Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([C:14]2[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[C:17]([Cl:24])=[CH:16][C:15]=2[F:25])[C:4](=[O:13])[C:5]([F:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH3:26][O-:27].[Na+]>CO>[Cl:24][C:17]1[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:19][C:14]([N:3]2[C:4](=[O:13])[C:5]([F:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=[C:2]2[O:27][CH3:26])=[C:15]([F:25])[CH:16]=1
Reactant: C[O-]
Reactant: CC(C)Oc1cc(-n2c(Cl)nc(C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(F)(F)F)c(F)c(=O)n1-c1cc(OC(C)C)c(Cl)cc1F

Procedure:
using 2-chloro-1-(4-chloro-2-fluoro-5 -isopropoxyphenyl)-5-fluoro-4-trifluoromethyl-6(1H)-pyrimidinone and sodium methylate in methanol there is obtained 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5 -fluoro-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 144°-146° C.;
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7][C:6]([NH:11][CH3:12])([C:9]#N)[CH2:5][CH2:4]1>C(OCC)C>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:3]2([N:2]([CH3:21])[CH3:1])[CH2:4][CH2:5][C:6]([NH:11][CH3:12])([C:9]3[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=3)[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CNC1(C#N)CCC(c2ccc(OC)cc2)(N(C)C)CC1
Solvent: CCOCC
Product: CNC1(c2ccccc2)CCC(c2ccc(OC)cc2)(N(C)C)CC1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
Phenyl lithium (12.9 mL, 23.3 mmol, 1.8 M solution in dibutyl ether) was provided in argon and mixed in drops with a solution of the title compound from step 3 (2.23 g, 7.76 mmol) in abs. diethyl ether (30 mL) at RT. During this, the reaction solution heated to 35° C. and a solid separated out. The reaction mixture was stirred for 1 h with reflux (bath 50° C.), then hydrolysed in the ice bath (0-10° C.) with 20% NH4Cl solution (20 mL) and the organic phase was separated. The aqueous phase was extracted with ether (3×50 mL). The combined organic solutions were dried over Na2SO4 and concentrated to low volume in a vacuum. By means of flash chromatography (100 g silica gel) with ethyl acetate/methanol (20:1→9:1→MeOH→MeOH+2% NH3) the non-polar diastereoisomer was obtained in a mixed fraction with starting substance and ketone and lastly the polar diastereoisomer. The mixed fraction with non-polar diastereoisomer was purified again by flash chromatography with dichloromethane/methanol (50:1→20:1→9:1→4:1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[NH:33]1[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35][CH2:34]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:33]2[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35][CH2:34]2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: OC1CCNCC1
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(N5CCC(O)CC5)c([N+](=O)[O-])c4)s3)cc2)CC1

Procedure:
This compound was prepared from the compound of Example 15 and 4-piperidinol (Aldrich) by the procedure used in Example 57. Mass spectrum (ES) MH+=538.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[F:14][C:15]([S:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])([F:17])[F:16]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([S:18][C:15]([F:17])([F:14])[F:16])[CH:20]=1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccc(SC(F)(F)F)c1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc(SC(F)(F)F)c1
Yield: 66 %

