Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]([F:9])[C:5](=[O:8])[CH2:6][CH3:7].[CH2:11](O)[CH2:12][OH:13].B(F)(F)F.CCOCC>C1CCCCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:10])[CH:4]([F:9])[C:5]1([CH2:6][CH3:7])[O:13][CH2:12][CH2:11][O:8]1
Reactant: OCCO
Reactant: CCC(=O)C(F)C(=O)OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCC1(C(F)C(=O)OC)OCCO1
Temperature: 25 °C

Procedure:
2-Fluoro-3-oxopentanoic acid methyl ester (2.21 g, 14.9 mmol), ethylene glycol (4.15 mL, 74.5 mmol), and BF3.Et2O (0.189 mL, 1.49 mmol) were mixed in cyclohexane (10 mL). The mixture was heated to reflux for 5 h, and allowed to cool to rt. The mixture was diluted with EtOAc, and washed with brine, water, aq. sat. NaHCO3, and brine again. The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The title compound was obtained as an oil (1.88 g, 52%).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[CH:35]1([CH2:40][CH2:41][C:42](Cl)=[O:43])[CH2:39][CH2:38][CH2:37][CH2:36]1.O>O1CCCC1>[CH:35]1([CH2:40][CH2:41][C:42]([C:2]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=2[O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[O:43])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(Cl)CCC1CCCC1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)CCC3CCCC3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 8 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) was dissolved in tetrahydrofuran (6 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.4 ml) was added to the cooled solution, and the mixture was stirred at −78° C. for 20 min. 3-Cyclopentylpropionyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (9 mg, yield 8%).
Reaction SMILES: C([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][S:19]([OH:22])(=[O:21])=[O:20])=[O:15])(OCC1C=CC=CC=1)=O.Br>CC(O)=O>[NH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][S:19]([OH:22])(=[O:20])=[O:21])=[O:15]
Reactant: O=C(CCNC(=O)OCc1ccccc1)NCCS(=O)(=O)O
Agent: Br
Solvent: CC(=O)O
Product: NCCC(=O)NCCS(=O)(=O)O
Temperature: 40 °C
Yield: 87.4 %

Procedure:
N-carbobenzoxy-β-alanyl-taurine (1.00 g, 3.4 mmol) was slurried in 23 ml glacial AcOH. To the mixture was added 3.4 mL HBr in AcOH (30 wt %) to result in a clear solution. The reaction was heated to 40° C. and allowed to mix overnight. The product precipitated out of solution and acetonitrile was added to force the precipitation. The mixture was filtered, the filter cake washed and the product collected. The crude Br salt was loaded onto an ion exchange column (Dowex AG1-XB8). The column was eluted with H2O. The product cut was collected and lyophilized to give 583 mg of β-alanyl-taurine (87.3%). The zinc salt was prepared by treatment with Zn(OH)2 in H2O, followed by lyophilization. (See FIG. 1 for reaction Scheme.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[N:10][N:11]3[C:16]([CH3:17])=[CH:15][N:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]([CH3:17])[CH:15]=[N:14][NH:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: Cc1cnnc2c(-c3ccc(F)cc3)c(-c3ccncc3)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1C=NNc2c(-c3ccc(F)cc3)c(-c3ccncc3)nn21
Temperature: 0 °C
Yield: 24.4 %

Procedure:
A mixture of 8-(4-fluorophenyl)-4-methyl-7-(pyridin-4-yl)pyrazolo[5,1-c][1,2,4]triazine (53 mg) and sodium borohydride (13 mg) in ethanol (1 ml) was refluxed for 3 hours, cooled and poured into ice-water. The separated oil was extracted with dichloromethane. The extract was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from diisopropyl ether to give 1,4-dihydro-8-(4-fluorophenyl)-4-methyl-7-(pyridin-4-yl)pyrazolo[5,1-c][1,2,4]triazine (13 mg).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([OH:19])=[O:18].CC(O)=O>CCOC(C)=O>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:23]3[CH:24]=[CH:25][C:20]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: O=C(O)c1ccc(B(O)O)cc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccc(C(=O)O)cc3)nc12

Procedure:
4-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzoic acid was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 4-carboxyphenylboronic acid following general procedures as described in these Examples. Silica gel chromatography using 50-100% [5% AcOH:EtOAc]/Hexanes as eluant gave 10 mg (6%) of a pale brown solid. M+H=324.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][CH:3]=1.[N:17]1[NH:18][C:19](=[O:23])[CH:20]=[CH:21][CH:22]=1>>[CH2:13]([N:12]([CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:18]2[C:19](=[O:23])[CH:20]=[CH:21][CH:22]=[N:17]2)=[CH:3][CH:4]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: O=c1cccn[nH]1
Reactant: CCN(CC)C[C@H]1C[C@@H]1c1ccc(Br)cc1
Product: CCN(CC)C[C@H]1C[C@@H]1c1ccc(-n2ncccc2=O)cc1

