Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:17])[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[I:18]Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:17])[C:11]3[N:12]([C:14]([I:18])=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2ccnc12
Reactant: ClI
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Yield: 79 %

Procedure:
Prepared from 6-(4-chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridine (example C.21 step 1) (6.65 g, 27 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as an off-white solid (8.0 g, 79%). MS (ISP) 369.0 [(M+H)+], 371 [(M+2+H) +].
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[Br:12]Br.N>CC(O)=O>[CH3:1][N:2]1[C:6]2[C:7]([Br:12])=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2ccc(N)cc21
Reactant: BrBr
Agent: N
Solvent: CC(=O)O
Product: Cn1cnc2ccc(N)c(Br)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 3-methyl-5-aminobenzimidazole (0.27 g, 1.8 mmol) in 10 ml of AcOH was added Br2 (0.10 ml). The reaction mixture was stirred for 1 h at 25° C. and concentrated in vacuo, yielding an oil which was subjected to column chromatography (NH3 sat'd 3% MeOH/CHCl3) to yield 0.14 g (0.62 mmol, 35%) of the desired product.
Reaction SMILES: [OH:1][CH:2]([CH2:23][OH:24])[CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Si:30]([O:24][CH2:23][CH:2]([OH:1])[CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CC(O)CO)cc2n(C)c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(-c3ccccc3)n(CC(O)CO[Si](C)(C)C(C)(C)C)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(2,3-Dihydroxypropyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 1)(1.66 g, 5.04 mmol), imidazole (0.686 g, 10.08 mmol) and DMAP (0.062 g, 0.504 mmol) were dissolved in DMF (25 ml) and TBS-Cl (0.836 g, 5.54 mmol) was added. The resulting mixture was stirred at RT overnight. Further TBS-Cl (0.836 g, 5.54 mmol) added and stirring continued for 2 hours. The reaction mixture was diluted with EtOAc and washed with sat. NaHCO3(aq) and brine (3×). The organic phase was dried over sodium sulphate and evaporated under vacuum. The residue was redissolved in DCM and evaporated onto silica. The silica was deposited onto a 25 g silica cartridge and the system eluted with 20% EtOAc/hexane, 40% EtOAc/hexane and 60% EtOAc/hexane. The product fractions were combined and evaporated to give tacky yellow solid. This solid was triturated with Et2O/hexane to afford the title compound;
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([C:14]([O:16]CC)=O)[C:4]1=[O:19])[CH3:2].Cl.[CH3:21][O:22][C:23](=[O:26])[CH2:24][NH2:25]>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([C:14]([NH:25][CH2:24][C:23]([O:22][CH3:21])=[O:26])=[O:16])[C:4]1=[O:19])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ccccc2n(CC)c1=O
Reactant: COC(=O)CN
Agent: Cl
Solvent: Cc1ccccc1
Product: CCn1c(=O)c(C(=O)NCC(=O)OC)c(O)c2ccccc21
Yield: 11 %

Procedure:
In 4 mL of toluene in a microwave vial, ethyl 1-ethyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (0.380 g, 1 mmol), glycine methyl ester hydrochloride (0.5 g, 4 mmol) was microwaved at 180° C. for 3 minutes and then purified by silica flash chromatography (with a 1-5% MeOH/DCM gradient to afford 0.050 g. Yield: 11%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][CH2:12][CH2:13][OH:14])[N:4]=1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][C:5]1[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(OC)nc(CCCO)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)nc(CCCOS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(4,6-dimethoxypyrimidin-2-yl)propan-1-ol (100 mg, 0.50 mmol) in DCM (2.0 mL), Et3N (0.21 mL, 1.51 mmol) was added. After stirring for 5 min at rt, the reaction mixture was cooled to 0° C. and methansulfonylchloride (0.05 mL, 0.61 mmol) was added. The reaction mixture was stirred for 10 min at 0° C. and for 20 min at rt, then poured onto ice water. The aq. layer was extracted with DCM, the org. layer was washed with 1 N aq. HCl-solution followed by sat. NaHCO3-solution, then dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield the tiltle compound as a yellow oil which was used immediately in the next step. The LC-MS conditions B: tR=0.60 min, [M+H]+=277.09.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.CC1C(O)CC(=[O:23])C=1CC=C.Cl>O1CCCC1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: C=CCC1=C(C)C(O)CC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 5 °C
Reaction time: 48 h
Yield: 51.8 %

