Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([N:36]([CH3:35])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:27])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: CNc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)N(C)c3ccccc3)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of N-methylaniline (104 mg, 0.968 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the objective product as powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:18]=[C:17]([CH2:19][CH2:20][C:21](OCC)=[O:22])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1>C(NCC)C>[CH2:9]([N:10]([CH2:11][CH3:12])[C:21](=[O:22])[CH2:20][CH2:19][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:18]=1)[CH3:5]
Reactant: CCOC(=O)CCc1nc(-c2cccc(OC)c2)nc2ccccc12
Solvent: CCNCC
Product: CCN(CC)C(=O)CCc1nc(-c2cccc(OC)c2)nc2ccccc12
Yield: 55.5 %

Procedure:
The procedure is as in Example 1, starting with ethyl 2-(3-methoxyphenyl)-4-quinazolinepropionate (1.2 g) and diethylamine (30 cc). After chromatography on silica gel with a cyclohexane/ethyl acetate (1:1 by volume) mixture as eluant, and crystallization in isopropyl ether, N,N-diethyl-2-(3-methoxyphenyl)-4-quinazolinepropanamide (0.36 g), m.p. 87° C., is obtained.
Reaction SMILES: [OH:1][C@:2]1([C:30]([OH:32])=O)[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9].Cl.NO.F[P-](F)(F)(F)(F)F.[N:43]1([O:52][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CC#N.O>[OH:52][NH:43][C:30]([C@@:2]1([OH:1])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:13][CH:12]=1)(=[O:9])=[O:10])=[O:32]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCC[C@]3(O)C(=O)O)cc2)c2ccccc2n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCC[C@]3(O)C(=O)NO)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of (1R,2R)-1-hydroxy-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid (0.08 g) in DMF (0.8 mL) was added hydroxylamine hydrochloride (2 eq), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (1.3 eq) and diisopropylethylamine (4 eq). The reaction was stirred overnight and injected directly onto a reverse phase HPLC (CH3CN/H2O) to afford (1R,2R)-N,1-dihydroxy-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxamide (0.03 g, 37%) as a white solid. MS: 472.1 (M+H)+
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:17])[C:11]=3[C:10]3=[N:18][O:19][C:20]([CH3:21])=[C:9]3[C:8]2=[O:22])[CH:4]=[CH:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:35]=[C:36]=[O:37])[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:12]1[C:11]2[C:10]3[C:9](=[C:20]([CH3:21])[O:19][N:18]=3)[C:8](=[O:22])[N:7]([CH:5]3[CH2:6][CH:2]([NH:1][C:36]([NH:35][C:27]4[CH:26]=[C:25]([O:24][CH3:23])[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=4)=[O:37])[CH:3]=[CH:4]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1onc2c1c(=O)n(C1C=CC(N)C1)c1cccc(Cl)c21
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(NC(=O)NC2C=CC(n3c(=O)c4c(C)onc4c4c(Cl)cccc43)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
To a stirred solution of 5-(4amino-cyclopent-2-enyl)9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (69 mg, 0.22 mmol) in CH2Cl2 (5 mL) was added 3,4,5-trimethoxy-isocyanato benzene (55 mg, 0.26 mmol) and DMAP (catalytic amount) and stirred at rt. for 18 hours. The mixture was diluted with CH2Cl2, washed (brine), dried Na2SO4), filtered and concentrated. Column chromatography (silica gel, hexanes/ethyl acetate, gradient) gave the title compound (116 mg, 100%). Mass Spectrum (FIA) (m/z) 425.3 (M+1) 1H NMR (CDCl3): δ 7.45 (d, 1H); 7.40 (t, 1H); 7.33 (d, 1H); 6.58 (m, 3H); 5.95 (m, 1H); 5.83 (m, 1H); 5.18 (s, 1H); 3.78 (s, 9H); 2.98 (m, 2H); 2.05 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1)[N:8]=[CH:7]2
