Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N:12][CH:11]=[CH:10]2>ClCCl.C(OCC)C>[Cl:4][C:8]1[C:7]([OH:6])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[CH:13]2
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1ccc2cnccc2c1
Solvent: CCOCC
Solvent: ClCCl
Product: Oc1ccc2cnccc2c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.8 %

Procedure:
0.61 mL (1.02 g, 7.6 mmol) of sulfuryl chloride were added to a solution of 1.0 g (6.9 mmol) of compound 7 in 30 mL of dichloromethane. Three drops diethyl ether were added and the reaction was stirred at room temperature for 5 h. The solvents were removed by distillation and the remainder was treated with aqueous NaHCO3 solution. The precipitate was filtered, washed with water and dried to give 1.1 g (89%) of compound 8 as a green-yellow solid.
Reaction SMILES: [CH:1]([N:6]1[C:12](=[O:13])[O:11][C:9](=O)[C:8]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:7]12)=[CH:2][C:3](=[CH2:5])[CH3:4].[H-].[Na+].C(OCC)(=O)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[OH:11][C:9]1[C:8]2[C:7](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]([CH:1]=[CH:2][C:3](=[CH2:5])[CH3:4])[C:12](=[O:13])[C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C=C(C)C=Cn1c(=O)oc(=O)c2ccccc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: C=C(C)C=Cn1c(=O)c(C(=O)OCC)c(O)c2ccccc21

Procedure:
Reagents: Comp 18 (1.3 mmols, 0.3 g); Sodium hydride (1.3 mmols, 0.065 g); Diethyl malonate (6.5 mmols, 1.0 g). Yield: 0.08 g (21%), white solid, m.p.=123° C.-124° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.Cl.Cl.[NH2:57][CH2:58][CH:59]([N:64]1[CH2:69][CH2:68][N:67]([CH2:70][CH3:71])[CH2:66][CH2:65]1)[C:60]([O:62][CH3:63])=[O:61].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:70]([N:67]1[CH2:66][CH2:65][N:64]([C@@H:59]([CH2:58][NH:57][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)[C:60]([O:62][CH3:63])=[O:61])[CH2:69][CH2:68]1)[CH3:71]
Reactant: CCN1CCN(C(CN)C(=O)OC)CC1
Reactant: Cc1cc(COc2ccc(C(=O)O)cc2)c2ccccc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN([C@@H](CNC(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
0.6 g (2.1 mmol) of 4-(2-methylquinolin-4-ylmethoxy)benzoic acid are dissolved in 10 ml of dimethylformamide then 0.7 g (2.3 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate and 1.1 ml (6.3 mmol) of diisopropylethylamine are added. After stirring for 15 minutes at ambient temperature, a solution of 700 mg (2.1 mmol) of methyl 3-amino-2-(4-ethylpiperazin-1-yl)propanoate trihydrochloride and 1.1 ml (6.3 mmol) of diisopropylethylamine in 10 ml of dimethylformamide is added. The reaction medium is stirred at ambient temperature for 18 h then is hydrolysed with a saturated aqueous solution of sodium hydrogen carbonate. After extraction with ethyl acetate, the organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under vacuum. The product is purified by chromatography over silica gel eluted with a 93/7 dichloromethane/methanol mixture to give 840 mg (81%) of methyl (S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzoylamino]propanoate in the form of a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([NH2:22])[CH:21]=1>>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:20]([NH:22][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccccc3)ccnc2n1

