Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl.Cl[CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31].O>CN(C)C=O>[CH2:28]([N:29]([CH2:32][CH3:33])[CH2:30][CH2:31][N:15]([C@@H:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11]1)[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH3:27]
Reactant: CCN(CC)CCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl [(R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate (6.0 g) was dissolved in 50 ml of N,N-dimethylformamide and, after addition of sodium hydride (1.1 g), stirred at room temperature for 30 minutes, and subsequently chlorethyldiethylamine hydrochloride (4.1 g) was added. The mixture was subsequently stirred at room temperature with exclusion of moisture for 4 hours. The reaction was stopped by adding water (50 ml), and this was followed by extraction with ethyl acetate (3×50 ml) and drying of the combined organic phases over magnesium sulfate, and removal of the solvent. This resulted in the product with the molecular weight of 406.53 (C21H34N4O4); MS (ESI): 407 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Yield: 146.2 %

Procedure:
4-(5-Chloro-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.4 g, 10.2 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated and the golden oil brought up in Et2O. A solid formed and was filtered, washed with Et2O and air dried to give 3.5 g (97%) of a white solid as a TFA salt. MS (electrospray): exact mass calculated for C12H15ClN2, 234.09; m/z found, 235.1 [M++H].
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[CH2:13][NH:14]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:24].[CH2:1]([O:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[CH2:13][NH2:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCC(=O)NCC(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 100 %

Procedure:
In 80 ml of chloroform were dissolved 14.8 g (42 mmol) of t-butyloxycarbonylglycine.dicyclohexylamine and 14.0 g (41.5 mmol) of glycine benzyl ester p-toluenesulfonic acid salt. To this solution, 70 ml of a chloroform solution containing 8.75 g (45.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) were added at -5° C. with stirring. The resulting mixture was stirred for 24 hours. The resulting chloroform solution was successively washed twice with a 10% by weight aqueous citric acid solution, then twice with water, then twice with a 4% by weight aqueous sodium hydrogen carbonate solution and finally twice with water. Thereafter, the organic phase was dried over anhydrous sodium sulfate. The solvent was then completely removed in vacuo to obtain a white oily material. This was crystallized from hexane to obtain 12.8 g (yield: 96%) of t-butyloxycarbonyl-glycylglycine benzyl ester as a white solid. In 10 ml of ethyl acetate were dissolved 8.0 g (24.8 mmol) of t-butyl oxycarbonylglycylglycine benzyl ester, to which 120 ml of 4N HCl/ethyl acetate were added. The mixture was stirred for 4 hours and then the solvent was removed in vacuo to obtain white precipitates. The precipitates were washed well with diethyl ether to obtain 6.4 g (yield: 100%) of glycylglycine benzyl ester hydrochloride as a white solid having the following physical properties:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][OH:6].[CH:7]1([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[CH:27]=[N:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[O:17])[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1>>[OH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[C:21]([C:20]1[CH:24]=[CH:25][N:26]=[CH:27][C:19]=1[NH:18][C:16]([C:14]1[C:13]([NH:28][C:29]2[CH:34]=[N:33][CH:32]=[N:31][CH:30]=2)=[CH:12][CH:11]=[C:10]([CH:7]2[CH2:8][CH2:9]2)[N:15]=1)=[O:17])=[O:22]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CNCCCO
Product: CN(CCCO)C(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 34 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3-methylamino-propan-1-ol with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (34%) as amorphous yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:21]([O:22]C)=[C:20]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[C:25]=4[CH3:33])[CH:19]=[N:18]3)=[N:15][CH:16]=2)=[O:10])[CH2:5][CH2:4]1)[CH3:2].CC(N(C)C)=O.[Cl-].[Li+]>CS(C)=O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:21]([OH:22])=[C:20]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[C:25]=4[CH3:33])[CH:19]=[N:18]3)=[N:15][CH:16]=2)=[O:10])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3OC)nc2)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)CC1
Yield: 36.5 %

