Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C@H:9]([NH:14][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([F:19])([F:18])[F:17])[C:10]([O:12]C)=[O:11]>CO.C1COCC1.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C@H:9]([NH:14][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([F:17])([F:18])[F:19])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)[C@H](Cc1ccccc1Cl)NC(c1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@H](Cc1ccccc1Cl)NC(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl 3-(2-chlorophenyl)-2(S)-(2,2,2-trifluoro-1(RS)-phenylethylamino)-propionate was dissolved in a mixture of MeOH (2 mL) and THF (5 mL) and IN NaOH (4 mL) was added and the reaction mixture was stirred at room temperature for 4 h. The solvent was evaporated using a rotavap and the pH was adjusted to 6 using 1N HCl. The precipitated yellow solid was filtered and dried to give 3-(2-chlorophenyl)-2(S)-(2,2,2-trifluoro-1(RS)-phenylethylamino)propionic acid (500 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=C(OC)C=CC=1C[N:13]([C:37]1[S:38][CH:39]=[CH:40][N:41]=1)[S:14]([C:17]1[CH:36]=[CH:35][C:20]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[O:22])=[CH:19][N:18]=1)(=[O:16])=[O:15].C(Cl)Cl.C(N(CC)CC)C>CCOCC>[S:38]1[CH:39]=[CH:40][N:41]=[C:37]1[NH:13][S:14]([C:17]1[CH:36]=[CH:35][C:20]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=2)=[O:22])=[CH:19][N:18]=1)(=[O:15])=[O:16]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)NCc3ccc(C(F)(F)F)cc3)cn2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccc(S(=O)(=O)Nc2nccs2)nc1
Reaction time: 0.5 h

Procedure:
TFA (750 L, 9.7 mmol) was added to a solution of 6-{[(2,4-dimethoxybenzyl)(1,3-thiazol-2-yl)amino]sulfonyl}-N-[4-(trifluoromethyl)benzyl]nicotinamide (Preparation 88, 1.15 g, 1.94 mmol) in methylene chloride (12 mL, 180 mmol). After 30 min, the reaction mixture was diluted with ether. Triethylamine was added until basic to neutralize the residual TFA. Celite was added, and the mixture was concentrated in vacuo. The residue was purified on the Isco (120 g SiO2 cartridge, chloroform to 12% MeOH in chloroform). The appropriate fractions were concentrated in vacuo. The residue was treated with acetonitrile, generating a white precipitate. The volume was reduced in vacuo, and the solids were collected via filtration, washing with acetonitrile. The off-white product was dried under vacuum (428 mg, 47%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:62](=[O:64])[CH3:63])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.CI.[C:69]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([N:61]([C:62](=[O:64])[CH3:63])[CH3:69])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N(C)C(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3S,8S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (29 mg) was reacted with methyl iodide and K2CO3 in DMF to give (S)-2-({(3S,8S)-7-[2-(acetyl-methyl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (LCMS (m/z): 982) according to General Procedure O. This product (26 mg) was hydrolyzed according to General Procedure B to furnish the title compound (22 mg). LCMS (m/z): 924.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](F)=[C:12]([F:17])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][C:20]=1[OH:29]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][C:20]=1[O:29][C:13]1[CH:14]=[CH:15][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:11][C:12]=1[F:17]
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(F)c1
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Product: O=C(O)Cc1ccc(Cl)c(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (i) and the product of example 1 step (iii).
