Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[C:6]([CH3:14])=[C:5]2O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:5]1[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[C:7]([CH3:13])[C:6]=1[CH3:14]
Reactant: Cc1nc2c(C)cc(Cl)cc2c(O)c1C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2c(C)cc(Cl)cc2c(Cl)c1C
Temperature: 25 °C

Procedure:
Prepared according to procedure S using 6-chloro-2,3,8-trimethylquinolin-4-ol (3.25 g, 1.65 mmol) in POCl3 (20 mL) and heating at reflux for 3 h. After this time the reaction mixture was cooled to rt and poured into ice water. The resulting solid was filtered and washed with water. The product was then dried under vacuum and 4,6-dichloro-2,3,8-trimethylquinoline was obtained as a white solid. Mass Spectrum (ESI) m/e=241 (M+1).
Reaction SMILES: C(OC(N[CH:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:10][CH:11]([OH:39])[CH:12]([NH:20][C:21](=[O:38])[C@H:22]([CH2:34][C:35](=[O:37])[NH2:36])[NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)(C)(C)C.CO.C([NH2:51])(C)C.C(Cl)(Cl)Cl>>[NH2:51][CH:10]([CH:11]([OH:39])[CH:12]([NH:20][C:21](=[O:38])[C@H:22]([CH2:34][C:35](=[O:37])[NH2:36])[NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)NC(CC(O)C(Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Yield: 95 %

Procedure:
Using the procedure of Example 11 with the resultant compound of Example 66 gave, after silica gel chromatography using methanol/isopropylamine/chloroform, the desired compound (RF 0.3; 2.5% methanol/2% isopropylamine/chloroform) in 95% yield. Mass spectrum (M+H)+ =519.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[C:28]=2[Cl:35])[C:7]=1[N:8]([C:18]([O:20][C:21]1C=CC=C[CH:22]=1)=[O:19])C(OC1C=CC=CC=1)=O)#[N:2].[CH2:36]([O:38]CCO)[CH3:37]>>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[C:28]=2[Cl:35])[C:7]=1[NH:8][C:18]([O:20][CH2:21][CH2:22][O:38][CH2:36][CH3:37])=[O:19])#[N:2]
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N(C(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Reactant: CCOCCO
Product: CCOCCOC(=O)Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl

Procedure:
A stirred mixture of 4-cyano-5-di(phenoxycarbonyl)amino-1-(2,3,4-trichlorophenyl)pyrazole (prepared as described in Example 27; 20 g) in 2-ethoxyethanol (400 ml) was heated at reflux for 4 hours. The reaction mixture was evaporated to dryness and the residue crystallized from ethyl acetate-n-hexane to give 4-cyano-5-[(2-ethoxy)ethoxycarbonylamino]-1-(2,3,4-trichlorophenyl)pyrazole (10 g), m.p. 122°-124° C., in the form of colourless crystals. The mother liquors were evaporated to dryness and the residue chromatographed on aluminium oxide (120 g; May & Baker grade) using dichloromethane as eluent. Evaporation of the eluate and crystallisation of the residue from ethyl acetate-n-hexane gave a further quantity of 4-cyano-[5-(2-ethoxy)ethoxycarbonylamino]-1-(2,3,4-trichlorophenyl)pyrazole (3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:9][CH2:10][CH2:11][N:12]2[CH2:23][CH2:22][C:15]3([O:19][C:18](=O)[O:17][C:16]3=[CH2:21])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH2:31]([NH2:35])[CH2:32][CH2:33][CH3:34].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][C:15]3([O:19][C:18](=[O:17])[N:35]([CH2:31][CH2:32][CH2:33][CH3:34])[C:16]3=[CH2:21])[CH2:22][CH2:23]2)=[CH:4][CH:3]=1
Reactant: C=C1OC(=O)OC12CCN(CCC=C(c1ccc(F)cc1)c1ccc(F)cc1)CC2
Reactant: CCCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: C=C1N(CCCC)C(=O)OC12CCN(CCC=C(c1ccc(F)cc1)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
A mixture containing 8.2 g of 8-[4,4-bis(4-fluorophenyl)-3-butenyl]-4-methylene-2-oxo-1,3-dioxa-8-azaspiro[4,5]decane, 25 ml of xylene and 2.0 ml of butylamine is stirred at room temperature for 18 hours, then 0.8 g of p-toluenesulfonic acid monohydrate and 70 ml of xylene are added and the reaction mixture is boiled while azeotropically distilling off the water formed in the reaction. After termination of the reaction which is observed by thin layer chromatography (TLC), the mixture is cooled down and made alkaline to a pH of 9 to 10 by adding 5% by weight aqueous sodium hydroxide solution. After washing the organic phase with water to neutral and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The crude product obtained as evaporation residue is recrystallized from ethanol under clarifying by activated carbon to give the title product in 72.5% yield, m.p.: 92°-93° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:38])=[CH:22][N:21]=1>>[CH:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([NH:18][C:20]3[N:25]=[C:24]([NH:26][C:27]4[C:28]([C:29](=[O:30])[NH:31][CH3:32])=[CH:33][CH:34]=[CH:35][C:36]=4[F:37])[C:23]([Cl:38])=[CH:22][N:21]=3)=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)OC(=O)N1CCCOc2cc(N)ccc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC(C)C)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid isopropyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid isopropyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as a yellow foam (76 mg, 42%). LCMS (m/e) 529 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.48-9.32 (m, 2H), 8.63-8.51 (m, 1H), 8.20 (s, 1H), 7.55-7.36 (m, 3H), 7.28 (s, 1H), 7.09 (d, 1H, J=8.8 Hz), 6.92 (d, 1H, J=8.5 Hz), 4.87-4.71 (m, 1H), 4.05-3.85 (m, 2H), 3.67-3.40 (m, 2H), 2.74 (d, 3H, J=4.2 Hz), 1.97-1.81 (m, 2H), 1.33-1.00 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26](=[O:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=2F)[CH2:10][CH2:9]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>O>[N:29]1([C:16]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:7]3[CH:6]=[CH:5][C:4]([C:26](=[O:28])[CH3:27])=[CH:3][C:2]=3[F:1])[CH2:13][CH2:12]2)=[O:25])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3F)CC2)c(F)c1
Reactant: C1COCCN1
Solvent: O
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)c(F)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of 1-{3-Fluoro-4-[4-(2-fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone (0.065 g, 0.167 mmol) in morpholine (0.29 ml) was heated for 30 minutes at 100° C. then cooled to room temperature and diluted with water. The resulting solid was filtered and dried to provide the title compound (71 mg, 93%) as a yellow solid, MS (m/e): 457.3 (M+H+, 100%)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][CH2:15][CH2:16][CH:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH2:7]([O:14][CH2:15][CH2:16][CH:17]([CH2:18][OH:19])[CH2:23][OH:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(CCOCc1ccccc1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(CO)CCOCc1ccccc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To a cooled, stirred suspension of lithium aluminum hydride (103 g, 2.7 mol) in dry ether (2.51) under nitrogen was added ethyl 4-benzyloxy-2-ethoxycarbonyl-butanoate (362 g, 1.23 mol) over a period of 3 hours. On completion of the addition, the reaction mixture was allowed to warm to room temperature, and then heated under reflux for 1 hour. It was then re-cooled and the excess lithium aluminium hydride destroyed by dropwise addition of water (100 ml), 2 M sodium hydroxide (100 ml) and water (300 ml). The reaction mixture was filtered, and the filter cake washed well with chloroform. The filtrate was dried (MgSO4), filtered, and evaporated to give 4-benzyloxy-2-hydroxymethylbutan-1-ol as a clear oil (226 g, 87%). δH (CDCl3) 1.35-2.05 (3 H, m, CHCH2CH2), 3.30-3.80 (8 H, m, 3×CH2O, 2×OH), 4.42 (2 H, s, OCH2Ph), 7.26 (5 H, s, Ar).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][NH:16][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: NC1CCCCC1
Solvent: CCO
Product: CCOC(=O)CCCNC1CCCCC1
Temperature: 25 °C
Yield: 107.1 %

