Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([OH:11])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.[Br:12]N1C(=O)CCC1=O.ClC1C2SC=CC=2NC=1C(O)=O>>[Br:12][C:7]1[C:8]2[S:1][CH:2]=[CH:3][C:4]=2[NH:5][C:6]=1[C:9]([OH:11])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1cc2sccc2[nH]1
Agent: O=C(O)c1[nH]c2ccsc2c1Cl
Product: O=C(O)c1[nH]c2ccsc2c1Br
Yield: 10.5 %

Procedure:
The title compound was synthesized from 4H-thieno[3,2-b]pyrrole-5-carboxylic acid (0.1 g, 0.60 mmol, 1 equiv) and N-bromosuccinimide (NBS) (0.107 g, 0.599 mmol, 1 equiv) according to the halogenation method reported for the chlorination of 4H-thieno[3,2-b]pyrrole-5-carboxylic acid (with NCS) to 6-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid, providing the desired 6-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid 71 (15.5 mg, 10.5%). LC/MS m/e 243.9 (M−H). tR of product: 2.5-2.8 min. 1H NMR (400 MHz, CD3OD) δ ppm 7.42 (d, J=5.32 Hz, 1H), 7.01 (d, J=5.32 Hz, 1H).
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:29]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][N:48]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:49]3=[O:58])[C:38]2=[O:59])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1>>[OH:27][C:28]1[C:29]([C:37]2([CH2:5][OH:16])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][N:48]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:49]3=[O:58])[C:38]2=[O:59])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1c2ccccc2C(=O)N1CCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, making variation to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 2-{2-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]ethyl}-1H-isoindole-1,3(2H)-dione, the title compound was obtained (56%): 1H NMR (300 MHz, CD3OD) δ 9.97 (s, 1H), 8.72-8.62 (m, 4H), 8.07-7.67 (m, 5H), 7.01 (s, 1H), 6.71 (s, 1H), 6.70 (s, 1H), 5.79 (t, 1H), 4.88-4.50 (m, 6H); MS (ES+) m/z 455 (M−17), 473 (M+1), 495 (M+23).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C(NC(C)C)(C)C.[Li].[CH3:17][C:18]([CH3:20])=[O:19]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[C:7]=1[C:18]([OH:19])([CH3:20])[CH3:17]
Reactant: CC(C)=O
Reactant: Fc1cncc(Br)c1
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(O)c1c(F)cncc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a round bottom flask is added 3-bromo-5-fluoropyridine (475 mg, 2.7 mmol) in 4 ml of dry THF at −78° C., followed by the addition of lithium diisopropylamine (1.6 ml, 3.2 mmol). The reaction mixture is stirred at −78° C. for 1 hour, followed by the addition of acetone (0.6 ml). The reaction mixture is warmed up and stirred at room temperature for 30 minutes. The reaction mixture is diluted with EtOAc, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 190 mg of 2-(3-bromo-5-fluoro-pyridin-4-yl)-propan-2-ol.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].Cl[C:9]1[C:10]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:15][C:11]=2[N:12]=[CH:13][N:14]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OC)(C)(C)C.O>[CH3:1][O:2][CH:3]([CH2:6][O:7][C:9]1[C:10]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)=[C:16]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:15][C:11]=2[N:12]=[CH:13][N:14]=1)[CH2:4][OH:5]
Reactant: COC(CO)CO
