Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([C:20]1[NH:21][C:22]([C:32]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:33]=2[N:34]=[C:35]([NH:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:36]([CH3:42])=[N:37]3)=[CH:23][C:24]=1C(OC(C)(C)C)=O)[NH:12][C:13]([O:15]C(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[C:20]2[NH:21][C:22]([C:32]3[CH:41]=[CH:40][CH:39]=[C:38]4[C:33]=3[N:34]=[C:35]([NH:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:36]([CH3:42])=[N:37]4)=[CH:23][C:24]=2[C:13](=[O:15])[NH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2cccc(-c3cc(C(=O)OC(C)(C)C)c(C(CCOCc4ccccc4)NC(=O)OC(C)(C)C)[nH]3)c2nc1NC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(CCOCc3ccccc3)NC4=O)c2nc1NC(C)(C)C
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
To a solution of tert-butyl 2-(3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)propyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (1.28 g, 1.98 mmol) in 20 mL of DCM at RT was added TFA (5 mL) and the dark red solution was heated in an oil bath at 40° C. for 4 h. It was concentrated under reduced pressure. 5 mL of toluene was added to the residue and concentrated to dryness again. The brown amorphous solid was stirred in 15 mL of hexanes and the liquid was decanted. The brown residue was treated with 5 mL of DMF and 30 mL of DCM, cooled at 0° C., and added DIPEA (2.06 mL, 11.88 mmol) followed by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.28 g, 2.47 mmol). It was stirred at 0° C. for 10 min followed by RT for 15 min, then diluted with 50 mL of DCM. The mixture was washed sequentially with 5 mL of water, 5 mL of 0.5 N NaOH, and 5 mL of brine. The DCM solution was concentrated. The residue was purified on a silica gel column (50-100% EtOAc in DCM followed by 5% MeOH in DCM) to give 6-(2-(benzyloxy)ethyl)-2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (0.65 g, 1.38 mmol, 70% yield) as a brown crystalline solid. m/z (ESI, +ve) 470.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:19]=O)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:24][CH:25]([CH:29]1[CH2:33][CH2:32][N:31]([C:34](OC(C)(C)C)=O)[CH2:30]1)[C:26]([OH:28])=[O:27].[CH2:41]=O>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19][N:24]([CH:25]([CH:29]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30]4)[C:26]([OH:28])=[O:27])[CH3:41])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)C(=O)O)C1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C(C(=O)O)C1CCN(C)C1

Procedure:
4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazoline-6-carbaldehyde was coupled with amino[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]acetic acid, deprotected and methylated by reaction with aqueous formaldehyde using analogous methods to those described for the equivalent steps in Example 68 to give [({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino](1-methylpyrrolidin-3-yl)acetic acid as a pale yellow foam; Mass Spectrum: (M+H)+ 488.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:11][C:12]([C:14]1[N:15]([CH2:30][CH3:31])[C:16]2[C:21]([C:22]=1[C:23](=O)[C:24]([O:26][CH3:27])=[O:25])=[CH:20][C:19]([F:29])=[CH:18][CH:17]=2)=O)C.O>C(O)(=O)C>[CH2:30]([N:15]1[C:16]2[CH:17]=[CH:18][C:19]([F:29])=[CH:20][C:21]=2[C:22]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12](=[O:11])[C:14]1=2)[CH3:31]
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1c(C(=O)C(=O)OC)c2cc(F)ccc2n1CC
Solvent: O
Solvent: CC(=O)O
Product: CCn1c2ccc(F)cc2c2c(C(=O)OC)nn(-c3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
18.4 ml (187.2 mmol) of phenylhydrazine are added, at room temperature, to a solution of 14 g (43.6 mmol) of methyl 2-(ethoxycarbonyl)-1-ethyl-5-fluoro-α-oxo-1H-indole-3-acetate in 150 ml of acetic acid and the reaction mixture is stirred for 30 min at room temperature and then for 2 h at reflux. The mixture is cooled, 100 ml of water are added and an insoluble material is separated by filtration, the insoluble material being washed on sintered glass with a 70/30 mixture of water and acetone. 10.5 g (28.6 mmol) of white solid are thus isolated, which solid is used as is in the following stage.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:36][CH:35]([OH:37])[CH:34]([N:38]=[N+]=[N-])[CH2:33][CH2:32][CH:31]1[CH3:41])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O.C1(C)C=CC=CC=1>[CH2:20]([O:27][C:28]([N:30]1[CH2:36][CH:35]([OH:37])[CH:34]([NH2:38])[CH2:33][CH2:32][CH:31]1[CH3:41])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC1CCC(N=[N+]=[N-])C(O)CN1C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CCC(N)C(O)CN1C(=O)OCc1ccccc1
Temperature: 45 °C

