Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1.[NH4+].[Cl-]>O1CCCC1.O=O>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:7][C:6]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)([OH:9])[CH2:5][CH2:4]1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: O=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCC(c3ccccc3)(N(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(dimethylamino)-4-phenylcyclohexanone (4.34 g, 20 mmol) was dissolved in absolute tetrahydrofuran (60 ml) with the exclusion of oxygen, mixed with 4-methoxy phenyl magnesium bromide solution (90 ml, 45 mmol, 0.5N) with ice cooling and boiled for 2 h with reflux. For work up the batch was mixed with saturated NH4Cl solution (50 ml) with ice cooling and stirred for 10 min at room temperature. The aqueous phase was separated off and extracted with ethyl acetate (3×25 ml). The combined organic phases were dried over Na2SO4 and then concentrated to low volume. A raw product was isolated that was purified by chromatography [silica gel 60 (50 g); ethyl acetate (1000 ml), methanol (1000 ml)]. 2.016 g (31%, mp 174-175° C.) of more non-polar and 2.51 g (39%, mp 149-151° C.) of more polar product were obtained. Both could be recrystallised from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23]1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCC(C)C2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCC(C)C2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(3-methylpyrrolidin-1-yl)ethanamine.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[NH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24].C(N(CC)C(C)C)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][P:21]([O:22][CH2:23][CH3:24])([O:25][CH2:26][CH3:27])=[O:28])[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: CCOP(=O)(CCCCON)OCC
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CCCCONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Temperature: 100 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
4,6-Dichloro-2,5-diformamidopyrimidine (0.35 g, 1.5 mmol), diethyl 4-(aminooxy)butylphosphonate (0.216 g, 0.93 mmol) and N,N-diisopropylethylamine (0.521 ml, 3 mmol) were dissolved in diglyme (15 ml) and stirred at 100° C. for 3 hr. The reaction mixture was then allowed to cool, the hydrochloride of N,N-diisopropylethylamine was filtered off and the filtrate was diluted with chloroform (150 ml). The resulting solution was washed with 4% aq. NaHCO3 (1×20 ml) and water (1×20 ml). The combined aqueous layers were extracted with chloroform (4×20 ml) and the combined chloroform solutions were evaporated to dryness. The residue was chromatographed on silica gel (eluted with chloroform-ethanol, 96:4) to yield the title compound (0.330 g, 81%). 1H NMR: δH ((CD3)2SO) 1.22 (6H, t, J=7Hz, (OCH2CH3)2), 1.7 (6H, m, CH2CH2CH 2 P), 3.87 (2H, t, J=5Hz, OCH2), 3.98 (4H, m, (OCH2CH3)2) 8.14 (1H, s, 5-NHCHO), 8.31 (1H, s, 6-NHCHO), 9.24 (1H, br.s, 2-NHCHO), 9.41 (1H, br.s, D2O exchangeable, NHOCH2), 10.81 (2H, br.s, D2O exchangeable, NHCHO, NHCHO).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH3:23])=[CH:20][C:19]([NH:24][C:25]1[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=1)=[CH:18][CH:17]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:57]1([CH2:62]/[CH:63]=[CH:64]/[CH2:65]O)[CH2:61][CH2:60][CH2:59][CH2:58]1>CN(C=O)C.ClCCl>[CH3:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH3:23])=[CH:20][C:19]([NH:24][C:25]1[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:65]/[CH:64]=[CH:63]/[CH2:62][N:57]4[CH2:61][CH2:60][CH2:59][CH2:58]4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=1)=[CH:18][CH:17]=2
Reactant: COc1cc2c(Nc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1O
Reactant: OC/C=C/CN1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OC/C=C/CN1CCCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
Diethyl azodicarboxylate (65 μl, 0.4 mmol) was added in portions to a suspension of 4-(2,3-dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg, 0.2 mmol), triphenylphosphine (107 mg, 0.4 mmol), (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (40 mg, 0.28 mmol) in DMF (0.4 ml) and dichloromethane (1.5 ml) cooled at 0° C. The reaction mixture was left to warm up to ambient temperature and was stirred overnight. The mixture was poured onto a column of silica and was eluted with methylene chloride followed by methylene chloride/methanol (98/2), followed by methylene chloride/3N ammonia in methanol (95/5 and 90/10) to give 4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-((E)-4-(pyrrolidin-1-yl)but-2-en-1-yloxy)quinazoline (51 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH2:12]([S:14](Cl)(=[O:16])=[O:15])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:14]([CH2:12][CH3:13])(=[O:16])=[O:15])[CH2:7][CH2:6][CH2:5]2
Reactant: CCS(=O)(=O)Cl
Reactant: Brc1ccc2c(c1)CCCN2
Product: CCS(=O)(=O)N1CCCc2cc(Br)ccc21
Yield: 36.5 %

