Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[NH:9]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[N+:2]=[N-:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[NH2:9][C@H:5]1[C@@H:4]([N:1]=[N+:2]=[N-:3])[NH:7][C:6]1=[O:8]
Reactant: [N-]=[N+]=N[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=N[C@H]1NC(=O)[C@H]1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.45 g of (3S,4R)-4-azido-3-tritylamino-2-oxoazetidine in 4 ml of acetone is added under ice-cooling 0.255 g of p-toluenesulfonic acid monohydrate, and the mixture is stirred for one hour at room temperature. The solvent is distilled off, and the resulting crystals are washed with ether. The crystals are collected by filtration to give 0.33 g of tosyl salt of (3S,4R)-3-amino-4-azido-2-oxoazetidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]([N:12]=[C:13]=[O:14])([F:11])[F:10]>C1(C)C=CC=CC=1>[C:2]1([NH:1][C:13]([NH:12][C:9]([F:11])([F:10])[F:8])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(F)(F)F
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)NC(F)(F)F
Reaction time: 1 h

Procedure:
A solution of aniline (93.12 grams; 1.0 mol) in toluene (200 ml) is charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and gas inlet tube. Trifluoromethyl isocyanate (111 grams; 1.0 mol) is slowly bubbled into the reaction medium with vigorous stirring. The temperature of the reaction mixture is kept below about 50° C. After the addition is completed the reaction mixture is stirred for an additional period of about 1 hour. After this time the toluene is stripped from the reaction mixture under reduced pressure. The residue is then recrystallized to yield N-phenyl-N'-trifluoromethyl urea.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:24]=[C:12]1[CH:13]=[C:14]([O:17][CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH:15]=[CH:16][N:11]1[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][CH2:26]2)=[CH:4][CH:5]=1
Reactant: CC(=O)NC1CCNCC1
Reactant: O=c1cc(OCc2ccsc2)ccn1CCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccsc4)cc3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 30 mg (0.45 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(thiophen-3-ylmethoxy)-1H-pyridin-2-one (example 4.1a) in 2.0 mL DCM is added 37 μL triethylamine (0.26 mmol) and subsequently 14 μL (0.18 mmol) methanesulfonyl chloride at RT. The reaction mixture is stirred 1 h at RT and additional 18 μL triethylamine (0.13 mmol) and 7 μL (0.09 mmol) methanesulfonyl chloride is added at RT and the reaction mixture is stirred 1 h at RT. 2.0 mL acetonitrile and 25 mg (0.18 mmol) N-piperidin-4-yl-acetamide are added and the reaction mixture is stirred for 1 h. A precipitate is formed and 1 mL of DMF is added and the reaction mixture is stirred overnight. The sole product formed (HPLC-MS analysis) is 1-[2-(4-chloromethyl-phenyl)-ethyl]-4-(thiophen-3-ylmethoxy)-1H-pyridin-2-one. The reaction mixture is diluted with EtOAc, washed twice with water and is dried over MgSO4. After filtration, the solvent