Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.[N:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]O[CH2:24][CH2:23]1>ClCCl.CCN(C(C)C)C(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:13][CH2:14][CH3:15])[CH:16]3[CH2:17][CH2:18][N:19]([C:28]([N:22]4[CH2:27][CH2:26][CH2:24][CH2:23]4)=[O:29])[CH2:20][CH2:21]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCCN(C1CCNCC1)C1CCc2ccc(Br)cc2C1
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(C1CCN(C(=O)N2CCCC2)CC1)C1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the (7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (200 μL of 0.25 M in dichloromethane, 50 μmol) was added 220 μL of 0.25 M solution of morpholine 4-carbonyl chloride in dichloromethane and 30 μL of DIEA. The reaction was stirred at 25° C. for 24 h. Concentrated in vacuo. The final product was isolated by preparative RPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford {4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-pyrrolidin-1-yl-methanone 34 (4.6 mg), [M+H]+=562.
Reaction SMILES: C(N(CC)[C:4]1[CH:28]=[CH:27][C:7]2[C:8](=[O:26])[C:9](=[C:11]3[C:15](=[O:16])[C:14]4[CH:17]=[CH:18][C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:20][C:13]=4[O:12]3)[O:10][C:6]=2[CH:5]=1)C>C(O)(=O)C.[Zn]>[CH2:24]([N:21]([CH2:22][CH3:23])[C:19]1[CH:18]=[CH:17][C:14]2[C:15](=[O:16])[C:11](=[C:9]3[C:8](=[O:26])[C:7]4[CH:27]=[CH:28][CH:4]=[CH:5][C:6]=4[O:10]3)[O:12][C:13]=2[CH:20]=1)[CH3:25]
Reactant: CCN(CC)c1ccc2c(c1)OC(=C1Oc3cc(N(CC)CC)ccc3C1=O)C2=O
Agent: [Zn]
Solvent: CC(=O)O
Product: CCN(CC)c1ccc2c(c1)OC(=C1Oc3ccccc3C1=O)C2=O
Reaction time: 0.25 h

Procedure:
0.10 g of the oxindigo 1a (from Example 14) is dissolved in 40 ml of glacial acetic acid. 1.67 g (25.5 mmol) of zinc powder are introduced into the dark red solution. After the solution has been heated to the boiling point, it gradually becomes yellow in colour. The zinc sediment is filtered off to give a clear, dark yellow solution of blue fluorescence. A cotton ribbon is impregnated in this solution for 15 minutes. Chiefly the blue cis form 2a is then formed by oxidation in the air. During a couple of months in air and sunlight (during days) visually no color change is observed.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])(=O)=O.[CH3:14][NH:15][CH2:16][CH2:17][OH:18]>>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][N:15]([CH2:16][CH2:17][OH:18])[CH3:14]
Reactant: CS(=O)(=O)OCc1ccccc1F
Reactant: CNCCO
Product: CN(CCO)Cc1ccccc1F
Temperature: 120 °C
Reaction time: 7 h