Procedure:
11.6 g of triethylamine and then 21.9 g of p-toluene sulfonyl chloride were added at -50° C under an inert atmosphere to a mixture of 11.6 g of (R) allethrolone in 100 ml of tetrahydrofuran and the mixture was stirred for 48 hours at 5° C after which it was poured with stirring into aqueous 0.1N hydrochloric acid solution. The aqueous phase was extracted with chloroform and the organic extracts were washed with water, dried and evaporated to dryness. The 29 g of residue was chromatographed over silica gel and was eluted with a 95-5 benzene-ethyl acetate mixture to obtain 6.8 g of p-toluene sulfonate of (R) allethrolone.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C=O>[Si:27]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 93.1 %

Procedure:
To a solution of 1.0 g of 3β-hydroxyandrost-5-en-17-one (Coffey S. in Rodd's Chemistry of Carbon Compounds, 1970, IID, 257) in 10 ml of dimethylformamide, 1.7 g of imidazole and 1.95 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 1.3 g of crude 3β-tert-butyldimethylsilyloxy-androst-5-en-17-one
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:39]1[CH2:42][CH:41]([OH:43])[CH2:40]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:43][CH:41]1[CH2:42][N:39]([C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[CH2:11]2)=[O:27])[CH2:40]1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1)c1ccccc1

Procedure:
80 mg (0.16 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 1.7 ml of DMF, and 51 mg (0.47 mmol) of azetidin-3-ol hydrochloride and 22 mg (0.16 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient).
Reaction SMILES: [F:1][C:2]([F:16])([C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O>[S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:16])([F:1])[C:12]([F:13])([F:14])[F:15])(=[O:31])=[O:30]
Reactant: OCCCCCCCCC(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCC(F)(F)C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
1.0 g of 9,9,10,10,10-pentafluorodecan-1-ol is dissolved in 8 ml of abs. pyridine, 985 mg of p-toluenesulphonyl chloride are added at 0° C. and the mixture is stirred in the cold for 2 hours. The reaction mixture is then added to water, extracted 3 times with ether, dried over magnesium sulphate and concentrated in vacuo. Preparative column chromatography on silica gel using a hexane-ethyl acetate gradient leads to 1.5 g of 9,9,10,10,10-penta-fluorodecyl tosylate as an oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][N:13]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.O>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:12][N:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: ON=C1CCc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)ON=C2CCc3ccccc32)cc1
Reaction time: 3 h

Procedure:
A solution of p-toluenesulfonyl chloride (266 g) in pyridine (300 ml) was added dropwise to a stirred solution of 2,3-dihydro-1-hydroxyimino-1H-indene (100.8 g) in pyridine (600 ml) at 0°-5°. The mixture was stirred for 3 hours at 0°, then was poured into water and the title compound filtered. This was washed several times with water and air-dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.Br[CH2:20][C@H:21]1[CH2:26][CH2:25][CH:24]=[CH:23][CH2:22]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C@H:21]1([CH2:20][C@H:7]2[C:6]([O:9][CH3:10])=[N:5][C@H:4]([CH:11]([CH3:13])[CH3:12])[C:3]([O:2][CH3:1])=[N:8]2)[CH2:26][CH2:25][CH:24]=[CH:23][CH2:22]1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: BrC[C@@H]1CC=CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C[C@@H]1CC=CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution, cooled to -78°, of 1.78 ml (10 mmol) of (2R)-(-)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine in 5 ml of absolute tetrahydrofuran is treated dropwise with 6.8 ml (11 mmol) of a solution of butyllithium in hexane. The reaction solution is left at -78° for 1 hour and at -20° for 1 hour and then again cooled to -78°. Subsequently, a solution of 1.75 g (10 mmol) of (S)-1-(bromomethyl)-3-cyclohexene in 5 ml of absolute tetrahydrofuran is added. After 2 hours at room temperature the solution is again cooled to -10°, treated with 5 ml of saturated ammonium chloride solution and extracted with ether. The organic phase is washed with water, dried over sodium sulphate and evaporated under reduced pressure. For purification, the residue is chromatographed twice on silica gel using a 9:1 mixture of toluene and ethyl acetate as the eluent. (2S,5R)-2-[(S)-3-Cyclohexen-1-ylmethyl]-2,5-dihydro-5-isopropyl-3,6-dimethoxypyrazine is obtained as a colourless oil; MS: 278 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:25]2[CH2:24][CH:23]3[CH:27]([C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:20][CH2:21][C:22]3=[O:28])[CH2:26]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccc(Cl)cc3)CC12
Reaction time: 1 h
Yield: 67.8 %