Reactant: Clc1ncc2cccc(Br)c2n1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O[C@H]1CC[C@H](Nc2ncc3cccc(Br)c3n2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 8-bromo-2-chloroquinazoline (7.3 g, 30 mmol) in acetonitrile (150 mL) was added trans-4-aminocyclohexanol (6.9 g, 60 mmol) to form a suspension. DBU (9.1 g, 60 mmol) was added. The reaction mixture was stirred at 45° C. overnight. A light yellow suspension was formed. The solvent was removed under reduced pressure, and the residue was taken into DCM (100 mL) and washed with water (100 mL). The organic layer was dried over Na2SO4 and purified by chromatography (eluting with DCM) to give the title compound as a light yellow solid (3.36 g, 35%). 1HNMR (DMSO-d6, 400 MHz): δ 9.10 (s, 1H), 8.02 (dd, J=1.2, 7.6 Hz, 1H), 7.81 (dd, J=1.2, 7.6 Hz, 1H), 7.62-7.60 (m, 1H), 7.12 (dd, J=7.6, 7.6 Hz, 1H), 4.62-4.60 (m, 1H), 3.85-3.82 (m, 1H), 2.05-2.02 (m, 2H), 1.89-1.86 (m, 2H), 1.36-1.26 (m, 4H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:7]([NH:14][C:15](=[O:37])[N:16]([C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:26][C:25]=2[OH:36])[CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:7]([NH:14][C:15](=[O:37])[N:16]([C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:26][C:25]=2[O:36][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCI
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCCC)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 500 μL (3.8 mmol, 5.4 eq) of 1-iodopentane and 300 mg (0.7 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 5.1 eq) of potassium carbonate at 80° C. for 12 hours, methyl 3-[3′-(3-heptyl-1-methylureido)-2-pentyloxybiphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.[W]>[Br:31][CH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(C)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(CBr)cn1
Yield: 45 %

Procedure:
Ethyl 5-methyl-2-pyrazinecarboxylate (10.0 g, 60.18 mmol), benzoyl peroxide (1.46 g, 6.02 mmol) and N-bromo succinimide (11.78 g, 66.19 mmol) in 80 mL CCl4 was heated to reflux while a 75 W tungsten lamp was shining on the reaction mixture. After 4 h the reaction mixture was cooled and the precipitate filtered off. The red filtrate was concentrated and the residue redissolved in EtOAc and washed with sat'd NaHCO3, 5% Na2S2O3, brine and the organics dried (Na2SO4), filtered and concentrated. Chromatography on silica gel using 1:1 Hexanes:EtOAc eluted the product. After concentration the title compound (6.64 g, 27.08 mmol, 45% yield) was isolated as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 9.22 (s, 1H), 8.80 (s, 1H), 4.58 (s, 2H), 4.49 (dd, J=14.3, 7.1 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([O:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[C:23]([F:24])=[CH:22][C:21]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:20][C:19]=2[F:36])[CH2:14][CH2:13]1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][CH2:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[C:19]([F:36])=[CH:20][C:21]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:22][C:23]=2[F:24])[CH2:16][CH2:17]1)=[O:11]
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(C3CCN(C(=O)COCc4ccccc4)CC3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(C3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Reaction time: 20 h

Procedure:
A mixture of (S)-(-)-N-[[3-[4-[1-[(benzyloxy)acetyl]-4-piperidinyl]-3,5-difluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 36, 207 mg) and 10% palladium-on-carbon (100 mg) in methanol (9 mL) is shaken on a Parr apparatus under a hydrogen atmosphere at 40 psi for 20 hours, the catalyst is removed by filtration through Celite and the filtrate is concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 20 g), eluting with a gradient of methanol/methylene chloride (5/95-10/90). Pooling and concentration of those fractions with an Rf =0.26 by TLC (methanol/chloroform, 10/90) and recrystallization from methylene chloride/diethyl ether gives the title compound, NMR (CDCl3, 400 MHz) 7.07, 6.80, 4.78, 4.69, 4.18, 3.99, 3.74, 3.63, 3.60, 3.16, 3.06, 2.90, 2.72, 2.00, 1.97, 1.75 δ.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:10]1[CH:11]=[C:12]([CH:31]=[CH:32][CH:33]=1)[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18](C(OCC2C=CC=CC=2)=O)[CH2:17][CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1CC=CCC=1>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:10]1[CH:33]=[CH:32][CH:31]=[C:12]([O:13][CH2:14][CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)c1
