Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:6]([OH:8])=O)#[N:2].Cl.[Cl:14][C:15]1[CH:16]=[C:17]([NH:27]C(=O)C2C=CN=C(OCC)C=2)[CH:18]=[CH:19][C:20]=1[C@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1>>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([NH:27][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([CH3:12])[N:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:18]=[CH:19][C:20]=1[C@@H:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1
Reactant: Cc1cc(C(=O)O)cc(C#N)n1
Reactant: CCOc1cc(C(=O)Nc2ccc([C@@H]3CNCCO3)c(Cl)c2)ccn1
Agent: Cl
Product: Cc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)c(Cl)c2)cc(C#N)n1

Procedure:
In analogy to example 83, step a) using 2-Cyano-6-methyl-isonicotinic acid instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-2-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (preparation described in example 91) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=1)(C)C.[C:14]([N:22]=C=O)(=[O:21])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:6]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([NH2:22])=[O:21])[CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccnc(N)c1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C#Cc1ccnc(NC(N)=O)c1
Temperature: 50 °C
Yield: 5.2 %

Procedure:
4-Trimethylsilanylethynyl-pyridin-2-ylamine (7.8 g, 42 mmol) and benzoyl isocynate (12.2 g, 82.9 mmol) are added into DCM (350 mL). The reaction mixture is heated at 50° C. for 16 hrs. Then the solvent is removed and the residue is dissolved in ethanol (350 mL). Potassium carbonate (8.58 g, 62.2 mmol) is added and the mixture is heated at 80° C. for 1 hr. The solvent is removed and the residue is partitioned between water (100 mL) and EtOAc (100 mL). The aqueous layer is separated and extracted with EtOAc (2×100 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using 33% EtOAc in hexanes affords 350 mg of the desired product.
Reaction SMILES: [I:1]Cl.ClCCl.[Cl:6][C:7]1[N:8]=[C:9]2[CH:15]=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1>N1C=CC=CC=1>[Cl:6][C:7]1[N:8]=[C:9]2[C:15]([I:1])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1
Reactant: ClI
Reactant: Clc1cnc2[nH]ccc2n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Clc1cnc2[nH]cc(I)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A 1 M solution of iodine monochloride in dichloromethane (9.84 mL, 9.84 mmol) was added dropwise to an ice-cold solution of 2-chloro-5H-pyrrolo[2,3-b]pyrazine (6.75 g, 11.07 mmol) in anhydrous pyridine (12 mL). The reaction mixture was stirred at 0° C. for 60 minutes, then concentrated. The residue was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The crude product was stirred with 15 mL of dichloromethane. The yellow solid material was collected by filtration, washed with dichloromethane and dried to give 2.86 g of the title product. Yield: 66%. MS (DCI+) m/z 280 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH:3]([CH2:31][CH3:32])[CH:4]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]=[C:15]([NH:17][CH2:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([O:24]C)=[O:23])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][N:2]([CH3:33])[CH:3]([CH2:31][CH3:32])[CH:4]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]=[C:15]([NH:17][CH2:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([OH:24])=[O:23])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCC(C(c1ccc2nc(NCc3cccc(C(=O)OC)c3)sc2c1)n1ccnc1)N(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(C(c1ccc2nc(NCc3cccc(C(=O)O)c3)sc2c1)n1ccnc1)N(C)C
Temperature: 50 °C

