Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].Cl.[C:25]1([CH:31]2[CH2:36][CH2:35][N:34]([C:37]3([C:40](O)=[O:41])[CH2:39][CH2:38]3)[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:40]([C:37]2([N:34]3[CH2:33][CH2:32][CH:31]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:36][CH2:35]3)[CH2:39][CH2:38]2)=[O:41])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C(O)C1(N2CCC(c3ccccc3)CC2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCC(c4ccccc4)CC3)CC2)CC1
Yield: 52 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-(4-phenylpiperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16H carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(4-phenylpiperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as an off-white solid (52%). MS ISP (m/e): 581.2 (100) [(M+H)]+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>O.C(OCC)(=O)C>[CH:13]([O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:21][CH:22]=1)([CH3:15])[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
A mixture of hydroxylammonium chloride (3.5 g), sodium hydrogen carbonate (5.0 g) and dimethyl sulfoxide (25 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.88 g) was added, and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (25 mL), N,N′-carbonyldiimidazole (0.97 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.90 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.54 g, 73%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[C:20]1([CH3:29])[C:21]([C:26](Cl)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7]/[C:6]/1=[N:12]\[C:26](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH3:29]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccccc1C
Yield: 44.5 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.45 mL, 3.2 mmol) and o-toloyl chloride (Aldrich, 0.22 g, 1.4 mmol) in 15 mL THF were processed using the method described in Example 129 to afford the title compound (0.15 g, 0.49 mmol, 46% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.23 (d, J=0.7 Hz, 3H), 2.26 (s, 3H), 2.70 (s, 3H), 3.31 (s, 3H), 3.77 (t, J=5.3 Hz, 2H), 4.35 (t, J=5.3 Hz, 2H), 7.23 (t, J=7.5 Hz, 2H), 7.27-7.35 (m, 1H), 8.08-8.14 (m, 1H); MS (DCI/NH3) m/z 305 (M+H)+; Anal. calculated for C16H20N2O2S: C, 63.13; H, 6.62; N, 9.20. Found: C, 63.43; H, 6.53; N, 9.14.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1B(O)O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=4[CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: Cc1ccc(C)c(B(O)O)c1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(C)ccc4C)c3O2)cc1
Yield: 80.7 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,5-dimethylphenyl)boronic acid (0.294 g, 1.96 mmol) generally according to the procedure described for Intermediate 184 provided 0.430 g (81%) of (±)-[7-(2,5-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[N:5][CH:4]=1)=[O:2].[NH2:13][C@@H:14]([CH3:30])[C:15]([NH:17][C@@H:18]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[C:19]([NH2:21])=[O:20])=[O:16].C(Cl)CCl.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[NH2:21][C:19](=[O:20])[C@@H:18]([NH:17][C:15](=[O:16])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)[CH3:30])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1
Reactant: C[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Reactant: O=Cc1cnc(NCC(=O)O)s1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)CNc1ncc(C=O)s1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
To a mixture of material from Example 3 (32.2 mg, 0.107 mmol), (S)-2-amino-N-((S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)propanamide (42.7 mg, 0.170 mmol), EDC (31.7 mg, 0.165 mmol) and 1-hydroxy-7-azabenzotriazole (10.0 mg, 0.073 mmol) is added anhydrous DMF (1.0 mL). The reaction is flushed with N2, treated with N-methylmorpholine (59 μl, 0.537 mmol), flushed with N2 and allowed to stir at room temp for 18 h. The reaction is diluted with DMF and purified by preparative HPLC (Condition A) using a PHENOMENEX® Luna Axia 30×100 mm S10 column from 10% Solvent B to 80% Solvent B over 12 min, ret. T=5.2 min. The product fractions are evaporated to dryness in a speed-vac for 18 h to give 26.7 mg (46.7%) of the title compound as a yellow solid as a TFA salt. LC/MS (Condition A): ret. T=1.65 min, (M+H)+ 420.09.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[N:7]2)([O-])=O.NN.O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[N:7]2
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2nc1-c1cccs1
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc2[nH]c(=O)c(-c3cccs3)nc2c1

Procedure:
The quinoxalin-2-one of the present example is prepared by reducing 6-nitro-3-thiophen-2-yl-1H-quinoxalin-2-one of Example 39 with H2NNH2.H2O in the presence of Pd/C in refluxing MeOH.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].[CH3:16][C:17](C)([O-])[CH3:18].[K+]>CN(C)C=O>[C:7]([C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)([CH:17]([CH3:18])[CH3:16])[CH2:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])#[N:8]
Reactant: N#CCc1ccsc1
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(C#N)(c1ccsc1)C(C)C
Reaction time: 5 h
Yield: 67 %

