Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1)[C:12]#[N:13].C(N(CC)CC)C.[CH:45]1([C:48](Cl)=[O:49])[CH2:47][CH2:46]1>C(Cl)Cl>[CH:45]1([C:48]([N:31]2[CH2:32][CH2:33][C:27]3[C:28](=[N:29][C:24]([N:21]4[CH2:20][CH2:19][CH:18]([O:17][C:16]5[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=5[F:8])[CH2:23][CH2:22]4)=[C:25]([NH:34][CH:35]([CH3:37])[CH3:36])[N:26]=3)[CH2:30]2)=[O:49])[CH2:47][CH2:46]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CNCC2
Reactant: O=C(Cl)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CN(C(=O)C1CC1)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile TFA salt (98.6 mg, 0.094 mmol) and triethylamine (0.039 mL, 0.283 mmol) in DCM (0.5 mL) was added cyclopropanecarboxylic acid chloride (0.017 mL, 0.188 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (8.1 mg, 15%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 0.69-0.79 (m, 4H), 1.18 (d, J=6.6 Hz, 6H), 1.91 (dd, J=19.5, 5.6 Hz, 2H), 2.13 (dd, J=14.3, 6.2 Hz, 2H), 2.52-2.53 (m, 1H), 2.57-2.64 (m, 0.9H), 2.75 (t, J=6.2 Hz, 1.1H), 2.88-2.99 (m, 2H), 3.22-3.31 (m, 2H), 3.72-3.77 (m, 0.9H), 3.95 (t, J=5.8 Hz, 1H), 4.10-4.16 (m, 1H), 4.42 (br s, 1.1H), 4.67 (br s, 0.9H), 4.80-4.87 (m, 1H), 5.61-5.67 (m, 1H), 7.50 (t, J=8.5 Hz, 1H), 7.65-7.70 (m, 1H), 7.86 (dd, J=11.2, 1.9 Hz, 1H); ESI-MS m/z [M+H]+ 479.5.
Reaction SMILES: [CH3:1][N:2]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[N:12]=[C:11]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[C:10](B(O)O)=[CH:9][CH:8]=1)=[O:5].I[C:37]1[N:41]2[CH:42]=[CH:43][C:44]([CH3:46])=[CH:45][C:40]2=[N:39][C:38]=1[C:47]1[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:32]([O:31][C:29](=[O:30])[N:2]([CH3:1])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:37]2[N:41]3[CH:42]=[CH:43][C:44]([CH3:46])=[CH:45][C:40]3=[N:39][C:38]=2[C:47]2[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=2)=[C:11]([C:13]#[C:14][Si:15]([CH:19]([CH3:20])[CH3:21])([CH:22]([CH3:23])[CH3:24])[CH:16]([CH3:18])[CH3:17])[N:12]=1)=[O:5])([CH3:34])([CH3:33])[CH3:35]
Reactant: CC(C(=O)Nc1ccc(B(O)O)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Reactant: Cc1ccn2c(I)c(-c3ccncc3)nc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccn2c(-c3ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc3C#C[Si](C(C)C)(C(C)C)C(C)C)c(-c3ccncc3)nc2c1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of [6-[2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoylamino]-2-[2-tri(propan-2-yl)silylethynyl]pyridin-3-yl]boronic acid D1a (1.5 g, 3.0 mmol), 3-iodo-7-methyl-2-pyridin-4-ylimidazo[1,2-a]pyridine Za (1.3 g, 3.9 mmol), Na2CO3 (0.95 g, 8.9 mmol), Dichlorobis(triphenylphosphine)palladium(II) (209 mg, 0.3 mmol), dioxane (30 ml) and water (5 ml) is stirred under argon atmosphere for 17 h at 70° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 965 mg (49%). HPLC-MS: M+H=667; tR=2.04 min (*Method—3).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[N:26]=[N:27][NH:28][N:29]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:36]>O1CCCC1.C(OCC)(=O)C>[ClH:36].[NH2:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[N:26]=[N:27][NH:28][N:29]=1)=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nn[nH]n3)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(-c3nn[nH]n3)ccc2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 97 %

