Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C[C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:16]3[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[CH:12]=[CH:13][C:14]=2[Cl:15])=[CH:5]C=1.Cl.ClC1C=CC([C:43]2[N:48]=[C:47](C(O)=O)C=CC=2C2C=CC=CC=2Cl)=CC=1OCCCN(C)C>>[Cl:15][C:14]1[CH:13]=[CH:12][C:11]([C:16]2[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])=[CH:10][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][N:48]([CH3:43])[CH3:47]
Reactant: COC(=O)c1ccc(-c2ccccc2Cl)c(-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)n1
Reactant: CN(C)CCCOc1cc(-c2nc(C(=O)O)ccc2-c2ccccc2Cl)ccc1Cl
Agent: Cl
Product: COC(=O)c1ccc(-c2ccccc2Cl)c(-c2ccc(Cl)c(OCCCN(C)C)c2)n1

Procedure:
According to the debenzylation/O-alkylation/saponification sequence described in Examples 1.7, 1.8 and 1.9, respectively, starting with 665 mg (1.35 mmol) of methyl 6-[3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]-5-(2-chlorophenyl)pyridine-2-carboxylate, 181 mg of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridine-2-carboxylic acid hydrochloride are obtained in the form of a gum.
Reaction SMILES: [CH3:1][C:2]([NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])([CH3:35])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]([OH:33])=O)=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[C:8]1=[O:34])=[O:5].[CH2:47]([NH2:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[C:48]1([CH2:47][NH:54][C:31]([C:26]2[C:25]([C:22]3[CH:21]=[CH:20][C:19]([CH2:18][N:9]4[C:10]5[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=5[CH2:12][CH2:13][C@@H:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([NH:36][C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])([CH3:1])[CH3:35])[C:8]4=[O:34])=[CH:24][CH:23]=3)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:33])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)O)cc2)C1=O)NC(=O)OCc1ccccc1
Reactant: NCc1ccccc1
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)NCc3ccccc3)cc2)C1=O)NC(=O)OCc1ccccc1

Procedure:
The title compound was prepared from 4'-[[2,3,4,5-tetrahydro-3(R)-[[3-methyl-1-oxo-3-[(benzyloxycarbonyl)amino]butyl]amino-]-2-oxo-1H-1-benzazepin-1yl]methyl][1,1'-biphenyl]-2-carboxylic acid (Example 72, Step B) and benzylamine according to the procedure described in Example 74, Step A. 1H NMR (200 MHz,CDCl3): 1.31 (s,3H), 1.35 (s,3H), 1.75 (m,1H), 2.30-2.65 (m,5H), 4.23 (d,5 Hz,2H), 4.47 (m,1H), 4.83 (d,14 Hz,1H), 5.02 (s,2H), 5.45 (m,1H), 5.60 (s,1H), 6.68 (d,6Hz,1H), 6.90 (m,2H), 7.10-7.50 (m,20H), 7.65 (m,1H). FAB-MS: calculated for C44H44N4O5 708; found 709 (M+H), 731 (M+Na, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[Cl:25])[CH2:17]2)=[O:15])[CH2:10][C@H:9]1[C:26](O)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH2:31][C@:32]1([C:37]([NH:39][S:40]([CH:43]2[CH2:45][CH2:44]2)(=[O:42])=[O:41])=[O:38])[CH2:34][C@H:33]1[CH2:35][CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.OS([O-])(=O)=O.[K+]>C(Cl)Cl.O>[Cl:25][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH2:24][N:16]([C:14]([O:13][C@@H:11]1[CH2:10][C@@H:9]([C:26](=[O:27])[NH:31][C@:32]3([C:37](=[O:38])[NH:39][S:40]([CH:43]4[CH2:45][CH2:44]4)(=[O:42])=[O:41])[CH2:34][C@H:33]3[CH2:35][CH3:36])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12]1)=[O:15])[CH2:17]2
Reactant: CC[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OC(=O)N2Cc3cccc(Cl)c3C2)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
(2S,4R)-1-(tert-butoxycarbonyl)-4-(4-chloroisoindoline-2-carbonyloxy)pyrrolidine-2-carboxylic acid (0.93 g, 2.26 mmol), (1R,2R)-1-amino-N-(cyclopropylsulfonyl)-2-ethylcyclopropanecarboxamide dihydrochloride (0.64 g, 2.38 mmol) and HATU (0.79 g, 2.078 mmol) in DCM (20 mL) was added DIEA (1.18 ml, 6.79 mmol) and the reaction was stirred at rt for 18 hours. H2O (10 mL) was added and acidified with saturated KHSO4 until PH=3˜4. The mixture was extracted with ether (30 mL), washed with brine and dried over sodium sulfate. After removal of solvent, it gave (3R,5S)-1-(tert-butoxycarbonyl)-5-((1R,2R)-1-(cyclopropylsulfonylcarbamoyl)-2-ethylcyclopropylcarbamoyl)pyrrolidin-3-yl 4-chloroisoindoline-2-carboxylate (1.36 g, 96%) as a white solid, which was used directly for the next step without purification. LCMS (APCI+): 525.1 (MH+−Boc).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][N:6]([CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:7]([NH:9][N:10]1[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]1=[O:12])=[O:8])C.[OH-].[Na+].Cl>C(O)C>[C:25]([O:24][C:22]([NH:21][CH2:20][CH2:19][N:6]([C:7]([NH:9][N:10]1[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]1=[O:12])=[O:8])[CH2:5][C:4]([OH:29])=[O:3])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)Nn1cc(C)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cn(NC(=O)N(CCNC(=O)OC(C)(C)C)CC(=O)O)c(=O)[nH]c1=O
Reaction time: 6 h

