Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[S:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([F:13])[C:6]=1O.CS(O)(=O)=O>C(Cl)Cl>[CH3:1][N:2]([CH3:16])[C:3]1[S:15][C:10]2[CH:9]=[C:8]([O:11][CH3:12])[C:7]([F:13])=[CH:6][C:5]=2[CH:4]=1
Reactant: COc1ccc(CC(=S)N(C)C)c(O)c1F
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: COc1cc2sc(N(C)C)cc2cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 139.3 %

Procedure:
A solution of 16.6 g (68.2 mmol) of N,N-dimethyl-3-fluoro-4-methoxy-2-hydroxyphenylthioacetamide (Part A) in 400 mL of CH2Cl2 was treated with 22.0 mL (339.0 mmol) of MeSO3H in a dropwise manner. The reaction was stirred at room temperature for 4 h, was cooled to 0° C., and was quenched by the careful addition of 500 mL of saturated aqueous NaHCO3. The two layers were separated and the aqueous layer was extracted with EtOAc (5×200 mL). The combined organic layers were washed with 500 mL of saturated aqueous NaHCO3 and 500 mL of H2O, dried over Na2SO4, and filitered. Evaporation of the solvent in vacuo afforded 21.4 g of an oil which was purified by flash chormatography (SiO2; gradient of 10% then 20% EtOAc in hexanes) to give 2.87 g (12.7 mmol; 19%) of the title compound as a light pink solid
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]=[C:10]=[S:11])=[C:4]([F:12])[CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>ClCCl>[Cl:1][C:2]1[C:7]([O:8][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:6][C:5]([N:9]=[C:10]=[S:11])=[C:4]([F:12])[CH:3]=1
Reactant: C1=COCCC1
Reactant: Oc1cc(N=C=S)c(F)cc1Cl
Solvent: ClCCl
Product: Fc1cc(Cl)c(OC2CCCCO2)cc1N=C=S
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.4 %

Procedure:
A dichloromethane solution containing 0.10 g of 4-chloro-2-fluoro-5-hydroxyphenylisothiocynate and 0.04 g of 2,3-dihydropyran, was stirred at room temperature for 5 hours. Then, dichloromethane was distilled off, and the residue was washed with diisopropyl ether to obtain 0.11 g of the above-identified compound as white crystals.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH:1]1([O:7][N:9]2[C:13](=[O:14])[C:12]3[C:11](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OC1CCCCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A solution of triphenylphosine (15.53 g, 59.2 mmol), cyclohexanol (6.25 mL, 59.2mmol), and N-hydroxypthalimide (9.66 g, 59.2 mmol) in anhydrous tetrahydrofuran (500 mL) under Argon was treated dropwise over approximately 20 minutes with a solution of di-tert-butyl azodicarboxylate (15.00 g, 65.14 mmol) in tetrahydrofuran (100 mL) with a water bath to control the exotherm. After the reddish color had dissipated, a mixture of di-tert-butyl azodicarboxylate (3.00 g, 13.0 mmol) and triphenylphosine (3.11 g, 11.8 mmol) in anhydrous tetrahydrofuran (50 mL) was added to the reaction mixture and allowed to stir overnight at ambient temperature. After evaporation in vacuo, the residue was treated with trifluoroacetic acid (100 mL) and stirred for 20 minutes. The reaction was evaporated in vacuo and the residue was partitioned between water and dichloromethane. The layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified twice by flash silica gel chromatography eluting with hexane : ethyl acetate (4:1 and 9:1). Pure fractions were concentrated in vacuo to a solid and dried under high vacuum to provide 2-(cyclohexyloxy)-1H-isoindole-1,3(2H)-dione as a solid (10.90 g, 75%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:30]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:29])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:28])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21]C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[N:6]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:46]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:30][C:4]1[S:3][C:2]([C:49]2[CH:50]=[C:45]([Cl:44])[CH:46]=[CH:47][C:48]=2[Cl:51])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:28])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH2:21])[CH2:16][CH2:15]1)=[O:29]
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: COCCOC
Solvent: O
Product: Cn1ncc(NC(=O)c2nc(-c3cc(Cl)ccc3Cl)sc2N)c1N1CCC[C@@H](N)CC1
Temperature: 130 °C
Reaction time: 6 h
Yield: 12.5 %

