Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH3:14][N:15]1[C:20]([C:21](Cl)=[O:22])=[C:19](N2CCCC2)[C:18]2[CH:29]=[CH:30][C:31]3[C:36]([C:17]=2[S:16]1(=[O:38])=[O:37])=[CH:35][CH:34]=[CH:33][CH:32]=3.CN1C=C(N2CCCC2)C2C=CC3C(C=2S1(=O)=[O:59])=CC=CC=3.C(Cl)(Cl)=O.C1(C)C=CC=CC=1>O1CCCC1>[OH:59][C:19]1[C:18]2[CH:29]=[CH:30][C:31]3[C:36]([C:17]=2[S:16](=[O:38])(=[O:37])[N:15]([CH3:14])[C:20]=1[C:21]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:22])=[CH:35][CH:34]=[CH:33][CH:32]=3
Reactant: Nc1nccs1
Reactant: CN1C=C(N2CCCC2)c2ccc3ccccc3c2S1(=O)=O
Reactant: CN1C(C(=O)Cl)=C(N2CCCC2)c2ccc3ccccc3c2S1(=O)=O
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 36.3 %

Procedure:
A solution of 0.9 gm (9 millimols) of 2-amino-thiazole and 0.78 gm (7.7 millimols) of triethylamine in 8 ml tetrahydrofuran was added dropwise at -40° C to a solution of 6.4 millimols of 2-methyl-4-(1-pyrrolidyl)-2H-naphtho[2,1-e]1,2-thiazine-3-carboxylic acid chloride-1,1-dioxide, which was obtained by reacting 2.0 gm (6.4 millimols) of 2-methyl-4-(1-pyrrolidyl)-2H-naphtho[2,1-e]-1,2-thiazine-1,1-dioxide with 4 ml of a solution (20%) of phosgene in toluene (7.7 millimols) in the presence of 0.78 gm (7.7 millimols) of triethylamine in 80 ml of tetrahydrofuran. The reaction mixture was warmed to room temperature over a period of 2 hours and afterwards stirred at room temperature for 36 hours. Ice water was then added to the mixture, and the aqueous mixture was extracted several times with ethylene chloride. The combined organic phases were evaporated, and the residue was refluxed with 2 N hydrochloricacid for 2 hours. After cooling, the mixture was extracted with ethylene chloride, the organic phase was evaporated, and the residue was purified by chromatography on silicagel, using chloroform/methanol (ratio by volume10:1) as the eluant. The eluates yielded 0.9 gm (35% of theory) of 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-naphtho [2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 248°-249° C (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>O1CCCC1>[CH3:31][O:32][CH2:33][C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[N:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1)=[O:35]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3ccc(N)cc3)cs2)c1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2nc(-c3ccc(NC(=O)COC)cc3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
In an ice-bath, to a solution (4 mL) of the crude compound (0.84 mmol) obtained in Example 36b in tetrahydrofuran were added triethylamine (0.15 mL, 1.1 mmol) and methoxyacetylchloride (110 mg, 1.0 mmol), and the mixture was stirred at room temperature overnight. After confirmation of the termination of the reaction by TLC, the resulting salt was removed. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (hexane-ethyl acetate) to give the title compound (250 mg, 74% in 2 steps) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[H-].[Na+].COC1C=C2C(=CC=1OC)N=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:45]=[CH:44][C:43](NC(NC2CCNCC2)=O)=[CH:42][CH:41]=1.[C:56](=O)([O-])[OH:57].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:32][CH2:31][CH2:30][O:39][C:40]2[CH:41]=[CH:42][CH:43]=[C:44]([O:57][CH3:56])[CH:45]=2)=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(O)cc3)c2cc1OC
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCNCC4)cc3)c2cc1OC
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OCCCOc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenol (100 mg) was dissolved in dimethylformamide (2 ml) to prepare a solution. Sodium hydride (16 mg) was then added to the solution, and the mixture was stirred at room temperature for 10 min. A solution of the compound (1) (91 mg) in dimethylformamide was added thereto, and the mixture was further stirred at room temperature for 2 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing three times with saturated brine. The extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (147 mg, yield 95%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([C:11]([OH:13])=O)[CH2:6]1)=[O:4].C1C=CC2N(O)N=[N:20][C:18]=2C=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH3:18][NH:20][C:11]([CH:7]1[CH2:8][CH2:9][CH2:10][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)=[O:13]
Reactant: COC(=O)[C@@H]1CCC[C@H](C(=O)O)C1
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CNC(=O)C1CCCC(C(=O)OC)C1
Reaction time: 8 h
Yield: 85.8 %

