Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]([CH3:48])[C:25]([N:27]([C:36]2[C:41]([Cl:42])=[C:40]([O:43][CH3:44])[CH:39]=[C:38]([O:45][CH3:46])[C:37]=2[Cl:47])[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[O:26])[CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:42][C:41]1[C:40]([O:43][CH3:44])=[CH:39][C:38]([O:45][CH3:46])=[C:37]([Cl:47])[C:36]=1[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])[C:25]([N:24]([CH3:48])[C:20]1[CH:19]=[C:18]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][C:9]=2[N+:14]([O-:16])=[O:15])[N:23]=[CH:22][N:21]=1)=[O:26]
Reactant: Nc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Cl)ncn2)c1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Nc3ccc(N4CCOCC4)cc3[N+](=O)[O-])ncn2)c1Cl
Temperature: 100 °C
Yield: 51.7 %

Procedure:
A degassed mixture of 4-morpholin-4-yl-2-nitro-phenylamine (290 g, 1.3 mmol), 1-(6-chloro-pyrimidin-4-yl)-3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-urea (Procedure 2E, step b; 624 g, 1.2 mmol), Pd2(dba)3 (110 g, 0.12 mmol), Xantphos (139 g, 0.24 mmol) and Cs2CO3 (782 g, 2.4 mmol) in toluene (15 mL) was heated at 100° C. for 2.5 hours. The reaction was concentrated, and the residue was purified by chromatography flash on silica to obtain the title compound (440 mg, yield: 49%) as a red solid. MS (ESI): 708 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]12[CH2:18][CH2:17][CH2:16][C:15]1([CH2:19][NH2:20])[CH2:14][CH2:13][CH2:12]2>>[N:11]12[CH2:18][CH2:17][CH2:16][C:15]1([CH2:19][NH:20][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:14][CH2:13][CH2:12]2
Reactant: NCC12CCCN1CCC2
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Product: O=[N+]([O-])c1ccc(NCC23CCCN2CCC3)cc1
Yield: 74.4 %