Procedure:
The product from Example 6, 9, is dissolved in ethanol (500 mL) and 2M sodium hydroxide (50 mL) is added. The reaction is stirred for 6 hours, then neutralized with 50 mL of 2M HCl solution, and evaporated to remove the ethanol. The residue is dissolved in dichloromethane (250 mL) and is extracted with water (2×50 mL), dried, filtered, and evaporated to a solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)=[O:13])(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: NCCCNC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.4 g (18.9 mmol) of {3-[3-(3-nitro-phenyl)-ureido]-propyl}-carbamic acid-tert-butyl ester is mixed with 22 ml of trifluoroacetic acid and stirred for 2 hours at room temperature. The solvent is drawn off, the batch is mixed with NaHCO3 solution and extracted from ethyl acetate. The combined organic phases are filtered through a Whatman filter and concentrated by evaporation. 4.4 g (18.5 mmol, corresponding to 97% of theory) of the product is obtained.
Reaction SMILES: [C:1]([C:9]1[CH:25]=[CH:24][C:12]([CH2:13][N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3N)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26]C1N=CN=C2C=1NC=N2.C(C1C=CC(CCl)=CC=1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]([C:9]1[CH:25]=[CH:24][C:12]([CH2:13][N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[Cl:26])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnc2c1ncn2Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: Clc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: O=C(c1ccccc1)c1ccc(CCl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)c1ccc(Cn2cnc3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
The synthesis of 9-(4-benzoylbenzyl) -9H-adenine (20) was achieved by the following procedure (Scheme 9). A mixture of 6-chloropurine (3.09 g, 20 mmol), 4-benzoyl-benzyl chloride (6.05 g, 22 mmol)and K2CO3 (3.04 g, 22 mmol) in DMF (50 ml) was stirred overnight at rt, diluted with water (400 ml), and extracted with EtOAc (3×100 ml) (Scheme 9)52. The combined organic layers were washed with water and brine, dried over MgSO4, concentrated in vacuo, and subjected to flash-chromatography on silica gel eluting with CH2Cl2 -acetone (80:20). The fractions containing the higher Rf, the major component, were combined and concentrated in vacuo to give 2.86 g (41%) of 9-(4-benzoylbenzyl)-6-chloro-9H-purine. To a solution of this iminochloride (1.05 g, 3 mmol) in EtOH (20 ml) was added a 2M solution of NH3 in MeOH. This medium was warmed overnight at 90° C. under pressure (constant volume). It was then cooled and concentrated in vacuo. The residue was washed successively with a 1M solution of NaHCO3, water, iPrOH, and hot CH2Cl2, and then was recrystallized from butanol to give 0.53 g (54%) of 9-(4-benzoylbenzyl)-9H-adenine (20). 1H NMR (DMSO) δ 5.49 (s, 2H, CH2), 7.27-7.71 (m, 9H, H-Ar), 8.15 (s, 1H, H-2), 8.30 (s, 1H, H-8). ##STR10## Synthesis of 9-[(4-bis-phenyl)buten-4-yl]-9H-adenine (21)
Reaction SMILES: [O:1]1CCO[CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[O:27][C:28](=[O:30])[CH3:29])=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7]>CC(C)=O.Cl(O)(=O)(=O)=O>[C:28]([O:27][C@@H:19]1[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[CH:6]([CH:2]=[O:1])[CH3:7])[CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18]1)(=[O:30])[CH3:29]
Reactant: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(C)=O
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Yield: 44.1 %