Procedure:
A mixture of (R)-tert-butyl 2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (122 mg, 0.20 mmol), Na2CO3 (42 mg, 0.40 mmol) and 2,5-dichlorobenzeneboronic acid (38 mg, 0.20 mmol) in DME (1.5 mL) and water (0.5 mL) was degassed by gently bubbling nitrogen through the mixture for 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (16 mg, 0.020 mmol) was added and the mixture degassed for a further 10 min before being heated in a microwave at 130° C. for 35 min. Water was added and the mixture extracted with EtOAc. The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane). The isolated intermediate was dissolved in a mixture of DCM (1.5 mL) and TFA (0.5 mL) and stirred at room temperature for 6 hr. The solvents were removed under reduced pressure and the residue dissolved in a mixture of MeOH/water (3 mL, 1:1) and K2CO3 (55 mg, 0.40 mmol) added. The mixture was heated at 60° C. for 3 hr. The mixture was concentrated under reduced pressure and the residue purified by preparative HPLC to yield 350 as a yellow solid (12 mg, 29%). 1H NMR (400 MHz, d4-MeOD) δ 8.35 (d, J=2.6 Hz, 1H), 7.56 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.39 (dd, J=8.6, 2.6 Hz, 1H), 3.76 (s, 3H), 3.35-3.31 (m, 4H), 3.11-3.09 (m, 1H), 2.04-1.91 (m, 3H), 1.76-1.67 (m, 3H). LCMS (ES+) m/z 480 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:37]=[CH:36][C:35]([C:38]2[N:43]=[C:42]3[N:44]=[C:45]([SH:55])[N:46](COCC[Si](C)(C)C)[C:41]3=[CH:40][C:39]=2[Cl:56])=[CH:34][CH:33]=1.[Si](O[C@H:71]1[C@H:75]2[O:76][CH2:77][C@H:78]([OH:79])[C@H:74]2[O:73][CH2:72]1)(C(C)(C)C)(C)C>C1COCC1>[C:32]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:37]=[CH:36][C:35]([C:38]2[N:43]=[C:42]3[N:44]=[C:45]([S:55][C@H:71]4[C@H:75]5[O:76][CH2:77][C@@H:78]([OH:79])[C@H:74]5[O:73][CH2:72]4)[NH:46][C:41]3=[CH:40][C:39]=2[Cl:56])=[CH:34][CH:33]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Reactant: C[Si](C)(C)CCOCn1c(S)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Sc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (34.1 mg, 0.130 mmol) and DEAD (0.021 ml, 0.130 mmol) were added to a stirred mixture of 5-([1,1′-biphenyl]-4-yl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-2-thiol (30.4 mg, 0.065 mmol) and (3S,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-ol (25.4 mg, 0.097 mmol) in THF (1 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative TLC, eluting with EtOAc/isohexane (2:8) to give the title compound. LC-MS: calculated for C36H48ClN3O4SSi2 709.26 observed m/e: 710.42 (M+H)+ (Rt 1.59/2 min);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[CH:9]1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)([O-:29])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([O:15][C:33]2[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=2)=[O:14])[N:10]=[CH:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(C(=O)O)c3)c(F)c2)C(=O)O1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
N-[(5S)-3-(3-Fluoro-4-(4-carboxyimidazol-1-y l)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (181 mg, 0.5 mM), 4-nitrophenol (139 mg, 1 mM), dicyclohexylcarbodiimide (144 mg, 0.7 mM) and 4-dimethylaminopyridine (61 mg, 0.5 mM) were dissolved in N,N-dimethylformamide (2 ml). The mixture was stirred at ambient temperature for 17 hours, diluted with dichloromethane (20 ml), washed with 1M aqueous sodium dihydrogen phosphate (10 ml), water (2×10 ml), and dried over magnesium sulfate. After filtration and evaporation to a suitable volume, the solution was chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give title product (210 mg).
Reaction SMILES: [Mg].[CH2:2]([N:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7]Cl)[CH3:3].BrC(Br)C.[CH3:15][N:16]1[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][C:21]=2[N:20]=[CH:19][C:18]2=[CH:27][CH:28]=[CH:29][N:17]12.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH2:2]([N:4]([CH2:5][CH2:6][CH2:7][C:19]1[C:18]2[N:17]([CH:29]=[CH:28][CH:27]=2)[N:16]([CH3:15])[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][C:21]=2[N:20]=1)[CH2:9][CH3:10])[CH3:3]
Reactant: CCN(CC)CCCCl
Reactant: CN1c2ccncc2N=Cc2cccn21
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(CC)CCCC1=Nc2cnccc2N(C)n2cccc21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To magnesium turnings (1.9 g) in 10 ml of diethyl ether and 10 ml of tetrahydrofuran, was added a solution of 11.66 g of 3-diethylaminopropyl chloride in 10 ml of tetrahydrofuran. The reaction was initiated by the addition of 1 ml of dibromoethane and the application of heat. After stirring at 70° C. for four hours, the reaction mixture cooled to room temperature and treated, dropwise, with a solution of 7.7 g of 5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine in 50 ml of tetrahydrofuran. The mixture was then stirred at room temperature for two hours, poured into an iced ammonium chloride solution, and extracted with ethyl acetate (3×). The combined extracts were washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. High pressure liquid chromatography of the concentrate (silica gel; elution with 15% methanol/dichloromethane) afforded 10-[3-(N,N-diethylamino)propyl]-5-methyl-5H-pyrido[3,4-f]pyrrolo-[1,2-b] [1,2,5]triazepine as an oil. The oil was dissolved in ethanol and acidified with an ethanol solution of fumaric acid. Diluting with diethyl ether precipitated 3.05 g of the corresponding sesquifumarate salt, mp 170°-172° C.
Reaction SMILES: [Cl:1][C:2](=[CH2:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:29](=S)=[S:30]>C(OCC)C>[Cl:1][C:2](=[CH2:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:10]=[C:29]=[S:30])=[CH:7][CH:6]=1
Reactant: C=C(Cl)COc1ccc(CN)cc1
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: C=C(Cl)COc1ccc(CN=C=S)cc1
Temperature: -10 °C
Reaction time: 12 h

