Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[N:14][CH:13]=[CH:12][N:11]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=2)=[CH:4][CH:3]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>C(#N)C>[CH:28]1([NH:31][C:20]2[N:19]=[C:18]([C:17]3[N:11]4[CH:12]=[CH:13][N:14]=[C:15]([CH3:16])[C:10]4=[N:9][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:23]=[CH:22][N:21]=2)[CH2:30][CH2:29]1
Reactant: Cc1nccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc12
Reactant: NC1CC1
Solvent: CC#N
Product: Cc1nccn2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-8-methylimidazo[1,2-a]pyrazine (Example #G.1; 3.66 g, 9.55 mmol) in ACN (70 mL) was added cyclopropylamine (3.31 mL, 47.7 mmol). The mixture was heated to about 80° C. After about 16 h, the mixture was treated with additional cyclopropylamine (3.0 mL, 43 mmol) and heated at about 80° C. for about another 4 h. The mixture was cooled to ambient temperature and filtered. The resulting solid was washed with ACN and dried to yield the title compound as a white solid (2.85 g, 83%): LC/MS (Table 1, Method b) Rt=2.0 min; MS m/z: 361.2 (M+H)+.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][N:16]([CH3:19])[C:15]1=[O:20])[CH2:6]2.[N:21]#[C:22][NH2:23]>O1CCOCC1.Cl>[ClH:1].[CH3:19][N:16]1[CH2:17][CH2:18][N:14]([CH2:13][CH2:12][N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([NH:2][C:22]([NH2:23])=[NH:21])[CH:4]=3)[CH2:8]2)[C:15]1=[O:20]
Reactant: N#CN
Reactant: CN1CCN(CCN2Cc3ccc(N)cc3C2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(CCN2Cc3ccc(NC(=N)N)cc3C2)C1=O

Procedure:
0.4 g I.21 (1-[2-(5-amino-1,3-dihydro-isoindol-2-yl)-ethyl]-3-methyl-imidazolidin-2-one hydrochloride) was added to a mixture of 0.37 g cyanamide in 3 ml dioxane and 1 ml 4 N hydrochloric acid in dioxane. The mixture was irradiated at 140° C. in a microwave for 30 min. The solvent was evaporated and the residue was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)CCl>[CH3:1][O:2][CH2:3][CH2:4][CH:5]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)[Br:13]
Reactant: COCCCc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: COCCC(Br)c1ccc(Cl)cc1
Yield: 108.5 %

Procedure:
A mixture of 3-(4-chlorophenyl)propyl methyl ether (8.6 g, 46.5 mmol), N-bromosuccinimide (NBS; 9.43 g, 52.9 mmol), and a catalyst amount of 2,2′-azobisisobutyronitrile in ethylene dichloride (236 ml) was heated at 65° to 70° C. for three hours. The cooled reaction mixture was washed successively with water, saturated aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford crude title compound (13.3 g) which was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]3)[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C(=O)OCC)C3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C(=O)OCC)C3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-ethoxycarbonyl-cyclohexyl-amino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:26])[C:7]2[N:8]([CH:23]=[N:24][CH:25]=2)[C:9]=1[N:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1)(=[O:3])[CH3:2].Cl.O1CCOCC1>>[ClH:26].[Cl:26][C:6]1[C:7]2[N:8]([CH:23]=[N:24][CH:25]=2)[C:9]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1
Reactant: CC(=O)c1cc(Cl)c2cncn2c1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1cc(Cl)c2cncn2c1N1CCNCC1
Reaction time: 0.25 h
Yield: 199.1 %

Procedure:
tert-Butyl 4-(6-acetyl-8-chloroimidazo[1,5-a]pyridin-5-yl)piperazine-1-carboxylate (19 mg, 0.051 mmol) was taken into a vial and 4.0 M hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) was added and was stirred for 15 minutes. The solvents were evaporated to give the desired compound (16 mg, quantitative). LCMS calculated for C13H16ClN4O (M+H)+: m/z=279.1. found: 278.9.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:16][C:17]1[C:21]2[C:22]([OH:30])=[C:23]([CH2:27][CH2:28][CH3:29])[CH:24]=[C:25]([F:26])[C:20]=2[O:19][CH:18]=1>C(Cl)CCl>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1]([C:18]2[O:19][C:20]3[C:25]([F:26])=[CH:24][C:23]([CH2:27][CH2:28][CH3:29])=[C:22]([O:30][C:1](=[O:10])[C:2]4[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=4)[C:21]=3[C:17]=2[CH3:16])=[O:10])=[CH:3][CH:4]=1
Reactant: CCCc1cc(F)c2occ(C)c2c1O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCc1cc(F)c2oc(C(=O)c3ccc(OC)cc3)c(C)c2c1OC(=O)c1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 65.2 %