Reaction SMILES: COC1C=CC(N2C3CCCC[C:12]=3[CH:11]=[C:10]2[C:18]2[CH:23]=CC=C[CH:19]=2)=CC=1.[CH:24](O)([CH3:26])[CH3:25]>[Pd]>[C:24]1([CH3:26])[CH:19]=[C:18]([CH3:23])[CH:10]=[C:11]([CH3:12])[CH:25]=1
Reactant: CC(C)O
Reactant: COc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1
Agent: [Pd]
Product: Cc1cc(C)cc(C)c1

Procedure:
Following a procedure similar to that of Example 1D but using 63 g. of 1-(4-methoxyphenyl)-2-phenyl-4,5,6,7-tetrahydroindole and 18 g. of 10% palladium-on-charcoal in 600 ml. mesitylene (18 hours reflux) there was obtained, on recrystallization first from isopropyl alcohol and then from tetrahydrofuran-hexane, 58.5 g. of 1-(4-methoxyphenyl)-2-phenylindole; m.p. 141°-142°C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[I-].[K+].[OH-].[K+].Cl[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(O)C>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2
Reactant: OCCCCCCCl
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2cc(OCCCCCCO)ccc2c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a stirred mixture of 25.00 g (133 mmol) of 6-hydroxy-2-naphthoic acid, 2.21 g (13 mmol) of potassium iodide, 4.28 g (13 mmol) of tetrabutylammonium bromide, and 77 g of ethanol, was added dropwise 18.63 g (332 mmol) of potassium hydroxide dissolved in 38 g of water. The mixture was heated to 60° C., 19.07 g (146 mmol) of 6-chloro-1-hexanol was added dropwise here, and the solution was refluxed for 34 hours. After adding hydrochloric acid dropwise, the reaction mixture was chilled with ice-water, and the precipitate was collected by filtration. Water was added to the precipitate, and the mixture was stirred for 30 minutes and filtered to recover the precipitate, which was dried in an oven at 40° C. overnight. The dried product was recrystallized from THF to yield the desired product, 6-(6-hydroxy-hexa-1-yloxy)-2-naphthoic acid as white solid (21.63 g, Yield: 56.5%).
Reaction SMILES: C(OC1C=CC(C(O)=O)=CC=1)CCCCC.ClCC[C@H](C)CCCOC1C=CC(O)=CC=1.[CH2:33]([O:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].[Cl:51][CH:52]([CH2:67][CH2:68][CH2:69][CH3:70])[CH2:53][C@H:54]([CH3:66])[CH2:55][CH2:56][CH2:57][O:58][C:59]1[CH:64]=[CH:63][C:62](O)=[CH:61][CH:60]=1>>[Cl:51][CH:52]([CH2:67][CH2:68][CH2:69][CH3:70])[CH2:53][C@H:54]([CH3:66])[CH2:55][CH2:56][CH2:57][O:58][C:59]1[CH:60]=[CH:61][C:62]([O:47][C:46](=[O:48])[C:45]2[CH:44]=[CH:43][C:42]([O:41][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:50][CH:49]=2)=[CH:63][CH:64]=1
Reactant: CCCCC(Cl)C[C@H](C)CCCOc1ccc(O)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Agent: CCCCCCOc1ccc(C(=O)O)cc1
Agent: C[C@@H](CCCl)CCCOc1ccc(O)cc1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(OCCC[C@@H](C)CC(Cl)CCCC)cc2)cc1

Procedure:
The procedure of Example 12 was followed except that the 4-n-hexyloxybenzoic acid and (R)-4-(6'-chloro-4'-methylhexyloxy)phenol were replaced by 4-n-octoxybenzoic acid and (R)-4-(6'-chloro-4'-methyldecyloxy)phenol ([α]D =+2.00°, C=1, CHCl3 solution, 26° C.) to thereby give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:6]=1)=[O:17])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (Example 58 c) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=380.0 [M+H]+.