Procedure:
(±)-cis-3-(Methoxycarbonyl)cyclohexanecarboxylic acid (500 mg, 2.69 mmol), methylamine, HCl (218 mg, 3.22 mmol), HOBT (493 mg, 3.22 mmol), EDC (618 mg, 3.22 mmol) and triethylamine (0.75 mL, 5.37 mmol) were mixed and stirred in methylene chloride (10 mL) at 25° C. The reaction was stirred overnight then washed with 1N HCl, sat'd sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give (±)-cis-3-(methyl 3-(methylcarbamoyl)cyclohexanecarboxylate (460 mg, 2.309 mmol, 86% yield) as a white glass. MS found: (M+H)+=200.10.
Reaction SMILES: [C:1]1(I)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[CH2:9].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:1]1(/[CH:9]=[CH:8]/[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccncc1
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C(=C/c1ccncc1)\c1ccccc1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
A mixture of phenyl iodide (100 ml, 0.89mol), 4-vinylpyridine (115 ml, 1.07 mol), palladium acetate (2.4 g, 0.01 mol), tri-o-tolylphosphine (6.08 g, 0.02 mol) and triethylamine (150 ml, 1.07 mol) was refluxed for 3 hours. The reaction was cooled to room temperature, the resulting solid dissolved in dichloromethane (2 l) and washed with saturated aqueous sodium carbonate solution (2 l). The aqueous phase was further extracted with dichloromethane (3×1.5 l) and the combined organic phases dried (MgSO4) and evaporated. The resulting solid was washed with ethyl acetate (1.5 l), filtered and dried in vacuo to give (E)-4-(2-phenylethenyl)pyridine (90 g, 56%); δH (CDCl3) 7.01 (1H, d, J 16.3 Hz, ArCH=CH), 7.25-7.41 (6H, m, PhH, ArCH=CH), 7.53 (2H, d, J 5.3 Hz, 3-H, 5-H), and 8.58 (2H, d, J 5.2 Hz, 2-H, 6-H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.Cl[C:41]1C=CC([C@@H](O)C(F)(F)F)=C(N2C=CC(C3CC3)=N2)[CH:42]=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:42][CH2:41]3)=[N:35]2)[C:23]([F:25])([F:24])[F:26])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Reactant: O[C@H](c1ccc(Cl)cc1-n1ccc(C2CC2)n1)C(F)(F)F
Product: Nc1nc(O[C@H](c2ccc(Cl)cc2-n2ccc(C3CC3)n2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-chloro-2-(3-cyclopropyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (Intermediate 42).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][CH2:19][CH:20]1[O:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:21]1>>[ClH:18].[CH2:26]([N:22]1[CH2:23][CH2:24][O:25][CH:20]([CH2:19][N:10]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]2=[O:17])[CH2:21]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: O=c1[nH]c2ccccc2n1Cc1ccccc1
Product: Cl
Product: O=c1n(Cc2ccccc2)c2ccccc2n1CC1CN(Cc2ccccc2)CCO1
Yield: 44.4 %

Procedure:
The condensation of 0.1 mol of 1-benzyl-2,3-dihydrobenzimidazol-2-one and 0.1 mol of 2-chloromethyl-4-benzyl-morpholine is carried out in accordance with the procedure of Example 1. 20 g of 4-benzyl-2-(1-benzyl-2,3-dihydro-benzimidazol-2-on-3-yl-methyl)-morpholine hydrochloride are obtained, m.p. 196° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)#[N:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+]>>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([NH2:20])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc2c(c1)OCCC2=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: N#Cc1ccc2c(c1)OCCC2N
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.6 %

