Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:20])=[C:5]2[C:16](=[CH:17][C:18]=1[CH3:19])[C:8]1[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=1[CH2:6]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:20])=[C:5]2[C:16](=[CH:17][C:18]=1[CH3:19])[C@H:8]1[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C@H:7]1[CH2:6]2
Reactant: COc1c(C)cc2c(c1C)Cc1c-2[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1c(C)cc2c(c1C)C[C@@H]1c3ccccc3N[C@H]21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5,10-Dihydro-2-methoxy-1,3-dimethylindeno[1,2-b]indole (1 g, 3.80 mmol) was stirred at room temperature in glacial acetic acid (15 cm3). Sodium cyanoborohydride (0.75 g, 3 equivalents) was added portionwise over 15 minutes, and the reaction stirred for a further two hours. The reaction was poured into ice/water (30 cm3), and stirred for a further 30 minutes. The solution was neutralised with aqueous sodium hydroxide, and extracted into diethyl ether. The organic extracts were copiously washed with water until the washings were free of cyanide ion. The solvent was removed in vacuo to give the title compound. This was purified by column chromatography to a colourless solid. Yield: 0.8 g (79%). M.p. 117° C. from EtOAc/petrol (60°-80° C.). Elementary analysis: Found: C 81.6, H 7.3, N 5.8, C18H19NO Calc. for C 81.5, H 7.2, N 5.9, 1H NMR (CDCl3) δ: 2.15 (3H, s,), 2.25 (3H, s,), 3.07 (1H, dd,), 3.36 (1H, dd,), 3.64 (3H, s,), 4.1 (1H, br,), 4.19 (1H, ddd,), 5.20 (1H, d,), 6.60 (1H, d,), 6.74 (1H, ddd,), 6.97 (1H, s,), 7.00 (1H, ddd,), 7.17 (1H, d,).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:19][N:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:12]1[C:11]2[CH:10]=[CH:9][C:8]([C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[C:3]([C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:4]=2
Reactant: CN(C)CCCn1c2ccccc2c2ccccc21
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)C(=O)c1ccc2c(c1)c1cc(C(=O)C(C)C)ccc1n2CCCN(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 48.1 %

Procedure:
Compound 30 (0.25 g, 1.0 mmol) was dissolved in nitrobenzene (5 mL). AlCl3 (0.6 g, 4.5 mmol) and then isobutyroyl chloride (0.6 mL, 5.7 mmol) were added in portions. The reaction mixture was stirred for 40 min (LC/MS monitoring). The obtained mixture was poured into ice/water mixture and extracted with CHCl3. The combined extracts were evaporated, and the residue was purified by chromatography in a short thick silica gel column (eluent: CHCl3/MeOH 99:1→90:10) to afford 0.189 g (47%) of the product. 1H NMR (DMSO-d6): δ 1.20 (12H, d, J=6.7 Hz); 1.90-1.97 (2H, m); 2.11 (6H, s); 2.18 (2H, t, J=6.7 Hz); 3.91 (2H, septet, J=6.7 Hz), 4.50 (2H, t, J=6.6 Hz); 7.76 (2H, d, J=8.7 Hz); 8.14 (2H, dd, J=8.7 Hz, J=1.5 Hz); 9.11 (2H, d, J=1.5 Hz). ELSD: 100%, ESI-MS: m/z 392 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[S:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[N:4][N:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1>>[CH2:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[C:5]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[N:4][N:3]=2)[CH2:22][CH2:23]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc2c(-c3ccc(C)s3)nnc(Cl)c2c1
Product: COc1ccc2c(-c3ccc(C)s3)nnc(NC3CCN(Cc4ccccc4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-7-methoxy-4-(5-methylthiophen-2-yl)phthalazine with 4-amino-1-benzylpiperidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([OH:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:22][S:19]([O:18][CH:16]([C:10]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:17])(=[O:21])=[O:20]
Reactant: CC(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(OS(C)(=O)=O)c1cc(Br)ccc1OCc1ccccc1
Temperature: -10 °C

Procedure:
1-(2-Benzyloxy-5-bromophenyl)-ethanol (3.74 g) was dissolved in pyridine (15 mL) and cooled to -10° C. under argon. Mesyl chloride (0.95 mL) was added dropwise over ten minutes and the mixture stirred allowing to come to ambient temperature over seventeen hours. The mixture was diluted with ethyl acetate (100 mL) and then washed with hydrochloric acid (1M, 3×70 mL) until the organic phase tested to pH 1. The ethyl acetate fraction was then washed with saturated sodium hydrogen carbonate solution (50 mL) and dried (MgSO4). After removal of solvent the oily residue was purified by MPLC (eluting 75% dichloromethane, 25% hexane, silica) to give 1-(2-benzyloxy-5-bromophenyl)ethanol methanesulphonate which was used rapidly without further purification, yield 1.19 g.