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC(CO)OC)c23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Put 1.014 g (9.65 mmol) 2-methoxypropane-1,3-diol in 20 ml THF. Add 542 mg (4.825 mmol) potassium tert.-butylate and stir for 15 min at RT. Then cool to 0° C. and add a solution of 650 mg (1.93 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 10 ml THF dropwise in the space of 30 min. Then leave to return to RT and stir overnight at RT. Next, dilute with tert.-butylmethyl ether and water. Acidify with 10% citric acid solution and separate the phases. Re-extract the aqueous phase once with tert.-butylmethyl ether. Combine the organic phases and wash once with satd. sodium chloride solution. Then dry over magnesium sulphate and concentrate by evaporation. Purify the residue by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 7:3); 587 mg (74.8% of theor.) of the target compound is obtained.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][C:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:7][N:6]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[C:23]([OH:29])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[C:23]([O:29][CH2:2][C:3]#[C:4][C:5]2[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:7][N:6]=2)[CH:22]=1
Reactant: FC(F)(F)c1c(C#CCBr)noc1-c1ccccc1
Reactant: O=Cc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Br)cc1OCC#Cc1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a mixture of 3-(3-bromoprop-1-ynyl)-5-phenyl-4-(trifluoromethyl)isoxazole (Preparation 62C, 0.219 g, 0.663 mmol) and 4-bromo-2-hydroxybenzaldehyde (0.133 g, 0.663 mmol) in dimethylformamide (2.0 mL) at room temperature was added potassium carbonate (0.115 g, 0.829 mmol). The reaction mixture was stirred at room temperature for 3 h, diluted with ethyl acetate (75 mL), washed with a 10% aqueous solution of lithium chloride (2×25 mL), and washed with brine (25 mL). The organic layer was collected, and the combined aqueous phases were extracted with ethyl acetate (2×25 mL). The combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a tan solid which was triturated with methanol with sonication to give 4-bromo-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)prop-2-ynyloxy)benzaldehyde (0.223 g, 0.495 mmol, 75% yield) as a white solid. The product had an HPLC ret. time=3.28 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=451.92. 1H NMR (500 MHz, CDCl3) δ ppm 5.12 (s, 2H), 7.28 (d, J=8.32 Hz, 1H), 7.34 (d, J=1.66 Hz, 1H), 7.51-7.55 (m, 2H), 7.56-7.61 (m, 1H), 7.72 (d, J=7.21 Hz, 2H), 7.75 (d, J=8.32 Hz, 1H), and 10.44 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[N:30]=[C:29]([CH2:31][N:1]3[CH:2]([C:10]4[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=4[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]3=[O:8])[CH:28]=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-n2cccn2)n1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2cccn2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 6-(1H-pyrazol-1-yl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 392.97 g/mol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[NH2:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: N#Cc1ncc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To the solution of 3,5-dichloropyrazine-2-carbonitrile (2.00 g, 11.5 mmol) in 30 mL NMP were added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (2.71 g, 12.6 mmol) and DIEA (4.07 mL, 13.8 mmol). The mixture was stirred at RT for 1.5 h. To it was poured 300 mL water. After stirring vigorously for 2 h, the solid was isolated by filtration, washed with water and dried in vacuum oven for overnight to afford tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate in quantitative yield.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[NH:14][N:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=1[CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[N:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc2[nH]ncc2cc1SCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(CO)c2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cccc(Cn3ncc4cc(SCc5ccccc5)c(F)cc43)c2C1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-(benzylthio)-6-fluoro-1H-indazole (1-2, 0.35 g, 1.35 mmol, 1.0 equiv) and tert-butyl 8-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.53 g, 2.03 mmol, 1.5 equiv) in THF (6.77 mL) at 0° C. was added polymer supported triphenylphosphine (0.71 g, 2.71 mmol, 2.0 equiv) followed by di-tertbutylazodicarboxylate (0.62 g, 2.71 mmol, 2.0 equiv) and the reaction mixture was stirred at 0° C. for 2.5 hours. The reaction was concentrated and purified using normal phase chromatography to yield the desired regioisomer. ESI+ MS [M+H]+ C29H30FN3O2S: 504.3 found, 504.6 required.