Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[NH:15][NH:16][C:17](=O)[CH2:18][CH2:19][Cl:20])[CH:2]=[CH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[C:17]([CH2:18][CH2:19][Cl:20])=[N:16][N:15]=[C:5]12)[CH:2]=[CH2:3]
Reactant: C=CCn1c(NNC(=O)CCCl)nc2ccccc2c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: C=CCn1c(=O)c2ccccc2n2c(CCCl)nnc12
Yield: 52.6 %

Procedure:
A mixture of 5.30 g of 3-allyl-2-[2-(3-chloropropionyl)hydrazino]quinazolin-4(3H)-one (0.0173 mol) and 10 mg of p-toluenesulfonic acid hydrate in 300 ml of ethanol was refluxed for 17 hours until TLC indicated that no starting material remained. The mixture was evaporated to dryness and the remaining yellow oil was dissolved in dichloromethane. The solution was washed twice with water, dried over MgSO4, filtered and evaporated. The resulting solid was purified by column chromatography using Kieselgel 60 with CH2Cl2 +1% MeOH as eluant and then was finally crystallized from ethanol to obtain 2.625 g (53% yield) of 4-allyl-1-(2-chloroethyl)[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one melting at 142.5°-144° C.
Reaction SMILES: [N:1]([CH2:4][CH:5]([CH3:12])[CH2:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11])=[C:2]=[O:3].[CH2:13]([CH:15]([NH:18][OH:19])[CH2:16][CH3:17])[CH3:14]>ClCCl>[CH3:12][CH:5]([CH2:6][CH2:7][CH2:8][NH:9][C:10]([N:18]([CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[OH:19])=[O:11])[CH2:4][NH:1][C:2]([N:18]([OH:19])[CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[O:3]
Reactant: CC(CCCN=C=O)CN=C=O
Reactant: CCC(CC)NO
Solvent: ClCCl
Product: CCC(CC)N(O)C(=O)NCCCC(C)CNC(=O)N(O)C(CC)CC
Yield: 34.7 %