Procedure:
Following the general procedure, reaction of 7c (2.87 g assayed, 10.2 mmol) with 3(2H)-pyridazinone (1.27 g, 13.2 mmol) afforded a solution of the free base of 8c in an assayed yield of 2.55 g (84% assay yield, 93% peak area).
Reaction SMILES: NCC1C2C(=CC=CC=2)CCN1CCCC(OCC)=O.[C:21]([NH:29][CH2:30][CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][N:32]1CCCl)(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)CC(OCC)=O.C(O[K])CCC>C(O)(C)(C)C>[NH2:32][CH2:33][CH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31][CH2:30][N:29]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(NCC1c2ccccc2CCN1CCCl)c1ccccc1
Agent: CCCCO[K]
Agent: CCOC(=O)CCCN1CCc2ccccc2C1CN
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CC(C)(C)O
Product: NCC1c2ccccc2CCN1Cc1ccccc1

Procedure:
1-aminomethyl-2-(3-carbethoxypropyl)-1,2,3,4-tetrahydroisoquinoline [obtainable by reacting 1-benzamidomethyl-2-(2-chloroethyl)-1,2,3,4-tetrahydroisoquinoline with diethyl malonate in the presence of tert.--C4H9OK in tert.-butanol, saponifying, decarboxylation, and esterification]
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20](=[O:25])[CH2:19]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl.O>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([CH:15]2[CH2:14][CH2:13][C:12](=[O:11])[CH2:17][CH2:16]2)[CH2:19][C:20]1=[O:25]
Reactant: CN1CCN([C@H]2CC[C@H](O)CC2)CC1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(C2CCC(=O)CC2)CC1=O
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
0.55 ml dimethylsulphoxide in 2 ml dichloromethane are added dropwise to 0.46 ml oxalyl chloride in 10 ml dichloromethane within two minutes at −60° C. After 5 minutes 1.0 g (trans)-1-hydroxy-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexane in 8 ml dichloromethane are added within 5 min. After 20 minutes 3.3 ml triethylamine are added and the mixture is stirred for 70 minutes at ambient temperature. 15 ml of water are added and the mixture is extracted with dichloromethane. After evaporation of the solvent the residue contains the product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([S:13]([NH2:16])(=[O:15])=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:57]([O:59][C:60](=[O:81])[C@H:61]([O:63][C:64]1[CH:69]=[C:68](Cl)[N:67]=[C:66]([S:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([F:79])[C:74]=2[F:80])[N:65]=1)[CH3:62])[CH3:58]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:80][C:74]1[C:75]([F:79])=[CH:76][CH:77]=[CH:78][C:73]=1[CH2:72][S:71][C:66]1[N:65]=[C:64]([O:63][C@H:61]([CH3:62])[C:60]([O:59][CH2:57][CH3:58])=[O:81])[CH:69]=[C:68]([NH:16][S:13]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)(=[O:15])=[O:14])[N:67]=1
Reactant: NS(=O)(=O)N1CCN(c2ccncc2)CC1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCN(c3ccncc3)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
To a solution of 1-pyridin-4-ylpiperazine (1.23 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 72 h. The reaction mixture was purified by loading onto SCX and eluting with (200 ml) MeOH/NH3. The eluent was then reduced in vacuo to yield 4-pyridin-4-ylpiperazine-1-sulfonamide as a white solid. A mixture of 4-pyridin-4-ylpiperazine-1-sulfonamide (0.260 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.438 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester ((the product of example 5 step i), 0.350 g) in dioxane (10 ml) was heated at reflux in a microwave at 100 C, 300 W, open vessel with cooling for 30 mins. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.720 g
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[N:10]O)[C:4]=2[CH:3]=[CH:2]1.CC(C[AlH]CC(C)C)C.[F-].[Na+].O>C(Cl)Cl>[NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][NH:10][C:4]=2[CH:3]=[CH:2]1
Reactant: ON=C1CCCc2[nH]ccc21
Agent: CC(C)C[AlH]CC(C)C
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: c1cc2c([nH]1)CCCCN2
Reaction time: 2 h
Yield: 33.4 %

Procedure:
To a stirred solution of 1,5,6,7-tetrahydro-indol-4-one oxime (1.2 g, 7.7 mmol) in DCM (anhydrous, 250 mL) was added DIBAL-H (1M solution in DCM, 35 mL) at 0° C. under nitrogen. After 2 hours, NaF (7 g) was added followed by water (2.24 g). After 20 mins, the reaction was filtered through celite and the solvent was removed to give 350 mg of 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:34])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][CH2:10][F:34])=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC(CCO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Solvent: ClCCl
Product: CCC(CCF)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 1 h