Procedure:
The title compound (1.26 g, 3.3 mmol) was prepared from 2-nitrobenzenesulfonyl chloride (1.1 g, 5.0 mmol) and 3-[(trifluoromethyl)sulfanyl]aniline (1.06 g, 5.5 mmol) using the methods of (IntA1), step 1.
Reaction SMILES: [H-].[Na+].C(O)(=O)C(O)=O.[CH3:9][N:10]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]2[CH:22]=[CH:21][C:20](C(F)(F)F)=[CH:19][CH:18]=2)[C@H:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:11]1.[F:33]C1C=CC(F)=CC=1>CN(C=O)C>[F:33][C:20]1[CH:21]=[CH:22][C:17]([O:16][C@@H:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][C@H:12]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:18][CH:19]=1
Reactant: CN1CC[C@@H](Oc2ccc(C(F)(F)F)cc2)[C@H](c2ccccc2)C1
Reactant: Fc1ccc(F)cc1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A mixture of 0.6 g of sodium hydride, 3.83 g of sodium hydride, 3.83 g of trans-1-methyl-3-phenyl-4-piperidinol of Example 1 and 30 ml of anhydrous DMF is heated to 90° C. for 1.5 hours, then cooled to room temperature. A solution of 2.85 g of p-difluorobenzene in 20 ml of DMF is added all at once; the mixture is stirred at 70°-80° C. under nitrogen for 48 hours. The mixture is cooled and partitioned between ether and saturated aqueous NaCl solution. The aqueous phase is extracted with ether, and the combined ether extracts are washed with water and saturated aqueous NaCl solution and then concentrated in vacuo to an oil. This material is dissolved in 200 ml of dichloromethane, and the solution is extracted with 2 N HCl solution. The dichloromethane phase is successively washed with 10% aqueous NaOH solution, water, saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo to afford an oil which crystallizes upon standing. This material is chromatographed on silica gel, using acetone and then 25% methanol/acetone as solvent to obtain trans-4-(4-fluorophenoxy)-1-methyl-3-phenylpiperidine, m.p. s 67°, 69.5°-71.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23].[CH3:28][NH:29][CH:30]([CH3:32])[CH3:31]>ClCCCl>[Cl:1][C:2]1[C:3]([S:22]([NH:25][C:26]([N:29]([CH:30]([CH3:32])[CH3:31])[CH3:28])=[O:27])(=[O:24])=[O:23])=[CH:4][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[C:6]([F:8])[CH:7]=1
Reactant: CNC(C)C
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S(=O)(=O)N=C=O)c(Cl)cc2F)c1=O
Solvent: ClCCCl
Product: CC(C)N(C)C(=O)NS(=O)(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
With stirring, 1.0 g (2.34 mmol) of 2-chloro-4-fluoro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-(2H)-pyrimidin-1-yl]benzenesulfonyl isocyanate in 1,2-dichloroethane was added to a solution of 0.34 g (4.68 mmol) of N-methylisopropylamine in 1,2-dichloroethane, and the mixture was stirred overnight. The reaction mixture was concentrated, the residue was taken up in methylene chloride and 0.5N hydrochloric acid was added. The organic phase was then dried and the solvent was removed. This gave 0.5 g (42% of theory) of the title compound as a colorless solid (m.p.: 145° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=3)[C:10]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[N:32]1[CH:37]=[CH:36][CH:35]=[N:34][C:33]=1[C:38](=[O:40])[CH3:39]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:38]([OH:40])([C:33]4[N:34]=[CH:35][CH:36]=[CH:37][N:32]=4)[CH3:39])[CH:15]=3)[C:10]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccc2c(C(=O)N(C)C)nn(-c3ccnc(N)n3)c2c1
Reactant: CC(=O)c1ncccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)c3ncccn3)ccc12
Temperature: 25 °C

