Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[N:12]1([C:17]2[N:21]=[C:20]([C:22](=O)[CH3:23])[S:19][N:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.C(OC(=O)[N:31]([CH2:42][CH2:43][NH2:44])[CH2:32][C:33]1[CH:41]=[CH:40][C:36]2[O:37][CH2:38][O:39][C:35]=2[CH:34]=1)(C)(C)C.O>O1CCOCC1.C(O)(C(F)(F)F)=O.C(Cl)Cl.CCOC(C)=O>[O:37]1[C:36]2[CH:40]=[CH:41][C:33]([CH2:32][NH:31][CH2:42][CH2:43][NH:44][CH:22]([C:20]3[S:19][N:18]=[C:17]([N:12]4[CH:16]=[CH:15][N:14]=[CH:13]4)[N:21]=3)[CH3:23])=[CH:34][C:35]=2[O:39][CH2:38]1
Reactant: CC(=O)c1nc(-n2ccnc2)ns1
Reactant: CC(C)(C)OC(=O)N(CCN)Cc1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(NCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Temperature: 67.5 °C
Yield: 6.9 %

Procedure:
A catalytic amount of TsOH (20 mg) was added to a solution of 1-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-ethanone obtained from Step 1 (233 mg, 1.20 mmol) and (2-amino-ethyl)-benzo[1,3]dioxol-5-ylmethyl-carbamic acid tert-butyl ester (565 mg, 1.92 mmol) in 1,4-dioxane (10 mL) under a nitrogen atmosphere at r.t. prior to heating at 65-70° C. for 4 h. The reaction was then cooled to r.t. and NaHB(OAc)3 (763 mg, 3.60 mmol) was added. After stirring for an additional hour, water was added and the solution was extracted with ethyl acetate (2×70 mL), washed with brine and dried over Na2SO4. Evaporation of the solvent gave a yellow residue which was dissolved in TFA/DCM (1:1, 6 mL) and stirred at room temperature for 30 min. The solvent was evaporated to afford a yellow solid. The crude product was diluted with EtOAc (100 mL), washed with 1M NaOH (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to an orange solid. Purification was achieved using column chromatography (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 31 mg (7%) of N-benzo[1,3]dioxol-5-ylmethyl-N′-[1-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-ethyl]-ethane-1,2-diamine as a white solid. [M+H]+ 372.97; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.74 (s, 1H), 7.13 (s, 1H), 6.84 (s, 1H), 6.76 (m, 2H), 5.93 (s, 2H), 4.12 (q, 1H), 3.73 (d, 2H), 2.91-2.77 (m, 4H), 2.19 (br s, 2H), 1.54 (d, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Mg]Br.O1C=CC=C1.CN(OC)[C:15]([CH:17]1[CH2:21][C:20](=[O:22])[N:19]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:18]1)=[O:16].Cl>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:15]([C@H:17]1[CH2:18][N:19]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[C:20](=[O:22])[CH2:21]1)=[O:16]
Reactant: CON(C)C(=O)C1CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: Br[Mg]c1ccco1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccoc1
Product: C[C@H](c1ccccc1)N1C[C@H](C(=O)c2ccco2)CC1=O
Reaction time: 0.5 h
Yield: 46 %

Procedure:
In an atmosphere of nitrogen, 0.5 mol/l of 2-furylmagnesium bromide (180 ml) prepared from furan was added dropwise to a tetrahydrofuran solution (160 ml) of N-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-carboxamide (8.30 g, 30.0 mmol), and the mixture was stirred for 30 minutes. The reaction solution was mixed with 1 mol/l hydrochloric acid (200 ml) under ice-cooling and extracted with ethyl acetate (200 ml×2), and then the organic layer was washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was applied to a silica gel column chromatography. By eluting with a n-hexane:ethyl acetate system of from (1:1) to (1:2), 3.94 g (46%) of the title compound was obtained as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([CH2:33][OH:34])=[CH:30][C:29]=2[CH:35]=1.C([O-])([O-])=O.[K+].[K+].[CH2:42](OC(Cl)=O)[C:43]1C=CC=CC=1>C1COCC1.O>[CH2:42]([O:34][CH2:33][C:31]1[O:32][C:28]2[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[C:6]=4[C:2]=3[CH3:1])=[CH:35][C:29]=2[CH:30]=1)[CH3:43]
Reactant: Cc1c(COc2ccc3oc(CO)cc3c2)oc2cccc(OCCCNCc3cccnc3)c12
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCc1cc2cc(OCc3oc4cccc(OCCCNCc5cccnc5)c4c3C)ccc2o1
Reaction time: 3 h