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: Cc1c[nH]cn1
Product: Cc1cn(-c2ccc(Br)cc2C#N)cn1

Procedure:
This compound was prepared from 5-bromo-2-fluorobenzonitrile and 4-methylimidazole, as described in US2006/0004013.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8](C(O)=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([N:17](CC)C(C)C)(C)C.P(N=[N+]=[N-])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(O)(=O)C>CN(C=O)C>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH2:17])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc2cccc(Br)c2s1
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1cc2cccc(Br)c2s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
156 mg (0.61 mmol) of 7-bromo-1-benzothiophene-2-carboxylic acid are mixed with 156.8 mg (1.21 mmol) of N,N-diisopropylethylamine in 4.0 ml of DMF. At 0° C., 183.7 mg (0.67 mmol) of diphenyl phosphorazidate are added. The reaction mixture is left to stand at 8° C. overnight and then stirred into ice-water. It is neutralized with acetic acid, and the resulting precipitate is filtered off with suction and carefully dried at 40° C. The solid is then suspended in xylene and heated under reflux for 1 h. The solvent is removed under reduced pressure, and the residue is put in water and heated for 3 h. The aqueous phase is extracted several times with ethyl acetate. The organic phase is dried over sodium sulfate and then the solvent is removed under reduced pressure. 128 mg of the title compound are isolated in a purity which is suitable for further reactions. The amine is reacted further without further purification.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[C:5]1([N:11]2[CH2:15][CH2:14][C:13](=[O:16])[NH:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.ClCCl.C1(C)C=CC=CC=1>[Cl:4][C:1]([N:12]1[C:13](=[O:16])[CH2:14][CH2:15][N:11]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(Cl)Cl
Reactant: O=C1CCN(c2ccccc2)N1
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)N1C(=O)CCN1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a rapidly mechanically stirred--78° C. solution of dichloromethane (250 ml), containing a 1 N toluene solution of phosgene (204 ml-0.204 mole), and protected by a nitrogen atmosphere, was added a solution of 1-phenyl-3-pyrazolidinone and diisopropylethylamine in 200 ml of a 1:1 mixture of dimethylacetamide (DMA) and dichloromethane [prepared by dissolving 30.0 g(0.185 mole)1-phenyl-3-pyrazolidone in 100 ml of DMA and adding next the dichloromethane and then the diisopropylethylamine (35.5 ml, 0.204 mole]. The addition was rapid but dropwise, requiring≈30 minutes; a precipitate began to appear about 2/3 through the addition. After 10 minutes additional stirring at -78° C., the reaction was quenched by adding 6 ml of concentrated HCl. The reaction was then added to 500 ml of cold 1 N HCL and 500 ml of dichloromethane. After brief shaking the layers were separated and the dichloromethane layer briefly washed with 500 ml of cold 1 N HCl. After drying over anhydrous MgSO4, the solution was concentrated in vacuo to approximately 300 ml and the precipitate which had appeared was collected and washed with ligroin. After drying in vacuo overnight the yield of this white solid was 34.7 g (83%).
