Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[N:15]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1cccnc1Nc1ccc(Cl)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixture of N2-(4-chlorophenyl)pyridine-2,3-diamine (64 mg, 0.291 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (61 mg, 0.32 mmol), HOAt (44 mg, 0.32 mmol), 4-methylmorpholine (70 μL, 0.641 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol) in DCM (10 mL) was stirred at RT for 1 h then left standing at RT for 64 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried and concentrated in vacuo. The resulting {(S)-1-[2-(4-chlorophenylamino)pyridin-3-ylcarbamoyl]ethyl}carbamic acid tert-butyl ester, as a brown oil (136 mg), was dissolved in AcOH (5 mL) and heated at 70° C. for 4 h. After cooling to RT, the volatiles were removed under reduced pressure. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting brown oil was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford the title compound as an orange/brown oil (99 mg, 91% over two steps). LCMS (Method C): RT 3.33 min [M+H]+ 373.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH2:12]([NH:14][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:23]=[CH:22][CH:21]=[C:20]2Cl)=[O:16])[CH3:13].C(OCC)(=O)C>CS(C)=O.O>[CH2:12]([NH:14][C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:23]=[CH:22][CH:21]=[C:20]2[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([Cl:9])[CH:4]=1)=[O:16])[CH3:13]
Reactant: Nc1ccc(O)cc1Cl
Reactant: CCNC(=O)c1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCNC(=O)c1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
After dissolving 4-amino-3-chlorophenol (379 mg, 2.64 mmol) in dimethylsulfoxide (10 ml), sodium hydride (106 mg, 2.64 mmol) was gradually added at room temperature and the mixture was stirred for 30 minutes. N6-Ethyl-7-benzyloxy-4-chloro-6-quinolinecarboxamide (720 mg, 2.11 mmol) was added, and the mixture was heated at 100° C. for 2 hours while stirring. Upon cooling to room temperature, the reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with ammonia water, water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (870 mg, 1.94 mmol, 92%) as brown crystals.
Reaction SMILES: [CH:1]1([C:4](=[O:25])[C:5](=[CH:21]OCC)[C:6]([C:8]2[CH:18]=[CH:17][C:11]3[S:12][CH:13]=[C:14]([O:15][CH3:16])[C:10]=3[C:9]=2[O:19][CH3:20])=[O:7])[CH2:3][CH2:2]1.Cl.[NH2:27]O.C([O-])(=O)C.[Na+].O>C(O)C>[CH:1]1([C:4]2[O:25][N:27]=[CH:21][C:5]=2[C:6]([C:8]2[CH:18]=[CH:17][C:11]3[S:12][CH:13]=[C:14]([O:15][CH3:16])[C:10]=3[C:9]=2[O:19][CH3:20])=[O:7])[CH2:3][CH2:2]1
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc2scc(OC)c2c1OC)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1csc2ccc(C(=O)c3cnoc3C3CC3)c(OC)c12
Yield: 44.5 %

Procedure:
A solution containing 5-(3-cyclopropyl-2-ethoxymethylene-1,3-dioxoprop-1-yl)-3,4-dimethoxybenzo[b]thiophene (0.59 g) and hydroxylamine hydrochloride (0.137 g) was stirred for 15 minutes in ethanol. Sodium acetate (anhydrous, 0.161 g) was added and the mixture stirred for 4 hours, before evaporation of the ethanol and addition of water. The mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulphate) and evaporated in vacuo. The residue was purified by column chromatography on silica, eluting with ether/cyclohexane to yield 5-cyclopropyl-4-(3,4dimethoxybenzo[b]thien-5-oyl)isoxazole (compound 3, 0.24 g) as an oil, NMR δ1.20 (2H,m), 1.35 (2H,m), 2.80 (1H,m), 3.84 (3H,s), 4.00 (3H,s), 6.39 (1H,s), 7.40 (1H, d), 7.59 (1H, d), 8.29 (1H,s).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CC)=[N+:2]=[N-:3].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Yield: 68880.4 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.262 g, 1.19 mmol) was reacted with 2-azidoethanamine (0.103 g, 1.19 mmol) and triethylamine (0.242 g, 2.39 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)dodecanamide (0,220 g, 69%). 1H NMR (300 MHz, CDCl3) δ 6.11 (s, 1H), δ 3.40 (d, 2H), δ 3.37 (d, 2H), δ 2.17 (t, 2H), δ 1.59 (q, 2H), δ 1.22 (s, 14H), δ 0.84 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 173.8, 51.1, 39.1, 36.8, 32.1, 29.8, 29.7, 29.6, 29.5, 29.5, 29.2, 25.9, 22.9, 14.3 ppm; HRMS (ESI) calcd for C14H28N4O (M+) 268.2263. Found 268.2259.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([NH:35][S:36]([N:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([OH:25])([C:21]([O:23]C)=[O:22])[CH:18]([OH:26])[C:17]4[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([NH:35][S:36]([N:39]([CH3:40])[CH3:41])(=[O:37])=[O:38])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([OH:25])([C:21]([OH:23])=[O:22])[CH:18]([OH:26])[C:17]4[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1(O)Cn2c(c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)C)cc32)-c2ccc(OC)cc2C1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(O)C(O)(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 80 °C
Yield: 74 %