Reaction SMILES: [CH:1]1([C:11](C2CCCCCCCCC2)(C2CCCCCCCCC2)[OH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:33]([OH:37])(=[O:36])[CH:34]=[CH2:35].CS(O)(=O)=O>COC1C=CC(O)=CC=1.CCCCCCC>[C:33]([OH:37])(=[O:36])[CH:34]=[CH2:35].[CH:1]1([CH2:11][OH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:1]1([CH2:11][OH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:1]1([CH2:11][OH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(C1CCCCCCCCC1)(C1CCCCCCCCC1)C1CCCCCCCCC1
Agent: C=CC(=O)O
Agent: COc1ccc(O)cc1
Agent: CS(=O)(=O)O
Solvent: CCCCCCC
Product: OCC1CCCCCCCCC1
Yield: 110.3 %

Procedure:
To a 500 mL flask equipped with a Dean-Stark trap was added tricyclodecyl methanol (50 g, 300 mmol), acrylic acid (23.8 g, 330 mmol), heptane (250 mL), methanesulfonic acid (3.0 g), and MEHQ (132 mg). The mixture was refluxed for 65 minutes under a mild air sparge, at which point 5.3 mL water (theoretical amount 5.4 mL) had collected in the Dean-Stark trap. The mixture was washed with sodium bicarbonate, dried over magnesium sulfate, and finally passed over silica gel. The solvent was removed by rotary evaporation to afford the product (64.3 g, 97.3% yield).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])[C:16]=3[CH:15]=[CH:14]2)[CH2:4]1.ClCCCl.O=[C:39]1[CH2:42][CH:41]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:40]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:33][O:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:21]1[C:16]2[CH:15]=[CH:14][N:13]([C@H:5]3[C@@H:6]4[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]4[C@@H:3]([CH2:2][NH:1][CH:39]4[CH2:40][CH:41]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:42]4)[CH2:4]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CCOC(=O)CCC1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)CCC1CC(NC[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 7-((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (8.00 g, 15.2 mmol) in 1,2-Dichloroethane (119.5 mL, 1517 mmol) was treated with ethyl 3-(3-oxocyclobutyl)propanoate (2.58 g, 15.2 mmol) and Acetic acid (0.86 mL, 15 mmol) dropwise followed by Sodium triacetoxyborohydride (3.86 g, 18.2 mmol) and the mixture was stirred at RT for 19 h. The reaction mixture was diluted with 150 mL CH2Cl2 and washed with 150 mL sat NaHCO3. The aqueous phase was washed with 70 mL CH2Cl2 and the combined organic phase was dried over Na2SO4, filtered and concentrated to yield a tan glass that produced a sticky foam when placed under high vac. The crude material was purified by flash chromatography (SiO2 eluting with 3-4% 7N NH3 in CH3OH/CH2Cl2) to yield a light yellow viscous oil that producted a sticky foam under high vacuum (5.03 g). MS 608.3 (M+H).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([O-:17])=[O:16].[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[OH-].[Na+]>C(Cl)Cl>[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)([O-:17])=[O:16]
Reactant: NC1CCOCC1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(CNC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaB(OAc)3H (11.87 mmol, 2.52 g) was added to a mixture of 3-nitrobenzaldehyde Compound 6a (9.89 mmol, 1.49 g) and 4-amino-tetrahydro-pyran Compound 3d (9.89 mmol, 1.00 g) in CH2Cl2 (50 mL) and the resulting suspension was stirred overnight at r.t. The reaction mixture was made basic with a 2N NaOH solution and extracted with CH2Cl2. The organic layer was washed with brine, then separated and dried over MgSO4. The drying agent was filtered and the solvent was removed in vacuo. The product was purified by flash column chromatography (9:1 CH2Cl2:MeOH) to yield (3-nitro-benzyl)-(tetrahydro-pyran-4-yl)-amine Compound 6b as a yellow oil (1.91 g, 82%). (This portion of Example 6 was adapted from Shiroshi, et al., J. Med. Chem., 2000, 43, 2049). MS m/e 237 (M+H, 100%); 1H NMR (300 MHz, CDCl3) δ 1.35-1.53 (m, 4H), 1.82-1.95 (d, 2H), 2.65-2.8 (m, 1H), 3.38 (dt, J=3.2 Hz, J=11.2 Hz, 2H), 3.92-4.05 (m, 4H), 7.45-7.54 (t, 1H), 7.65-7.72 (d, 1H), 8.07-8.15 (d, 1H), 8.22 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH:11](Cl)[CH3:12].[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:10][CH:11]1[CH3:12]
Reactant: Cc1cccc(C)c1NCC(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1N1CC1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