Procedure:
Combined 4-(1-(5-(4-ethylpiperazine-1-carbonyl)pyridin-2-yl)-5-methoxy-1H-pyrazol-4-yl)-2-fluoro-3-methylbenzonitrile (70 mg, 0.156 mmol) and DMA (1561 μl) then added lithium chloride (66.2 mg, 1.561 mmol) and heated at 70° C. overnight. The crude reaction was then diluted with DMSO (500 uL) and purified via preparative HPLC (acetonitrile-water, with TFA) to give the title compound (24.6 mg, 0.057 mmol, 36.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.33 Hz, 3H) 2.33 (d, J=2.27 Hz, 3H) 3.16 (t, J=7.20 Hz, 2H) 3.24-4.06 (m, 8H) 7.49-7.84 (m, 2H) 8.04-8.30 (m, 2H) 8.43 (br. s., 1H) 8.60 (dd, J=2.15, 0.63 Hz, 1H). ESI-MS m/z [M+H]+ 435.3.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=1[F:31]>C(#N)C>[Br-:20].[F:31][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:22]=1[CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(F)c1CBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(F)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Triphenylphosphine (31.2 g, 119 mmol) was added to a solution of 2-(bromomethyl)-1-fluoro-3-nitrobenzene (27.9 g, 119 mmol) in Acetonitrile (445 mL) (degassed with nitrogen) and the reaction stirred at ambient temperature for 10 min then heated to 85° C. for 2 hrs. The solvent was evaporated under reduced pressure to afford the title compound (59.1 g, 119 mmol, 100% yield) as a yellow powder, MS (ESI): m/z=416.2 (MH+); 100% pure by LCMS.
Reaction SMILES: [C:1]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17]S(C)(=O)=O)=[CH:9][CH:8]=1)([O:3][CH2:4][CH3:5])=[O:2].[C:34]1(O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:4]([O:3][C:1]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([I:32])=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:16][O:17][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:11][CH:12]=1)=[O:2])[CH3:5]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(I)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccccc2)NS(=O)(=O)c2ccc(I)cc2)cc1
Yield: 63.4 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(carbethoxymethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (400 mg) was reacted with phenol (123 mg) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-phenoxypropanamide (252.62 mg).
Reaction SMILES: CC([OH:4])C.CC1(C)O[C@H](CN2C=CC(N[C:18](=[O:38])[C@@H:19]([N:24]3[CH2:28][C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:26][C:25]3=[O:37])[CH2:20][CH:21]([CH3:23])[CH3:22])=N2)CO1.Cl.C(OC)(C)(C)C>O>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[O:29][C:27]1[CH2:28][N:24]([C@@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:18]([OH:38])=[O:4])[C:25](=[O:37])[CH:26]=1
Reactant: CC(C)O
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a 200-L glass-lined reactor was charged with 42.7 kg of 2-propanol and 13.6 kg (27.0 mol) of ((S)-2-[4-(2-Chlorophenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide. The suspension was stirred at 25-30° C. until the solids dissolved. After adjusting the batch temperature to <15° C., 59.5 kg of 2.0N hydrochloric acid was added over 3.5 h while maintaining a batch temperature of 9-17° C. The mixture was warmed to 18 to 23° C. and stirred for 5.5 h. HPLC analysis at 2 h indicated the reaction was complete. The reaction mixture was transferred into a 500 L glass-lined reactor and diluted with 28.6 kg of purified water and 166.1 kg of methyl tert-butyl ether. The aqueous phase was separated and the organic phase was washed with 1.0N sodium hydroxide solution, 10.7 wt % sodium chloride solution, and 1.0 wt % sodium chloride solution subsequently. The organic phase was transferred into a 200 L glass-line reactor. Solvents were removed by distillation in vacuo at 10-26° C. to a volume of ca. 27 L. The resulting oil was diluted with 107.6 kg of ethanol and solvents were removed by distillation in vacuo at 12-30° C. to afford 19.85 kg (10.04 kg corrected by wt %, 80.4% of yield) of (S)-2-[4-(2-Chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl-1H-pyrazol-3-yl]-amide in ethanol. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3 H), 0.94 (d, J=6.3 Hz, 3 H), 1.33-1.50 (m, 1 H), 1.49-1.67 (m, 1 H), 1.68-1.85 (m, 1 H), 3.16-3.32 (m, 2 H), 3.70-3.93 (m, 2 H), 4.09 (m, J=13.6, 3.6 Hz, 1H), 4.21 (d, J=18.4 Hz, 1H), 4.61 (d, J=18.4 Hz, 1 H), 4.71 (t, J=5.6 Hz, 1 H), 4.79 (s, 1 H), 4.88 (dd, J=10.6, 4.8 Hz, 1 H), 4.94 (d, J=5.1 Hz, 1 H), 6.41 (d, J=1.5 Hz, 1 H), 7.37 (t, J=7.5 Hz, 1 H), 7.46 (t, J=7.5 Hz, 1 H), 7.50-7.56 (m, 2 H), 7.65 (d, J=7.5 Hz, 1 H), 10.78 (s, 1 H).
Reaction SMILES: C[N:2]([CH3:4])Cl.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)C.[CH2:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C.Cl>C(Cl)Cl.O>[CH2:4]([NH2:2])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: C=CCCCCCCCCCCCC
Reactant: CN(C)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCN
Temperature: -35 °C
Reaction time: 0.08 h
Yield: 6.7 %