Procedure:
A dry, 200 mL round bottom flask was charged with 0.85 g (4.83 mmol) of 7-(cyano)-4-chromanone, 3.72 g (48.30 mmol) of ammonium acetate, and 0.91 g (14.45 mmol) of sodium cyanoborohydride. The flask was then purged with argon, and 30 mL of dry methanol was added by syringe. The solution was stirred at room temp for 48 hours. Concentrated HCl was slowly added dropwise until pH<2 was reached. The methanol was then evaporated by rotovap, and 30 mL of water was added to the suspension, which was then washed 3 times with ethyl acetate. The pH was then brought to >10 by adding sodium hydroxide pellets to the stirring aqueous mixture. Saturated sodium chloride was added, and the mixture was then extracted several times with ether and ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered and evaporated to give 0.51 g (60%) of the desired 7-(cyano)-4-chromanylamine as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:20][O:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2[C:31]3=[N:32][CH:33]=[CH:34][C:35](Cl)=[C:30]3[C:29]([CH3:37])=[N:28]2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][C:35]1[CH:34]=[CH:33][N:32]=[C:31]2[N:27]([CH2:26][C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:39][CH:38]=3)[N:28]=[C:29]([CH3:37])[C:30]=12
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Reactant: O=C1Nc2ccccc2CN1c1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N5Cc6ccccc6NC5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a round bottom flask were added 3-(3-fluoro-4-hydroxyphenyl)-3,4-dihydroquinazolin-2(1H)-one (19 mg, 0.074 mmol) and DMF (0.7 mL). 1-(4-Methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (25.4 mg, 0.088 mmol), prepared according to the procedure of Example 43, Step E, was added followed by potassium carbonate (12.2 mg, 0.088 mmol) and a 1 M solution of potassium t-butoxide in THF (0.088 mL, 0.088 mmol). The mixture was stirred at 110° C. for 4 hours under nitrogen. The reaction was cooled to room temperature and the reaction mixture was partitioned between water (10 mL) and ethyl acetate (20 mL). The organic layer was separated and the aqueous layer was extracted with a second portion of ethyl acetate (10 mL). The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give 29.8 mg of brown oil. The crude oil was triturated with a dichloromethane:ether mixture and the resulting solid was filtered and dried to afford the desired product as a tan solid (17.6 mg, 47%). LRMS (APCI pos): m/e 510.2 (M+1).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(Cl)(Cl)Cl.ClC(OCC)=O.[NH3:29]>C(N(CC)CC)C>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]([NH2:29])=[O:18])=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: N
Reactant: CCC[C@H]1CC[C@H](c2ncc(C(=O)O)cn2)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC[C@H]1CC[C@H](c2ncc(C(N)=O)cn2)CC1
Temperature: 2 °C
Reaction time: 0.25 h

Procedure:
A solution of 13.85 g of trans-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylic acid, 260 ml of chloroform and 7.8 ml of triethylamine is cooled to 2° C. and treated with 5.32 ml of ethyl chloroformate. The mixture is stirred at 2° C. for 15 minutes and then a strong stream of ammonia gas is conducted in for 10 minutes (while cooling with an ice-bath). The resulting suspension is stirred at 20° C. for a further 1 hour and then evaporated in vacuo. The solid residue is stirred up with 210 ml of water for 45 minutes and then filtered off under suction and dried. There are obtained 9.6 g of crude trans-2-(4-propylcyclohexyl)-5-pyrimidinecarboxamide (m.p. 234°-235° C.) which can be purified by sublimation at 175° C./0.05 mmHg; m.p. 249.3°-250.5° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:44]=[CH:43][C:13]([CH2:14][O:15][C@@H:16]2[C@@H:23]([CH2:24][OH:25])[O:22][C@H:19]([O:20][CH3:21])[C@H:18]([OH:26])[C@H:17]2[O:27][C:28](=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:12][CH:11]=1.[C:45](Cl)(=[O:59])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:4]([CH2:3][CH2:2][C:1]([O:25][CH2:24][C@H:23]1[O:22][C@H:19]([O:20][CH3:21])[C@H:18]([O:26][C:45](=[O:59])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[C@@H:17]([O:27][C:28](=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C@@H:16]1[O:15][CH2:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:44][CH:43]=1)=[O:7])([OH:6])=[O:5]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCCCCCCC(=O)O[C@@H]1[C@@H](O)[C@@H](OC)O[C@H](CO)[C@H]1OCc1ccc(OC)cc1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCC(=O)O[C@@H]1[C@@H](OC(=O)CCCCCCCCCCCCC)[C@@H](OC)O[C@H](COC(=O)CCC(=O)O)[C@H]1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.6 %

