Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[Li].O.O.C([O:7][C:8]([C:10]1([CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]2([C:27]([O:29]CC)=[O:28])[CH2:26][CH2:25][CH2:24]2)[CH2:13][CH2:12][CH2:11]1)=[O:9])C>CCO>[C:27]([C:23]1([CH2:22][CH2:21][CH2:20][CH2:19][C:18](=[O:32])[CH2:17][CH2:16][CH2:15][CH2:14][C:10]2([C:8]([OH:9])=[O:7])[CH2:11][CH2:12][CH2:13]2)[CH2:26][CH2:25][CH2:24]1)([OH:29])=[O:28]
Reactant: CCOC(=O)C1(CCCCC(=O)CCCCC2(C(=O)OCC)CCC2)CCC1
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: O=C(CCCCC1(C(=O)O)CCC1)CCCCC1(C(=O)O)CCC1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
LiOH.H2O (3.94 g, 93.9 mmol) and H2O (30 mL) were added to a solution of ethyl 1-9-[1-(ethoxycarbonyl)cyclobutyl]-5-oxononyl-1-cyclobutanecarboxylate (9.20 g, 23.3 mmol) in EtOH (90 mL) and the resulting mixture was stirred at reflux temperature for 17 h, allowed to cool to rt and concentrated in vacuo to a smaller volume. H2O (150 mL) was added and the resulting mixture was extracted with Et2O (50 mL), acidified with aqueous HCl (6 M, 25 mL) and extracted with Et2O (1×100 mL, 2×50 mL). The latter organic layers were combined, washed with brine (50 mL), dried (Na2SO4) and evaporated in vacuo. The remaining residue was recrystallized from a mixture of iPr2O and heptane to give 1-[9-(1-carboxycyclobutyl)-5-oxononyl]-1-cyclo-butanecarboxylic acid (4.41 g, 56%) as small, white granules. mp 69-70° C. 1H NMR (CDCl3): δ=11.2 (br s, 2H), 2.50-2.37 (m, 4H), 2.39 (t, J=7.2 Hz, 4H), 1.96-1.84 (m, 8H), 1.81-1.75 (m, 4H), 1.57 (quintet, J=7.4 Hz, 4H), 1.26-1.12 (m, 4H). 13C NMR (CDCl3): δ=210.6, 183.4 (2×), 47.6 (2×), 42.7 (2×), 37.8 (2×), 30.1 (4×). 24.7 (2×), 24.1 (2×), 15.7 (2×). Anal. calcd for C19H30O5: C, 67.43; H, 8.93, found: C, 67.19; H, 8.97.
Reaction SMILES: C([CH2:8][NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19](=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1.CCO.C(OC(C)C)(=O)C>C(Cl)Cl>[CH3:8][NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19](=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:13]1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(CCNCCc2ccccc2)CC1
Solvent: CCO
Solvent: CC(=O)OC(C)C
Solvent: ClCCl
Product: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Yield: 69.2 %

Procedure:
To a Parr hydrogenation flask was added biphenyl-2-ylcarbamic acid 1-[2-(benzylmethylamino)ethyl]piperidin-4-yl ester (40 g, 0.09 mol; prepared as described in Preparation 8) and EtOH (0.5 L). The flask was flushed with nitrogen gas and palladium on activated carbon (15 g, 10 wt % (dry basis), 37% wt/wt) was added along with HOAc (20 mL). The mixture was kept on the Parr hydrogenator under a hydrogen atmosphere (˜50 psi) for 3 hours. The mixture was then filtered and washed with EtOH. The filtrate was condensed and the residue was dissolved in a minimal amount of DCM. Isopropyl acetate (10 volumes) was added slowly to form a solid which was collected to provide 22.0 g of the title compound (70% yield). MS m/z: [M+H+] calcd for C21H27N3O2, 354.2; found, 354.3. Rf=2.96 min (10-70 ACN:H2O, reverse phase HPLC).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7](=[O:20])[CH:8]=[C:9]2[C:13]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]=12)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:22]([NH:24][CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][CH2:25][N:24]([CH2:22][CH3:23])[C:7](=[O:20])[CH2:8][C:9]1[C:13]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]=1[C:5](=[O:6])[C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc2oc3c(C(C)(C)C)oc(=O)cc3c2c1
Reactant: CCNCCC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCC(C)(C)C)C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 45 °C