Procedure:
7 g of 4-bromobutyric acid ethyl ester and 20 g of cyclohexylamine were added to 50 mL of ethanol, and the mixture was stirred at a room temperature for one week. The stirred mixture was concentrated under reduced pressure and extracted with 200 mL of ethyl acetate. The extracted material was washed with purified water, dried with magnesium sulfate, and then concentrated. The obtained residue was distilled under reduced pressure to give 8.2 g of N-cyclohexyl-gamma-aminobutyric acid ethyl ester. The obtained N-cyclohexyl-gamma-aminobutyric acid ethyl ester was added to sodium hydroxide solution (1.68 g of sodium hydroxide/100 mL of purified water), and THF was added thereto till the mixture became homogeneous. After stirring at room temperature for 3 hours, the mixture was neutralized with DOWEX50W [H+ form] and concentrated under reduced pressure. The obtained residue was recrystallized to give 4.1 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[CH3:36].[C:37](OC(=O)C)(=[O:39])[CH3:38]>>[CH3:36][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:2]=1[NH:1][C:37](=[O:39])[CH3:38])[C:6]([N:8]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:21][CH2:20]1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)c(C)c2)c1
Product: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NC(C)=O)c(C)c2)c1
Yield: 89.2 %

Procedure:
Using 4-amino-3-methyl-N-{2-[4-(4-fluorobenzoyl)piperidino]-ethyl}-N-(3-methoxyphenyl)benzamide (489.0 mg, 1.00 mmol) and acetic anhydride (0.19 ml, 2.00 mmol), the procedure of Inventive Example 94 was repeated to obtain 474.0 mg (89.3%) of the title compound in a colorless amorphous form.
Reaction SMILES: [OH:1][CH:2]1[CH:19]([CH2:20][CH2:21][CH:22]([O:28]C2CCCCO2)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]2[CH2:6][C:7]3[C:12]([CH2:13][CH:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:9][CH:8]=3.[F:35][C:36]([F:40])([F:39])[CH2:37][NH2:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(OC)(C)C>[OH:1][CH:2]1[CH:19]([CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]2[CH2:6][C:7]3[C:12]([CH2:13][CH:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([NH:38][CH2:37][C:36]([F:40])([F:39])[F:35])=[O:18])[CH:10]=[CH:9][CH:8]=3
Reactant: CCCCCC(CCC1C(O)CC2Cc3c(cccc3OCC(=O)O)CC21)OC1CCCCO1
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: COC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCC(O)CCC1C(O)CC2Cc3c(cccc3OCC(=O)NCC(F)(F)F)CC21
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.8 %

Procedure:
A solution of {2-Hydroxy-1-[3-(tetrahydro-pyran-2-yloxy)-octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy}-acetic acid (94 mg, 0.2 mmol), trifluoroethylamine (54 mg, 0.6 mmol) and DIPEA (104 μl, 0.6 mmol) in DMF (2 ml) was treated with HATU and stirred 24 hr at RT. The reaction mixture was diluted with MTBE and washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography. This resulting material was dissolved in MeOH (4 ml), treated with Amberlite IR120H and stirred 24 hr. The reaction mixture was filtered and concentrated to yield 2-[2-hydroxy-1-(3-hydroxy-octyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yloxy]-N-(2,2,2-trifluoro-ethyl)-acetamide (46 mg) as an oil. 1HNMR (400 MHz, CDCl3) δ 7.06 (d, 1H, J=7.6); 6.80 (d, 1H, J=7.2); 6.63 (d, 1H, J=8.0); 4.86 (quint., 1H, J=6.4); 4.60 (s, 2H); 3.7-3.8 (m, 1H); 3.55-3.65 (m, 1H); 2.85-2.95 (ddd, 1H); 2.70-2.80 (dd, 1H); 2.50-2.60 (ddd, 1H); 2.40-2.50 (dd, 1H); 2.15-2.3 (m, 2H); 1.75-1.95 (m, 2H); 1.24-1.70 (m, 17H); 1.20 (d, 3H, J=6.4); 0.85-0.95 (m, 8H); MS: m/z 494 [M+Na]+
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36]>CN(C)C=O>[C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][N:26]3[C:27](=[O:36])[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34]3=[O:35])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2cccc3ccccc23)CC1
Temperature: 90 °C