Procedure:
A mix of 2-Fluorobenzyl methanesulfonate (Step A, 5 g, 24.5 mmol) and 2-(Methylamino)-ethanol (18.4 g, 244.9 mmol) was heated under argon at 120° C. with stirring for 7 hours. The mixture was cooled to room temperature and concentrated. The crude residue was purified by flash chromatography on silica gel column (chloroform:methanol, 90:10 spiked with triethylamine) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[CH2:12]2)=[C:4]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])[N:3]=1.N1C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:53]=[CH:52][C:35]([C:36](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>C(Cl)Cl.CO>[Br:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:16][C@H:15]([CH2:17][O:18][C:36]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[C:35]3[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:53][CH:52]=3)[C@@H:13]([OH:14])[CH2:12]2)=[C:4]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])[N:3]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CN(C)C=Nc1nc(Br)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N=CN(C)C)nc(Br)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
The compound was produced as described in example 9. The following were used: compound from example 17 (250 mg, 0.65 mmol), pyridine (2 ml), 4,4′-dimethoxytrityl chloride (330 mg, 0.98 mmol). FC cf. 9. Colourless solid (260 mg, 58%). TLC (CH2Cl2/MeOH, 9:1): Rf 0.37. 1H-NMR ((D6)DMSO): 2.23, 2.68 (2m, H—C(2′)); 3.01, 3.09 (2s, CH3—N); 3.57, 3.58 (2s, CH3O); 3.84 (m, H—C(4′)); 4.33 (m, H—C(3′)); 5.24 (d, J=4.5 Hz, HO—C(3′)); 6.22 (“t”, J=5.8 Hz, H—C(1′)); 6.6-7.2 (m, aromat. H); 8.21 (s, H—C(8)); 8.69 (s, H—C(N═)). Anal. calc. for C34H35BrN6O5 (687.59): C, 59.39; H, 5.13; N, 12.22; found: C, 59.46; H, 5.40; N, 12.09.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH2:27]([NH:29][CH2:30][CH3:31])C>>[CH2:30]([N:29]([CH3:27])[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])[C:31]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCNCC
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Product: CN(Cc1ccccc1)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and diethylamine. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 498.5 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:22]([F:25])([F:24])[F:23])=[C:5]([C:20]#[N:21])[C@H:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:19])[C:7]=1[C:8]#[N:9].C(=O)([O-])O.[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34]>C(O)C>[C:8]([C:7]1[C@@H:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:19])[C:5]([C:20]#[N:21])=[C:4]([C:22]([F:23])([F:25])[F:24])[N-:3][C:2]=1[CH3:1])#[N:9].[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: CC1=C(C#N)[C@@H](c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)N1
Agent: C[N+](C)(C)CCO
Agent: O=C([O-])O
Solvent: CCO
Product: CC1=C(C#N)[C@@H](c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)[N-]1

Procedure:
To a suspension of 100 mg (0.29 mmol) (4R)-2-methyl-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile (Example 5) in ethanol (2.1 ml) under argon atmosphere was added 41 μl (0.29 mmol) 2-hydroxy-N,N,N-trimethylethanaminium hydrogencarbonate solution (choline bicarbonate, 80% in water), and the mixture was stirred at reflux temperature for 40 min. Subsequently, the solution was evaporated, and the residue was dried in vacuo. The precipitate was stirred in 1.5 ml THF/pentane (9:1 v/v) for 3 days and then centrifuged to yield 84 mg (64% of th.) of the title compound as a solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1[C:22]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][C:11]=1[C:23]([OH:25])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:69])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[O:51]=[C:50]([N:52]1[CH2:53][CH2:54][N:55]([C:58](=[O:69])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:56][CH2:57]1)[CH2:49][NH:48][C:23]([C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:21][C:22]=2[CH:10]=1)=[O:25]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc2c(c1)Cc1ccccc1-2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
DIPEA (184 mg, 0.24 mL, 1.42 mmol) was added to a stirred solution of 9H-fluorene-2-carboxylic acid (100 mg, 0.47 mmol) in DMF (2 mL). HOBT (64 mg, 0.47 mmol) and EDCI (109 mg, 0.57 mmol) were then added at room temperature. After 2 minutes 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (167 mg, 0.47 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, filtered the solid precipitated. The solid obtained was recrystallized from a mixture of ethyl acetate and hexane afford 105 mg (43.4%) of 9H-fluorene-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 98.25%. 1H NMR (DMSO-d6): δ 8.6 (m, 1H), 8.1 (s, 1H), 8.0-7.4 (m, 10H), 4.2 (bs, 2H), 4.0 (s, 2H), 3.8-3.4 (m, 6H), 3.2 (b, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.C(N(CC)CC)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:41]([NH:40][CH2:38][CH3:39])=[O:42])[CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@@H]4CCCNC4)ncnc32)cc1
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCC[C@@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 63.9 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-piperidin-3-yl]-9H-purin-6-amine (20 mg, 0.046 mmol, 1 eq.) in 2 mL of THF was added triethylamine (0.02 mL, 0.137 mmol, 3 eq.) and ethyl isocyanate (0.005 mL, 0.068 mmol, 1.5 eq). The reaction is stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 15 mg (65%) of (3R)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}-N-ethylpiperidine-1-carboxamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.03-1.34 (m, 3 H) 1.56-1.96 (m, 4 H) 2.18 (br. s., 1 H) 3.07 (br. s., 2 H) 3.32 (br. s., 1 H) 3.73-4.42 (m, 3 H) 5.05 (br. s., 1 H) 6.02 (d, J=5.84 Hz, 1 H) 7.09-7.63 (m, 8 H) 8.45 (br. s., 1 H), [M+H]+ 510.3.
Reaction SMILES: ClCC1C(CCl)=C(Cl)C(Cl)=C(Cl)C=1Cl.[S:15](=[O:17])=[O:16].[CH2:18]1[CH2:22][NH2+:21][CH2:20][CH2:19]1.[CH2:23]1[O:27][CH:26]2[O:28][CH:24]1[C:25]2([CH:40]([I:42])[I:41])[CH2:29][CH2:30][C:31]1([CH:37]([I:39])[I:38])[CH:35]2[O:36][CH:32]1[CH2:33][O:34]2>>[S:15](=[O:27])(=[O:17])=[O:16].[CH2:18]1[CH2:22][NH2+:21][CH2:20][CH2:19]1.[CH2:23]1[O:27][CH:26]2[O:28][CH:24]1[C:25]2([CH:40]([I:41])[I:42])[CH2:29][CH2:30][C:31]1([CH:37]([I:38])[I:39])[CH:35]2[O:36][CH:32]1[CH2:33][O:34]2
Reactant: O=S=O
Agent: C1CC[NH2+]C1
Agent: ClCc1c(Cl)c(Cl)c(Cl)c(Cl)c1CCl
Agent: IC(I)C1(CCC2(C(I)I)C3COC2O3)C2COC1O2
Product: O=S(=O)=O