Reaction SMILES: Br[C:2]1[C:3]([OH:14])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].ClCCl.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:48]1[N:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:51]=[CH:50][N:49]=1>O1CCOCC1>[C:10]([C:8]1[CH:9]=[C:2]([C:48]2[N:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:51]=[CH:50][N:49]=2)[C:3]([OH:14])=[C:4]([CH:7]=1)[CH:5]=[O:6])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2nccc(C(F)(F)F)n2)c1
Temperature: 85 °C
Yield: 27.7 %

Procedure:
To a nitrogen de-gassed mixture of 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde [CAS #119646-68-3] (1.00 g, 3.89 mmol), bis(pinacolato)diboron (1.98 g, 7.80 mmol), and potassium acetate (1.15 g, 11.7 mmol) in dioxane (50 mL) under a nitrogen was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (285 mg, 0.39 mmol) and the reaction mixture heated to 85° C. for 16 hours. The reaction was allowed to cool to 25° C. at which time 2M aqueous sodium carbonate (9.7 mL, 19.5 mmol) and 2-chloro-4-trifluoromethylpyrimidine (1.42 g, 7.78 mmol) were added and the solution degassed with nitrogen. A second portion of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (285 mg, 0.39 mmol) was added and the mixture heated at 85° C. under a nitrogen atmosphere for 6 hours. The cooled reaction mixture was then partitioned between ethyl acetate (100 mL) and a saturated aqueous solution of sodium bicarbonate (100 mL). The organic phase was separated, concentrated under reduced pressure and purified using flash chromatography on silica eluting with a solvent gradient of 0 to 70% ethyl acetate in hexanes to give 5-(tert-butyl)-2-hydroxy-3-(4-(trifluoromethyl)pyrimidin-2-yl)benzaldehyde (350 mg, 28% yield) as a cream solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][C@H:28]1[CH2:32][CH2:31][O:30][CH2:29]1>>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][C@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: BrCC[C@H]1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CC[C@H]3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 215 from N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and (3R)-3-(2-Bromoethyl)tetrahydrofuran.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH:10]=[CH2:11])[N:3]=1.C(C1C=CC(C#N)=CN=1)C>>[CH2:10]([C:4]1[N:3]=[C:2]([CH3:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH3:11]
Reactant: C=Cc1nc(C)ccc1C#N
Agent: CCc1ccc(C#N)cn1
Product: CCc1nc(C)ccc1C#N

Procedure:
Compound 386B was prepared from 386A by a route analogous to that used for the preparation of 384B. HPLC retention time=1.18 min. (Condition A), M+=147.
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[C:7]1([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][Cl:25])[CH2:18][CH2:17]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:25].[ClH:5].[C:7]1([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][SH:3])[CH2:18][CH2:17]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(N)=S
Reactant: ClCCCN1CCN(CCCc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: SCCCN1CCN(CCCc2ccccc2)CC1
Yield: 81.9 %

Procedure:
The procedure described in Example 1(b) was followed, using 19.0 g of thiourea, 44.0 g of 1-(3-phenylpropyl)-4-(3-chloropropyl)piperazine dihydrochloride, 25 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 10.0 g of sodium hydroxide in 50 ml of water. Work-up, as described above, gave 35.8 g (82% of theory) of 3-[4-(3-phenylpropyl)piperazin-1-yl]propanethiol dihydrochloride as a white crystalline solid, M.p. 237°-239° C.
Reaction SMILES: ClC1C=C2C(=C(C(OCC3(C4C=CC(F)=CC=4)CCN(C(OC(C)(C)C)=O)CC3)C(OC)=O)C=1)NN=C2.[Cl:38][C:39]1[CH:47]=[C:46]([CH:48]([O:54][CH2:55][C:56]2([C:69]3[CH:74]=[CH:73][C:72]([F:75])=[CH:71][CH:70]=3)[CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]2)[C:49]([N:51]([CH3:53])[CH3:52])=[O:50])[C:45]2[C:41](=[CH:42][N:43](COCC[Si](C)(C)C)[N:44]=2)[CH:40]=1>>[Cl:38][C:39]1[CH:40]=[C:41]2[C:45](=[C:46]([CH:48]([O:54][CH2:55][C:56]3([C:69]4[CH:70]=[CH:71][C:72]([F:75])=[CH:73][CH:74]=4)[CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:67])([CH3:68])[CH3:66])=[O:63])[CH2:58][CH2:57]3)[C:49]([N:51]([CH3:53])[CH3:52])=[O:50])[CH:47]=1)[NH:44][N:43]=[CH:42]2
Reactant: CN(C)C(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Agent: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Product: CN(C)C(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12

Procedure:
Prepared according to the procedure used to prepare tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-methoxy-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate using tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-(dimethylamino)-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate as the starting material. 1H-NMR (CDCl3, 500 MHz) δ 10.84 (bs, 1H), 7.94 (s, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.31 (m, 2H), 7.00-7.10 (m, 3H), 5.12 (s, 1H), 3.72 (m, 2H), 3.59 (d, J=8.9 Hz, 1H), 3.38 (d, J=8.9 Hz, 1H), 3.02 (m, 2H), 2.87 (s, 3H), 2.77 (s, 3H), 2.17 (m, 2H), 1.85 (m, 2H), 1.42 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 168.9, 161.6 (d, J=247 Hz), 155.0, 138.1, 136.3, 133.7, 128.8 (d, J=7.7 Hz), 125.9, 124.9, 124.5, 120.3, 119.8, 115.6 (d, J=21 Hz), 80.6, 79.6, 79.1, 41.3, 40.0 (br), 36.6, 36.5, 32.4, 32.2, 28.5.
