Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([N:5]([C@H:9]1[CH2:14][CH2:13][C@@H:12]([C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])=[O:16])[CH2:11][CH2:10]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:5][C@@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:26])([F:27])[F:28])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)N(C(=O)[O-])[C@H]1CC[C@@H](C(=O)NCc2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@@H](C(=O)NCc2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A 500 mL round bottom flask equipped with a magnetic stir bar was charged with 1,1-dimethylethyl{cis-4-[({[2(trifluoromethyl)phenyl]methyl}amino)carbonyl]cyclohexyl}carbamate (24.88 g, 62.1 mmol) and dichloromethane (100 mL). Trifluoroacetic acid (100 mL) was added slowly, and the reaction mixture was stirred at room temperature for 1 h. The volatile components were removed by rotary evaporation, and the crude oil was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution (3×200 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give 18.3 g of the title compound (98%) as an off-white solid. MS (ES) m/e 301 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:23](=[N-])(=[O:25])=[O:24]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22][S:23]2(=[O:25])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=S(=O)=O
Reactant: Nc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Solvent: c1ccncc1
Product: O=S1(=O)Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Then, 590 mg of 1-benzyl-4-[N-(o-aminobenzyl)-amino]-piperidine, 600 mg of sulfurylamide and 12 ml of pyridine are mixed and refluxed with heating for 2 hours. The reaction mixture is cooled to room temperature and poured into 50 ml of ice water. The white crystals deposited are separated by filtration, washed with 10 ml of water and dried to obtain 520 mg of the desired product as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.[CH2:22](Br)[CH2:23][CH2:24]C>>[CH2:20]([O:19][C:18]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:21])[CH2:22][CH2:23][CH3:24]
Reactant: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1
Reactant: CCCCBr
Product: CCCCOc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 3-N-(4-chlorophenyl)-4-methoxyisophthalamide and butyl bromide by the same procedure as in the manufacturing method described in Example 1-1-2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([CH:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH:52]([CH3:54])[CH3:53])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:40]=1[NH2:55].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:55][C:40]3[CH:41]=[CH:42][C:43]([CH:45]4[CH2:46][CH2:47][N:48]([CH2:51][CH:52]([CH3:54])[CH3:53])[CH2:49][CH2:50]4)=[CH:44][C:39]=3[O:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: COc1cc(C2CCN(CC(C)C)CC2)ccc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(C4CCN(CC(C)C)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 120 °C
Yield: 51.1 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 2-(methyloxy)-4-[1-(2-methylpropyl)-4-piperidinyl]aniline (Example 160, step C) (47 mg, 0.18 mmol), and p-toluenesulfonic acid (90 mg, 0.47 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (67 mg, 0.092 mmol, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.37 (d, J=6.78 Hz, 1H), 8.50 (s, 1H), 8.24 (d, J=5.31 Hz, 1H), 8.04 (d, J=2.01 Hz, 1H), 7.67-7.75 (m, 2H), 7.64 (d, J=8.06 Hz, 1H), 7.41-7.46 (m, 1H), 7.32-7.40 (m, 1H), 7.25 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.15 Hz, 2H), 6.94-6.98 (m, 2H), 6.78 (dd, J=8.24, 1.46 Hz, 1H), 6.59 (d, J=5.31 Hz, 1H), 4.25 (q, J=6.84 Hz, 2H), 3.82 (s, 3H), 2.90 (d, J=10.44 Hz, 2H), 2.42-2.46 (m, 1H), 2.02 (d, J=7.14 Hz, 2H), 1.91 (t, J=10.44 Hz, 2H), 1.65-1.75 (m, 5H), 1.41 (t, J=6.87 Hz, 3H), 0.84 (d, J=6.41 Hz, 6H). MS (ESI): 732 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:3][OH:4].[CH:24](=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.CCCCCCC>C1(C)C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25](/[CH:24]=[N:1]/[C@H:2]([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:3][OH:4])=[CH:26][CH:27]=1
Reactant: COc1ccc(C=O)cc1
Reactant: N[C@@H](CO)COc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: COc1ccc(/C=N/[C@@H](CO)COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A solution of Example 1G (3.236 kg) and para-anisaldehyde (1.484 kg) in toluene (6.631 kg) was heated at 80° C. for 2 hours, treated with heptane (33.147 kg) over 50 minutes, cooled to room temperature over 20 hours, and filtered. The filter cake was rinsed with heptane (6.994 kg), air dried, then vacuum dried (100 mmHg) at 50° C. to provide 4.297 kg (97.6%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ8.35 (s, 1H), 7.73 (dt, 2H, J=8.9, 2.9 Hz), 7.61 (dt, 2H, J=8.8, 2.9 Hz), 7.41 (dd, 2H, J=8.9, 1.1 Hz), 7.05 (dt, 2H, J=8.8, 2.9 Hz), 7.01 (dt, 2H, J=8.8, 2.9 Hz), 4.87 (br s, 1H), 4.31 (dd, 1H, J=9.9, 4.1 Hz), 4.13 (dd, 1H, J=9.9, 7.4 Hz), 3.81 (s, 3H), 3.64-3.80 (m, 2H), 3.56 (dd, 1H, J=10.0, 6.3 Hz).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:11][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][N:2]([CH3:1])[S:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CNCC(O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(O)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of α-(methylaminomethyl)benzyl alcohol (1.00 g, 6.61 mmol) in 15 mL of THF was cooled in an ice bath. Benzenesulfonyl chloride (0.886 mL, 1.23 g, 6.94 mmol) and N,N-diisopropylethylamine (2.3 mL, 1.7 g, 13 mmol) were added and mixture was allowed to warm to room temperature. After 30 min, the solvent was evaporated and the residue was partitioned between 50 mL of ethyl acetate and 40 mL of saturated aqueous sodium bicarbonate. The aqueous layer was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried over sodium sulfate, and evaporated. Purification by flash column chromatography on silica gel, eluting with 20-50% ethyl acetate in hexane, gave the title compound in quantitative yield.
Reaction SMILES: O1CCC[CH2:2]1.C[Mg]Br.[CH:9]([C:11]1[N:12]=[C:13]([CH2:58][CH2:59][CH3:60])[N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:10].C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[OH:10][CH:9]([C:11]1[N:12]=[C:13]([CH2:58][CH2:59][CH3:60])[N:14]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[N:37]=[N:36][N:35]=3)=[CH:26][CH:27]=2)[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2]
Reactant: C1CCOC1
Reactant: CCCc1nc(C=O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 3 h