is evaporated and 30 mg (95% yield) of 1-[2-(4-chloromethyl-phenyl)-ethyl]-4-(thiophen-3-ylmethoxy)-1H-pyridin-2-one is isolated. To 30 mg (0.09 mmol) 1-[2-(4-chloromethyl-phenyl)-ethyl]-4-(thiophen-3-ylmethoxy)-1H-pyridin-2-one in 2.0 mL DMF is added 26 mg (0.18 mmol) N-piperidin-4-yl-acetamide and 37 mg (0.27 mmol) potassium carbonate at RT. The reaction mixture is stirred overnight at RT, filtered and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][C:43]1[C:47]([S:48](Cl)(=[O:50])=[O:49])=[C:46]([CH3:52])[O:45][N:44]=1>C(#N)C>[CH3:42][C:43]1[C:47]([S:48]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:50])=[O:49])=[C:46]([CH3:52])[O:45][N:44]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1noc(C)c1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 23.5 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0291 g, 0.0630 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3,5-dimethylisoxazol-4-sulfonyl chloride (0.0382 g, 0.195 mmol) to obtain 4-(3,5-dimethylisoxazol-4-ylsulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0092 g, yield 23%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([C:20](Cl)=[O:21])[N:14]=[N:13]2)=[CH:8][CH:7]=1>CC(C)=O.C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([C:20]([N:1]=[N+:2]=[N-:3])=[O:21])[N:14]=[N:13]2)=[CH:8][CH:7]=1
Reactant: CC(C)c1c(C(=O)Cl)nnn1-c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)c1c(C(=O)N=[N+]=[N-])nnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium azide (610 mg in 2.5 mL of H2O, 9.39 mmol) was added to a cooled (0° C.) solution of 1-(4-chlorophenyl)-5-isopropyl-triazole-4-carbonyl chloride in acetone (7.5 mL). The resulting mixture was stirred at room temperature for 30 min, diluted with CH2Cl2 (100 mL), washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated in vacuo to give the crude 1-(4-chlorophenyl)-5-isopropyl-triazole-4-carbonyl azide (777 mg) which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:25][C:26]([F:31])([CH2:29][NH2:30])[CH2:27][NH2:28]>>[O:24]=[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:28][CH2:27][C:26]([F:31])([F:25])[CH2:29][NH2:30])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC(F)(F)CN
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(NCC(F)(F)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 18-1 in Scheme 6 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and 2,2-difluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 431, 1H NMR (400 MHz, CD3OD) δ ppm 7.93 (s, 1 H), 7.81-7.79 (m, 1 H), 7.76-7.74 (d, 2 H), 7.62-7.52 (m, 3 H), 6.25 (s, 1 H), 5.45-5.41 (d, 1 H), 5.05 (d, 1 H), 4.75 (m, 1 H), 4.45 (m, 1 H), 4.23-4.16 (m, 2 H), 3.72-3.64 (t, 2 H), 3.50 (m, 2 H), 2.47 (s, 3 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH3:17])[CH:3]=1.CO>CCOC(C)=O.[Pd]>[F:16][C:14]1[CH:13]=[CH:12][C:11]([CH3:17])=[C:10]([C:4]2[CH:3]=[CH:2][N:7]=[CH:6][C:5]=2[NH:8][CH3:9])[CH:15]=1
Reactant: CNc1cnc(Cl)cc1-c1cc(F)ccc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNc1cnccc1-c1cc(F)ccc1C
Reaction time: 4 h

