Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:13].[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>CCOC(C)=O>[CH3:6][C:7]1[CH:12]=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][N+:8]=1[O-:13]
Reactant: Cc1cccc[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A 25 mL round bottom flask was charged with conc. H2SO4 (1 mL) and cooled to 0° C. 2-Methylpyridine 1-oxide (0.4 g, 0.003 mol, Aldrich) was added in one portion, followed by the addition of fuming HNO3 (1 mL, spectrochem, india) in a drop-wise fashion. The reaction was stirred at rt for 30 min and a further 12 h at 70° C. Reaction progress was monitored by TLC (50% EtOAc in petroleum ether). After completion of the reaction, EtOAc (10 mL) was added to the reaction mixture after cooling to 0° C. and the reaction was neutralized to pH˜8-9 with 40% NaOH solution, and extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (d, J=5.4 Hz, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.92 (dd, J=1.8, 5.1 Hz, 1H), 2.64 (s, 3H).
Reaction SMILES: CO.[Br:3][C:4]1[CH:5]=[C:6]([Cl:13])[C:7]([Cl:12])=[C:8]([CH:11]=1)[CH:9]=[O:10].[BH4-].[Na+]>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([Cl:13])[C:7]([Cl:12])=[C:8]([CH2:9][OH:10])[CH:11]=1
Reactant: O=Cc1cc(Br)cc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(Br)cc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 5:1 (v/v) MeOH:THF solution (0.38 M) of 5-bromo-2,3-dichlorobenzaldehyde (1 eq.) from Step 1, Amine 5 was added at 0° C. sodium borohydride (1.1 eq.) portionwise over 45 min. The reaction solution was stirred at 0° C. for 2 h before the volatiles were removed in vacuo. The resulting residue was then partitioned between ether and 10% aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc) afforded the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]1[O:27][C:26]2[C:21](=[C:22]([OH:28])[CH:23]=[CH:24][CH:25]=2)[O:20]1>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:28][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[O:27][CH2:19][O:20][C:21]=23)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Oc1cccc2c1OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2cccc3c2OCO3)ncn1
Temperature: 80 °C
Reaction time: 7 h
Yield: 68 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate, and 138 mg of 2,3-methylenedioxyphenol, followed by stirring at 80° C. for 7 hours and then at 120° C. for 3 hours. The reaction mixture was then left for cooling to room temperature and subjected to phase separation three times between ethyl acetate and an aqueous sodium chloride solution. The organic layers were dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 193 mg of 4-(2-butynyloxy)-6-(2,3-methylenedioxyphenoxy)pyrimidine (the present compound (64)).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[C:11]([NH:15][C:16](=[O:32])[C:17]([NH:28][C:29](=[O:31])[CH3:30])([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:18][CH2:19][CH:20]=[CH2:21])([CH3:14])([CH3:13])[CH3:12].Cl[C:34]1[O:35][C:36]2[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:37]=2[N:38]=1>CC(N(C)C)=O.C(OCC)C>[C:29]([NH:28][C:17]([CH:22]1[CH2:27][CH2:26][N:25]([C:34]2[O:35][C:36]3[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:37]=3[N:38]=2)[CH2:24][CH2:23]1)([CH2:18][CH2:19][CH:20]=[CH2:21])[C:16]([NH:15][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:32])(=[O:31])[CH3:30]
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CCNCC1
Reactant: Clc1ccc2nc(Cl)oc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)C1CCN(c2nc3ccc(Cl)cc3o2)CC1
