Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].P([O-])([O-])([O-])=O>CN(C=O)C>[Si:32]([O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:18])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCCOCCCCCCBr
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO[Si](C)(C)C(C)(C)C)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.83 g) in DMF (20 ml) was treated with sodium hydride (60% dispersion in mineral oil, 0.20 g) and the mixture stirred under nitrogen at 20° C. for 30 min. A solution of {2-[(6-bromohexyl)oxy]ethoxy}(tert-butyl)dimethylsilane (1.47 g) in DMF (4 ml) was added and the mixture stirred at 20° C. for 90 min. Phosphate buffer (20 ml, pH6.5) was added, before partitioning between EtOAc (50 ml) and water (50 ml). The layers were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic layer was washed with water (3×50 ml) and dried over Na2SO4 before filtering. Solvent evaporation in vacuo gave a residue which was purified by flash chromatography on silica. Elution with EtOAc-cyclohexane (1:1) followed by solvent evaporation in vacuo gave the title compound (0.84 g). LCMS RT=4.11 min, ES+ve 507 (MH)+.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[N:23]=[CH:22][CH:21]=[CH:20][C:13]=1[C:14]([NH:16][CH2:17][C:18]#[CH:19])=[O:15].[N:24]([CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=1)=[N+:25]=[N-:26].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[CH3:35][O:34][C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([O:36][CH3:37])[CH:31]=1)[CH2:27][N:24]1[CH:19]=[C:18]([CH2:17][NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][CH:22]=[N:23][C:12]=2[NH:11][C:4]2[CH:3]=[CH:8][C:7]([O:9][CH3:10])=[CH:6][CH:5]=2)[N:26]=[N:25]1
Reactant: C#CCNC(=O)c1cccnc1Nc1ccc(OC)cc1OC
Reactant: COc1cc(CN=[N+]=[N-])cc(OC)c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(Nc2ncccc2C(=O)NCc2cn(Cc3cc(OC)cc(OC)c3)nn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.8 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 2,4-dimethoxyaniline (9e, 153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10g as pure product. To a solution of 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10 g, 150 mg, 0.48 mmol) and 1-(azidomethyl)-3,5-dimethoxybenzene (12d, 102 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 12 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 6e (175 mg, 72%); mp: 147-149° C.; 1H NMR (500 MHz, CDCl3) δ 10.36 (s, 1H), 8.25 (dd, J=5.0, 3.0 Hz, 1H), 7.73 (dd, J=7.0 Hz, 1H), 7.53 (s, 1H), 7.15 (brs, 1H), 6.58-6.54 (m, 1H), 6.47-6.43 (m, 2H), 6.36 (s, 3H), 5.41 (s, 2H), 4.66 (d, J=5.2 Hz, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 3.74 ppm (s, 6H) MS (ESI m/z): 505 [M+H]+. Yield: 72%
Reaction SMILES: N1C=CC=CC=1.C(OC(=O)C)(=O)C.[C:14]([N:17]1[CH2:21][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:19]([O:28][C@H:29]([C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=2)[CH3:30])[CH2:18]1)(=[O:16])[CH3:15]>C(Cl)Cl>[C:14]([N:17]1[CH2:21][C@H:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:19]([O:28][C@@H:29]([C:31]2[CH:32]=[C:33]([C:41]([F:42])([F:43])[F:44])[CH:34]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:36]=2)[CH3:30])[CH2:18]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1C[C@H](O[C@@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccccc2)C1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1C[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 200 mg intermediate step E (0.47 mmol) in 3 mL dry methylene chloride at 0° C. was added 0.097 mL pyridine (1.18 mmol) followed by 0.089 mL acetic anhydride (0.94 mmol). The reaction mixture was stirred for 6 hr at ambient temperature then the volatiles were removed under vacuum. The residue was partitioned between 2N aq. NaOH (5 mL) and methylene chloride (10 mL). The layers were separated and the aqueous layer extracted with methylene chloride (2×5 mL). The combined organic extracts were dried over sodium sulfate, filtered and solvent evaporated under vacuum. The resulting material was purified by preparative TLC eluting with methylene chloride/methanol (9/1). The resulting material was further purified by prep HPLC on Chiralpak AD column eluting with heptanes/ethanol (97/3) to afford a minor faster moving isomer A (3R,4S)-1-acetyl-3-({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-phenylpyrrolidine and the title compound. 1H-NMR (CDCl3) rotamers: δ: 1.45 (t, 3H, 6.5 Hz), 2.15 (2s, 3H) 3.38-3.63 (m, 3H), 3.85-4.03 (m, 3H), 4.58 (m, 1H), 7.1 (m, 2H), 7.25 (m, 3H), 7.61 (s, 2H), 7.78 (s, 1H)ppm. MS: 446 (MH)+ observed.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][N:3]=1.ClCCl.ClC1C=CC=CN=1.[NH2:30][NH2:31]>>[CH3:13][C:11]1[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:30][NH2:31])=[N:3][CH:4]=2)=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1
Reactant: Cc1nc(-c2ccccc2)c(-c2ccc(Cl)nc2)o1
Reactant: NN
Agent: Clc1ccccn1
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)c(-c2ccc(NN)nc2)o1
Temperature: 70 °C