Procedure:
To a solution of N-(1-(3-(4-chlorophenyl)-1-hydroxypentan-3-yl)-1H-indol-4-yl)methanesulfonamide (20 mg, 0.05 mmol), as described in Example 40 Step I, in DCM (5 mL) was added DAST (16 mg, 0.1 mmol) at 0° C. The mixture was stirred for 1 h, then quenched with saturated aqueous ammonium chloride (5 mL) and extracted with ethyl acetate. The combined organics were washed with water (5 mL) and brine (5 mL), dried over MgSO4, filtered and concentrated. The resulting crude product was purified by Pre-HPLC (Mobile phase: acetonitrile/water (0.03% TFA)) to afford the title racemic compound as a white solid. The racemic compound was submitted to chiral SFC separation using IC (30% MeOH (0.1% DEA)/CO2, 4.6×250 mm, 41° C.) to give two separated enantiomers. LC/MS m/z=409.1[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23]([C:25]3[O:29][C:28]([O:30]C)=[N:27][CH:26]=3)=[O:24])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@@H:15]([NH:22][C:23]([C:25]3[O:29][C:28](=[O:30])[NH:27][CH:26]=3)=[O:24])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cnc(OC)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-methoxyoxazole-5-carboxamido)butanoate, intermediate 14, (103 mg, 0.23 mmol) in dioxane (3 mL) is added 4 N solution of HCl in dioxane (0.29 mL, 1.16 mmol). The crude was stirred at room temperature for 2 hrs. The crude is concentrated and is diluted in water and EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated. 50% of the crude is purified via RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-oxo-2,3-dihydrooxazole-5-carboxamido)butanoate (38 mg) as a white solid. HPLC retention time=1.66 minutes (condition A); MS (m+1)=429.4; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.1 Hz, 3H) 2.51-2.69 (m, 2H) 2.95 (dd, 1H) 3.05 (dd, 1H) 4.19 (q, 2H) 4.58-4.75 (m, 1H) 6.83 (d, J=8.8 Hz, 1H) 7.26-7.33 (m, 4H) 7.35 (t, J=7.7 Hz, 1H) 7.45 (dt, J=7.6, 1.5 Hz, 1H) 7.51 (d, J=8.3 Hz, 2H) 7.56 (t, J=1.8 Hz, 1H) 8.45 (br. s., 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][OH:21])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[Br:35][C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=1[CH2:46]Br.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:46][C:37]4[CH:38]=[CH:39][C:40]([C:42]([F:43])([F:45])[F:44])=[CH:41][C:36]=4[Br:35])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: FC(F)(F)c1ccc(CBr)c(Br)c1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CO)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(C(F)(F)F)cc4Br)nn23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.200 g, 0.421 mmol) and 2-bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene (0.268 g, 0.843 mmol) in DMF (1 mL) was added sodium hydride (0.051 g, 1.264 mmol). The mixture was stirred at rt. After 30 min, the reaction was quenched with water and extracted with EtOAc (3×'s). The organic phases were combined and washed with brine, dried, filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 25 CV) to give the title compound (0.200 g, 0.281 mmol, 66.7% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=0.7 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.59 (dd, J=8.6, 1.0 Hz, 1H), 6.59 (s, 1H), 6.02 (ddt, J=17.0, 10.4, 5.1 Hz, 1H), 5.95-5.85 (m, 1H), 5.53-5.39 (m, 1H), 5.19 (dd, J=10.5, 1.7 Hz, 1H), 4.87 (s, 2H), 4.77 (s, 2H), 4.30-4.14 (m, 2H), 4.02 (d, J=5.1 Hz, 2H), 2.62 (s, 3H), 2.06-1.61 (m, 3H), 1.35 (s, 3H), 1.25 (s, 12H) 5 piperidine protons not visible. LCMS (M+H) calcd for C33H43BrF3N4O5: 712.33. found: 713.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:31]([N:34]=[C:35]=[S:36])([CH3:33])[CH3:32]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:35]([NH:34][CH:31]([CH3:33])[CH3:32])=[S:36])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Reactant: CC(C)N=C=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(=O)(=O)NC(=S)NC(C)C)CC1
Yield: 59.5 %