Procedure:
Tert-butyl[2-isobutyl-1-oxo-4-phenyl-6-(2H-tetrazol-5-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.15 g, 0.32 mmol) was dissolved in tetrahydrofuran (4 mL) and a solution (4 mL) of 4N hydrogen chloride in ethyl acetate was added thereto. This mixture was stirred at room temperature for 17 h, and the precipitated crystals were collected by filtration to give the title compound (0.13 g, 97%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:3]=1.[K].[C:23]1([CH2:29][CH2:30][S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CS(C)=O.O>[Cl:15][C:6]1[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:3]=[C:2]([NH:34][S:31]([CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:32])=[O:33])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: NS(=O)(=O)CCc1ccccc1
Reactant: Cc1ccc(-c2c(Cl)nc(-c3ccncc3)nc2Cl)cc1
Agent: [K]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2c(Cl)nc(-c3ccncc3)nc2NS(=O)(=O)CCc2ccccc2)cc1
Yield: 21.8 %

Procedure:
A solution of 4,6-dichloro-2-(4-pyridyl)-5-(p-tolyl)-pyrimidine (1.5 g), 2-phenyl-ethanesulfonic acid amide potassium salt (1.44 g, Referential Example 1e) and Hunig's base (1 ml) in DMSO (20 ml) was stirred at rt for 24 h before it was diluted with water (150 ml) and extracted twice with diethyl ether. The aqueous layer was acidified with acetic acid. The precipitate was collected, and further purified by column chromatography on silica gel eluting with hexane:EA 1:1 to give 2-phenyl-ethanesulfonic acid (6-chloro-2-pyridin-4-yl-5-p-tolyl-pyrimidin-4-yl)-amide (480 mg) as a foam. LC-MS: tR=5.08 min, [M+1]+=465.13, [M−1]−=462.96.
Reaction SMILES: [C:1]1([CH:7]([SeH:12])[CH2:8][O:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[C:1]1([CH:7]([SeH:12])[CH2:8][O:9][CH2:10][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCOCC([SeH])c1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(COCC([SeH])c1ccccc1)OCC
Yield: 81 %

Procedure:
A solution of 27 (25g, 0.1 mol) and triethyl phosphite was heated at 110° C. for 2.5 hours. After evaporation of volatile in vacuo, the residual oil was chromatographed on silica gel using CH2Cl2 -6% MeOH as eluant to give 28 (30 g, 81%) as a slightly yellow oil. 1H-NMR (300 MHz, CDCl3) 1.27 (t, J=7.24Hz, 6H), 3.01 (t, J=7.5Hz, 2H), 3.70-3.75 (m, 4H), 4.10-4.18 (m, 4H), 7.2-7.5 (m, 5H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CO[C@@H]2CCNC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (R)-3-(4-chlorobenzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.88 mmol) in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI-MS m/z: 211(M+1), WV retention time: 0.97 min.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.[N:25](OCCCC)=[O:26]>C(OCC)C>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([N:25]=[O:26])[CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCCCON=O
Reactant: Cc1ccc2c(c1)OCC(c1ccccc1)=N2
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cc1ccc2c(c1)OCC(c1ccccc1)N2N=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a mixture of 7-methyl-3-phenyl-2H-1,4-benzoxazine (22.5 g, 99.87 mmol) in ethyl ether (300 mL) is added trifluoroacetic acid (7.7 mL, 99.87 mmol). The resulting solution is chilled to 5° C. in an ice bath and n-butyl nitrite (12.26 mL, 99.87 mmol) is added dropwise. The mixture is stirred for 1 h; solids formed during the reaction. The solids are collected by filtration and washed with ether. The filtrates are partitioned between ether and water and the organic layers are washed three times with water (500 mL), dried over magnesium sulfate, and concentrated to dryness. The combined solids gave 23.22 g (97%) of 7-methyl-4-nitroso-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[C:13]([CH:15](CC)[C:16]([O-:18])=[O:17])#[N:14].N1CCC[CH2:23][CH2:22]1.Cl>N1C=CC=CC=1>[CH2:22]([O:18][C:16]([C:15]([C:13]#[N:14])=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:17])[CH3:23]
Reactant: CCC(C#N)C(=O)[O-]
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(-c2cccs2)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C#N)=Cc1ccc(-c2cccs2)s1
Yield: 86 %