Procedure:
Triphenylphosphine (1.94 g, 7.4 mmol) was added to a solution of racemic (2R,5S,6S)-5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (1.5 g, 4.93 mmol) in THF (185 ml) and H2O (0.7 ml), then was heated to 45 degrees C. overnight. The reaction mixture was then diluted with toluene (100 ml×2) and was azeotroped in vacuo by rotary evaporation twice. The resulting oil was dissolved in MeOH and HCl in Et2O and the resulting salt was collected following filtration and was used in the next reaction without further purification (1.4 g, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2].[O:19](S(C(F)(F)F)(=O)=O)[S:20]([C:23]([F:26])([F:25])[F:24])(=O)=[O:21].Cl>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:21])=[O:19])=[CH:11][C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C(OCC)c1c(F)cc(O)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(OCC)c1c(F)cc(OS(=O)(=O)C(F)(F)F)cc1F
Temperature: 0 °C
Yield: 97.9 %

Procedure:
A solution of (RS)-(2,6-difluoro-4-hydroxy-phenyl)-ethoxy-acetic acid ethyl ester (500 mg) in pyridine (5 ml) was placed under N2 and cooled to 0° C. Tf2O (813 mg) was added and the resulting solution was left to stir in the ice bath. After 18 h the reaction mixture was poured on a mixture of 50 ml 1 N HCl and ice. The product was extracted with AcOEt. The organic layer was washed with more 1 N HCl (50 ml), water (50 ml) and brine (30 ml). The aqueous layers were extracted with more AcOEt. After drying (MgSO4) the solvent was evaporated to obtain 738 mg (98%) of (RS)-(2,6-difluoro-4-trifluoromethanesulfonyloxy-phenyl)-ethoxy-acetic acid ethyl ester. Yellow oil. MS 393.4 ([M+H]+).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[C:9]3[C:10]([CH2:13][CH2:14][CH2:15][C:16]3=[O:18])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCCc1ccc(C2CCCCC2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C1CCCc2ccc(C3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a mixture of 4-(4-cyclohexylphenyl)butyric acid (10.2 g), thionyl chloride (7.4 g) and toluene (50 ml), pyridine (1 drop) was added. After refluxing for 1.5 hours, the solvent was evaporated off under reduced pressure. The residue was dissolved in dichloromethane (20 ml); this solution was added dropwise to a suspension of powdered anhydrous aluminum chloride (8.3 g) in dichloromethane (100 ml) under ice cooling conditions. After stirring at room temperature for 3 hours, the reaction mixture was poured into 1.2N HCl (150 ml), followed by stirring for 30 minutes. The organic layer was collected, while the aqueous layer was extracted with dichloromethane. The extract was combined with the organic layer, succesively washed with water and brine, and dried (MgSO4), after which the solvent was evaporated off. The residual oil was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:10, v/v) to yield 7-cyclohexyl-1-tetralone (9.4 g, 100%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[F:15][S:16]([O:19][CH3:20])(=[O:18])=[O:17]>C(COC)OC>[F:15][S:16]([O-:19])(=[O:18])=[O:17].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:20])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=c1ccn(-c2ccc(Cl)cc2)cc1
Reactant: COS(=O)(=O)F
Solvent: COCCOC
Product: COc1cc[n+](-c2ccc(Cl)cc2)cc1
Product: O=S(=O)([O-])F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 18.7 g. (0.091 mole) of dried 1-(4-chlorophenyl)-4(1H)-pyridinone prepared by the process set forth in D. Vorlander, Ber., 58, 1908 (1925)! in 160 ml. of dimethoxyethane was heated to reflux. Without further external heating, 14.2 g. (0.123 mole) of methyl fluorosulfonate was added gradually. The mixture boiled vigorously during the addition and crystalline product started to separate. After the addition was complete, the mixture was stirred at room temperature for 1 hour and then cooled to 10° C. The product was collected by filtration, washed with cold dimethoxyethane and ether and dried in vacuo: yield 28.0 g. (96.5%); m.p 182°-185° C.; NMR (DMSO-d6) δ4.26 (s, 3H, CH3O), 6.27 (d, 2H, β-pyridyl H), 6.32 (s, 4H, aromatics), 7.62 (d, 2H, α-pyridyl H). The elemental analyses for C, H, N and Cl were within ±0.4% of the theoretical values.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][C:3]=1[Cl:11].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([Cl:11])[CH:4]=2)[C:15](=[O:14])[CH:16]=1
Reactant: Cc1ccc(CNN)cc1Cl
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(Cn2[nH]c(N)cc2=O)cc1Cl
Reaction time: 2 h