Procedure:
A solution of methyl 3-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]-thiazol-2-yl)amino)methyl)benzoate (18 mg, 0.037 mmol) in 500 μL THF was treated with LiOH (10 mg, 0.238 mmol, 6.5 equiv) in 500 μL water. This was heated at 50° C. overnight. Afterwards the reaction was neutralized with 240 μL of 1N HCl and concentrated in vacuo. The residue was purified by prep-TLC using a 1 mm silica plate eluting twice with 20% MeOH/DCM to provide
Reaction SMILES: C[Mg+].[Br-].CCOCC.[CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[C:19]#[N:20]>C1(C)C=CC=CC=1>[CH:9]([N:12]([CH:13]([CH3:15])[CH3:14])[C:19](=[NH:20])[C:18]1[C:17]([Cl:16])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:25])([CH3:11])[CH3:10]
Reactant: N#Cc1c(Cl)cccc1Cl
Reactant: CC(C)NC(C)C
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)N(C(=N)c1c(Cl)cccc1Cl)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
A solution of MeMgBr in ether (10 mL, 3.0 M, 30 mmol) was added to a solution of diisopropylamine (3.38 g, 33.5 mmol) in toluene (50 mL) at 50° C. The mixture was stirred for 1 h and a white precipitate formed. Next, the mixture was cooled to 0° C. and 2,6-dichlorobenzonitrile (5.0 g, 29 mmol) was added. The mixture was allowed to warm to room temperature and the mixture was stirred for 16 h subsequently. The conversion, determined by GC, appeared to be 100%. The mixture was quenched with an aqueous NH4Cl solution (1%, 150 mL). The organic phase was separated from the aqueous phase and the latter was extracted with CH2Cl2 (250 mL) twice. The combined organic phases were dried over Na2SO4, filtered and the solvents were removed under reduced pressure resulting in a sticky residue. Pure product 2.50 g (31%) was obtained by rinsing the residue with ligroin. A second portion of pure ligand (5.20 g (65%)) was obtained by evaporating the solvent slowly. Total yield: 7.70 g (97%). The ligand was characterized by 1H NMR (300 MHz) (CDCl3) δ (ppm): 7.3 (m, 2H), 7.1 (m, 1H), 3.6 (p, 1H), 3.2 (p, 1H), 1.6 (d, 6H), 1.1 (d, 6H) and by 13C-NMR (75.5 MHz) (CDCl3) δ (ppm) 160.7, 138.5, 132.7, 129.5, 128.6, 52.7, 46.2, 21.5, 20.2.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)CC1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@:4]([OH:12])([CH3:1])[CH2:8][CH2:7][N:6]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:23])([F:25])[F:24])[CH:15]=1)[CH3:11]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(C(F)(F)F)c2)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (200 mg), 4-fluoro-2-(trifluoromethyl)benzonitrile (325 mg) and lithium carbonate (187 mg), the title compound was obtained as pale-yellow oil (yield: 306.6 mg, yield: 90%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C=O)C>[C:22]1([S:19]([N:18]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH:13]=2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(CCOc2cccc(NS(=O)(=O)c3ccccc3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1cccc(OCCc2ccc(C#N)cc2)c1)S(=O)(=O)c1ccccc1

Procedure:
N-{3-[2-(4-Cyanophenyl)ethoxy]phenyl}benzenesulfonamide (0.179 g; 0.47 mmol; from Example 1(iv) above), K2CO3 (0.082 g; 0.59 mmol) and ethyl bromoacetate (63 μL; 0.57 mmol) were stirred in DMF (10 mL) for 1 hour at room temperature, then 1 hour at 60° C. The mixture was filtered and the solvent removed in vacuo. The residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted with EtOAc. The combined organic portions were dried (Na2SO4) and the solvent evaporated to afford the sub-title compound in a quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:19])[N:7]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=3)(=[O:22])[CH3:21]
Reactant: O=c1c2ccc(Cl)cc2nc2[nH]c3ccccc3n12
Reactant: CC(=O)Cl
Product: CC(=O)n1c2ccccc2n2c(=O)c3ccc(Cl)cc3nc12

Procedure:
6-Acetyl-3-chlorobenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3-chlorobenzimidazo[2,1-b]quinazolin-12(6H)one and acetyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8](Cl)=[O:9])[CH2:4][CH:3]=1.[OH-:11].[Na+]>CO.O1CCCC1>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:9])=[O:11])[CH2:4][CH:3]=1
Reactant: [OH-]
Reactant: CC1=CCC(C(=O)Cl)CC1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=CCC(C(=O)O)CC1