Procedure:
A solution of 6-chloro-4-(5-fluoro-2-methylphenyl)-N-methylpyridin-3-amine (0.2 g, 798 μmol, example 253, intermediate a) in EtOAc (1 mL) and MeOH (1.0 mL) under argon was treated with palladium on carbon (21.2 mg, 19.9 μmol) and stirred under an hydrogen atmosphere (0.5 bar overpressure) for 4 hours. Stirring was continued overnight at room temperature. The reaction mixture was filtered over Dicalite and evaporated. The residue was taken up in CH2Cl2 and saturated aqueous NaHCO3 solution and the layers were separated. The aqueous layer was extracted three times with CH2Cl2. The organic layers were dried over MgSO4, filtered and evaporated. Light brown solid (0.16 g; 92%). MS (ESI): m/z=217.11 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[C:17]([Mg]Cl)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1cc2c(cc1C)C(=O)CCC2(C)C
Reactant: CC(C)(C)[Mg]Cl
Product: COc1cc2c(cc1C)C(C(C)(C)C)=CCC2(C)C
Yield: 9.7 %

Procedure:
Following General Procedure F, 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 30, 2.0 g, 9.2 mmol) was reacted with a solution of 2 M tert-butylmagnesiumchloride (46 mL, 92.0 mmol), and the crude product was purified by flash column (hexane:ethyl acetate=4:1) to give 0.23 g (10%) of the title product as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8].[CH:16]1([CH2:19][NH:20][C:21](=[O:37])[C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])O.[Na+]>CC(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:10]1([NH:9][C:7]([C:6]2[CH:13]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([NH:20][CH2:19][CH:16]4[CH2:18][CH2:17]4)=[O:37])=[CH:23][CH:24]=3)[C:3]([CH3:15])=[CH:4][C:5]=2[F:14])=[O:8])[CH2:12][CH2:11]1
Reactant: Cc1cc(F)c(C(=O)NC2CC2)cc1Br
Reactant: CC1(C)OB(c2ccc(C(=O)NCC3CC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cc(F)c(C(=O)NC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 90 °C

Procedure:
5-Bromo-N-cyclopropyl-2-fluoro-4-methylbenzamide (Intermediate 22, 30 mg), N-cyclopropylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (28 mg), tetrakis(triphenylphosphine)palladium (1 mg) and aqueous sodiumhydrogen carbonate (1M, 0.5 ml) were mixed in propan-2-ol (2 ml) and heated at 90° C. under nitrogen for 24 hrs. The reaction was absorbed onto silica and applied to a SPE (Si, 5 g) and eluted with an ethyl acetate/cyclohexane gradient (0–100% ethyl acetate). The product fractions were reduced to dryness under vacuum and the residue recrystallised from ethyl acetate to give N3-cyclopropyl-N4′-(cyclopropylmethyl)-4-fluoro-6-methyl-1,1′-biphenyl-3,4′-dicarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C@@H:6]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[OH:17])[CH2:7][N+:8]([O-])=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.O>O1CCCC1>[NH2:8][CH2:7][C@H:6]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[OH:17])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])C[C@@H](c1ccc(Cl)cc1)[C@@H]1CCCC[C@H]1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC[C@@H](c1ccc(Cl)cc1)[C@@H]1CCCC[C@H]1O
Reaction time: 8 h

Procedure:
A solution of 1.9 g (6.7 mmol) of rac-(1R*)-trans-2-[(R*)-4-chloro-α-(nitromethyl)benzyl]cyclohexanol in 30 ml of dry tetrahydrofuran is added dropwise while stirring to a suspension of 1 g of lithium aluminium hydride in 60 ml of dry tetrahydrofuran under argon, whereupon the mixture is stirred at 50° overnight. After cooling the reaction mixture is treated with tetrahydrofuran/water (1:1), the precipitate is filtered off under suction, the filtrate is evaporated, the residue is treated with water and extracted with ether. The rac-(1R*)-trans-2-[(R*)-α-(aminomethyl)-4-chlorobenzyl]cyclohexanol obtained is a colourless oil and is processed directly.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].Cl[C:34]([O:36][CH3:37])=[O:35]>O1CCCC1>[CH3:37][O:36][C:34]([C:10]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH3:23])[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:24])=[O:35]
Reactant: COC(=O)Cl
Reactant: COc1ccc(C2CCCN(Cc3ccccc3)C2=O)c(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccc(OC)cc2OC)CCCN(Cc2ccccc2)C1=O
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A solution of 1 mmol of 1-benzyl-3-(2,4-dimethoxy-phenyl)-piperidin-2-one [597553-90-7] in 20 ml of tetrahydrofuran is cooled to −70° C. and treated drop wise with a solution of 1.2 mmol of lithium diisopropyl-amide in 5 ml of tetrahydrofuran. The mixture is stirred 15 minutes at −70° C. A solution of 1.2 mmol of methyl chloroformate in 5 ml of tetrahydrofuran is added at −70° C. and the reaction mixture is allowed to come to room temperature over a period of 7 hours. The reaction mixture is quenched with water and extracted with tert-butyl methyl ether (3×). The combined organic phases are dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the basis of the Rf value.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[CH:39][C:40]([OH:42])=[O:41])=[CH:34][CH:33]=1)=O>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:32]3[CH:33]=[CH:34][C:35](/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41])=[CH:36][CH:37]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)/C=C/c1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 3-(4-formyl-phenyl)-acrylic acid according to the procedure of Example 66. MS (ESI) m/z 553.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[NH2:24].[H+].[B-:26]([F:30])([F:29])([F:28])[F:27].[N:31]([O-])=O.[Na+]>C1COCC1.O>[F:27][B-:26]([F:30])([F:29])[F:28].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:24]#[N:31]
Reactant: COc1cc2c(Cl)c(N)cnc2cc1OCCCN1CCCCC1
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(Cl)c([N+]#N)cnc2cc1OCCCN1CCCCC1
Temperature: 0 °C
Yield: 80 %