Procedure:
A suspension of 1.17 g (5.52 mmol) of 1-(1-naphthyl)piperazine (Tetrahedron Letters, 1998, 39(15), 2219-2222), 0.99 g (7.15 mol) of potassium carbonate and 1.68 g (6.62 mmol) of 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione in 15 ml of N,N-dimethylformamide is heated at 90° C. for 2 hours.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:8]=[C:7]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=1.[Cl:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][C@H:25]2[C@:23]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)([CH2:24]2)[CH2:22]1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CS(C)=O.O>[ClH:17].[ClH:1].[CH3:2][C:3]1[N:8]=[C:7]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[N:13]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][C@H:25]4[C@:23]([C:27]5[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=5)([CH2:24]4)[CH2:22]3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(-c2c[nH]c(=O)[nH]c2=O)n1
Reactant: FC(F)(F)c1ccc([C@]23C[C@H]2CN(CCCCl)C3)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2cn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)n1

Procedure:
A solution of 5-(6-methyl-pyridin-2-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep50, 171 mg, 0.72 mmol), (1S,5R)-3-(3-chloro-propyl)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep13, 240 mg, 0.79 mmol), and DIPEA (278 μl, 2.2 mmol) in DMSO (3 mL) was heated at 125° C. for 3 hours in a microwave oven. Water was added and the product was extracted with ethyl acetate. The crude was purified by preparative LC/MS followed by SCX cartridge washing with MeOH and eluting with MeOH/NH3 95:5 The free base obtained was treated with 4N HCl in dioxane (2 eq), to give the title compound as a white powder. (40 mg)
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([C:43]([O:45][CH3:46])=[O:44])=[N:23][C:24]=2[NH:28][CH2:29][CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([C:43]([O:45][CH3:46])=[O:44])=[N:23][C:24]=2[NH:28][CH2:29][CH:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Yield: 93.6 %