Procedure:
50 g of 4-methyl-3-chlorobenzylhydrazine were added dropwise, under nitrogen, to a solution of 46.7 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulphonic acid in 200 ml of ethanol. After stirring for a further two hours, the compound identified above precipitated. It was filtered off and recrystallised from ethanol. Melting point: 130°-131°, 35 g (50%).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH:21]([CH2:25][OH:26])[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:19]2[CH2:24][CH2:23][O:22][CH:21]([CH2:25][OH:26])[CH2:20]2)=[CH:13][CH:12]=1
Reactant: OCC1CNCCO1
Reactant: O=Cc1ccc(Oc2nc3ncccc3s2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: OCC1CN(Cc2ccc(Oc3nc4ncccc4s3)cc2)CCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
To a solution of 4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzaldehyde (150 mg, 0.585 mmol) and morpholin-2-yl-methanol (82 mg, 0.702 mmol, 1.2 equiv.) in DCE (3.1 mL) was added sodium triacetoxyborohydride (211 mg, 0.995 mmol, 1.7 equiv.) in two portions over 5 min. The mixture was then allowed to stir at rt for 4 h. The mixture was then filtered and purified using preparative reverse phase HPLC to afford the desired product as a light yellow oil (116 mg, 56%). 1H NMR (600 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.01 (dd, J=7.9, 1.6, 1H), 7.42-7.35 (m, 4H), 7.20 (dd, J=7.9, 4.8, 1H), 3.95-3.87 (m, 1H), 3.75-3.61 (m, 3H), 3.60-3.48 (m, 3H), 2.70 (t, J=12.8, 2H), 2.22 (dt, J=11.5, 3.5, 1H), 2.07-1.99 (m, 1H), 1.93-1.86 (m, 1H). MS (ESI): mass calcd. for C18H19N3O3S, 357.12; m/z found, 358.1 [M+H]+.
Reaction SMILES: [OH-:1].[Ni+2:2].[OH-].[Ni].O.[C:6]([OH:9])(=[O:8])[CH3:7]>>[OH2:8].[OH2:1].[OH2:8].[OH2:8].[C:6]([O-:9])(=[O:8])[CH3:7].[Ni+2:2].[C:6]([O-:9])(=[O:8])[CH3:7]
Reactant: CC(=O)O
Reactant: [OH-]
Agent: [Ni+2]
Agent: [Ni]
Solvent: O
Product: CC(=O)[O-]

Procedure:
The nickel hydroxide (line 144) is transferred to the nickel re-slurry tank 147 where water (line 145) and 100 wt % acetic acid (146) are added to produce the final product, nickel acetate tetrahydrate (line 148). The reaction is shown below 2H2O+Ni(OH)2+2CH3COOH→Ni(CH3COO)2.4H2O
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=O.[C:10]([OH:13])(=[O:12])[CH3:11]>>[C:10]([OH:13])(=[O:12])[C:11]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1.[CH:7](=[O:12])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: Cc1ccccc1
Agent: O=O
Product: O=C(O)c1ccccc1
Product: O=Cc1ccccc1

