Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[H-].[Na+].Br.Br[CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(#N)C>CN(C=O)C.O>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([S:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:22])=[C:12]([CH3:21])[N:13]2[CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: BrCc1ccncc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: Cc1c(Sc2cccc(C(=O)O)c2)c2ccc(Cl)cc2n1Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.050 g, 0.15 mmol) was dissolved in DMF (4 mL), cooled to ° C., and sodium hydride (60% dispersion in mineral oil, 0.015 g, 0.375 mmol) was added. After 15 minutes, 4-(bromomethyl)pyridine hydrobromide (0.057 g, 0.225 mmol) was added and the reaction stirred at room temperature for 70 minutes. The reaction was then heated to 50° C. for 2 hours then submitted to standard aqueous workup. Preparatory HPLC (10-100% ACN in H2O) afforded the title compound as a minor component.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[N:7]3[C:21]([CH3:24])=[N:22][N:23]=[C:6]3[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=2[N:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[S:36][CH:37]=[CH:38][N:39]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:20])[N:7]4[C:21]([CH3:24])=[N:22][N:23]=[C:6]4[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=3[N:3]=[C:2]2[C:35]2[S:36][CH:37]=[CH:38][N:39]=2)=[CH:13][CH:14]=1
Reactant: CCCCCn1c2nc(Br)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc(-c3nccs3)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Yield: 78.4 %

Procedure:
To the mixture of 7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (100 mg, 0.22 mmol), 2-(tributylstannyl)-1,3-thiazole (122 mg, 0.33 mmol) in toluene (14 mL) was added tetrakis(triphenylphosphine)palladium(0) (12.6 mg, 0.011 mmol) under N2. The mixture was refluxed overnight. The reaction mixture was concentrated in vacuo. The crude residue was purified using preparative LCMS to yield the desired product (80 mg, 79%). LCMS calculated for C23H26N7O2S (M+H): 464.2; found 464.2.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:31]([NH2+:30][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].[CH2:31]([N:30]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4](=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:1]([O-:6])=[O:11])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: O=C1OC(=O)c2ccccc21
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1ccccc1C(=O)[O-]
Product: CCCCCCCCCCCCCCCCCC[NH2+]CCCCCCCCCCCCCCCCCC

Procedure:
Reaction of phthalic anhydride and dioctadecyl amine to form N,N-dioctadecyl phthalamic acid dioctadecyl ammonium salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Li+].O1CCCC1.Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(S(C)(=O)=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cc(Br)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 3-bromo-5-(methylsulfonyl)benzoate (0.65 g, 2.2 mmol), lithium hydroxide (0.26 g, 11 mmol), tetrahydrofuran (25 mL) and water (5 mL) was stirred at room temperature for 3 h. Water (50 mL) was added and the mixture was acidified with 1N aq. HCl to pH 2-3 and extracted with EtOAc (100 mL). The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated to yield a white solid. LC-MS: 278.6 [M−1]−; 1H NMR (400 MHz, CDCl3): 8.59 (m, 1H), 8.50 (m, 1H), 8.33 (m, 1H), 3.13 (s, 3H).
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[C:10]([Cl:16])[CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]#[N:25])[CH:18]=1.N1CCCC[CH2:27]1.C(O)C>C(OCC)C>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](/[C:23](=[CH:27]/[C:14]2[C:13]3[C:8](=[CH:9][C:10]([Cl:16])=[CH:11][C:12]=3[Cl:15])[NH:7][C:6]=2[C:1]([O:3][CH2:4][CH3:5])=[O:2])/[C:24]#[N:25])[CH:18]=1
Reactant: N#CCc1cccnc1
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Reactant: C1CCNCC1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1/C=C(\C#N)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Combine 2-carboethoxy-4,6-dichloroindole (1.43 g, 5.0 mmol), pyrid-3-ylacetonitrile (0.59 g, 5.0 mmol), piperidine (0.2 mL), and ethanol (30 mL). Heat to reflux. After 16 hours, cool to ambient temperature. Add diethyl ether to give a solid. Filter, rinse with diethyl ether, dry, recrystallize from acetone/water, filter, and dry to give the title compound: mp; 233-234° C. (dec). 1H NMR (DMSO-d6) δ 12.41 (br s, 1H), 8.86 (s, 1H), 8.57 (d, 1H, J=1 Hz), 8.16 (s, 1H), 7.94 (d, 1H, J=6.1 Hz), 7.41-7.36 (m, 1H), 7.41 (s, 1H), 7.06 (m, 1H), 4.30 (q, 2H, J=7.05 Hz), 1.23 (t, 3H, J=7.05 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1.FC(F)(F)C(O[Si](C)(C)C)=O.[CH:26](OCC)(OCC)OCC.[N:36]([Si](C)(C)C)=[N+:37]=[N-:38]>C(OCC)(=O)C>[N:1]1([C:2]2[N:3]=[CH:4][C:5]3[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=3[N:7]=2)[CH:26]=[N:36][N:37]=[N:38]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)C1Cc2cnc(N)nc2C1
Agent: C[Si](C)(C)OC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)C1Cc2cnc(-n3cnnn3)nc2C1
Temperature: 25 °C