Procedure:
A mixture of 120 mg of 2-chloro-5-(2-methyl-4-phenyl-oxazol-5-yl)-pyridine in 1 mL of hydrazine (98%) was heated at 70° C. for 45 min before adding 0.5 mL of dichloromethane to get better mixing of the hydrazine and the chloro-pyridine. When the dichloromethane had evaporated 0.5 mL of ethanol was added and the mixture was heated for 11 hours. The layers were separated. The ethanol layer was diluted with ethyl acetate and washed with aqueous sodium carbonate (2×), dried (magnesium sulfate), filtered, and the filtrate was evaporated to give 110 mg of crude 5-(2-Methyl-4-phenyl-oxazol-5-yl)-pyridin-2-yl-hydrazine as an orange solid. This material was used with out purification in the next step.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.[CH:9]([C@H:12]1[CH2:16][O:15][C:14](=[O:17])[NH:13]1)([CH3:11])[CH3:10].[H-].[Na+]>CN(C=O)C.O>[F:1][C:2]1[N:7]=[C:6]([N:13]2[C@@H:12]([CH:9]([CH3:11])[CH3:10])[CH2:16][O:15][C:14]2=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccnc(F)n1
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(F)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.6 %

Procedure:
A solution of 2,4-difluoropyrimidine (3.5 mL, 41 mmol) and (S)-4-isopropyloxazolidin-2-one (5.3 g 41 mmol) in 30 mL DMF was cooled to 0° C. under N2 atmosphere. NaH (2.1 g of 60% suspension, 53 mmol) was slowly added. Bubbling exotherm observed. Internal temp was kept below 5° C. After 5 minutes, cold bath was removed. Reaction mixture (a sandy suspension) was allowed to warm to room temp and stir 18 h. The reaction mixture was diluted with water (100 mL) and extracted with (3×75 mL) EtOAc. Organic layer was washed with 50 mL each water, and brine. Dried over Na2SO4, and concentrated on silica gel in vacuo. Column chromatography (EtOAc/heptane 10 to 100% gradient) gave 3.1 g (S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (IV) as a crystalline white solid (33%). 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=5.8, 2.2 Hz, 1H), 8.19 (dd, J=5.8, 3.8 Hz, 1H), 4.79 (dt, J=8.1, 3.5 Hz, 1H), 4.48-4.34 (m, 2H), 2.64 (heptd, J=7.0, 3.6 Hz, 1H), 1.01 (d, J=7.0 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H). MS m/z 471.8 and 471.8 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[O:30][CH3:31].C(O)(C(F)(F)F)=O>>[CH:14]1([N:7]2[CH2:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Yield: 64.2 %

Procedure:
2-Chloro-9-cyclopentyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (Intermediate 1) (0.70 g, 2.5 mmol, 1 eq), 4-amino-3-methoxybenzoic acid (1.25 g, 7.5 mmol, 3 eq) and TFA (0.93 mL, 12.5 mmol, 5 eq) were heated to reflux in TFE (25 mL) for 20 hours. Solvent was evaporated in vacuo and the resulting residue was triturated with MeOH to give 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (0.66 g, 64%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N(CC)CC)C.[C:23](=[S:25])=[S:24].Cl>CS(C)=O>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:23]([SH:25])=[S:24]
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)S
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
(3S)-3-Hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (2.02 g) is dissolved in dimethylsulfoxide (10 ml), and thereto are added triethylamine (1.67 ml) and CS2 (0.72 ml), and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured onto ice-water and is neutralized with 10% HCl. The precipitated crystals are collected by filtration, washed with water and then recrystallized from methanol to give the title compound (1.46 g, 60%) as colorless needles, m.p. 225°-227° C. IR νmaxNujol (cm-1): 3480, 3340; Mass m/e: 278 (M+), 244 (M+ --H2S); [α]D20 +170.0° (c=1.0, methanol).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28][C:23]=3[N:24]([CH3:27])[C:25]=2[CH:26]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+].C>CS(C)=O.C(Cl)Cl.[Cu]I>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[C:22]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28][C:23]=5[N:24]([CH3:27])[C:25]=4[CH:26]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.4 %