Procedure:
To a mixture containing 21.8 mg 1-tert-butyl-6-methoxy-3H-pyrano[3,4-b][1]benzofuran-3-one from the Step B above and 21.6 mg N-Ethyl-3,3-dimethylbutan-1-amine hydrochloride from the Step A above in 0.75 mL DMF was 26 μL DIEA. The mixture was heated in 45° C. oil bath over night. It was purified directly on RP-HPLC using 65˜85% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.38 min. (m/Z=318.2, 402.3, 424.3). Alternative preparation of N-(3,3-dimethylbutyl)-2-[2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]-N-ethylacetamide
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][N:5]=[C:6]=[S:7].O.[NH2:11][NH2:12]>C(O)C>[CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][NH:5][C:6](=[S:7])[NH:11][NH2:12]
Reactant: NN
Reactant: COC(CN=C=S)OC
Solvent: CCO
Solvent: O
Product: COC(CNC(=S)NN)OC
Reaction time: 12 h
Yield: 70.4 %

Procedure:
2,2-Dimethoxyethyl isothiocyanate (37.7 g) is added in the course of 1 hour to a solution of hydrazine hydrate (14.35 g) in ethanol (40 cc), whilst stirring at a temperature of between 5° and 9° C. After 12 hours at 4° C., the mixture is concentrated to dryness at 20° C. under reduced pressure (20 mm Hg; 2.7 kPa). The yellow syrup obtained crystallises after seeding. The solid is dissolved in hot methanol (50 cc) and the solution is filtered and diluted with diethyl ether (200 cc). After about ten hours at 4° C., the mixture is filtered and 4-(2,2-dimethoxyethyl)-thiosemicarbazide (32.3 g) is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[C:4]#[C:5][CH3:6].[CH2:8]([NH:10][NH2:11])[CH3:9]>C(O)CCC.O>[CH2:8]([N:10]1[C:5]([CH3:6])=[CH:4][C:3]([CH2:2][CH3:1])=[N:11]1)[CH3:9]
Reactant: CC#CC(=O)CC
Reactant: CCNN
Solvent: CCCCO
Solvent: O
Product: CCc1cc(C)n(CC)n1
Temperature: 25 °C

Procedure:
A solution of 18.9 g (0.2 mol) of hex-4-yn-3-one (from Step B) in 120 mL of n-butanol was treated with 40 mL (0.227 mol) of ethyl hydrazine, 34% solution in water. The resulting mixture was heated at reflux for 1.5 h, then cooled to rt. The mixture was concentrated to ˜150 μL volume; this was partitioned between 1 L of ether and 250 mL of water. The layers were separated and the organic layer was dried and concentrated to afford the title compound, which was used without further purification. 1H-NMR (400 MHz) δ 1.22 (t, J=7.6, 3H), 1.37 (t, J=7.2, 3H), 2.23 (s, 3H), 2.59 (q, J=7.6, 2H), 4.01 (q, J=7.2, 2H), 5.81 (s, 1H).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.O>O1CCCC1.CO>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCc1ccccc1-3
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of methyl 13-cyclohexyl-6,7-dihydro-5H-benzo[3,4]azepino[1,2-a]indole-10-carboxylate (55 mg, 0.147 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 4N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and 2N hydrochloric acid (2.5 ml) and water were added to the reaction mixture. The precipitated solid was collected by filtration, washed with water and dried in vacuo to give 13-cyclohexyl-6,7-dihydro-5H-benzo[3,4]azepino[1,2-a]indole-10-carboxylic acid (44 mg, yield 83%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].C(#N)C.C(N(CC)CC)C.[CH3:34][S:35][C:36](SC)=[CH:37][N+:38]([O-:40])=[O:39]>>[CH3:34][S:35]/[C:36](/[N:7]1[CH2:8][CH2:9][C@H:10]([C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)=[O:12])[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)=[CH:37]\[N+:38]([O-:40])=[O:39]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: COC(=O)[C@H]1CNCC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(/C(=C/[N+](=O)[O-])SC)CC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Temperature: 85 °C
Yield: 53.4 %