Procedure:
To a mixture of Methyl 2-amino-6,7-dihydro-5H-cyclopenta[d]pyrimidine-6-carboxylate (65.2 mg, 0.364 mmol) in ethyl acetate (5 mL) was added trimethylsilyl trifluoroacetate (0.107 mL, 0.619 mmol) at room temperature. The mixture was stirred at room temperature then triethyl orthoformate (0.103 mL, 0.619 mmol) was added. The mixture was stirred for another 5 minutes then azidotrimethylsilane (0.081 mL, 0.619 mmol) was added. The reaction was stirred at room temperature overnight then concentrated in vacuo and the residue was triturated twice with dichloromethane. The resulting solid was collected by centrifugation and dried in vacuo to afford the title compound: LC/MS: [(M+1)]+=233.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].S(Cl)([Cl:14])=O.[CH3:16]O>C(OCC)(=O)C.CN(C=O)C>[ClH:14].[Br:2][C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccncc1Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccncc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 3-bromoisonicotinic acid hydrochloride (27.4 g, 0.10 mol) in ethyl acetate (250 ml) was added one drop of DMF followed by thionyl chloride (18.5 g, 0.16 mol). The mixture was heated at reflux for 1 h and allowed to cool to room temperature. The mixture was then concentrated under reduced pressure to give an off-white solid. To this was added methanol and this was refluxed for 2 hrs. The mixture was then concentrated under reduced pressure and diluted with ethyl acetate. The precipitate was collected on filter paper on a Buchner funnel. The white solid was washed with ethyl acetate and air-dried. The white solid was placed in a vacuum oven at 60° C. overnight with a nitrogen bleed. Yield: 18.5 g (71% th).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.Cl.NO.CO[CH:21](OC)[N:22](C)C>>[CH2:12]([O:11][C:9]([C:8]1[CH:21]=[N:22][O:7][C:6]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][CH:14]=1)=[O:10])[CH3:13]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Agent: Cl
Agent: NO
Product: CCOC(=O)c1cnoc1-c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of ethyl (4-bromobenzoyl)acetate (1.19 g, 4.39 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) was stirred at 100° C. for 1 hour. The mixture was concentrated, and the residue was dissolved in EtOH (10 mL). Hydroxylamine hydrochloride (0.454 g, 6.57 mmol) was added, and the reaction was stirred at 100° C. for 1 hour. After cooling to room temperature, the mixture was partitioned between EtOAc and H2O, and the organic layer was separated, dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH:4](O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH:17]1[CH:24]=[CH:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].B(F)(F)F>C(O)(=O)C>[OH:19][C:18]1[N:20]=[C:21]([OH:22])[C:23]([CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:2]=2[Cl:1])=[CH:24][N:17]=1
Reactant: OC(c1ccccc1)c1ccc(Cl)cc1Cl
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: FB(F)F
Solvent: CC(=O)O
Product: Oc1ncc(C(c2ccccc2)c2ccc(Cl)cc2Cl)c(O)n1