Procedure:
A suspension of 4-(4-fluorobenzyloxy)pyridin-2(1H)-one (79 mg, 0.36 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (150 mg, 0.40 mmol), 8-hydroxyquinoline (11 mg, 0.072 mmol) and Cs2CO3 (129 mg, 0.40 mmol) in DMSO (10 mL) was degassed under reduced pressure for 40 min. CuI (82 mg, 0.43 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 2×5 min. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 5 min. Celite was added, and the suspension was stirred for 5 min. The suspension was filtered through Celite, and the filtrate was washed with brine. The resulting solution was dried over Na2SO4 and concentrated under reduced pressure. Purification by preparative TLC (DCM/MeOH/concentrated ammonia 98:1.8:0.2) gave partially purified product, which was dissolved in DCM and stirred with charcoal for 10 min. The suspension was filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (0.12 g, 64%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.52 (t, J=8.0 Hz, 1H), 7.41 (dd, J=8.5, 5.5 Hz, 2H), 7.31 (d, J=7.5 Hz, 1H), 7.24 (s, 1H), 7.10 (t, J=8.5 Hz, 2H), 7.00 (d, J=8.5 Hz, 1H), 6.07 (s, 1H), 6.02 (dd, J=7.5, 2.0 Hz, 1H), 5.01 (s, 2H), 3.78-3.63 (m, 4H), 3.64 (s, 3H), 3.05-2.98 (m, 4H), 1.50-1.48 (m, 9H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][NH2:18]>C1COCC1>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[N:18][CH3:17]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN
Solvent: C1CCOC1
Product: CN=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A solution of 3,5-bis(trifluoromethyl)-benzaldehyde (412 μL) in dry THF (5 mL) was added dropwise to a solution of methylamine (2M in MeOH—3.12 mL) in dry THF (5 mL) at 23° C. under a nitrogen atmosphere. The reaction mixture was stirred overnight, then the solvent was evaporated in vacuo to give the title compound (385 mg) as a colourless oil.
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:21][C:22]#[N:23]>CN(C)C=O>[S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:21][C:22]#[N:23])[CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCl
Reactant: Oc1cccc2c1SCCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1SCCC2
Temperature: 60 °C
Yield: 98.8 %

Procedure:
Under argon, 2 g (12.03 mmol) of 8-thiochromanol are dissolved in 15 cm3 of DMF. 5 g (36.09 mmol) of potassium carbonate and a catalytic amount of potassium iodide are added. Then 5.45 g (72.18 mmol) of chloroacetonitrile dissolved in 5 cm3 of dimethylformamide (DMF) are added dropwise. The mixture is heated at 60° C. for 4 hours, and then the solvent is evaporated off. The residue is taken up in H2O and extracted with methylene chloride and then dried over MgSO4. After evaporation, the product is purified over a silica column. Eluant: methanol/CH2Cl2 1:99. 2.44 g of 2-(thiochroman-8-yl-oxy)acetonitrile are obtained (melting point: 66° C.).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=[C:3]([NH2:10])C=1F.Cl.Cl.Cl.Cl.[CH3:17][N:18]([CH3:35])[CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][NH:31][NH:32][CH:33]=O)[CH:28]=2)[NH:23][CH:22]=1.N1C=NC=NC=1>C(O)C>[CH3:17][N:18]([CH3:35])[CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][N:31]3[CH:3]=[N:10][CH:33]=[N:32]3)[CH:28]=2)[NH:23][CH:22]=1
Reactant: CN(C)CCc1c[nH]c2ccc(CNNC=O)cc12
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Agent: c1ncncn1
Solvent: CCO
Product: CN(C)CCc1c[nH]c2ccc(Cn3cncn3)cc12
Yield: 84 %

