Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14](Cl)[C:5]2=[N:4][CH:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Br:1][C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:20][CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]2=[N:4][CH:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: CC(C)CN
Reactant: Clc1nc2ccccc2n2c(Br)cnc12
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNc1nc2ccccc2n2c(Br)cnc12
Temperature: 170 °C
Yield: 93.3 %

Procedure:
To a stirred solution of 1-bromo-4-chloro-imidazo[1,2-a]quinoxaline (14.13 g, 50 mmol) in NMP (400 mL) was added isobutylamine (9.94 mL, 100 mmol) and DIPEA (26.13 mL, 150 mmol) at room temperature in a microwave reactor. The solution was heated at 170° C. under microwave irradiation for 60 min. After cooling, water was added to the solution and the precipitate was filtered and the residue was washed with water and dried to give (1-bromo-imidazo[1,2-a]quinoxalin-4-yl)-isobutyl-amine (14.89 g, 93.3%): 1H-NMR (300 MHz, d6-DMSO): δ=9.17 (1H, d), 8.01 (1H, d), 7.92 (1H, s), 7.78 (1H, dd), 7.70 (1H, dd) ppm. UPLC-MS: RT=1.14 min; m/z 284.6 [MH+]; required MW=283.5.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[SH:14].I[CH2:16][C:17]#[N:18]>CN(C)C=O>[NH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:5]=1[S:14][CH2:16][C:17]#[N:18]
Reactant: N#CCI
Reactant: Nc1cc(C(F)(F)F)ccc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCSc1ccc(C(F)(F)F)cc1N
Reaction time: 0.25 h

Procedure:
Sodium hydride (2.93 g, 60% dispersion in mineral oil) was added at 5-10° C. under nitrogen in small portions to a stirred and cooled solution of 2-amino-4-trifluoromethyl-benzenethiol (8.00 g) dissolved in dry dimethylformamide (125 ml). After stirring for 45 min iodoacetonitrile (2.65 ml) was added. Stirring was continued at ˜0° C. for 15 min and then at room temperature for 1 h. The mixture was concentrated in vacuo at 55° C. and the oily residue was extracted with petroleum ether (3×50 ml) in order to remove the mineral oil. The residue was partitioned between water (50 ml) and ethyl acetate (100 ml). The organic phase was washed with water (2×50 ml) and then with brine (30 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. The crude product was purified by flash chromatography on silica gel eluted with ethyl acetate-heptane 3:7 giving the title compound as a yellow oil. Yield 6.1 g (75%); 1H-NMR (DMSO-d6) δ (ppm): 7.54 (d, J=8.3 Hz, 1H), 7.09 (d, J=1.8 Hz, 1H), 6.86 (dd, 1H), 5.97 (br, 2H), 4.02 (s, 2H); 13C-NMR (DMSO-d6) δ (ppm): 150.0, 135.7, 130.8 (q, J=31 Hz), 124.2 (q, J=272 Hz), 117.7, 117.1, 112.1 (q, J=3.8 Hz), 110.6 (q, J=3.9 Hz), 18.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15](Cl)=[O:16])[CH:5]=[CH:4][C:3]1=2.[NH2:19][C:20]1[CH:31]=[CH:30][C:23]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:22][CH:21]=1>>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:30][CH:31]=3)=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)Cl)ccc21
Reactant: C=CCOC(=O)c1ccc(N)cc1
Product: C=CCOC(=O)c1ccc(NC(=O)Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example l(d), by reaction of 4.5 g (16.8 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl -2-naphthylacetyl chloride with 3 g (16.8 mmol) of allyl 4-aminobenzoate, 5.1 g (75%) of the expected ester are obtained in the form of a slightly yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:13]([CH2:29][CH2:30][N:31]=3)[C:14]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)=[N:15][C:16]=2[C:17]=1[O:18][CH3:19].C(N(CC)C(C)C)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>CN(C)C=O>[CH3:19][O:18][C:17]1[C:16]2[N:15]=[C:14]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[N:13]3[CH2:29][CH2:30][N:31]=[C:12]3[C:11]=2[CH:10]=[CH:9][C:8]=1[O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:42]([CH3:41])(=[O:44])=[O:43]
Reactant: COc1c(OCCOCCN)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OCCOCCNS(C)(=O)=O)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.4 %

