Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.O>CC(C)=O>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(OCc2ccc(F)cc2)cc1
Yield: 92.7 %

Procedure:
Methyl 4-hydroxyphenylacetate (6.00 g, 36.11 mmol) was dissolved in acetone (72 ml), and potassium carbonate (7.49 g, 54.16 mmol) and 4-fluorobenzyl chloride (6.47 ml, 54.16 mmol) were added thereto. After being refluxed for 24 hours, the mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over MgSO4, and then the solvent was evaporated out. The obtained residue was purified by silica gel column chromatography (5% ethyl acetate/hexane), to give methyl 2-{4-[(4-fluorobenzyl)oxy]phenyl}acetate (9.18 g, 93%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]([C:30]1[C:31]([CH3:45])=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1)[S:26]([CH3:29])(=[O:28])=[O:27]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:34]5[CH:35]=[C:30]([N:25]([CH3:24])[S:26]([CH3:29])(=[O:27])=[O:28])[C:31]([CH3:45])=[N:32][CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N(C)S(C)(=O)=O
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1N(C)S(C)(=O)=O

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-methyl-N-[2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-methanesulfonamide (Stage 75.1.1) to give the title compound as a white solid. (HPLC: tR 2.19 min (Method A); M+H=492 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.55-8.51 (m, 1H), 8.16-8.10 (m, 2H), 8.03-7.97 (m, 1H), 7.95-7.91 (m, 1H), 7.60-7.56 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 3.23 (s, 3H), 3.16 (s, 3H), 2.53 (s, 3H), 1.96 (s, 3H))
Reaction SMILES: O1[CH:6]2[CH:2]1[C:3](=[O:34])[CH:4]([CH:23]([OH:33])[C:24]#[C:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:5]2[CH:7]=[CH:8][CH:9]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.[OH:42][CH:43]([CH2:46][OH:47])[CH2:44][SH:45].S([O-])(O)(=O)=O.[K+]>CO>[OH:42][CH:43]([CH2:46][OH:47])[CH2:44][S:45][C:2]1[C:3](=[O:34])[CH:4]([CH:23]([OH:33])[C:24]#[C:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:5]([CH:7]=[CH:8][CH:9]([O:15][Si:16]([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17])[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=1
Reactant: OCC(O)CS
Reactant: COC(=O)CCCC#CC(O)C1C(=O)C2OC2C1C=CC(O[Si](C)(C)C(C)(C)C)C1CCCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCCC#CC(O)C1C(=O)C(SCC(O)CO)=CC1C=CC(O[Si](C)(C)C(C)(C)C)C1CCCC1
Reaction time: 2 h
Yield: 62 %

Procedure:
A 49 mg amount of 2,3-epoxy-5-(1-hydroxy-6-methoxycarbonyl-2-hexynyl)-4-(3-t-butyldimethylsilyloxy-3-cyclopentyl-1-propenyl)cyclopentanone was dissolved in 1 ml of methanol and 21 μl of triethylamine was added. Then, 12 mg of 2,3-dihydroxypropanethiol was added thereto, followed by stirring for 2 hours. The reaction mixture was poured on an aqueous saturated solution of potassium hydrogen sulfate, followed by extracting with ethyl acetate. The extracted solution was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering and concentrating, the concentrate was subjected to silica gel chromatography to give 36 mg (yield 62%) of 2-(2,3-dihydroxypropylthio)-5-(1-hydroxy-6-methoxycarbonyl-2-hexynyl)-4-(3-t-butyldimethylsilyloxy-3-cyclopentyl-1-propenyl)-2-cyclopentenone.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.[CH3:13][C:14]1[N:19]=[C:18]([NH2:20])[N:17]=[C:16]([NH2:21])[C:15]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.F[C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[CH:31][CH:30]=1.[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:20][C:18]1[N:17]=[C:16]([NH2:21])[C:15]([N:22]2[CH2:27][CH2:26][N:25]([C:29]3[CH:30]=[CH:31][C:32]([S:35]([N:38]([CH3:40])[CH3:39])(=[O:36])=[O:37])=[CH:33][CH:34]=3)[CH2:24][CH2:23]2)=[C:14]([CH3:13])[N:19]=1
Reactant: Cc1nc(N)nc(N)c1N1CCNCC1
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1nc(N)nc(N)c1N1CCN(c2ccc(S(=O)(=O)N(C)C)cc2)CC1
Temperature: 120 °C
Yield: 33.2 %

Procedure:
A mixture of 10.4 g (0.05 mole) of 6-methyl-5-(1-piperazinyl)-2,4-pyrimidinediamine triacetate, 10.1 g (0.05 mole) of 4-fluoro-N,N-dimethylbenzenesulfonamide, 6.4 g (0.055 mole) of anhydrous potassium fluoride, and 27.6 g (0.2 mole) of powdered potassium carbonate in 100 ml of dimethylsulfoxide was heated at 120° C. for four hours. The reaction mixture was cooled and poured into 300 ml of ice water. The solid was collected and washed with ml of water. Recystallization from N,N-dimethylformamide gave 6.5 g of the product as an off-white solid, mp 301°-304° C.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][OH:14]>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:21])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:13][O:14][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: CC(CO)(CCCCBr)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Under N2 atmosphere and cooling with an ice bath, 3,4-dihydro-2H-pyran (33.86 g, 0.40 mol) was added dropwise to a stirred solution of 206d (88.0 g, 0.32 mol) and p-toluenesulfonic acid hydrate (0.05 g, 0.03 mmol) in CH2Cl2 (700 mL). After the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The solution was filtered through aluminum oxide (160 g) and the aluminum oxide was washed with CH2Cl2 (800 mL). The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel (hexanes/ethyl acetate=10/1) to give 207d (80.0 g, 70%) as an oil. 1H NMR (CDCl3): δ 7.40-7.14 (m 10H), 4.53 (t, 1H, J=3.4), 4.49 (t, 1H, J=3.4), 3.82 (d, 1H, J=9.4), 3.81 (t, 1H, J=9.4), 3.76-3.60 (m, 2H), 3.44 (m, 2H), 3.36 (d, 2H, J=9.4), 3.33 (t, 4H, J=7.0), 1.90-1.42 (m, 14H), 1.79 (t, 4H, J=6.8), 1.37 (s, 6H), 1.34-1.10 (m, 6H). 13C NMR (CDCl3=77.0 ppm): δ 145.67, 127.91, 127.91, 126.39, 126.37, 125.7, 98.95, 98.81, 76.11, 76.07, 62.78, 61.77, 61.66, 41.88, 41.78, 37.93, 37.75, 33.50, 33.44, 30.59, 30.44, 25.41, 25.37, 22.77, 22.71, 22.62, 19.65, 19.23, 19.15. HRMS (LSIMS, nba): Calcd for C15H28BrO2 (MH+): 355.1272, found: 355.1272.
Reaction SMILES: P(Cl)[Cl:2].P([O-])[O-].[CH2:7]([P:16](OCC)[O:17][CH2:18][CH3:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.C(P(Cl)Cl)C1C=CC(OC)=CC=1>CCOCC>[CH2:7]([P:16]([Cl:2])[O:17][CH2:18][CH3:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: ClPCl
Reactant: CCOP(Cc1ccc(OC)cc1)OCC
Agent: COc1ccc(CP(Cl)Cl)cc1
Agent: [O-]P[O-]
Solvent: CCOCC
Product: CCOP(Cl)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This and other phosphonochloridous esters were best prepared by the procedure of Steininger (Chem. Ber., 1962, 95, 2993) for the comproportionation of the corresponding phosphonous dichloride and phosphonite. Thus, a solution of diethyl p-anisylphosphonite (7.5 g, 36 mmol) in dry ether (20 mL) was added to a solution of p-anisylphosphonous dichloride (8.2 g, 36 mmol) in ether (75 mL) at 5° C. The solution was warmed to room temperature and stirred two hours, then concentrated and distilled (Kugelrohr) at 105°-110° C. (0.1 mmHg). Yield: 9.4 g (60%); IR (neat) 1595, 1500, 1255, 1095, 1025, 930, 824 cm-1 ; 1H NMR (CDCl3) δ7.9-7.5 (m, 2H), 8.1-7.8 (m, 2H), 4.0 (m, 2H), 3.82, (s, 3H), 1.30 (t, J=7 Hz, 3H); 31P NMR (CDCl3) δ177.2 (ca. 90%).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14]C)=[O:13])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[K+].Cl>CCO.O>[C:1]([NH:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([OH:14])=[O:13])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Nc1ccsc1C(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC(=O)Nc1ccsc1C(=O)O
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Methyl 3-(butyrylamino)thiophene-2-carboxylate (1-2, 2.70 g, 11.9 mmol) was dissolved in 1: 1 EtOH/H2O (10 mL) and treated with KOH pellets (2.00 g, 35.6 mmol). The resulting solution was stirred 12 h at 80° C., poured into 1N HCl and cooled to 0° C. The precipitate was filtered, washed with cold Et2O and dried under vacuum to provide 3-(butyrylamino)thiophene-2-carboxylic acid (1-3). MS 214 found 213.2 required.