Agent: [Pd]
Agent: CC1=CCC=CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC2CCNCC2)c1
Temperature: 80 °C
Yield: 85.6 %

Procedure:
To a stirred solution of benzyl 4-((3-(((tert-butoxycarbonyl)amino)(phenyl)-methyl)phenoxy)methyl)piperidine-1-carboxylate (1.12 g, 2.11 mmol) in ethanol (10 mL), was added 10% palladium on charcoal (0.22 g) and 1-methyl1,4-cyclohexadiene (1.18 mL, 10.55 mmol). The reaction mixture was heated to 80° C. for 7 hours. The reaction mixture was filtered through a pad of celite, and the filter-pad washed with further ethanol. The filtrate was evaporated at reduced pressure to afford the title compound (0.716 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:39]=[CH:38][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:39]=[CH:38][C:27]([O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[CH:26][CH:25]=1
Reactant: Brc1ccc(OCCCN2CCOCC2)cc1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCOCC4)cc3)cc12
Temperature: 110 °C
Yield: 40 %

Procedure:
A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (45 mg, 0.14 mmol), 4-[3-(4-bromophenoxy)-propyl]-morpholine (42 mg, 0.14 mmol) prepared using the procedure in Le Sann, C.; Huddleston, J.; Mann, J. Tetrahedron, 2007, 63, 12903-12911, and 2 M potassium carbonate solution (0.28 mL, 0.56 mmol) in toluene (0.9 mL) and ethanol (0.3 mL) was degassed with nitrogen for 5 minutes then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.0 mg, 0.007 mmol). The reaction vessel was sealed and heated at 110° C. for 2.5 h. The cooled reaction mixture was poured into water and ethyl acetate. The layers were separated and the aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using flash column chromatography eluting with heptanes/ethyl acetate (4:1 to 0:1) and ethyl acetate/methanol (9:1) to give the title compound (24 mg, 40%). MS (ES+) 429.2 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.37 (br. s., 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.55 (s, 1H), 7.33 (d, J=8.59 Hz, 2H), 6.97 (d, J=8.78 Hz, 2H), 4.11 (t, J=5.95 Hz, 2H), 3.84 (s, 3H), 3.79 (t, J=4.69 Hz, 4H), 2.89-2.97 (m, 2H), 2.86 (m, 4H), 2.11 (dt, J=15.42, 5.86 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:22][CH2:23][C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)=[N:4][C:5]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)=[CH:6][C:7]=1[NH:8]C(=O)OC(C)(C)C.[N:34]([O-])=O.[Na+].[OH-].[Na+].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>O.C(O)(=O)C>[CH3:21][N:19]1[CH:20]=[C:16]([C:5]2[N:4]=[C:3]3[N:22]([CH2:23][C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[N:34]=[N:1][C:2]3=[C:7]([NH2:8])[CH:6]=2)[CH:17]=[N:18]1
Reactant: O=N[O-]
Reactant: Cn1cc(-c2cc(NC(=O)OC(C)(C)C)c(N)c(NCc3ccc4ncccc4c3)n2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cn1cc(-c2cc(N)c3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
tert-Butyl 3-amino-6-(1-methyl-1H-pyrazol-4-yl)-2-(quinolin-6-ylmethylamino)pyridin-4-ylcarbamate (890 mg, 2 mmol) was added to a solution of acetic acid (5 mL) and water (5 mL) at 0° C., followed by the addition of NaNO2 (300 mg, 4 mmol) in H2O (0.5 mL). The reaction was stirred at 0° C. for 1 h, then basified with 30% NaOH to pH=8. The resulting mixture was filtered to afford a solid. The solid was treated with TFA (3 mL), and then stirred at room temperature for another 0.5 h, before treated with aqueous Na2CO3 to adjust the pH to 8. The resulting mixture was purified by chromatography to afford the title compound (190 mg). MS: 358 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[H][H].[C]=O>C1(C)C=CC=CC=1.[Pd].[C]>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [C]=O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C(F)(F)F)cc1
