Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(C)(C)C[O:4]C1C=CC(C#N)=CC=1F.[CH3:16][N:17]([CH3:32])[C:18]([CH3:31])([CH3:30])[CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#N)=[CH:23][C:22]=1[F:29]>>[CH3:16][N:17]([CH3:32])[C:18]([CH3:31])([CH3:30])[CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:4])=[CH:23][C:22]=1[F:29]
Reactant: CN(C)C(C)(C)COc1ccc(C#N)cc1F
Reactant: CC(C)(N)COc1ccc(C#N)cc1F
Product: CN(C)C(C)(C)COc1ccc(C=O)cc1F

Procedure:
Synthezised from 4-(2-amino-2-methylpropoxy)-3-fluorobenzonitrile according to an analogous synthetic method to Preparation Example 18, 4-(2-dimethylamino-2-methylpropoxy)-3-fluorobenzonitrile (1.4 g) was used according to an analogous synthetic method to Preparation Example 16 to provide the title compound (965 mg).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([N:17]1[C:23]2[N:24]=[CH:25][C:26]([CH2:28][CH2:29][OH:30])=[CH:27][C:22]=2[C:21](=[O:31])[N:20]([CH3:32])[C:19]2[CH:33]=[CH:34][CH:35]=[N:36][C:18]1=2)[CH3:16].[Br:37][C:38]1[CH:43]=[CH:42][C:41](O)=[C:40]([CH3:45])[CH:39]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:37][C:38]1[CH:43]=[CH:42][C:41]([O:30][CH2:29][CH2:28][C:26]2[CH:25]=[N:24][C:23]3[N:17]([CH2:15][CH3:16])[C:18]4[N:36]=[CH:35][CH:34]=[CH:33][C:19]=4[N:20]([CH3:32])[C:21](=[O:31])[C:22]=3[CH:27]=2)=[C:40]([CH3:45])[CH:39]=1
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2cccnc21
Reactant: Cc1cc(Br)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccc(Br)cc3C)cc2C(=O)N(C)c2cccnc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
A solution of DIAD (0.44 mL, 2.40 mmol) in THF (1.0 mL) was added dropwise to an ice-cold solution of 11-ethyl-5,11-dihydro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (480 mg, 1.61 mmol), 4-bromo-2-methylphenol (318 mg, 1.70 mmol) and PPh3 (629 mg, 2.40 mmol) in THF (20 mL) at 25° C. The mixture was stirred at 0° C. for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (Hexane:EtOAc, 7:3) to yield the title compound (437 mg, 58% yield) as a white solid.
Reaction SMILES: [C:1]1([C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][CH:21]([O:20][C:18]([N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:19])[CH3:23]
Reactant: CC(C)OC(=O)Cl
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)OC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A 15.00 g portion of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 9.22 g of isopropyl chloroformate were added to a mixture of 75 ml of toluene, 10.43 g of potassium carbonate and 45 ml of water and stirred at 20° C. for 2 hours, and then the organic layer was washed with 50 ml of water. The thus obtained organic layer was concentrated under a reduced pressure and then dried to obtain 21.71 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid propan-2-yl ester (1H-NMR (DMSO-d6, tetramethylsilane internal standard, 80° C.): δ 1.18 (3H, d, J=6.4 Hz), 1.22 (3H, d, J=6.4 Hz), 2.73-2.93 (2H, m), 3.25-3.34 (1H, m), 3.83-3.92 (1H, m), 4.80-4.91 (1H, m), 6.22 (1H, s), 7.06-7.33 (9H, m), mass spectrum: m/z=296 [M +H]+ (FAB)).
Reaction SMILES: C(S([C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:24])[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][N:13]2[CH2:16][CH2:17][F:18])=[CH:8][C:7]=1[F:25])(=O)=O)C.[C:26]([N:29]([CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)[CH3:30])(=[O:28])[CH3:27].C(N(CC)CC)C>C(O)C>[C:26]([N:29]([CH:31]1[CH2:35][CH2:34][N:33]([C:6]2[N:15]=[C:14]3[C:9]([C:10](=[O:24])[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][N:13]3[CH2:16][CH2:17][F:18])=[CH:8][C:7]=2[F:25])[CH2:32]1)[CH3:30])(=[O:28])[CH3:27]
Reactant: CC(=O)N(C)C1CCNC1
Reactant: CCOC(=O)c1cn(CCF)c2nc(S(=O)(=O)CC)c(F)cc2c1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CCF)c2nc(N3CCC(N(C)C(C)=O)C3)c(F)cc2c1=O
Yield: 82.3 %