Procedure:
In 10 ml of acetone was dissolved 100 mg of 20-(1,3-dioxolan-2-yl)-1α-acetoxy-3β-(methoxymethyl)oxypregna-5,7-diene, followed by addition of one drop of 70% perchloric acid, and the mixture was refluxed in an atmosphere of argon gas for 2 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 40 mg of 1α-acetoxy-3β-(methoxymethyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: C(OC(=O)C)(=O)C.[Br:8][C@@:9]1([O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:21]([F:29])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]1[O:12][C:13](=[O:15])[CH3:14])[OH:10]>N1C=CC=CC=1>[Br:8][C@@:9]1([O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@H:21]([F:29])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]1[O:12][C:13](=[O:15])[CH3:14])[OH:10]
Reactant: CC(=O)OC[C@H]1O[C@@](O)(Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1F
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@](O)(Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1F
Yield: 44 %

Procedure:
100 mg (0.55 mmol) of 3 are reacted with 3.5 ml of pyridine and 3.5 ml of acetic anhydride in analogy to the preparation of compound 2. 89 mg (44%) of 4 are obtained as an amorphous solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([C:30](=[NH:33])[NH:31][OH:32])[CH:27]=[CH:26][C:25]=4[CH3:34])=[CH:20][CH:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH:36]1([C:39](Cl)=O)[CH2:38][CH2:37]1>>[O:35]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[C:28]([C:30]5[N:33]=[C:39]([CH:36]6[CH2:38][CH2:37]6)[O:32][N:31]=5)[CH:27]=[CH:26][C:25]=4[CH3:34])=[CH:22][CH:23]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(C(=N)NO)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Product: Cc1ccc(-c2noc(C3CC3)n2)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1