Procedure:
3.9 g of 5-formyl-2,2'-bithiophene, 2.4 ml of cyano-ethyl-acetate, 15 ml of pyridine and 2.4 ml of piperidine were heated at 80°-85° C. for 2 hours. After cooling, the mixture was acidified by diluted HCl and then filtered. The orange crude product was recrystallized from ethanol to give a crystal product (5.02 g). The melting point of the product was 131° C. The yield was 86%.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][S:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1)([O-:14])=[O:13]>ClCCl>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][S:25](=[O:9])[CH2:24][CH2:23]2)=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CN2CCSCC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CN2CCS(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
11.7 g (58 mmol) of m-chloroperbenzoic acid are added to a solution of 11.5 g (48 mmol) of 4-(4-nitrophenylmethyl)-thiomorpholine in 100 ml of dichloromethane at ambient temperature. The reaction solution is stirred for 4 hours at ambient temperature and then washed with 1N sodium hydroxide solution and water and evaporated to dryness. Chromatography on silica gel (dichloromethane/methanol=9:1) yields the product.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](SC)[C:6]([F:11])=[CH:5][N:4]=1.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:13][NH2:14])[C:6]([F:11])=[CH:5][N:4]=1
Reactant: CSc1ncc(F)c(SC)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CSc1ncc(F)c(NN)n1
Temperature: 0 °C
Yield: 86 %

Procedure:
A 1 liter (L) flask equipped with a condensor and thermometer was charged with 80g (0.42 moles) of 2,4-bis(methylthio)-5-fluoropyrimidine, 200 mL of ethanol and 105g (2.1 moles) of hydrazine hydrate. The reaction mixture was poured onto 350 mL of ice-water. The solid product was isolated by filtration. After washing with water, the product was dried under vacuum at 60° C. to give 62.8g (86 percent yield) of 2-methylthio-4-hydrazino-5-fluoropyrimidine having a melt point of 146°-147° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:23]=1[NH2:24]>>[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:23]=1[NH:24][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)n1
Reactant: COc1ccc(OC)c(N)c1
Product: COc1ccc(OC)c(Nc2cc(-c3ccccn3)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture 4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 2,5-dimethoxyaniline (21 mg, 0.140 mmol) similar to Example 111 and isolated as a yellow oil (2 mg, 6%). 1H NMR (CDCl3): 8.86-8.84 (m, 1H), 8.70-8.64 (m, 3H), 8.11 (s, 1H), 7.92 (s, 1H), 7.91-7.85 (m, 2H), 7.65 (s, 1H), 7.43-7.36 (m, 2H), 6.87 (d, J=9.0 Hz, 1H), 6.61 (dd, J=3.0, 9.0 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: C[N:2]([CH3:8])[CH2:3][CH2:4][N:5]([CH3:7])C.C(N[CH:13]([CH3:15])[CH3:14])(C)C.C([Li])CCC.CCCCCC.[C:27](N)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30]C=1>O1CCCC1>[N:30]1[C:7]2[NH:5][C:4]3[CH:3]=[N:2][CH:8]=[CH:14][C:13]=3[CH2:15][C:27](=[O:34])[C:28]=2[CH:33]=[CH:32][CH:31]=1
Reactant: CN(C)CCN(C)C
Reactant: CC(C)NC(C)C
Reactant: NC(=O)c1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1Cc2ccncc2Nc2ncccc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
N,N,N′,N′-tetramethylethylenediamine (8.0 mL, 0.053 mol) and N,N-diisopropylamine (7.4 mL, 0.053 mol) were mixed in tetrahydrofuran (43 mL) and then cooled to −78° C. To the mixture was added 2.50 M of n-butyllithium in hexane (21 mL, 0.0525 mol) and stirred at −78° C. for 10 minutes then at 0° C. for 10 minutes. In a separate flask was added N,N-diethyl-2-[4-methylpyridin-3-yl)amino]nicotinamide (5.00 g, 0.0176 mol) in tetrahydrofuran (100 mL) and then cooled to 0° C. under an atmosphere of nitrogen. The mixture from the first flask was added to the second flask and the resulting mixture stirred at 0° C. for 30 minutes. The reaction was quenched with (aq)NH4Cl and was extracted with ethyl acetate. The organic extracts were washed with brine, dried over MgSO4, concentrated, and purified by column chromatography on silica gel (10% methanol 90% ethyl acetate) to give 3.34 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 8.49 (s, 1H), 8.41-8.45 (m, 2H), 8.34 (dd, 1H, J1=7.8 Hz, J2=1.5 Hz), 7.78 (br s, 1H), 7.24-7.26 (m, 1H), 6.97-7.25 (m, 1H), 3.89 (s, 2H). MS [M+H]=212.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.[CH:29]([NH2:32])([CH3:31])[CH3:30]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:28])=[CH:5][N:6]=3)=[C:16]([C:17]([F:18])([F:20])[F:19])[O:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Yield: 97 %