Procedure:
A solution of methyl 9-{(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-[(acetyloxy)methyl]-tetrahydro-2-furanyl}6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 15) (2.0 g, 3.17 mmol), sodium carbonate (35 mg) and dry methanol (40 ml) was stirred at room temperature for 3.5 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient elution with dichloromethane:methanol (94:6, by volume) then dichloromethane:methanol (92:8, by volume) to afford the title compound as a white powder (1.5 g).
Reaction SMILES: C(OC(OCC)[C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[CH2:17][CH2:18][C:19]4[NH:20][C:21](=[O:24])[CH:22]=[CH:23][C:14]([C:15]=43)=[CH:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1)C.S(=O)(=O)(O)O.C[CH2:34][OH:35]>O>[O:24]=[C:21]1[NH:20][C:19]2[CH2:18][CH2:17][N:16]3[C:11]([C:7]4[CH:6]=[CH:5][C:10]([CH:34]=[O:35])=[CH:9][CH:8]=4)=[N:12][CH:13]=[C:14]([C:15]=23)[CH:23]=[CH:22]1
Reactant: CCO
Reactant: CCOC(OCC)c1cccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
1-(3-Diethoxymethyl-phenyl)-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (0.79 g, 2.18 mmol) was dissolved in EtOH (22 mL) and water (22 mL). Concentrated sulfuric acid (0.5 mL) was added, and the reaction brought to reflux for 5 h. The reaction mixture was cooled to rt, and the EtOH removed in vacuo. The residue was diluted with saturated NaHCO3, and the resulting solids were filtered and washed with water, then dried under vacuum overnight to produce 0.47 g (74%) of white solid: 1H NMR (DMSO-d6) δ 3.54-3.55 (m, 2H), 4.50-4.51 (m, 2H), 7.39 (t, 1H, J=7.8 Hz), 7.88-7.96 (m, 2H), 8.09-8.10 (m, 4H), 8.46-8.50 (m, 1H), 10.13 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=[C:5]2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.C(O)(=O)C.[CH3:33][N:34]([CH3:39])[C:35](=[O:38])[CH2:36][NH2:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:33][N:34]([CH3:39])[C:35]([CH2:36][NH:37][C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=1)=[O:13])=[O:38]
Reactant: CN(C)C(=O)CN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)cnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CN(C)C(=O)CNC(=O)c1cnc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 43.2 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid dimethylcarbamoylmethyl-amide (25 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (48 mg), glycine dimethylamide acetate (21 mg), HBTU (53 mg), and DIEA (31 uL). LC/MS: m/z 493.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.46 (t, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 4.13 (d, 2H), 3.65 (bs, 3H), 3.03 (s, 3H), 2.87 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[N:6][OH:7].[Cl:14]N1C(=O)CCC1=O>>[OH:7][N:6]=[C:5]([Cl:14])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[C:2]([F:12])([F:13])[F:1]
Reactant: ON=Cc1ccccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Product: ON=C(Cl)c1ccccc1C(F)(F)F
Reaction time: 15 h
Yield: 92.5 %

Procedure:
2-(trifluoromethyl)benzaldehydeoxime (30.0 g, 158.60 mmol) was dissolved in dimethylformimide (300 mL), and added with N-chlorosuccinimide (23.31 g, 174.46 mmol), followed by stirring for 15 hours. After the reaction was completed, the resultant solution was vacuum evaporated, added with ethylacetate (1,500 mL), washed with saturated sodium chloride aqueous solution (1,000 mL) and purified water (1,000 mL), respectively, dried with anhydrous sodium sulfate, and vacuum-evaporated to provide a pale yellow solid required compound (32.81 g, 146.70 mmol, 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37].CCCCCC>C(OCC)(=O)C>[ClH:37].[CH2:1]([O:8][C:9]1[C:10]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(CC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1nc(CC2CCNCC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
tert-Butyl 5-(benzyloxy)-2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate (4.4 g, 8.8 mmol) was dissolved in ethyl acetate (44 mL), and a solution of hydrogen chloride in ethyl acetate (4 M, 68 mL, 270 mmol) was added, followed by stirring at room temperature for 3 hours. Hexane (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, whereby a solid was deposited. The resulting solid was collected by filtration, and dried under reduced pressure to afford the title compound (3.7 g, 8.5 mmol) as a white solid (yield 95%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]3[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=3)=[C:4]([F:28])[CH:3]=2)=[CH:31][C:30]=1[F:29])=[O:37]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(C(C/C(=N\O)c3ccc(=O)n(C)c3)c3ccccc3C)c(F)c2)cc1F

Procedure:
In analogy to example 166, step 1, 5-{3-(4-bromo-2-fluoro-phenyl)-1-[(E)-hydroxyimino]-3-o-tolyl-propyl}-1-methyl-1H-pyridin-2-one (example 193, step 4) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid in the presence of dichloro(1,1′-bis(diphenylphosphino)-ferrocene)palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution to give the title compound as a light brown solid, MS (ESI+): m/z=517.4 [M+H]+.