Procedure:
To a solution of methyl rac-(5R,6S)-13-cyclohexyl-10-((((dimethylamino)sulfonyl)amino)carbonyl)-5,6-dihydroxy-3-(methyloxy)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-6-carboxylate (57 mg, 0.10 mmol) in MeOH/THF (1:1, 2 mL) was added 1M NaOH aq. (0.5 mL). The reaction was sealed and heated at 80° C. for 20 min with microwave irradiation. The reaction was quenched with 1N HCl aq. (0.5 mL), diluted with H2O and concentrated to remove the organic solvents. The resulting precipitates were collected by filtration and dried under vacuum to yield rac-(5R,6S)-13-cyclohexyl-10-((((dimethylamino)sulfonyl)amino)carbonyl)-5,6-dihydroxy-3-(methyloxy)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (42 mg, 0.074 mmol, 73%) as a yellow solid. 1HNMR (300 MHz, CD3OD) δ 0.73-2.20 (m, 10H), 2.92-3.05 (m, 1H), 3.02 (s, 6H), 3.54 (d, J=14.8 Hz, 1H), 3.93 (s, 3H), 4.71 (d, J=14.8 Hz, 1H), 4.94 (s, 1H), 7.05 (dd, J=8.4, 2.6 Hz, 1H), 7.40 (d, J=2.6 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.59 (dd, J=8.4, 1.5 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 8.05 (d, J=1.5 Hz, 1H). LCMS: m/e 572 (M+H)+, ret time 3.34 min, column B, 4 minute gradient.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C:9](=O)[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:28])(=[O:3])[CH3:2].[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30].S(C)C>ClCCl.Cl[Ti](Cl)(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.Cl[Ti](Cl)(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:8][CH2:7][C@@H:6]1[N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:13]1=[O:28])(=[O:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(=O)N[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a solution of TiCl4 (1M in dichloromethane, 36 ml, 36 mmol) in dichloromethane (30 ml) at 0° C. was added Ti(OiPr)4 (10.8 ml, 36 mmol). The mixture was then stirred at room temperature for 10 min. To a solution of benzyl (S)-1-((1S,2R)-2-acetamido-4-oxocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (23.25 g, 60 mmol) in dichloromethane (600 ml) was added tert-butylamine (30 ml, 300 mmol) at room temperature, followed by the addition of the TiCl4/Ti(OiPr)4 solution at −50° C. The reaction was allowed to warm slowly to room temperature. The reaction was finished after 2 h (The reaction was monitored on HPLC by quenching an HPLC sample with NaBH4 in methanol). The solution was cooled to 10° C. and BH3.SMe2 (1M in dichloromethane, 66 ml, 66 mmol) was added. The mixture was stirred at room temperature for 5 then quenched with Na2CO3 aqueous solution (300 ml). The precipitate was filtered off. The two layers were separated and the aqueous layer was extracted with dichloromethane (600 ml). The combined dichloromethane layers were extracted with 1N HCl twice (150 ml and 15 ml). (The product and the undesired trans isomer were both in the acidic aqueous phase.) The combined acidic aqueous layers were neutralized with 12 M aqueous solution of NH4OH (12 ml) to pH-8 and extracted with dichloromethane twice (600 ml, 450 ml). (The product was in organic phase, while the trans isomer was still in aqueous layer.) The combined organic layers were washed with NH4Cl aqueous solution 3 times (3×200 ml) until there was no trans isomer left in organic layer. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by crystallization in EtOAc/Hexane(200 ml/800 ml) to give the desired benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (20.80 g, 78% yield) as a white solid with 99.5% purity. 1H-NMR (500 MHz, DMSO-d6) δ ppm 8.76 (s, 1H), 7.27-7.46 (m, 6H), 5.03 (m, 2H), 4.14 (m, 1 H), 4.07 (q, J=8.80 Hz, 1H), 3.83 (m, 1H), 3.36 (m, 2H), 2.91 (s, 1H), 2.18 (m, 1H), 2.04 (m, 1H), 1.78 (s, 3H), 1.41-1.74 (m, 7H), 1.04 (s, 9H). m/z: 445.54 [M+H].
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].CO.[F:10][C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>C(N(CC)CC)C>[F:10][C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[N:2][C@H:3]([CH3:4])[C:5]([NH2:7])=[O:6])=[CH:18][CH:17]=1
Reactant: C[C@@H](N)C(N)=O
Reactant: O=Cc1ccc(OCc2cccc(F)c2)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H](N=Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 49.1 %