Procedure:
1,5-Diisocyanato-2-methylpentane (3.2 ml, 20 mmol) was added dropwise to a solution of N-(1-ethylpropyl)hydroxylamine (4.4 g, 43 mmol) in dichloromethane (200 ml). The reaction was maintained overnight and then concentrated (in vacuo) to a volume of approximately 20 ml. Purification of the sample by flash column chromatography (96:4 dichloromethane.backslash.methanol, Rf 0.26) followed by recrystallization from N,N-dimethylformamide.backslash.water provided 2.6 g of the desired product as a white powder: MP: 124.0-125.0° C.; 1H NMR (300 MHz, DMSO): δ 8.70 (s, 1H), 8.66 (s, 1H), 6.73 (t, J=6.0 Hz, 1H), 6.68 (t, J=7.0 Hz, 1H), 3.81-3.72 (m, 2H), 3.02-2.78 (m, 4H), 1.60-0.98 (m, 13H), 0.83-0.77 (m, 15H); 13C NMR (75 MHz, DMSO): δ 160.95, 160.92, 59.9, 45.4, 39.6, 33.1, 31.2, 27.5, 24.5, 17.5, 11.1; IR (KBr): 3428, 3177, 2969, 2930, 2876, 1639, 1540, 1462, 1378, 1266, 1167, 1142, 1062, 1034, 929, 770 cm-1 ; MS (FAB): m/e 375.2957 (375.2971 calc'd for C18H39N4O4, M+H); Anal. calc'd for C18H38N4O4 : C, 57.73; H, 10.23; N, 14.96. Found: C, 57.90; H, 10.19; N, 14.93.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[Cl:13][C:14]1[CH:26]=[C:25](F)[C:24]([F:28])=[CH:23][C:15]=1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:25]2[CH:26]=[C:14]([Cl:13])[C:15]([C:16]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:17])=[CH:23][C:24]=2[F:28])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: O=C(c1cc(F)c(F)cc1Cl)N1CCCC1
Product: O=C(O)Cc1cc(Cl)cc(Oc2cc(Cl)c(C(=O)N3CCCC3)cc2F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 18 step (iv) and the product from step (i).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([C:10]([O:12]CC)=[O:11])=[CH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.CCO.O>[C:1]([C:5]1[O:6][C:7]([C:10]([OH:12])=[O:11])=[CH:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)o1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ncc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
To a stirring suspension of ethyl 2-tert-butyloxazole-5-carboxylate (1.0 g, 5.07 mmol) in 1:1:1 THF/EtOH/H2O (15 ml) at RT was added LiOH.H2O (486 mg) and the mixture was stirred at RT for 3 hours. The reaction mixture was checked by LC-MS and the completed reaction was concentrated to an aqueous residue, acidified (pH 3-4) with 3M HCl and extracted with EtOAc (3×). The combined organics were washed with brine (1×), dried (MgSO4) and evaporated to afford desired product, 2-tert-butyloxazole-5-carboxylic acid (0.67 g, 78% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.9 (brs, 1H), 8.62 (s, 1H), 1.30 (s, 9H); (ESI) m/z: 170.0 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[N:14][C:15]=4[CH:16]=[CH:17][C:18]=3[F:21])[CH2:10]2)[CH2:4][CH2:3]1.[CH:23]([C:25]1[N:41]=[CH:40][C:28]2[O:29][CH2:30][CH2:31][N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:27]=2[CH:26]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]2[N:14]=[CH:13][C:12](=[O:22])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:4][CH2:3][CH:2]([NH:1][CH2:23][C:25]5[N:41]=[CH:40][C:28]6[O:29][CH2:30][CH2:31][N:32]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:27]=6[CH:26]=5)[CH2:7][CH2:6]4)[C:19]=1[C:20]=23
Reactant: NC1CCN(CC2Cn3c(=O)cnc4ccc(F)c2c43)CC1
Reactant: CC(C)(C)OC(=O)N1CCOc2cnc(C=O)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOc2cnc(CNC3CCN(CC4Cn5c(=O)cnc6ccc(F)c4c65)CC3)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
A solution of 6-[(4-amino-1-piperidinyl)methyl]-7-fluoro-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxalin-3-one (95 mg, 0.31 mmol) and 1,1-dimethylethyl 7-formyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (83 mg, 0.31 mmol) in chloroform/methanol (1:1, 8 ml) was stirred with molecular sieves overnight, then heated under reflux for 3 h. After cooling, sodium triacetoxyborohydride (164 mg) was added and the mixture was stirred for 5 h at room temperature. The mixture was basified and the aqueous phase was extracted with 10% methanol/dichloromethane. Combined organic fractions were dried and evaporated. Chromatography on silica, eluting with 0-20% (2M ammonia in methanol)/dichloromethane, gave impure material. Further chromatography on silica, eluting with 0-10% methanol/dichloromethane, gave the pure product (91 mg).
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].II>CO>[C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C=C\C(=O)O
Agent: II
Solvent: CO
Product: O=C(O)/C=C/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.9 %

Procedure:
cis,trans-Muconic acid (105 mg, 0.739 mmol) is dissolved in methanol (10 mL) at room temperature and a crystal of iodine (26 mg, 0.102 mmol) is added. The reaction mixture is allowed to stir at room temperature for 24 hours. The precipitate is filtered, washed with ice-cold acetonitrile and dried under reduced pressure to yield 65 mg of trans,trans-muconic acid, a 62 percent yield.
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1>CN(C)C=O>[N:13]1([C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:12])[NH:7]3)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Reactant: c1nc[nH]n1
Solvent: CN(C)C=O
Product: O=c1ccc2c(-n3cncn3)nccc2[nH]1
Yield: 52.8 %