Procedure:
4.0 ml of a 1M solution of methylmagnesium bromide tetrahydrofuran were added dropwise at -10° C. to a solution of 1.2 g of ethyl 4-formyl-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 5 ml of tetrahydrofuran, and the resulting mixture was stirred at a temperature between -10° C. and 0° C. for 3 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate and with an aqueous solution of ammonium chloride, and the mixture was stirred at room temperature for 20 minutes. The ethyl acetate layer was then separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using 1:4 and 1:2 by volume mixtures of ethyl acetate and methylene chloride as the eluent, to give 1.23 g of the title compound as a viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]2[S:12][C:13]([CH2:16]Cl)=[CH:14][CH:15]=2)[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2].[CH2:18]([C:21]1[NH:22][C:23]2[C:24]([N:31]=1)=[N:25][C:26]([CH3:30])=[CH:27][C:28]=2[CH3:29])[CH2:19][CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1([C:11]2[S:12][C:13]([CH2:16][N:31]3[C:24]4=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]4[N:22]=[C:21]3[CH2:18][CH2:19][CH3:20])=[CH:14][CH:15]=2)[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(CCl)s2)CC=CC1
Reactant: CCCc1nc2nc(C)cc(C)c2[nH]1
Product: CCCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2(C(=O)OCC)CC=CC2)s1

Procedure:
Alkylation was performed on (5) as described in Example 1, Step 5, above, using 2-propyl-5,7-dimethylimidazo[4,5-b]pyridine (10) to yield the title compound (9).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][C:38]1[C:39]([N:48]2[CH2:53][CH2:52][N:51]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:50][CH2:49]2)=[CH:40][C:41]([O:45][CH2:46][CH3:47])=[C:42]([NH2:44])[CH:43]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(O)C(F)(F)F.CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:42]3[CH:43]=[C:38]([CH3:37])[C:39]([N:48]4[CH2:53][CH2:52][N:51]([CH2:54][CH2:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:50][CH2:49]4)=[CH:40][C:41]=3[O:45][CH2:46][CH3:47])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 54.4 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (2.9 g, 5.7 mmol) and (5-methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (2.0 g, 5.7 mmol) in trifluoroethanol (100 mL) was added p-toluene sulfonic acid (2.2 g, 11 mmol), and the vial was sealed and heated to 80° C. overnight. The reaction was then cooled to rt and excess 0.5 M NaOMe in MeOH was added. The solution was transferred to a roundbottom flask and silica was added. The solvent was removed on a rotovap and the product purified on a 120 g ISCO column. Desired fractions were combined and rotovaped down. The resulting foam was dissolved in DCM and ether was added to provide the title compound 2.5 g, 3.1 mmol, 54% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 9.33 (d, J=6.7 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J=5.4 Hz, 1H), 8.02 (s, 1H), 7.73-7.70 (m, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.53 (s, 1H), 7.43-7.31 (m, 2H), 7.23 (d, J=8.6 Hz, 1H), 7.16 (t, J=8.0 Hz, 2H), 6.92 (t, J=6.6 Hz, 1H), 6.71 (s, 1H), 6.56 (d, J=5.1 Hz, 1H), 4.23 (q, J=7.2 Hz, 2H), 4.04 (q, J=7.0 Hz, 2H), 3.33-3.25 (m, 2H), 3.03 (s, 3H), 2.84-2.78 (m, 4H), 2.74 (t, J=6.6 Hz, 2H), 2.63-2.46 (m, 4H), 2.11 (s, 3H), 1.40 (t, J=6.8 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H). MS (ESI) m/z=811 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([NH:1][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:3]=1)#[N:6]
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Cc1ccc(C#N)cc1N
Agent: Br
Product: Cc1ccc(C#N)cc1NC(C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 54.3 %