Procedure:
To a stirred solution of (3R,4S)-4-((R)-3-phenyl-pyrrolidine-1-carbonyl)-piperidine-3-carboxylic acid methyl ester (3.10E2 mg, 0.000980 mol) in anhydrous acetonitrile (9.8 mL, 0.19 mol) at rt was added triethylamine (274 uL, 0.00196 mol) and 1,1-bis(methylthio)-2-nitroethylene (248 mg, 0.00147 mol). The reaction mixture was heated to reflux (oil bath temperature: 85° C.) for 19 h. The reaction mixture was concentrated in vacuo. The residue was purified by Combiflash with 40-95% EtOAc/Hex to give the product as a yellow viscous oil (227 mg, 53% in yield). MS (ESI): (M+H)+=434.1.
Reaction SMILES: [NH2:1][C:2]1([C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[O:6])[CH2:4][CH2:3]1.IC.[CH2:27](N(CC)CC)C>C(Cl)Cl>[CH3:27][NH:1][C:2]1([C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[O:6])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccccc1-c1ccc(CNC(=O)C2(N)CC2)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CI
Product: CNC1(C(=O)NCc2ccc(-c3ccccc3C(=O)OC)cc2)CC1
Yield: 34.8 %

Procedure:
Methyl 4′-({[(1-aminocyclopropyl)carbonyl]amino}methyl)-1,1′-biphenyl-2-carboxylate (200 mg, 0.62 mmol), prepared according to Example 1, was dissolved in 5 mL of DCM along with iodomethane (130 mg, 0.93 mmol) and triethylamine (75 mg, 0.74 mmol). After no reaction was observed at ambient temperature, the reaction mixture was heated to reflux for about two days. After the first day, additional iodomethane was added (ca. 3–5 equiv.). After two days >50% of the starting material was consumed. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography eluting with 1–10% MeOH in DCM to afford 73 mg of methyl 4′-[({[1-(methylamino)cyclo-propyl]carbonyl}amino)methyl]-1,1′-biphenyl-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=2)[C:5](=[O:18])[CH:4]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH2:26])[CH:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]([C:9]2[S:10][C:11]([C:15]([NH:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[O:17])=[C:12]([CH3:14])[N:13]=2)[C:5](=[O:18])[CH:4]=1
Reactant: COc1ccn(-c2nc(C)c(C(=O)O)s2)c(=O)c1
Reactant: NCc1cccnc1
Product: COc1ccn(-c2nc(C)c(C(=O)NCc3cccnc3)s2)c(=O)c1
Yield: 58 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-methoxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 58% yield: mp 200-202° C. (dichloromethane/methanol); 1H NMR (300 MHz, CDCl3) δ 8.64 (d, J=8.1 Hz, 1H), 8.60-8.59 (m, 1H), 8.52-8.51 (m, 1H), 7.51-7.68 (m, 1H), 7.29-7.24 (m, 1H), 6.30 (t, J=5.8 Hz, 1H), 6.17 (dd, J=8.1, 2.6 Hz, 1H), 5.96 (d, J=2.6 Hz, 1H), 4.61 (d, J=5.8 Hz, 2H), 3.82 (s, 3H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.4, 162.4, 162.1, 153.6, 152.6, 149.2, 149.0, 135.7, 133.7, 131.4, 123.6, 121.8, 103.9, 96.2, 56.0, 41.4, 17.3; MS (ES+) m/z 357.2 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][CH2:16][C@@H:17]([C:19]([NH:21][CH2:22][C:23]([O:25]C)=O)=[O:20])[NH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO.C(N(CC)CC)C>[CH2:8]([O:15][CH2:16][CH:17]1[NH:18][C:23](=[O:25])[CH2:22][NH:21][C:19]1=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)CNC(=O)[C@@H](N)COCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNC(=O)C(COCc2ccccc2)N1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A 250 ml, round-bottomed flask was charged with methyl O-benzyl-L-serylglycinate trifluoroacetate (9.37 g, 24.64 mmol) and 3:1 MeOH/triethylamine (50 mL). The mixture was then heated to reflux for 16 h. The reaction was then cooled to room temperature, concentrated, and diluted with ice cold 50% aqueous EtOH (50 mL). The resulting precipitate was collected by filtration and dried under reduced pressure to give 3-(benzyloxymethyl)piperazine-2,5-dione (3.95 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Cl.Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=1>>[CH3:1][C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1cccc(CCl)n1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Agent: Cl
Product: Cc1cccc(Cn2cc(C#Cc3cccc(C#N)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=313.2 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-chloromethyl-6-methyl-pyridine hydrochloride.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH:9]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)=O.N1CCCCC1>C(O)C>[C:1](/[C:3](=[CH:9]/[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)/C(C#N)=C\c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl cyanoacetate (2.59 g, 22.88 mmol) and 4-formylbenzonitrile (3.0 g, 22.88 mmol) are dissolved in ethanol (100 ml). Piperidine (100 mg, 1.14 mmol) is added, and the reaction mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo, and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[C@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[SH:75]CC(O)=O>O1CCCC1>[SH:75][C@@H:14]1[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:16]([C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([N+:53]([O-:55])=[O:54])=[CH:49][CH:48]=3)=[O:44])[CH2:36][CH2:35]2)=[O:33])[CH2:15]1
Reactant: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)CS
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
A solution of 36.5 g of diethyl azodicarboxylate in 100 ml of tetrahydrofuran was added dropwise, whilst ice-cooling, to a solution of 105 g of (2S,4R)-4-hydroxy-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in steps 90(b)(i), 90(b)(i') and 90(b)(i") above] and 55 g of triphenylphosphine in 700 ml of tetrahydrofuran, and the resulting mixture was stirred at the same temperature for 10 minutes. A solution of 15.9 g of mercaptoacetic acid in 100 ml of tetrahydrofuran was then added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the concentrate was dissolved in 1.5 liters of ethyl acetate. The resulting solution was then washed with water and with an aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and then the residue was mixed with 400 ml of diisopropyl ether. The diisopropyl ether-soluble materials were extracted and discarded. The same extraction operations were repeated four times, and then the resulting residue was purified by column chromatography through 3 kg of silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol ranging from 1:0 to 20:1 by volume as the eluent, to give 88.4 g of the title compound, as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.S([O-])([O-])(=O)=O.[Mg+2].[CH:16](=O)/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([CH:18]=[CH:17][CH:16]=[N:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: COc1ccc(N)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc(N=CC=Cc2ccccc2)cc1
Reaction time: 2 h
Yield: 88.3 %