Procedure:
This compound was prepared according to the general procedure for sulfonylation of indolines and tetrahydroquinolines described in Example 4 using 6-bromo-1,2,3,4-tetrahydroquinoline (0.40 g, 1.89 mmol) and ethanesulfonyl chloride (0.26 mL, 2.8 mmol) to provide 6-bromo-1-(ethylsulfonyl)-1,2,3,4-tetrahydroquinoline (0.21 g). MS (ES) m/z 303.7; HPLC purity 94.8% at 210-370 nm, 9.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)=O.[CH3:14][C:15]1([CH3:28])[C@@H:17]2[CH2:18][C:19]3[C:23]([C@H:16]12)=[C:22]([CH3:24])[S:21][C:20]=3[C:25](=[O:27])[CH3:26].[OH-].[K+].Cl>CO.O>[O:27]=[C:25]([C:20]1[S:21][C:22]([CH3:24])=[C:23]2[C:19]=1[CH2:18][C@H:17]1[C:15]([CH3:28])([CH3:14])[C@H:16]12)[CH:26]=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(CCC(=O)O)cc1
Reactant: CC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1sc(C(=O)C=Cc2ccc(CCC(=O)O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Yield: 41.1 %

Procedure:
A solution of 3-(4-formyl-phenyl)-propionic acid (142 mg, 0.80 mmol), (1aS,5aR)-1-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (176 mg, 0.80 mmol), KOH (2.8 g, 50 mmol) in methanol (25 mL) is stirred at 70° C. for 1 h. The reaction mixture is diluted with water (400 mL) and acidified by adding 2 N aq. HCl. The mixture is extracted twice with DCM, the organic extracts are combined, dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC (Waters Xterra MS18 30×75 mm, 10 to 95% acetonitrile in water containing 0.5% formic acid) to give 3-{4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propenyl]-phenyl}-propionic acid (125 mg) as yellow resin; LC-MS: tR=1.07 min, [M+1]+=381.18.
Reaction SMILES: C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[CH2:13]([O:15][P:16]([O-:20])[O:17][CH2:18][CH3:19])[CH3:14].[C:21]1(=[O:27])[CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]1.Cl>ClCCl>[CH2:13]([O:15][P:16]([CH:23]1[CH2:24][CH2:25][CH2:26][C:21](=[O:27])[CH2:22]1)(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]
Reactant: CCOP([O-])OCC
Reactant: O=C1C=CCCC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: CCOP(=O)(OCC)C1CCCC(=O)C1
Reaction time: 1 h
Yield: 95 %

Procedure:
0.52 mmol trimethylsilyltriflate is added dropwise to 11.4 mmol diethylphosphite and 12.4 mmol N,O-bis-(trimethylsilyl)acetamide in 5 ml dichlormethane at 0° C. After 30 minutes of stirring at the same temperature 0.52 mmol 2-cyclohexen-1-one are added dropwise thereto and is stirred for 1 h. The enolsilane intermediate product is hydrolized by 3 ml 1 n HCl during 3 hours of stirring. The organic phase is separated, dried over magnesiumsulfate and concentrated. The raw product can be chromatographed on SiO2 and after concentration of the desired fractions results in 3-oxo-cyclohexylphosphonic acid diethylester 2(a) in a 95% yield.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=O)[NH2:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.S(Cl)([Cl:17])=O>P(Cl)(Cl)(Cl)=O>[Cl:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: NC(=O)c1ccc2ncnc(O)c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2ncnc(Cl)c2c1

Procedure:
A mixture comprising 2 g of 4-hydroxy-6-carbamoylquinazoline, 30 ml of thionyl chloride and 60 ml of phosphorus oxychloride was heated under reflux for 20 hours. The reaction mixture was concentrated under a reduced pressure and the obtained residue was dissolved in 100 ml of ethyl acetate. The obtained solution was washed with water (150 ml), dried over magnesium sulfate and concentrated under a reduced pressure. The obtained residue was introduced into a silica gel column, followed by eluting with ethyl acetate and acetone to give 800 mg of the title compound.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37](N3C(=O)CCC3=O)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>CC(C)=O.O>[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([N:1]3[C:10]4[C:5](=[CH:6][C:7]([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CC(CC(=O)O)c1ccc2c(c1)CCCN2
Reactant: O=C1CCC(=O)N1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(CC(=O)O)c1ccc2c(c1)CCCN2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.8 %