Procedure:
The procedure of Example 3, when applied to 31.3 g of α,α',3,4,5,6-hexachloro-o-xylene, mp 92°-92.5° C., yielded an intensely purple solution but essentially no sulfur dioxide evelution even during a refluxing period of 3 hours. The intermediate biradical was identified by its nuclear magnetic resonance peak at 4.65 ppm (present in about 8-10% abundance in the reaction mixture), whereas the dioxonium compound (90-92% of the reaction mixture) had the chemical shift of its protons at 6.31-6.33 ppm. After the stripping of the excess of sulfur trioxide, the dioxonium compound was obtained as a dark amber colored viscous oil in quantitative yield (63.5 g) and was further identified by its hydrolysis to three mole equivalents of sulfuric acid, two mole equivalents of hydrochloric acid and one mole equivalent of the cyclic sulfate of 3,4,5,6-tetrachloro-o-xylene-1,2-diol (see Example 32).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Solvent: CO
Product: CN1CCN(C(=N)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)CC1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 1-methylpiperazine (23 mg, 0.23 mmol) via procedure W to afford 35 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(imino(4-methylpiperazin-1-yl)methyl)benzamide. MS (Q1) 434 (M)+.
Reaction SMILES: [CH:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br.[O:16]=O>C(O)(=O)C.C(C(C)=O)C(C)C>[O:16]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]([NH:11][C:12](=[O:14])[CH3:13])[CH2:2][CH2:3]1
Reactant: O=O
Reactant: CC(=O)NC1CCCc2ccccc21
Agent: Br
Solvent: CC(=O)O
Solvent: CC(=O)CC(C)C
Product: CC(=O)NC1CCC(=O)c2ccccc21
Temperature: 62 °C
Reaction time: 17 h

Procedure:
A mixture of N-(1,2,3,4-tetrahydro-1-naphthyl)-acetamide (30 g), cobaltous acetate tetrahydrate (13.12 g), 30% hydrobromic acid in acetic acid (4.28 g), methyl isobutyl ketone (400 ml) and acetic acid (100 ml) is stirred and oxygen is introduced via a capillary gas dispersion tube. The mixture is heated gradually to 62° C. and the reaction is run 17 hours at 62° C. The reaction mixture is then cooled, the oxygen flow terminated and water (500 ml) is added. The mixture is extracted with chloroform (500 ml and 2×300 ml), the chloroform extracts are combined, washed with saturated sodium chloride solution and evaporated to dryness in vacuo. Benzene (200 ml) is added to the residue, the solution is filtered and the filtrate evaporated to dryness in vacuo to afford 40.3 g (damp) of the title compound.
Reaction SMILES: ClC[CH2:3][C:4]([CH3:7])([OH:6])[CH3:5].[C:8]([O-:13])(=[O:12])[C:9]([CH3:11])=[CH2:10].[Na+].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(#N)CCC.CCCCCC>[C:8]([O:13][CH2:3][C:4]([OH:6])([CH3:7])[CH3:5])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)[O-]
Reactant: CC(C)(O)CCCl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCC#N
Solvent: CCCCCC
Product: C=C(C)C(=O)OCC(C)(C)O
Temperature: 25 °C