Procedure:
As described for example 137, 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol) was converted, using isopropylamine instead of methylamine, to the title compound (104 mg, 97%) which was obtained as an off white solid. MS: m/e=424.1 [M+H]+.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:20]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH:30]([CH3:32])[CH3:31])=[N:28][N:29]=3)[N:26]=2)=[CH:19][NH:18][N:17]=1.S(O[CH:44]1[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45]1)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:20]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH:30]([CH3:32])[CH3:31])=[N:28][N:29]=3)[N:26]=2)=[CH:19][N:18]([CH:48]2[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47]2)[N:17]=1
Reactant: CC(C)c1nnc2ccc(-c3c[nH]nc3-c3ccc(F)cc3F)nn12
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1nnc2ccc(-c3cn(C4CCN(C(=O)OC(C)(C)C)C4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To a round bottom flask was added NaH (0.065 g, 1.6 mmol), DMF (4 mL) and 6-(3-(2,4-difluorophenyl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.500 g, 1.47 mmol, Example #L.1.1). The reaction mixture was stirred for about 30 min at ambient temperature. tert-Butyl 3-(tosyloxy)pyrrolidine-1-carboxylate (0.652 g, 1.91 mmol, prepared according to US 2002/0151712, Example #34c) was added and the reaction mixture was stirred for about 30 min at ambient temperature. The reaction mixture was heated to about 75° C. for about 1 h. The reaction mixture was diluted with DCM (50 mL), washed with water (50 mL), dried with MgSO4, filtered and concentrated in vacuo. The reaction mixture was purified by flash chromatography (40 g RediSep® silica gel; DCM/MeOH gradient from 1:0 to 90:10) to give the title compound (0.446 g, 60%) as a mixture of regioisomers: LC/MS (Table 1, Method g) Rt=3.66 min; MS m/z: 510.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[NH:25][C:26]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)=[CH:27][N:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([C:26]4[NH:25][C:24]([C:23]([F:37])([F:36])[F:22])=[N:28][CH:27]=4)=[CH:30][CH:31]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc(-c2cnc(C(F)(F)F)[nH]2)cc1
Product: CC(C(=O)Nc1ccc(-c2cnc(C(F)(F)F)[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
67 mg (0.22 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 49 mg (0.22 mmol) of 4-[2-(trifluoromethyl)-1H-imidazol-5-yl]aniline (Example 1.3B) were reacted according to General Method 1. Yield: 26 mg (22% of theory)
Reaction SMILES: N1C=CC=CC=1.Cl.[NH2:8][OH:9].[CH:10]([C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:42])[NH:20][CH2:21][C:22]([N:24]([CH2:31][C:32]([N:34]([CH3:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[CH:15]=[CH:16][CH:17]=1)=O>O.CO>[OH:9]/[N:8]=[CH:10]/[C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:42])[NH:20][CH2:21][C:22]([N:24]([CH2:31][C:32]([N:34]([CH3:41])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:23])[CH:15]=[CH:16][CH:17]=1
Reactant: CN(C(=O)CN(C(=O)CNC(=O)Nc1cccc(C=O)c1)c1ccccc1)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: CN(C(=O)CN(C(=O)CNC(=O)Nc1cccc(/C=N/O)c1)c1ccccc1)c1ccccc1
Yield: 48.4 %