Procedure:
5′-(N-Hydroxycarbamimidoyl)-2′-methyl-biphenyl-4-carboxylic acid [4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (50 mg) and cyclopropylcarbonyl chloride (0.02 ml) was heated in a microwave at 150 C for 40 min. The solvent was then evaporated and the residue purified on silica gel. Gradient elution with 0-30% 20:8:1 CH2Cl2/EtOH/NH3 in CH2Cl2 gave the title compound as a white solid (24 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:10][C:11]1[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14])(=[O:9])[CH3:8].Cl.C([O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:28])C>C(N(CC)CC)C>[C:7]([O:10][C:11]1[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:12]=1[C:13]([NH:28][C@H:27]([C:26]([OH:36])=[O:25])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:14])(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1c(Cl)cc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(Cl)cc(Cl)cc1C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
In one non-limiting example of a synthesis method for N-(2-hydroxy-3,5-dichlorobenzoyl)-L-phenylalanine, synthesis begins with reaction of 3,5-dichlorosalicylic acid with acetic anhydride to obtain 2-acetoxy-3,5-dichlorobenzoic acid which in turn is converted into the acid chloride by the action of oxalyl chloride. The 2-acetoxy-3,5-dichlorobenzoic acid chloride is then reacted in situ with phenylalanine ethyl ester hydrochloride, in the presence of triethylamine, to yield ethyl ester of N-(2-acetoxy-3,5-dichlorobenzoyl)-L-phenylalanine. The last step of the synthesis method introduces novel and highly specific hydrolysis of both ester functions of N-(2-acetoxy-3,5-dichloro benzoyl)-L-phenylalanine ethyl ester to obtain the OTA template, N-(2-hydroxy-3,5-dichlorobenzoyl)-L-phenylalanine (I) with 98% yield. This synthesis reaction is summarized in FIG. 2.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[C:12]([F:13])=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[F:15])([CH3:6])([CH3:5])[CH3:4].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18](=[O:19])[CH2:17][O:14][C:10]1[CH:9]=[C:8]([F:15])[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[C:12]([F:13])[CH:11]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)c1c(F)cc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1cc(F)c(C(C)(C)C)c(F)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a suspension of sodium hydride (75 mg, 1.9 mmol) in THF (5 ml) was added 4-tert-butyl-3,5-difluorophenol (290 mg, 1.6 mmol) at 0° C., followed by stirring for 30 minutes. Then, tert-butyl bromoacetate (370 mg, 1.9 mmol) was added and the mixture was refluxed at 90° C. for 1 hour. The reaction was quenched with saturated ammonium chloride aqueous solution and the product was extracted with EtOAc, washed with brine, dried over magnesium sulfate. Then, filtration, evaporation, and purification through silica gel column chromatography eluting with hexane/EtOAc (20:1 to 4:1) gave the tert-butyl(4-tert-butyl-3,5-difluorophenoxy)acetate (403 mg, 86%). The DCM (2.0 ml) solution of tert-butyl(4-tert-butyl-3,5-difluorophenoxy)acetate (400 mg, 1.34 mmol) and TFA (2.0 ml), was stirred for 1 hour at room temperature. Evaporation gave the residue which was triturated with Hexane to furnish the title compound as a white solid (253 mg, 77%). 1H NMR (300 MHz, CDCl3): δ 1.42 (9H, t, J=2.2 Hz), 4.63 (2H, s), 6.39 (2H, d, J=12.1 Hz). MS (ESI) m/z 243 (M−H)−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:13][CH2:14][C:15]([F:18])([CH3:17])[CH3:16])[CH3:12])=[CH:2]1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=1)=O>C1(C)C=CC=CC=1>[F:18][C:15]([CH3:17])([CH3:16])[CH2:14][N:13]1[C@H:11]([CH3:12])[CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]=2[C@H:19]1[C:21]1[CH:22]=[CH:23][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:26]=1
Reactant: C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(C)F
Reactant: COC(=O)/C=C/c1ccc(C=O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2CC(C)(C)F)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine (obtained as described in Example 1, preparation of starting materials) (450 mg, 1.81 mmol) and (E)-methyl 3-(4-formylphenyl)acrylate (345 mg, 1.81 mmol) were dissolved in toluene (15 ml) acetic acid (5 ml) and molecular sieves were added. The reaction was stirred at 110° C. for 16 hours under nitrogen then cooled to room temperature. The crude product was purified by ion exchange chromatography, using an SCX-2 column. The desired product was eluted from the column using 7M NH3/methanol and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (317 mg, 41.6%) as a yellow solid. 1H NMR (400 MHz, CDCl3, 30° C.) δ 1.09 (3H, d), 1.30 (3H, d), 1.47 (3H, d), 2.48-2.78 (4H, m), 3.30 (1H, m), 3.79 (3H, s) 5.09 (1H, s) 6.40 (1H, d), 7.12 (1H, td), 7.17 (1H, td), 7.29 (1H, d), 7.34 (2H, d), 7.43 (2H, d), 7.54 (1H, d), 7.66 (2H, nm). m/z: ES+ [M+H]+ 421.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18](=[O:20])[CH3:19])[CH2:13][C:12]=3[C:21](=[O:23])[O:22][C:4]=2[CH:3]=1.[H][H]>CN(C)C=O.[Ni]>[NH2:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]2[O:22][C:21](=[O:23])[C:12]3[CH2:13][N:14]([CH2:17][C:18](=[O:20])[CH3:19])[CH2:15][CH2:16][C:11]=3[C:5]=2[CH:6]=1
Reactant: [H][H]
Reactant: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c([N+](=O)[O-])cc23)C1
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c(N)cc23)C1
Yield: 70.5 %