Temperature: 95 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Hunigs base (2.5 mL) was added to a stirred suspension of 2-acetylamino-2-piperidin-4-yl-hex-5-enoic acid tert-butylamide hydrochloride (250 mg, 0.73 mmol) and 2,6-dichlorobenzoxazole (172 mg, 0.91 mmol) in anhydrous dimethylacetamide (5 mL). The reaction was stirred at 95° C. overnight under an atmosphere of nitrogen. After heating over night, the reaction mixture was cooled to room temperature and then diluted with diethyl ether. The organic layer was washed with saturated aqueous sodium chloride (3×), dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, 20-80% ethyl acetate in heptane) to give 2-acetamido-N-tert-butyl-2-(1-(6-chlorobenzo[d]oxazol-2-yl)piperidin-4-yl)hex-5-enamide as an off-white solid (240 mg, 72%). 1H NMR (CDCl3, 300 MHz) δ 7.24 (d, J=2 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.12 (dd, J1=8.5 Hz, J2=2 Hz, 1H), 7.02 (s, NH, 1H), 5.79 (m, 1H), 5.50 (s, NH, 1H), 4.98 (m, 2H), 4.34 (m, 2H), 3.00 (m, 3H), 2.49 (tt, J1=12.5 Hz, J2=3 Hz, 1H), 2.10-1.96 (m, 1H), 2.03 (s, 3H), 1.74-1.93 (m, 3H), 1.49 (m, 1H), 1.33 (s, 9H), 1.18-1.28 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([F:8])[CH:5]=[CH:6][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1c(F)cccc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(F)ccc([N+](=O)[O-])c1Cl
Reaction time: 0.08 h

Procedure:
1-Chloro-3-fluoro-2-methylbenzene (1.00 mL, 8.24 mmol) was dissolved in sulfuric acid (18 M, 10 mL) and cooled in an ice bath. Potassium nitrate (0.87 g, 8.65 mmol) dissolved in sulfuric acid (18 M, 10 mL) was added dropwise to the cold solution. The reaction mixture was stirred for 5 min, then the ice bath was removed and stirring was continued for another 2 h. The reaction mixture was poured onto ice (25 g) stirred for 5 min and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give a clear yellow oil (1.34 g, purity 85%). The product was used without further purification in the next reaction step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].I[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCCCCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 90 °C
Reaction time: 3.75 h

Procedure:
4-Bromo-4′-hydroxybiphenyl (12.5 g, 50.2 mmol) was added to a solution of NaOH (2.28 g, 97% pure, 55.2 mmol) in deionized H2O (150 ml), followed by the addition of 1-iodopentane (11.9 g, 60.2 mmol) and tetrabutylammonium bromide (0.82 g, 2.51 mmol). The mixture was stirred at 90° C. for 3.75 h until the solids went into solution. Then, as the reaction proceeded, the desired product began to precipitate. The mixture was slowly cooled and then filtered to provide a solid which was washed with deionized water until the pH of the filtrate was neutral and then dried for 16 h in a vacuum oven at 30° C. Yield: 15.41 g (96%) of 5a. Rf 0.5 (97:3 hexanes/EtOAc). 1H NMR: δ 0.93 (t, 3H, J=6.9 Hz); 1.41 (m, 4H); 1.79 (m, 2H); 3.97 (t, 2H, J=6.6 Hz); 6.98 (m, 2H); 7-23 (m, 6H). 13C NMR: δ 14.03; 22.43; 28.22; 28.98; 68.12; 114.91; 120.71; 127.93; 128.27; 131.77; 132.24; 139.82; 159.03. MS(FAB+): m/z 320. IR(CHC13): 2960, 2936, 2874, 1608, 1518, 1485, 1475 cm−1. Analysis for C17H19BrO: Calcd: C, 63.96; H, 6.00; Br, 25.0. Found: C, 64.10; H, 5.97; Br, 25.28.
Reaction SMILES: [C:1]([C:3]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)#[N:2].Cl.[CH3:23][NH2:24]>>[C:1]([C:3]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]1[CH2:7][CH2:8][CH:9]([C:12]([NH:24][CH3:23])=[O:14])[CH2:10][CH2:11]1)#[N:2]
Reactant: CN
Reactant: N#Cc1c(OC2CCC(C(=O)O)CC2)cccc1[N+](=O)[O-]
Agent: Cl
Product: CNC(=O)C1CCC(Oc2cccc([N+](=O)[O-])c2C#N)CC1

Procedure:
Prepared as in Example Da from 4-(2-cyano-3-nitrophenoxy)cyclohexanecarboxylic acid (Example 22d) and methylamine hydrochloride as an orange solid (80%). MS 304 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:20]([OH:24])[C:21]([NH2:23])=[O:22].O[NH-].O=[N-]>>[NH2:23][C:21](=[O:22])[C:20](=[O:24])[CH:19]([NH:18][C:15]([C@H:9]1[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:17])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)[C@H]1CCCC(=O)N1Cc1ccccc1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCCC(=O)N1Cc1ccccc1

Procedure:
Coupling of (R)-1-benzyl-6-oxo-piperidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [C:1]([CH:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:7][CH:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5]1)(=[O:3])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[NH:31][CH2:32][C:33](O)=[O:34])[CH:26]=[CH:27][CH:28]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[C:1]([CH:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]([C:33](=[O:34])[CH2:32][NH:31][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=2)=[O:36])[CH:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(=O)C1CC(C(=O)OC(C)(C)C)NC1c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CC(=O)C1CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C)c2)C1c1ccccc1
Yield: 13.6 %

Procedure:
The reaction is carried out in a way analogous to that described in Example 2B, but from 4.5 g of tert-butyl (2RS,4RS,5SR)-4-acetyl-5-phenylpyrrolidine-2-carboxylate, 3.2 g of 2-[3-(3-methylphenyl)ureido]acetic acid and 3.5 g of N,N'-dicyclohexylcarbodiimide in 50 cm3 of acetonitrile. After treatment, there is obtained 1 g of tert-butyl (2RS,4RS,5SR)-4-acetyl-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylpyrrolidine-2-carboxylate, melting at 100° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([CH:11]1[CH2:15][CH:14]([NH:16][C:17]([C:19]2[CH:20]=[CH:21][C:22]3[S:27][CH2:26][C:25](=[O:28])[NH:24][C:23]=3[CH:29]=2)=[O:18])[CH2:13][N:12]1[CH2:30][CH:31]1[CH2:44][C:43]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([O:45][CH3:46])[CH:41]=3)[N:36]=[CH:35][C:34]=2[S:33][CH2:32]1)=O>O1CCCC1>[OH:8][CH2:9][CH:11]1[N:12]([CH2:30][CH:31]2[CH2:44][C:43]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([O:45][CH3:46])[CH:41]=4)[N:36]=[CH:35][C:34]=3[S:33][CH2:32]2)[CH2:13][CH:14]([NH:16][C:17]([C:19]2[CH:20]=[CH:21][C:22]3[S:27][CH2:26][C:25](=[O:28])[NH:24][C:23]=3[CH:29]=2)=[O:18])[CH2:15]1
Reactant: COC(=O)C1CC(NC(=O)c2ccc3c(c2)NC(=O)CS3)CN1CC1CSc2cnc3ccc(OC)cc3c2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2ncc3c(c2c1)CC(CN1CC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1CO)CS3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium aluminium hydride (2.0 M solution in tetrahydrofuran, 85 μL, 0.17 mmol, 1.1 eq) is cautiously added at room temperature to a stirred solution of 1-(6-methoxy-3,4-dihydro-2H-1-thia-9-aza-phenanthren-3-ylmethyl)-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester (110 mg, 0.15 mmol, 1.0 eq) in tetrahydrofuran (5 mL). After 1 hour stirring at room temperature, the reaction mixture is cautiously quenched with ice-water (5 mL) and extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [5-hydroxymethyl-1-(6-methoxy-3,4-dihydro-2H-1-thia-9-aza-phenanthren-3-ylmethyl)-pyrrolidin-3-yl]-amide as an off-white lyophilized powder (14 mg, 16% yield).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH3:19])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:20][C:21]1[N:22]=[CH:23][N:24]([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=1>>[CH3:19][C:6]1[S:5][C:4]2[NH:1][C:2](=[S:3])[N:29]([CH2:28][CH2:27][CH2:26][N:24]3[CH:25]=[C:21]([CH3:20])[N:22]=[CH:23]3)[C:9](=[O:11])[C:8]=2[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cn(CCCN)cn1
Reactant: COC(=O)c1c(N=C=S)sc(C)c1-c1ccccc1
Product: Cc1cn(CCCn2c(=S)[nH]c3sc(C)c(-c4ccccc4)c3c2=O)cn1

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-5-methyl-4-phenylthiophene-3-carboxylate (0.100 g. 0.35 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.048 g, 0.35 mmol) as described above.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1S(C1C=CC(C)=CC=1)(=O)=O.C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[CH:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[C:7]1[CH2:2][CH2:3][CH2:4][CH2:5][N:6]12