Procedure:
To a solution of 4-methylcyclohex-3-enecarbonyl chloride (2 ml) in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml) was added aqueous sodium hydroxide (4N, 20 ml). The resultant mixture was stirred at ambient temperature for 1 hour, and evaporated. The residue was taken up into a mixture of water and ethyl acetate and adjusted pH to around 1. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give 4-methylcyclohex-3-enecarboxylic acid, which was used without further purification.
Reaction SMILES: O=P(Cl)(Cl)Cl.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].CN([CH:21]=[O:22])C>>[CH:21]([C:10]1[S:6][C:7]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:9]=1)=[O:22]
Reactant: CN(C)C=O
Reactant: COC(=O)CCCc1cccs1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)CCCc1ccc(C=O)s1
Temperature: 110 °C
Yield: 83 %

Procedure:
Freshly distilled POCl3 (0.4 MI, 4.12 mmol) was added to a solution of methyl 4-(thiophen-2-yl)butanoate (1.1 g, 5.97 mmol) in dry DMF (0.7 MI) at 0° C. The reaction mixture was further heated to 110° C. for 1.5 h, then cooled to room temperature and quenched with ice water. The Ph of the reaction mixture was adjusted to ˜7 using aqueous Na2CO3 solution. The organic product was extracted with diethyl ether and the combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get methyl 4-(5-formylthiophen-2-yl)butanoate (1.0 g, yield 83%), which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 9.82 (s, 1H), 7.63-7.61 (d, J=3.7 Hz, 1H), 6.94-6.92 (m, 1H), 3.68 (s, 3H), 2.96-2.91 (t, J=7.5 Hz, 2H), 2.42-2.37 (m, 2H), 2.09-1.99 (m, 2H). MS (ESI) m/z: Calculated for C10H12O3S: 212.05. found: 212.9 (M+H)+
Reaction SMILES: [NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:18]([NH:20][C@H:21]([C:23]([NH:25][C@H:26]([C:37]([O:39]C)=[O:38])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:24])[CH3:22])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[Li+].[OH-].C1(NC2CCCCC2)CCCCC1.CCOCC>C1COCC1.CO>[NH:1]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[C@H:2]([C:18]([NH:20][C@H:21]([C:23]([NH:25][C@H:26]([C:37]([OH:39])=[O:38])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:24])[CH3:22])=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 63.7 %