Procedure:
A solution of p-anisoyl chloride (2.70 gm; 15.5 mmoles) in ethylene dichloride (10 mL) was added slowly to a cooled suspension of aluminium chloride (3.0 gm; 21.8 mmoles) in ethylene dichloride (100 mL). After stirring for a period of 10 minutes, 3-methyl-4-hydroxy-5-propyl-7-fluorobenzofuran (0.79 gm; 3.8 mmoles) in dichloroethylene (5 mL) was added over a period of 2 minutes. The reaction mixture was stirred at room temperature for 1 hour. It was cooled with an ice bath and ice was added slowly. When the vigorous reaction subsided, the organic layer was separated and the aqueous phase was extracted with methylene chloride. The organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 10% ethylacetate in hexane to yield 1.18 gm (63%) of 2-(p-methoxybenzoyl)-3-methyl-4-(p-methoxybenzoyloxy)-5-propyl-7-fluorobenzofuran.
Reaction SMILES: [Si]([O:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)(C(C)(C)C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][N:50]1[C:59]2[C:54](=[CH:55][N:56]=[C:57]([CH3:60])[CH:58]=2)[CH:53]=[C:52]([C:61]2[CH:62]=[C:63]([NH:68]/[C:69](/[NH2:72])=[N:70]/O)[CH:64]=[CH:65][C:66]=2[CH3:67])[C:51]1=[O:73]>CN(C=O)C>[OH:8][C@@H:9]([C:10]1[O:12][N:70]=[C:69]([NH:68][C:63]2[CH:64]=[CH:65][C:66]([CH3:67])=[C:61]([C:52]3[C:51](=[O:73])[N:50]([CH3:49])[C:59]4[C:54]([CH:53]=3)=[CH:55][N:56]=[C:57]([CH3:60])[CH:58]=4)[CH:62]=2)[N:72]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc([C@H](O)C(C)C)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-2-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid (83 mg, 0.35 mmol) in DMF (2 mL) were added DIPEA (52 μL, 0.3 mmol) and HATU (0.11 g, 0.3 mmol). After stirring at rt for 15 min, 17 (0.10 g, 0.3 mmol) was added as a solution in DMF (1 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then was heated at 100° C. for 1 h. Subsequently, the reaction was cooled to rt, partitioned with EtOAc (30 mL) and 5% aq NaHCO3 (20 mL). The aqueous layer was extracted with fresh EtOAc (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and reduced to dryness. The crude material was dissolved in THF and was added TBAF (2.7 mL of a 1.0 M solution in THF). The mixture was stirred at rt for 2 h. Subsequently the reaction was diluted with EtOAc (20 mL) and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and reduced to dryness. The crude product was purified by preparative LCMS to give (R)-3-(5-(5-(1-hydroxy-2-methylpropyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A92). 1H NMR (400 MHz, d6-DMSO) δ 9.87 (s, 1H), 8.81 (s, 1H), 7.94 (s, 1H), 7.43 (s, 1H), 7.39 (dd, J=8, 2 Hz, 1H), 7.30 (d, J=2 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 6.02 (d, J=6 Hz, 1H), 4.48 (bt, J=6 Hz, 1H), 3.67 (s, 3H), 2.61 (s, 3H), 2.07 (s, 3H) 0.94 (d, J=6 Hz, 3H), 0.87 (d, J=6 Hz, 3H). MS m/z 420.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].Br[CH2:33][CH:34]1CC1>>[CH:29]1([CH2:28][O:27][C@H:19]2[CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:18]2[NH:17][C:12]2[C:11]([CH2:30][CH3:31])=[N:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:14]([CH2:15][CH3:16])[N:13]=2)[CH2:34][CH2:33]1
Reactant: BrCC1CC1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1OCC1CC1