Procedure:
To a solution of the compound in Example 40 (15 mg, 0.03 mmol) in anhydrous THF/H2O were added K2CO3 and benzyloxycarbonyl chloride (3 eq), the mixture was stirred for 3 hours. The crude mixture was purified over SiO2 column. The product was dissolved in anhydrous DMF (2 ml), NaH (5 mg) was added. The mixture was stirred for 10 minutes. Ethyl bromide (excess) was added to the reaction flask. The mixture was stirred for one hour. The crude product was hydrogenated over 10% Pd/C in MeOH to give the desired product as a colorless oil. ESI-MS: m/z 501 (MH+); 1H-NMR (CDCl3): δ 1.36 (3H, t, J=6.9 Hz), 2.16 (2H, m), 2.43 (3H, s), 2.98 (2H, t, J=6.9 Hz), 3.72 (2H, q, J=6.9 Hz), 3.94 (2H, s), 4.25 (2H, t, J=5.9 Hz), 4.68 (2H, s), 5.20 (2H, s), 5.40 (2H, s), 6.69 (1H, d, J=7.9 Hz), 6.73 (1H, s), 7.08 (1H, dd, J=9 Hz, 2.5 Hz), 7.18 (1H, d, J=18 Hz), 7.25-7.32 (3H, m), 7.46 (1H, d, J=9 Hz), 7.75 (1H, d, J=7.9 Hz), 8.59 (1H, dd, J=5 Hz, 1.5 Hz), 8.66 (1H, d, J=1.5 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:8]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[OH:17])=[CH:7][C:6](=[O:19])[CH:5]2[CH:3]1[O:4]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[OH:17][C:12]1[N:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([NH:9][C:8]1[CH:2]([OH:1])[CH:3]2[CH:5]([C:6](=[O:19])[CH:7]=1)[O:4]2)=[O:18]
Reactant: O=C(NC1=CC(=O)C2OC2C1=O)c1cccnc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C(NC1=CC(=O)C2OC2C1O)c1cccnc1O
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a solution of compound 7a (30 mg, 0.092 mmol, 80% purity) in methanol (4 mL) cooled to 0° C. under an inert nitrogen atmosphere was added sodium triacetoxyborohydride (30 mg, 0.142 mmol) in one portion. The solution was stirred at this temperature for 15 minutes before bringing to room temperature. After stirring an additional 45 minutes, the reaction was judged complete by TLC. The methanol was evaporated to approx. 2 mL volume and the flask was cooled in an ice bath for 10 minutes. The precipitate was then filtered and rinsed with methanol (2×3 mL). After drying under high vacuum, 10 mg (42% yield) of compound 8a as a pale yellow solid was isolated. The purity was 95% by HPLC (Restek Pinnacle II column, C18, 5μ, 250×4.6 mm; mobile phase: 5 minutes at 5% acetonitrile in water, then 5 to 100% acetonitrile in water over 20 min.; flow rate: 1.5 mL/min; detector: 316 nm (VWD). The product structure was confirmed by 1H NMR. NMR (DMSO-d6): δ12.70 (br.s, 1H), 12.50 (br.s, 1H), 8.35 (m, 1H), 7.85 (m, 1H), 6.90 (m, 1H), 6.55 (m, 2H), 4.80 (m, 1H), 3.80 (m, 1H), 3.40 (m, 1H) ppm.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].Cl.CN(C)C.[C:24]1([CH3:36])[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[S:32](Cl)(=[O:34])=[O:33]>ClCCl.O>[CH3:36][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[S:32]([O:8][CH2:9][CH2:10][NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])(=[O:33])=[O:34]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)OCCNC(=O)OC(C)(C)C)c(C)c1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 86.9 %