Procedure:
6.7 g of 4-(2-chloro-2-propeneoxy)benzylamine was added dropwise to a mixture of 7.7 g of DCC, 20 ml of carbon disulfide and 100 ml of diethyl ether with stirring at -10° C. The temperature of the mixture was returned to room temperature, and it was left to stand for 12 hours. The reaction solution was filtered, and the residue was washed with diethyl ether and combined with the filtrate. The solvent was evaporated under reduced pressure. The resulting oily product was purified by column chromatography (silica gel; developing solvent hexane) to give 6.6 g of the desired 4-(2-chloro-2-propeneoxy)benzyl isothiocyanate as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([F:42])[CH:40]=3)[NH:35][CH:34]=2)[CH2:29]1.C(N(CC)CC)C>CS(C)=O>[F:42][C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[C:33]2[CH2:32][CH:30]1[CH2:31][N:28]([CH2:16][CH:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)[CH2:29]1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Fc1ccc2[nH]cc(CC3CNC3)c2c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(Cc2c[nH]c4ccc(F)cc24)C1)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.35 g,.0.80 mmol), 3-azetidin-3-ylmethyl-5-fluoro-1H-indole (0.19 g, 0.96 mmol) and triethylamine (0.16 mL, 1.2 mmol) in dimethylsulfoxide (20 mL) was heated at 90° C. under nitrogen overnight. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×80 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The resulting crude oil was column chromatographed on silica gel (3% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.090 g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate and collected as 0.068 g of a yellow solid, m.p. 125° C. (dec).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])[C:6](=[O:12])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:3].[CH:24]([Mg]Br)=[CH2:25]>C1COCC1>[CH3:3][CH:2]([CH2:4][C@H:5]([NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])[C:6]([OH:12])([CH:24]=[CH2:25])[CH2:7][CH2:8][CH:9]([CH3:10])[CH3:11])[CH3:1]
Reactant: C=C[Mg]Br
Reactant: Cc1ccccc1S(=O)(=O)N[C@@H](CC(C)C)C(=O)CCC(C)C
Solvent: C1CCOC1
Product: C=CC(O)(CCC(C)C)[C@H](CC(C)C)NS(=O)(=O)c1ccccc1C
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred 0° C. solution of the resultant compound of Example 37 (79 mg, 0.23 mmol) in dry THF (8 ml) was added vinyl magnesium bromide (1.5 ml of a 1.0M solution in THF) dropwise. The mixture was warmed (room temperature, 10 hours), quenched (8 ml H2O+2 ml brine), acidified with 0.1M H3PO4 (pH=7), and extracted with ether (3×4 ml). The combined ether phase was washed (4 ml brine), dried (Na2SO4), filtered, and evaporated to give 81 mg (95%) of the desired product as a 4:1 mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([N+:23]([O-:25])=[O:24])=[C:13]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:12]=1)C(OCC)=O)[CH3:2]>CC(O)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:11]1[CH:12]=[C:13]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:14]([N+:23]([O-:25])=[O:24])=[C:15]([O:17][CH2:18][C:19]([F:21])([F:22])[F:20])[CH:16]=1)[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(OCC(F)(F)F)c([N+](=O)[O-])c(OCC(F)(F)F)c1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc(OCC(F)(F)F)c([N+](=O)[O-])c(OCC(F)(F)F)c1
Yield: 56.6 %

