3) to afford the title compound as a colourless oil (1.37 g, 3.95 mmol, 81%), MS m/e=346.1 (M+).
Reaction SMILES: [CH2:1]([C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:39]([OH:45])[CH2:40][CH:41]([OH:44])[CH2:42]O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:19]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[O:44][CH:41]([CH2:40][CH2:39][OH:45])[CH2:42][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCCC(O)CO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)CCCCCCCC/C=C\C/C=C\CCCCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCCC/C=C\C/C=C\CCCCC)OCC(CCO)O1
Temperature: 25 °C

Procedure:
A mixture of dilinoleyl ketone (I, previously prepared as described in Example 1, 527 mg, 1.0 mmol), 1,3,4-butanetriol (technical grade, ca. 90%, 236 mg, 2 mmol) and pyridinium p-toluenesulfonate (50 mg, 0.2 mmol) in 50 mL of toluene was refluxed under nitrogen overnight with a Dean-Stark tube to remove water. The resulting mixture was cooled to room temperature. The organic phase was washed with water (2×30 mL), brine (50 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent resulted in a yellowish oily residual (0.6 g). The crude product was purified by column chromatography on silica gel (230-400 mesh, 100 mL) with dichloromethane as eluent. This afforded 0.5 g of pure II as colourless oil. 1H NMR (400 MHz, CDCl3) δ: 5.25-5.48 (8H, m, 4×CH═CH), 4.18-4.22 (1H, m, OCH), 4.08 (1H, dd, OCH), 3.82 (2H, t, OCH2), 3.53 (1H, t, OCH), 2.78 (4H, t, 2×C═C—CH2—C═C), 2.06 (8H, q, 4×allylic CH2), 1.77-1.93 (2H, m, CH2), 1.52-1.68 (4H, m, 2×CH2), 1.22-1.45 (32H, m), 0.86-0.94 (6H, t, 2×CH3) ppm.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1>>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][CH2:8][N:10]1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16]1)=[O:4]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: COC(=O)C(Br)CCBr
Product: CCOC(=O)N1CCC(N2CCC2C(=O)OC)CC1
Yield: 50 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with ethyl 4-aminopiperidine-1-carboxylate 18K yielded ethyl 4-(2-(methoxycarbonyl)azetidin-1-yl)piperidine-1-carboxylate as a yellow oil (50%). MS ISP (m/e): 271.3 (100) [(M+H)]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][CH2:14]3)[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:24]([CH3:31])=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=1.CCOC(C)=O>CO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][CH2:14]3)=[CH:7][C:2]([NH:22][C:23]2[C:24]([CH3:31])=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=2)=[N:3][CH:4]=1
Reactant: CN1CCc2cccc(Nc3cc(Cl)ncc3Cl)c2C1=O
Reactant: Cc1nn(CCO)cc1N
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nn(CCO)cc1Nc1cc(Nc2cccc3c2C(=O)N(C)CC3)c(Cl)cn1

Procedure:
This compound was prepared from 8-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one and 2-(4-amino-3-methyl-pyrazol-1-yl)ethanol. Column chromatography (SiO2, 50 equiv.; 95:5; EtOAc:MeOH) followed by prep. TLC (SiO2: 20×20 cm; 1000 μM, Analtech, EtOAc:MeOH; 95:5) furnished 45 mg of the desired compound. 1H NMR spectrum (CDCl3) 2.09 (s, 3H), 2.91 (t, 2H), 3.11 (s, 3H), 3.25 (bs, 1H), 3.51 (t, 2H), 3.86-3.95 (m, 2H), 4.05-4.10 (m, 2H), 5.89 (s, 1H), 6.44 (s, 1H), 6.68 (d, 1H), 7.14-7.29 (m, 2H), 7.44 (s, 1H), 7.88 (s, 1H), 11.09 (s, 1H); Mass spectrum: ESI+ MH+ 427
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][N:3]=1.Cl[CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C.Cl>CN(C=O)C>[CH3:7][N:6]1[CH:5]=[N:4][N:3]=[C:2]1[S:1][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)[CH2:14][CH2:13]1
Reactant: Cn1cnnc1S
Reactant: FC(F)(F)c1cccc(N2CCN(CCCCl)CC2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cnnc1SCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 54.5 %