Procedure:
To a reactor of the type used in Example 1 is charged a cold solution of N,N-dimethylchloramine (0.87 moles), chilled to -77° C, in 300 ml of methylene chloride, followed by aluminum chloride (0.3 moles). The mixture is stirred for 5 minutes and then diethyl ether (0.4 moles) is added. After stirring for an additional 5 minutes, an additional portion of diethyl ether (0.4 moles) and 1-tetradecene (0.3 mol) is added to the stirred solution. The chilled reaction mixture is heated to -35° C and the reaction mixture stirred for one hour. At the end of this time an 80 g portion of hydrochloric acid (28% by weight) and 100-300 g of water are added to the reaction mixture and stirred for a half hour. The organic and water layers are then separated and the organic layer is stirred for an additional half-hour with 80 g of the same strength hydrochloric acid used previously. Again the organic and water layers are separated. The organic layer is filtered to yield 0.02 mol of tetradecyl amine salt. This represents a 6.68% yield based on the amount of 1-tetradecene charged.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[O:3]1.O[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2[CH:28]=[C:29]([CH:32]([CH3:34])[CH3:33])[CH:30]=[CH:31][C:24]=2[S:23]1(=[O:36])=[O:35]>CC(OCC)=O>[O:35]=[S:23]1(=[O:36])[C:24]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][C:25]=2[C:26](=[O:27])[N:22]1[CH2:21][CH2:20][CH2:19][CH2:18][N:10]1[CH2:9][CH2:8][CH:7]([N:6]2[C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[O:3][C:2]2=[O:1])[CH2:12][CH2:11]1
Reactant: O=c1oc2ccccc2n1C1CCNCC1
Reactant: CC(C)c1ccc2c(c1)C(=O)N(CCCCO)S2(=O)=O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc2c(c1)C(=O)N(CCCCN1CCC(n3c(=O)oc4ccccc43)CC1)S2(=O)=O