Procedure:
A mixture containing 5.6 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 100 ml of dimethylformamide and 6.9 g of 1,2,4-triazole was refluxed on an oil bath for 21 hours and then allowed to cool. The separated solid was collected, washed with ethanol and dried in a vacuum oven at 90° C. to yield 2.8 g of 5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p.>300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:34]([C:35]4[O:36][C:37]([CH3:40])=[N:38][N:39]=4)=[CH:33][N:32]=[C:31]4[NH:41][CH:42]=[CH:43][C:30]=34)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:34]([C:35]4[O:36][C:37]([CH3:40])=[N:38][N:39]=4)=[CH:33][N:32]=[C:31]4[NH:41][CH:42]=[CH:43][C:30]=34)[CH2:27][CH2:28]2)=[O:22])=[CH:6][CH:7]=1
Reactant: Cc1nnc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@H](CN(C(=O)OC(C)(C)C)C(C)C)c3ccc(Cl)cc3)CC2)o1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@H](CNC(C)C)c3ccc(Cl)cc3)CC2)o1
Yield: 50.4 %

Procedure:
(S)-tert-Butyl 2-(4-chlorophenyl)-3-(4-(5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (50 mg, 0.082 mmol) in TFA (3 mL) was stirred for 30 minutes and then concentrated to dryness. The resulting residue was dissolved in minimal DCM (0.2 mL) and added to 2N HCl in ether. The resulting solid was filtered and dried under nitrogen to yield (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (21 mg, 50% yield) hydrochloride as a solid. 1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 8.84 (s, 1H), 8.35 (s, 2H), 7.52-7.48 (m, 2H), 7.46-4.42 (m, 1H), 7.40-7.36 (m, 2H), 6.64 (s, 1H), 4.58 (m, 1H), 3.70-3.20 (m, 10H), 3.01 (s, 1H), 2.78 (s, 1H), 2.54 (s, 3H), 1.24 (dq, 6H); m/z (ESI pos) 508.4 (100%) [M].
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.N12CCCN=C1CCCCC2.[O:35]1[CH2:44][CH:36]1[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(O)C.C(O)(C)C.C(Cl)(Cl)Cl>[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:44][CH:36]([OH:35])[CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc(CC2CO2)cc1
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Agent: I
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1onc2c1c(=O)n(C1CCCN(CC(O)Cc3ccccc3)C1)c1cccc(Cl)c21
Temperature: 60 °C
Yield: 84 %

Procedure:
To a suspension of 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (100 mg, 0.22 mmol) in ethanol (5 mL) add 1,8-diazabicyclo[5.4.0]undec-7-ene (40 μL, 0.27 mmol). Stir the solution under nitrogen. To the solution add (2,3-epoxypropyl)-benzene and heat to approximately 60° C. and stir under nitrogen overnight. Concentrate the reaction and dissolve in 20% isopropanol/chloroform, wash with 1N HCl, 1N sodium thiosulfate, saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–1.5% methanol/chloroform) to give 85.0 mg of the title compound as a white solid, 84% yield. 1H NMR: consistent with structure. MS (ion spray) 452 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ncc(Br)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To a solution of 5-bromo-2-(methyloxy)-3-nitropyridine (45 g, 193 mmol) in ethyl acetate (1 L) was added tin(II)chloride dihydrate (174 g, 772 mmol). The reaction mixture was heated at reflux for 4 h. LC/MS indicated some starting material remained, so added 20 mol % tin(II)chloride dihydrate and continued to heat at reflux. After 2 h, the reaction was allowed to cool to ambient temperature and concentrated in vacuo. The residue was treated with 2 N sodium hydroxide and the mixture stirred for 1 h. The mixture was then with methylene chloride (1 L), filtered through Celite, and washed with methylene chloride (500 mL). The layers were separated and the organics dried over magnesium sulfate and concentrated to give 5-bromo-2-(methyloxy)-3-pyridinamine (23 g, 113 mmol, 58.7% yield). The product was used crude in subsequent reactions. MS(ES)+ m/e 201.9, 203.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 15.9 %