Reactant: Cc1ccc(S(=O)(=O)c2cc3ccccc3n2CCCCBr)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)cc1n2CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a refluxing solution of 1-(4-bromobutyl)-2-tosyl-1H-indole (178 mg, 0.44 mmol) in 9.5 mL toluene was added dropwise over 5 min a mixture of tributyltin hydride (285 μL, 1.06 mmol) and 2,2′-azobisisobutyronitrile (14 mg, 0.088 mmol) in 22.5 mL toluene. The reaction mixture was refluxed 2 h, then concentrated in vacuo. To the crude product was added 125 μL H2O, 3 mL ethyl acetate, and 150 mg KF and stirred at room temperature overnight. Potassium carbonate was added and the mixture filtered and concentrated in vacuo. The process was repeated with another 125 μL H2O, 3 mL ethyl acetate, and 150 mg KF and stirred at room temperature 2 h. Potassium carbonate added and the mixture filtered and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 10% ethyl acetate in hexanes to give a final yield of 58 mg (0.34 mmol). 1H NMR (500 MHz, CDCl3, δ): 1.89-2.05 (m, 2H), 2.10-2.24 (m, 2H), 3.06 (t, J=6.1 Hz, 2H), 4.11 (t, J=6.1 Hz, 2H), 6.29 (s, 1H), 7.18 (t, J=7.1 Hz, 1H), 7.23 (t, J=7.4 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 21.76, 23.93, 24.75, 42.78, 97.98, 109.03, 120.06, 120.58, 128.71, 136.76, 137.63. MS m/z 172 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C1N=C[N:16](C(N2C=NC=C2)=O)C=1.C(=O)([O-])[O-].[NH4+].[NH4+].O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([NH2:16])=[O:5]
Reactant: CN(C)c1ccc(Br)c(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(Br)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
To a solution of give 2-bromo-5-(dimethylamino)benzoic acid (7.89 g, 32.3 mmol) in DMF (25 mL) was added N,N-carbonyldiimidazole (13.1 g, 80.8 mmol). The reaction mixture was allowed to stir at rt for 30 min and then ammonium carbonate (14.0 g, 145 mmol) was added. The reaction mixture was allowed to stir at rt overnight and then poured into water. The mixture was extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered and concentrated to give 2-bromo-5-(dimethylamino)benzamide (2.14 g, 27%). The product could be further purified by recrystallization from MeOH.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:7]([CH:20]=[CH:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(2,4-dichlorophenyl)-5-(pent-1-enyl)pyridine (Example 147) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.80 (t, J=7.0 Hz, 3 H), 1.12-1.48 (m, 18 H), 2.12 (m, 1 H), 2.35 (m, 1 H), 3.26 (m, 1 H) 3.45 (m, 1 H), 4.31 (AB, J=12.0 Hz, 2 H), 7.16 (d, J=8.0 Hz, 1 H), 7.36 (dd, J=8.0, 2.0 Hz, 1 H), 7.54 (d, J=2.0, 1 H). Rf0.38 (10% ethyl acetate/n-hexane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[CH2:4][CH:5]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C:6]([CH3:37])([CH3:36])[C:7](=[O:35])[CH:8]([CH3:34])[CH:9]([OH:33])[CH:10]([CH3:32])[CH2:11][CH2:12][CH2:13][C:14]([CH3:31])=[CH:15][CH2:16][CH:17]([O:27][C:28](=[O:30])[CH3:29])[C:18]([CH3:26])=[CH:19][C:20]1[N:21]=[C:22]([CH3:25])[S:23][CH:24]=1.N1C=CN=C1.[CH2:52]([Si:54](Cl)([CH2:57][CH3:58])[CH2:55][CH3:56])[CH3:53]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:46])[CH2:4][CH:5]([O:38][Si:39]([C:42]([CH3:44])([CH3:43])[CH3:45])([CH3:41])[CH3:40])[C:6]([CH3:36])([CH3:37])[C:7](=[O:35])[CH:8]([CH3:34])[CH:9]([O:33][Si:54]([CH2:57][CH3:58])([CH2:55][CH3:56])[CH2:52][CH3:53])[CH:10]([CH3:32])[CH2:11][CH2:12][CH2:13][C:14]([CH3:31])=[CH:15][CH2:16][CH:17]([O:27][C:28](=[O:30])[CH3:29])[C:18]([CH3:26])=[CH:19][C:20]1[N:21]=[C:22]([CH3:25])[S:23][CH:24]=1
Reactant: COC(=O)CC(O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)C(C)C(O)C(C)CCCC(C)=CCC(OC(C)=O)C(C)=Cc1csc(C)n1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C(C)CCCC(C)=CCC(OC(C)=O)C(C)=Cc1csc(C)n1)C(C)C(=O)C(C)(C)C(CC(=O)OC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 115 mg (0.17 mmol) 15-acetoxy-3-(tert-butyl-dimethyl-silanyloxy)-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-thiazol-4-yl)-5-oxo-heptadeca-12,16-dienoic acid methyl ester (289) and 36 mg (0.50 mmol) imidazole in 1000 μl absolute DMF was cooled to 0° C. After addition of 84 μl (0.50 mmol) triethylsilylchloride, the icebath was removed and the solution was stirred for 3 h 15 min at ambient temperature before 5.0 mL diethylether were added. The organic layer was washed with demi water (2×1000 μl) as well as with brine (1×1000 μl), dried over Na2SO4, filtrated and concentrated in vacuo. The remaining oil was purified via flash chromatography (column dimensions: 1.0×20.0 cm, diethylether/petroleum ether=1:1).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:5][C:6]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O)[CH3:4].[BH4-].[Na+]>>[CH2:3]([O:5][C:6]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][CH2:1][NH2:2])[CH3:4]