Procedure:
One method of preparation involves the reaction of, for example, 2,4-dichlorobenzhydrol with uracil in glacial acetic acid in the presence of BF3. This yields the 2,4-dihydroxy-5-(2,4-dichlorobenzhydryl)pyrimidine. Treatment with phosphorus oxychloride in excess yields the 2,4-dichloro-5-(2,4-dichlorobenzhydryl)pyrimidine.
Reaction SMILES: [CH3:1][C:2]([CH3:49])([CH3:48])[C@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:4](=[O:42])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](=[O:41])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C@@H:30]3[CH2:34][CH2:33][CH2:32][NH:31]3)=[O:29])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1.[CH2:50]([N:52]([CH2:63][CH3:64])[C@H:53]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:54](O)=[O:55])[CH3:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O.O>[CH2:63]([N:52]([CH2:50][CH3:51])[C@H:53]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:54]([N:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:19]([CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:10]([C@@H:6]3[CH2:7][CH2:8][CH2:9][N:5]3[C:4](=[O:42])[C@@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:2]([CH3:49])([CH3:48])[CH3:1])=[O:41])=[CH:17][CH:16]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:22][CH:23]=1)=[O:29])=[O:55])[CH3:64]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccccc2)cc1)C(C)(C)C
Reactant: CCN(CC)[C@@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)(C)C)cc2)c2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 58.3 %

Procedure:
The product from Example 10A (15 mg, 0.022 mmol) was combined with (R)-2-(diethylamino)-2-phenylacetic acid (6.04 mg, 0.029 mmol), HATU (9.38 mg, 0.025 mmol) and Hunig's base (0.024 mL, 0.135 mmol) in DMSO (1.0 mL) and the mixture was stirred at room temperature for 45 min. Diluted with water and collected the solid by filtration. The product was purified by chromatography on silica gel, eluting with 0-5% MeOH in CH2Cl2 to give the title compound (11 mg, 57.2% yield). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.87 (t, J=7.10 Hz, 6 H) 0.94 (s, 9 H) 1.59-1.68 (m, 1 H) 1.78-1.86 (m, 2 H) 1.92-2.00 (m, 1 H) 2.04-2.12 (m, 2 H) 2.43-2.52 (m, 2 H) 2.55-2.67 (m, 4 H) 3.23-3.30 (m, 1 H) 3.56-3.61 (m, 2 H) 3.62 (s, 3 H) 3.71-3.78 (m, 1 H) 4.30 (d, J=9.61 Hz, 1 H) 4.48 (s, 4 H) 4.55 (s, 1 H) 4.72-4.77 (m, 2 H) 5.31 (d, J=9.77 Hz, 1 H) 6.63 (t, J=7.25 Hz, 1 H) 6.67 (d, J=7.93 Hz, 2 H) 7.06-7.12 (m, 6 H) 7.24-7.32 (m, 3 H) 7.33 (d, J=8.54 Hz, 2 H) 7.35-7.42 (m, 4 H) 9.22 (s, 1 H) 9.64 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:43]=[CH:42][C:6]([CH2:7][C@@:8]2([CH3:41])[N:12]3[C:13]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([NH:26][C@H:27](C)[C:28]([OH:30])=O)=[O:25])(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=3)[C:9]2=[O:40])=[CH:5][CH:4]=1)#[N:2].[CH3:44]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NC[C@@H](O)C>C(Cl)Cl>[OH:30][C@@H:28]([CH3:44])[CH2:27][NH:26][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[S:16]([C:13]1[N:12]2[C@@:8]([CH2:7][C:6]3[CH:42]=[CH:43][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)([CH3:41])[C:9](=[O:40])[N:10]([C:32]3[CH:33]=[C:34]([Cl:39])[CH:35]=[C:36]([Cl:38])[CH:37]=3)[C:11]2=[N:15][CH:14]=1)(=[O:18])=[O:17])=[O:25]
Reactant: C[C@@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[C@H](O)CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](O)CNC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
To a stirred solution of (S)-1-[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (see Example 5) (82 mg, 0.14 mmol) in anhydrous methylene chloride (1 mL) and HATU (82 mg, 0.21 mmol) was added DIPEA (73 μL, 0.42 mmol) and the mixture was stirred for 10 min at room temperature under nitrogen. (S)-1-Amino-propan-2-ol (0.21 mmol) was added and the mixture was stirred for 2 h at room temperature under nitrogen. The material was purified by column chromatography over silica gel to provide 62 mg of the title compound as a white solid (M+1, 631.2).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:6]1(=[O:22])=[O:21].[CH3:23][NH2:24]>O1CCCC1>[ClH:1].[O:21]=[S:6]1(=[O:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:24][CH3:23])[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN
Reactant: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccccc1
Solvent: C1CCOC1
Product: CNCCCN1Cc2ccccc2N(c2ccccc2)S1(=O)=O
Product: Cl
Temperature: 50 °C
Reaction time: 20 h
Yield: 92 %

