Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].C([Li])CCC.C([O:21][B:22](OC(C)C)[O:23]C(C)C)(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[F:10][C:9]([F:12])([F:11])[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:22]([OH:23])[OH:21]
Reactant: FC(F)(F)Oc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OB(O)c1ccccc1OC(F)(F)F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
A solution of 2-bromo-trifluoromethoxybenzene (1.0 g, 4.15 mmol) in dry tetrahydrofuran (20 mL) was cooled to −70° C. A 2.5 M solution of n-butyllithium in hexanes (2.0 mL, 4.98 mmol) was slowly added over a 5 min period, keeping the temperature below −65° C. After stirring at −70° C. for 30 min, triisopropylborate (1.5 mL, 6.22 mmol) was added over a 5 min period. After stirring at −70° C. for 30 min, the solution was stirred at room temperature overnight. An aqueous solution of 2N HCl (10 mL) was added and the mixture stirred for 2 hr. The solution was diluted with ethyl acetate (100 mL). The layers were separated and the organic layer successively washed with 2N HCl (2×25 mL), water (1×25 mL), and saturated salt solution (1×25 mL). The solution was dried over anhydrous magnesium sulfate, filtered and concentrated by rotoevaporation to a pale crystalline solid which was triturated with a little hexanes and filtered. The filtrate was concentrated to a white solid. The two solids were combined to yield 434 mg of the title compound which was used without further purification in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH:32]=O)[C:13](OS(C4C(C)=CC(C)=CC=4C)(=O)=O)=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:34]([CH3:36])[CH3:35])=[CH:4][CH:3]=1.[CH2:37]([NH2:40])[CH2:38][NH2:39].[BH4-].[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[CH:15]=[CH:14][C:13]4[NH:40][CH2:37][CH2:38][NH:39][CH2:32][C:12]=4[C:11]=3[O:10][C:9]=2[CH:34]([CH3:35])[CH3:36])=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Oc2ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc3c2C=O)c(C)c1
Reactant: NCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)c1oc2c3c(ccc2c(=O)c1-c1ccc(Cl)cc1)NCCNC3
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 2,4,6-trimethylbenzenesulfonic acid 3-(4-chlorophenyl)-8-formyl-2-isopropyl-4-oxo-4H-chromen-7-yl ester (141 mg, 0.269 mmol) and ethylene diamine (0.6 ml) in anhydrous pyridine (3.5 ml) in a sealed 5 ml microwave tube is heated under microwave irradiation at 100° C. for 1 h. A further aliquot of ethylene diamine (0.6 ml) is added, and the mixture is heated at 140° C. for 30 min. A further aliquot of ethylene diamine (0.4 ml) is then added, and the mixture is heated at 160° C. for 50 min and finally at 150° C. for 2 h. The mixture is cooled to room temperature, and the volatiles are removed under reduced pressure. The residue is dissolved in dry methanol (4 ml), and the solution is cooled to 0° C. Sodium borohydride (15 mg, 0.4 mmol) is added, and the mixture is stirred for 18 h as it warms to room temperature. The mixture is quenched by the addition of water (30 ml) and extracted with dichloromethane (3×20 ml). The organic phases are combined, washed with saturated brine (50 ml), dried (MgSO4), filtered and evaporated under reduced pressure. The residue is purified by preparative reversed phase chromatography using 90% water/-acetonitrile to 100% acetonitrile as eluant. The pure product-containing fractions are combined and evaporated to dryness, and the residue is triturated with n-hexane containing a small amount of dichloromethane. The resulting colourless powder is recovered by filtration and dried.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH2:30][C@H:31]5[CH2:33][O:32]5)[CH2:22][CH2:21]4)[C:14]3=[O:34])[CH:7]=2)[CH2:3][CH2:2]1.[CH2:36]([NH2:38])[CH3:37]>>[CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH2:30][C@H:31]([OH:32])[CH2:33][NH:38][CH2:36][CH3:37])[CH2:22][CH2:21]4)[C:14]3=[O:34])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OC[C@H]3CO3)CC2)c1=O