Procedure:
A suspension of (R/S) 3-(1,2,3,4-tetrahydro-quinolin-6-yl)-butyric acid (2.6 g) and sodium bicarbonate (2.2 g) in acetone (40 ml) and water (40 ml) was treated with 2,5-dioxo-pyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (4.0 g) and the resulting mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate evaporated to low bulk. The residue was treated with dilute hydrochloric acid and the resulting gummy precipitate was extracted into a mixture of tetrahydrofuran, ethyl acetate and dichloromethane. This solution was washed with brine, then dried and then evaporated to give the title compound (5.8 g) as a light brown oil, which solidified on standing. MS (ES+) 464 (MNa+), MS (ES−) 440 (M−).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[OH:13][C:14]1[CH:18]=[C:17]([N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:19]1([C:17]2[S:16][C:15]([C:28]([O:30][CH3:31])=[O:29])=[C:14]([O:13][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=3)[CH:18]=2)[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[N:21]=[CH:20]1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1cccc(C(F)(F)F)c1

Procedure:
In a similar manner as described for example B14, 102.8 mg of 3-(trifluoromethyl)benzyl bromide, 100 mg of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate, 59.7 mg of potassium carbonate in 3 ml anhydrous DMF yield the title compound.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([CH2:30][C:31](=O)[CH3:32])[C:27]([CH3:29])=O>C(O)(=O)C.C1C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([N:25]5[C:31]([CH3:32])=[CH:30][CH:26]=[C:27]5[CH3:29])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Reactant: CC(=O)CCC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: Cc1ccc(C)n1-c1ccc2c(c1)ncn2-c1ccnc(N[C@@H](C)c2ccccc2)n1
Temperature: 25 °C

Procedure:
2-[(S)-1-Phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine (EXAMPLE 79) (100 mg) and acetonyl acetone(0.04 mL)and acetic acid (20 drops) were dissolved in benzene (10 mL) and refluxed with Dean-Stark apparatus for 2 hours. After cooling to room temperature, the solution was then diluted with 10 mL of aqueous saturated NaHCO3 and extracted with 2×10 mL of of EtOAc. The combined organic extracts were then dried (MgSO4) and concentrated under reduced pressure. The residue was purified with preparatory thin-layer chromatography (SiO2, 5% MeOH in CH2Cl2) to yield 17 mg of the title compound. Mass spectrum (ESI) 408.1 (M+).
Reaction SMILES: C([O:3][C:4](=[O:25])[C@@H:5]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=2[F:23])=[CH:12][C:11]1=[O:24])[CH2:6][CH:7]([CH3:9])[CH3:8])C.O.[OH-].[Li+]>O1CCCC1>[F:23][C:17]1[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:13]1[CH2:14][N:10]([C@@H:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:25])=[O:3])[C:11](=[O:24])[CH:12]=1
Reactant: CCOC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(C)c2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Temperature: 20 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution containing (S)-2-[4-(2-fluoro-3-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (1.50 g, 0.004 mol) in tetrahydrofuran (40 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 20 mL, 0.010 mol). The mixture was stirred at 20° C. for 2 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(2-fluoro-3-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1.2 g, 87%) as a tan solid.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2F)[N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+]>O1CCCC1>[F:23][C:20]1[CH:21]=[C:22]2[C:17]([C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)=[N:8][N:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:18][CH:19]=1
Reactant: CN1CCN(C(=NNc2ccccc2)c2ccc(F)cc2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2nn(-c3ccccc3)c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution, under nitrogen, 17.0 g of 1-[(phenylhydrazono)(2,4-difluorophenyl)methyl]-4-methylpiperazine in 200 ml of tetrahydrofuran was added dropwise a solution of 7.1 g of potassium t-butoxide in 75 ml of tetrahydrofuran. The reaction mixture was stirred at ambient temperature for 2 hours, then concentrated, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to yield 6-fluoro-1-phenyl-3-(4-methyl-1-piperazinyl)-1H-indazole as an oil. The oil was dissolved in ethanol-diethyl ether and treated with ethereal hydrogen chloride to precipitate the hydrochloride salt. Recrystallization from methanol yielded 9.0 g, (45%) of 6-fluoro-1-phenyl-3-(4-methyl-1-piperazinyl)-1H-indazole hydrochloride, m.p. 298°-300°. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:24]N1C(=O)CCC1=O>CC(N(C)C)=O.ClCCl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[C:9]([Br:24])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Nc1ncnc2[nH]c(Br)c(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (302 mg) was dissolved in dimethylacetamide (10 ml) and dichloromethane (50 ml) and then treated with N-bromosuccinimide (178 mg) in dichloromethane (10 ml). The mixture was left stirring ambient temperature for 16 hours. The mixture was evaporated under reduced pressure and the residue was triturated with water to give a solid which was collected by filtration and dried to give 4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine, m.p. 282-283° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>S1(CCCC1)(=O)=O>[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: CSc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 150 °C
Yield: 99.7 %