Procedure:
The product from Example 2g (65 mg, 0.3 μmol) was reacted with the product from Example 1f (68 mg, 0.31 mmol) for 24 h following the procedure from Example 1g giving the title compound as a hydrochloride salt as a solid which was triturated with ether giving (10 mg, 84%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 2.38 (qnt, J=7.35 Hz, 2H) 2.99 (dd, J=7.35 Hz, J=7.72 Hz, 2H) 6.31 (d, J=7.35 Hz, 1H) 7.23 (s, 5H) 7.35 (m, 4H) 7.79 (d, J=8.46 Hz, 1H) 8.38 (d, J=6.98 Hz, 1H) 9.01 (d, J=8.46 Hz, 1H) 11.10 (s, 1H) 14.35 (br s, 1H); MS (ESI+) m/z 386 (M−Cl)+; (ESI−) m/z 384 (M−HCl)−.
Reaction SMILES: [F:1][C:2]([F:5])(O)[CH3:3].[CH3:6][C:7]1([CH3:25])[C@@H:9](/[CH:10]=[CH:11]\[C:12](=[O:14])[OH:13])[C@H:8]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)(Cl)Cl>[CH3:6][C:7]1([CH3:25])[C@@H:9](/[CH:10]=[CH:11]\[C:12](=[O:13])[O:14][CH2:3][CH:2]([F:5])[F:1])[C@H:8]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: CC(O)(F)F
Reactant: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)O
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)OCC(F)F

Procedure:
Using the procedure of Example 53, difluoro-ethanol and the product of Step B of Example 57 were reacted to obtain benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-(2,2-difluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+52° (c=0.2% in chloroform).
Reaction SMILES: ClC(OCC(C)C)=O.[CH3:9][C:10]1([C:15]([OH:17])=O)[CH2:14][S:13][S:12][CH2:11]1.C([N:20](CC)CC)C.N>C1COCC1.O.C(O)(C)C>[CH3:9][C:10]1([C:15]([NH2:20])=[O:17])[CH2:14][S:13][S:12][CH2:11]1
Reactant: CC1(C(=O)O)CSSC1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC1(C(N)=O)CSSC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
Alternatively, method (Ex. 5-b), 1.2 equivalents of isobutyl chloroformate are added, at 0° C., to a solution of 1 g of Compound 1 in THF with 1.2 equivalents of triethylamine. After 2 hours at room temperature, the reaction medium is added to a cooled solution of ammonia, either at 28% in water or at 2N in isopropanol. The medium is stirred at room temperature for the time required, and then concentrated under vacuum. The crude product is then taken up in toluene, to give Compound 2 after precipitation. Yield=60%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](C4C=CC=C(B5OC(C)(C)C(C)(C)O5)C=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Br[C:43]1[N:52]=[CH:51][C:50]2[O:49][CH2:48][N:47]([CH2:53][C:54]3[CH:59]=[CH:58][C:57]([F:60])=[CH:56][CH:55]=3)[C:46](=[O:61])[C:45]=2[CH:44]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:60][C:57]1[CH:58]=[CH:59][C:54]([CH2:53][N:47]2[C:46](=[O:61])[C:45]3[CH:44]=[C:43]([C:18]4[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[C:11]=5[CH:17]=4)[N:52]=[CH:51][C:50]=3[O:49][CH2:48]2)=[CH:55][CH:56]=1
Reactant: O=C1c2cc(Br)ncc2OCN1Cc1ccc(F)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cc4c(cn3)OCN(Cc3ccc(F)cc3)C4=O)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzofuran-3-carboxamide (134 mg, 0.27 mmol) and 6-bromo-3-(4-fluorobenzyl)-2H-pyrido[4,3-e][1,3]oxazin-4(3H)-one (75 mg, 0.22 mmol) in DMF (2 mL) were added Pd(dppf)Cl2 (18 mg, 0.02 mmol) and K3PO4 (331 mg, 0.66 mmol) under N2. After being stirred at 100° C. overnight, the reaction mixture was cooled to RT and filtered. The filtrate was washed with brine and dried over Na2SO4. After being concentrated, the residue was purified by prep-TLC (PE:EtOAc=1:1) to give the product of 5-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydro-2H-pyrido[4,3-e][1,3]oxazin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (80 mg, yield: 57%). 1H-NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 8.08 (s, 1H), 8.01˜7.97 (m, 3H), 7.69 (s, 1H), 7.35 (dd, J=6.0, 8.4 Hz, 2H), 7.20 (t, J=8.4 Hz, 2H), 7.08 (t, J=8.4 Hz, 2H), 5.91 (s, 1H), 5.23 (s, 2H), 4.77 (s, 2H), 3.27 (s, 3H), 3.01 (d, J=4.8 Hz, 3H), 2.85 (s, 3H). MS (M+H)+: 633.
Reaction SMILES: [OH:1][CH2:2][C:3](CO)(COCC(CO)(CO)CO)CO.C(OCC(CO)(COCC(CO)(CO)CO)CO)(=O)C.[C:38]([O:41][CH2:42][C:43]([CH2:59][OH:60])([CH2:49][O:50][CH2:51][C:52]([CH2:57][OH:58])([CH2:55][OH:56])[CH2:53][OH:54])[CH2:44][O:45][C:46](=[O:48])[CH3:47])(=[O:40])[CH3:39]>>[C:38]([O:41][CH2:42][C:43]([CH2:59][OH:60])([CH2:49][O:50][CH2:51][C:52]([CH2:55][OH:56])([CH2:57][OH:58])[CH2:53][O:54][C:2](=[O:1])[CH3:3])[CH2:44][O:45][C:46](=[O:48])[CH3:47])(=[O:40])[CH3:39]
Reactant: OCC(CO)(CO)COCC(CO)(CO)CO
Reactant: CC(=O)OCC(CO)(COCC(CO)(CO)CO)COC(C)=O
Agent: CC(=O)OCC(CO)(CO)COCC(CO)(CO)CO
Product: CC(=O)OCC(CO)(CO)COCC(CO)(COC(C)=O)COC(C)=O