Procedure:
To a solution of methyl 6-chloro-5-(4-methylphenyl)-1H-indole-3-carboxylate (80 mg, 0.22 mmol) in methanol (8 mL) was added 1.0M aqueous NaOH (2.0 mL, 2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by reverse phase HPLC to give the title compound (10 mg, 13% yield) as a white solid. MS (ES+) 286.1 (M+H)+. 1H NMR (400 MHz, DMSO): 612.20-11.95 (br. s, 1H), 11.90 (br. s, H), 8.10 (s, 1H), 7.95 (s, 1H), 7.65 (s, 1H), 7.35-7.20 (m, 4H), 2.35 (s, 3H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:15])=O>>[CH3:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([Cl:15])=[O:6]
Reactant: Cc1ccc(C)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: Cc1ccc(C)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Part A. A 500-mL, three-necked, round bottomed flask equipped with an addition funnel, reflux condenser, and a nitrogen sweep to an HCl gas scrubber was charged with 2,5-dimethylbenzoic acid (50.0 g, 332.9 mmol). The apparatus was cooled in an ice bath and thionyl chloride (125 mL, 1714 mmol) was added over a period of about 5 minutes. After complete addition, the ice bath was removed and the reaction mixture was warmed to about 50° in order to completely dissolve the 2,5-dimethylbenzoic acid. The reaction mixture was allowed to gradually cool with stirring to room temperature overnight. The excess thionyl chloride and the HCl and SO2 reaction side-products were removed by vacuum distillation to afford 2,5-dimethylbenzoyl chloride as an oil, which was used without further purification. This material was transferred immediately to an addition funnel and added dropwise with stirring to a commercial 40% dimethylamine solution (188 mL, 1670 mmol) which was maintained between -5° and 5° by periodic immersion in a dry ice-acetone bath. After complete addition, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ether. The combined organic extracts were washed with water, dried, and concentrated. The resulting pale yellow oil was distilled under vacuum to afford N,N,2,5-tetramethylbenzamide (29.1 g, 164.2 mmol, 49% yield) as a clear, colorless oil: bp 100° (1.0 torr); IR(CHCl3) 1637 cm-1 ; MS m/e 178(M+ +H); 1H NMR(CDCl3) δ 7.00-7.13(m,2H), 6.90-7.00(m,1H), 3.13(s,3H), 2.84(s,3H), 2.31(s,3H), 2.23(s,3H). Anal. Calcd for C11H15NO: C,74.54; H,8.53; N,7.90. Found: C,74.30; H,8.77; N,7.73.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:4]1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:5]2[CH2:6][CH2:7][O:8][CH:3]([CH2:2][NH:1][C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:4]2)=[CH:11][CH:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Solvent: CN(C)C=O
Product: O=C(NCC1CN(Cc2ccc(F)cc2)CCO1)Nc1ccccc1
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of 2-aminomethyl-4-(p-fluorobenzyl)-morpholine (1.0 g, 4.5 mmol) in dimethylformamide (10 ml) was added under ice-cooling phenyl isocyanate (0.53 ml, 4.9 mmol) and the mixture was stirred for 30 minutes. To the reaction mixture was added purified water (20 ml) and the crystals thus separated out were then recovered by filtration to give the title compound (1.1 g). Yield=72%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.CCCCCC>CO.C(Cl)Cl>[NH2:1][C:2]1[N+:7]([O-:32])=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)n1
Solvent: CCCCCC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)[n+]1[O-]

Procedure:
20.6 g of methyl 2-amino-6-[(p-tolylsulphonyl)oxy]-4-pyrimidinecarbamate are suspended in 120 ml of methanol and 720 ml of methylene chloride. While stirring there are added thereto at room temperature 20.5 g of m-chloroperbenzoic acid and after 6 hours a further 16.3 g of m-chloroperbenzoic acid. The mixture is stirred overnight and subsequently treated with 1.5 l of hexane, whereby a precipitate separates. The precipitate is filtered off under suction and dried, there being obtained crude methyl 2-amino-6-[(p-tolylsulfonyl)oxy]-4-pyrimidinecarbamate-3-oxide of melting point 139°-142°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17](Cl)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>C(#N)C>[N:24]1[CH:25]=[CH:26][C:21]([NH:20][C:17]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:12]=2[C:13]([F:16])([F:15])[F:14])=[O:18])=[CH:22][CH:23]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1ccncc1)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 60 °C

