Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([C:25]4[CH:26]=[N:27][CH:28]=[C:29]([C:31]#[C:32][Si](C)(C)C)[CH:30]=4)[CH2:22][C:23]#[N:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(Cl)Cl.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].[OH-].[K+].CO>>[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43].[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[C:31]([C:29]1[CH:30]=[C:25]([CH:21]([N:19]2[CH:20]=[C:16]([C:15]3[C:10]4[CH:9]=[CH:8][NH:7][C:11]=4[N:12]=[CH:13][N:14]=3)[CH:17]=[N:18]2)[CH2:22][C:23]#[N:24])[CH:26]=[N:27][CH:28]=1)#[CH:32]
Reactant: C[Si](C)(C)C#Cc1cncc(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: C#Cc1cncc(C(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36 %

Procedure:
3-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-{5-[(trimethylsilyl)ethynyl]pyridin-3-yl}propanenitrile (0.050 g, 0.000092 mol) was dissolved in DCM (5.0 mL, 0.078 mol) and TFA (2.0 mL, 0.026 mol). The reaction mixture was stirred at room temperature, for 90 minutes and was concentrated in vacuo. The dry residue dissolved in methanol cooled in an ice bath and a solution of potassium hydroxide (0.482 g, 0.00859 mol) in methanol (10 mL, 0.2 mol) was added. The reaction solution was stirred for 30 min was concentrated and the crude product was purified by preparative HPLC eluting with a water:ACN gradient with 0.2% TFA, to give the title compound as a white amorphous solid (15 mg, 35.85%). LCMS (M+1)+: 340, 1H NMR (400 MHz, DMSO-d6): δ 12.1 (bs, 1H), 9.02 (s, 1H), 8.80 (s, 1H), 8.70 (m, 2H), 8.48 (s, 1H), 8.00 (s, 1H), 7.80 (d, 1H), 7.15 (d, 1H), 6.20 (m, 1H), 4.82 (s, 1H), 3.90 (m, 1H), 3.70 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.C[N:30](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:30])=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CC(N)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a mixture of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (100 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (42 mg) and N,N-dimethylformamide (6 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (53 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=9:1-ethyl acetate), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (82 mg, yield: 82%) as pale-yellow prism crystals. MS:435(MH+). melting point 193-194° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[CH:14][C:13]=1[CH2:29][OH:30].C(N(CC)CC)C>C(Cl)Cl>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:22][CH:23]=2)=[CH:14][C:13]=1[CH:29]=[O:30]
Reactant: OCc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1Br
Temperature: 25 °C