Procedure:
A mixture of ethyl 7-ethylsulfonyl-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (26.7 g) obtained according to the Reference Example 2, 3-(N-acetyl-N-methylamino)pyrrolidine (15.5 g), triethylamine (10.0 ml), and ethanol (300 ml) was heated under reflux for one hour. The reaction mixture was concentrated to a half volume under reduced pressure. To the mixture was added water (200 ml), and the resulting crystals were collected by filtration, and recrystallized from chloroform-ethanol to give 24.8 g of ethyl 7-[3-(N-acetyl-N-methylamino)-1-pyrrolidinyl]-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate melting at 227°-229° C. A solution of the above ester (20.0 g) in 20% hydrochloric acid (120 ml) was heated under reflux for 3 hours. After the reaction was completed, water (60 ml) and ethanol (120 ml) were added to the reaction mixture, and the resulting crystals were collected by filtration. The crystals were dissolved in hot water (800 ml) and the solution was treated with charcoal. The filtrate was adjusted to pH 8.5-9.0 by addition of 27% aqueous ammonia. The crystals were collected by filtration, washed with water, and dried to give 11.0 g of the compound 4, m.p. 243°-245° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:19][CH2:20][CH3:21])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23].CN(C)C=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[CH2:19]([N:8]([C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][C:24]([CH:22]=[O:23])=[CH:25][CH:26]=2)[CH:7]=[CH:6][CH:5]=1)[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])[CH2:20][CH3:21]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCCCCCCNC(=O)N(CCC)c1cccc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(CCC)c1cccc(-c2ccc(C=O)cc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
135 mg (5 mol %) of tetrakis(triphenyl-phosphine)palladium are added to a solution of 830 mg (2.34 mmol, 1 eq) of 1-(3-bromophenyl)-1-propyl-3-heptylurea and 460 mg (3.0 mmol, 1.3 eq) of 4-formylphenylboronic acid in 10 mL of a mixture of dimethylformamide and of 2M potassium phosphate solution (8/2). The reaction mixture is stirred for 3 hours at 90° C. The reaction is stopped by addition of 50 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 735 mg of 1-propyl-1-(4′-formylbiphenyl-3-yl)-3-heptylurea are obtained in oil form. Yield=82%
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:16]=[CH:15][C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[CH3:17]COC(C)=O.CCCCCC>CS(C)=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:8]2[CH2:17][C@H:9]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Reaction time: 0.05 h
Yield: 46.7 %

Procedure:
To a vigorously stirring mixture of (CH3)3S(I)O (7.76 g, 35.3 mmol) in DMSO (75 mL) was added NaH (0.972 g, 36.5 mmol) in small portions over 5 min. Following complete addition, the reaction was left to stir for 10 min before the rapid dropwise addition of ethyl trans-4-bromocinnamate (2.21 mL, 11.8 mmol), which is commercially available from, for example, Sigma-Aldrich. After 3 h the reaction was partitioned between EtOAc (100 mL) and H2O (200 mL). The aq. phase washed with EtOAc (2×75 mL) wherein the combined organics were washed with H2O (2×50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting solid was absorbed onto Celite® and subjected to flash chromatography (SiO2—40 g; gradient elution: 5% EtOAc/Hexane isocratic for 3 min then 5-30% EtOAc/Hexane over 20 min at 40 mL/min to afford 1.48 g 13Ai as a white solid (46.7% yield). 1H NMR (500 MHz, CDCl3) δ 7.46-7.33 (m, 2H), 6.97 (d, J=8.6 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 2.47 (ddd, J=9.2, 6.4, 4.3 Hz, 1H), 1.86 (ddd, J=8.5, 5.4, 4.2 Hz, 1H), 1.59 (dt, J=9.5, 4.8 Hz, 1H), 1.35-1.18 (m, 4H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]([F:30])([F:29])[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:4]1[CH2:5][CH:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:25]([C:22]3[CH:21]=[CH:20][C:19]([CH:17]([CH3:18])[C:16]([F:15])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])=[CH:12][CH:13]=2)[CH2:7]1)[CH2:2][CH3:3]
Reactant: CC(c1ccc(S(=O)(=O)Cl)cc1)C(F)(F)F
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C(F)(F)F)cc3)cc2)C1
Yield: 18 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (100 mg, 0.52 mmol) in CH2Cl2/pyridine 9:1 (15 ml) was treated with 4-(2,2,2-trifluoro-1-methyl-ethyl)-benzenesulfonyl chloride (145 mg, 0.52 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provided the title compound (40 mg, 18%) as a pale yellow gum.
Reaction SMILES: [K+].[Br:2][C:3]1[C:8]2[N:9]=[C:10]([S-:12])[S:11][C:7]=2[CH:6]=[C:5]([C:13]#[N:14])[CH:4]=1.[K].S[C:17]1SC2C(N=1)=NC=C(C(OCC)=O)C=2>>[Br:2][C:3]1[C:8]2[N:9]=[C:10]([S:12][CH3:17])[S:11][C:7]=2[CH:6]=[C:5]([C:13]#[N:14])[CH:4]=1
Reactant: N#Cc1cc(Br)c2nc([S-])sc2c1
Reactant: CCOC(=O)c1cnc2nc(S)sc2c1
Agent: [K+]
Agent: [K]
Product: CSc1nc2c(Br)cc(C#N)cc2s1