Procedure:
200 g solution in acetic acid and containing 4.0 g catalyst consisting 85% cobaltic acetate 8% ferric acetate, 5% cobaltous acetate, and 2% ferrous acetic and 50 g toluene was reacted with oxygen at a space velocity of 40 h-1 at 85° C. for four hours. The oxidation product on and work up yielded 61.7 g benzoic acid, 2.1 g benzaldehyde and 1.0 g unreacted toluene. This corresponded to 98% hydrocarbon conversion and 95% selectivity to benzoic acid and more than 40% benzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[CH3:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([CH3:44])=[C:22]([NH:21][C:7]([C:3]5[N:4]=[CH:5][S:6][C:2]=5[CH3:1])=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1scnc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1ncsc1C
Yield: 61.3 %

Procedure:
In the same manner as in Example 259 and using 5-methyl-1,3-thiazole-4-carboxylic acid (74 mg, 0.52 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (170 μL, 2.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (130 mg, 0.40 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (110 mg, 60%) was obtained as a white solid.
Reaction SMILES: [CH:1]1([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[C:13]([CH2:24][O:25][C:26]2[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=2)=[C:12]3[CH:36]=[O:37])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.[F:49][C:50]([F:56])([F:55])[S:51]([NH2:54])(=[O:53])=[O:52].C1COCC1>C(OCC)(=O)C.O>[CH:36]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([NH:8][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:10]=2)[N:14]([CH2:18][CH2:19][CH2:20][C:21](=[O:22])[NH:54][S:51]([C:50]([F:56])([F:55])[F:49])(=[O:53])=[O:52])[C:13]=1[CH2:24][O:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)=[O:37]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=Cc1c(COc2ccc3ccccc3c2)n(CCCC(=O)O)c2ccc(NC(=O)C3CCCC3)cc12
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1c(COc2ccc3ccccc3c2)n(CCCC(=O)NS(=O)(=O)C(F)(F)F)c2ccc(NC(=O)C3CCCC3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
The acid (1 eq) from step 1 of Example 53A was weighed into a flask and to this was added EDCI (1.35 eq) DMAP (1.1 eq), trifluoromethanesulfonamide (1.05 eq) followed by anhydrous THF (0.026 M) and the reaction mixture was stirred at 25° C., 3 h. Worked up with ethyl acetate/water followed by washing the organic layer with 0.05N HCl, saturated bicarbonate and brine. Chromatographic purification then afforded the desired product in 94% yield.
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][C:5]([F:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21].[CH3:22][O-:23].[Na+]>C1COCC1.CO>[F:1][C:2]1[C:7]([O:23][CH3:22])=[CH:6][C:5]([F:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(F)c([N+](=O)[O-])c(Nc2ccc(I)cc2F)c1F
Reaction time: 1 h

Procedure:
To a solution of 2,3,5-trifluoro-N-(2-fluoro-4-iodophenyl)-6-nitrobenzenamine (Intermediate 12. 700 mg, 1.7 mmol) in THF (20 mL) was added NaOMe solution at −78° C. (which was prepared by dissolving Na metal (39 mg, 1.7 mmol) in 4 mL of methanol). The reaction mixture was brought to rt and stirred for 1 h at same temperature. The progress of reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and extracted with ether. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography to yield 2,5-difluoro-N-(2-fluoro-4-iodophenyl)-3-methoxy-6-nitrobenzenamine as yellow solid (597 mg). 1H-NMR (400 MHz, CDCl3): δ 3.95 (3H, s), 6.51-6.56 (1H, m), 6.57-6.65 (1H, m), 7.34 (1H, d, J=8.8), 7.42 (1H, dd, J=1.6, 10), 7.7 (1H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].[H-].[Na+].[H][H].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1>CN1CCCC1=O>[N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: [H][H]
Reactant: O=C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C1COCCN1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.6 %