Procedure:
Triethylamine (65 mL, 465.3 mmole, 1.5 eq) was added in one portion to a solution of tert-butyl N-(2-hydroxyethyl)carbamate (50.11 g, 310.2 mmole, 1.0 eq.) in dichloromethane (250 mL, 5 vols). The solution was cooled to −10° C. and trimethylamine hydrochloride (14.84 g, 155.1 mmole, 0.5 eq.) was added in one portion. The resultant mixture was cooled further to −15° C., stirred for 5 minutes, then treated with a solution of mesitylenesulfonyl chloride (74.74 g, 341.2 mmole, 1.1 eq) in dichloromethane (250 mL, 5 vols), over 28 minutes such that the internal temperature remained below −10° C. Once the addition was complete a precipitate had formed and the mixture was stirred at −10° C. for a further 30 minutes. Water (400 mL, 8 vols) was added and all of the precipitate dissolved. The mixture was stirred rapidly for 5 minutes, and then the two layers were separated. A solvent swap from dichloromethane to IPA was carried out by distillation at reduced pressure. Solvent was removed (450 mL) and replaced with IPA (450 mL) (initial pressure was 450 mbar, b.p. 24° C.; final pressure was 110 mbar, b.p. 36° C.). At the end of the distillation, solvent (150 mL) was removed to bring the volume down to 350 mL (7 vols with respect to the amount of tert-butyl N-(2-hydroxyethyl)carbamate used). The solution was cooled to 25° C., then water (175 mL) was added slowly with stirring, causing the solution gradually to turn cloudy. No solid had precipitated at this stage. More water (125 mL) was added, and a solid precipitate started to form after about 75 mL had been added. The internal temperature rose from 25° C. to 31° C. The mixture was stirred slowly and cooled to 7° C. The solid was collected by filtration, washed with IPA:water (1:1, 150 mL) and dried in vacuo at 40° C. for 21 hours to give the title compound as a white crystalline solid (92.54 g, 87%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:14][CH:13]=1.C(N(CC)CC)C>>[Cl:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]([CH3:23])([CH3:22])[CH:20]=[O:21])=[CH:14][CH:13]=1
Reactant: CC(C)(CO)Oc1ccc(Cl)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C=O)Oc1ccc(Cl)nc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
An oven dried flask (50 ml, round bottom) containing dry dichloromethane (13 ml) is cooled to −78° C. (dry ice/acetone bath) under argon atmosphere. Oxalyl chloride (0.23 ml, 2.67 mmol) is added followed by the addition of dry dimethyl sulfoxide (0.31 ml, 4.31 mmol) via drop-wise addition. The mixture is stirred for 10 minutes and then a solution of 2-(6-chloropyridin-3-yloxy)-2-methylpropan-1-ol (451 mg, 2.06 mmol) [dissolved in dichloromethane (4 ml)] is added via slow drop-wise addition. The cooled solution was stirred for 30 minutes and then triethylamine (1.15 ml, 8.2 mmol) was added and the cooling bath was removed. The mixture was stirred and warmed to ambient over 1 hour. A saturated solution of sodium bicarbonate (20 ml) was added and also dichloromethane (20 ml). The material was transferred and shaken in a reparatory funnel. The dichloromethane phase was collected and washed with brine solution (25 mL). The aqueous phase was back extracted with methylene chloride (2×20 mL) and the organic phases combined, dried over magnesium sulfate, filtered and stripped. The material was purified by filtration through a short column of silica gel (20 g), eluting with 30% ethyl acetate/hexanes, which provided the product as a light yellow oil (361 mg). (M+H)+=200 m/e.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([NH:20][C:21]3[CH:29]=[C:28]4[C:24]([CH:25]=[N:26][NH:27]4)=[CH:23][CH:22]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:37])C(=O)C1>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[C:15]([NH:20][C:21]3[C:29]([Br:37])=[C:28]4[C:24]([CH:25]=[N:26][NH:27]4)=[CH:23][CH:22]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2Br)cc1
Temperature: 80 °C

Procedure:
A mixture of N-[4-(tert-butyl)phenyl][2-(1H-indazol-6-ylamino)(3-pyridyl)]carboxamide (620 mg) (Example 8) and NBS (330 mg) in benzene (50 ml) was heated at 80° C. for 3 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography to give the title compound. MS (ES+):464 (M+H)+; (ES−): 462 (M−H). Calc'd. for C23H22BrN5O—463.1.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:13][C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)[CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[CH:4]([CH2:20][C:21]([O:23]CC)=[O:22])[O:3]1.[OH-].[Li+].Cl>C1COCC1.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:13][C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)[CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[CH:4]([CH2:20][C:21]([OH:23])=[O:22])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Oc2cnccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.1 %