Reaction SMILES: [C-]#[N:2].[K+].O.[NH:5]1[C:9]([C@@H:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[S:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=3)=[CH:14][CH:13]=2)[CH3:11])=[CH:8]C=N1.C([O-])(=O)CC.CC(O)=O.[NH4+].[Cl-].[NH4+].[OH-]>>[NH2:5][CH:9]([C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[S:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=2)=[CH:14][CH:13]=1)[CH3:11])[C:8]#[N:2]
Reactant: [C-]#N
Reactant: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1ccn[nH]1
Agent: CCC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)C(N)C#N
Reaction time: 18 h

Procedure:
To a cooled (0-5° C.) solution of potassium cyanide (0.2 g, 3.66 mmol) in water (15 ml) (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanal (1.0 g, 3.33 mmol) (prepared according the procedure described for intermediate 7b and starting from the corresponding propanoate) was added over 30 min. At the same temperature AcOH (3.66 mmol) was dripped and the reaction mixture stirred for 18 h. The solution of the intermediate cyanohydrin was slowly added to another solution of NH4Cl (0.5 g, 9.66 mmol) in NH4OH (14N in H2O; 4.0 mmol) (5 ml). The resulting reaction mixture was stirred at room temperature for 18 h and then extracted with CH2Cl2 (3×15 ml). The organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to give (3R)-2-amino-3-{4-[(4-(trifluoromethyl)-1,3-thiazol-2-yl)amino]phenyl}butanenitrile (0.705 g, 2.16 mmol) as red oil, used for the next step without further purification. 1H-NMR (DMSO-d6): δ 9.25 (bs, 1H, NH), 7.40 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 7.00 (s, 1H), 5.00 (s, 1H), 3.90 (q, 1H, J=7 Hz), 2.35 (bs, 2H), 1.75 (d, 3H, J=7 Hz).
Reaction SMILES: Br.[CH3:2][CH:3]([CH3:15])[CH2:4][C@H:5]([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6]([OH:8])=O.Cl.[NH2:17][C@@H:18]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)[C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.N[C@@H](CC1C=CC(OCC2C=CC=CC=2)=CC=1)C(NC(C)(C)C)=O>C(OCC)C.CN(C=O)C>[CH2:34]([O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH:18]([NH:17][C:6](=[O:8])[CH:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:4][CH:3]([CH3:2])[CH3:15])[C:19](=[O:20])[NH:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:28][CH:29]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)C[C@@H](C(=O)O)N1CCCCC1
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)CC(C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)N1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
(S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (S)-4-Methyl-2-piperidin-1-yl-pentanoic acid monohydrobromide (0.493 g, 1.76 mmol) was mixed with dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this mixture were added in succession N,N-diisopropylethylamine (1.23 mL, 7.05 mmol ) and solid O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.667 g, 1.76 mmol ). The resulting reaction mixture was stirred at that temperature for 30 minutes, solid (S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide monohydrochloride (0.639 g, 1.76 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 45 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane). Recrystallization from EtOAC/hexanes and subsequent drying under vacuum provided 0.4 g (45%) of the pure titled compound as a white crystalline solid.