Procedure:
N-{8-[2-(2-Aminoethoxy)-ethoxy]-7-methoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl}-nicotinamide (Step 4, 75 mg, 0.18 mmol) was dissolved in dimethylformamide (2 mL). N,N-diisopropylethylamine (0.03 mL) was added, followed by methanesulfonyl chloride (0.01 mL, 0.14 mmol). The mixture was stirred at rt for 3 h, then was quenched by the addition of water. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted several times with dichloromethane. The combined organic extracts were dried and concentrated to afford a residue, which was purified by preparative HPLC (gradient elution of 10-70% acetonitrile in water, 0.1% TFA). The product fractions were free based with saturated aqueous sodium bicarbonate, and the desired was isolated by extraction with dichloromethane. The organic layer was dried over sodium sulfate, and concentrated to give the title compound (8.7 mg, 12%). HPLC MS RT=1.79 min, MH+=503.2. 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.89 (3H, s), 3.11 (2H, t), 3.56 (2H, t), 3.85 (2H, m), 4.03 (3H, s), 4.26 (2H, m), 4.43 (2H, m), 4.57 (2H, m), 7.50 (1H, d), 7.86 (1H, m), 8.02 (1H, d), 8.83 (1H, m), 8.94 (1H, m), 9.47 (1H, m).
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:40]=[N:39][C:34]3=[N:35][CH:36]=[CH:37][N:38]=[C:33]3[CH:32]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:40]=[N:39][C:34]4=[N:35][CH:36]=[CH:37][N:38]=[C:33]4[CH:32]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cnc3nccnc3c2)OC1(C)C
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4cnc5nccnc5c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrido[2,3-b]pyrazine (from Combi-Blocks). LCMS calculated for C23H21N6O2(M+H)+: m/z=413.2. Found 413.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[C:20]([C:22]([N:24]3[CH:33]4[CH:28]([CH2:29][CH2:30][CH2:31][CH2:32]4)[CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:19]=[C:18]([O:34][C:35]3[CH:40]=[CH:39][C:38]([C:41](=[NH:44])[NH:42][OH:43])=[CH:37][CH:36]=3)[CH:17]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:46](OC(=O)C)(=[O:48])[CH3:47]>>[C:1]([O:5][C:6](=[O:45])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[C:20]([C:22]([N:24]3[CH:33]4[CH:28]([CH2:29][CH2:30][CH2:31][CH2:32]4)[CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:19]=[C:18]([O:34][C:35]3[CH:36]=[CH:37][C:38]([C:41](=[NH:44])[N:42]([OH:43])[C:46](=[O:48])[CH3:47])=[CH:39][CH:40]=3)[CH:17]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3ccc(C(=N)NO)cc3)cc(C(=O)N3CCCC4CCCCC43)c2)cc1
Product: CC(=O)N(O)C(=N)c1ccc(Oc2cc(Oc3ccc(CNC(=O)OC(C)(C)C)cc3)cc(C(=O)N3CCCC4CCCCC43)c2)cc1