Yield: 82.9 %

Procedure:
In an apparatus as in Example 2, 100 g of 4-trifluoromethylbenzoyl chloride which had been prepared analogously to Example 1 were hydrogenated in the course of 4 hours at 90° C. in 700 ml of dry toluene with the aid of 3.5 g of Pd-carbon (Pd content: 5% by weight); the conversion was 95%. The Pd-carbon catalyst had been exposed, before the hydrogenation, for 30 minutes in toluene at the boil to a mixture containing 50% by volume each of hydrogen and carbon monoxide. By distillation it was possible to obtain 69.2 g of 4-trifluoromethylbenzaldehyde which had a boiling point of 70°-71° C./20 mbars and an nD20 of 1.4639. Yield: 83% of theory.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C@H:9]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:46][C:47]([F:61])([F:60])[O:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][CH2:56][C@@H:57]([NH2:59])[CH3:58])=[CH:51][CH:50]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][C@H:9]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[C:10]([NH:59][C@@H:57]([CH3:58])[CH2:56][NH:55][C:52]2[CH:51]=[CH:50][C:49]([O:48][C:47]([F:46])([F:60])[F:61])=[CH:54][CH:53]=2)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](N)CNc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)[C@H](CCC1CCCCC1)CC(=O)N1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@H](CCC1CCCCC1)CC(=O)N1CCOCC1

Procedure:
2-(R)-(2-Cyclohexyl-ethyl)-4-morpholin-4-yl-4-oxo-butyric acid (98 mg, 0.33 mmol, 1.0 eq.) dissolved in DMF (2 mL) and treated with HATU (137 mg, 0.36 mmol, 1.1 eq.), (S)-N1-(4-Trifluoromethoxy-phenyl)-propane-1,2-diamine (85 mg, 0.36 mmol, 1.1 eq.) and DIPEA (63 μL, 0.36 mmol, 1.1 eq.). Alternatively CH2Cl2 can be used as the reaction solvent based on starting material solubility. The reaction is monitored by LC/MS. The reaction mixture is diluted with ethyl acetate (20 mL) and extracted with 0.5 M HCl (2×10 mL), saturated NaHCO3, and brine. The organic layer is dried over MgSO4, filtered and evaporated. Alternatively, the crude reaction can be directly purified by mass-directed HPLC. Mass-directed HPLC provides the title compound as a white solid after evaporation and lyophilization: 1H NMR (CD3OD, 400 MHz) δ 0.74-0.82 (m, 2H), 1.08-1.65 (m, 13H), 1.21(d, J=6.8 Hz, 3H), 2.38(dd, J=4.8, 15.6 Hz, 1H), 2.65(m, 1H), 2.74(dd, J=9.6, 15.6 Hz, 1H), 3.10(m, 2H), 3.54-3.66(m, 8H), 4.11(m, 1H), 6.45(m, 2H), 6.97(m, 2H). HPLC-MS calcd. for C26H38F3N3O4 (M+H+) 514.3. found 514.2.
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])[CH2:4][CH3:5]>ClCCl>[Br:1][CH:4]([CH3:5])[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: BrBr
Reactant: CCC(=O)c1ccccc1
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 82 g (0.51 mol) of bromine in 100 ml of dichloromethane is added dropwise to a solution of 72 g (0.5 mol) of propiophenone in 500 ml of dichloromethane, at 20° C. After 30 minutes, the solution is evaporated down. 2-Bromopropiophenone is obtained quantitatively, and is directly reacted further.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][NH2:19]>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:19][CH2:18][C:14]1[S:13][CH:17]=[CH:16][CH:15]=1)#[N:2]
Reactant: COC(=NC#N)c1ccccn1
Reactant: NCc1cccs1
Solvent: CO
Product: N#CNC(=NCc1cccs1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 54.8 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 ml), 2-thiophenemethylamine (0.38 g, 3.4 mmol) was added, and the resulting mixture was stirred at room temperature for 40 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from dichloromethane-diethyl ether to give the title compound (0.40 g, 1.7 mmol, yield: 54%) as colorless needles.
