Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2[C:7]#[C:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11][CH:12]([OH:13])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20].N1C=CC=CC=1>C(Cl)Cl>[N+:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][C:19](=[O:20])[O:13][CH:12]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=3[C:7]#[C:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH2:11]2)=[CH:27][CH:26]=1)([O-:30])=[O:29]
Reactant: OC1Cc2ccccc2C#Cc2ccccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1Cc2ccccc2C#Cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To a solution of 45 (0.22 g, 1 mmol) in CH2Cl2 (30 mL) was added 4-nitro-phenyl chloroformate (0.4 g, 2 mmol) and pyridine (0.4 ml, 5 mmol). After stirring 4 hours at ambient temperature, the reacting mixture was washed with brine (2×10 mL), and the organic layer was dried (MgSO4). The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 10/1, v/v) to afford 47 (0.34 g, 89%). 1H NMR (300 MHz, CDCl3): δ 8.23-8.18 (2H, aromatics), 7.56-7.54 (2H, aromatics), 7.46-7.18 (8H, aromatics), 5.5 (1H, dd, J=3.9, 15.3 Hz, CHOH), 3.2 (1H, dd, J=3.9, 15.3 Hz, CH2), 2.9 (1H, dd, J=3.9, 15.3 Hz, CH2). 13C NMR (75 MHz, CDCl3): δ 154.5, 150.7, 149.1, 148.7, 129.0, 127.4, 127.3, 126.7, 126.5, 125.5, 125.2, 124.3, 124.0, 122.6, 122.4, 120.8, 120.6, 120.2, 112.2, 108.5, 80.6, 44.8. MALDI HRMS: m/z 408.0852 [M+Na+]. Calcd for C23H15NNaO5: 408.0848.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]1([NH:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:39])OC5C=CC=CC=5)[CH:25]=4)=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)=[O:13])[CH2:10][CH2:9]1.C1(NC(N2C3C(=CC(OC4C=CN=C(NC(N5CCC(N6CCCC6)CC5)=O)C=4)=CC=3)C=C2)=O)CC1>CN(C)C=O>[CH:8]1([NH:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:5]5[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]5)=[O:39])[CH:25]=4)=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)=[O:13])[CH2:9][CH2:10]1
Reactant: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)Oc1ccccc1
Reactant: OC1CCNCC1
Agent: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCC(N2CCCC2)CC1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCC(O)CC1
Reaction time: 8 h
Yield: 46.5 %

Procedure:
N,N-Dimethylformamide (5 ml) and 4-hydroxypiperidine (433 mg, 4.29 mmol) were added to a mixture (470 mg) of phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate obtained in Example 68; the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated to yield the title compound as white crystals (220 mg, 0.51 mmol, 39%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][C:38]1[C:39]([CH:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH3:55])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH3:37])[C:39]([CH:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH3:55])[CH2:49][CH2:48]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCCN1CCC(c2cc(OC)c(N)cc2C)CC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCN1CCC(c2cc(OC)c(Nc3nccc(-c4c(-c5ccc(OCC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)cc2C)CC1
Temperature: 120 °C
Yield: 49.4 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (100 mg, 0.2 mmol), 5-methyl-2-(methyloxy)-4-(1-propyl-4-piperidinyl)aniline (Example 157, step D) (47 mg, 0.18 mmol), and p-toluenesulfonic acid (90 mg, 0.47 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (65 mg, 0.089 mmol, 50%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 9.38 (d, J=6.41 Hz, 1H), 8.46 (s, 1H), 8.24 (d, J=5.31 Hz, 1H), 8.03 (d, J=2.01 Hz, 1H), 7.66-7.76 (m, 2H), 7.53 (s, 1H), 7.41-7.46 (m, 1H), 7.32-7.41 (m, 1H), 7.25 (d, J=8.61 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.95 (t, J=6.68 Hz, 1H), 6.89 (s, 1H), 6.57 (d, J=5.13 Hz, 1H), 4.25 (q, J=6.90 Hz, 2H), 3.80 (s, 3H), 2.90-3.02 (m, 2H), 2.57-2.68 (m, 1H), 2.21-2.32 (m, 2H), 2.17 (s, 3H), 1.91-2.02 (m, 2H), 1.62-1.74 (m, 4H), 1.38-1.49 (m, 5H), 0.85 (t, J=7.33 Hz, 3H). MS (ESI): 732 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CCO>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]([C:14]([O:16][CH3:17])=[O:15])=[C:2]([N:1]=[CH:20][N:21]([CH3:23])[CH3:22])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N
Solvent: CCO
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C