Procedure:
In each of Runs 1 to 4 shown in Table 1 below, a mixture having a melting point of 70° to 92° C. and composed of dipentaerythritol, dipentaerythritol monoacetate, dipentaerythritol diacetate and dipentaerythritol triacetate was produced by melting the materials together.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]([C:21]([O:23][CH3:24])=[O:22])([CH3:20])[CH3:19])=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CO.[Cl-].[Na+].O>[CH3:24][O:23][C:21](=[O:22])[C:18]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[NH:8][CH:9]=1)([CH3:20])[CH3:19]
Reactant: COC(=O)C(C)(C)c1cn(C(=O)OC(C)(C)C)c2ccc(F)cc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)C(C)(C)c1c[nH]c2ccc(F)cc12
Yield: 53.1 %

Procedure:
A solution of 5-fluoro-3-(1-methoxycarbonyl-1-methyl-ethyl)-indole-1-carboxylic acid tert-butyl ester (5.2 mmol) in MeOH (25 mL) is treated with K2CO3 (720 mg, 5.2 mmol) and heated at reflux for 2 h. The mixture is diluted with brine (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 2-(5-fluoro-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (650 mg, 53%, 2 steps), which is used in the next step without further purification. MS: 236 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 7.35 (m, 1H), 7.30 (m, 1H), 7.14 (m, 1H), 6.91 (m, 1H), 3.54 (s, 3H), 1.57 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10](I)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C([Li])CCC.CCCCCC.C1(C)C=CC(S([C:32]#[N:33])(=O)=O)=CC=1>O1CCCC1>[Cl:1][C:2]1[C:10]([C:32]#[N:33])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: Clc1nn2ccccc2c1I
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1c(Cl)nn2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled −78° C. solution of the title compound from Example 1 Step A (0.20 g, 0.718 mmol) in tetrahydrofuran (3.59 ml) was added a solution of n-butyllithium in hexane (1.6 M, 0.494 ml, 0.790 mmol). After 5 minutes, p-toluenesulfonyl cyanide (0.169 g, 0.934 mmol) was added, and the resulting reaction mixture was allowed to warm to room temperature. After 18 hours, the mixture was concentrated under reduced pressure. Purification by column chromatography on silica gel (0-30% ethyl acetate in hexanes) provided the title compound: LCMS m/z 177.91 [M+H]+, 179.86 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J=6.9 Hz, 1 H), 7.70 (d, J=9.0 Hz, 1 H), 7.52 (dd, J=8.0, 8.0 Hz, 1 H), 7.26-7.20 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:15]=[C:14]([CH3:31])[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH:30][S:39]([C:36]3[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=3)(=[O:41])=[O:40])[N:15]=[C:14]([CH3:31])[N:13]=2)(=[O:9])=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(C)nc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(C)nc1OCCNS(=O)(=O)c1ccc(C)cc1