Procedure:
4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-ylamine (0.300 g) was dissolved in THF (5 ml) with stirring and then cooled in ice-water bath to below 0° C., to this added 48% aqueous fluoboric acid (0.7 ml) and mixture stirred for 10 mins. A solution of sodium nitrite (0.10 sg) in water (1 ml) was added keeping the temperature below 10° C. The reaction mixture was the stirred for 1 hr, during that time yellow solid precipitated. This solid was filtered, dried to give 4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-diazonium tetrafluoroborate (0.250 g, 80%)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[N:6][C:7]([Cl:23])=[CH:8][C:9]=1[C:10]([C:12]1[CH:21]=[C:20]([CH3:22])[C:15]2[NH:16][C:17](=[O:19])[O:18][C:14]=2[CH:13]=1)=[O:11].I[CH3:25]>CN(C=O)C>[Cl:3][C:4]1[N:5]=[N:6][C:7]([Cl:23])=[CH:8][C:9]=1[C:10]([C:12]1[CH:21]=[C:20]([CH3:22])[C:15]2[N:16]([CH3:25])[C:17](=[O:19])[O:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: Cc1cc(C(=O)c2cc(Cl)nnc2Cl)cc2oc(=O)[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(Cl)nnc2Cl)cc2oc(=O)n(C)c12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
85 mg (2.1 mmol) sodium hydride (55%, suspension in mineral oil) were added to 0.65 g (2.0 mmol) 6-(3.6-dichloro-pyridazine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 10 mL DMF while cooling with ice. The reaction mixture was stirred for 20 min. Then 0.19 mL (3.1 mmol) iodomethane were added while cooling with ice and the mixture was stirred for 2 h at RT. The reaction mixture was mixed with ice water, the precipitate formed was suction filtered and dried.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[N:13]1([C:18]2[CH:19]=[C:20]([C@@H:24]([NH2:26])[CH3:25])[CH:21]=[CH:22][CH:23]=2)[CH:17]=[CH:16][N:15]=[CH:14]1>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:26][C@H:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH:19]=1)[CH3:25])=[O:8]
Reactant: C[C@H](N)c1cccc(-n2ccnc2)c1
Reactant: O=C(O)C=Cc1ccccc1F
Product: C[C@H](NC(=O)C=Cc1ccccc1F)c1cccc(-n2ccnc2)c1