Procedure:
N,N'-Carbonyldiimidazole (1.3 g) is added to a solution of 2-(4-chlorophenyl)acetic acid (1.36 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 1 hour at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.62 g) and triethylamine (1.12 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 2 hours at +5° C. and 16 hours at 20° C.; it is washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile (5 cc) and isopropyl ether (10 cc). The crystals obtained are drained and dried. The residue is recrystallized from acetonitrile (40 cc). The crystals obtained are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(4-chlorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (2.4 g) melting at 213° C. is obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][C:7]([N:11]2[C:16](=[O:17])[CH2:15][CH:14]([C:18]([F:21])([F:20])[F:19])[CH2:13][C:12]2=[O:22])=[C:6]([F:23])[CH:5]=1.[C:24]1([S:30][CH2:31]Cl)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Cl:3][C:4]1[C:9]([O:10][CH2:31][S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:7]([N:11]2[C:16](=[O:17])[CH2:15][CH:14]([C:18]([F:20])([F:19])[F:21])[CH2:13][C:12]2=[O:22])=[C:6]([F:23])[CH:5]=1
Reactant: O=C1CC(C(F)(F)F)CC(=O)N1c1cc(O)c(Cl)cc1F
Reactant: ClCSc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(C(F)(F)F)CC(=O)N1c1cc(OCSc2ccccc2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
While kept under N2, 0.15 g (3.7 mmol, 60% dispersion in oil) sodium hydride was washed with pentanes (2×0.5 ml), then suspended in 2 ml of dry THF (fleshly distilled from sodium/benzophenone). To the suspension, cooled in an ice bath, were added 1.1 g (3.4 mmol) of N-(4'-chloro-2'-fluoro-5'-hydroxyphenyl)-3-(trifluoromethyl)glutarimide (Compound 19) dissolved in 3.5 ml of dry THF (freshly distilled from sodium/benzophenone) and two 1 ml rinses of dry THF. The reaction was then allowed to warm to room temperature and stirred for 15 minutes. The flask was again cooled in an ice bath while a solution of chloromethyl phenyl sulfide (0.46 ml, 0.54 g, 3.4 mmol) in 3 ml dry THF was added dropwise. The reaction mixture was allowed to warm slowly to room temperature and stirred for about 24 hours, then warmed to 50° C. for 54 hours. The THF was evaporated in vacuo (2-10 Torr) and the reaction mixture was taken up in 12 ml anhydrous dimethylformamide. The reaction was heated to 100° C. for 8 hours then cooled to room temperature. The reaction mixture was suction filtered through a short pad of neutral alumina and rinsed with 30 ml EtOAc. The filtrate was evaporated in vacuo and the residue was dried in the vacuum oven for 12 hours (20-50 Torr, 50° C.). The resulting oil was vacuum distilled (2-10 Torr, 70° C.). The residue was chromatographed (silica gel, 1:1 hexanes/methylene chloride) to yield 350 mg (23% yield) of the desired product as a white solid, m.p. 108°-109.5° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][N:19]2[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:15]([Sn](C)(C)C)[CH:14]=1>CN(C)C=O.[Cu]I>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][N:19]2[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:23])=[O:24])=[C:15]([C:2]2[O:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=2)[CH:14]=1
Reactant: C[Sn](C)(C)c1cc(Cl)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1cnc(Cl)o1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(-c2cc(Cl)cc3c2cnn3S(=O)(=O)c2ccccc2)o1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
In 4 batches, tetra is(triphenylphosphine)palladium(0) (3.37 g, 2.92 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (6.65 g, 37.9 mmol, available from Apollo Scientific) and copper(I) iodide (1.11 g, 5.83 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (13.28 g, 29.2 mmol) in N,N-dimethylformamide (52 ml). In 3 of the batches, tetra is(triphenylphosphine)palladium(0) (1.03 g, 0.89 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (2.03 g, 11.59 mmol) and copper(I) iodide (0.34 g, 1.78 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (4.06 g, 8.91 mmol) in N,N-dimethylformamide (16 ml). In the fourth batch, tetra is(triphenylphosphine)palladium(0) (0.28 g, 0.24 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (0.55 g, 3.14 mmol) and copper(I) iodide (0.09 g, 0.48 mmol) were added to a solution of 6-chloro-1-(phenylsulfonyl)-4-(trimethylstannanyl)-1H-indazole (1.10 g, 2.42 mmol) in N,N-dimethylformamide (4 ml). Each batch was heated and stirred at 100° C. under microwave irradiation for 30 min. The mixtures were allowed to cool to RT and the combined precipitated product suspended in diethyl ether and collected by filtration, washing with further diethyl ether then drying in a vacuum oven for 72 h. Approximately 5.2 g of the resultant solid was dissolved in dichloromethane and passed through Celite, eluting with further dichloromethane. The solvent was evaporated in vacuo to give the title compound as a pale orange solid (4.95 g).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[O:46][C:47]([CH3:50])=[N:48][N:49]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[O:46][C:47]([CH3:50])=[N:48][N:49]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Cc1nnc(CCl)o1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nnc(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)o1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole and isolated as colorless gum. MS (m/e): 379.3 (MH+).
Reaction SMILES: F[C:2]1[N:14]=[C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[CH:19]=[CH:18]3)[C:12]([CH:25]=[CH2:26])=[C:11](F)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:28][C:29]([CH3:32])([O-:31])[CH3:30].[K+]>C1COCC1>[C:29]([O:31][C:2]1[N:14]=[C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[CH:19]=[CH:18]3)[C:12]([CH:25]=[CH2:26])=[C:11]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])([CH3:32])([CH3:30])[CH3:28]
Reactant: CC(C)(C)[O-]
Reactant: C=Cc1c(-c2ccc3c(ccn3C)c2)nc(F)c(C(=O)OC(C)(C)C)c1F
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1c(-c2ccc3c(ccn3C)c2)nc(OC(C)(C)C)c(C(=O)OC(C)(C)C)c1OC(C)(C)C
Yield: 196.4 %