Procedure:
4-Bromo-2-(methylthio)benzo[d]thiazole-6-carbonitrile was synthesized as a yellow solid (1.0 g, 12%) using a procedure analogous to that described in Step 2 of Example 114, substituting 4-bromo-6-cyanobenzo[d]thiazole-2-thiolate potassium salt from the previous step for ethyl 2-mercaptothiazolo[4,5-b]pyridine-6-carboxylate potassium salt used in Example 114. LCMS (ESI) m/z 284, 286 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.O.O.[OH-].[Li+]>O1CCOCC1>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1
Reactant: COCc1cnc(C(=O)OC)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COCc1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 5-(methoxymethyl)pyrazine-2-carboxylate, 8-(1), (55 mg, crude) was dissolved in 1,4-dioxane (1 mL) and water (1 mL) was added followed by lithium hydroxide monohydrate (50 mg). After stirring at RT for 1 h, water (20 mL) was added and the mixture was extracted with ether (20 mL). The aqueous portion was acidified to pH 2 and extracted with EtOAc (2×25 mL). The combined EtOAc layers were dried over MgSO4 and evaporated to afford the title compound (19 mg). 1H NMR (400 MHz, CDCl3) δ ppm 3.58 (s, 3 H), 4.77 (s, 2 H), 8.80 (br. s., 1 H), 9.38 (br. s., 1 H)
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.C(#N)C>O>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[C:16]([Br:24])[C:17]([N:19]([CH3:23])[CH:20]([CH3:21])[CH3:22])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: CC(C)N(C)c1nc2c(nc1Br)CN(Cc1ccccc1)CCO2
Temperature: 50 °C
Reaction time: 24 h
Yield: 19.5 %

Procedure:
A mixture of 8-benzyl-N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (500 mg), N-bromosuccinimide (342 mg) and acetonitrile (10 mL) was stirred at room temperature for 16 hr and at 50° C. for 24 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient: 0-40% ethyl acetate/hexane) to give the title compound (122 mg, 20%) as a colorless oil.
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][CH2:6][CH2:7][CH3:8])[CH:3]=[O:4].[CH2:9]([O:11][C:12](=[O:16])[CH2:13][N+:14]#[C-:15])[CH3:10]>>[CH2:9]([O:11][C:12]([CH:13]1[CH:3]([C:2]([CH2:5][CH2:6][CH2:7][CH3:8])=[CH2:1])[O:4][CH:15]=[N:14]1)=[O:16])[CH3:10]
Reactant: C=C(C=O)CCCC
Reactant: [C-]#[N+]CC(=O)OCC
Product: C=C(CCCC)C1OC=NC1C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-hexanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(hexen-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which is hydrolysed in a manner analogous to that described in Example 15 to 2-formylamino-3-hydroxy-4-butyl-4-pentenoic acid ethyl ester. Reaction of the 2-formylamino-3-hydroxy-4-butyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite analogously to Example 1 yields E-2-formylamino-4-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [NH2:1][C@@H:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[CH2:18]([CH:20]1[O:22][CH2:21]1)[Cl:19]>CO>[Cl:19][CH2:18][CH:20]([OH:22])[CH2:21][NH:1][C@@H:2]([C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: ClCC1CO1
Reactant: N#Cc1cccc([C@@H](N)c2ccc(Cl)cc2)c1
Solvent: CO
Product: N#Cc1cccc([C@@H](NCC(O)CCl)c2ccc(Cl)cc2)c1