Procedure:
p-Anisidine (12.32 g) is dissolved in 160 ml of methylene chloride and 20 g of anhydrous magnesium sulfate is added. The mixture is cooled in an ice bath and 13.22 g of transcinnamaldehyde is added. The mixture is stirred under nitrogen for 2 hours and then filtered. The filtrate is evaporated to give a solid. The crude product is recrystallized from methylene chloride-petroleum ether to give 20.96 g of the title compound as a solid.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>C1C=CC=CC=1>[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([N:7]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]2[CH:5]=[CH:6][C:1]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:2][CH:3]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: CCOC(=O)CCCNc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CCOC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Yield: 63.1 %

Procedure:
Analogously to Example 47b), 10.0 g of ethyl 4-(biphenyl-4-yl)aminobutyrate and 4.6 g of ethyldiisopropylamine in 70 ml of benzene are reacted with 6.2 g of p-chlorobenzoyl chloride to obtain 9.4 g (62.9% of theory) of ethyl 4-[p-chloro-N-(biphenyl-4-yl)benzamido]butyrate as a viscous non-distillable oil. Saponification of this ester, analogously to Example 47c), yields 7.0 g (79.7% of theory) of 4-[p-chloro-N-(biphenyl-4-yl)-benzamido]butyric acid, MP 192° to 194°.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]=[C:2]1[C:6]#[N:7].C(N(CC)CC)C.FC(F)(F)C(O)=O.[CH2:22]([N:29]([CH2:35]OC)[CH2:30][Si](C)(C)C)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([N:29]1[CH2:30][C:2]2([C:6]#[N:7])[CH:3]([CH2:4][CH2:5][O:1]2)[CH2:35]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: N#CC1=CCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#CC12CN(Cc3ccccc3)CC1CCO2
Temperature: 40 °C
Reaction time: 15 h