Procedure:
2 mol (202 g) of morpholin-3-one (E. Pfeil, U. Harder, Angew. Chem. 79, 1967, 188) are dissolved in 2 l of N-methylpyrrolidone (NMP). Over a period of 2 h, 88 g (2.2 mol) of sodium hydride (60% in paraffin) are then added a little at a time. After the evolution of hydrogen has ceased, 282 g (2 mol) of 4-fluoronitrobenzene are added dropwise with cooling at room temperature, over a period of 1 h, and the reaction mixture is then stirred overnight. At 12 mbar and 76° C., 1.7 l of the liquid volume are then distilled off, the residue is poured into 2 l of water and this mixture is extracted twice with in each case 1 l of ethyl acetate. After washing of the combined organic phases with water, the mixture is dried over sodium sulphate and the solvent is distilled off under reduced pressure. Purification is carried out by silica gel chromatography using hexane/ethyl acetate (1:1) and subsequent crystallization from ethyl acetate. This gives 78 g of product as a colourless to brownish solid, in a yield of 17.6% of theory.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:13].[F:30][C:31]([F:37])([F:36])[C:32]([OH:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([O:35][C:32]([CH3:34])([CH3:33])[C:31]([F:37])([F:36])[F:30])=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1
Reactant: CC(C)(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cn2)CC1)C(F)(F)F
Reaction time: 1 h

Procedure:
A solution of (2-fluoro-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone (compound 2.3) (20 mg), 2-trifluoromethyl-2-propanol (0.053 mL), potassium carbonate or cesium carbonate (3 equivalents) in dimethylacetamide was heated at 150° C. for 30 min and then at 180° C. for 1 h in a microwave oven. After such time the reaction mixture was concentrated and purified by column chromatography (SiO2) to yield the title compound as a light yellow solid (4.9 mg). MS (m/e): 540.3 (M+H+, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8]O)[CH:2]=1.S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl>[ClH:12].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][Cl:12])[CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1cccnc1
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCCc1cccnc1
Temperature: 25 °C

Procedure:
In 100 ml of CHCl3 was dissolved 6.39 g (0.052 mole) of 2-(3-pyridyl)ethanol followed by dropwise addition of 15.6 ml of thionyl chloride with stirring at room temperature. Then, the mixture was stirred for 1.5 hours, after which the solvent was distilled off. After addition of ether, crystals were recovered by filtration and dried. The procedure gave 9.13 g of 2-(3-pyridyl)ethyl chloride hydrochloride as white crystals.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[C:4](OC)=[O:5].[OH-].[NH4+:18]>O>[NH2:2][CH:3]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[C:4]([NH2:18])=[O:5]
Reactant: COC(=O)C(N)Cc1cc(F)cc(F)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: O
Product: NC(=O)C(N)Cc1cc(F)cc(F)c1
Yield: 51 %

Procedure:
A solution of methyl 2-amino-3-(3,5-difluorophenyl)propanoate hydrochloride (3.67 g, 14.6 mmol) in aqueous ammonium hydroxide (5.5 mL) and water (22 mL) was stirred at ambient temperature for 18 hours and extracted with dichloromethane (4×50 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to dryness to give 2-amino-3-(3,5-difluorophenyl)propanamide as a colorless solid (1.50 g, 51%): 1H NMR (300 MHz, CD3OD) δ 6.92-6.75 (m, 3H), 3.56 (dd, J=7.3, 6.3 Hz, 1H), 3.00 (dd, J=13.4, 6.3 Hz, 1H), 2.83 (dd, J=13.4, 7.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:7]1([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH2:6]2.Br[CH2:19][C:20]([OH:22])=[O:21].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:7]1([CH2:12][CH2:11][N:10]([CH2:19][C:20]([OH:22])=[O:21])[CH2:9][CH2:8]1)[CH2:6]2
Reactant: COc1ccc2c(c1)CC1(CCNCC1)C2=O
Reactant: O=C(O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CC1(CCN(CC(=O)O)CC1)C2=O
Yield: 65.9 %

Procedure:
A stirred solution of 5-methoxyspiro[indene-2,4′-piperidin]-1(3H)-one (511 mg, 1.93 mmol), bromoacetic acid (349 mg, 2.51 mmol) and DIPEA (1.013 mL, 5.80 mmol) in DMF (5 mL) was heated at 100° C. for 20 min via microwave. The reaction mixture was diluted with 20 mL of ethyl acetate, washed with 5 mL of water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column (gradient of 100:0 to 85:15 CH2Cl2/MeOH with 5% NH4OH over 20 min) to give the title compound (368 mg, 1.272 mmol). MS calculated for C16H19NO4 290.3. found (ESI) m/z 290.1 (M+H)+, retention time 1.10 min.