Procedure:
3-amino-4-methylbenzonitrile (108 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(5-cyano-2-methylphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (50 mg, 53%) as a white solid. Mass Spectrum: M+H+ 461.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:16])[CH2:14]O)=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].P(Br)(Br)[Br:18]>>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:16])[CH2:14][Br:18])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1ccc(CC(C)CO)cc1
Reactant: BrP(Br)Br
Product: CCC(C)(C)c1ccc(CC(C)CBr)cc1
Reaction time: 16 h

Procedure:
32.2 g of 3-(p-tert.amyl-phenyl)-2-methyl-propanol are added dropwise at 20°-30° C. over a period of 2 hours to 21.8 g of phosphorus tribromide and the mixture is left to stand for 16 hours. The mixture is subsequently heated to 55°-60° C. for a period of 1.5 hours, cooled down to ca 10° C. and cautiously poured on to ice. The aqueous solution is exhaustively extracted with ether, the combined ether phases are washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. By fractional distillation there is obtained pure 3-(p-tert.amyl-phenyl)-2-methyl-propyl bromide of boiling point 117°-119° C./0.035 Torr.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[C@@H:7](C1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)CC(NN1[C@@H](CC2C=CC=CC=2)COC1(C)C)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:44][C:45]([CH3:73])([CH3:72])[C@H:46]([NH:51][C:52](=[O:71])[CH2:53][C:54]1[O:58][C:57]([C:59]2[CH:64]=[CH:63][C:62]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:61][CH:60]=2)=[CH:56][CH:55]=1)[C:47](=[O:50])[NH:48][CH3:49].C([Li])CCC>>[C:1]([O:5][C:6](=[O:43])[CH2:7][CH:53]([C:54]1[O:58][C:57]([C:59]2[CH:60]=[CH:61][C:62]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:63][CH:64]=2)=[CH:56][CH:55]=1)[C:52]([NH:51][C@H:46]([C:47](=[O:50])[NH:48][CH3:49])[C:45]([CH3:73])([CH3:72])[CH3:44])=[O:71])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)[C@@H](NC(=O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1)C(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@H](CC(=O)NN1[C@@H](Cc2ccccc2)COC1(C)C)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Agent: [Li]CCCC
Product: CNC(=O)[C@@H](NC(=O)C(CC(=O)OC(C)(C)C)c1ccc(-c2ccc(-c3ccccc3)cc2)o1)C(C)(C)C
Yield: 7 %

Procedure:
According to the procedure described in Example 13 for the preparation of N-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2(R)-(biphenyl-4-yl-1H-pyrrol-3-yl)succinamic acid t-butyl ester, but N-(2,2-dimethyl-1(S)-(N-methylcarbamoyl)-propyl)-2-(2-biphenyl-4-yl-furan-5-yl)-acetamide was instead deprotonated with n-butyllithium (3.1 equiv) and alkylated to furnish 17 mg(7%) of N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3-(2-(biphenyl-4-yl)-furan-5-yl)succinamic acid t-butyl ester as an amorphous solid. 1H NMR: δ 7.70 (d, 2H, J=8.1 Hz), 7.62-7.59 (m, 4H), 7.45 (t, 2H, J=7.5 Hz), 7.35 (t, 1H, J=7.4 Hz), 6.63 (d, 1H, J=3.3 Hz), 6.50 (d, 1H, J=9.6 Hz), 6.33 (d, 1H, J=3.3 Hz), 5.09 (bm, 1H), 4.19-4.10 (m, 2H), 3.15 (dd, 1H, J=8.5, 16.6 Hz), 2.86-2.73 (m, 4H), 1.41 (s, 9H), 0.89 (s, 9H). HRMS: Calculated for C31H39N2O5 (M+H+): 519.2859. Found: 519.2865.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[CH:10][C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.O>C(O)C>[Cl:20][C:14]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:11]1[CH:10]=[N:9][N:5]2[C:6]([NH2:8])=[CH:7][C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:3][C:4]=12
Reactant: Nc1cc(Cl)nc2c(Cc3cccc(Cl)c3Cl)cnn12
Reactant: C1COCCN1
Solvent: O
Solvent: CCO
Product: Nc1cc(N2CCOCC2)nc2c(Cc3cccc(Cl)c3Cl)cnn12
Temperature: 150 °C
Reaction time: 3 h