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (bromomethyl)cyclopropane and making non-critical variations provided the title compound as a yellow amorphous solid. IR (liq.) 3442, 2971, 2935, 2874, 1565, 1552, 1498, 1471, 1393, 1206, 1184, 1101, 1077, 1021, 740 cm−1; OAMS supporting ions at: ESI+ 481.8; MS (EI) m/z 481 (M+); HRMS (FAB) calcd for C27H29CL2N3O+H1 482.1766, found 482.1775. [α]25D=−65 (c 0.73, methylene chloride); Anal. Calcd for C27H29Cl2N3O: C, 67.22; H, 6.06; N, 8.71. Found: C, 67.15; H, 6.08; N, 8.66.
Reaction SMILES: C[Si](Cl)(C)C.[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]([OH:16])[CH2:14]O)[CH:10]=[CH:11][CH:12]=1.C(OCC)(OCC)(OCC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[CH2:14][O:16]2)[CH:10]=[CH:11][CH:12]=1
Reactant: OC[C@H](O)c1cccc(Cl)c1
Agent: CCOC(C)(OCC)OCC
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Clc1cccc([C@@H]2CO2)c1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
At about 0° C., trimethylsilyl chloride (3.7 g, 34.06 mmol, 1.5 equiv.) was added to a solution of (R)-1-(3-chlorophenyl)ethane-1,2-diol (4 g, 23.17 mmol, 1 equiv.) and triethyl orthoacetate (5.6 g, 34.52 mmol, 1.5 equiv.) in dichloromethane (20 mL). After stirring the solution for about 1 hour, the solvent was removed by evaporation. The resulting crude product was resuspended in dry methanol (20 mL) and then potassium carbonate (8 g, 57.88 mmol, 2.5 equiv.) was added. The suspension was stirred vigorously for about 2 hours, and then filtered. The resulting filtrate was washed with dichloromethane and then concentrated in vacuo. The resulting crude was purified by silica gel column chromatography (ethyl acetate:petroleum ether (1:15)) to obtain the title product as a colorless oil (2.2 g; yield=61%). 1H NMR (300 MHz, DMSO-d6) δ: 7.25-7.43 (m, 4H), 3.97 (m, 1H), 3.13 (m, 1H), 2.88 (m, 1H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[CH:28][N:27]([CH3:30])[C:26]4=[O:31])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.O.[OH-].[NH4+]>ClCCl.CO>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH:29]=[CH:28][N:27]([CH3:30])[C:26]4=[O:31])=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)=[CH:11][CH:12]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4ccn(C)c4=O)cc3)CC2)cc1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cn1ccn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Reaction time: 120 h
Yield: 68.5 %

Procedure:
To a stirred and cooled (ice-bath) amount of 200 ml of a boron tribromide solution in dichloromethane 1M was added dropwise a solution of 14.6 parts of 1,3-dihydro-1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-methyl-2H-imidazol-2-one in 665 parts of dichloromethane. Stirring was continued for 5 days at room temperature and then the reaction mixture was poured into a mixture of 200 parts of water, 158 parts of methanol and 180 parts of ammonium hydroxide. After stirring for 1 hour, the precipitate was filtered off, washed with dichloromethane and water and dried (=first fraction of product). The organic layer of the filtrate was separated and evaporated. The residue was triturated in dichloromethane. The solid was filtered off and dried (=second fraction). The two fractions were combined and crystallized from N,N-dimethylformamide, yielding 9.6 parts (68.5%) of 1,3-dihydro-1-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3-methyl-2H-imidazol-2-one; mp. 283.1° C. (interm. 14).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([O:20]C)[CH:14]=[C:13]([O:22]C)[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([OH:20])[CH:14]=[C:13]([OH:22])[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cc(I)ccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cc(I)ccc4Cl)oc23)[C@@H]1CO

Procedure:
Compound of example 137 (0.1 g, 0.18 mmol) was subjected to demethylation using pyridine hydrochloride (1 g, 8.65 mmol) as described in example 17, to obtain the title compound.
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.[Mg].[CH2:6]([N:8]([CH2:27][CH3:28])[C:9]([C:11]1[CH:26]=[CH:25][C:14]([C:15]([C:17]2[CH:18]=[C:19]([O:23][CH3:24])[CH:20]=[CH:21][CH:22]=2)=[O:16])=[CH:13][CH:12]=1)=[O:10])[CH3:7].[Cl-].[NH4+]>O1CCCC1>[CH:1]1([C:15]([C:14]2[CH:25]=[CH:26][C:11]([C:9](=[O:10])[N:8]([CH2:27][CH3:28])[CH2:6][CH3:7])=[CH:12][CH:13]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[OH:16])[CH2:3][CH2:2]1
Reactant: CCN(CC)C(=O)c1ccc(C(=O)c2cccc(OC)c2)cc1
Reactant: BrC1CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(O)(c2cccc(OC)c2)C2CC2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A solution of cyclopropyl bromide (0.31 ml) dissolved in tetrahydrofuran (1.5 ml) was added with magnesium (46.9 mg) and stirred at 60° C. for 1 hour to prepare a Grignard reagent. The Grignard reagent was added with a solution of 3-(4-diethylcarbamoylbenzoyl)anisole (150 mg) synthesized in accordance with the method described in WO97/10230, which was dissolved in tetrahydrofuran (1.5 ml), and then stirred at 60° C. for 2 hours. The reaction mixture was added with saturated aqueous ammonium chloride (4 ml) with ice cooling to terminate the reaction and then extracted twice with dichloromethane (4 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=2:1→1:1) to obtain 90.9 mg of the title compound. Yield: 53%.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])[CH3:3].[C:16]1([CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][NH2:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14]([NH:24][CH2:23][CH:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:15])[CH3:1]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: NCC(c1ccccc1)c1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC(c1ccccc1)c1ccccc1