22.8 g (0.115 moles) of 1-(2,6-dimethylphenyl-amino)-2-chloro-propane, prepared as described in Step (a) of Example 11, are dissolved in 300 ml of ethanol. 50 ml of a 10 n aqueous sodium hydroxide solution are added, and the mixture is boiled for one hour. The mixture is allowed to cool, poured onto 500 ml of ice water, and the resulting mixture is extracted thrice with 100 ml of chloroform, each. The chloroform solutions are combined, washed thrice with 100 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The oily residue is distilled under reduced pressure. 15.9 g (86.2%) of 1-(2,6-dimethylphenyl)-2-methyl-aziridine are obtained; b.p.: 70°-74° C./40 Pa.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].C(N(CC)CC)C.[NH:17]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:18]([C:29](ON1C(=O)CCC1=O)=[O:30])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>CN(C=O)C>[NH:17]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:18]([C:29]([NH:1][C@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:30])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1
Reactant: CSCC[C@H](N)C(N)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
5.78 g (0.039 mole) of H-Met-NH2 was dissolved in 50 ml of DMF, then 5.46 ml of triethylamine and further 18.70 g (0.047 mole) of Boc-Trp-OSu were added under cooling with ice, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, and extracted with ethyl acetate. The extract was washed with 1N citric acid, saturated saline solution, saturated sodium bicarbonate solution, and saturated saline solution in series. The resulting organic layer was dried over anhydrous sodium sulfate, distilled in vacuo to remove the solvent, and solidified with hexane. The solid was recrystallized from ethyl acetate-hexane, giving 12.45 g of Boc-Trp-Met-NH2 ; yield 73.5%, m.p. 155°-157° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([N+:15]#[C-:16])=[C:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])[CH3:2].C(N(CC)CC)C.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:5]1[N:15]=[CH:16][N:29]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])=[O:17])[CH3:2]
Reactant: CC(C)CN
Reactant: [C-]#[N+]C(C(=O)OCC)=C(Br)c1ccccc1Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncn(CC(C)C)c1-c1ccccc1Br
Yield: 71 %

Procedure:
A 0.5 M solution of 3-bromo-3-(2-bromophenyl)-2-isocyano-acrylic acid ethyl ester (2.55 g; 7.11 mM) and triethylamine (990 μl; 7.11 mM) in dimethylformamide (DMF) is added drop by drop at room temperature with isobutylamine (850 μl; 8.53 mM). The reaction mixture is kept at room temperature until complete reaction, then is quenched with a NaHCO3 saturated solution, extracted with ethyl acetate, washed with water, dried over Na2SO4, and evaporated under reduced pressure. The crude is purified by flash chromatography, eluting with ethyl acetate, to obtain 1.77 g of 5-(2-bromophenyl)-1-isobutyl-1H-imidazole-4-carboxylic acid ethyl ester. (Yield: 71%).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[C:10]([Cl:11])[C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[C:3]=1[O:22][CH3:23].[Cu][C:25]#[N:26].O.C(OCC)(=O)C>CN(C)C=O>[Cl:11][C:10]1[C:6]2[CH:5]=[C:4]([O:20][CH3:21])[C:3]([O:22][CH3:23])=[C:2]([C:25]#[N:26])[C:7]=2[S:8][C:9]=1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13]
Reactant: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2c(Br)c1OC
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2c(C#N)c1OC

Procedure:
(7-Bromo-3-chloro-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (0.7 g) and copper(I) cyanide (2.3 g) in N,N-dimethylformamide were irradiated in a microwave oven at 180° C. for 1.5 hours. To the mixture water (40 ml) and ethyl acetate (40 ml) were added. The solid was filtered and the organic phase was evaporated and dried in vacuum. The product was purified by flash chromatography using heptane-ethyl acetate as an eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[NH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]1
Reactant: O=C1CCNCC1
Reactant: COc1ccc2[nH]ccc2c1
Agent: O=[Pt]=O
Product: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Yield: 73.8 %

Procedure:
This compound was prepared following the procedure described in example 1 (parts A and B) starting with 5.9 g (40 mmol) of 5-methoxyindol and 15.5 g (100 mmol) of 4-piperidone. In this case the hydrogenation took place for 24 hours at 30 psi and the catalyst used was platinum (IV) oxide. 6.8 g (74% of yield) of 5-methoxy-3-piperidin-4-yl-1H-indole were obtained.