Procedure:
p-Chloronitrobenzene and (1-azabicyclo[3.3.0]octan-5-yl)methylamine were reacted in the same manner as in Example 1 to obtain the titled compound as an oil in a yield of 74.4 %.
Reaction SMILES: Cl[C:2]1([NH2:20])[N:19]=[CH:18][N:17]=[C:16]2[C:3]1=[N:4][CH2:5][N:6]2[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].O.[NH2:22][NH2:23]>CO>[NH:22]([NH:20][C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:16]=2[N:17]=[CH:18][N:19]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])[NH2:23]
Reactant: NC1(Cl)N=CN=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NN
Solvent: CO
Solvent: O
Product: NNNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 6-chloroadenosine (1 g, 3.5 mmol) and hydrazine monohydrate (5 mL) in MeOH (10 mL) was stirred at 50° C. for 1 hr. The reaction mixture was allowed to cool to room temperature and was then concentrated in vacuo to provide a crude residue which was suspended in MeOH and (10 mL) and stirred at room temperature. The solid product that separated out from the suspension was filtered, washed with MeOH and dried in vacuo to provide N6-hydrazinoadenosine (970 mg) which was used without further purification.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[OH-].[Na+].[CH2:7]([N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18](=[C:23]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)[CH2:19]2)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:2]([NH:4][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([C:23](=[C:18]2[CH2:17][CH:16]3[N:15]([CH2:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:32][CH:31]=1)[CH3:3]
Reactant: O=C(Cl)c1ccc(C(=C2CC3CCC(C2)N3CCc2ccccc2)c2ccccc2)cc1
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCNC(=O)c1ccc(C(=C2CC3CCC(C2)N3CCc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
A mixture of 11.4 g (0.14 mole) of ethylamine hydrochloride and 150 mL of 3N NaOH and 100 mL of CH2Cl2 were cooled in an ice bath. A solution of 4.7 g (0.015 mole) of 4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzoyl chloride prepared using Procedure E in 60 mL of CH2Cl2 was added. After the addition was complete, the ice bath was removed and the reaction stirred at room temperature for 2 h. The organics were separated off and washed with water, brine and dried (K2CO3). The solvent was evaporated in vacuo and converted to the HCl salt with Et2O/HCl to give 1.86 g of N-ethyl-4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)phenylmethyl]benzamide; mp 296-298° C. (Decomp). MS m/z (MH+) 451. 1H NMR (DMSO-d6) δ 8.5 (ar, 1H); 7.8 (d, 2H); 7.4-7.1 (ar, 12H); 4.05 (bs, 2H); 3.4-3.2 (m, 3H); 3.1 (s, 3H); 2.9 (d, 2H); 2.4 -2.1 (m, 4H); 1.8 (m, 2H); 1.1 (t, 3H).
Reaction SMILES: [CH2:1]([C:8]1([O:18][CH3:19])[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([C:8]1([O:18][CH3:19])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1(Cc2ccccc2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COC1(Cc2ccccc2)CCC(=O)CC1
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of Example 11B (8.5 g, 32.5 mmol) in acetone (200 mL) was treated with water (100 mL) and p-toluenesulfonic acid monohydrate (1 g), heated to reflux, stirred overnight, and concentrated to remove the acetone. The remaining aqueous solution was extracted with ethyl acetate (3×100 mL) and the combined extracts were washed sequentially with 1N NaOH, water, and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product (6.95 g, 95%). MS (CI) m/e 236.2 (M+18)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:6]=1.[Li]CCCC.[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=1[N:39]([CH2:51][CH:52]([CH3:54])[CH3:53])[S:40]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]=[O:50])=[CH:45][CH:44]=1)(=[O:42])=[O:41].C(O)=O>O1CCCC1.ClCCl>[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=1[N:39]([CH2:51][CH:52]([CH3:54])[CH3:53])[S:40]([C:43]1[CH:48]=[CH:47][C:46]([CH:49]([OH:50])[CH2:1][C:2]2[N:3]=[N:4][NH:5][N:6]=2)=[CH:45][CH:44]=1)(=[O:42])=[O:41]
Reactant: Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C=O)cc2)c(C)c1
Agent: [Li]CCCC
Solvent: O=CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(O)Cc3nn[nH]n3)cc2)c(C)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5-methyl-2-trityl-2H-tetrazole (68.5 mg, 0.21 mmol) in tetrahydrofuran (THF) (1 mL), stirred under nitrogen at −70° C., was added a solution of n-BuLi (1.6 M in hexanes, 0.144 mL, 0.231 mmol) and tetrahydrofuran (THF) (1 mL) dropwise over 1 minute. The reaction mixture was stirred at −78° C. for 45 minutes. N-(2,4-dimethylphenyl)-4-formyl-N-isobutylbenzenesulfonamide (222 mg, 0.643 mmol) in tetrahydrofuran (THF) (1 mL) was then added dropwise at −78° C. over 1 minute. The reaction mixture was stirred at −78° C. for 2 hours, then allowed to warm to room temperature. The reaction was carefully quenched using a few drops of water under nitrogen. Ethyl acetate (3 mL) and water (2 mL) were added and the reaction stirred vigorously for 5 minutes. The organic phase was separated (hydrophilic frit) then evaporated in vacuo to give a residue. The residue was redissolved in dichloromethane (DCM) (2 mL) and treated with formic acid (0.5 mL, 13.04 mmol). The solution was stood overnight, then the solvent evaporated in vacuo and the crude purified by MDAP (Method F) to give the required product, 17.3 mg. LCMS (M+1) 430, RT 1.09 mins.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:10])C.Cl>O1CCCC1>[CH3:10][C@H:9]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:8](=[O:22])[NH:7][CH2:6][CH2:5][CH:4]=[O:3]
Reactant: CCOC(CCNC(=O)[C@H](C)NC(=O)OCc1ccccc1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Yield: 101.6 %

Procedure:
By using an analogous procedure to that described for Reference Example 14, benzyl (1S)-2-[(3,3-diethoxypropyl)amino]-1-methyl-2-oxoethylcarbamate (2.39 g, 6.79 mmol, obtained from Reference Example 19) in tetrahydrofuran (14 ml) was reacted with 0.5 N hydrochloric acid (14 ml) for 45 minutes, to provide benzyl (1S)-1-methyl-2-oxo-2-[(3-oxopropyl)amino]ethylcarbamate (1.92 g, 100%) as a pale yellow waxy solid.
Reaction SMILES: N#N.[CH2:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]1[N:15]=[N:16][C:17](Cl)=[C:18]([CH3:21])[C:19]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[F-].[Cs+]>O1CCOCC1>[CH2:3]([NH:10][CH2:11][CH2:12][NH:13][C:14]1[N:15]=[N:16][C:17]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[C:18]([CH3:21])[C:19]=1[CH3:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1c(Cl)nnc(NCCNCc2ccccc2)c1C
Reactant: OB(O)c1ccc(F)cc1
Agent: N#N
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: Cc1c(NCCNCc2ccccc2)nnc(-c2ccc(F)cc2)c1C
Temperature: 95 °C