Procedure:
14.4 g (0.15 mol) of 4,5-dihydrofuran-2-carbonitrile are introduced in 300 ml of absolute methylene chloride, 1.8 g of triethylamine and 1.8 g of trifluoroacetic acid are added, and the mixture is warmed to 40° C. 42.6 g (0.15 mol) of N-benzyl-N-methoxymethyl-N-trimethylsilylmethylamine are added dropwise to this mixture which is then stirred at 40° C. for 15 hours. It is then washed with 50 ml of saturated sodium hydrogen carbonate solution, dried over MgSO4, concentrated and distilled twice.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]([O:14]C)=[O:13])=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[C:8]([C:16]([F:19])([F:17])[F:18])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cnc(N2CCCC2)cc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(N2CCCC2)cc1C(F)(F)F

Procedure:
A mixture of 2.5 g (9.12 mmol) of methyl 6-(pyrrolidin-1-yl)-4-(trifluoromethyl)pyridine-3-carboxylate, obtained in step 11.1, and of 0.76 g (13.67 mmol) of potassium hydroxide in 50 ml of methanol and 2 ml of water is stirred for 24 hours at 20° C. The mixture is subsequently concentrated under reduced pressure. 100 ml of water are subsequently added and the solution is washed with 100 ml of dichloromethane and then acidified to pH 4 by the addition of concentrated hydrochloric acid. A precipitate is recovered by filtration and is washed with 50 ml of water. After drying under reduced pressure, 2.2 g of the expected compound are isolated.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=O)=[CH:11][CH:10]=2)[C:6]=1[C:7]#[N:8].Cl.Cl[C:20]([NH2:22])=[NH:21].[OH2:23]>COCCOCCOC>[N+:15]([C:12]1[CH:11]=[CH:10][C:9]([C:5]2[C:6]3[C:7]([NH2:8])=[N:21][C:20]([NH2:22])=[N:1][C:2]=3[S:3][CH:4]=2)=[CH:14][CH:13]=1)([O-:17])=[O:23]
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)csc1N
Reactant: O
Reactant: N=C(N)Cl
Agent: Cl
Solvent: COCCOCCOC
Product: Nc1nc(N)c2c(-c3ccc([N+](=O)[O-])cc3)csc2n1
Temperature: 25 °C

Procedure:
A suspension of Example 58B (1 g, 4.08 mmol) and chloroformamidine hydrochloride (1.17 g, 10.2 mmol) in diglyme (40 mL) was heated to 130° C. for 15 hours. The mixture was cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was further concentrated under a stream of nitrogen, and purified by silica gel chromatography with 5 to 7% methanol/dichloromethane to provide 0.26 g of the desired product. MS (ESI(+)) m/e 288 (M+H)+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:22]1[N:27]=[CH:26][C:25](F)=[CH:24][N:23]=1.[CH3:29][OH:30]>CS(C)=O.ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([O:18][C:22]4[N:27]=[CH:26][C:25]([O:30][CH3:29])=[CH:24][N:23]=4)[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Reactant: Fc1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cnc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
To a stirred solution of 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (50 mg, 0.197 mmol) in DMSO (2 ml) was added NaH (16 mg of a 60% dispersion in mineral oil, 0.40 mmol) at room temperature in one portion. The suspension was stirred for 2 hours at room temperature then 2-chloro-5-fluoro-pyrimidine (26 mg, 0.20 mmol) was added in one portion. The mixture was heated at 60° C. in a sealed tube for 16 hours. After cooling to room temperature the solution was treated with MeOH (8 μl, 0.20 mmol) and NaH (16 mg, 0.40 mmol, 60 in mineral oil) and heated at 60° C. in a sealed tube for 16 hours. After cooling to room temperature the reaction was diluted with dichloromethane (30 ml) and washed twice with saturated NaHCO3 (15 ml), dried (Na2SO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 90:10:1) to provide the title compound as colourless oil (20 mg, 28%).