Reaction SMILES: [NH2:1][CH:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:3]1.[C:18]([O:22][C:23](NC(C1C=CC=CC=1)C#N)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([NH:1][CH:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C@@H:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH2:3]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: C[C@H](c1ccccc1)N1CC(N)C2(CCC2)C1
Reactant: CC(C)(C)OC(=O)NC(C#N)c1ccccc1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CC(NC(=O)OC(C)(C)C)C2(CCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To an ice-cooled solution of 2.9 g of 8-amino-6-[1-(R)-phenylethyl]-6-azaspiro[3.4]octane in 30 ml of tetrahydrofuran there was added 3.3 g of 2-(tert-butoxycarbonyl-amino)-2-phenylacetonitrile and the resulting mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure, and ethyl acetate was added to the resulting residue. The mixture was washed with a 1N sodium hydroxide aqueous solution three times and then dried. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography using 50 g of silica gel. The column was eluted with chloroform, chloroform containing methanol and 4.1 g of the titled compound was obtained from a eluate when the eluant was chloroform containing 1% (v/v) of methanol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:30]([C:32]1[O:36][C:35]([CH2:37][N:38]2[C:43]3[CH:44]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[S:46][C:42]=3[C:41](=[O:53])[N:40]([CH:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[C:39]2=[O:60])=[N:34][CH:33]=1)[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:57]4[CH2:58][CH2:59][CH:54]([N:40]5[C:41](=[O:53])[C:42]6[S:46][C:45]([C:47]7[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=7)=[CH:44][C:43]=6[N:38]([CH2:37][C:35]6[O:36][C:32]([CH2:30][CH3:31])=[CH:33][N:34]=6)[C:39]5=[O:60])[CH2:55][CH2:56]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCc1cnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5ncc(CC)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10), 1-[(5-ethyl-1,3-oxazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (191.5 mg; compound B26) and HBTU (167 mg) in DCM (3 ml) is added DIPEA (0.28 ml) and the mixture is stirred for 1 h at RT. After 1 h an additional amount of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (40 mg) is added and the mixture is stirred for 15 min in order to complete the reaction. Subsequently the solvent is removed and the residue is purified by flash column chromatography [amino phase silica gel, eluent: EtOAc/MeOH, 97.5/2.5 (v/v)] and afterwards by preparative HPLC to yield the title compound as a solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:30]1[CH:31]=[C:32]([NH:37][S:38]([N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)(=[O:40])=[O:39])[C:33]([Cl:36])=[N:34][CH:35]=1.O>C1COCC1>[Cl:36][C:33]1[N:34]=[CH:35][C:30]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)=[CH:31][C:32]=1[NH:37][S:38]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)(=[O:40])=[O:39]
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)N4CCCCC4)c3)cc2s1
Reaction time: 0.17 h
Yield: 12.8 %

Procedure:
To a microwave vial equipped with a stirbar and charged with N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.16 g, 0.51 mmol), cesium carbonate (0.41 g, 1.3 mmol), Pd Cl2 (dppf)-DCM (0.062 g, 0.076 mmol), N-(5-bromo-2-chloropyridin-3-yl)piperidine-1-sulfonamide (0.150 g, 0.42 mmol) in THF (3 ml) was added water (0.5 ml). The vial was capped and placed into CEM Microwave for 10 minutes at 100° C., while 100 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed desired material in the mixture. The organic layer was extracted from the microwave vial by pipet and then diluted the organic with acetonitrile (15 ml) and TFA (0.1 ml). The crude was purified by reverse-phase HPLC. The fractions with desired product were combined and concentrated. The crude was recrystallized from 5:1 EtOAc/Methanol and Hexanes to give N-(6-(6-chloro-5-(piperidine-1-sulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.025 g, 13% yield) as a tan crystalline solid. MS (ESI pos. ion) m/z: 466 (MH+). Calc'd exact mass for C19H20ClN5O3S2: 465. 1H NMR (400 MHz, DMSO-d6): 1.39 (s, 2H), 1.47 (s, 3H), 1.65 (s, 4H), 2.14 (s, 3H), 2.93 (s, 3H), 7.51 (s, 1H), 7.69 (s, 11H), 7.74 (s, 1H), 7.90 (s, 1H), 8.02 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[Br:19][C:7]1[C:8]([NH2:11])=[N:9][CH:10]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCc1cnc(N)cn1