Procedure:
To a solution of ethyl 2-(1-hydroxy-4-methoxy-6-(pyrazin-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (150 mg, 0.44 mmol) in THF (2 mL) was added an aqueous solution of lithium hydroxide (90 mg, 2.2 mmol) in 3 mL of water at 0° C., The reaction mixture was stirred at room temperature for 1.5 hr and acidified to pH=2 using diluted hydrochloride acid. The resulting mixture was extracted with ethyl acetate (15 mL×2) and combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by HPLC to give the title compound as a white solid (71 mg, Y: 51.0%). 1H NMR (400 MHz, DMSO-d) δ 9.28 (s, 1H), 8.56 (s, 1H), 8.39-8.40 (d, J=2.4 Hz, 1H), 8.24 (s, 1H), 7.00-7.02 (d, J=10.8 Hz, 2H), 5.44-5.46 (m, 1H), 3.81 (s, 3H), 3.13-3.16 (m, 1H), 2.14-2.20 (m, 1H). MS (ESI) m/z=317 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][C:28](=[O:47])/[CH:29]=[CH:30]/[C:31]1[CH:35]=[CH:34][N:33]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:32]=1)([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:23]([O:27][C:28](=[O:47])/[CH:29]=[CH:30]/[C:31]1[CH:35]=[CH:34][N:33]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][N:9]([CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:22])[CH3:21])[CH2:10][CH2:11][C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:32]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCNCCc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CBr)cc2)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CN(CCO[Si](C)(C)C(C)(C)C)CCc3c[nH]c4ccccc34)cc2)c1
Reaction time: 43 h

Procedure:
[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amine (compound E2) (830 mg, 2.60 mmol) is dissolved in ethanol (200 ml). (E)-3-[1-(4-bromomethyl-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester (compound D4) (1.01 g, 2.37 mmol) is added and the mixture is stirred for 43 hours and evaporated. The residue is purified by a silica gel flash chromatograph using petrol ether-ether eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[NH:15][CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:23][O:24][C:25]([C@@H:27]1[CH2:31][C@@H:30](OS(C)(=O)=O)[CH2:29][N:28]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:26].[H-].[Na+].COC1C=C(C#CC2C3C(=NC=NC=3N)NN=2)C=C(OC)C=1.CS(OC1CCN(C(OC(C)(C)C)=O)C1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CN1C(=O)CCC1>[NH2:22][C:20]1[C:21]2[C:13]([C:12]#[C:11][C:5]3[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:14][N:15]([C@@H:30]3[CH2:29][N:28]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:27]([C:25]([O:24][CH3:23])=[O:26])[CH2:31]3)[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: COc1cc(C#Cc2c[nH]c3ncnc(N)c23)cc(OC)c1
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Agent: COc1cc(C#Cc2n[nH]c3ncnc(N)c23)cc(OC)c1
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](n2cc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)CN1C(=O)OC(C)(C)C

Procedure:
In accordance with Example 1 (Step 3), except that the 5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine obtained in Step 4, the (2S,4R)-4-(methylsulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester-2-methylester obtained in Step 5, sodium hydride, and NMP were individually used in place of 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate, potassium carbonate, and DMF, the title compound was obtained as a colorless, amorphous substance. Physical properties: m/z [M+H]+ 522.4
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]1[O:22][CH:23]=[CH:24][N:25]=1.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][N:40]=2)[C:35](O)=[O:36])[CH2:28][CH2:27]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][N:40]=[C:32]([N:29]4[CH2:28][CH2:27][O:26][CH2:31][CH2:30]4)[CH:33]=3)=[C:4]([C:21]3[O:22][CH:23]=[CH:24][N:25]=3)[N:5]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccnc(N2CCOCC2)c1
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccnc(N2CCOCC2)c1

Procedure:
N-(7-Chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-2-morpholin-4-yl-isonicotinamide was prepared starting from intermediate A and 2-morpholinoisonicotinic acid. MS calcd. for C29H25ClN5O4 [(M+H)+] 542.2, obsd. 542.2.
Reaction SMILES: Br[CH:2]([CH2:14][CH3:15])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C)C=O>[C:16]1(=[O:26])[N:20]([CH:2]([CH2:14][CH3:15])[C:3]([NH:5][C:6]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:13])=[O:4])[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12
Reactant: CCC(Br)C(=O)Nc1c(C)cccc1C
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CCC(C(=O)Nc1c(C)cccc1C)N1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A mixture of 20.0 g (74 mmoles) of N-(2-bromo-butyryl)--2,6-dimethyl-aniline, 27.8 g (0.15 moles) of potassium phthalimide and 150 ml of dry dimethyl formamide is stirred at 60° C. for 2 hours. The mixture is cooled, poured onto 750 ml of ice water, the separated crystalline substance is filtered off, washed with water and dried. The resulting crude product, weighing 35.7 g, is dissolved in 200 ml of chloroform, the solution is washed thrice with 50 ml of 1 n aqueous sodium hydroxide solution and thrice with 50 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. 17.7 g (71.1%) of N-(2-phthalimido-butyryl)-2,6-dimethyl-aniline are obtained; m.p.: 195°-196° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:12]O>>[Cl:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Reactant: CO
Product: COC(=O)c1nc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 3-neck round bottom flask equipped with a reflux condenser was added 3,6-dichloropyridine-2-carboxylic acid (50.0 g, 260.42 mmol) in methanol (200 mL). HCl(g) was bubbled in until solution became saturated and stirred at room temperature for 2 hr. The solution was concentrated to dryness in vacuo. Diethyl ether was added to make a slurry that was subsequently added to a flask filled with a 1:1 mixture of saturated sodium bicarbonate/diethyl ether and stirred for 10 min. The aqueous phase was extracted with diethyl ether (3×300 mL). The combined extracts were dried (MgSO4) and concentrated to give 46.6 g of a light yellow solid. 1H NMR(CDCl3): δ 4.00 (s, 3H); 7.41 (d, 1H); 7.80 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: O=C(O)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Product: COC(=O)[C@@H]1C[C@H](OC(=O)c2ccccc2)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 75 %