Procedure:
The title compound, mp 175°-176° C., was prepared from 2,6-bis(1-methylethyl)phenyl isocyanate and 2,2-diphenylethylamine according to the method of Example 1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([NH:22][C@H:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH3:21])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)nc(N[C@@H](C)c2ccc(F)cc2)c1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
8.3 g of methyl 2,6-dichloroisonicotinate, 6.1 ml of (S)-(−)-1-(4-fluorophenyl)ethylamine, 20.5 g of cesium carbonate, 2.1 g of (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 505 mg of palladium acetate were added in turn to 100 ml of degassed 1,4-dioxane, and the mixture was stirred at 70° C. for 7 hours under argon atmosphere. The reaction mixture was purified by silica gel column chromatography to obtain 4.4 g of the objective compound as pale yellow powder.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:7]=[C:8](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:17](=[O:19])/[CH:16]=[CH:15]/[C:8]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:6]([OH:5])[CH:7]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)/C=C/c1ccc([N+](=O)[O-])c(O)c1
Reactant: Nc1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc([N+](=O)[O-])c(O)c1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
Thionyl chloride (0.83 mL, 6.6 mmol) was added portionwise to a suspension of (E)-3-(3-hydroxy-4-nitro-phenyl)-acrylic acid (1.05 g, 5.0 mmol) in DCM-DMF (20-2 mL). After stirring the resulting solution at RT for 1.5 hrs, 3-chloro-aniline (2.12 mL, 20 mmol) was added dropwise and the mixture was stirred at RT for additional 2 hrs. Then the reaction mixture was diluted with DCM and washed with water, aqueous hydrochloric acid, and brine. The organic layer was dried over sodium sulphate and evaporated. The resulting raw material was purified first by column chromatography (eluant DCM/MeOH), yielding 1.25 g of the title compound.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)[NH2:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2[C@H:32]3[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)[C:26](=[O:33])N(CCO)N=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2[C@H:32]3[C@H:27]([CH2:28][CH:29]=[CH:30][CH2:31]3)[C:26](=[O:33])[N:1]([C:3]3[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=3)[N:2]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: NNc1ccc(CC(=O)O)cc1
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(c3ccc(CC(=O)O)cc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 4-hydrazinophenylacetic acid as described for compound 35. Crystallized from diethyl ether. M.p. 162° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17](/[CH:25]=[CH:26]/[C:27]3[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][C:28]=3[C:29]([OH:31])=[O:30])[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[C:17]([CH:25]3[CH2:26][C:27]4[C:28](=[CH:32][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:34][CH:35]=4)[C:29](=[O:31])[O:30]3)[CH:18]=[C:19]([C:21]([CH3:23])([CH3:22])[CH3:24])[CH:20]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cc(/C=C/c2ccc(NS(C)(=O)=O)cc2C(=O)O)cc(-c2cccnc2OCc2ccccc2)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2cccnc2OCc2ccccc2)cc(C2Cc3ccc(NS(C)(=O)=O)cc3C(=O)O2)c1
Temperature: 0 °C

Procedure:
step b—A solution of 199a, TFA (3 mL), H2O (1 mL) and DCM (10 mL) was heated at reflux for 3 h, cooled and diluted with a ice-water mixture. The pH of the solution was adjusted to ca. 3 with sat'd. NaHCO3 and extracted with EtOAc. The combined extracts were washed with brine, dried, filtered and evaporated to afford N-{3-[3-(2-benzyloxy-pyridin-3-yl)-5-tert-butyl-phenyl]-1-oxo-isochroman-7-yl}-methanesulfonamide (199b)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([N+:15]([O-])=O)[CH:12]=[CH:13][CH:14]=2)[CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[NH2:15])[CH:4]=1
Reactant: COc1ccnc(-c2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccnc(-c2cccc(N)c2)c1
Yield: 100.3 %

Procedure:
A suspension of 3-(4-methoxypyridin-2-yl)nitrobenzene (1.8 g) in ethanol (40 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 800 mg) under a hydrogen atmosphere for 5 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-(4-methoxypyridin-2-yl)aniline (1.57 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:18]=1[CH:19]=O>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:18]=1[CH:19]1[N:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:13])([F:14])[F:1])=[CH:10][CH:9]=2)[C:5](=[O:4])[CH2:6][CH2:7][CH2:8]1
Reactant: COc1cccc(OC)c1C=O
Reactant: NCc1ccc(OCC(F)(F)F)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OCC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available (4-(2,2,2-trifluoroethoxy)phenyl)methanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.80 min.; [M+H]+: 424.08 g/mol.