Procedure:
3-Methyl-2-(3-thienyl)butanenitrile (6.23 g) obtained using 3-thienylacetonitrile as a starting material in accordance with the method of Example 114 described in JP-A 11-206862 and ethyl acrylate (4.53 g) were dissolved in dimethylformamide (15 ml), and added at a room temperature to a solution of potassium tert-butoxide (423 mg) in dimethylformamide solution (60 ml). After stirring 5 hours as it was, the organic layer was separated by adding an aqueous saturated ammonium chloride and diethyl ether thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), to give the title compound as a yellow oil (6.66 g, 67%).
Reaction SMILES: [C:1](=[O:24])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][CH3:13])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[ClH:34].Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>CN(C=O)C>[ClH:36].[ClH:34].[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([N:43]2[CH2:48][CH2:47][N:46]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:9]3)=[O:24])[CH2:45][CH2:44]2)=[CH:41][CH:42]=1
Reactant: COCCN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCN1CCC(COC(=O)N2CCN(c3ccc(Cl)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.5 %

Procedure:
(1-(2-methoxyethyl)piperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 3; 1.01 g, 3.0 mmol) was dissolved in DMF (10 mL). DIPEA (1.74 mL, 5.0 mmol) and, 4-(4-chlorophenyl)piperazine dihydrochloride (808 mg, 3.0 mmol) were added and the reaction mixture was stirred at room temperature for 14 hours, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (50 mL) and washed with 1M aq Na2CO3 solution (5×30 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 96:4 mixture of DCM:MeOH) followed by reverse phase column chromatography (gradient eluting with MeOH in water, 0-100%). The residue was dissolved in DCM (10 mL) and 2M HCl in Et2O (3 mL) was added. The reaction mixture was then concentrated in vacuo to give [1-(2-methoxyethyl)piperidin-4-yl]methyl 4-(4-chlorophenyl)piperazine-1-carboxylate dihydrochloride (468 mg, 39.5%) as white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[N:5]=[CH:4]1)C.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1>C(#N)C>[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH:21][S:8]([C:6]2[N:5]=[CH:4][N:3]([CH3:1])[CH:7]=2)(=[O:10])=[O:9])[CH2:14][CH2:13]1
Reactant: NCCCN1CCOCC1
Reactant: CCn1cnc(S(=O)(=O)Cl)c1
Solvent: CC#N
Product: Cn1cnc(S(=O)(=O)NCCCN2CCOCC2)c1

Procedure:
Analogously to Example 7, 10 g (51 mmol) of 1-ethyl-4-imidazolesulfonyl chloride from Example C-2 are reacted with 7.5 ml (51 mmol) of 3-morpholinopropylamine in 200 ml of acetonitrile and the mixture is correspondingly worked up. The hydrochloride thus obtained is dissolved in methanol and converted into the free base by means of an equivalent amount of methanolic sodium methylate solution. The oil remaining after evaporating in vacuo crystallizes after addition of an equimolar amount of ethanolic fumaric acid as the hydrogenfumarate of melting point 148°-149° C.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11]([NH:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)=[S:12])(=[O:9])=[O:8].[Na].[CH3:29]I.O>C(#N)C.C(O)C>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11](=[N:13][C:14]1[N:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[N:19]=1)[S:12][CH3:29])(=[O:9])=[O:8]
Reactant: CI
Reactant: Cc1cc(C)nc(NC(=S)NS(=O)(=O)c2ccccc2-c2ccccc2)n1
Agent: [Na]
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: CSC(=Nc1nc(C)cc(C)n1)NS(=O)(=O)c1ccccc1-c1ccccc1
Yield: 38.8 %

Procedure:
3.98 g of 1-(2-biphenylylsulfonyl)3-(4,6-dimethylpyrimidin-2-yl)thiourea was suspended in 50 ml of dry acetonitrile, and a solution of 0.3 g of metallic sodium in 10 ml of ethanol was added, and the mixture was heated under reflux for 30 minutes. After cooling, 1.85 g of methyl iodide was added, and the mixture was heated under reflux for 5 hours. The reaction mixture was cooled, and then poured into 100 ml of water. The product was extracted with methylene chloride. Methylene chloride was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 1.6 g of the desired 1-(2-biphenylylsulfonyl)3-(4,6-dimethylpyrimidin-2-yl)2-methylisothiourea (compound No. II-1) which was the same as obtained in Example 1. mp. 154°-157° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])[CH:19]=[C:18]([Cl:28])[C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][CH:24]=[C:25]([Cl:27])[Cl:26])[CH:19]=[C:18]([Cl:28])[C:17]=1[O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:12][CH2:13][CH3:14]
Reactant: CCOC(COCCCCO)OCC
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(COCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)OCC
Yield: 92.1 %