Procedure:
A solution of the dihydrochloride of formic acid N′-[3-(2-dimethylamino-ethyl)-1H-indol-5-ylmethyl]-hydrazide (Example 18; 6.665 g, 20 mmol), and 1,3,5-triazine (1.081 g, 13.3 mmol) in ethanol (50 ml) is heated at reflux for six hours under a nitrogen atmosphere. From the slightly hazy yellow solution, the solvent is removed on the rotavapor, and the yellow residue is stirred with sodium hydroxide (100 ml 2N solution) and chloroform (100 ml). The organic layer is separated, washed with water (100 ml) and brine (100 ml) and dried (sodium sulfate). Removal of the solvent gives the product (4.54 g, 84%) as a slightly brown oil which solidifies on standing. 1H-NMR (CDCl3, 300 MHz) δ 2.26 (s, 6H, N(CH3)2); 2.56 (m, 2H, CH2); 2.83 (m, 2H, CH2NMe2); 5.27 (s, 2H, CH2N); 6.88 (d, 1H, J=2.0 Hz, H-2); 6.92 (dd, 1H, J=8.2 Hz, J=1.8 Hz, H-6); 7.15 (d, 1H, H-7); 7.40 (d, 1H, H-4); 7.84 (s, 1 H, triazol H-?); 7.89 (s, 1H, triazol H-?); 9.24 (br s, 1H, NH). 13C-NMR (CDCl3, 75 MHz) δ 23.68 (CH2); 45.50 (N(CH3)2); 54.88 (CH2N); 60.31 (CH2NMe2); 112.18 (C-7); 114.01 (C-3); 119.26 (C-4); 122.26 (C-6); 123.24 (C-2); 124.94 (C-5); 127.87 (C-9); 136.53 (C-8); 143.00 (triazol C-5); 151.88 (triazol C-3).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:22])/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].C1(N)CCCCC1.O>CO>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]([OH:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:15]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(O)/C=C/C(O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: NC1CCCCC1
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Yield: 62 %

Procedure:
Prepared analogous to Example 46 from the sodium salt of the 4-(3',4'-dichloro-4-biphenylyl)-4-hydroxy-crotonic acid in methanol. Yield: 62% of theory. Melting point of the cyclohexylamine salt: 158°-159° C. (from water).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:14])[C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[I-].[K+].Cl[CH2:18][CH2:19][CH2:20][C:21]#[CH:22].[OH-].[K+]>C(#N)C>[CH3:14][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([CH3:1])[C:12]=1[O:13][CH2:22][CH2:21][CH2:20][C:19]#[CH:18])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(C)c(O)c(C)c1
Reactant: C#CCCCCl
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: C#CCCCOc1c(C)cc(C(=O)OCC)cc1C
Yield: 86 %

Procedure:
A suspension of 6.42 g ethyl 3,5-dimethyl-4-hydroxybenzoate, 5.5 g potassium iodide, 3.7 g 1-chloro-4-pentyne and 2.3 g powdered potassium hydroxide in 650 ml acetonitrile was heated at reflux under nitrogen for 16 hrs. The mixture was filtered, concentrated in vacuo and subjected to flash filtration (silica gel, 4:1 hexane/ethyl acetate) to give 7.4 g ethyl 3,5-dimethyl-4-(3-ethynylpropoxy)benzoate as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].O.[C:10](OCC)(=[O:12])[CH3:11]>>[C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8])(=[O:12])[CH3:11]
Reactant: CCOC(C)=O
Reactant: NCCCCCCN
Solvent: O
Product: CC(=O)NCCCCCCN
Reaction time: 48 h
Yield: 65.8 %