Procedure:
Treat a N2 degassed mixture of N1-benzyl-N2-(6-chloro-4,5-dimethylpyridazin-3-yl)ethane-1,2-diamine (6.40 g, 22.0 mmol), 4-fluorophenylboronic acid (9.24 g, 66.0 mmol) and CsF (10.0 g, 66.0 mmol) in 1,4-dioxane (220 mL) with (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (2.70 g, 3.30 mmol). Heat the reaction mixture at 95° C. overnight. Cool, and partition between saturated NaHCO3 (aq) and EtOAc. Separate the layers, and extract the aqueous layer with EtOAc. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 6% 2M NH3/MeOH in CH2Cl2) to afford the title compound as a waxy solid (4.91 g, 64%). ES/MS m/z 351.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:16][C:15]2[C:6](=[C:7]([NH2:18])[C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([Cl:17])=[CH:10][CH:9]=3)[CH2:5][CH2:4]1.[S:19]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25](O)=[O:26])[S:20]1.C1[C@@H](CC(O)=O)SSC1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[NH2:18][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:6]=1[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:25](=[O:26])[CH2:24][CH:21]1[CH2:22][CH2:23][S:19][S:20]1)[CH2:16]3)=[CH:12][C:11]([Cl:17])=[CH:10][CH:9]=2
Reactant: O=C(O)CC1CCSS1
Reactant: NCC1CCc2c(nc3cc(Cl)ccc3c2N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C[C@@H]1CCSS1
Solvent: CN(C)C=O
Product: Nc1c2c(nc3cc(Cl)ccc13)CC(CNC(=O)CC1CCSS1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
A solution of 16 (140 mg, 0.53 mmol) and [1,2]dithiolan-3-yl-acetic acid (Chen, Yaun-Shek and Lawton, Richard G. An efficient synthetic route to 2-(1,2-dithiolan-3-yl)acetic acid. Trisnorlipoic acid and amide derivatives. Tetrahedron Letters 1997, 38, 5785-5788) (90 mg, 0.55 mmol) in anhydrous DMF (5 mL), under N2, was cooled to 0° C. and then additioned with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (113 mg, 0.59 mmol); the reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h in the dark. Solvent was then evaporated, accurately avoiding heating up the mixture. An oily residue was obtained which was purified by gravity column. Elution with petroleum ether/CH2Cl2/MeOH/aqueous 30% ammonia solution (5:4:1:0.1) afforded 17 as a waxy solid: 40% yield; 1H NMR (200 MHz, CD3OD) δ 8.03 (d, J=9.2 Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 7.30 (dd, J=8.8, 2.2 Hz, 1H), 4.05 (m, 1H), 2.95-3.34 (m, 5H), 2.46-2.59 (m, 6H), 1.99-2.20 (m, 3H), 1.48-1.52 (m, 1H). Anal. Calculated for C19H22ClN3OS2: C, 55.93; H, 5.44; N, 10.30. Found: C, 56.01; H, 5.45; N, 10.11.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C@@H:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:20]([CH3:23])[CH:21]=O)[C:13]3=[O:30])[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C@@H:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:20]([CH3:23])[CH2:21][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[C:13]3=[O:30])[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)C=O)c1=O
Reactant: C1CCNCC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)[C@@H](C)CN2CCCCC2)c1=O