Procedure:
Compound 35 was synthesized using a procedure similar to that described in Example 29 from 8a using benzoic acid to afford 0.19 g (75%) of 35 as a white crystalline solid, mp 223-225° C.; 1H NMR (CDCl3): δ 1.13 (3H, s); 1.40 (1H, dd, J=11.6, 13.1); 1.50 (3H, s); 1.64 (2H, m); 1.84 (1H, dd, J=2.9, 11.3); 2.10 (2H, m); 2.37 (1H, ddd, J=3.0, 4.2, 12.3); 2.45 (1H, m); 2.50 (1H, m); 2.62 (1H, s); 3.01 (1H, dd, J=4.4, 12.5); 3.73 (3H, s); 5.00 (1H, dd, J=3.0, 3.0); 5.52 (1H, dd, J=4.7, 11.4); 6.32 (1H, dd, J=0.8, 2.0); 7.32 (1H, m); 7.36 (1H, dd, J=1.8, 1.8); 7.50 (2H, m); 7.65 (1H, tt, J=1.6, 7.5); 8.03 (2H, m); 13C NMR (CDCl3): δ15.6, 16.2, 18.3, 31.3, 35.2, 38.9, 43.4, 43.6, 51.4, 51.4, 52.1, 61.8, 72.2, 77.5, 108.5, 125.7, 129.0, 129.0, 129.9, 134.1, 139.3, 143.8, 165.4, 171.4, 172.2, 204.8; anal. C 67.85%, H 6.14%, O 25.70%, calcd for C28H30O8, C 68.00%, H 6.11%, O 25.88%.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1([C:13]([OH:15])=[O:14])C(O)=O.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C:13]([O:15][CH2:21][CH3:22])=[O:14]
Reactant: CCO
Reactant: O=C(O)C1(C(=O)O)Cc2ccccc2C1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1Cc2ccccc2C1

Procedure:
11.7 g of 2,2-indandicarboxylic acid was heated at 200° C. for 30 minutes. After liberation of bubbles ceased, the reaction product was cooled and dissolved in 150 ml of ethanol. 4 ml of concentrated sulfuric acid was added to the solution and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated in vacuo and the residue was neutralized by addition of sodium carbonate. The mixture was extracted with chloroform. The extract was washed with water and dried and then concentrated in vacuo to give 9.4 g of ethyl 2-indancarboxylate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:19][C:20]([S:23]([NH2:25])=[O:24])([CH3:22])[CH3:21].CCOC(C)=O.C([O-])(O)=O.[Na+]>CCCCCCC.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]1)[C:8]2=[N:25][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24]
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCC(F)(F)CC2
Temperature: 120 °C
Yield: 31.3 %

Procedure:
6′-Bromo-4,4-difluorospiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 11, 819 mg, 2.60 mmol), 2-methylpropane-2-sulfinamide (630 mg, 5.20 mmol) and titanium ethoxide (1.874 mL, 9.10 mmol) were dissolved in 2-Me THF (9 mL) and heated to 120° C. with MW for 1 h. EtOAc (20 mL) and NaHCO3 (aq., sat, 2 mL) were added under stirring. The mixture was left to stand without stirring for 1 h. The organic phase was collected by filtration, dried over MgSO4 and concentrated. Flash chromatography with a gradient of 0-50% EtOAc in n-heptane gave the title compound (340 mg, 31% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.25 (s, 9H), 1.56-1.71 (m, 2H), 2.10 (br. s., 6H), 3.12 (s, 2H), 7.49 (d, 1H), 7.81 (dd, 1H), 8.43-8.63 (m, 1H). MS (ES+) m/z 418 [M+H]+.