Procedure:
1.15 g (10 mmol) of 3-mercapto-4-methyl-4H-1,2,4-triazole, 3.1 g (10.1 mmol) of 1-(3-chloropropyl)-4-(3-trifluoromethylphenyl)piperazine and 1.5 g (15 mmol) of triethylamine in 5 ml of DMF were stirred at 100° C. for 1 hour. The mixture was then poured into 5% strength hydrochloric acid and extracted with ethyl acetate. The aqueous phase was made alkaline with sodium hydroxide solution and then extracted again with ethyl acetate, and the organic phase was dried over MgSO4 and concentrated. The residue was purified by chromatography (mobile phase: CH2Cl2/CH3OH=95/5). 2.1 g of product were obtained as a yellowish oil (=55% yield).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH2:4][CH:5]=[CH2:6])[CH3:3].C(N(CC)CC)C.Cl[P:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][C:2]([O:7][P:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:4][CH:5]=[CH2:6])[CH3:3]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: C=CCC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCC(C)(C)OP(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a stirred solution of 2-methyl-pent-4-en-2-ol (5.0 g; CAS 624-97-5) in THF (50 ml) were added sequentially 4-dimethylaminopyridine (1.22 g), triethylamine (8.32 ml) and chlorodiphenylphosphine (10.2 ml). The resulting mixture was stirred at room temperature overnight. The reaction mixture was evaporated and purified by column chromatography (basic alumina; gradient: heptane/EtOAc) to give (2-methyl-pent-4-en-2-oxy)diphenylphosphine (8.0 g, 56%) as a colourless oil which was used immediately in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:11]([O:13][C:14](=[O:21])[CH:15]=[C:16]([NH2:20])[O:17][CH2:18][CH3:19])[CH3:12]>>[CH2:11]([O:13][C:14]([C:15]1[CH:4]([C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])[CH:15]([C:14]([O:13][CH2:11][CH3:12])=[O:21])[C:16]([O:17][CH2:18][CH3:19])=[N:20][C:16]=1[NH2:20])=[O:21])[CH3:12]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C=C(N)OCC
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1ccc(Cl)cc1Cl
Yield: 68 %

Procedure:
Upon boiling a solution of 8.8 g of 2,4-dichlorobenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 6 hours, 2-amino-4-(2,4-dichlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 98° C (ethyl acetate/petroleum ether) is obtained.
Reaction SMILES: [O:1]([N:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[Si](C(C)(C)C)(C)C.F[B-](F)(F)F.[Na+]>>[CH2:17]([N:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:1])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)[Si](C)(C)ON(Cc1ccccc1)Cc1ccccc1
Agent: F[B-](F)(F)F
Agent: [Na+]
Product: ON(Cc1ccccc1)Cc1ccccc1
Yield: 82 %

Procedure:
tert-Butyldimethylsiloxy-N,N-dibenzylamine, Compound 1, was heated with sodium tetrafluoroborate at about 200° C. for 30 minutes. The tert-butyldimethylfluorosilane could be distilled off at 62°-64° C. in 82% yield. N,N-dibenzylhydroxylamine was isolated from the reaction. Similar results were obtained using sodium salts of hexafluorophosphate and hexafluoroantimonate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([O:30][CH3:31])[CH:25]=4)=[CH:22][N:23]=3)[N:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C1COCC1.Cl.CCN(CC)CC>O1CCOCC1.O>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:21]2[N:19]3[N:20]=[C:15]([NH:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:16]=[CH:17][C:18]3=[N:23][CH:22]=2)[CH:29]=[CH:28][N:27]=1
Reactant: COc1cc(-c2cnc3ccc(NC4CCN(C(=O)OC(C)(C)C)CC4)nn23)ccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2cnc3ccc(NC4CCNCC4)nn23)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
280 mg (0.66 mmol) of 4-[3-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-6-ylamino]piperidine-1-carboxylic acid tert-butyl ester were introduced into 3 ml of THF and, after addition of 0.8 ml of HCl in dioxane (4M), stirred at RT overnight. HCl (conc.) was added, and the mixture was heated at 70° C. for 4 hours. The reaction was diluted with water, adjusted to pH 11 with Et3N and extracted three times with ethyl acetate. The combined organic phases were filtered through a silicone filter (from Whatman) and concentrated. In the final fractionation by chromatography on silica gel, 92 mg of the desired product were isolated.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])O[CH2:12][CH3:13]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:12]([O:9][C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)[CH3:13]
Reactant: O=C1CCCCCCC1
Reactant: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC1=CCCCCCC1
Yield: 44.2 %