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-ethynyl-N,N-dimethylindazole-3-carboxamide (80 mg, 0.217 mmol) in THF (1.0 mL) at −78° C. under nitrogen was added 2M LDA in THF (0.27 mL, 0.54 mmol). After 5 minutes 1-pyrimidin-2-yl-ethanone (79 mg, 0.65 mmol) in THF (0.5 mL) was added and the reaction was allowed to warm to RT after 20 minutes. After a further 30 minutes the reaction mixture was quenched by addition of saturated aqueous NH4Cl (0.5 mL). The volatiles were removed in vacuo and the mixture was diluted with DCM (10 ml) and washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage, 0-2% methanol in DCM). Trituration of the partially purified product from EtOAc-heptane gave the title compound: 1H NMR (250 MHz, MeOD) delta 1.93-2.02 (3H, m), 3.22 (3H, s), 3.41 (3H, s), 7.24 (1H, d, J=5.79 Hz), 7.40-7.55 (2H, m), 7.97 (1H, d, J=8.38 Hz), 8.29 (1H, d, J=5.79 Hz), 8.88 (2H, d, J=5.03 Hz), 9.12 (1H, s); LC-MS: m/z=+429.45 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:26])[CH:9]2[CH2:25][CH2:24][C:12]3([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:28][N:29]1[C:37]([CH3:38])=[C:36]2[C:31]([CH:32]=[C:33]([NH2:39])[CH:34]=[CH:35]2)=[N:30]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:28][N:29]1[C:37]([CH3:38])=[C:36]2[C:31]([CH:32]=[C:33]([NH:39][C:2]3[N:7]=[C:6]([N:8]([CH3:26])[CH:9]4[CH2:10][CH2:11][C:12]5([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13]5)[CH2:24][CH2:25]4)[CH:5]=[CH:4][N:3]=3)[CH:34]=[CH:35]2)=[N:30]1
Reactant: Cc1c2ccc(N)cc2nn1C
Reactant: CN(c1ccnc(Cl)n1)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1c2ccc(Nc3nccc(N(C)C4CCC5(CC4)CCN(C(=O)OC(C)(C)C)C5)n3)cc2nn1C
Temperature: 150 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a suspension of tert-butyl 8-((2-chloropyrimidin-4-yl)(methyl)amino)-2-azaspiro[4.5]decane-2-carboxylate (500.0 mg, 1.3 mmol) and 2,3-dimethyl-2H-indazol-6-amine hydrochloride (778.6 mg, 3.9 mmol) in n-BuOH (10 mL) was added DIPEA (1.04 g, 8.0 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight, then cooled down to rt, and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a yellow solid (657 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].C([O:15][C@@H:16]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[CH2:27][S:26][C@H:17]1[O:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](Br)[CH:24]=1)(=O)C>>[O:18]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)[CH:24]=1)[C@@H:17]1[S:26][CH2:27][C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:16]1[OH:15]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: O[C@@H]1[C@@H](O)[C@H](Oc2cncc(-c3ccc(F)c(Cl)c3)c2)SC[C@H]1O

Procedure:
By following a procedure analogous to Example 122 starting from 3-chloro-4-fluorophenylboronic acid and 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, 5-(3-chloro-4-fluorophenyl)-3-pyridinyl 5-thio-β-D-xylopyranoside is obtained in the form of a white powder (yield=59%).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:26])[C:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH:5]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:27]([O:23][C@H:19]1[CH2:20][C@@:21]2([CH3:22])[C@@H:7]([CH2:6][CH:5]=[C:4]2[C:3](=[O:26])[CH2:2][Cl:1])[C@H:8]2[C@@:18]1([F:24])[C@:16]1([CH3:17])[C:11]([CH2:10][CH2:9]2)=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]1)(=[O:29])[CH3:28]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)O[C@H]1C[C@]2(C)C(C(=O)CCl)=CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Temperature: 25 °C