Procedure:
The title compound was prepared following the procedure described in WO2003033476. Condensation of 2.00 g of methyl 3-amino-5-(4-chlorophenyl)-thiophene-2-carboxylate with dimethylformamide dimethyl acetal for 3 hr in refluxing EtOH yielded 2.52 g (100%) after removal of the volatiles under vacuum. 1H NMR (CDCl3) δ 3.06 (s, 3H), 3.08 (s, 3H), 3.81 (s, 3H), 6.98 (s, 1H), 7.35 (d, J=8.79 Hz, 2H), 7.53 (d, J=8.24 Hz, 2H), 7.69 (s, 1H); 13C NMR (CDCl3) δ 34.31, 40.26, 51.44, 112.43, 122.28, 126.95, 129.09, 132.18, 134.45, 145.79, 156.09, 159.16, 163.22; HPLC (Method #1): 2.45 min retention time; MS (ES): m/z 323 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:47][C@@H:48]1[CH2:53][CH2:52][CH2:51][CH2:50][C@H:49]1[OH:54]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:47][C@@H:48]1[CH2:53][CH2:52][CH2:51][CH2:50][C@H:49]1[OH:54])=[O:9]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(OCC2CC2)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
5-Bromo-6-cyclopropylmethoxy-nicotinic acid (2.3 g, 8.5 mmol) was dissolved in DMF (75 mL). To the solution was added TBTU (2.99 g, 9.3 mmol), N,N-diisopropylethyl amine (7.2 mL, 42 mmol) and (trans)-2-amino-cyclohexanol (1.4 g, 9.3 mmol). The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 2.5 g of the title compound as a white solid, MS (ISP) 368.9, 371.0 (M+H)+.
Reaction SMILES: NC1C2C(=CC=CC=2)C=CC=1.[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].[C:22]1([O:28][CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)(=O)C1C=CC(OC)=CC=1>>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([C:25]1[CH:26]=[CH:27][C:22]([O:28][CH3:29])=[CH:23][CH:24]=1)=[O:16]
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccccc1F
Agent: COc1ccc(C(=O)Cl)cc1
Agent: Nc1cccc2ccccc12
Product: COc1ccc(C(=O)c2ccccc2F)cc1

Procedure:
The procedure of Example 10 was followed except as follows. In Part A, 1-amino napthalene (47 g) was used in place of 4-methoxy aniline. In Step 1 of Part B, 2-fluorobenzoyl chloride (15.8 g) and anisole (10.8 g) were used in place of 1,3-dimethoxybenezene and p-anisoyl chloride respectively to produce (2-fluoro-phenyl)-(4-methoxy-phenyl)-methanone. An NMR spectrum showed the final product to have a structure consistent with 12-ethoxy-3-(2-fluorophenyl)-3-(4-methoxy)-3H-benzo[h]pyrano[3,2-c]quinoline.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[NH2:6].[OH-].[Na+].[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>C1(C)C=CC=CC=1>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([NH:6][C:27](=[O:28])[N:26]([CH3:30])[CH3:25])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Reactant: CN(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 45.4 %

Procedure:
3-Trifluoromethyl-4-(2-naphthyloxy)aniline (9.1 g) was dissolved in 200 ml of toluene, and 30 ml of 40% aqueous sodium hydroxide solution and 6.5 g of N,N-dimethylcarbamyl chloride were added thereto. The reaction mixture was heated under reflux for 10 hours and then cooled to room temperature. The toluene layer was washed with water, the solvent was removed by distillation under reduced pressure and the residue was rerecrystallized from ethanol to obtain 5.1 g of N'-[3-trifluoromethyl-4-(2-naphthyloxy)phenyl]-N,N-dimethylurea as white needles. M.P. 210°-211° C.
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH2:16][CH:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=3)[CH2:14]2)=[O:12])=CC=1)([O-])=O.[NH2:25][C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1>>[N:27]1[CH:28]=[CH:29][N:30]=[CH:31][C:26]=1[NH:25][C:11]([N:13]1[CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=2)[CH2:16]1)=[O:12]
Reactant: Nc1cnccn1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(Oc2ccc(Br)cn2)C1
Product: O=C(Nc1cnccn1)N1CC(Oc2ccc(Br)cn2)C1
Yield: 56.4 %