Procedure:
To a mixture of 2.30 g of 4-(2,2-diethoxyethoxy)butanol, 2.94 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 2.94 g of triphenylphosphine and 30 ml of tetrahydrofuran was slowly added dropwise 2.48 g of diisopropyl azodicarboxylate with stirring under ice cooling. After stirring at room temperature for 24 hours, the reaction mixture was concentrated. The residue was subjected to silica gel chromatography, which afforded 4.48 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene (yield, 73%), nD24.5 1.5165.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.Cl.[NH2:18][CH:19]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[C:20]1[CH:21]=[C:22]([P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=1.CCN(CC)CC>O=S(Cl)Cl.C(Cl)Cl>[OH:1][C:2]1[C:7]([C:8]([NH:18][CH:19]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:20]2[CH:21]=[C:22]([P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1
Reactant: CCOP(=O)(OCC)c1cccc(C(N)c2ccc(OC)cc2)c1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1cccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccc(OC)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
The 4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid, 1-1-h, (500 mg, 2.3 mmol) was dissolved in SOCl2 (10 ml), the mixture was stirred at RT for 3 hours, then concentrated under vacuo. The residue was dissolved with 20 ml DCM, and dropwise to a solution of diethyl 3-(amino(4-methoxyphenyl)methyl)phenylphosphonate hydrochloride (5-d, 802 mg, 2.30 mmol) and Et3N (464 mg, 4.6 mmol) in DCM (30 ml) at 0° C., the mixture was stirred at room temperature overnight. Then added water, the water phase was concentrated under vacuo and purified on silica gel chromatography to provide the product, 5-e, (990 mg, 78.4%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.Cl.Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:14]=2)=[CH:3][CH:2]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1ccc(C#Cc2ccncc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C(#Cc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccncc1

Procedure:
A mixture of 4-(2-(pyridin-4-yl)ethynyl)phenol (335 mg, 1.72 mmol), 2-(chloromethyl)quinoline hydrochloride (385 mg, 1.8 mmol), and cesium carbonate (2.2 g, 6.87 mmol) was stirred in dimethylformamide (8 mL) at 65° C. for 3 h. Water (20 mL) was added and the mixture was extracted with dichloromethane (3×15 mL). The organic layers were dried, concentrated, and the residue chromatographed on silica eluted with a gradient of 10% to 80% ethyl acetate-hexanes giving 450 mg (78%) of a yellow solid. 1H NMR (CDCl3, 400 mHz) δ 8.56 (m, 2H), 8.20 (d, 1H, J=8.7 Hz), 8.08 (d, 1H, J=8.3 Hz), 7.82 (d, 1H, J=7.9 Hz), 7.74 (ddd, 1H, J=8.4, 7, 1Hz), 7.63 (d, 1H, J=8.7 Hz), 7.55 (ddd, 1H, J=8, 7, 1 Hz), 7.47 (m, 2H), 7.35 (m, 2H), 7.01 (m, 2H), 5.41 (s, 2H). MS (AP+) m/e 337 (MH+).
Reaction SMILES: [CH:1]([S:4][S:5][CH2:6][CH:7]([NH:17][C:18](=[O:24])[O:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:8](=[O:16])[NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:3])[CH3:2].[O:25]=[P:26]([Cl:29])(Cl)[Cl:27].[CH3:30]CN(CC)CC>C(Cl)Cl>[C:1]([S:4][S:5][CH2:6][CH:7]([NH:17][C:18](=[O:24])[O:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:8]([NH:9][CH:10]1[CH2:11][CH2:12][N:13]([P:26]([Cl:29])([Cl:27])=[O:25])[CH2:14][CH2:15]1)=[O:16])([CH3:30])([CH3:3])[CH3:2]
Reactant: CC(C)COC(=O)NC(CSSC(C)C)C(=O)NC1CCNCC1
Reactant: CCN(CC)CC
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)COC(=O)NC(CSSC(C)(C)C)C(=O)NC1CCN(P(=O)(Cl)Cl)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the compound from Example 61 (7.746 g, 18.12 mmol) in DCM (200 ml) at −78° C. was slowly injected POCl3 (1.69 ml, 18.12 mmol) under Ar, followed by the addition of Et3N (7.58 ml, 54.36 mmol). The reaction was stirred at RT for 5 h, concentrated to remove excess base and solvent. The title compound was given as white solid after ISCO purification (50% EtAc/Hexane).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:21]=[CH:22][C:23]=3[O:24][CH3:25])[NH:14]C(=O)C(F)(F)F)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[K+]>CO>[C:1]12([C:11]3[CH:12]=[C:13]([CH:21]=[CH:22][C:23]=3[O:24][CH3:25])[NH2:14])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COc1ccc(NC(=O)C(F)(F)F)cc1C12CC3CC(CC(C3)C1)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(N)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 50 °C
Reaction time: 18 h