Product: CCNC[C@@H](O)COc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CC1

Procedure:
The title compound was prepared using a similar method to that described for Example 299b from (R)—N-cyclopropyl-4-methyl-3-(3-(1-(2-(oxiran-2-ylmethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)benzamide (Example 299a) and ethylamine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:5][C:6]=1[CH:7]([OH:11])[CH2:8][CH:9]=[CH2:10].[OH2:22].[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)[S:5][C:6]=1[CH:7]([OH:11])[CH2:8][CH2:9][CH2:10][OH:22]
Reactant: C=CCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)CCCO
Reaction time: 1 h

Procedure:
To a solution of [rac]-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-but-3-en-1-ol [200 mg, 0.64 mmol; PCT Int. Appl. (2002), WO 02/062774 A1] in tetrahydrofuran (2 ml) was added a 1 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (1.28 ml, 1.28 mmol) at ambient temperature under an argon atmosphere. The yellow solution was stirred for 1 h, water (1 ml), 3 M aqueous NaOH solution (0.2 ml) and 35% aqueous H2O2 solution (0.2 ml) were added and stirring was continued for 1 h. Water and ethyl acetate were added, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed two times with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give 212 mg (0.64 mmol, quant.) of the title compound which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[CH2:9]([O:11][C:12](=[O:26])[CH:13]([CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=O)[CH3:15])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:17]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:1]([C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)[C:14]=1[CH3:15])=[O:26])[CH3:10]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Cc1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(C)c2)c1C

Procedure:
m-Toluidine (5 mmol, 0.5 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in methylene chloride, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4, then the solids were separated and the solvents evaporated under vacuum. The crude product was recrystallized from ethanol to yield the named product (m.p. 103° C.-104.5° C.).
Reaction SMILES: I[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[CH:5][CH:6]=1.[CH3:16][C:17]([CH3:21])([CH3:20])[C:18]#[CH:19].O>N1CCCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][C:17]([CH3:21])([CH3:20])[C:18]#[C:19][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[CH:5][CH:6]=1
Reactant: C#CC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(I)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCNCC1
Solvent: O
Product: CC(C)(C)C#Cc1ccc(-c2ccccc2[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-iodo-5-(2-nitro-phenyl)-thiophene (28 g, 84 mmol) in piperidine (235 ml) were added successively copper(I) iodide (0.8 g, 4.2 mmol), bis(triphenylphosphine)palladium(II) chloride (2.9 g, 4.2 mmol) and 3,3-dimethyl-1-butyne (14 g, 0.17 mol). This mixture was stirred for 16 hours at room temperature. Subsequently, it was poured into 1 litre of water, stirred for 15 minutes and extracted with tert-butyl methyl ether. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated. The remaining oil was purified by silica gel chromatography using ethyl acetate and hexane as eluents, giving Compound No. 6.030.i (22 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[Cl:19]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:19][C:7]1[CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:4]=[CH:5][C:6]=1[NH:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O

Procedure:
To the m-phenoxybenzyl ester of N-(p-trifluoromethylphenyl)valine (1.57 g) in about 15 ml benzene, with stirring and under nitrogen, is added N-chlorosuccinimide (0.53 g). The reaction mixture is heated to reflux for about 2 hours. The reaction is cooled and partitioned between ether and water. Aqueous phase is back-extracted with ether. The combined ether phases are washed with water and brine, dried over sodium sulfate, filtered and evaporated. The reaction product is put on preparative TLC plates and eluted using 10% ether/hexane to yield the m-phenoxybenzyl ester of N-(2-chloro-4-trifluoromethylphenyl)valine, MS m/e 477.1 (M+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13](O)=[O:14])[CH:12]=[C:6]2[C:5]=1[NH:16][C@@H:17]([C:19]1([CH3:22])[CH2:21][CH2:20]1)[CH3:18])(=[O:3])[NH2:2].C1C=CC2N(O)[N:30]=[N:29]C=2C=1.C(Cl)CCl.NN>CN(C=O)C.O>[NH:29]([C:13]([C:11]1[CH:12]=[C:6]2[C:5]([NH:16][C@@H:17]([C:19]3([CH3:22])[CH2:20][CH2:21]3)[CH3:18])=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=[N:8][N:7]2[CH:10]=1)=[O:14])[NH2:30]
Reactant: On1nnc2ccccc21
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(C(=O)O)cc12)C1(C)CC1
Agent: NN
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(C(=O)NN)cc12)C1(C)CC1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of (R)-3-carbamoyl-4-((1-(1-methylcyclopropyl)ethyl)amino)pyrrolo[1,2-b]pyridazine-6-carboxylic acid (1.11 g, 3.67 mmol) in DMF (Volume: 10 mL) was added HOBT (0.675 g, 4.41 mmol) and EDC (0.915 g, 4.77 mmol) which was stirred at 23° C. for 1 hr. To the reaction mixture was added hydrazine (0.576 mL, 18.36 mmol) dropwise and stirred for 30 minutes, followed by the addition of 50 mL of water and stirred for 20 minutes. The solid was collected as the desired product (1.54 g). MS (ES+) m/z: 317.08 (M+H); HPLC: 91%, retention time: 1.935 min (analytical HPLC Method B).
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:27])[CH2:10][N:11]([CH3:26])[S:12]([C:15]2[C:16]3[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[C:17]=3[S:18][C:19]=2Br)(=[O:14])=[O:13])=[CH:5][CH:4]=1.Cl>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:27])[CH2:10][N:11]([CH3:26])[S:12]([C:15]2[C:16]3[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[C:17]=3[S:18][C:19]=2[NH2:1])(=[O:14])=[O:13])=[CH:5][CH:4]=1
Reactant: N
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1c(Br)sc2c1CCCC2=O
Agent: Cl
Solvent: O
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1c(N)sc2c1CCCC2=O
Temperature: 110 °C

Procedure:
A concentrated aqueous ammonia (24 mL) was added to 2-bromo-7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonic acid[2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-amide (210 mg). After heating at 110° C. for 4 hours, the reaction solution was poured into water, brought to pH 9 with 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, the residue resulting from the removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (145 mg) was obtained as a colorless film.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]([CH:17]=O)[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CO.[CH3:21][NH2:22]>>[Br:1][C:2]1[CH:16]=[C:15]([CH2:17][NH:22][CH3:21])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CN
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1Br
Solvent: CO
Product: CNCc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
t-Butyl 2-(2-bromo-4-formylphenoxy)acetate (1) (10.11 g, 32.1 mmol, 1 eq) was dissolved in a 2 M solution of methylamine in methanol (30 mL, 60 mmol, 1.9 eq) and stirred at room temperature for 4 h. The solvent and excess methylamine were removed in vacuo and the resultant imine was dissolved in anhydrous methanol (200 mL). Sodium Borohydride (2.4 g) was added slowly under argon and the mixture was stirred for 2 h. Saturated NaHCO3 (100 mL) was added and allowed to stir for 15 minutes at which point the methanol was removed in vacuo. The resultant aqueous mixture was extracted with DCM (2×50 mL) and the combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated in vacuo to yield 6.2 g (58%) of t-butyl 2-(2-bromo-4-((methylamino)methyl)phenoxy)acetate (2). 1HNMR (CDCl3, 300 MHz): δ 7.50 (d, 1H), 7.15 (m, 1H), 6.72 (d, 1H), 4.55 (s, 2H), 3.65 (s, 2H), 2.41 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.O>CN(C)C=O>[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:31][CH2:32][N:33]([C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([Br:11])=[CH:10][C:2]=3[F:1])[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Br)cc1F)N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