Procedure:
In a 250 mL, 4 necked round bottom flask, equipped with mechanical stirrer, thermometer, reflux condenser and under a flow of nitrogen, D-alaninamide hydrochloride (6.1 g) and methanol (80 mL) are charged and stirred for 15 min at 20° C. Triethylamine (5 g) is added at such a rate that the temperature remains below 30° C. The mixture is stirred for 10 min, whereupon solid 4-(3-fluorobenzyloxy)benzaldehyde (10 g, Example 10 b) is added portion wise in about 30 min. After stirring for 3 hours at 20° C., the mixture is cooled to 5° C. After stirring for 3 hours at this temperature, the solid is filtered and washed with small amount of pre-cooled methanol. The wet solid is dried under vacuum for 12 hours a 25° C., yielding 6.4 g of title compound as white solid, with 46.4% yield; m.p 111.9.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][S:19][C:20]#[N:21])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)C>[CH3:2][O:3][C:4](=[O:9])[CH:5]([NH:6][C:20]1[S:19][CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][CH:13]=2)[N:21]=1)[CH2:7][OH:8]
Reactant: N#CSCC(=O)c1ccc(Br)cc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)C(CO)Nc1nc(-c2ccc(Br)cc2)cs1
Temperature: 60 °C
Yield: 77 %

Procedure:
Serine methyl ester hydrochloride (1.02 g, 4 mmol) was dissolved in 50 mL of ethanol and 2-(4-bromophenyl)-2-oxoethyl thiocyanate (0.686 g, 4.4 mmol), prepared in step 1 of Example 1, was added followed by triethylamine (0.63 mL, 4.4 mmol). The mixture was heated to 60° C. for 18 h and then cooled and concentrated under reduced pressure. Flash chromatography (1% methanol/chloroform) afforded 1.1 g of 2-[4-(4-bromophenyl)-1,3-thiazol-2-ylamino]-3-hydroxy-propionic acid methyl ester (1.1 g, 79%) as a white solid.
Reaction SMILES: C([O:8]C1C=C(O)C=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([OH:34])(=[O:8])=[O:33]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Oc1cccc(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(O)c1ccccc1Cl
Yield: 185.2 %

Procedure:
3-Benzyloxyphenol (2.97 g, 15 mmol), as prepared in the preceding step, in methylene chloride (50 mL) was treated with diisopropylethylamine (2 mL) and 2-chlorobenzenesulfonyl chloride (3.27 g, 15.5 mmol) at 0° C. for 2 h and at room temperature for 2 h. The reaction mixture was diluted with 200 mL of methylene chloride, washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (1:1 hexane:methylene chloride) to give the title compound as a colorless liquid (5.35 g, 95%). 1H-NMR (300 MHz, CDCl3) δ 4.97 (s, 2H), 6.71 (dd, 1H, J=1.1, 4.1 Hz), 6.78 (t, 1H, J=2.3 Hz), 6.85 (dd, 1H, J=1.1,4.1 Hz), 7.17 (t, 1H, J=8.3 Hz), 7.37 (m, 5H), 7.58 (m, 2H), and 7.91 (dd, 1H, J=1.1, 4.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:13][C@@H:14]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[CH:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:40])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:15]1>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:13][C@@H:14]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[CH:16]([CH2:17][CH2:18][C@@H:19]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:40])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:15]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](NC(=O)CNC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
By using tert-butyloxycarbonylglycine (522 mg, 2.98 mmol) and 3α-aminocholestane (1.16 g, 2.99 mmol), the title compound was obtained in the same manner as in Synthetic Example BB1 (1.65 g, quantitative).
Reaction SMILES: [C:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([NH:15][CH:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:14][CH2:13]1)(=[O:19])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 67.7 %