Procedure:
The title compound was prepared from N-cyclopropyl-3-fluoro-4-methyl-5-[3-{[(1R,2R)-2-methyl-3-oxo-1-phenylpropyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide (Example 328e) and piperidine using a similar method to that described for Example 328f.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([NH:25][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[N:11]=1
Reactant: NC1CCCC1
Reactant: CSc1nc(Cc2cccc(Cl)c2)[nH]c(=O)c1C#N
Product: N#Cc1c(NC2CCCC2)nc(Cc2cccc(Cl)c2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.34 mmol) of 2-(3-chlorobenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 292 mg (3.43 mmol) of cyclopentylamine to give 10 mg (9% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:22]([O:26][C:27](=[O:35])[NH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:35])[NH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:18][C:16]2[CH:15]=[N:14][CH:13]=[C:12]([C:7]3[N:8]([CH3:11])[C:9]4[C:5]([C:6]=3[C:20]#[N:21])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH:17]=2)[CH2:31][CH2:30]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: Cn1c(-c2cncc(CN3CCC(NC(=O)OC(C)(C)C)CC3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and piperidin-4-yl-carbamic acid tert-butyl ester are processed according to the method described in Example 170 to give {1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester. MS (ESI) m/z 480.1 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=1)=[O:4].[NH3:14]>CO.O>[C:10]([C:8]1[CH:9]=[C:5]([C:3]([NH2:14])=[O:4])[NH:6][CH:7]=1)#[N:11]
Reactant: N
Reactant: N#Cc1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Solvent: O
Solvent: CO
Product: N#Cc1c[nH]c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-trichloroacetylpyrrole-4-carbonitrile (20 g, 84.2 mmol) in methanol is treated with ammonia (51 mL), stirred at room temperature for 30 minutes and diluted with water. The aqueous mixture is filtered to obtain the title product as a white solid (7.0 g, mp 253°-256° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12](OS(C)(=O)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:20]=[N+:21]=[N-:22])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N=[N+]=[N-])CC1
Temperature: 65 °C

Procedure:
A solution of methanesulfonic acid trans-4-tert-butoxycarbonylamino-cyclohexyl ester (21 g, 72 mmol) in DMSO (350 mL) was charged with sodium azide (14 g, 216 mmol) and heated at 65° C. for 14 h. After cooling to RT, the solution was diluted with EtOAc and washed successively with water, 5% aq. NaHCO3, water, and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo, and the resulting residue was purified via flash chromatography to afford (cis-4-azido-cyclohexyl)-carbamic acid tert-butyl ester (16 g, 92% yield). MS found: (M+H)+=241.7.
Reaction SMILES: [F:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[O:9][C:8]([C:10]([NH2:12])=O)=[CH:7][C:6]=2[CH:13]=1.P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>>[F:1][C:2]1[C:3]([F:14])=[CH:4][C:5]2[O:9][C:8]([C:10]#[N:12])=[CH:7][C:6]=2[CH:13]=1
Reactant: NC(=O)c1cc2cc(F)c(F)cc2o1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2cc(F)c(F)cc2o1
Temperature: 0 °C
Yield: 88 %

Procedure:
1.5 g (7.61 mmol) of 5,6-difluorobenzofuran-2-carboxamide were treated with 8 ml of phosphorus oxychloride and heated under reflux over a period of 5 minutes while stirring. Subsequently, the clear solution was added dropwise while stirring to a mixture of 36 ml of ammonium hydroxide solution and 64 g of ice, with the temperature not exceeding 20°. The mixture was stirred for a further 30 minutes and the beige crystals were subsequently filtered off. There were obtained 1.2 g (88%) of 5,6-difluorobenzofuran-2-carbonitrile as a beige solid with m.p. 103°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1([S:17]([C:20]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:21]OCC)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:17]([C:20]([S:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])=[CH:21][NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)(=[O:18])=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CCOC=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Product: O=[N+]([O-])c1ccc(NC=C(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)nc1
Yield: 73.8 %

Procedure:
An intimate mixture of 2-amino-5-nitropyridine (19.0 g) and 1,1-bis(phenylsulphonyl)-2-ethoxyethene (30 g) was heated at 180°-190° C. for 1 hour. After cooling, the solid cake was pulverised and recrystallised from a mixture of methyl ethyl ketone and methanol, to give 1,1-bis(phenylsulphonyl)-2-(5-nitropyrid-2-ylamino)ethene (28 g) m.p. 229°-231° C.
Reaction SMILES: [H-].[Na+].[F:3][CH2:4][CH2:5][CH2:6][OH:7].Cl[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=1.[OH-].[Na+]>CN(C)C=O.C(O)C>[F:3][CH2:4][CH2:5][CH2:6][O:7][C:9]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OCCCF
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1ccc(OCCCF)nc1
Reaction time: 0.42 h