Procedure:
DMSO (0.69 mL, 9.72 mmol) was added dropwise to oxalyl chloride (0.42 mL, 4.86 mmol) in 4 mL DCM at −78° C. After 20 minutes a DCM solution (6 mL) of the intermediate from Step C (1.2 g, 3.47 mmol) was added dropwise. After stirring for 15 minutes at −78° C. triethylamine (2.42 mL, 17.35 mmol) was added. The reaction mixture was then allowed to warm to room temperature. The solution was partitioned between aqueous saturated NH4Cl and DCM. The organic phase was washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 10.43 (s, 1H); 8.12 (d, J=2.4 Hz, 1H); 7.75 (d, J=8.6 Hz, 1H); 7.67-7.65 (m, 1H); 7.63 (d, J=8.5 Hz, 2H); 7.34 (d, J=8.5 Hz, 2H). LCMS1 4.09 min. (M+H)=345
Reaction SMILES: [Si:1]([CH3:5])([CH3:4])(Cl)Cl.[C:6]([Li])#[C:7][CH3:8].CCOCC.[NH4+].[Cl-].[CH2:17]1[CH2:21]OC[CH2:18]1>>[CH3:4][Si:1]([CH3:5])([C:18]#[C:17][CH3:21])[C:6]#[C:7][CH3:8]
Reactant: [Li]C#CC
Reactant: C1CCOC1
Reactant: C[Si](C)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC#C[Si](C)(C)C#CC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a well stirred solution of (CH3)2SiCl2 (150 mg, 1.2 mmol) in THF (5 mL), propynyl lithium (140 mg, 3 mmol) was added and continued stirring for 4 h at room temperature. The reaction mixture was then treated with Et2O-aq. NH4Cl solution. The organic layer was separated and dried over anhydrous Na2SO4. The yellow liquid so obtained was chromatographed over silica gel using hexane. The dimethyldipropynyl silane was obtained as a colorless liquid in quantitative yields.
Reaction SMILES: [CH:1]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:16]([O-:19])(=[O:18])[CH3:17].[Na+].O.C(OO)(=[O:24])C>C(Cl)Cl>[CH:1]12[O:18][CH:15]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.[CH:16]12[O:19][CH:1]1[CH:2]1[O:24][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:17]2
Reactant: CC(=O)OO
Reactant: C1=CCCCCCCC=CCCCCC1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C1=CCCCCCC2OC2CCCCCC1
Product: C1CCCCCC2OC2C2OC2CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture consisting of 100 g (0.49 moles) cyclopentadeca-1,8-diene, 217 g (1.6 moles) sodium acetate×3 H2O and 1000 ml methylene chloride, 78 ml 40% by wt. (0.47 moles) peracetic acid is added dropwise within 2 hours under stirring. The reaction temperature is 2° C. Subsequently, stirring is continued for another 30 minutes at the same temperature and the mixture is subsequently heated to room temperature. After another 2 hours of stirring at room temperature, the reaction mixture is washed first with 5×100 ml water, subsequently with 100 ml 5% by wt. sodium bicarbonate solution, and finally with 100 ml saturated sodium chloride solution and thus rendered neutral and free from peroxide. Subsequently, the phases are separated. The organic phase is dried over sodium sulfate. After removing the solvent, the product mixture is subjected to fractional distillation. 53 grams of the desired product is obtained in additon to 35 g initial substance (cyclopentadeca-1,8 -diene) and 11 g cyclopentadecadiene dioxide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH2:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[C:38](=[O:40])[NH:27][C:16]=2[CH:17]=1)=[O:22])[CH:25]=[CH2:26]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C=CCOC(=O)c1ccc2c(c1)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
To a stirred solution of 4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (20.0 g, 53.27 mmol, 1.0 equiv; example 1/step 4) in toluene (200 mL) and N-ethyldiisopropylamine (17.21 g, 133.17 mol, 2.5 equiv) was added a solution of triphosgene (18.97 g, 63.92 mmol, 1.2 equiv) in toluene (200 mL) and the reaction mixture stirred at 70° C. for 1.5 h. The solvent was evaporated, the residue diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water and a sat. solution of NaCl, dried over Na2SO4 and concentrated by evaporation under reduced pressure. The crude material was further washed with a mixture of hexane/ethyl acetate (95:5) to yield 15.5 g (73%) of the title product as wvhite solid. 1H NMR (400 MHz, DMSO): δ 1.43 (s, 9H), 1.72 (d, J=10.8, 2H), 2.17-2.23 (m, 2H), 2.88 (br s, 2H), 4.09 (d, J=8.6 Hz, 2H), 4.38 (t, J=12.2 Hz, 1H), 4.77 (d, J=5.3 Hz, 2H), 5.26 (d, J=10.4 Hz, 1H), 5.40 (dd, J=17.2 Hz, J=1.4 Hz, 1H), 5.99-6.09 (m, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.53 (d, J=1.3 Hz, 1H), 7.69-7.71 (m, 1H), 11.17 (s, 1H). 13C-NMR (100 MHz, DMSO): δ 28.04, 28.43, 50.32, 64.78, 78.79, 108.13, 109.18, 117.70, 121.69, 121.71, 122.67, 128.20, 132.81, 133.39, 153.78, 153.82, 165.36. MS (ISP): 402.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]2[CH2:10][N:5]([CH2:6][CH2:7][CH2:8]2)[CH2:4][C:3]=1[C:11]1[C:12](Cl)=[N:13][S:14][N:15]=1.[CH2:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[ClH:1].[Cl:1][C:2]1[CH:9]2[CH2:10][N:5]([CH2:6][CH2:7][CH2:8]2)[CH2:4][C:3]=1[C:11]1[C:12]([O:23][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:13][S:14][N:15]=1
Reactant: ClC1=C(c2nsnc2Cl)CN2CCCC1C2
Reactant: CCCCCCO
Product: CCCCCCOc1nsnc1C1=C(Cl)C2CCCN(C1)C2
Product: Cl