Procedure:
3-(3-chloropropyl)-1-phenyl-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.030 g, 0.089 mmol) was dissolved in an 8 M solution of methylamine in tetrahydrofuran (5 mL), treated with KI (0.030 g, 0.18 mmol), and stirred in a capped vial at 50° C. for 20 hours. The reaction mixture was evaporated and the residue purified by flash chromatography (SiO2, 0-5% 7 M NH3-methanol/dichloromethane). The purified free-base was dissolved in ethyl ether (10 mL) and treated with hydrogen chloride (1.0 mL of a 2 M solution in ethyl ether), resulting in a white precipitate that was isolated by decantation and dried under vacuum to afford 3-(2,2-dioxido-1-phenyl-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl)-N-methylpropan-1-amine hydrochloride (0.030 g, 92%) as a white solid:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)[CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C[Si]([N:44]=C=O)(C)C>C(Cl)Cl>[Cl:32][C:21]1[N:22]=[C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:24]2[S:25][C:17]([CH2:16][N:12]3[CH2:13][CH:14]4[CH2:15][N:8]([C:6]([NH2:44])=[O:7])[CH2:9][CH:10]4[CH2:11]3)=[CH:18][C:19]=2[N:20]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 5-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (250 mg, 0.52 mmol) in DCM (4.5 mL) was added TFA (0.5 mL). The reaction mixture stirred at RT for 1 h, then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH, and concentrated in vacuo. The resultant residue was dissolved in DCM (5 mL) and trimethylsilyl isocyanate (139 μL, 1.0 mmol) was added. The reaction mixture was stirred at RT for 1 h, then partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with brine, then dried (Na2SO4) and concentrated in vacuo to give the title compound as a colourless oil (185 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH:14]3[CH2:16][CH2:15]3)([CH:12]=C)[C:6]=2[CH:17]=1.[O:18]=[O+][O-].[BH4-].[Na+].CC(C)=O>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH:14]3[CH2:16][CH2:15]3)([CH2:12][OH:18])[C:6]=2[CH:17]=1
Reactant: C=CC1(C2CC2)OC(=O)Nc2ccc(Cl)cc21
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CO
Product: O=C1Nc2ccc(Cl)cc2C(CO)(C2CC2)O1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
6-Chloro-4-cyclopropyl-4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (590 mg, 2.36 mmol) was dissolved in dichloromethane (2.5 mL) and methanol (2.5 mL), and the resulting solution was stirred at −78° C. in an ozone atmospher. After it was confirmed by thin-layer chromatography that the raw materials disappeared, the ozone atmospher was replaced by a nitrogen atmospher, and the solution was stirred for 5 minutes. The temperature of the reaction solution was raised to 0° C., and sodium borohydride (26.8 mg, 7.1 mmol) was added thereto. The reaction solution was stirred at 0° C. for 30 minutes, and then, acetone was added thereto to stop the reaction. After the solvent was evaporated under reduced pressure, water (50 mL) and 1 N hydrochloric acid were added to the residue and the pH thereof was adjusted to about 4, and then, the solution was stirred at room temperature. The resulting white solid was collected by filtration, washed with water and then dried under reduced pressure, whereby the objective compound (487 mg, 81%) was obtained.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]3[NH:11][C:12](=[S:14])[NH:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[CH2:24](N(CC)CC)C.CI>C1COCC1>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]3[NH:11][C:12]([S:14][CH3:24])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: Fc1cc2[nH]c(=S)[nH]c2cc1-c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nc2cc(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Temperature: 40 °C