Solvent: ClCCl
Product: COCCc1cnc(N)c(Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(2-methoxyethyl)pyrazin-2-amine (80 mg, 0.522 mmol) in DCM (1.7 mL) was added NBS (93 mg, 0.522 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After quenched with NaHCO3, the reaction mixture was extracted with DCM 3 times. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate. The crude material was used in next step reaction without purification. LCMS (m/z): 232.1/234.1 (MH+), 0.49 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate (350 mg, 1.28 mmol) and 1-phenylpiperazine (208 mg, 1.28 mmol) were dissolved in anhydrous tetrahydrofuran and thereto DBU (195 mg, 1.28 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours and concentrated under the reduced pressure to remove the solvent, and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([CH3:8])=[CH:6][S:5][CH:4]=1.C1(C)C=CC=CC=1.[Br:16][CH2:17]CO.OS([O-])(=O)=O.[Na+]>CO>[Br:16][CH2:17][CH2:1][O:2][C:3]1[C:7]([CH3:8])=[CH:6][S:5][CH:4]=1
Reactant: COc1cscc1C
Reactant: OCCBr
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cscc1OCCBr
Yield: 55 %

Procedure:
4.2 g of 3-methoxy-4-methylthiophene was added to a mixture of 40 mL of toluene, 8.2 g of 2-bromo-1-ethanol (Aldrich) and 500 mg of NaHSO4. The resulting mixture was heated until the produced methanol had been distilled off and the temperature rose to 110° C. The product was cooled and washed several times with water and, subsequently, extracted with diethyl ether. The organic phase was dried with magnesium sulfate and then evaporated. The product was purified by column chromatography using silica gel and hexanes as eluent. Yield=55%.
Reaction SMILES: Br[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([O:21]C)=O)[C:11](=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH3:24]>COCCO>[CH:6]1[C:5]2[N:4]3[C:19](=[O:21])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]=[C:3]3[CH2:2][NH:24][C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: N
Reactant: COC(=O)c1ccccc1-n1c(CBr)nc2ccccc2c1=O
Solvent: COCCO
Product: O=C1NCc2nc3ccccc3c(=O)n2-c2ccccc21
Yield: 44 %

Procedure:
14.7 g (0.05 mol) of 2-bromomethyl-3-(2-methoxycarbonylphenyl)-4H-quinazolin-4-one and 25 ml of liquid ammonia in 100 ml of ethylene glycol monomethyl ether are heated to 100° C. for 5 hours in an autoclave. After cooling the mixture, the colourless crystals are filtered off and washed several times with methanol. 6.1 g (44% theory) of 6,7-dihydro-5H,13H-quinazolino[3,2-a][1,4]benzodiazepine-5,13-dione are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:27][CH3:28])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:29]=[CH:30][N:31](C)C)#[N:2].[CH:34]1(N)[CH2:37][CH2:36][CH2:35]1.ClCCl.CO>CO>[CH:34]1([NH:2][C:1]2[C:3]3[C:4](=[CH:5][C:6]([O:11][CH2:12][C:13]4[CH:14]=[C:15]([S:19]([CH2:27][CH3:28])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:16]=[CH:17][CH:18]=4)=[C:7]([O:9][CH3:10])[CH:8]=3)[N:29]=[CH:30][N:31]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Reactant: NC1CCC1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc3ncnc(NC4CCC4)c3cc2OC)c1
Yield: 91 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-ethylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (50 mg, 0.11 mmol) with cyclobutylamine (9.1 mg, 0.13 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 91% yield (48 mg).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][NH2:36]>>[NH2:36][CH2:35][CH2:34][CH2:33][N:32]([CH3:31])[C:8](=[O:7])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([F:25])[C:18]=2[F:26])[C:11]=1[C:27]([NH2:28])=[O:29]
Reactant: CNCCCN
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1F