Procedure:
The compound was made as described in example 44 by reacting 4-chloro-3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.3.1]non-3-ene with 1-hexanol. The free base was crystallized as the hydrochloride from ether. (Compound 94). M.p. 100-101° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:32]([F:33])=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[CH2:23][O:22][C:21]4=[O:30])[CH2:16][CH2:15]3)=[O:13])=[C:10]([O:34][CH3:35])[CH:9]=2)[CH2:3][CH2:2]1.[C:36](OC(=O)C)(=[O:38])[CH3:37].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:36]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:32]([F:33])=[CH:31][C:11]([C:12]([N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[CH2:23][O:22][C:21]4=[O:30])[CH2:18][CH2:19]3)=[O:13])=[C:10]([O:34][CH3:35])[CH:9]=2)[CH2:3][CH2:2]1)(=[O:38])[CH3:37]
Reactant: COc1cc(OC2CCNCC2)c(F)cc1C(=O)N1CCC(N2C(=O)OCc3ccccc32)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC2CCN(C(C)=O)CC2)c(F)cc1C(=O)N1CCC(N2C(=O)OCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 1-(1-(4-(4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one of Example 16 (200 mg, 0.41 mmol) in DCM (5 mL) at ambient temperature was added acetic anhydride (77 mg, 0.75 mmol) and DIEA (0.17 mL, 1.0 mmol). The solution was stirred at ambient temperature for 24 h, diluted with DCM (20 mL), washed with saturated aqueous NaHCO3 (50 mL), dried (MgSO4), and filtered. The solvent was removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using a gradient elution of 2-5% MeOH-DCM. 1-(1-(4-(N-acetyl-4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl) -4H-3,1-benzoxazin-2(1H)-one was obtained as an amorphous solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.II.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].S(=O)(=O)(O)O>O1CCCC1.[Zn]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCOCC1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCOCC1
Yield: 69.3 %

Procedure:
To a solution of tetrahydro-4H-pyran-4-one (5.5 g, 51.6 mmol), a zinc powder (4.05 g, 61.9 mmol) and a small amount of iodine in tetrahydrofuran (60 ml) was added dropwise ethyl bromoacetate (6.28 ml, 56.7 mmol) under a nitrogen atmosphere. After heating under reflux for 6 hrs., 10% sulfuric acid (50 ml) was carefully added under ice-cooling and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous MgSO4 and concentrated under reduced pressure to give the title compound (6.73 g, 69%) as a colorless oil.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14].CO>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:14])=[O:15]
Reactant: COc1ccccc1S(N)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: NS(=O)(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
22.2 ml of boron tribromide are added dropwise, under nitrogen and at room temperature, over 15 minutes to a suspension of 39 g of 2-methoxyphenylsulfonamide in 210 ml of dry methylene chloride. The reaction mixture is then stirred for 1 hour at room temperature. After the mixture has been cooled to 0° C., 200 ml of methanol are added over 15 minutes and the clear solution is concentrated. The oily residue is taken up in ethyl acetate and the solution is washed twice with water, dried over sodium sulfate, and evaporated to dryness. The residue is triturated with petroleum ether, affording 25.1 g of 2-hydroxyphenylsulfonamide with a melting point of 136°-138° C.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:12]=[CH:11][CH:10]=[CH:9][C:4]=2[N:5]=[C:6]([SH:8])[N:7]=1.[CH3:13][O-].[Na+].CO.CI>C(O)(=O)C>[OH:1][C:2]1[C:3]2[N:12]=[CH:11][CH:10]=[CH:9][C:4]=2[N:5]=[C:6]([S:8][CH3:13])[N:7]=1
Reactant: Oc1nc(S)nc2cccnc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: CC(=O)O
Product: CSc1nc(O)c2ncccc2n1