Procedure:
This compound was prepared by the method outlined for example 5 step 4. Thus 3-(5-bromo-pyridin-2-yloxy)-azetidine-1-carboxylic acid 4-nitro-phenyl ester (905 mg, 2.30 mmol) was reacted with 2-aminopyrazine (243 mg, 2.53 mmol) to afford the title compound (454 mg, 56%) as off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14](F)=[O:15])=[N:9]1.C([O-])([O-])=O.[K+].[K+].[C:34]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]([NH:43][S:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:42])=[O:41])=[O:15])=[N:9]1
Reactant: COc1ccc(COc2ccc(Cl)cc2Cn2nc(C(=O)F)cc2C)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(COc2ccc(Cl)cc2Cn2nc(C(=O)NS(=O)(=O)c3ccccc3)cc2C)cc1
Reaction time: 16 h

Procedure:
To a solution of 1-[5-chloro-2-(4-methoxy-benzyloxy)-benzyl]-5-methyl-1H-pyrazole-3-carbonyl fluoride, 15, 0.06 g (0.18 mmol) and K2CO3 0.100 g (0.72 mmol) in dry DCM (2 mL), benzenesulfonamide 0.055 g (0.35 mmol) was added. The mixture was stirred under a nitrogen atmosphere for 16 hours before diluting with EtOAc. The organic phase was washed with 2M HCl, followed by brine, dried over MgSO4 and evaporated to dryness. The crude acyl sulphonamide was purified on silica to yield N-{1-[5-chloro-2-(4-methoxy-benzyloxy)-benzyl]-5-methyl-1H-pyrazole-3-carbonyl}-benzenesulfonamide, 16.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13]>N1C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:21][C:18]1[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1I
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(OS(=O)(=O)c2ccccc2I)cc1
Yield: 70.6 %

Procedure:
A solution of 2-iodobenzenesulphonyl chloride (obtained as described in J. Org. Chem. 1977, 42, 3265) (8.28 g) and 4-nitrophenol (3.81 g) in pyridine (50 ml) was heated at 100° C. for 3 hours. Volatile material was removed by evaporation and water (200 ml) was added to the residue. The mixture was extracted with ethyl acetate (2×200 ml) and the combined extracts were washed with 1M hydrochloric acid (2×200 ml) and dried (MgSO4). Solvent was removed by evaporation and the residue was recrystallised from a mixture of ethyl acetate and hexane to give 4-nitrophenyl 2-iodobenzenesulphonate (7.83 g), m.p. 131-133° C.; mass spectrum (+ve CI): 405 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].[F:11][C:12]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=O.[OH-].[Na+]>CCOC(C)=O.O>[Br:8][C:6]1[CH:5]=[C:4]([F:9])[C:3]2[O:10][C:14]([C:13]3[CH:17]=[CH:18][C:19]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:20][C:12]=3[F:11])=[N:1][C:2]=2[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Reactant: Nc1cc(Br)cc(F)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2nc3cc(Br)cc(F)c3o2)c(F)c1
Temperature: 195 °C

Procedure:
2-Amino-4-bromo-6-fluorophenol (2.6 g, 9.7 mmol) and 2-fluoro-4-(methylsulfonyl)benzoic acid (2.1 g, 9.7 mmol) were dissolved in polyposphoric acid (63.5 g). This mixture was heated at 195° C. for three and half hours. Reaction mixture cooled to rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (EtOAc/H2O) followed by evaporation of EtOAc afforded the crude. Crude (3.1 g) was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:18]1(C)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:1]([C:2]([C:8]([F:11])([F:10])[F:9])([C:12]([F:13])([F:14])[F:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(Oc1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate (12.0 g.) is added, dropwise at 0° C. under nitrogen, to a stirred mixture of toluene (200 ml.) and sodium hydride (2.0 g. of a 60% dispersion in oil from which the oil has been washed with toluene). The mixture is stirred at ambient temperature for 1.5 hours, and phenyl-2-thienyliodonium trifluoroacetate (20.0 g.) is added. The mixture is heated under reflux with continued stirring for 1 hour, then cooled, and filtered. The filtrate is evaporated in vacuo, and the residual red oil (22.2 g.) is fractionally distilled at 24 mm. pressure to give ethyl 2-phenoxy-3,3,3-trifluoro-2-trifluoromethylpropionate, b.p. 103°-105° C. (9.4 g.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[CH:5][CH:4]=1.CC(C)=[O:30].OS(O)(=O)=O.O=[Cr](=O)=O.C(OCC)(=O)C.O>CC(C)=O>[NH2:23][S:20]([C:17]1[CH:16]=[CH:15][C:14]([N:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([OH:30])=[O:1])=[CH:8][CH:7]=3)=[CH:10][C:11]([C:24]([F:25])([F:26])[F:27])=[N:12]2)=[CH:19][CH:18]=1)(=[O:22])=[O:21]
Reactant: CC(C)=O
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(CO)cc2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(C(=O)O)cc2)cc1