Procedure:
A solution of 14.0 g (58 mmole) of 3-[(S)-amino(4-chlorophenyl)methyl]benzonitrile and 10.8 g (120 mmole) of epichlorhydrin in 200 mL of methanol was stirred in the dark for 72 hours. The solution was partitioned between CH2Cl2 and water and the layers were separated. The organic layer was dried over Na2SO4 and concentrated to afford the title compound, which was used in the next step without purification; 335 (M+1, 35Cl); 337 (M+1, 37Cl).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[N:6][CH:7]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: Brc1ccc(OCCN2CCCC2)nc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)nc3)nc2)cc1

Procedure:
Prepared according to general working method I from 5-bromo-2-(2-pyrrolidin-1-yl-ethoxy)-pyridine (90 mg, 0.33 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (80 mg, 0.37 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1O>CO.ClCCl>[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: Cc1ccc(O)c(C)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(OC(=O)COc2ncc(C(=O)Nc3ccc(F)cc3)cn2)c(C)c1
Yield: 71 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 2,4-dimethylphenol (16 mg, 0.13 mmol) as the source alcohol. Chromatography (5% methanol/dichloromethane) through SiO2 yielded 48 mg (71%) of the titled compound as a white solid. ESI-MS m/z 396 (MH+), 394 (M−H−).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>C(O)C>[F:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1ccc(F)c(F)c1
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(F)c(F)c1
Yield: 71.6 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-quinoline-3-carbonitrile, 250 ml ethanol and 2.55 ml (25.8 mmol) 3,4-difluoroaniline was heated to reflux under N2. Removed heat at 3½ hours and made basic with saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids and air dried. Washed with water and dried in vacuo. Dissolved in ethyl acetate, stirred with Darco, filtered, stripped solvent and dried in vacuo, giving 5.02 g of yellow solid: mass spectrum (electrospray m/e): M+H=327.1.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][O:46][CH2:47][CH2:48]O>CN(C=O)C>[CH3:45][O:46][CH2:47][CH2:48][O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCCOC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A solution of N-(carbobenzyloxy)-L-phenylalanine (10.0 g, 33.4 mmol) in DMF (75 mL) was treated with HOBT (6.8 g, 50.1 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.7 g, 40.1 mmol), 2-methoxyethanol (2.8 g, 36.8 mmol) and a catalytic amount of 4-N,N-dimethylaminopyridine. The reaction was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue taken up in ethyl acetate and washed with 1M hydrochloric acid, saturated sodium hydrogen carbonate and brine. The solution was dried over sodium sulphate, filtered and concentrated under reduced pressure to provide N-(carbobenzyloxy)-L-phenylalanine 2-methoxy-ethyl ester as a yellow foam (8.8 g, 74%). 1H-NMR; δ (CDCl3), 7.44-7.12 (10H, m), 5.27 (1H, d), 5.11 (2H, s), 4.72 (1H, dd), 4.26 (2H, m), 3.57 (2H, t), 3.38 (3H, s) and 3.15 (2H, m).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([N:15]1[CH2:20][CH:19]=[CH:18][CH:17]([OH:21])[CH2:16]1)=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:23]([O:21][CH:17]1[CH:18]=[CH:19][CH2:20][N:15]([C:13](=[O:14])[C@@H:9]([CH:10]([CH3:12])[CH3:11])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:16]1)([CH3:22])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC=CC(O)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC=CC(OS(C)(=O)=O)C1
Reaction time: 24 h