Procedure:
A mixture of 22.1 g (0.123 mot) of 4-hydroxypyrido[3,2-d]pyrimidine-2-thiol, 65 mL of 25 percent sodium methoxide in methanol (0.28 mol), 8.9 mL (20.1 g, 0.142 mol) of methyl iodide, and 500 mL of methanol was prepared and allowed to react at ambient temperature with stirring until the starting material thiol disappeared as determined by high pressure liquid chromatography (HPLC). The mixture was then acidified with acetic acid and the volatile components were removed by evaporation under reduced pressure. The residue was diluted with water and the solids were recovered by filtration, washed with ether, and dried overnight in a vacuum oven. The resultant white powder was the title compound melting at 229°-231° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[N:9]([CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[CH2:4][CH2:3]1.[S]>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:7][C:8](=[O:15])[N:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC1CCc2c(-c3ccccc3)nc(=O)n(C(C)C)c2C1
Agent: [S]
Solvent: Cc1ccccc1C
Product: Cc1ccc2c(-c3ccccc3)nc(=O)n(C(C)C)c2c1
Reaction time: 8 h

Procedure:
To 50 ml. of xylene are added 1.35 g. of 7-methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1H)-quinazolinone and 0.32 g. sulfur. The mixture is boiled overnight (about 16 hours). The resulting solution is evaporated under pressure and the catalyst crystalline residue is recrystallized from ether/petroleum ether to give 7-methyl-1-isopropyl-4-phenyl-2(1H)-quinazolinone.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:20][CH2:21][CH:22]([OH:24])[CH3:23]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:14]([O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:20]([CH2:21][CH:22]([OH:24])[CH3:23])[C:5]=32)=[CH:10][CH:9]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)COc1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)COc1ccc2c(c1)-c1c(ccn1CC(C)O)C2
Reaction time: 0.75 h
Yield: 57 %

Procedure:
A solution of 2.3 g of (RS)-2-(2-oxoethyl)-6-isobutoxy-1-indanone and 70 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.93 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 1:4). 1.52 g (57%) of (RS)-1-(7-isobutoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a red oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].C(N(CC)CC)C.[CH2:15]([S:27][C:28]([S:30][C:31]([CH3:36])([CH3:35])[C:32](Cl)=[O:33])=[S:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[N:1]([CH2:4][CH2:5][CH2:6][O:7][C:32](=[O:33])[C:31]([S:30][C:28]([S:27][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[S:29])([CH3:36])[CH3:35])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCSC(=S)SC(C)(C)C(=O)Cl
Reactant: [N-]=[N+]=NCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCSC(=S)SC(C)(C)C(=O)OCCCN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
3-Azidopropanol (265 mg, 2.62 mmol, 1.0 equiv) is dissolved in methylene chloride (5 mL) in a 50 mL round-bottom flask, and the solution is cooled to approximately 0° C. A solution of triethylamine (0.73 mL) in methylene chloride (5 mL) is added dropwise over 10 min. A solution of DMP-Cl (1.0 g, 2.6 mmol) in methylene chloride (5 mL) is added dropwise, and the solution is allowed to reach room temperature while stirring for 3 h. The solution is concentrated under reduced pressure, diluted with ethyl ether (100 mL), and washed with saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL), and saturated NaCl solution (50 mL), successively. The organic layer is separated, dried over MgSO4 (1.0 g), and filtered. The supernatant is concentrated under reduced pressure to yield the product (1.05 g, 90% yield) as a residual oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7](=[O:14])[CH2:8][CH2:9][NH:10][S:11](=[O:13])(=[O:12])[C:5]=2[CH:4]=[CH:3]1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:19][CH2:18][CH2:17][CH2:16][N:10]1[CH2:9][CH2:8][C:7](=[O:14])[C:6]2[N:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[S:11]1(=[O:13])=[O:12]
Reactant: ClCCCBr
Reactant: Cn1ccc2c1C(=O)CCNS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1ccc2c1C(=O)CCN(CCCCl)S2(=O)=O
Yield: 94.6 %