Procedure:
11.03 g (31.2 mmol) of 3-(1-adamantyl)4-methoxy-N-(trifluoroacetyl)aniline dissolved in 40 ml of methanol and 160 ml of water are treated with 7.12 g (51.5 mmol) of potassium hydroxide. The reaction medium is heated to 50° C. for 20 hours and then 80° C. for 18 hours. After evaporation to dryness, the residue is taken up with ethyl ether, the insoluble matter is filtered off and the filtrate is dried over magnesium sulphate and evaporated. The solid is washed in hexane to yield, after drying, 7.44 g (93%) of 3-(1-adamantyl)-4-methoxyaniline, melting point 140°-141° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH2:27]([CH2:30][NH2:31])[CH:28]=C.[CH3:32]N(C=O)C>>[CH2:30]([N:31]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2)[CH3:32])[CH:27]=[CH2:28]
Reactant: C=CCCN
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)OCCCCCc1ccc2c(ccn2-c2ccc(F)cc2)c1
Product: C=CCN(C)CCCCCc1ccc2c(ccn2-c2ccc(F)cc2)c1
Yield: 98 %

Procedure:
130 mg (0.26 mmol) Methanesulfonic acid 5-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-pentyl ester and 0.5 ml (5.2 mmol) N-allylmethylamine in 0.5 ml DMF were stirred at 60° C. for 2 h. The solution was concentrated and dissolved in water and CH2Cl2. 2M NaOH was added and the inorganic phase was extracted with CH2Cl2. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography with CH2Cl2/MeOH 19:1 yielded 90 mg (98%) Allyl-{5-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-pentyl}-methyl-amine as orange oil, MS: 351(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:12])[S:8][C:9]=1[CH2:10][OH:11])=[O:4]>C(Cl)(Cl)Cl.C(OCC)C.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH2:12])[S:8][C:9]=1[CH:10]=[O:11])=[O:4]
Reactant: COC(=O)c1nc(N)sc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(N)sc1C=O
Temperature: 25 °C
Yield: 75.3 %

Procedure:
The compound (1.05 g) obtained in Step 2 was suspended in chloroform (50 ml), manganese dioxide (4.86 g) was added, with stirring at room temperature, and the mixture was stirred at the same temperature for 3 days. The reaction mixture was concentrated, tetrahydrofuran (150 ml) and activated carbon were added, and the mixture was heated under reflux. The insoluble material was filtered off when it was hot, and the insoluble material was washed with a heated mixed solvent (tetrahydrofuran:N,N-dimethylformamide:methanol=8:1:1). The filtrate was concentrated under reduced pressure, and the obtained crude crystals were suspended in diethyl ether, collected by filtration and dried to give the title compound (782 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(#N)C>[CH2:12]([N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[CH3:1])=[O:6])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: c1ccc(Cn2ccnc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1cccc(C(=O)c2nccn2Cc2ccccc2)c1C
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A solution of 2,3-dimethylbenzoic acid (100 g, 666 mmol) in thionyl chloride (350 ml) was heated at 80° C. for 1 h, before cooling to room temperature and concentrating in vacuo. To the residue was added toluene (100 ml) and the solution was again concentrated in vacuo. The intermediate acid chloride was added to a mixture of 1-benzylimidazole (100 g, 632 mmol) and triethylamine (100 ml) in acetonitrile (1 l) and the reaction mixture was heated at reflux for 18 h. The reaction mixture was concentrated in vacuo and to the residue was added diethyl ether (500 ml) and ethyl acetate (50 ml). This solution was washed with water (500 ml) and saturated aqueous sodium hydrogen carbonate solution (500 ml), filtered through silica gel (100 g) and concentrated in vacuo to give the title compound (182 g).