Procedure:
Into a solution of tert-butyl 2,4-difluoro-6-(1-methyl-1H-indol-5-yl)-5-vinylnicotinate (72 mg, 0.2 mmol) in THF (1.0 mL) at −78° C. was added a solution of potassium tert-butoxide (1.0 M×0.48 mL, 0.48 mmol). The temperature was allowed to rise to room temperature and the reaction was quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate. The organic layers were combined, dried, evaporated and purified by silica chromatography (0-10% ethyl acetate in hexanes) to give tert-butyl 2,4-di-tert-butoxy-6-(1-methyl-1H-indol-5-yl)-5-vinylnicotinate (94 mg, 47%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[Cl:17][C:18]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCl>[Cl:17][C:18]1[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([N:7]1[CH2:8][CH2:9][N:4]2[CH:3]=[CH:2][N:1]=[C:5]2[CH2:6]1)=[O:21]
Reactant: c1cn2c(n1)CNCC2
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2ccnc2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.4 %

Procedure:
5,6,7,8-Tetrahydroimidazo[1,2-a]pyrazine (0.099 g, 0.804 mmol) was suspended in dichloromethane (DCM) (8 ml). Triethylamine (0.123 mL, 0.884 mmol) and 2-chloro-3-(trifluoromethyl)benzoyl chloride (0.195 g, 0.804 mmol) were added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo, the residue dissolved in 1:1 DMSO/MeOH and purified by mass-directed automated preparative HPLC. Product fractions were concentrated in vacuo to yield an orange gum. This was partitioned between DCM (10 ml) and saturated aqueous sodium bicarbonate (4 ml) and the organic layer separated. This was concentrated in vacuo to yield 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.131 g, 0.397 mmol, 49.4% yield) as a yellow gum.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[C:4]([CH3:9])=[N:3]1.[NH2:10][C:11]1[CH:16]=[N:15][C:14]([Br:17])=[CH:13][N:12]=1.[B-][N+](C)(C)C.C(O)(=O)C>C(OCC)(=O)C>[Br:17][C:14]1[N:15]=[CH:16][C:11]([NH:10][CH2:7][C:5]2[C:4]([CH3:9])=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:12][CH:13]=1
Reactant: Nc1cnc(Br)cn1
Reactant: Cc1nn(C)cc1C=O
Agent: [B-][N+](C)(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nn(C)cc1CNc1cnc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A mixture of 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (142 mg, 1.145 mmol), 2-amino-5-bromopyrazine (200 mg, 1.149 mmol), borane trimethylamine complex (126 mg, 1.73 mmol) and glacial acetic acid (137 mg, 2.29 mmol) in anhydrous methonol (3 ml) was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over MgSO4 and filtered. The filtrate was concentrated to give 300 mg of (5-bromo-pyrazin-2-yl)-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)amine as crude product, which was used for next step reaction without further purification. Crude yield: 93%.