Procedure:
Crude 2-[4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-malonic acid diethyl ester (20.8 g, 43.6 mmol) was dissolved in a mixture of AcOH/12 N HCl (150 mL/150 mL) and the reaction mixture was refluxed for 16 h. The solvent was evaporated and water (100 mL) was added. The reaction mixture was extracted with EtOAc (3×100 mL). The organic layers were combined, washed with water (3×100 mL), and dried over MgSO4. The solvent was evaporated under reduced pressure to give a brown solid, which was washed with a mixture of Heptane/Et2O (100 mL/100 mL) to give [4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester as a solid (10.0 g, 57%). 1H NMR (300 MHz, CDCl3/TMS): δ 6.71 (s, 2H), 4.45 (q, J=7.7 Hz, 4H), 4.18 (q, J=7.2 Hz, 2H), 3.63 (s, 2H), 1.28 (t, J=7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ 169.7, 149.6, 138.5, 132.4, 122.4 (q, 1JCF=277.6 Hz), 109.4 (two signals), 67.0 (q, 2JCF=37.2 Hz), 61.6, 41.4, 14.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[CH:14]=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1.C1C(=O)N([I:24])C(=O)C1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([I:24])=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccccc1-c1ccc2[nH]ccc2n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1ccc2[nH]cc(I)c2n1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
A solution of 5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridine (199 mg, 0.938 mmol) in THF (10 mL) was treated with n-iodosuccinimide (232 mg, 1.031 mmol, Alfa-Aesar). The reaction was stirred at 23° C. under N2. After 45 min, the solution was diluted with EtOAc (75 mL) and washed with brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 15-30% EtOAc/hexane), affording 5-(2-fluorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (231 mg, 73%). MS (ESI, pos. ion) m/z: 339.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([CH3:21])=[CH2:20])=[CH:4][N:3]=1.[CH3:22][N:23]1[C:27]([NH2:28])=[CH:26][C:25]([CH3:29])=[N:24]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[CH3:22][N:23]1[C:27]([NH:28][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([CH3:21])=[CH2:20])=[CH:4][N:3]=2)=[CH:26][C:25]([CH3:29])=[N:24]1
Reactant: C=C(C)c1cnc(Cl)cc1Nc1ccccc1C(=O)NC
Reactant: Cc1cc(N)n(C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=C(C)c1cnc(Nc2cc(C)nn2C)cc1Nc1ccccc1C(=O)NC
Reaction time: 0.75 h