Procedure:
1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.100 g, 0.324 mmol) was added to a solution of 4-aminopyridine (0.036 g, 0.387 mmol) and pyridine (0.078 mL, 0.969 mmol) in acetonitrile (10 mL). The reaction mixture was heated at 60° C. for 12 h, concentrated and the crude product was purified by column chromatography on silica gel to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid pyridine-4-ylamide. LCMS m/z=366.9 (M+H)+.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:21][C:30](=[O:31])[CH2:29][CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)CCc1ccccc1
Yield: 62.3 %

Procedure:
Add 13β-ethyl-17β-hydroxy-gon-4-en-3-one (0.11 g.) in dry pyridine (0.35 cc.) at -20° to 3-phenylpropionyl chloride (0.11 g.) in benzene (0.3 cc.). Keep this at -10° for 16 hours, add ice-cold water and extract with a mixture of equal volumes of ether and benzene. Wash the extracts in turn with 2N potassium hydroxide solution, water, 2N hydrochloric acid solution, and brine, and dry. Evaporate solvent to give a residue and recrystallize from a mixture of ether and ethyl acetate to obtain the title compound (0.10 g.), m.p. 135°-40°; infrared absorption peaks at 5.81, 5.99, 8.51, 13.3, 14.3 μ, showing no absorption due to hydroxyl.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[N:36]1([S:33]([C:29]2[CH:28]=[C:27]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)[CH:32]=[CH:31][CH:30]=2)(=[O:34])=[O:35])[CH2:37][CH2:38][O:39][CH2:40][CH2:41]1
Reactant: O=S(=O)(c1cccc(Br)c1)N1CCOCC1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1)N1CCOCC1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-(3-bromo-benzenesulfonyl)-morpholine (example B.31) (275 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (490 mg, 84%). MS (ISP) 581.2 [(M+H)+]; mp 203–204° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][C@H:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([O:25]CC2C=CC=CC=2)=[O:24])=[C:19]([F:33])[CH:18]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(O)C>[C:1]([O:5][C:6](=[O:34])[CH2:7][C@H:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[C:19]([F:33])[CH:18]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CC(=O)OC(C)(C)C)Oc1ccccc1-c1ccc(C(=O)OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](CC(=O)OC(C)(C)C)Oc1ccccc1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 95.7 %

Procedure:
To an ethanol solution (80 ml) of benzyl 2′-{[(1R)-3-tert-butoxy-1-methyl-3-oxopropyl]oxy}-3-fluorobiphenyl-4-carboxylate (12.8 g) was added 10% palladium carbon (2.54 g), followed by stirring at room temperature for 7 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 2′-{[(1R)-3-tert-butoxy-1-methyl-3-oxopropyl]oxy}-3-fluorobiphenyl-4-carboxylic acid (9.87 g).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([NH:21]O)=[NH:20])[CH:13]=[CH:12]2>CC1C=C(C)C=C(C)N=1>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1[N:20]=[C:5]([CH3:6])[O:7][N:21]=1)[CH:13]=[CH:12]2
Reactant: N=C(NO)c1ccc2cc(Br)ccc2c1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: Cc1nc(-c2ccc3cc(Br)ccc3c2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.11 ml acetic anhydride are added to 4.40 g 6-bromo-N-hydroxy-naphthalene-2-carboxamidine in 30 ml 2,4,6-trimethylpyridine. The reaction mixture is stirred for one hour at ambient temperature and then heated to 130° C. for four hours. After the reaction has ended the mixture is evaporated down in vacuo and the flask residue is stirred with ethyl acetate and petroleum ether, suction filtered and dried.