Procedure:
A suspension of 21-chloro-9-fluoro-11β-hydroxypregna-1,4,16-triene-3,20-dione (2.1g) in a mixture of glacial acetic acid (30 ml) and acetic anhydride (30 ml) containing p-toluenesulfonic acid hydrate (2.1g) is stirred at room temperature. After 30 hours the solution is mixed with sodium acetate hydrate (5.0g) and evaporated in vacuo. The residue is dissolved in chloroform, washed with water, dried and evaporated to afford the title compound. One crystallization from acetone affords 1.85g of the title compound, melting point 222°-223° C. (dec).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1I.C(N(CC)CC)C.[CH3:17][C:18]([CH3:22])([CH3:21])[C:19]#[CH:20]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1COCC1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:20]#[C:19][C:18]([CH3:22])([CH3:21])[CH3:17]
Reactant: C#CC(C)(C)C
Reactant: Cc1cccc(I)c1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(C#CC(C)(C)C)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with bis(triphenylphosphine)palladium(II)chloride (0.042 g, 0.060 mmol) and copper(I) iodide (0.023 g, 0.120 mmol) under nitrogen atmosphere. THF (4.6 mL) was added, followed by 2-bromo-1-iodo-3-methylbenzene (0.594 g, 2 mmol), triethylamine (2.3 mL, 16.50 mmol) and 3,3-dimethylbutyne (0.251 mL, 2.040 mmol). The reaction mixture was allowed to stir at RT overnight. The reaction mixture was filtered through a plug of silica gel and the plug was rinsed with Et2O. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (0-2% EtOAc/hexanes). 2-Bromo-1-(3,3-dimethylbut-1-ynyl)-3-methylbenzene was obtained as a light-yellow clear oil.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14](O)=[O:15])[CH:12]=2)[C:7]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[CH:6]1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:35][C@@H:36]([CH2:50][C:51]1[CH:56]=[C:55]([F:57])[CH:54]=[C:53]([F:58])[CH:52]=1)[C@H:37]([OH:49])[CH2:38][NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH3:48])[CH:42]=1>ClCCl>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH:35][C@@H:36]([CH2:50][C:51]3[CH:52]=[C:53]([F:58])[CH:54]=[C:55]([F:57])[CH:56]=3)[C@H:37]([OH:49])[CH2:38][NH:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH3:48])[CH:42]=3)=[O:15])[CH:12]=2)[C:7]([C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCn1cc(C(=O)C(F)(F)F)c2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCCCn1cc(C(=O)C(F)(F)F)c2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
1-Butyl-3-(trifluoroacetyl)-1H-indole-6-carboxylic acid (0.141 g) was dissolved in dichloromethane (10 mL). 1,1′-Carbonyldiimidazole (0.080 g) was added and the mixture was stirred at room temperature for 2 h. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.166 g) in dichloromethane was added and the mixture was allowed to stir overnight at room temperature. The mixture was then partitioned between dichloromethane and water, dried over sodium sulfate, filtered, and concentrated. Chromatography on silica gel using methanol/ethyl acetate/heptane/dichloromethane (3/10/10/77 to 6/10/10/74) gave 1-butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(trifluoroacetyl)-1H-indole-6-carboxamide (0.155 g). MS (ESI+) for C34H36F5N3O3+H1 m/z 630.28 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([OH:20])=O)[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[CH2:21]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[O:20])[NH:15][C:14]=12)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Reactant: NCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccncc1)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
A mixture of 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Reference Example 4) (398 mg, 1.11 mmol), 4-(aminomethyl)pyridine (169 mg, 1.56 mmol), 1-ethyl-3-dimethylaminopropylcarbodiimide (EDCI) (299 mg, 1.56 mmol), 1-hydroxybenzotriazole (HOBt) (211 mg, 1.56 mol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 h. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0:10 to 1:10 methanol/ethyl acetate). Recrystallization from hexanes/ethyl acetate gave 7-(dibenzylamino)-N-(4-pyridinylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (419 mg, 84%) as colorless crystals: Rf 0.20 (silica gel, ethyl acetate); mp 119-120° C.; 1H NMR (300 MHz, CDCl3) δ4.62 (2H, d, J=6.0 Hz), 4.90 (4H, s), 6.40-6.52 (1H, m), 6.75 (1H, s), 7.01 (1H, d, J=5.6 Hz), 7.21 (2H, d, J=5.9 Hz), 7.25-7.38 (10H, m), 7.91 (1H, d, J=5.6 Hz), 8.57 (2H, d, J=5.9 Hz), 8.98 (1H, br s); ESI MS m/z 448 [C28H25N5O+H]+; HPLC (Method A) >99% (AUC), tR=15.7 min.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.N1CCCCC1>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:5]#[C:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6])=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1ccc(Br)cc1
Reactant: C#CCCC(=O)O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C#CCCC(=O)O)cc1
Temperature: 80 °C