Procedure:
A mixture of 1-chloromethyl-2-methyl-2-propanol (21.80 g, 0.20 mole), sodium methacrylate (32.40 g, 0.30 mole), Adogen 464 (7.00 g, 0.015 mole) (phase transfer catalyst purchased from Aldrich Chemical Co.), and phenothiazine (60 mg) in butyronitrile (200 ml) was heated to reflux under nitrogen in a three-necked round bottomed flask equipped with a condenser and a mechanical stirrer. After cooling the contents to room temperature, the mixture was diluted with hexane (200 ml) and filtered through celite. The solvents were removed under aspirator vacuum (40-80° C.). The residue was distilled under high vacuum. The 22.50 grams of the product was collected between 72-80° C. at 2 mm pressure as a clear liquid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH:11]=O.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1/[CH:11]=[CH:21]/[CH:22]=[O:23]
Reactant: O=Cc1cnc2ccccc2n1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1cnc2ccccc2n1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 2-quinoxalinecarboxaldehyde (prepared as described in J. Chem. Soc. 1956, 2052) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 185 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25]1>>[OH:20][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][CH2:19][CH:10]([N:9]([CH2:21][CH2:22][CH3:23])[CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([C:33]([C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:24][CH:25]=3)=[O:34])[CH2:3][CH2:2]1)[CH2:11]2
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Reactant: O=C(O)c1c[nH]c2ccccc12
Product: CCCN(CCN1CCN(C(=O)c2c[nH]c3ccccc23)CC1)C1CCc2c(O)cccc2C1
Yield: 51.6 %

Procedure:
Compound 10f was prepared following Procedure G using 39b (50 mg, 0.16 mmol) and indole-3-carboxylic acid (35 mg, 0.21 mmol) to give 40f (38 mg, 53%) after column chromatography. 1H NMR (400 MHz, CD3OD) δ 1.03-1.07 (t, 3H, J=7.2 Hz), 1.83-1.96 (m, 3H), 2.32 (s, 1H), 2.53-2.67 (m, 5H), 2.81-2.83 (m, 2H), 3.09-3.18 (m, 4H), 3.41-3.47 (m, 2H), 3.56-3.59 (m, 1H), 3.79 (bs, 4H), 6.61-6.63 (d, 1H, J=8.4 Hz), 6.64-6.66 (d, 1H, J=8.4 Hz), 6.96-6.99 (t, 1H, J=7.2 Hz), 7.13-7.21 (m, 1H), 7.41-7.51 (m, 1H), 7.62-7.64 (m, 1H), 7.71-7.73 (d, 1H, J=7.2 Hz), 7.83-7.84 (1H, J=7.2 Hz). The free base of 40f was converted into its HCl salt. m.p. 147-151° C. Anal. [C28H36N4O2.3HCl] C, H, N.
Reaction SMILES: C([O:8][C:9](=[O:43])[CH2:10][C@@H:11]([C:24]1[CH:28]=[CH:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH:25]=1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CCO.CCOC(C)=O>[C:41]([C:38]1[CH:39]=[CH:40][C:35]([C:32]2[CH:31]=[CH:30][C:29]([N:26]3[CH:27]=[CH:28][C:24]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:17])[CH3:18])=[O:13])[CH2:10][C:9]([OH:43])=[O:8])=[CH:25]3)=[CH:34][CH:33]=2)=[CH:36][CH:37]=1)#[N:42]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(C)(C)C
Yield: 87 %

Procedure:
According to the procedure described in Example 1(a), 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester was hydrogenolyzed in EtOH/EtOAc after 6 hours to give in 87% yield 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C@H:32]3[CH2:37][CH2:36][C@H:35]([O:38][CH3:39])[CH2:34][CH2:33]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C@H:32]3[CH2:33][CH2:34][C@H:35]([O:38][CH3:39])[CH2:36][CH2:37]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C[C@H]2CC[C@H](OC)CC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: COc1cn(C(C[C@H]2CC[C@H](OC)CC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.5 h