Reactant: CCOc1c(C=O)cccc1C(C)C
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Product: CCOc1c(CCN)cccc1C(C)C
Reaction time: 72 h
Yield: 94 %

Procedure:
A solution of methylamine (30 mL of a 2.0 M solution, 60 mmol) was added to 2-ethoxy-3-isopropylbenzaldehyde (1.49 g, 7.75 mmol) and the mixture was stirred for 72 h. The solution was concentrated under reduced pressure. The residue was dissolved in EtOH (30 mL) and treated with NaBH4 (0.293 g, 7.75 mmol). After stirring for 18 h, the reaction mixture was concentrated under reduced pressure and then dissolved in 1 N NaOH (30 mL). The mixture was extracted with Et2O (3×50 mL). The combined organics were collected, washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (1.51 g, 94%) as a light yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.21-7.13 (m, 2H), 7.04 (t, J=7.5 Hz, 1H), 3.79 (q, J=7.0 Hz, 2H), 3.63 (s, 2H), 3.28-3.23 (m, 1H), 2.29 (s, 3H), 1.93 (br s, 1H), 1.35 (t, J=3.8 Hz, 3H), 1.16 (d, J=6.9 Hz, 6H).
Reaction SMILES: C([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:6]=1[C:15]([F:18])([F:17])[F:16])(=O)C>Cl>[NH2:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:6]=1[C:15]([F:18])([F:16])[F:17]
Reactant: CC(=O)Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Agent: Cl
Product: Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Yield: 83 %

Procedure:
A mixture of 2-acetamido-5-chloro-3-nitrobenzotrifluoride (354 mg, 1.252 mmol) in concentrated HCl (3 mL) was refluxed overnight, and it was extracted by ethyl acetate (2×3 mL). The extract was dried (Mg2SO4) and evaporated to give 250 mg (83% ) of 2-amino-5-chloro-3-nitrobenzotrifluoride. 1H NMR (CDCl3): δ 6.663 (s, 2H), 7.717 (s, 1H), 8.360 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[N:9]2[CH3:22])[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:22])[CH:8]([C:4]1[CH:3]=[C:2]([NH:23][C:24]3([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]3)[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18])#[N:21]
Reactant: CN1c2ccc(C#N)cc2C(C)(C)CC1c1cccc(Br)c1
Reactant: NC1(C(=O)O)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1c2ccc(C#N)cc2C(C)(C)CC1c1cccc(NC2(C(=O)O)CC2)c1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
A solution of 2-(3-bromo-phenyl)-1,4,4-trimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (354.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(6-cyano-1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (113.4 mg, 30.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 376.3.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N1CCOCC1)C.[NH2:46][C@H:47]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[CH3:58])[CH2:48][C:49]([OH:51])=[O:50]>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:13]([NH:46][C@H:47]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:58])[CH2:48][C:49]([OH:51])=[O:50])=[O:15])[CH:3]=1
Reactant: Nc1cc(C(=O)O)nn1-c1ccccc1
Reactant: Cc1ccccc1[C@@H](N)CC(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1cc(N)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.492 mmol) of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid are dissolved in 5 ml of DMF, 194 mg (0.59 mmol) of TOTU and 142 mg (1.23 mmol) of N-ethyl-morpholine is added. After stirring for 10 minutes at RT 97 mg (1.1 Eq, 0.54 mmol) of (S)-3-amino-3-(2-methyl-phenyl)-propionic acid are added and the resulting mixture is stirred overnight at RT. Solvent is removed in vacuo and the obtained crude product is submitted to HPLC chromatography: Yield: 32 mg, 18%