Procedure:
A solution of 4-pentynoic acid (2.15 g, 22 mmol), 4-bromobenzonitrile (3.64 g, 20 mmol) and piperidine (40 mL) was degassed by bubbling nitrogen through the solution for 5 min prior to the addition of tetrakis(triphenylphosphine) palladium (0) (240 mg, 0.2 mmol). The reaction vial was sealed and warmed to 80° C. for 1.5 h. After cooling to 23° C., the reaction mixture was diluted with ethyl acetate (200 mL), filtered, and concentrated in vacuo. The residue was diluted with ethyl acetate (300 mL), washed with 5% HCl (2×100 mL), washed with water (1×100 mL), and extracted with 3% sodium carbonate (2×200 mL). The basic aqueous layer was treated with decolorizing carbon, filtered, and acidified to pH=2. The resultant solid was filtered, washed with water, dried, and purified by flash chromatography (gradient ethyl acetate:methylene chloride:acetic acid 1:9:0.005) and fractional recrystallization (methylene chloride-ether) to afford the title compound as a white solid: m.p. 149°-152° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](Br)[CH:37]=[CH2:38]>>[CH2:38]([O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH:37]=[CH2:36]
Reactant: C=CCBr
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Product: C=CCOc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1OC

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with allyl bromide
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:7]=1.Cl>CO.[OH-].[Na+].CCOCC>[CH3:26][C:24]([CH3:27])([O:23][C:21]([NH:20][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:7]=1)[C:3]([OH:28])=[O:2])=[O:22])[CH3:25]
Reactant: COC(=O)[C@H](Cc1ccc(CC(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)Cc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Yield: 77.9 %

Procedure:
A solution of 1.471 g of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-4-[2-(1,1-dimethylethoxy)-2-oxoethyl]-benzenepropanoic acid methyl ester in 25 mL of methanol and 5 mL of 1N sodium hydroxide solution was stirred at room temperature for 2 hours. The mixture was acidified with a slight excess of hydrochloric acid, was diluted with 100 mL of ether, and was washed with water and saturated sodium chloride solution. The residue obtained after filtration and evaporation was chromatographed over 100 g of silica gel, eluting with 40:59:0.5 ethyl acetate-hexane-acetic acid. The product containing fractions were combined, evaporated, diluted with toluene and evaporated finally under high vacuum to give 1.105 g of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-4-[2-(1,1-dimethylethoxy)-2-oxoethyl]-benzenepropanoic acid [α]D +21.41 (ethanol).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:14])([CH3:13])[C:5]1=[O:15])(=O)C.Cl.C(OC)(C)(C)C>O>[CH3:13][C:6]1([CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:5]1=[O:15]
Reactant: CC(=O)N1C(=O)C(C)(C)c2ccccc21
Agent: Cl
Solvent: O
Solvent: COC(C)(C)C
Product: CC1(C)C(=O)Nc2ccccc21

Procedure:
3.50 g (17.2 mmol) 1-acetyl-3,3-dimethyl-1,3-dihydro-indol-2-one were refluxed in 50 mL of a 6N hydrochloric acid solution for 1h. After cooling the reaction mixture was divided between tert-butylmethylether and water. The organic phase was washed with water, dried and evaporated down. The residue was crystallised from PE. The solid was suction filtered and dried at 80° C. in the CAD.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C>O>[CH2:7]([NH:6][CH2:5][C:4]([OH:14])=[O:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CNCc1ccccc1
Solvent: O
Product: O=C(O)CNCc1ccccc1

Procedure:
225.8 g (1.17 mol) of N-benzylglycine ethyl ester (J. Am. Chem. Soc. 72, 1238 (1950)) are heated under reflux overnight in 600 ml of water. Product which has crystallized out is filtered off with suction and the filtrate is extracted once with tert.-butyl methyl ether. The aqueous phase is concentrated and the crystals obtained are dried over phosphorus pentoxide in a desiccator together with the product filtered off.