Procedure:
1.10 g (1.86 mmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-methoxycyclohexyl)propanoyl}amino)benzoate (racemate) in 67 ml of ethanol/water (2.6/1) were reacted with 3.09 g (9.48 mmol) of caesium carbonate according to General Method 4. After complete conversion, the pH was adjusted to 5-6 with hydrochloric acid (1N) and the mixture was stirred for another 30 min. The precipitate was filtered off with suction, washed with a little water and dried under high vacuum. Yield: 690 mg (purity 89%, 59% of theory)
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:5]=1[C:6]#[N:7])=[C:2]=[O:3].[OH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=O)=[CH:16][CH:15]=1.C(N(CC)CC)C>CS(O)(=O)=O.C(O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:4]2[NH:1][C:2](=[O:3])[N:21]3[N:20]=[C:18]([C:17]4[CH:22]=[CH:23][C:14]([OH:13])=[CH:15][CH:16]=4)[N:7]=[C:6]3[C:5]=2[CH:8]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: N#Cc1cc(Cl)ccc1N=C=O
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1[nH]c2ccc(Cl)cc2c2nc(-c3ccc(O)cc3)nn12
Yield: 53 %

Procedure:
The intermediate prepared from 2-isocyanato-5-chlorobenzonitrile (6.1 g) and 4-hydroxybenzoylhydrazine (7.0 g) in 53% yield as described in Example 23 is added to a mixture of triethylamine (31 ml), methanesulphonic acid (25 drops) and ethanol (300 ml) and stirred at reflux under nitrogen for two hours. The reaction mixture is concentrated to dryness at reduced pressure, redissolved in ethanol and treated with water. The solid is collected, washed with water and dried under high vacuum to afford pure 9-chloro-2-(4-hydroxy-phenyl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)one, mp>350°
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2[N:9]=[C:10]([CH2:49][CH2:50][CH3:51])[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[N:29](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:28]=[N:27][N:26]=4)=[CH:15][CH:14]=3)[C:5]=2[CH:4]1[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH3:2].C(O)(=O)/C=C/C(O)=O>C(O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2[N:9]=[C:10]([CH2:49][CH2:50][CH3:51])[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[NH:29][N:28]=[N:27][N:26]=4)=[CH:15][CH:14]=3)[C:5]=2[CH:4]1[C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH3:2]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)N(CC)CC2
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OCC)N(CC)CC2
Yield: 87.8 %

Procedure:
A mixture of ethyl 5-ethyl-2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.10 g), fumaric acid (1.2 g) and ethanol (20 ml) is refluxed for one hour. The mixture is evaporated, and the residue is dissolved in chloroform, and the mixture is washed with a saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 5-ethyl-2-n-propyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.65 g) as a white foam.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[O:15][CH2:14][CH2:13][C@@H:12]3[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])O1.[OH-:28].[Na+].OO>O1CCCC1>[OH:28][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C@@H:12]2[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCOc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of tert-butyl (4S)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-4-ylcarbamate (1.09 g, 2.90 mmol) in tetrahydrofuran (10 mL) was added sodium hydroxide (6 mL, 1 N, 6 mmol) followed by hydrogen peroxide (10 mL, 30%). The reaction mixture was stirred at room temperature for 2 h and then quenched with sodium hydrogen sulfite (5 g in 10 mL of water). The mixture was adjusted to pH 4 with 2 N sodium hydroxide and then extracted with ethyl acetate (3×50 mL). The combined extracts were washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Flash chromatography (silica gel, 10-25% ethyl acetate/hexanes) provided (650 mg, 85%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.89 (s, 1H), 6.75 (d, J=2.7 Hz, 1H), 6.72-6.63 (m, 1H), 5.03 (d, J=7.5 Hz, 1 H), 4.77-4.75 (m, 1H), 4.16-4.08 (m, 2H), 2.30 (s, 1H), 2.16-2.13 (m, 1H), 2.05-1.99 (m, 1H), 1.47 (s, 9H).