Procedure:
According to the procedure described in Example 4a) 94 mg 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with 4-methylbenzenesulfonylchloride to give 82 mg 5-methyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.86 min, [M+1]+=600.59, [M−1]−=598.55.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[Cl:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1>>[Cl:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:30][CH2:29]5)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:46])=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc(Cl)cc3)CN2C1=O
Yield: 54.9 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-chlorobenzoyl chloride (45 μL, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 68 mg (55%) of 18-(4-chlorobenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.5% pure (HPLC), MS m/z 705 (M−H)−, HRMS: calcd. 707.2518 and found 707.2499 (M+H)+, mp 143-145° C.
Reaction SMILES: C([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])C1C=CC=CC=1.[CH2:19]([O:21][C:22](=[O:28])[CH:23](Br)[CH:24]([CH3:26])[CH3:25])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([O:21][C:22](=[O:28])[CH:23]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[NH:8]2)[CH:24]([CH3:26])[CH3:25])[CH3:20]
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: CCOC(=O)C(Br)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1cccc2[nH]c(C)cc12)C(C)C

Procedure:
A mixture of 4-hydroxy-2-methylindole (1) (1.5 g, 0.010 mole), 2-bromo-3-methyl-butyric acid ethyl ester (2.2 g, 0.010 mole) and potassium carbonate (excess) in acetone (50 mL) was refluxed for 3 days. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (20:1 Hex:EtOAc) to afford intermediate 2. Yield: 1.88 g, 71%
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=2)[C:10]([I:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:23]=C=NCCCN(C)C.Cl>CN(C=O)C>[C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=[C:10]2[I:20])(=[O:18])[NH2:23]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cc(C(=O)O)ccc21
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(I)c2cc(C(N)=O)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To solution of 1-(tert-butoxycarbonyl)-3-iodo-1H-indole-5-carboxylic acid (1 g, 2.57 mmol) in DMF (10 mL) at 0° C. was added EDC.HCl (741 mg, 3.86 mmol) and HOBT-NH3 complex (825 mg, 5.15 mmol). The reaction mixture was stirred at RT for 3 h and then extracted with DCM (15 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by column chromatography to obtain title compound as an off white solid (550 mg, 50%). MS (ESI, Neg. ion) m/z: 286.9 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][CH2:5][C:4]([C:8](=[O:32])[NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C(=O)C(C)(C)C)=[C:14]([O:25][C:26](=O)C(C)(C)C)[CH:13]=2)=[CH:3]1.[2H]C(Cl)(Cl)Cl.[2H]O[2H]>>[CH3:1][N:2]1[CH:7]=[CH:6][CH2:5][C:4]([C:8](=[O:32])[NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:25][CH3:26])[CH:13]=2)=[CH:3]1
Reactant: CN1C=CCC(C(=O)NCCc2ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c2)=C1
Agent: [2H]C(Cl)(Cl)Cl
Agent: [2H]O[2H]
Product: COc1cc(CCNC(=O)C2=CN(C)C=CC2)ccc1O

Procedure:
This compound was prepared following the same method as for the preparation of compound 5c. The crude solid obtained showed the same NMR (CDCl3 /D2O) pattern as compound 5a, except for a peak at 6 3.5 for the OCH3 protons. It was sufficiently pure for the determination of its retention time following the HPLC method of analysis detailed in Example 37 below. No trials were made for its further crystallization or elemental analysis.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:31]([O:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH3:32]>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:37][CH2:36][CH2:35][CH2:34][O:33][CH2:31][CH3:32])=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CCOCCCN
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Agent: Cl
Product: CCOCCCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1