Procedure:
A suspension of 214 mg (1 mmol) of Compound 14, 630 mg (4 mmol) of 1-bromo-3-chloropropane and 276 mg (2 mmol) of potassium carbonate in 5 ml of acetone was refluxed for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate/hexane=1/2), whereby 275 mg of the title compound were obtained (yield: 95%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.Cl.Cl.[O:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH:29]([NH2:31])[CH3:30].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH:29]([NH:31][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=2)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=1)=[O:13])[CH3:30]
Reactant: CC(N)c1ncco1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)c1ncco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A round-bottomed flask was charged with 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (300 mg, 0.81 mmol) and 1-oxazol-2-yl-ethylamine dihydrochloride (244 mg, 1.0 mmol). DMF (4 ml) was added followed by N,N-diisopropylethylamine (0.9 ml, 5.15 mmol) and HATU (337 mg, 0.89 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and diluted with petroleum ether. The resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 268 mg (71%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide as an off-white powder.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>ClC(Cl)C.O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:14][CH:15]=1
Reactant: C1COCCN1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N3CCOCC3)nc12
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a stirred solution of 145 mg (0.38 mmol) (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester in 6 ml dichloroethane and 2 ml tetrahydrofuran at room temperature was added 0.16 ml (1.88 mmol) morpholine and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) followed by trituration in ether afforded 48 mg (34%) morpholine-4-carboxylic acid (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-amide as a white crystalline solid. ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: [I-].[Na+].[C:3]([NH:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[C:12]([NH:22][C:23](=[O:26])[CH2:24]Cl)[CH:11]=1)(=[O:5])[CH3:4].[Cl-].[Cl:28][C:29]1[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=1)[O:32][CH:33]1[CH2:38][CH2:37][NH2+:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>C1COCC1.C(#N)C>[C:3]([NH:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[C:12]([NH:22][C:23](=[O:26])[CH2:24][N:36]2[CH2:35][CH2:34][CH:33]([O:32][C:31]3[CH:39]=[CH:40][CH:41]=[C:29]([Cl:28])[CH:30]=3)[CH2:38][CH2:37]2)[CH:11]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)NCCNc1cc(NC(=O)CCl)nc(-c2ccccc2)n1
Reactant: Clc1cccc(OC2CC[NH2+]CC2)c1
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)NCCNc1cc(NC(=O)CN2CCC(Oc3cccc(Cl)c3)CC2)nc(-c2ccccc2)n1

Procedure:
Large scale reaction: Sodium iodide (2.45 g; 16.3 mmol) was added to a suspension of chloroacetamide 6 (5.67 g; 16.3 mmol), piperidinium chloride 7.5 (4.85 g; 19.5 mmol) and DIPEA (7.0 mL; 40.2 mmol) in 3:1 acetonitrile:THF (480 mL). After 19.5 h the reaction was concentrated on a rotary evaporator. EtOAc (250 mL) was added and the suspension was washed with 50% saturated NaHCO3 (1×50 mL), water (2×25 mL) and saturated NaCl (2×35 mL). The orange-brown solution was dried over MgSO4; charcoal (0.86 g) was added and this was filtered then concentrated leaving a light orange foam. The crude material was purified on silica gel (850 mL) with 12-9:1 EtOAc:i-PrOH. Product was obtained as a pale yellow/off-white hard foam (7.82 g; 92%).