Procedure:
A solution of 1,2,3,4-tetrahydro-8-methyl-9-nitro-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (17.2 g, 0.054 moles) in N,N-dimethylformamide (300 ml) is hydrogenated at 50 psi at 24° C. in the presence of Raney Nickel until the required amount of hydrogen has been taken up. The catalyst is filtered off and rinsed with hot N,N-dimethylformamide until free of organic material. The filtrate is slightly concentrated and cooled to give the product (10.9 g), mp 196°-198° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:16]([OH:18])=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:16]([OH:18])=[O:17])=[O:11]
Reactant: Cc1cc(CO)cc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C=O)cc(C(=O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
In a 1 liter 4-necked round-bottomed flask were placed 500 ml of methylene chloride and cooled down to -78° C. 41.3 g (0.33 mole) of oxalyl chloride were added slowly, followed by dropwise addition of 56.4 g (0.72 mole) of dry dimethylsulfoxide in 30 ml of methylene chloride, all the while keeping the temperature below -70° C. After the addition was completed the reaction mixture was stirred at -78° C. for 30 minutes and 60 g (0.36 mole) of the previously prepared 3-hydroxymethyl-5-methylbenzoic acid were added in 1 portion, followed by dropwise addition of 131.4 g (1.3 mole) of triethylamine, keeping the temperature below -65° C. during each of the additions. The reaction mixture was then warmed up slowly to room temperature, stirred for 90 minutes and then washed with 2% aqueous sodium hydroxide (3×500 ml). The combined basic layers were washed with hexane once and acidified with concentrated hydrochloric acid and then extracted with ethyl acetate (4×500 ml). The combined organic layers were washed with water (1×500 ml) and then with brine (1×300 ml) and dried over anhydrous magnesium sulfate. The solvent was then eliminated in a rotavap. The resulting oily product was triturated with hexane and filtered yielding 52 g (88%) 3-formyl-5-methylbenzoic acid as a tan solid.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N:27]1[CH2:28][CH2:29][N:30]([C:9]([C:8]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=2[N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:10])[CH2:31][CH2:32]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc(F)cc2F)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 2-Morpholin-4-yl-5-nitro-benzoyl chloride and 1-(2,4-difluorophenyl)-piperazine (87%, yellow solid, MS (m/e): 433.4 (M+H, 100%)
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:9]([C:10]([CH3:15])=[C:11]([CH3:14])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.C1COCC1>[CH3:14][C:11]1[CH:12]=[C:13]2[N:9]([C:10]=1[CH3:15])[CH:8]=[CH:7][CH:6]=[C:5]2[CH2:3][OH:2]
Reactant: COC(=O)c1cccn2c(C)c(C)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc2c(CO)cccn2c1C
Reaction time: 0.5 h

Procedure:
A solution of the 2,3-dimethyl-indolizine-8-carboxylic acid methyl ester (265 mg, 1.3 mmol) in ether (10 ml) was cooled to 0° C. and treated with LAH (1.0M in THF, 1.6 ml, 1.6 mmol, dropwise addition). After 3.5 h the reaction was quenched with sodium sulfate decahydrate (added in small portions until gas evolution ceased). The resulting mixture was stirred for 0.5 h and the precipitated solids were removed via filtration and washed with EtOAc. The combined filtrates were concentrated to give the product which was used without further purification.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH3:11])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[N:20]2[CH2:23][C:22](=[CH:24][S:25]([CH2:28][C:29]3[CH:30]=[C:31]([N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:32]=[CH:33][CH:34]=3)(=[O:27])=[O:26])[CH2:21]2)=[CH:15][CH:14]=1>C(OCC)(=O)C.O>[CH3:11][O:10][C:8]([N:38]1[CH2:39][CH2:40][N:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][S:25]([CH:24]=[C:22]3[CH2:21][N:20]([CH:19]([C:16]4[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=4)[C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=4)[CH2:23]3)(=[O:26])=[O:27])[CH:30]=2)[CH2:36][CH2:37]1)=[O:9]
Reactant: COC(=O)Cl
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 6 h
Yield: 103.2 %

Procedure:
2 cm3 of pyridine and then 10.4 mg of methyl chloroformate are successively added, at a temperature close to 20° C., to 54.25 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 6 hours at a temperature close to 20° C., the reaction medium is concentrated to dryness under reduced pressure (5 kPa) at a temperature close to 30° C. The residue obtained is taken up in 5 cm3 of ethyl acetate and 5 cm3 of water. After separating after settling out, the organic phase is washed with 2 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 62 mg of 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid methyl ester are thus obtained in the form of a beige lacquer [1H NMR spectrum (400 MHz, CDCl3), δ in ppm): 2.75 (s, 3H), 3.15 (broad t, J=5.5 Hz, 4H), 3.62 (mt, 4H), 3.74 (s, 3H), 3.80 (mt, 2H), 4.32 (mt, 2H), 4.49 (s, 1H), 6.81 (d, J=8 Hz, 1H), 6.90 (dd, J=8 and 2.5 Hz, 1H), 6.99 (broad s, 1H), from 7.20 to 7.40 (mt, 9H)].