Procedure:
188 mg (0.5 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 326 mg (1 mmol) of cesium carbonate were heated in 5 ml of N-methyl-2-pyrrolidone with 0.1 ml (0.9 mmol) of isopropyl isothiocyanate at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid and extracted three times with 10 ml of dichloromethane each time. The combined organic phases were dried over sodium sulfate and filtered after addition of activated carbon. The crude product obtained after removal of the solvent was recrystallized from methanol. 142 mg (60%) of the title compound were obtained as a colorless solid.
Reaction SMILES: [CH3:1][CH:2](O)[CH3:3].[Bi](Br)(Br)Br.[OH:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11]>ClC(Cl)(Cl)Cl>[CH3:19][O:18][C:16](=[O:17])[C:15]1[CH:20]=[CH:21][C:12]([CH:10]([O:9][CH:2]([CH3:3])[CH3:1])[CH3:11])=[CH:13][CH:14]=1
Reactant: CC(C)O
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: Br[Bi](Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(C)OC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To the solution of propan-2-ol (100 mg, 1.67 mmol) in perchloromethane (80 mL) was added bismuth(III) bromide (743 mg, 1.67 mmol), the mixture was stirred for 30 minutes at room temperature, then methyl 4-(1-hydroxyethyl)benzoate (300 mg, 1.67 mmol) was added to the solution, the mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated and Then the mixture was concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give methyl-4-(1-isopropoxyethyl)benzoate (161 mg, 43%) as oil. 1H-NMR (300 MHz, CD3OD) δ 7.96 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 4.68-4.61 (m, 1H), 3.54-3.46 (m, 1H), 1.38 (d, 3H), 1.15 (d, 3H), 1.06 (d, 3H),
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]([CH3:16])([OH:15])[CH3:14])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.N1C=CN=C1.C(OCC)C.[CH3:27][Si:28](Cl)([CH3:30])[CH3:29]>C(Cl)Cl.O.CO>[Cl:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]([CH3:16])([O:15][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH3:14])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(O)C#Cc1c[nH]c2ncnc(Cl)c12
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C#Cc1c[nH]c2ncnc(Cl)c12)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
Charge 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbut-3-yn-2-ol (3.35 g, 1.0 eq), imidazole (2.9 g, 3.0 eq), TEA (2.16 g, 1.5 eq) and diethyl ether (84 mL) at RT. Cool the reaction mass to 0° C. and add trimethyl silyl chloride (1.53 g, 1.0 eq). Stir the reaction mass at RT for 4 h. Monitor the reaction by TLC (5% MeOH in DCM). Charge chilled DM water and extract with diethyl ether. Wash the ether layer with saturated aq. sodium chloride. Dry the organic layer over anhydrous Na2SO4 and concentrate it under vacuum to get the desired compound (3.06 g, 70%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][N:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])([CH3:3])[CH3:2].C(C1C=CC=CC=1N)(C)C.C(#N)CC#N.O.[NH2:33][NH2:34]>>[NH2:14][C:13]1[C:12](=[N:11][NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:2])[CH3:3])[C:15]([NH2:16])=[N:34][N:33]=1
Reactant: NN
Reactant: CC(C)c1ccccc1NN=C(C#N)C#N
Agent: CC(C)c1ccccc1N
Solvent: N#CCC#N
Solvent: O
Product: CC(C)c1ccccc1NN=C1C(N)=NN=C1N
Yield: 73 %

Procedure:
This compound was prepared using 106 mg (0.5 mmol) of 2-[(2-isopropylphenyl)-hydrazono]malononitrile, which was derived from 2-isopropylaniline (142 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 5 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 90 mg (73%) of the title compound as a greenish yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[N:7]([CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=2)[NH:27][C:26]=1[C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[CH:38]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]S(C)(=O)=O)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:45])[N:7]([CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=2)[NH:27][C:26]=1[C:37]1[CH:38]=[C:39]([CH3:44])[CH:40]=[C:41]([CH3:43])[CH:42]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[C:16]([S:47]([CH3:46])(=[O:49])=[O:48])[C:17]=1[S:47]([CH3:46])(=[O:49])=[O:48])([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)C(=O)OC(C)(C)C)c1
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
To a solution of {2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethyl}-[4-(4-methanesulfonylaminophenyl)butyl]carbamic acid tert-butyl ester (300 mg in 7 mL methylene chloride) at 0° C. was added 0.135 mL triethylamine and 0.066 mL methanesulfonyl chloride and the mixture sired at low temperature. After 30 minutes, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate and partitioned between water and ethyl acetate. The organic portion was washed successively with saturated ammonium chloride, saturated sodium bicarbonate and brine, then dried over sodium sulfate and concentrated in vacuo to give the crude title compound (330 mg).
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:24]=[CH:23][C:12]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[N:14][S:15][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:12]3[CH:23]=[CH:24][C:9]([O:8][CH2:7][C:6]([OH:25])=[O:5])=[CH:10][C:11]=3[S:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
3.89 g (9.3 mmol) [3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-acetic acid tert-butyl ester in 35 ml CH2Cl2 were added 17 ml TFA at 0° C. The solution was stirred at RT for 2 h, concentrated and triturated with ether to yield 3 g (89%) [3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-acetic acid as white solid, MS: 362 (M−H, 1Br).