Procedure:
The title compound was prepared from 2-fluorocinnamic acid and (S)-1-(3-imidazol-1-yl-phenyl)-ethylamine following the general procedures as described for Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][O:40][C:41](=[O:46])[C@H:42]([OH:45])[CH2:43][NH2:44].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][O:40][C:41](=[O:46])[C@H:42]([OH:45])[CH2:43][NH:44][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([CH:18]([O:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=3)=[CH:12][CH:13]=2)[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:31][CH:30]=1
Reactant: COC(=O)[C@H](O)CN
Reactant: CC(C)CC(Oc1ccc(-c2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a mixture of 4-[1-(4′-tertbutyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid (120 mg) in methylene chloride (3 mL) are added triethyl amine (0.12 mL, 0.87 mmol), DMAP (5 mg), 3-Amino-2(R)-hydroxy-propionic acid methyl ester (67.3 mg, 0.43 mmol) and EDCI (166 mg, 0.87 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving 3-{4-[1-(4′-tert-butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-2(R)-hydroxy-propionic acid methyl ester (60 mg).
Reaction SMILES: ClC(Cl)(Cl)C([N:5]=[C:6]=[O:7])=O.[CH3:10][O:11][N:12]=[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[C:14]([OH:16])=[O:15]>O1CCOCC1>[CH3:10][O:11][N:12]=[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:6](=[O:7])[NH2:5])[CH:18]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CON=C(C(=O)O)c1cccc(O)c1
Solvent: C1COCCO1
Product: CON=C(C(=O)O)c1cccc(OC(N)=O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trichloroacetyl isocyanate (70 ml) was dropwise added over 6 minutes at ambient temperature to a solution of 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (40 g) in dry dioxane (200 ml), and the resulting mixture was stirred for 5 hours at ambient temperature. Dioxane was distilled off and to the residue were added ethyl acetate (200 ml) and by small portions water (200 ml) under ice-cooling. The mixture containing trichloroacetylcarbamoyl 2-methoxyimino-2-(3-trichloroacetylcarbamoyloxyphenyl)acetate was stirred for 5 hours at ambient temperature keeping the pH value of the mixture at 6.0 to 6.4 by adding an aqueous solution of sodium bicarbonate. The resulting mixture was wahsed twice with ethyl acetate. The aqueous layer was adjusted to pH 2 with a 10% hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed twice with an aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and precipitating crystals were collected by filtration to give colorless crystals of 2-methoxyimino-2-(3-carbamoyloxyphenyl)acetic acid (syn isomer) (15 g), mp 163° C. (dec.). The same compound (5.4 g) was obtained from the mother liquor.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[C:11]([CH3:12])=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([CH3:24])[O:23][CH2:22][CH2:21][O:20]4)=[CH:15][CH:14]=3)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:6]2=[N:7][CH:8]=1)[NH2:2].O.NN.[CH:36](OCC)(OCC)OCC>>[CH3:12][C:11]1[C:5]2[N:4]3[CH:36]=[N:2][N:1]=[C:3]3[CH:8]=[N:7][C:6]=2[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:10]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH3:24])[O:20][CH2:21][CH2:22][O:23]2)=[CH:15][CH:14]=1
Reactant: CCOC(OCC)OCC
Reactant: Cc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc(NN)nc12
Agent: NN
Solvent: O
Product: Cc1c(-c2ccc(C3(C)OCCO3)cc2)n(COCC[Si](C)(C)C)c2ncc3nncn3c12
Temperature: 100 °C
Yield: 60 %

Procedure:
To a flask was added 2-hydrazinyl-7-methyl-6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.357 g, 0.784 mmol, prepared using O from Preparation #20 with hydrazine hydrate) in triethyl orthoformate (3.91 mL, 23.5 mmol). The mixture was heated to about 100° C. for about 20 h. The mixture was concentrated in vacuo to give a residue. The residue was loaded directly on a silica gel column and eluted with 0 to 8% MeOH/DCM to provide 8-methyl-7-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.220 g, 60%): LC/MS (Table 2, Method g) Rt=1.66 min; MS m/z 466 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[C:13]([CH3:16])=[CH:14][S:15][C:3]=12.[CH3:17]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].IC>O>[CH3:16][C:13]1[C:4]2[N:5]([CH3:17])[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2](=[O:1])[C:3]=2[S:15][CH:14]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cnc2c(C)csc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cn(C)c2c(C)csc2c1=O
Temperature: 0 °C

Procedure:
A 500 mL three-necked flask fitted with an overhead stirrer and argon inlet is charged with 21.9 g of ethyl 7-hydroxy-3-methylthieno[3,2-b]pyridine-6-carboxylate and 150 mL of DMF. The mixture is stirred while 25.5 g of powdered potassium carbonate is added in portions, then is cooled to 0° C. Iodomethane (15 mL) is added dropwise over 45 min, and the completed mixture is stirred vigorously and allowed to warm slowly as the ice in the bath melts. The following day, the mixture is diluted slowly with water to a final volume of 800 ml, and the resulting solid is filtered, washed well with water, and dried under vacuum to provide 17.2 g of the title compound as a brown crystalline solid. Flash chromatography of 12.2 g using 2-4% MeOH in CH2Cl2 affords 11.43 g of tan solid.