Procedure:
A mixture of 23.6 g (0.150 mole) of 4-nitrochlorobenzene, 23.1 g (0.165 mole) of 4-(methylthio)phenol, 22.8 g (0.165 mole) of anhydrous K2CO3 and 150 ml of sulfolane was heated at 150° C. for 6 hrs. The product was recovered (39.1 g, 99.7% yield) as described in Example 1 and recrystallized from ethanol, which gave purified 1-(methylthio)-4-(4-nitrophenoxy)benzene, mp 59°-61° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH:5]=[C:6]([O:8]C)[CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C>C(#N)C.O>[I:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH:3]=1
Reactant: COc1cc(I)cc(-c2ccsc2)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Oc1cc(I)cc(-c2ccsc2)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a suspension of 3-(3-iodo-5-methoxy-phenyl)-thiophene (2.08 g, 6.7 mmol) and sodium iodide (65.73 mmol, 9.85 g) in acetonitrile (80 mL) was added trimethylsilyl chloride (32.86 mmol, 4.16 mL) at room temperature. Then, the resulting light yellow suspension was heated to reflux for 48 h. Then, it was cooled to room temperature and diluted with water (50 mL). The organic compound was extracted into ethyl acetate (2×75 mL) and the combined ethyl acetate extracts were washed with saturated sodium thiosulfate solution (100 mL) to remove the iodine color and was also washed with brine solution (100 mL). Then, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by using an ISCO 120 g column, eluting with 0-20% ethyl acetate in hexanes to obtain 3-iodo-5-thiophen-3-yl-phenol (1.92 g, 97%) as a light brown oil: ES(+)-HRMS m/e calculated for C10H7IOS (M−H)+ 300.9189, found 300.9189.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=1.[CH2:9]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>N1C=CC=CC=1>[CH2:9]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[S:3][C:4]([CH2:7][CH3:8])=[N:5][N:6]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1nnc(N)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CC)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
2-Amino-5-ethyl-1,3,4-thiadiazole (169 mg, 1.3 mmol) was suspended in pyridine (0.5 mL). p-Dodecylbenzenesulfonyl chloride (300 mg, 0.87 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred at this temperature for 1 h. The reaction mixture was then added to aqueous 10% HCl (5 mL) and the resulting mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and volatiles evaporated to yield a solid mass. Chromatography on silica gel (70-230 mesh) eluted with 2% MeOH in CH2Cl2 gave the product (225 mg, 0.51 mmol, 59%). Recrystallization from hexanes:ethyl acetate (3:7) gave an analytical sample, mp 93-94° C.; 1H NMR (500 MHz, CDCl3) δ 0.88 (3, t, J=6.5 Hz), 1.20-1.36 (18, m), 1.33 (3, t, J=7.5 Hz), 1.54-1.63 (2, m), 2.63 (2, t, J=7.5 Hz), 2.84 (2, q, J=7.5 Hz), 7.25 (2, d, J=8.5 Hz), 7.83 (2, d, J=8.5 Hz), 12.30 (1, br s); 13C NMR (125 MHz, CDCl3) δ 12.6, 14.1, 22.7, 24.4, 29.2, 29.3, 29.4, 29.5, 29.6, 31.1, 31.9, 35.9, 126.5, 128.8, 138.4, 148.2, 160.1 168.2; MS (ESI+, m/z) Calcd for C22H36N3O2S2 438.2249. found 438.30 (M+H)+; HRMS (ESI+, m/z) Calcd for C22H36N3O2S2 438.2249. found 438.2247 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][N:12]=2)[CH2:3][CH2:2]1.[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl>[F:17][C:18]([F:28])([F:29])[O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:9][C:10]([C:13]([F:16])([F:14])[F:15])=[N:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1nnc(NC2CCNCC2)s1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCCl
Product: FC(F)(F)Oc1cccc(CN2CCC(Nc3nnc(C(F)(F)F)s3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
A mixture of piperidin-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amine (D4) (0.025 g, 0.10 mmol), 3-trifluoromethoxy-benzaldehyde (0.034 ml, 0.29 mmol) and polymer supported triacetoxyborohydride (2.07 mmol/g) (0.165 g, 0.29 mmol) in 1,2-dichloroethane (2 ml) was shaken at room temperature for 16 h. After this period, the reaction mixture was filtered through an Isolute SCX-2 cartridge. The cartridge was washed with methanol. The crude product was eluted with a 7M solution of ammonia in methanol. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 5% ammonia in methanol (7M)/dichloromethane) to yield E13 (0.029 g, 68%) as a white solid. C16H16F6N4OS requires 426. Found 427 (MH+).