Procedure:
{4-[3-[4-(N-Hydroxycarbamimidoyl)phenoxy]-5-(octahydroquinoline-1-carbonyl)-phenoxyl]benzyl}carbamic acid tert-butyl ester, 1.4 g (2.28 mmol) was acetylated with 0.26 g (2.5 mmol) of acetic anhydride using the procedure of Example 2(e) to afford 1.04 g of the required product. Percentage purity (LCMS): 36.1%, (M+1)=654.3+1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:35]([C:29]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=3[F:27])(=[O:37])=[O:36])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
To a solution of 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (35 g, 89.5 mmol) (Intermediate 27) in pyridine (400 mL), 2,5-difluorobenzene-1-sulfonyl chloride (20.9 g, 98.5 mmol) was added dropwise. The reaction was stirred at rt for 2 h. Then the reaction was washed with water (400 mL), and extracted with DCM (2×400 mL). The organic layer was washed with water, brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:DCM 1:2) to afford the title compound (22.7 g, 44.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.75-10.83 (br, 1H), 8.32 (d, J=5.3 Hz, 1H), 7.28-7.60 (m, 6H), 6.48 (d, J=5.3 Hz, 1H), 3.65-3.80 (m, 4H), 3.50-3.65 (m, 4H); m/z (ES+): 568 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=O)[S:4][N:3]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:7][C:5]1[S:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[CH3:10]
Reactant: Cc1cc(C=O)sn1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1cc(C)ns1

Procedure:
prepared by reaction of 3-methyl-isothiazole-5-carbaldehyde (Buttimore D. et al J. Chem. Soc. 1963, 2032-2039) with 2M ethylamine in THF.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl>[Cl:13][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCc1ccncc1
Solvent: ClC(Cl)Cl
Product: ClCCCc1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a stirred solution of 3-(4-pyridyl)propanol (22.05 g, 0.16 mol) in 100 mL of dry chloroform (CHCl3) at 0° C. was added dropwise a CHCl3 solution of thionylchloride (SOCl2, 17.5 mL, 0.24 mol). The reaction was allowed to warm to room temperature, stirred for 1 hour, and then brought to reflux for 1 hour. After cooling the reaction to room temperature, it was stripped of all solvent under reduced pressure and the residue was partitioned between CH2Cl2 and water that had been made basic with concentrated NH4OH. The aqueous phase was washed 2x with CH2Cl2 and the combined organic phase was dried (Na2SO4), filtered, and stripped of solvent to yield 24 g of crude product. This material was vacuum distilled at 68°-71° C. (0.3 mm) to give 24 g of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C@H:9]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:36][OH:37])=[O:33])[CH2:28][C:29](=[O:31])[NH2:30])=[O:25])[C@@H:21]([CH3:23])[OH:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:42]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:43]([C:48](ON1C(=O)CCC1=O)=[O:49])[C@H:44]([CH2:46][CH3:47])[CH3:45].C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C>CN(C=O)C>[NH:42]([C:58]([O:60][C:61]([CH3:63])([CH3:62])[CH3:64])=[O:59])[C@H:43]([C:48]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:36][OH:37])=[O:33])[CH2:28][C:29](=[O:31])[NH2:30])=[O:25])[C@@H:21]([CH3:23])[OH:22])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:49])[C@H:44]([CH2:46][CH3:47])[CH3:45]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccccc1)[C@@H](C)O
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)OC)[C@@H](C)O
Yield: 85.9 %

Procedure:
A solution cooled on an ice bath of 5.14 g of TFA, H-Phe-Thr-Asn-Ser-OMe (8.78 mM) in 100 ml of DMF has 3.17 g of Boc-Ile-OSu (9.66 mM), 1.30 g of HOBt (9.62 mM) and N-ethyl morpholine added thereto until a pH of 7 is obtained. After 20 hours of reaction at ambient temperature, the solution is concentrated under reduced pressure and the residue taken up in ether gives a precipitate which is filtered and dried in vacuo. 5.24 g of product are obtained.
Reaction SMILES: [C:1]([C:4]([C:6]1[C:14]2[C:9](=[N+:10]([O-:17])[CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[NH:8][CH:7]=1)=[O:5])([OH:3])=O.C(N(CC)CC)C.[C:25]1([N:31]2[C:35]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:34][N:33]=[N:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][N+:10]([O-:17])=[C:9]2[NH:8][CH:7]=[C:6]([C:4](=[O:5])[C:1](=[O:3])[N:39]3[CH2:40][CH2:41][N:36]([C:35]4[N:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:32]=[N:33][N:34]=4)[CH2:37][CH2:38]3)[C:14]=12
Reactant: c1ccc(-n2nnnc2N2CCNCC2)cc1
Reactant: COc1cc[n+]([O-])c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[n+]([O-])c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Yield: 4 %