Procedure:
The trans-N-boc-1,4-cyclohexanediamine (1.00 g, 4.67 mmol) was dissolved in DCM (50 mL). Next, TEA was added (1.301 mL, 9.33 mmol), followed by methanesulfonyl chloride (0.397 mL, 5.13 mmol). The reaction was allowed to stir at rt for 22 h. The reaction mixture was partitioned between DCM (100 mL) and water (25 mL). The phases were separated and the aqueous phase was extracted with DCM (50 mL). Combined organic layer was dried over MgSO4 for 20 h overnight. Filtered and evaporated to dryness to give the title compound of Step A as a solid (0.924 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.32 (s, 8H), 2.89 (s, 3H), 1.83-1.91 (m, 1H), 1.70-1.78 (m, 1H), 1.37 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1.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>>[S:32]1[CH:33]=[CH:34][N:35]=[C:31]1[CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: NCc1nccs1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCc3nccs3)ccc21
Yield: 86.9 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (thiazol-2-ylmethyl)-amide (44 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), 2-aminomethyl-thiazole (38 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 506. 1H NMR (DMSO-d6, 400 MHz): δ 9.36 (br, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.82 (br, 1H), 7.75 (d, 1H), 7.63 (d, 1H), 7.54 (d, 1H), 7.36 (d, 1H), 4.77 (d, 2H), and 3.67 (s, 3H).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([CH:25]=1)[C:23]#[N:24])=O.[NH2:27][C:28]([NH2:30])=[O:29].Cl>CCO>[OH:26][C:21]1[CH:20]=[CH:19][C:18]([CH:16]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:30][C:28](=[O:29])[NH:27]2)=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: N#Cc1cc(C=O)ccc1O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: N#Cc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)ccc1O
Temperature: 90 °C
Reaction time: 40 h

Procedure:
To a solution of 1,2-diphenylethanone (720 mg, 3.67 mmol), 5-formyl-2-hydroxybenzonitrile (Intermediate 47a) (450 mg, 3.06 mmol) and urea (551 mg, 9.18 mmol) in EtOH (23 mL) was added concentrated HCl (0.9 mL). The mixture was stirred at 90° C. for 40 h. Followed standard aqueous workup procedure and recrystallized from EA (6 mL), then further purified by prep-HPLC to afford Compound 96 as a white power (36 mg, 3%). 1H NMR (MeOH-d4 500 MHz): δ 7.50 (t, J=7.5 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.25 (s, 5H), 7.05 (t, J=2.5 Hz, 3H), 6.93 (d, J=8.5 Hz, 1H), 6.85 (t, J=4.0 Hz, 2H), 5.30 (s, 1H); MS (ESI): m/z 368.1 [M+1]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[C:19]([OH:22])(=[O:21])[CH3:20].C([CH:25]1[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][C:26]1=O)C>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:25]3[CH:30]([CH2:20][C:19]([OH:22])=[O:21])[CH2:29][CH:28]([CH3:31])[CH2:27][C:26]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCC1CCC(C)CC1=O
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: Cl
Product: CC1Cc2c(n(Cc3ccc(Cl)cc3)c3ccc(F)cc23)C(CC(=O)O)C1

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and ethyl 4-methyl-2-cyclohexanone acetate as starting materials, the title compound was prepared. m.p. 205°-206° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].S(Cl)(Cl)=O.C(N(C(C)C)CC)(C)C.Cl.[NH2:25][CH2:26][C:27]1[C:32]([CH2:33][CH3:34])=[N:31][C:30]2[N:35]([CH2:38][CH3:39])[N:36]=[CH:37][C:29]=2[C:28]=1[NH:40][CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>ClCCl>[CH2:38]([N:35]1[C:30]2=[N:31][C:32]([CH2:33][CH3:34])=[C:27]([CH2:26][NH:25][C:8]([C:5]3([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]3)=[O:10])[C:28]([NH:40][CH:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)=[C:29]2[CH:37]=[N:36]1)[CH3:39]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: COC(=O)C1(C(=O)O)CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)OC)CC1
Temperature: 0 °C

Procedure:
To 1-[(methyloxy)carbonyl]cyclopropanecarboxylic acid (7.00 g, 48.5 mmol) in a 250 mL round-bottom flask under nitrogen in dichloromethane (DCM) (75 mL) was added thionyl chloride (19.33 mL, 265 mmol) and the solution heated to reflux. After 1.5 h the solvent and excess thionyl chloride was evaporated off. The clear residue was dissolved in DCM (120 mL), cooled under nitrogen to 0° C. and then diisopropylethylamine (23.13 mL, 132 mmol) was added dropwise. This gave white fumes and a red-brown solution that was stirred in an ice bath while adding 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride salt (15 g, 44.1 mmol) as a solid. After 15 min the icebath was removed. After 2.5 h the reaction was quenched, the mixture was partitioned between dichloromethane and saturated sodium bicarbonate and the aqueous layer extracted well with dichloromethane. The combined organics were washed with water and brine, dried (MgSO4), filtered and evaporated. This gave a dark brown oil/foam, 23.6 g, (>100%). The crude product was purified on a 330 g Companion XL silica cartridge, eluting with 0-100% ethyl acetate in dichloromethane over 10 column volumes. Much of the dark material came straight off the column and product appeared to come off in two broad peaks that were evaporated separately. The early fractions contained the desired product 12.25 g, (65%). HPLC 1.86 min (ret time), 98.4%; LC-MS m/z 430 (M+H)+, 0.79 min (ret time).