Procedure:
0.894 g of N—(N-BOC-(R)-valyl)-1,2,3,6-tetrahydropyridin-3-ol dissolved in 10 ml of CH2Cl2 are treated with 0.844 g of 4-dimethylaminopyridine and 0.31 g of methanesulfonic acid chlorid (mesylchloride) and stirred for ca. 24 hours, the mixture obtained is treated with 0.1 N HCl and CH2Cl2, the organic phase obtained is washed with H2O and aqueous NaHCO3-solution, the solvent is evaporated and the evaporation residue is dried. 3-Mesyloxy-N—(N-BOC-(R)-valyl)-1,2,3,6-tetrahydropyridine is obtained. 1H-NMR (CDCl3): 6.1-5.85(m,2H,HIV,HV), 4.5(m,1H,NHCHCO), 3.7(s,3H,CH3SO2), 1.2-0.9(m,6H,(CH3)2.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](NC2C=CC=C(F)C=2)(C(N)=O)[CH2:13][CH2:12]1.[BH4-].[Na+].C(N)=[O:32]>>[CH3:1][C:2]1([CH3:28])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=[O:32])[CH2:13][CH2:12]1
Reactant: CC1(C)C2CCC(CCN3CCC(Nc4cccc(F)c4)(C(N)=O)CC3)C1C2
Reactant: NC=O
Agent: [BH4-]
Agent: [Na+]
Product: CC1(C)C2CCC(CCN3CCC(=O)CC3)C1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 29.3 g (76 mmol) of (29a) in 400 ml formamide was heated for 2 h at 200° C. The solution turned from yellow to black. The reaction was monitored by 1H-NMR. After completed reaction the mixture was cooled to room temperature and poured into ice-water (800 g). The mixture was extracted with DCM (6×1 l). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in 1.2 l of methanol and 4.3 g (114 mmol) of sodiumborohydride were added portion wise. The mixture was stirred for 1 h at room temperature and another hour at 60° C. The reaction mixture was cooled to room temperature and quenched with 25 ml of water. The solvent was evaporated in vacuo. The residue was dissolved in 750 ml of ammonia and extracted with DCM (7×1.5 l). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 24.8 g of crude product, which was purified by column chromatography (SiO2, heptane:EtOAc, 1:1→1:3). Trituration with Et2O of the eluated product yielded 3.44 g (8.6 mmol, 11.3% from compound (26)) of compound (30a) as a white solid.
Reaction SMILES: [Li][NH2:2].[C:3]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl.C([O-])(O)=O.[Na+]>COCCOC>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([NH2:2])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: [Li]N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)c1ccc(N)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 71.7 %

Procedure:
(CyPF-t-Bu)PdCl2 (7.30 mg, 1.00×10−2 mmol), LiNH2 (0.230 g, 10.0 mmol) and 4-t-butyl-1-bromobenzene (0.213 g, 1.00 mmol) were weighed into a 24 mL vial. DME (20.0 mL) was then added. The vial was sealed with a cap containing a PTFE septum, and the reaction mixture was stirred for 24 h at 80° C. The reaction mixture was allowed to cool to room temperature before pouring into ice water (20.0 mL). To this mixture was added HCl aqueous solution (10.0 mL, 1.0 M). The mixture was stirred at room temperature for 5 min and was then neutralized with a saturated solution of NaHCO3 (5.00-10.0 mL). After extraction with CH2Cl2 (3×20.0 mL), the organic layer was separated and dried over MgSO4. The solvent was evaporated, and the crude product isolated by eluting with hexane/ethyl acetate (80/20) to give 107.0 mg (72%) of 4-t-butylaniline as a pale yellow liquid.
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]([O:7]CC)=O.Cl.[OH:11][CH:12]([CH3:16])[C:13]([NH2:15])=[NH:14].C(O)(=O)C>O>[OH:11][CH:12]([C:13]1[NH:15][C:5](=[O:7])[CH:4]=[CH:3][N:14]=1)[CH3:16]
Reactant: CCOC(=O)C=CO
Reactant: CC(O)C(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CC(O)c1nccc(=O)[nH]1
Reaction time: 48 h

Procedure:
To a solution of ethyl 3-hydroxy-acrylate sodium salt (prepared according to the method of Preparation Twelve, Step C, 1301 g, 9.42 mol) in water (1.3 L) was added a solution of 2-hydroxy-propionamidine hydrochloride (prepared according to the method of Preparation Twelve, Step B, 610 g, 4.9 mol) in water (1.3 L) at ambient temperature and stirred for 48 h. The solution was adjusted to pH 7.0 with acetic acid then continuously extracted with chloroform for 48 h. The extract was dried over sodium sulfate and filtered. The filtrate was concentrated to a solid, slurried in ethyl ether, filtered, and dried to give the title compound as a solid, 232 g (38%). mp: 121-124° C.; 1H NMR (DMSO-d6, 400 MHz) δ 1.30 (d, 3H), 4.46 (q, 1H), 5.62 (br s, 1H), 6.13 (d, 1H), 7.80 (d, 1H).