Procedure:
To a 10 mL microwave tube was added 2-(2-chloro-5-isopropenyl-pyridin-4-ylamino)-N-methyl-benzamide (0.075 g, 0.25 mmol, 1 eq), 2,5-dimethyl-2H-pyrazol-3-ylamine (0.055 g, 0.50 mmol, 2 eq), Cs2CO3 (0.24 g, 0.74 mmol, 3 eq) and 1,4-dioxane (3 mL). The resulting mixture was degassed with N2 for 30 minutes. Then Pd(OAc)2 (0.015 g, 0.07 mmol, 0.27 eq) and BINAP (0.046 g, 0.074 mmol, 0.3 eq) were added and the mixture degassed again with N2 for another 10 minutes. The resulting reaction mixture was irradiated in a CEM microwave at 110° C. and 150 W for 45 min. The progress of the reaction was monitored by LCMS. After it was complete, Cs2CO3 was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by column chromatography over neutral alumina using 0.2% MeOH-DCM as the eluant. This gave the title compound as an off white solid (180 mg, 48%). 1H-NMR (400 MHz, DMSO-d6): δ 2.02-2.10 (m, 6H), 2.73-2.74 (d, 3H, J=4.48 Hz), 3.53 (s, 3H), 5.05 (s, 1H), 5.31 (s, 1H), 5.97 (s, 1H), 6.67 (s, 1H), 6.90-7.05 (m, 1H), 7.4-7.55 (m, 2H), 7.61-7.63 (d, 1H, J=7.04 Hz), 7.76 (s, 1H), 8.48 (s, 1H), 8.54-8.67 (brs, 1H), 9.61 (s, 1H). LC-MS [M+H]+=377.4.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[CH2:14]([NH:21][C:11]([C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCOCC
Product: O=C(NCc1ccccc1)C12CC3CC(CC(C3)C1)C2

Procedure:
Dissolve 2.0 g. of (10 mmoles) of 1-adamantane carboxylic acid chloride in 20 ml. of ethyl ether and add to 3.0 ml. (28.0 mmoles) of benzylamine and repeat the process of Example 11 to obtain the product of this example, m.p. 170°-172°C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[C@@H:13]([OH:14])[CH2:12][CH2:11][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:9]1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[F:25][C:26]([F:47])([F:46])[C:27]1[CH:28]=[C:29]([C@@H:37](OC(=N)C(Cl)(Cl)Cl)[CH3:38])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>>[F:25][C:26]([F:46])([F:47])[C:27]1[CH:28]=[C:29]([C@H:37]([O:14][C@H:13]2[CH2:12][CH2:11][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C@@H:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH3:38])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: CCOC(=O)[C@H]1[C@H](c2ccccc2C)[C@@H](O)CC[C@@H]1C(=O)OCC
Reactant: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCOC(=O)[C@H]1[C@H](c2ccccc2C)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)OCC

Procedure:
The title compound was prepared from the first eluting isomer diethyl (1S,2S,3R,4S)-3-(2-methylphenyl)-4-hydroxycyclohexane-1,2-dicarboxylate (step G) and (1S)-1-[3,5-bis(trifluoromethyl)-phenyl]ethyl-2,2,2-trichloroethanimidoate (Example 1, step H) according to the procedure of Example 1, step I. 1H-NMR (CDCl3): δ: 7.65 (1H, s), 7.15 (2H, s), 7.08-6.92 (4H, m), 4.25 (1H, q, J=6.0 Hz), 4.20-4.10 (2H, m), 3.85-3.66 (2H, m), 3.42 (1H, m), 3.21 (1H, t), 2.90-2.79 (2H, m), 2.35 (1H, m), 2.25 (1H in), 2.22 (3H, s), 1.69-1.56 (2H, m), 1.30 (3H, d, J=6.0 Hz), 1.23 (3H, t, J=7.2 Hz), 0.77 (3H, t, J=7.2 Hz). Unreacted starting alcohol could be recovered by flushing the column with EtOAc and reused in the above reaction.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][OH:18])[CH:12]=[N:11][C:10]=12)=[O:5])C.Cl>[OH-].[Na+]>[OH:18][CH2:17][CH2:16][CH2:15][C:13]1[CH:12]=[N:11][C:10]2[N:9]([N:8]=[CH:7][C:6]=2[C:4]([OH:5])=[O:3])[CH:14]=1
Reactant: CCOC(=O)c1cnn2cc(CCCO)cnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnn2cc(CCCO)cnc12

Procedure:
A mixture of 6-(3-hydroxy-propyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (5 mg) and an aqueous solution of sodium hydroxide (5 drops) was stirred at room temperature for 16 hours. The reaction mixture was then acidified by addition of an aqueous solution of hydrochloric acid (3 M). The precipitate was collected by filtration to give 6-(3-hydroxy-propyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. MS=222 [M+H]+.