Reaction SMILES: N1CC[CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18])=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH3:19][N:20]1[CH2:24][CH2:23]N[C:21]1=O>>[CH3:19][N:20]([CH3:21])[CH2:24][C:23]#[C:2][CH2:3][N:15]1[CH2:16][CH2:17][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])[C:14]1=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCNC1=O
Reactant: C1CCNC1
Reactant: CN1CCNC1=O
Product: CN(C)CC#CCN1CCN(C(=O)OC(C)(C)C)C1=O

Procedure:
This product, a liquid, was prepared according to Example 1 by substituting dimethylamine for pyrrolidine and 1-t-butyoxycarbonyl-2-imidazolidinone for 1-methyl-2-imidazolidinone.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl[CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1>>[CH3:21][N:18]1[CH2:19][CH2:20][CH:15]([N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:16][CH2:17]1
Reactant: CN1CCC(Cl)CC1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: CN1CCC(n2cnc(-c3cc(C#N)ccn3)c2)CC1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-1-methylpiperidine according to the procedure for the preparation of Example 43, part A. [M+H] Calc'd for C15H17N5, 268. Found, 268.
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@H:19]([O:34]C(OC)=O)[CH2:20][C@@H:21]3[O:29]C(OC)=O)=[CH:16][C@H:15]4[O:39]C(OC)=O)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.C[O-].[Na+]>CO.O>[CH3:44][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:34])[CH2:20][C@@H:21]3[OH:29])=[CH:16][C@H:15]4[OH:39])[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: COC(=O)O[C@H]1CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
In 5 ml of methanol was dissolved 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3α,7α- tris(methoxycarbonyloxy)pregn-5-ene, followed by addition of 30 mg of sodium methoxide, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured in water and extracted with methylene chloride. The extracts were pooled, washed with aqueous sodium chloride solution and concentrated under reduced pressure. The concentrate was recrystallized from ethyl acetate to give 65 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregn-5-ene-1α,3β,7α-triol showing the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([S:20][CH3:21])=[C:17]([C:22]#[N:23])[C:16]=3[CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:12]([CH3:30])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:31]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35]Br)[CH3:32].Br.CC(C)([O-])C.[Na+]>C1COCC1.C(Cl)Cl.CO>[CH:24]1([C:16]2[C:17]([C:22]#[N:23])=[C:18]([S:20][CH3:21])[S:19][C:15]=2[C:13]2[C:12]([CH3:30])=[CH:11][N:10]=[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:32][CH2:31][N:33]([CH2:37][CH3:38])[CH2:34][CH3:35])[CH:3]=3)[N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CSc1sc(-c2nc(Nc3cccc(N)c3)ncc2C)c(C2CCCCC2)c1C#N
Reactant: CCN(CC)CCBr
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCNc1cccc(Nc2ncc(C)c(-c3sc(SC)c(C#N)c3C3CCCCC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of 5-[2-(3-aminophenylamino)-5-methyl-pyrimidin-4-yl]-4-cyclohexyl-2-methylsulfanyl-thiophene-3-carbonitrile (20 mg, 45.91 micromol) and N,N-diethyl-2-aminobromoethane.HBr (12 mg, 45.91 micromol) in THF was added sodium t-butoxide (9 mg, 91.82 micromol) and the reaction was stirred at ambient temperature overnight. TLC indicated conversion to product (10% MeOH:CH2Cl2). The reaction was partitioned between EtOAc and water, the organics were dried over sodium sulfate then concentrated in vacuo. The crude product was purified by chromatography (silica gel, 5% MeOH:CH2Cl2) to afford VI-26 in 33% yield. δ 0.95 (bs, 6H), 1.0–1.8 (m, 10H), 2.0 (s, 3H), 2.6 (s, 3H), 2.75 (bs, 2H), 3.4 (s, 1H), 3.6 (bs, 2H), 4.0 (bs, 2H), 5.2 (s, 1H), 6.5 (d, 1H), 6.55 (s, 1H), 6.6 (d, 1H), 7.0 (t, 1H), 8.1 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[CH:23]=[CH:22][C:11]([CH2:12][C:13]3[C:19]([Cl:20])=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=3[Cl:21])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[N:26]([O-])=O.[Na+].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.O.Cl[Sn]Cl>C(O)(=O)C.O.Cl>[CH:30](=[N:26][NH:17][C:16]1[CH:18]=[C:19]([Cl:20])[C:13]([CH2:12][C:11]2[CH:22]=[CH:23][C:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=3)=[CH:9][CH:10]=2)=[C:14]([Cl:21])[CH:15]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(Cl)c(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cc2c(Cl)cc(NN=Cc3ccccc3)cc2Cl)cc1