Procedure:
To a solution of 13-4 (2.23 g, 6.9 mmol) in 40 mL of THF was added triethylamine (2.2 mL), followed by the dropwise addition of methyliodide (0.43 mL, 6.9 mmol). The reaction mixture was heated to 40° C. for 2 h. The solvent was then removed in vacuo and the residue was taken up in EtOAc and washed two times with 100 mL portions of saturated aqueous ammonium chloride and a 100 mL portion of brine. The combined organic layers were dried over MgSO4 filtered and concentrated to dryness in vacuo. Then 150 mL of CH2Cl2 were added and the resulting precipitate was collected by vacuum filtration to give title compound 13-5.
Reaction SMILES: C[NH:2]CCO.F[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:2][C:13]1[CH:14]=[CH:7][CH:8]=[CH:9][C:10]=1[CH:11]=[O:12]
Reactant: CNCCO
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ccccc1C=O
Temperature: 95 °C

Procedure:
Following the procedure described in U.S. Pat. No. 4,808,332, a reactor is charged with 2-(methylamino)ethanol (134 g, 1.8 moles), 4-fluorobenzaldehyde (74.4 g, 0.6 mole), potassium carbonate (82.8 g, 0.6 mole) and dimethylsulfoxide (750 ml), and the mixture is heated at 95° C. for 72 hours. The product mixture is cooled and poured into three liters of ice water. The yellow solid that precipitates is filtered, washed with water, and dried in a vacuum oven, mp 72° C. The 4-[N-(2-hydroxyethyl)-N-methylamino]benzaldehyde product is recrystallized from water as needle-like crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=3)=[CH:11][C:10]([C:20](O)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:44]3[CH2:49][CH2:48][NH:47][C:46](=[O:50])[CH2:45]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=3)=[CH:11][C:10]([C:20]([N:44]3[CH2:49][CH2:48][NH:47][C:46](=[O:50])[CH2:45]3)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccnc(Cl)c2)n(-c2cccc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3ccnc(Cl)c3)n(-c3cccc(Cl)c3)n2)CCN1

Procedure:
100 mg (0.30 mmol) of the compound of Example 69A is reacted analogously to the synthesis of the compound of Example 4 with 32 mg (0.32 mmol) of 2-oxopiperazine. 111 mg (890% of theory) of the title compound is obtained.
Reaction SMILES: [N:1]1([CH:10]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([P:21](=[O:32])([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([F:20])[F:19])=[CH:14][CH:13]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Li]CCCC.[CH:44]([O:47][C:48]1[CH:60]=[C:59]([C:61]2[CH:66]=[CH:65][C:64]([CH2:67]Br)=[CH:63][CH:62]=2)[CH:58]=[CH:57][C:49]=1[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])([CH3:46])[CH3:45]>CCCCCC.C1COCC1>[N:1]1([C:10]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([P:21]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:32])([F:19])[F:20])=[CH:16][CH:17]=2)[CH2:67][C:64]2[CH:63]=[CH:62][C:61]([C:59]3[CH:58]=[CH:57][C:49]([C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])=[C:48]([O:47][CH:44]([CH3:46])[CH3:45])[CH:60]=3)=[CH:66][CH:65]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CC(c2ccccc2)n2nnc3ccccc32)cc1
Reactant: CC(C)Oc1cc(-c2ccc(CBr)cc2)ccc1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)Oc1cc(-c2ccc(CC(Cc3ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc3)(c3ccccc3)n3nnc4ccccc43)cc2)ccc1C(=O)OC(C)(C)C

Procedure:
To a solution of di(tert-butyl) {4-[2-(1H-1,2,3-benzotriazol-1-yl)-2-phenylethyl]phenyl}(difluoro)methylphosphonate (0.060 g, 0.110 mmol) in TRF (1.0 mL) were added n-BuLi 1.6 M in hexane (0.086 mL) and the bromide of Example 11, Step 1 (0.045 g, 0.111 mmol) in THF (1.0 mL). Then using the same protocol as described for Example 14 Step 1 the title compound was obtained.