Procedure:
50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)benzoic acid hydrochloride (Example 75) and 20.1 mg (0.23 mmol) of 3-ethoxypropylamine are reacted together by general method E. 23.4 mg (37.1% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][CH:2]([N:11]([C:13]([CH2:15][NH2:16])=[O:14])[CH3:12])[CH:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[C:22]1([CH2:28][CH2:29][CH2:30]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C1COCC1.CCOC(C)=O>[OH:10][C@@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C@@H:2]([N:11]([CH3:12])[C:13](=[O:14])[C@H:15]([NH2:16])[CH2:30][CH2:29][CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:1]
Reactant: BrCCCc1ccccc1
Reactant: CC(C(O)c1ccccc1)N(C)C(=O)CN
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]([C@@H](O)c1ccccc1)N(C)C(=O)[C@H](N)CCCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of pseudoephedrine glycinamide (1.5 g, 6.75 mmol), prepared and used by the method of Myers et al. (J. Am. Chem. Soc. 1997, 119, 656), and LiCI (1.71 g, 40.5 mmol) in THF (30 mL) was cooled to −78° C. and n-BuLi was added (13.16 mmol, 5.25 mL of a 2.5 M solution). After stirring for 20 min at −78° C., the reaction was warmed to 0° C. and stirred an additional 20 minutes. 3-Phenyl-1-bromopropane (1.3 mL, 7.42 mmol) was added and the reaction was stirred for 2 h at 0° C. Aqueous 1 N HCl (50 mL) and EtOAc (50 mL) were added, the organic phase was separated and extracted with 1 N HCl (50 mL). The aqueous extracts were combined, cooled in an ice bath and slowly basified to pH 14 with 6 N NaOH. The product was extracted with CH2Cl2 (4×50 mL) and the combined extracts were dried over MgSO4 and concentrated to give a yellow oil. Purification by flash chromatography (SiO2 gel, 92:4:4, CH2Cl2:MeOH:triethylamine) delivered 400 mg (78%) of the Product of Example 199, Step A: +APcI MS (M+1)+ 341; 1H NMR=400 MHz (CDCl3) δ: 7.38 (m, 10H), 5.26 (m, 1H), 4.15 (m, 1H), 3.86 (m, 1H), 2.36 (s, 3H).
Reaction SMILES: O[CH:2]([C:12]1[CH:13]=[C:14]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:15]([NH:17][C:18]1([C:27]([OH:29])=[O:28])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:16])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.Cl.[H][H]>C(O)C.CO.[Pd]>[CH3:34][O:33][C:32]1[CH:31]=[CH:30][C:14]([C:15]([NH:17][C:18]2([C:27]([OH:29])=[O:28])[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:26]2)=[O:16])=[CH:13][C:12]=1[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1C(O)COc1cccc(C)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1CCOc1cccc(C)c1

Procedure:
The compound of example 114 (20 mg, 0.043 mmol) was dissolved in ethanol (2 ml), a 0.5 M solution of hydrogen chloride in methanol (0.2 ml) was added and the mixture was hydrogenated overnight in the presence of palladium on charcoal (10%) at room temperature at a hydrogen pressure of 5 bar (complete conversion of the starting compound). After filtration over a small plug of silica gel and evaporation, the residue was purified by preparative RP HPLC (water/ACN gradient).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH:14]([CH2:17][C:18](OCC)=[O:19])[NH:13][C:12]=2[CH:23]=1.C(=O)=O.[OH-].[Na+]>O1CCCC1.O.CC(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH:14]([CH2:17][CH2:18][OH:19])[NH:13][C:12]=2[CH:23]=1
Reactant: CCOC(=O)CC1COc2ccc(Cl)cc2N1
Agent: O=C=O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: OCCC1COc2ccc(Cl)cc2N1
Reaction time: 1.5 h
Yield: 132.3 %

Procedure:
150 ml of tetrahydrofuran are placed in a 1 litre reactor which is cooled with a mixture of ice and salt, and, under an argon atmosphere, 5.92 g (0.156 mol) of lithium aluminium hydride are added, followed by dropwise addition of 23.52 g (0.0973 mol) of ethyl (±)-6-chloro-3,4-dihydro-2H-1,4-benzoxazine-3-acetate dissolved in 150 ml of tetrahydrofuran, and the mixture is stirred for 1.5 hours. The reactor is cooled with a mixture of cardice and acetone, 40 ml of water and 20 ml of 1N sodium hydroxide are added dropwise and the mixture is stirred for 0.5 hour. The precipitate is filtered on kieselgel and rinsed with tetrahydrofuran and then with ethyl acetate, and the solvent is evaporated off. 27.5 g of crude product are isolated, which product is purified by chromatography on a column of silica gel, eluting with a cyclohexane/ethyl acetate (1/1 ratio) mixture.