Procedure:
From 4-(2-oxo-3-benzoxazolinyl)-piperidine and 2-(4-hydroxybutyl)-1,1-dioxido-5-(2-propyl)-1,2-benzothiazol-3(2H)-one using the procedure described for Example 66, Steps 4-6 there was obtained a white solid: 1H NMR (400 MHz, CDCl3) 7.9 (s, 1H), 7.8 (d, 1H), 7.7 (d, 1H), 7.3 (m, 1H), 7.2-7.0 (br m, 3H), 4.2 (m, 1H), 3.8 (m, 2H), 3.1 (m, 3H), 2.7-2.5 (br m, 2H), 2.1 (m, 2H), 2.0-1.8 (br m, 4H), 1.7-1.6 (m, 4H), 1.35 (d, 6H) Analysis calculated for C25H30 N3O6S·HCl·1.6 CH3CO2CH2CH3 C: 57.64, H: 6.69, N: 6.23 found C: 57.06, H: 6.12, N: 6.56.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:26](=[CH:27][CH:28]=1)[C:12]1[NH:13][C:14]([C:16]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])=[N:15][C:11]=1[C:10]1[CH:9]=[CH:8][C:7]([Cl:29])=[CH:6][C:5]2=1.[H-].[Na+].[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl>C1COCC1>[Br:1][C:2]1[CH:28]=[CH:27][C:26]2[C:12]3[N:13]=[C:14]([C:16]4[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][C:17]=4[C:18]#[N:19])[N:15]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[C:11]=3[C:10]3[C:5](=[CH:6][C:7]([Cl:29])=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1cccc(C#N)c1-c1nc2c3ccc(Cl)cc3c3cc(Br)ccc3c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2c(C#N)cccc2C#N)nc2c3ccc(Br)cc3c3cc(Cl)ccc3c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
To a solution of 2-(6-bromo-9-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile (5 g, 10.9 mmol) from Example 36 in THF (30 mL) was added NaH (60% dispersion in oil, 1.31 g, 32.7 mmol). The mixture was stirred at room temperature for 10 minutes, after which 2-(trimethylsilyl)ethoxymethylchloride (5.8 mL, 32.7 mmol) was added. After 1 hour, the reaction was quenched by slow addition of water. The aqueous layer was extracted with ethyl acetate, the organic layer washed once with water, once with brine, dried over anhydrous MgSO4 and concentrated to afford crude 2-(6-bromo-9-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile (6.06 g).
Reaction SMILES: [NH2:1][C:2]([CH2:8][CH3:9])=[CH:3][C:4](OC)=[O:5].[C:10]([O:18]CC)(=O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C[O-].[Na+].ClC1C=CC=CC=1Cl>CO.C(O)C>[C:12]([C:11]1[C:10](=[O:18])[NH:1][C:2]([CH2:8][CH3:9])=[CH:3][C:4]=1[OH:5])([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCC(N)=CC(=O)OC
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1c(O)cc(CC)[nH]c1=O
Temperature: 160 °C

Procedure:
113.6 g (0.88 mol) of methyl 3-amino-2-pentenoate and 128 g (0.8 mol) of diethyl malonate are added to a solution of 259.2 g (0.8 mol) of 21% strength sodium methoxide solution in methanol and 130 g of ethanol. After addition of 800 ml of 1,2-dichlorobenzene, a mixture of methanol and ethanol is removed by distillation in the course of one hour and the remaining suspension is heated to 160° C. for two hours. After cooling, 600 ml of water are added, and the organic phase is separated off, extracted using water and then discarded. The combined aqueous phases are washed with ether, and the aqueous phase is separated off, acidified using hydrochloric acid and filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]2)=[C:4]2[CH:15]=[N:16][CH:17]=[CH:18][C:3]=12.C(N(CC)CC)C.[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:32]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:33])[C@@H:10]([CH3:14])[CH2:9]2)=[C:4]2[CH:15]=[N:16][CH:17]=[CH:18][C:3]=12
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1
Reactant: O=C(Cl)N1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H]1CN(c2nnc(Cl)c3ccncc23)CCN1C(=O)N1CCCCC1
Reaction time: 8 h

Procedure:
To a solution of (S)-1-chloro-4-(3-methylpiperazin-1-yl)pyrido[3,4-d]pyridazine 4 (500 mg, 1.90 mmol) in 10 mL of CH2Cl2 was added triethylamine (529 μl, 3.79 mmol), followed by 1-piperidinecarbonyl chloride (364 μl, 2.47 mmol). The reaction was allowed to stir overnight and then diluted with 100 mL of ethyl acetate. The crude mixture was washed with 1×10 mL of sat. NaHCO3, 1×10 mL of water, and 1×10 mL of brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography afforded (S)-(4-(1-chloropyrido[3,4-d]pyridazin-4-yl)-2-methylpiperazin-1-yl)(piperidin-1-yl)methanone 7.
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)[CH2:6][NH2:7].[CH:17]1([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[C:39]([CH:40]=O)=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH2:26][CH2:25]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1)[CH2:6][NH:7][CH2:40][C:39]1[C:30]([N:27]2[CH2:26][CH2:25][N:24]([CH2:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:29][CH2:28]2)=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: O=Cc1cc2ccccc2nc1N1CCN(CC2CCCCC2)CC1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: FC(F)(F)c1cc(CNCc2cc3ccccc3nc2N2CCN(CC3CCCCC3)CC2)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 67.4 %