Procedure:
DMAP (8.1 mg, 0.06 mmol) and succinic anhydride (67 mg, 0.67 mmol) were added to a stirred solution of derivative 16 (0.35 g, 0.67 mmol) in dry pyridine (5 mL) and the resulting mixture was stirred for 16 h at rt under argon. After that, myristoyl chloride (0.21 ml, 0.80 mmol) was added dropwise, and the reaction mixture was stirred for 2 h at rt. After that, the resulting mixture was concentrated under the reduced pressure. The residue was dissolved in CH2Cl2 (30 mL) and washed successively with 1N HCl (2×15 mL), water (2×15 mL) and brine (15 mL). The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-hexane gradient elution) to give compound 17 (0.43 g, 0.52 mmol) as white syrup in 79% yield. Analytical data for 17: Rf=0.55 (ethyl acetate-hexane 1/1, v/v); [α]D24+42.4° (c=1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ, 0.87 (t, 6H, 2×CH3), 1.25 (br. s, 40H, 20×CH2), 1.59 (m, 4H, 2×CH2), 2.26 (m, 2H, CH2), 2.33 (m, 2H, CH2), 2.61 (m, 4H, 2×CH2), 3.36 (s, 3H, OCH3), 3.59 (dd, 1H, J4,5=9.5 Hz, H-4), 3.90 (m, 1H, H-5), 4.28 (dd, 2H, J5,6b=4.4 Hz, J6a,6b=11.5 Hz, H-6a, 6b), 4.44 (d, 1H, J2=10.7 Hz, ½CH2Ph), 4.54 (d, 1H, J2=10.7, ½CH2Ph), 4.87 (m, 2H, H-1, 2), 5.55 (dd, 1H, J3,4=9.5 Hz, H-3), 6.84 (d, 2H, J=8.7 Hz, aromatic), 7.16 (d, 2H, J=8.6 Hz, aromatic) ppm; 13C NMR (75 MHz, CDCl3): δ, 14.3, 22.8, 25.1, 28.8, 29.2, 29.3, 29.4 (×2), 29.5, 29.6, 29.7, 29.8, 32.1, 34.2, 34.5 (×3), 55.4, 62.7, 68.6, 71.8, 71.9, 74.3, 75.7, 96.9, 114.0, 129.5, 129.8, 159.6, 171.7, 172.8, 173.7 ppm; HR FAB MS [M+Na]+ calcd for C47H78O12Na 857.5391. found 857.5410.
Reaction SMILES: [NH2:1][CH:2]([CH2:21][CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[N:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:20]=[CH:19][C:14]3[O:15][CH2:16][CH2:17][O:18][C:13]=3[CH:12]=2)[CH2:6]1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[O:15]1[C:14]2[CH:19]=[CH:20][C:11]([N:7]3[CH2:6][CH:5]([CH2:4][CH2:3][CH:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:21][CH2:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[N:31]=5)[N:26]=[CH:25][CH:24]=4)[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[O:18][CH2:17][CH2:16]1
Reactant: COc1ccc2nccc(CCC(N)CCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1ccc2nccc(CCC(CCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)NS(C)(=O)=O)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A solution of the compound of Example 116 (0.05 g, 0.1 mmol) in DCM (2 mL) at rt was treated sequentially with TEA (0.03 mL, 2 eq.) and MsCl (0.013 mL, 1.5 eq.). The mixture was stirred at rt for 2 h, washed with water and purified by FC (EA, EA/MeOH 9:1) to give the title compound as a colourless foam (0.052 g, 89% yield).
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[OH:8][CH2:9][CH2:10][NH:11][C:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:23])[C:13]=1[N:24]([CH3:28])[C:25](=O)[CH3:26]>C(O)C>[Cl-:1].[OH:8][CH2:9][CH2:10][N:11]1[C:12]2[C:21](=[O:22])[C:20]3[C:15]([C:14](=[O:23])[C:13]=2[N+:24]([CH3:28])=[C:25]1[CH3:26])=[CH:16][CH:17]=[CH:18][CH:19]=3
Reactant: Cl
Reactant: CC(=O)N(C)C1=C(NCCO)C(=O)c2ccccc2C1=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1n(CCO)c2c([n+]1C)C(=O)c1ccccc1C2=O
Product: [Cl-]
Temperature: 45 °C
Reaction time: 1 h

Procedure:
4 M hydrogen chloride/ethyl acetate solution (3 ml) was added to a suspension of N-[3-(2-Hydroxyethyl)amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl]-N-methylacetamide (0.4 g) in ethanol (3 ml) and the mixture was stirred at 45° C. for 1 hour. After cooling, the resulting precipitate was collected by filtration and washed with ethyl acetate. The obtained solid was recrystallized from ethanol-ethyl acetate to give 1-(2-hydroxyethyl)-2,3-dimethyl-4,9-dihydro-4,9-dioxo-1H-naphtho[2,3-d]imidazol-3-ium chloride (0.28 g) as a colorless powder.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]([CH:16]1[CH2:21][NH:20][C:19]2[CH:22]=[C:23]([O:26][C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:25][C:18]=2[O:17]1)=[O:15].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]([CH:16]1[O:17][C:18]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:22][C:19]=2[NH:20][CH2:21]1)=[O:15]
Reactant: Cc1ccc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(Br)c1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(C#CCO)c1
Temperature: 75 °C
Yield: 72.8 %