Reaction time: 0.17 h
Yield: 40 %

Procedure:
In 15 ml of acetic acid was dissolved 2.10 g of 4-[4-(4-chlorobenzoyl)benzyl]-3,5-dichloroaniline, and 1.8 ml of conc. hydrochloric acid was added. A solution of 0.41 g of NaNO2 in 1 ml of water was dropwise added to the mixture with stirring at 5 to 10 uA for a period of 10 minutes. The pale brown mixture was stirred at the same temperature for 1 hour, and then 0.60 g of benzaldehyde was added. A solution of 3.36 g of SnCl2.2H2O in 3.4 ml of conc. hydrochloric acid was added for a period of 15 minutes, and the resulting mixture was reacted at 20 to 25° C. for 3 hours. Precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give the above-identified compound as yellow cryatals (yield: 40%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([S:29]([C:32]2[S:33][C:34]([Cl:37])=[CH:35][CH:36]=2)(=[O:31])=[O:30])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[N:13](C(OC(C)(C)C)=O)[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[Cl:37][C:34]1[S:33][C:32]([S:29]([N:10]([S:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:8])=[O:9])[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[NH:13][N:12]=2)(=[O:30])=[O:31])=[CH:36][CH:35]=1
Reactant: COc1cccc2c1c(N(S(=O)(=O)c1ccc(Cl)s1)S(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1cccc2[nH]nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled, ice/water bath, solution of 1,1-dimethylethyl 3-{bis[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazole-1-carboxylate (for a preparation see Intermediate 9) (4.17 g, 6.68 mmol) in DCM (20 mL) was added TFA (10.29 mL, 134 mmol) and the solution was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM (100 mL) and water (50 mL). The organic phase was passed through an hydrophobic frit and the solvent was removed in vacuo to give the product (3.78 g) as a white solid. This was dried in vacuo at 45° C. for 2 days to give the title compound (3.55 g, 100%) as a white solid. LCMS (System A) RT=1.33 min, ES+ve m/z 524/526/528 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(F)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (45 mg, 0.20 mmol) was dissolved in 3 mL of CH2Cl2, treated with 4-fluorophenylisocyanate (28 μL, 0.24 mmol), and stirred at room temperature overnight. The compound of interest precipitated out of solution and was filtered and washed with CH2Cl2 to afford Compound 31 as a white solid, 56 mg, 77% yield: LCMS m/z (%)=359 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.12 (s, 1H), 8.08 (s, 1H), 7.63 (ddd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.54 (m, 2H), 7.48 (d, J=2.8 Hz, 1H), 7.38 (d, JH,F=4.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.05 (dd, J1=9.0 Hz, J2=9.0 Hz, 2H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −123.08 (m, 1F), −177.41 (d, JH,F=5.3 Hz, 1F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH3:12])[C:9]#[N:10].[CH2:13](N)[CH2:14][NH2:15]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:9]1[NH:15][CH2:14][CH2:13][N:10]=1)[CH2:11][CH3:12]
Reactant: CCC(C#N)c1ccccc1F
Reactant: NCCN
Product: CCC(C1=NCCN1)c1ccccc1F

Procedure:
rac-2-[1-(2-Fluoro-phenyl)-propyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2-fluoro-phenyl)-butyronitrile and ethylene diamine in analogy to Example 19 b): light yellow powder; MS (ISP): 207.0 ((M+H)+.).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[NH2:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[F:1][C:2]([F:20])([F:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: FC(F)(F)CCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A mixture of 18.5 g. of 15-(trifluoromethyl)pentadecyl bromide, 17.0 g. of ethyl 4-aminobenzoate, 7.1 g. of potassium carbonate, and 75 ml. of hexamethylphosphoramide is stirred for 16 hours at 120° C., allowed to cool, diluted with water, and filtered. The solid is dissolved in methylene chloride and the solution is dried over anhydrous magnesium sulfate and evaporated. The residual brown oil is crystallized from ethanol and recrystallized from acetonitrile to yield the product as a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:15](=[O:16])[C:14]2=[CH:17][N:18]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[N:19]=[C:13]2[N:12]([CH2:31][C:32]([CH3:34])=[CH2:33])[C:11]1=[O:35].CC1C=C[C:40]([S:43](OCCCO[Si](C)(C)C(C)(C)C)(=O)=S)=[CH:39]C=1.[C:58](=[O:61])(O)[O-].[Na+]>O1CCCC1>[OH:61][CH2:58][CH2:39][CH2:40][S:43][C:17]1[N:18]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[N:19]=[C:13]2[C:14]=1[C:15](=[O:16])[N:10]([CH3:9])[C:11](=[O:35])[N:12]2[CH2:31][C:32]([CH3:34])=[CH2:33]
Reactant: C=C(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3cccc4ccccc34)nc21
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=S)OCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)n(Cc3cccc4ccccc34)nc21
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of lithium diisopropylamide (1.12 mmol) in tetrahydrofuran (6 ml) was added dropwise to a stirred solution of 5-methyl-7-(2-methyl-2-propenyl)-2-(1-naphthalenylmethyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6[5H,7H]-dione (0.20 g) and 3-{[dimethyl(1,1-dimethylethyl)silyl]oxy }propyl 4-methylphenylthiosulfonate (J. Med. Chem. 1995, 38, 2557) (0.262 g) in anhydrous tetrahydrofuran (20 ml) at -70° C. The solution was stirred for a further 1 hour at -70° C. and then allowed to warm to room temperature. Saturated aqueous sodium bicarbonate solution (10 ml) was added and the mixture was extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual oil was purified by column chromatography over silica eluting with acetone:hexane (1:5). The product was dissolved in acetonitrile (5 ml) and treated with 40% aqueous hydrofluoric acid (1 ml). After 5 minutes, the solution was neutralised with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica eluting with acetone:hexane (1:5 then 1:3) followed by recrystallisation from diethyl ether/hexane to give the title compound (0.11 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][C:11]([NH:13][CH:14]([B:27]3[O:35][CH:34]4[C:29]([CH3:39])([CH:30]5[CH2:36][CH:32]([CH2:33]4)[C:31]5([CH3:38])[CH3:37])[O:28]3)[CH2:15][C:16]3[C:17]([O:25][CH3:26])=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=[O:20])=[O:12])=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:40]=O>[Pd].CO>[CH3:26][O:25][C:17]1[C:16]([CH2:15][CH:14]([NH:13][C:11](=[O:12])[CH2:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][N:2]([CH3:40])[CH2:3]3)[B:27]2[O:35][CH:34]3[C:29]([CH3:39])([CH:30]4[CH2:36][CH:32]([CH2:33]3)[C:31]4([CH3:38])[CH3:37])[O:28]2)=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: C=O
Reactant: COc1c(CC(NC(=O)Cc2ccc3c(c2)CNC3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Agent: [Pd]
Solvent: CO
Product: COc1c(CC(NC(=O)Cc2ccc3c(c2)CN(C)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Reaction time: 18 h

Procedure:
A solution of 3-[2-(2-2,3-Dihydro-1H-isoindol-5-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid (0.110 g, 0.207 mmol), formaldehyde (37% in H2O, 0.06 mL, 0.740 mmol), and methanol (2.5 mL) was purged with argon. Palladium on carbon (10%, 0.049 g) was added, the flask evacuated, and the reaction placed under hydrogen for 18 hr. The reaction mixture was filtered through a Celite-plugged filter frit, washed with CH3OH and CH2Cl2, and concentrated. The crude product was carried forward without purification. ESI-MS m/z 547 (MH)+.