Procedure:
0.18 g of pyridine and then 0.17 g of hydroxylamine hydrochloride in solution in 3 cm3 of water are added to a solution of 1 g of 2-{2-[3-(3-formylphenyl)ureido]-N-phenylacetamido}-N-methyl-N-phenylacetamide in 6 cm3 of methanol. The mixture is heated under reflux for 3 hours. After cooling, the insoluble product is separated off by filtration, washed with 3 times 3 cm3 of water and air-dried. After recrystallization from a dimethylformamide/water mixture (50/50 by volume), 0.5 g of (E)-2-{2-[3-(3-hydroxyiminomethylphenyl)ureido]-N-phenylacetamido}-N-methyl-N-phenylacetamide melting at 219° C is obtained.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.C([O:34][C:35]1[CH:45]=[CH:44][C:38]([CH2:39][C:40]2([NH2:43])[CH2:42][CH2:41]2)=[CH:37][CH:36]=1)C1C=CC=CC=1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH2:21][NH:43][C:40]2([CH2:39][C:38]3[CH:44]=[CH:45][C:35]([OH:34])=[CH:36][CH:37]=3)[CH2:42][CH2:41]2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: NC1(Cc2ccc(OCc3ccccc3)cc2)CC1
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(cc(O)cc2C(O)CNC2(Cc3ccc(O)cc3)CC2)N1

Procedure:
Prepared according to general method 3 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 253 mg (1 mmol) 1-(4-benzyloxy-benzyl)-cyclopropylamine. Yield: 47 mg (10%, trifluoroacetate); mass spectroscopy: [M+H]+=371.
Reaction SMILES: ClC[CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10]Cl.[OH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)[CH:4]=[CH2:3]
Reactant: ClCCCCOCCCCCl
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOCCCCOc1ccc(C(=O)O)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution comprising 14 g of allyl (4-chlorobutyl ether, 14 g of 4-hydroxybenzoic acid, 14 g of potassium carbonate and 50 ml of dimethylformamide was stirred at 90° C. for 3 hours. Water was added thereto, and the liquid was extracted with toluene. The toluene layer was washed well with water, and toluene was distilled off. Sodium hydroxide 20 g, water 50 ml and ethanol 200 ml were added to the resulting residue, and the solution was refluxed for 2 hours. Ethanol was distilled off, and hydrochloric acid was added to acidify the solution. It was extracted with diethyl ether and dried on anhydrous magnesium sulfate. The solvent was distilled off, and a residue thus obtained was recrystallized from a mixed solvent of ethanol and water to obtain 29 g of 4-(4-allyloxybutyloxy)benzoic acid. Phase transition temperature: C 94 N 107 I
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH2:12][C:13]#[N:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22]([CH3:28])=[CH:21][N:20]=1>O1CCCC1>[CH3:28][C:22]1[CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:19]([C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:11][CH2:12][C:13]#[N:14])=[N:20][CH:21]=1
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)C(CCC#N)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC#N)(C(=O)OCC)c1ncc(C)cc1[N+](=O)[O-]
Yield: 37.4 %

Procedure:
2-(2-Cyanoethyl)malonic acid diethylester (40 g) was reacted with sodium hydride (4.4 gm) in tetrahydrofuran at 20° C. 2-Chloro-5-methyl-3-nitro-pyridine (35 g) was added and the internal temperature was raised to 100° C. (some tetrahydrofuran distilled off) over 4.25 hrs. The reaction mixture was partitioned between chloroform and water and treated with charcoal. Vacuum distillation of the chloroform extract and then chromatography (CHCl3, silica column) of the distillation residues gave 4-(5-methyl-3-nitropyrid-2-yl)-4,4-bis(carbethoxy)butyronitrile (24.5 g) as a yellow solid m.p. 48°-49° C.