Procedure:
compound NR66. Saponification of N-Boc-Tyr(Bn)-Ala-Trp-OMe (580 mg, 0.902 mmol) in THF (5 mL) by 1 M aqueous LiOH (2 mL, 2 mmol) at 4° C. for 1 hour, afforded after acidic treatment and precipitation of the residue with water crude N-Boc-Tyr(Bn)-Gly-Trp-OH. The crude product in MeOH (0.5 mL) was treated by dicyclohexylamine (0.18 mL, 0.91 mmol) and then ether (10 mL). After filtration, the resulting solid was dissolved in CH2Cl2 (10 mL) and washed by 10% aqueous citric acid. The organic phase was dried over MgSO4 and concentrated to afford N-Boc-Tyr(Bn)-Ala-Trp-OH (361 mg, 64%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (d, J=7 Hz, 3H, CH3), 1.28 (s, 9H, (CH3)3), 2.62 and 2.86 (ABX system, 2H, CH2β), 3.09 and 3.18 (ABX system, 2H, CH2β), 4.10 (m, 1H, CHα), 4.35 (m, 1H, CHα), 4.46 (m, 1H, CHα), 5.03 (s, 2H, CH2 (OBn)), 6.87-7.54 (m, 15H, 14 aromatic H+1 NH), 7.96 (d, J=7.5 Hz, 1H), 8.13 (d, J=7.5 Hz, 1H), 10.84 (s, 1NH). 13C NMR (75 MHz, CDCl3) δ 18.2 (CH3), 27.2 (CH2 Trp), 28.3 ((CH3)3), 37.3 (CH2 Tyr), 48.9, 53.3, 55.7 (CHα Ala, Tyr or Trp), 70.0 (CH2 (OBn)), 80.7 (C(CH3)3), 109.5 (aromatic C), 111.5, 115.0, 118.6, 119.5, 121.9, 123.8, 127.5, 127.6, 128.1, 128.6, 130.4 (aromatic CH), 136.1, 137.0, 137.1 (aromatic C), 155.8, 157.8 (Car-O or CO carbamate), 171.9, 172.3, 174.2 (2 CO amide or CO acid). Anal. Calcd. for C35H40N4O7, 1.5H2O: C, 64.11%; H, 6.61%; N, 8.54%. Found: C, 64.19%; H, 6.36%; N, 8.79%.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5](N)=[CH:4][C:3]=1[O:11][CH3:12].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[Na+].II.S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([I:22])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: [I-]
Reactant: COc1cc(N)cc(OC)c1Cl
Agent: II
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(I)cc(OC)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
4-Chloro-3,5-dimethoxyaniline (2) (6.61 g, 35.2 mmol) was added to a mixture of sulfuric acid (9.39 mL, 176 mmol) and H2O (100 mL) at 00° C. Sodium nitrite (3.16 g, 45.8 mmol) was added and the reaction mixture was stirred at 0° C. for 30 min. The mixture was added to a pre-warmed mixture of sodium iodide (21.1 g, 141 mmol), iodine (4.47 g, 17.6 mmol), sulphuric acid (8 mL) and H2O (100 mL) at 80° C. and the resulting mixture was heated at reflux for 30 min. The mixture was allowed to cool to RT and then 40% sodium thiosulfate solution (200 mL) was added. The product was extracted with EtOAc (300 mL), the solvent was removed in vacuo and the residue was purified by silica gel chromatography (120 g, 0-50% EtOAc in isohexanes) to afford 2-chloro-5-iodo-1,3-dimethoxybenzene (3) (7.16 g, 67% yield).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[F:27].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([F:27])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH2:25][CH3:26])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(C(=O)OC)c(F)c2)c1C#Cc1ccc(N)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ncnc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
Temperature: 25 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 17.8 g (47.3 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoic acid methyl ester using 3.97 g (94.6 mmoL) LiOH in 30 mL water and 300 mL THF. The reaction mixture is stirred over night at RT. The solvent is removed under reduced pressure and the residie is taken up in water. Aqueous 1 M HCl is added until pH 5 is reached. The precipitated product is filtered off and washed with ACN. After drying 17.1 g (85%) of the desired product are obtained a solid material.
Reaction SMILES: C1OC2C=CC(C(NC3(C(OCC)=O)CCCCC3)=O)=CC=2O1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][C:36]2([C:42]([O:44]CC3C=CC=CC=3)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][C:36]2([C:42]([OH:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)cc1
Agent: CCOC(=O)C1(NC(=O)c2ccc3c(c2)OCO3)CCCCC1
Product: COc1ccc(S(=O)(=O)NC2(C(=O)O)CCCCC2)cc1
Yield: 57.4 %

Procedure:
Subsequently, the same procedure as in Reference Example 4 was repeated except that the ethyl 1-[N-(3,4-methylenedioxyphenylcarbonyl)amino]cyclohexanecarboxylate was replaced by 1.0 g (2.5 mmol) of phenylmethyl 1-[N-(4-methoxybenzenesulfonyl)amino]cyclohexanecarboxylate, whereby 450 mg of the captioned 1-[N-(4-methoxybenzenesulfonyl)amino]cyclohexanecarboxylic acid was obtained in a yield of 26%.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][NH:6][NH2:7])[CH3:2].C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C>C(O)C>[NH2:19][C:18]1[N:6]([CH2:5][CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])[N:7]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: CCOC=C(C#N)C#N
Reactant: CCOC(CNN)OCC
Solvent: CCO
Product: CCOC(Cn1ncc(C#N)c1N)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.2 %