Reaction SMILES: [C:1]([O:7][CH2:8]I)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[K].[C:11]([C:14]1[N:15]2[CH:18]([S:19][CH2:20][C:21]=1[CH2:22][S:23][C:24]1[S:28][C:27]([CH3:29])=[N:26][N:25]=1)[CH:17]([NH:30][C:31](=[O:39])[CH2:32][C:33]1[S:34][C:35](=[O:38])[S:36][CH:37]=1)[C:16]2=[O:40])([OH:13])=[O:12].C(OCC)(=O)C>CN(C)C=O.O>[CH3:29][C:27]1[S:28][C:24]([S:23][CH2:22][C:21]2[CH2:20][S:19][CH:18]3[N:15]([C:16](=[O:40])[CH:17]3[NH:30][C:31](=[O:39])[CH2:32][C:33]3[S:34][C:35](=[O:38])[S:36][CH:37]=3)[C:14]=2[C:11]([O:13][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:12])=[N:25][N:26]=1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4csc(=O)s4)C3SC2)s1
Reactant: CC(C)(C)C(=O)OCI
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)C(NC(=O)Cc4csc(=O)s4)C3SC2)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47.2 %

Procedure:
Iodomethyl pivalate (2.66 g.) is added to a suspension of the potassium salt of 2-carboxy-3-[(2-methyl-1,3,4-thiadiazol-5-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene (5.18 g.) in dimethyl formamide (100 cc.) cooled to 0° C. The reaction mixture is stirred for 10 minutes at 5° C.; it becomes limpid and is poured into a decanting funnel containing ethyl acetate (100 cc.) and water (200 cc.). The organic phase is washed with a saturated sodium bicarbonate solution (100 cc.) and then with a saturated sodium chloride solution (100 cc.). The organic phase is dried over sodium sulphate, treated with decolourising charcoal, filtered and concentrated to dryness under reduced pressure (20 mm Hg). The residue (5 g.) is chromatographed on silica (80 g.). A product (4.5 g.) is eluted with a 70-30 by volume mixture of ethyl acetate and cyclohexane, and is crystallised from a mixture of ethyl acetate and cyclohexane (50-50 by volume) (60 cc.). 3-[(2-Methyl-1,3,4-thiadiazol-5-yl)-thiomethyl]-8-oxo-7-[(1,3-dithiol-2-on-4-yl)-acetamido]-2-pivaloyloxymethoxycarbonyl-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (3 g.) is thus obtained as white crystals m.p. approximately 110° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:18])=[C:5]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]2)[N:6]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C(O)C>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[S:3][C:4]([CH3:18])=[C:5]([CH2:7][N:8]3[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]3)[N:6]=2)[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(Br)sc2C)c1
Reactant: OB(O)c1cc(Cl)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3cc(Cl)cc(C(F)(F)F)c3)sc2C)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of the compound (230 mg, 0.71 mmol) obtained in Example 80e and 3-chloro-5-trifluoromethylphenylboronic acid (210 mg, 0.92 mmol) in 1,2-dimethoxyethane/ethanol (v/v=3/1, 4 mL) were added 2N aqueous sodium carbonate solution (0.71 mL, 1.4 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (60 mg, 0.071 mmol), and the mixture was stirred at 90° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=75/25) to give the title compound (230 mg, 76%) as colorless crystals.