Reaction SMILES: [F:1][C:2]1[C@H:3]([OH:33])[C@@H:4]2[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]2[C:11]=1[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>C(Cl)Cl>[CH3:41][S:42]([O:33][C@@H:3]1[C@H:4]2[C@H:5]([O:6][C:7]([CH3:10])([CH3:9])[O:8]2)[C:11]([CH2:12][O:13][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:2]1[F:1])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(F)[C@@H]2O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(F)[C@@H]2OS(C)(=O)=O
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Compound 10 (787 g (corrected), 1 wt), (gross input 1292 g), was dissolved in DCM (7.87 L, 10 vol) and cooled to 0 to 5° C. Triethylamine (368 mL, 0.468 vol, 1.5 eq) was charged followed by MsCl (164 mL, 0.208 vol, 1.3 eq) whilst maintaining the temperature at 0 to 5° C. IPC by 1H NMR analysis after 30 minutes indicated that 94.2% conversion had been achieved. An additional charge of triethylamine (28 mL) and MsCl (16 mL) (2 mol % per 1% conversion remaining) was made. IPC analysis after 30 minutes indicated that the conversion had increased to 97.3%. A second additional charge of triethylamine (13 mL) and MSCl (7.5 mL) was made. After a further 30 minutes IPC by 1H NMR analysis indicated that 100% conversion had been achieved. Water (7.87 L, 10 vol) was charged to the reaction and the mixture warmed to 15 to 25° C. Once the reaction was within the temperature range it was stirred for 10 minutes and the phases separated. The organic phase was returned to the flask, saturated NaHCO3 (7.87 L, 10 vol) charged and the two phases mixed for 10 to 20 minutes, then separated. The organic phase was dried over Na2SO4 (787 g, 1 wt) for 10 minutes, filtered and the filter cake washed with DCM (2×787 mL, 2×1 vol). The combined filtrate and washes were concentrated at up to 30° C. on a rotary evaporator under vacuum to obtain 11 as an orange oil. 1H-NMR (400 MHz, CDCl3) δ 7.7 ppm, d, 4H, TBDPS-F stage 1 by-product, δ 7.25 to 7.5 ppm, 21H. Trityl group and TBDPS-F by-product, δ 5.23 ppm, (d, J=5.8 Hz, 1H) (CH), δ 5.10 ppm, (t, J=7.1 Hz, 1H) (CH), δ 4.77 ppm, (m, J=2.8 Hz, 1H) (CH), δ 4.0 ppm, (d, J=12.6 Hz, 1H), 3.9 ppm, (d, J=12.6 Hz, 1H) (CH2), δ 3.1 ppm, s, 3H, Mesylate, (CH3), δ 1.4 ppm, 6H, Acetonide, (2×CH3), δ 1.1 ppm, 3, 9H, (3×CH3, TBDPSF), Solvents δ 5.8 ppm, s, 2H DCM.
Reaction SMILES: Cl[C:2]1[CH:3]=C(C2C3N=CC=CC=3C(=O)NN=2)C=C[CH:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]3[CH:36]=[CH:35][CH:34]=[N:33][C:28]=3[C:29](=[O:32])[NH:30][N:31]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]3[CH:36]=[CH:35][CH:34]=[N:33][C:28]=3[C:29](=[O:32])[N:30]([CH:2]([CH3:3])[CH3:7])[N:31]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2ncccc12
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2cccnc12
Product: CC(C)n1nc(-c2cccc(Cl)c2)c2cccnc2c1=O

Procedure:
Following the procedures of Example 18A and substituting for 8-(3-chlorophenyl) pyrido[2,3-d]pyridazin-5-one with 5-(3- chlorophenyl) pyrido[2,3-d]pyridazin-8-one there is obtained 5-(3-chlorophenyl)-7-(2-propyl) pyrido[2,3-d]-pyridazin-8-one.