Procedure:
Prop-2-yn-1-ol (195 mg, 202 μL, 3.48 mmol), N-(2-bromo-4-methyl-phenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (300 mg, 0.69 mmol), PdCl2(PPh3)2 (122 mg, 0.17 mmol), CuI (19.88 mg, 0.10 mmol), and triethylamine (970 μL, 6.96 mmol) were combined in DMF (5 mL) and heated at 75° C. for 18 h. Purification by silica gel chromatography (0-50% ethyl acetate/hexanes) provided N-(2-(3-hydroxyprop-1-ynyl)-4-methylphenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide (204 mg, 72% yield). LC/MS m/z 407.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[C:17]12[CH2:24][CH2:23][C:20]([C:25]([NH:27][NH:28][C:29](=[O:37])[CH:30]([CH3:36])[CH2:31][C:32]([F:35])([F:34])[F:33])=O)([CH2:21][CH2:22]1)[CH2:19][CH2:18]2.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.CC#N>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:14])([F:16])[F:15])=[N:5][N:4]=[C:3]1[C:17]12[CH2:24][CH2:23][C:20]([C:25]3[O:37][C:29]([CH:30]([CH3:36])[CH2:31][C:32]([F:34])([F:35])[F:33])=[N:28][N:27]=3)([CH2:21][CH2:22]1)[CH2:19][CH2:18]2
Reactant: CC(CC(F)(F)F)C(=O)NNC(=O)C12CCC(c3nnc(-c4ccccc4C(F)(F)F)n3C)(CC1)CC2
Solvent: CC#N
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(CC(F)(F)F)c1nnc(C23CCC(c4nnc(-c5ccccc5C(F)(F)F)n4C)(CC2)CC3)o1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To 13-B in toluene (3 mL) was added thionyl chloride (2 mL) and, fitted with a reflux condenser, the solution was heated to 85° C. under a nitrogen atmosphere. After 1 hour the solvent was stripped off in vacuo. The residue was dissolved in CH3CN (4 ml) and product was purified by Masslynx reverse phase chromatography eluting with a 10-90% CH3CN (0.1% TFA)/water (0.1% TFA) gradient. Solvent was removed in vacuo and the product free based from methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was washed with brine and dried over MgSO4. The solvent was removed and the product lyopholyzed from CH3CN and water to afford 13-C as a white solid. MS (ESI+)=514.22 (M+1); 1H NMR (500 MHz, CDCl3): δ 7.85-7.83 (m, 1 H), 7.72-7.68 (m, 2 H), 7.52 (t, 1 H), 3.48 (s, 3 H), 3.46 (m, 1 H), 2.86-2.74 (m, 1 H), 2.51-2.39 (m, 1 H), 2.28 (m, 6 H), 2.14 (m, 6 H), 1.50 (d, 3 H) ppm.
Reaction SMILES: C1COCC1.[C:6]1([C@H:16]([N:18]([CH2:26][C@@H:27]2[C@@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][NH:29][CH2:28]2)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[CH:38]1[N:42]=[CH:41][N:40]([C:43](N2C=NC=C2)=[O:44])[CH:39]=1>C(N(CC)CC)C>[N:40]1([C:43]([N:29]2[CH2:30][C@H:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:27]([CH2:26][N:18]([C@@H:16]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)[CH3:17])[C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH2:28]2)=[O:44])[CH:39]=[CH:38][N:42]=[CH:41]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)n2ccnc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 107.4 %

Procedure:
A 10 ml THF solution of 940 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate was mixed with 0.3 ml of triethylamine and 3.54 g of CDI and stirred at room temperature for 2Hours. The reaction solution was concentrated under a reduced pressure and diluted with ethyl acetate. This was washed with 1 M hydrochloric acid and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. By evaporating the solvent under a reduced pressure, 1.23 g of tert-butyl {[(3R,4S)-1-(1H-imidazol-1-ylcarbonyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate was obtained as a pale yellow amorphous substance. EP: 525.