Procedure:
To the product from Example 11 in 2 mL of acetone was added 1.33 M Jones reagent until an orange color persisted. The reaction was poured into 20 mL of ethyl acetate and 20 m of H2O and the organic layer separated, washed with saturated sodium bisulfite and dried over MgSO4. The crude was product was filtered through silica gel/Celite to afford the title compound as a yellow solid: HRMS m/z 411.0507 (calc'd for C17H12N3O4SF3, 411.0500).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ccc(C)nc4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccc(C)nc4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-3-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.20 g) in methylene chloride (6.0 ml) was added dropwise a solution of m-chloroperbenzoic acid (80 mg) in methylene chloride (4.0 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography and recrystallized from ethanol, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-3-pyridinyl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 253) (104 mg).
Reaction SMILES: [CH3:1][N:2]([CH:16]1[C:20]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:19][NH:18][CH2:17]1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)[N:4]=1.[C:25](O)(=[O:28])[CH:26]=[CH2:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)[N:4]=1)[CH:16]1[C:20]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:19][N:18]([C:25](=[O:28])[CH:26]=[CH2:27])[CH2:17]1
Reactant: CN(c1ccnc(Nc2cnn(C)c2)n1)C1CNCC12CCCC2
Reactant: C=CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CC(N(C)c2ccnc(Nc3cnn(C)c3)n2)C2(CCCC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.1 %

Procedure:
To a suspension of N4-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(2-azaspiro[4.4]nonan-4-yl)pyrimidine-2,4-diamine (0.10 g, 0.31 mmol) in DCM (8.0 mL) was added acrylic acid (55 mg, 0.76 mmol), HATU (0.14 g, 0.37 mmol) and Et3N (62 mg, 0.61 mmol). The mixture was stirred at room temperature for 4 h, then diluted with DCM (50 mL), and washed with water (20 mL) followed by brine (20 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by preparative-TLC (DCM/MeOH (v/v)=12/1) to give the product as a light yellow solid (25 mg, 21%).
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([C:9]([OH:11])=O)=[CH:5][CH:6]=[CH:7][CH:8]=1.O.[NH2:14][NH2:15]>C(O)C>[C:9]1(=[O:11])[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:2]=[N:15][NH:14]1
Reactant: O=C(O)c1ccccc1C(Br)Br
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]ncc2ccccc12
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A solution of 29.4 g (0.1 mole) of α,α-dibromo-o-toluic acid and 16 g (0.32 mole) of hydrazine hydrate in 200 ml of ethanol was heated under reflux with stirring for 1 hour. The solvent was evaporated under reduced pressure, and the residue recrystallized from ethanol to give 12.8 g (yield: 88%) of 1-phthalazinone having a melting point of 181°-182° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:24]=1
Reactant: COc1ccc(F)cc1
Reactant: O=C(O)Cc1cccc(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1cccc(F)c1)c1cc(F)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
3-Fluorophenylacetic acid (7.33 g, 47.56 mmoles) was dissolved in 25 ml dichloromethane. To this mixture, oxalylchloride (7.54 g, 59.46 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 25 ml dichloromethane. To this mixture, 4-fluoroanisole (5.00 g, 39.64 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (7.95 g, 59.46 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as colourless solid (4.5 g, 45% yield. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 11.34(s,1H), 7.75(dd, J=9.4,3.1Hz, 1H), 7.42(m, 2H), 7.12(m, 3H), 7.05(dd, J=9.0,4.5Hz, 1H), 4.47(s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH:23]1([C:26]2[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=2)[CH2:25][CH2:24]1>>[CH:23]1([C:26]2[CH:30]=[C:29]([CH2:31][NH:32][C:20]([C:10]3[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:9]=3)=[O:21])[O:28][N:27]=2)[CH2:25][CH2:24]1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Reactant: NCc1cc(C2CC2)no1
Product: O=C(NCc1cc(C2CC2)no1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1

Procedure:
The title compound was synthesized in analogy to Example 41, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 3-cyclopropyl-5-isoxazolemethanamine (CAN 851434-73-6) as starting materials, LC-MS (UV peak area/ESI) 92.9%, 453.2 (M+H)+.