Procedure:
5-chloro-3-[(2,3-dichlorophenyl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine (1.7 g, 4.43 mmol) and morpholine (1.36 g, 15.6 mmol) were mixed in ethanol (10 mL) in a microwave tube. The reaction mixture was irradiated (microwave) and stirred at 150° C. for 3 hours. Reaction mixture was dropped into cold water (100 mL) to precipitate while stirring. Precipitate was collected by filtration. It was washed with water (10 mL) and dried. The titled product was obtained. (1.90 g, 97%); LC/MS: MS (ES+) m/e 378 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.43 (br. s., 1H) 3.45 (d, J=5.05 Hz, 3H) 3.63-3.71 (m, 4H) 4.00 (s, 2H) 5.55 (s, 1H) 7.16 (s, 2H) 7.22-7.30 (m, 1H) 7.30-7.40 (m, 1H) 7.46 (dd, J=7.83, 1.77 Hz, 1H) 7.72 (s, 1H).
Reaction SMILES: [CH2:1]([OH:8])[CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][OH:6].CO[C:11](OC)([CH3:13])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:12][C:11]1([CH3:13])[O:7][CH:2]([CH2:3][CH2:4][CH2:5][OH:6])[CH2:1][O:8]1
Reactant: OCCCC(O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OCC(CCCO)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Pentane-1,2,5-triol (5.00 g) was dissolved in acetone (150 mL), 2,2-dimethoxypropane (10.5 mL) and 4-methylbenzenesulfonic acid (794 mg) were added, and the mixture was stirred at room temperature for 1.5 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→50:50) to give the title compound (3.79 g) as a colorless oil.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:11][C:12]1[CH:31]=[CH:30][CH:29]=[CH:28][C:13]=1[C:14]([NH:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21]CC)=[O:20])=[O:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>N1C=CC=CC=1.C(Cl)Cl>[C:3]([NH:11][C:12]1[CH:31]=[CH:30][CH:29]=[CH:28][C:13]=1[C:14]([NH:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([OH:21])=[O:20])=[O:15])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1ccccc1NC(=O)c1ccccc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1C(=O)Nc1ccccc1C(=O)O)c1ccccc1
Reaction time: 3 h
Yield: 70 %

Procedure:
NaOH (aq, 2 M, 0.7 mL) was added to a stirred solution of ester 23a (53.1 mg, 0.14 mmol) in pyridine (0.7 mL) at room temperature. After 3 h, the reaction was diluted with DCM and washed with HCl (3×, 1 M in brine), NaHCO3 (aq, sat), brine and dried over Na2SO4 before being purified by preparative HPLC to give acid 23b in 70% yield (35 mg).
Reaction SMILES: [CH:1]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]2[CH:4]=[C:3]([C:14]([O:16]CC)=[O:15])[N:2]=1.[OH-].[K+].O.[ClH:22]>CCO>[ClH:22].[CH:1]1[C:6]2=[CH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:5]2[CH:4]=[C:3]([C:14]([OH:16])=[O:15])[N:2]=1
Reactant: CCOC(=O)c1cn2c(cn1)cc1ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c(cn1)cc1ccccc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 34 %

Procedure:
To a solution of ethyl pyrazino[1,2-a]indole-3-carboxylate (0.49 g, 2.0 mmol) in EtOH (30 mL) is added crushed potassium hydroxide (1.1 g, 20.0 mmol) followed by water (30 mL). The resulting dark colored solution is stirred at rt for 40 min and then neutralized with conc. HCl to pH ˜2. The acidic mixture is concentrated to dryness to afford pyrazino[1,2-a]indole-3-carboxylic acid hydrochloride. HRMS (FAB) calcd for C12H8N2O2+H 213.0664, found 213.0658.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=2)[N:12]([C:14]2[CH:15]=[C:16]([N:20]3[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]3)[CH:17]=[CH:18][CH:19]=2)[CH:13]=1.[Br:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][C:11]3[N:12]([C:14]4[CH:15]=[C:16]([N:20]5[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]5)[CH:17]=[CH:18][CH:19]=4)[CH:13]=[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:10]=3)=[CH:30][CH:31]=2)=[CH:39][CH:38]=1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(I)cc3)c2)S(=O)(=O)N1
Reactant: OB(O)c1ccc(Br)cc1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[4-(2,4-Dichloro-phenyl)-2-(4-iodo-benzyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (3.2 g, 5 mmol) was treated as described in general procedure G using 4-bromophenylboronic acid (2.0 g, 10 mmol) to give 5-{3-[2-(4′-bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.