Procedure:
To a solution of hydrazinoacetaldehyde diethyl acetal (52.6 g) in ethanol (110 ml) was added dropwise a solution of ethoxymethylenemalononitrile (41.5 g) in ethanol (420 ml) at room temperature. The mixture was stirred at ambient temperature for 24 hours. The reaction mixture was evaporated in vacuo. To the residue was added diethyl ether (400 ml) and the resultant precipitate was filtered off. The filtrate was subjected to column chromatography on silica gel using a mixture of ethyl acetate and hexane (2:3) as an eluent. Fractions containing the object compound were combined and evaporated to give 5-amino-4-cyano-1-(2,2-diethoxyethyl)pyrazole (23.0 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[NH:39]1[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]1>>[O:45]=[S:42]1(=[O:46])[CH2:43][CH2:44][N:39]([CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:6][C:7](=[O:31])[C:8]2[CH:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[O:26][CH:27]=[CH:28][C:29]=4[CH3:30])=[O:24])[CH:17]=3)[CH:11]=[N:10][CH:9]=2)[CH2:40][CH2:41]1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCN3CCS(=O)(=O)CC3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and thiomorpholine-1,1-dioxide were converted to the title compound.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][N:15]3[N:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][N:15]3[N:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)=[N:11][CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cnc(Cn3ncc([N+](=O)[O-])n3)s2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2cnc(Cn3ncc(N)n3)s2)OCCO1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-4-nitro-2H-[1,2,3]triazole (220 mg, 0.74 mmol), iron powder (125 mg, 2.22 mmol) and NH4Cl (200 mg, 3.70 mmol) in a mixture of EtOH (3.0 mL) and water (1.5 mL) was stirred at 75° C. for 60 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by 1N NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil: TLC:rf (19:1 CH2Cl2-MeOH)=0.2. LC-MS-conditions 02: tR=0.66 min.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:27][C:28]([F:39])([F:38])[O:29][C:30]1[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][CH:31]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:38])[F:39])=[CH:35][CH:34]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: FC(F)(F)Oc1ccc([Mg]Br)cc1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(OC(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-trifluormethoxyphenylmagnesium bromide.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:31][NH2:32]>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:32][CH2:31][C:30]1[CH:29]=[C:28]([F:27])[CH:35]=[C:34]([F:36])[CH:33]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: NCc1cc(F)cc(F)c1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2cc(F)cc(F)c2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 44.4 %

Procedure:
A mixture of intermediate 59 (0.50 g, 1.36 mmol), 3,5-difluorobenzylamine (0.481 mL, 4.07 mmol) and MeOH (0.1 mL) is heated at 100° C. for 3 days. The reaction mixture is cooled to RT, and is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (75:25-60:40) gives 0.28 g of the product 89. 1H NMR (CDCl3) δ 7.10-6.60 (m, 14 H), 5.45-5.35 (m, 2 H), 4.75-4.55 (m, 2 H), 1.16 (s, 9 H); MS: m/z 464 (M++1).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[C:19]([O:23][C:24](=[O:44])[NH:25][CH2:26][C@H:27]([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[CH3:28])([CH3:22])([CH3:21])[CH3:20]>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:32]1[CH:31]=[CH:30][C:29]([C@H:27]([CH3:28])[CH2:26][NH:25][C:24](=[O:44])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:34][CH:33]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CNC(=O)OC(C)(C)C)cc1
Yield: 61.3 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.46 mmol) was reacted with (S)-tert-butyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (251 mg, 0.69 mmol) to afford the desired product (135 mg, 62%) as a light brown solid: ESI MS m/z 479 [C27H30N2O4S+H]+.