Procedure:
A mixture of the solid containing 3-(carboxycarbonyl)-4-methoxy-1H-pyrrolo[2,3-b]pyridine 7-oxide from above (200 mg, 0.84 mmol), triethylamine (0.5 mL, sssss), 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (234 mg, 1.01 mmol) and TBTU (404 mg, 1.26 mmol) was stirred at rt in DMF (1 mL) for 24 h. H2O was added and the reaction mixture was concentrated under reduced pressure. The residue was purified using reverse phase prep HPLC to afford the title compound as a white solid (15 mg, 4%). 1H NMR (500 MHz, CDCl3) δ ppm 3.32 (s, 2 H) 3.37 (s, 2H) 3.56 (s, 2 H) 3.79 (s, 2 H) 4.13 (s, 3 H) 6.83 (d, J=7.32 Hz, 1 H) 7.53 (d, J=6.71 Hz, 1 H) 7.54-7.60 (m, 3 H) 8.16 (s, 1 H) 8.34 (d, J=6.71 Hz, 1H). LCMS: m/e 449 (M+H)+, ret time 0.99 min (method 2).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2([NH:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[CH2:27][CH2:26]1)=[O:24])[C:13]1[C:14]([O:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=1)#[N:2].[H-].[Na+].N1C2C(=CC=CC=2)CC1=O.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C.ClCCl.CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:58]([C:55]1[CH:54]=[CH:53][C:52]([O:51][CH3:50])=[CH:57][CH:56]=1)(=[O:60])=[O:59])[C:7](=[O:12])[C:6]2([NH:22][C:23]([N:25]1[CH2:26][CH2:27][N:28]([CH:31]2[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]2)[CH2:29][CH2:30]1)=[O:24])[C:13]1[C:14]([O:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=1)#[N:2]
Reactant: CCOc1ncccc1C1(NC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)Nc2ccc(C#N)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: O=C1Cc2ccccc2N1
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1ncccc1C1(NC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
80.0 mg (0.16 mmol) of N-[5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide were dissolved in dimethylformamide, and 7.63 mg (0.19 mmol, 60% w/w) of sodium hydride were added at 0° C. For the deprotonation of the 1,3-dihydro-2H-indol-2-on derivative, the mixture was stirred for 10 minutes, and 39.4 mg (0.19 mmol) of 4-methoxybenzenesulphonyl chloride were then added. The mixture was then allowed to warm to room temperature and stirred for 30 minutes. The progress of the reaction was monitored by TLC (silica gel, dichloromethane/methanol 1:1). Saturated sodium bicarbonate solution and ethyl acetate were added to the reaction mixture, and the phases were then separated. The aqueous phase was reextracted with ethyl acetate (1×). The combined organic phase was washed with water (1×) and saturated sodium chloride solution (1×), dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative MPLC (ISCO Companion, 4 g NP cartridge) using the mobile phases dichloromethane/methanol (5-20%). What was isolated were 27.3 mg (0.04 mmol, 23% yield, 90% purity) of N-[5-cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][N:4]1[C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]3=[O:25])[C:11]([F:13])=[CH:12][C:7]=2[N:6]=[C:5]1[C:26]([F:29])([F:28])[F:27].C(=O)([O-])[O-].[K+].[K+].[NH2:37]OS(C1C(C)=CC(C)=CC=1C)(=O)=O>O1CCCC1.O>[NH2:37][N:16]1[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][C:19](=[O:20])[N:14]([C:10]2[C:11]([F:13])=[CH:12][C:7]3[N:6]=[C:5]([C:26]([F:27])([F:29])[F:28])[N:4]([CH2:3][CH:2]([CH3:30])[CH3:1])[C:8]=3[CH:9]=2)[C:15]1=[O:25]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CC(C)Cn1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cn1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(N)c3=O)cc21
Reaction time: 1 h