Procedure:
3,5-Bis(trifluoromethyl) benzylamine (0.305 g, 1.25 mmol) was added to a solution of 2-(4-cyclohexylmethyl-piperazin-1-yl)-quinoline-3-carbaldehyde (0.4 g, 1.23 mmol) in methanol followed by acetic acid (0.15 mL) at ambient temperature under nitrogen atmosphere. After stirring 1 h, sodium cyanoborohydride (0.237 g, 3.77 mmol) was added carefully, and the reaction was stirred at RT for overnight. The reaction mixture was evaporated to dryness, and water (30 mL) and ethyl acetate (30 mL) were added to the residue, and this was then extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to afford a pale yellow crude product. Purification by silica gel column chromatography and eluting with 2.5% methanol/dichloromethane afforded the title compound (0.468 g, yield: 67%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH:19]=[C:18]([Si](C)(C)C)[N:17]=[N:16]3)[O:11][C:10]2=[O:24])[CH:6]=[CH:5][C:4]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][CH2:33][C:34]2[N:35]=[N:36][N:37]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[CH:38]=2)=[CH:27][CH:26]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(O)(=O)C>[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:24])[CH:6]=[CH:5][C:4]=1[C:25]1[CH:26]=[CH:27][C:28]([CH2:31][NH:32][CH2:33][C:34]2[N:35]=[N:36][N:37]([CH2:39][C:40]3[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)[CH:38]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2cc(CNCc3ccc(-c4ccc(N5CC(Cn6cc([Si](C)(C)C)nn6)OC5=O)cc4F)cc3)nn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(CNCc3ccc(-c4ccc(N5C[C@H](Cn6ccnn6)OC5=O)cc4F)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.2 %

Procedure:
A solution of 3-[2-Fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (SC-167-63-2, 0.22 g, 0.343 mmol) in an 1 M solution of tetrabutylammonium fluoride in THF (TBAF, 1.4 mL, 1.4 mmol, 4.0 equiv) was treated with acetic acid (HOAc, 5.0 mL) at room temperature, and the resulting reaction mixture was stirred at room temperature for 24 h. When TLC and HPLC/MS showed that the reaction was complete, the solvents were removed in vacuo. The residue was treated with H2O (30 mL) at room temperature and the resulting mixture was stirred at room temperature for 1 h. The solids were collected by filtration, washed with H2O (2×10 mL) and 20% EtOAc/hexane (2×20 mL), dried in vacuo. The crude, desired (5R)-3-[2-Fluoro-4′-({[1-(4-methoxy-benyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one (SC-167-71, 0.17 g, 0.195 g theoretical, 87%) was obtained as off-white powders, which by HPLC/MS and 1H NMR was found to be essentially pure and was directly used in the subsequent reactions without further purification. For SC-167-71: 1H NMR (300 MHz, DMSO-d6) 3.73 and 3.75 (two, s, 4H), 3.94-3.97 (m, 1H), 4.29 (t, 1H), 4.85 and 4.87 (dd, 2H), 5.15-5.20 (m, 1H), 5.48 (s, 1H), 6.91 and 6.94 (d, 2H), 7.28-7.58 (m, 10H, aromatic-H), 7.78 (s, 1H, triazole-H), 7.98 (s, 1H, triazole-H), 8.19 (s, 1H, triazole-H); C30H29FN8O3, LCMS (EI) m/e 568 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8][CH:7]=1.Cl.[OH:16][NH2:17].C([O-])(=O)C.[Na+]>CO.O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[N:17][OH:16])=[CH:8][CH:7]=1
Reactant: NO
Reactant: COC(=O)COc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.3 %

Procedure:
A solution of methyl-(4-formylphenoxy)acetate (100 g, 0.515 mol) in methanol (500 mL) was cooled to 0-5° C. To this was added a solution of hydroxyamine hydrochloride (54 g) and sodium acetate (64 g) in water (500 mL) drop-wise and stirred at rt for 6 h. The reaction mixture diluted with water and filtered off the solid. The solid was washed with water and dried under vacuum to give the title compound (80 g, 74%).