Procedure:
In the presence of 0.3 g of para-toluenesulfonic acid, 20 g (0.16 mol) of cyclooctanone and 27 g (0.18 mol) of ethyl orthoformate were stirred at room temperature overnight. The resultant mixture was heated at 100° C. for 15 hours and distilled under reduced pressure to give 10.9 g (45% in yield) of 1-ethoxycyclooctene having a boiling point of 97.5° to 98.5° C./25 mmHg.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13]2)[CH:3]=1.C[S-:24].[Na+].Cl>CN(C)C=O.O>[CH2:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[CH2:16][CH2:17][CH2:18][N:12]1[C:4]1[CH:3]=[C:2]([SH:24])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Clc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (2 g, 6.47 mmol) and sodium thiomethoxide (2.4 g, 34 mmol) in dry N,N-dimethylformamide (20 mL) was heated with stirring overnight under reflux. The reaction mixture was cooled to 50° C. and the volatile components were evaporated under reduced pressure to give a residue which was dissolved in 30 mL of chilled water and carefully acidified with 20% hydrochloride aid to pH 4-5 under argon. The resultant solution was extracted with chilled dichloromethane (30 mL×3). The dichloromethane fractions were combined and washed with chilled brine (30 mL×2) and then concentrated under reduced pressure at room temperature to give the crude product. It was used in next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:26])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[F:26][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[C:14]([CH3:15])=[C:13]2[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(C)(=O)=O)cc1
Reaction time: 15 h
Yield: 87.3 %

Procedure:
To a solution of [6-fluoro-4-(4-methansulfonyl-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (77.7 mg, 0.2 mmol) in THF (10 mL) was added a solution of lithium hydroxide monohydrate (83.92 mg, 2.0 mmol) in water (2 mL) at room temperature. The resulting clear solution was stirred for 15 hours. The reaction mixture was concentrated to remove THF. The residue was diluted with water (˜30 mL) to obtain a clear solution. The basic aqueous layer was acidified with 1.0 N hydrochloric acid. The precipitated solids were collected by filtration and washed with water and hexanes. After drying in air, [6-fluoro-4-(4-methansulfonyl-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid (65 mg, 87%) was isolated as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (br. s, 1 H), 8.11 (d, J=8.2 Hz, 2 H), 8.02 (dd, J=9.0, 6.0 Hz, 1 H), 7.92 (s, 1 H), 7.54 (d, J=8.2 Hz, 2 H), 7.39 (td, J=9.0, 2.3 Hz, 1 H), 6.71 (dd, J=11.3, 2.3 Hz, 1 H), 3.86 (s, 2 H), 3.35 (s, 3 H), 2.08 (s, 3 H). HRMS calcd. for C20H18FO4S [(M+H)+] 373.0905, obsd. 373.0904.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[C:17]([C:18]#[N:19])=[C:13]2[NH:12][CH2:11][CH2:10]1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:37]>>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[C:17]([C:18]([NH2:19])=[O:37])=[C:13]2[NH:12][CH2:11][CH2:10]1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Reactant: CNc1ccccc1C1CCNc2c(C#N)c(-c3ccc(Oc4ccccc4)cc3)nn21
Product: CNc1ccccc1C1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn21

Procedure:
The desired product was prepared from 7-(2-(methylamino)phenyl)-2-(4-phenoxy phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile using the procedure similar to step 2 for compound 2. 1H NMR (DMSO-d6) δ 7.49 (d, J=8.8 Hz, 2H), 7.44-7.35 (m, 2H), 7.18-7.01 (m, 6H), 6.76 (s, 1H), 6.58 (d, J=7.6 Hz, 2H), 6.54 (t, J=7.6 Hz, 1H), 6.28 (dd, J=1.2, 7.6 Hz, 1H), 5.60-5.57 (m, 1H), 5.50-5.49 (m, 1H), 3.29-3.24 (m, 1H), 2.98-2.93 (m, 1H), 2.76 (d, J=4.8 Hz, 3H), 2.24-2.18 (m, 1H), 2.06-2.03 (m, 1H). MS (ESI) m/e [M+1]+ 439.8.