Product: Cc1cc(F)c(COc2nsc(NC(=O)N(C)CCCN)c2C(N)=O)c(F)c1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,3,6-trifluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N-methyl-propane-1,3-diamine by the procedure analogous to Example 1. MS (APCl, m/z): 432 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl.Cl[CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31].O>CN(C)C=O>[CH2:28]([N:29]([CH2:32][CH3:33])[CH2:30][CH2:31][N:15]([C@@H:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11]1)[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl [(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate (6.0 g) was dissolved in 50 ml of N,N-dimethylformamide and, after addition of sodium hydride (1.1 g), stirred at room temperature for 30 minutes, and subsequently chlorethyldiethylamine hydrochloride (4.1 g) was added. The mixture was subsequently stirred at room temperature with exclusion of moisture for 4 hours. The reaction was stopped by adding water (50 ml), and this was followed by extraction with ethyl acetate (3×50 ml) and drying of the combined organic phases over magnesium sulfate, and removal of the solvent. This resulted in the product with the molecular weight of 406.53 (C21H34N4O4); MS (ESI): 407 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2.[CH3:15]OS(OC)(=O)=O>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:15])[C:9](=[O:14])[CH2:8]2
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CC(=O)N2C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A dry round-bottom flask was charged with NaH (60% wt) (64 mg, 1.61 mmol) and toluene (2.0 mL). The suspension was heated to 100° C. and then 5-methoxyindolin-2-one (250 mg, 1.53 mmol) was added. After 30 min at 100° C., Me2SO4 (0.16 mL, 1.68 mmol) was added and the temperature maintained at 100° C. for 2.5 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, hexanes/EtOAc, 3:1 to 2:1) to give the product as a beige solid (144 mg, 53%); MS ESI 164.1 [M+H]+, calcd for [C9H9NO2+H]+ 164.07.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.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.[NH2:65][C:66]1[CH:67]=[C:68]([CH:71]=[CH:72][CH:73]=1)[CH2:69][OH:70]>C(Cl)Cl>[OH:70][CH2:69][C:68]1[CH:67]=[C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:30])[CH:73]=[CH:72][CH:71]=1
Reactant: Nc1cccc(CO)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(CO)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 104 mg, 0.27 mmol) was added followed by the addition of DIPEA (80 uL,) and 3-amino benzyl alcohol (Aldrich, 80 uL). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified reverse phase HPLC (24 g column, eluent, ACN/water, 20-90) to give a white solid. 40 mg.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:20]([C:19]1[CH:23]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[O:24][CH3:25])=[O:21])[CH2:3][CH2:4][CH3:5]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: ClCCl
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of Example 1A (780 mg, 2.5 mmol) and 5-chloro-2-methoxy-benzoyl chloride (515 mg, 2.5 mmol) in CH2Cl2 (25 mL) under N2 atmosphere at 0° C. was added 4-dimethylaminopyridine (DMAP) (1.22 g. 10 mmol) and the mixture was allowed to warm to room temperature. The mixture was stirred for 20 hours, washed sequentially with saturated sodium bicarbonate and brine. The methylene chloride solution was dried (anhydrous MgSO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography over silica gel (hexane-EtOAc 1:1 as eluent) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.39 (sextet, J=7 Hz, 2H), 1.66 (quintet, J=7 Hz, 2H), 2.15 (s, 3H), 2.20 (s, 3H), 3.85 (s, 3H), 3.90 (t, J=7 Hz, 2H), 6.54 (s, 1H), 7.10 (d, J=9 Hz, 1H), 7.40 (dd, J=9 Hz, 3 Hz, 1H), 7.65 (d, J=3 Hz, 1H); MS (ESI) m/z 352 (M+H)+. Anal calcd for C18H22ClNO2S: C, 61.44; H, 6.30; N, 3.98. Found: C, 61.34; H, 6.17; N, 3.86.
Reaction SMILES: [C:1](#[N:7])[CH2:2][CH2:3][CH2:4][C:5]#[N:6].N[NH:9][C:10]([NH2:12])=[S:11].O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[CH2:2]([C:1]1[S:11][C:10]([NH2:12])=[N:9][N:7]=1)[CH2:3][CH2:4][C:5]1[S:11][C:10]([NH2:12])=[N:9][N:6]=1
Reactant: NNC(N)=S
Reactant: N#CCCCC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(CCCc2nnc(N)s2)s1
Temperature: 85 °C
Yield: 106.6 %

Procedure:
A mixture of glutaronitrile (5.00 g, 53.13 mmol) and thiosemicarbazide (9.68 g, 106.26 mmol) in TFA (50 mL) was heated at 85° C. for 4 h. The reaction was cooled to room temperature and poured into a mixture of ice and water. Sodium hydroxide pellets were added to the mixture until it was basic (pH 14). The white precipitate was collected by suction filtration, rinsed with water and dried to provide 5,5′-(propane-1,3-diyl)-bis(1,3,4-thiadiazol-2-amine) (1004, 13.72 g). 1H NMR (300 MHz, DMSO-d6) δ 7.06-7.03 (s, 4H), 2.87 (t, J=7.5 Hz, 4H), 2.02-1.95 (m, 2H).