Procedure:
Sodium hydride (0.220 g, 5.50 mmol) was added to a solution of 3-fluoropropan-1-ol (0.390 g, 5 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred under an atmosphere of nitrogen for 25 min and added a solution of ethyl 6-chloronicotinate (0.928 g, 5.00 mmol) in N,N-dimethylformamide (2.5 mL). The reaction mixture was stirred for 35 min and then quenched with water. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. Purification by column chromatography using a gradient of ethyl acetate in heptane yielded an oil. The crude was dissolved in 1M sodium hydroxide, (16.50 mL, 16.50 mmol) and ethanol (20 mL) and heated to 50° C. for 1.5 h. The organic solvent was removed in vacuo, and the residual aqueous solution was cooled on ice. 2 M hydrochloric acid was added until an acidic pH was reached. The obtained precipitate was filtered off, washed with ice-water, and dried in vacuo affording the title compound, 0.53 g (81%) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (dd, 1 H), 8.14 (dd, 1 H), 6.90 (dd, 1 H), 4.65 (t, 1 H), 4.54 (t, 1 H), 4.43 (t, 2 H), 2.05-2.19 (m, 2 H); MS (APPI/APCI) m/z 228[M+H+].
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH:5]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)[C:6]#[N:7].[OH-].[K+].C(OCC)(=[O:25])C.Cl>CC(O)(C)C>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1)[C:6]([NH2:7])=[O:25]
Reactant: COc1cc(C(C#N)CCN(C)C)cc(OC)c1OC
Reactant: CCOC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: COc1cc(C(CCN(C)C)C(N)=O)cc(OC)c1OC

Procedure:
In 8 ml of 2-methyl-2-propanol was dissolved 0.84 g of 4-dimethylamino-2-(3,4,5-trimethoxyphenyl)butyronitrile, followed by addition of 1.0 g of ground potassium hydroxide. The mixture was refluxed for 1 hour. After cooling the reaction mixture, the insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. To the residue thus obtained were added ethyl acetate and 10% hydrochloric acid. The aqueous layer was separated and made strongly basic with sodium hydroxide for salting-out and the basic substance was extracted with ethyl acetate. The ethyl acetate layer was washed with a mixture of water and saturated aqueous sodium chloride (1:1) and a saturated aqueous solution of sodium chloride in turn, then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crystalline residue thus obtained (0.59 g) was recrystallized from ethyl acetate to provide 0.35 g of 4-dimethylamino-2-(3,4,5-trimethoxyphenyl)butyramide. Physicochemical properties:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[CH:19]=[C:20]([CH:31]=[C:32]([O:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=3)[CH:33]=2)[O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:49](Br)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C>[CH2:49]([O:27][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][C:22]([O:21][C:20]2[CH:31]=[C:32]([O:34][C:35]3[CH:36]=[CH:37][C:38]([C:41]#[N:42])=[CH:39][CH:40]=3)[CH:33]=[C:18]([C:16](=[O:17])[NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][CH2:11]3)[CH:19]=2)=[CH:23][CH:24]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C(=O)O)cc3)c2)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C(=O)OCc4ccccc4)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.2 %

Procedure:
0.6 g (1.05 mmol) of 4-[3-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-5-(4-cyano-phenoxy)-phenoxy]-benzoic acid was dissolved in 5 ml of DMF. At 0° C. 50 mg (0.35 mmol) of potassium carbonate followed by 45 mg (0.26 mmol) benzylbromide were added and the reaction mixture was stirred for 4 h at RT. Reaction progress was monitored by TLC. Upon completion of the reaction the contents were diluted with 50 ml of ice-water and extracted with 3×50 ml of ethyl acetate, dried over anhydrous sodium sulphate and concentrated under vacuo. Thus obtained crude residue was purified by column chromatography using 60-120 mesh silica-gel and eluted with ethylacetate:hexane (1:9) to give 0.38 mg of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.18 (1H, m), 3.66 (1H, m), 5.36 (2H, s), 6.76 (1H, d), 7.22 (5H, m), 7.46 (7H, m), 7.88 (2H, d), 8.05 (2H, d), 8.36 (1H, d).