Procedure:
A 50.1 g amount of 1,6-diaminohexane was admixed with 20 ml of water and 13.2 g of ethyl acetate to form a solution. The solution was kept at room temperature for 2 days and then water and ethanol were removed by distillation. The residue was distilled under reduced pressure. When 30 g of 1,6-diaminohexane were distilled as a fraction having a boiling point of 82°- 84° C (12 mmHg), 14.9 g of 6-acetamidohexylamine were obtained as a fraction having a boiling point of 170°- 175° C (7 mmHg) (yield 65.8%).
Reaction SMILES: COC1C=C(NC2N=CC3CC(=O)NC4C=CC(C(O)=O)=CC=4C=3N=2)C=CC=1OC.C(OC(=O)NCCCN)(C)(C)C.C(OC(=O)[NH:49][CH2:50][CH2:51][CH2:52][NH:53][C:54]([C:56]1[CH:82]=[CH:81][C:59]2[NH:60][C:61](=[O:80])[CH2:62][C:63]3[CH:68]=[N:67][C:66]([NH:69][C:70]4[CH:75]=[CH:74][C:73]([O:76][CH3:77])=[C:72]([O:78][CH3:79])[CH:71]=4)=[N:65][C:64]=3[C:58]=2[CH:57]=1)=[O:55])(C)(C)C>>[NH2:49][CH2:50][CH2:51][CH2:52][NH:53][C:54]([C:56]1[CH:82]=[CH:81][C:59]2[NH:60][C:61](=[O:80])[CH2:62][C:63]3[CH:68]=[N:67][C:66]([NH:69][C:70]4[CH:75]=[CH:74][C:73]([O:76][CH3:77])=[C:72]([O:78][CH3:79])[CH:71]=4)=[N:65][C:64]=3[C:58]=2[CH:57]=1)=[O:55]
Reactant: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)NCCCNC(=O)OC(C)(C)C)ccc2NC(=O)C3)cc1OC
Agent: CC(C)(C)OC(=O)NCCCN
Agent: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)O)ccc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)NCCCN)ccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described in Method N, 2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylic acid (I-43) and 3-amino-propyl-carbamic acid tert-butyl ester were converted to (3-{[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carbonyl]-amino}-propyl)-carbamic acid tert-butyl ester, which was subsequently deprotected (Method K) and purified by C-18 RP LC-MS chromatography to give I-76 (14%): HRMS Calcd. for C24H26N6O4: 463.2093, Found 463.2085.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N+:4]([O-])[C:3]=1[C:10]1[N+:11]([O-:16])=[CH:12][CH:13]=[CH:14][CH:15]=1.[C:17]([O:20]C(=O)C)(=[O:19])[CH3:18]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([C:10]2[N+:11]([O-:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:4][C:5]([CH2:8][O:20][C:17](=[O:19])[CH3:18])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C)[n+]([O-])c1-c1cccc[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1ccc(C)c(-c2cccc[n+]2[O-])n1
Reaction time: 20 h

Procedure:
A solution of 4 g (0.018 mol) of 3,6-dimethyl-2,2'-bipyridine 1,1'-dioxide in 20 ml chloroform is added dropwise, at 60° C. and under a nitrogen atmosphere, to 20 ml of acetic anhydride. The mixture is stirred for 20 hours at 60°-65° C. and then concentrated in vacuo. After the addition of 50 ml of water and 50 ml of ethyl acetate, the mixture is rendered alkaline with potassium carbonate. The water phase is separated off and washed with four times 50 ml of ethyl acetate/THF (ratio about 2:1 by volume). The combined organic phases are dried over sodium sulfate. After the solvent has been distilled off in vacuo, 4.44 g (96% of theory) of a brown crude product are obtained, which can be caused to crystallise at 0° C. The crude product can be employed direct for further reactions. After recrystallisation from diethyl ether, 73% of pure 3-methyl-6-acetoxymethyl-2,2'-bipyridine 1' -oxide are obtained; melting point 105°-107° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Cl:22][C:23]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:24]=1[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:25]([C:24]2[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:23]=2[Cl:22])=[O:26])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2cc(Br)ccc2Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 10 %

Procedure:
To a mixture of 4-amino-N-[(1,1-dimethylethoxy)carbonyl)-L-phenylalanine methyl ester (20 mmol, 5.88 g), 2-chloro-5-bromobenzoic acid (22 mmol, 5.18 g) and HBTU (22 mmol, 8.34 g) in DMF (70 mL) was added diisopropylethylamine (50 mmol, 8.7 mL) at room temperature. The suspension was stirred for 48 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, the mixture was diluted with water (100 mL) and the solids were collected by filtration and washed with water (150 mL). After air drying, the crude product was purified by silica gel column chromatography to obtain 1.02 g (10%) of a white solid: mp 158-161° C. HR MS (C22H24BrClN2O5): Ob, 533.0442. Calcd mass, 533.0455 (M+Na).