Procedure:
A solution of 1.3 grams (0.003 mole) of 3-[1-(2-methylpropyl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil (prepared as in Example 2, Steps A-H) in 30 mL of tetrahydrofuran is stirred, and 0.5 gram (0.003 mole) of potassium carbonate, then 0.7 gram (0.003 mole) of 1-aminooxysulfonyl-2,4,6-trimethylbenzene are added. Upon completion of the addition, the reaction mixture is stirred for one hour. The reaction mixture is then diluted with water and extracted with three portions of ethyl acetate. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue, which is purified by column chromatography, yielding 1-amino-3-[1-(2-methylpropyl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:10][O:11][C:12]=2[CH2:13][O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH:23]1([NH:29][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[N:10][O:11][C:12]=3[CH2:13][O:14][CH3:15])[CH:5]=[CH:4][N:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCCCC1
Reactant: COCc1onc(-c2ccc(F)cc2)c1-c1ccnc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COCc1onc(-c2ccc(F)cc2)c1-c1ccnc(NC2CCCCC2)c1
Temperature: 80 °C
Yield: 44 %

Procedure:
To a stirred solution of the above Compound 19b (20 mg, 0.050 mmol), cyclohexylamine (11 μL, 0.13 mmol), and BINAP (4.7 mg, 0.0075 mmol) in toluene (0.4 mL) at 25° C. was added Pd2(dba)3 (2.3 mg, 0.0025 mmol) followed by NaOtBu (12 mg, 0.13 mmol). The solution was heated to 80° C. for 15 h. The solution was cooled, poured into H2O (5 mL), extracted with EtOAc (4×5 mL), dried (MgSO4), filtered and concentrated. HPLC (gradient elution, 90–10% H2O—CH3CN) provided the title compound (9.1 mg, 0.022 mmol, 44%).
Reaction SMILES: I[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[SH:34][C:35]1[S:36][CH2:37][CH2:38][N:39]=1>>[S:36]1[CH2:37][CH2:38][N:39]=[C:35]1[S:34][CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12
Reactant: SC1=NCCS1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CI
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CSC1=NCCS1

Procedure:
Prepared according to Procedure F using Compound 4 and 2-mercaptothiazoline, the crude product was purified on a silica gel column using 3% ethanol in dichloromethane to obtain the pure product in 65% yields.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cnn2c(-c3cccc(F)c3)ccnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1cnn2c1NCC=C2c1cccc(F)c1
Reaction time: 16 h

Procedure:
A 136.3 g amount of 7-(3-fluorophenyl) pyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared as described in Example 5) in one liter of glacial acetic acid was stirred at room temperature, then 83.6 g of sodium cyanoborohydride was added portionwise under nitrogen. The mixture was stirred for 16 hours then the precipitated crystals were collected by filtration and triturated with saturated sodium bicarbonate until pH 7-8 was achieved. The crystals were washed with water and dried in vacuo to give 63.0 g of the product as cream-colored crystals, m.p. 122°-125° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:19][C:20]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[CH2:33][OH:34])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)C>C(Cl)Cl>[CH2:12]([O:19][C:20]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:24]=1[CH:33]=[O:34])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1CO)OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ccc(C(F)(F)F)cc1NC(=O)OCc1ccccc1
Reaction time: 0.75 h
Yield: 80 %

Procedure:
Molecular Sieves 4A (20 g) and pyridinium chlorochromate (6.8 g, 31.5 mmol) were added to a solution of 2-benzyloxycarbonylamino-4-trifluoromethyl-1-hydroxymethylbenzene (6.83 g, 21.0 mmol), prepared in step (c), in methylene chloride (200 ml), and the mixture was stirred under ice cooling for 45 min. Diethyl ether was added to the reaction mixture, and the mixture was filtered through Florisil and silica gel. The solvent was then removed under reduced pressure to give 2-benzyloxycarbonylamino-4-trifluoromethylbenzaldehyde (5.43 g, 80%).