A solution of 2-fluoro-4-bromobenzoic acid (0.24 g) in dry dimethylformamide (10 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.17 g) and stirred for 30 minutes at ambient temperature under argon. A solution of 1-(4-pyridyl)piperazine (1.6 g) in dry dimethylformamide (3 ml) was added to the mixture and the mixture cooled to 50° C. The reaction was then allowed to warm to room temperature and stirred overnight. The solution was poured into water and then extracted into diethyl ether, washed with aqueous sodium hydrogen carbonate solution, water, brine. dried (Na2SO4) and evaporated to yield a colourless oil. This oil was then triturated with diethyl ether and recrystallised from ethyl acetate/isohexane to give 1-(4-pyridyl)-4-(2-fluoro-4-bromobenzoyl)piperazine (0.14 g) as a solid, m.p. 125-126° C.: microanalysis, found: C, 52.6; H, 4.1; N, 11.2%; C16H15BrFN3O requires: C, 52.8; H, 4.15; N, 11.5%; NMR: (CDCl3) 3.32(t,2H), 3.46(t,4H), 3.94(t,2H), 6.68(dd,2H), 7.29-7.43(m,3H), 8.33(d,2H); MS: m/z 364 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:12]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:23])[NH:17]2)[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].C(O)(=O)C.[Cl:28][C:29]1[C:34]([CH2:35][N:36]2[CH2:56][CH2:55][C:39]3([O:44][CH2:43][CH2:42][N:41]([C:45]([C:47]4[N:48]=[C:49]([CH:52]([CH3:54])[CH3:53])[S:50][CH:51]=4)=[O:46])[CH2:40]3)[CH2:38][CH2:37]2)=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:57][CH:58]=O.C([BH3-])#N.[Na+]>CO>[Si:5]([O:4][C@H:3]([C:12]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:23])[NH:17]2)[CH2:2][NH:1][CH2:58][CH2:57][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([CH2:35][N:36]2[CH2:37][CH2:38][C:39]3([O:44][CH2:43][CH2:42][N:41]([C:45]([C:47]4[N:48]=[C:49]([CH:52]([CH3:53])[CH3:54])[S:50][CH:51]=4)=[O:46])[CH2:40]3)[CH2:55][CH2:56]2)[C:29]=1[Cl:28])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CC=O)c4Cl)CC3)C2)cs1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4Cl)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of (R)-5-(2-amino-1-(tert-butyldimethylsilyloxy)ethyl)-8-hydroxyquinolin-2(1H)-one (WO2004106333) (0.261 g) in methanol (2 mL) was treated with acetic acid (0.030 mL) and stirred for 10 minutes. A solution of 2-(2-chloro-3-((4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenyl)acetaldehyde (example 80, step f) (0.247 g) in methanol (3 mL) was then added, and the resulting mixture was stirred at room temperature for 10 minutes, before cooling in ice-water and treating with sodium cyanoborohydride (0.102 g). The cooling bath was removed and the mixture was stirred at room temperature overnight. More sodium cyanoborohydride (0.101 g) was added, and the mixture was stirred over a second night. The solution was then concentrated onto flash silica in vacuo, and the resulting powder was purified by flash chromatography on silica eluted with 1:3:96 to 1:5:94 triethylamine:methanol:dichloromethane to afford the subtitled compound as a yellow oil. Yield 0.130 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[CH:31]([NH:34][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1)([CH3:33])[CH3:32]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(Cl)n1
Reactant: CC(C)N
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(NC(C)C)n1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-4-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)anilino]pyrimidine (0.2 g) and isopropylamine (5 ml) was heated to 100° C. in a sealed tube for 24 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic phase was washed with brine, dried over sodium sulphate and evaporated. The resultant solid was recrystallised from tert-butyl methyl ether to give the title compound (0.145 g); NMR Spectrum: (DMSOd6) 1.04 (s, 3H), 1.06 (s, 3H), 2.17 (s, 3H), 3.5 (m, 4H), 3.7 (m, 4H), 3.97 (m, 1H), 5.82 (m, 1H), 6.2 (br m, 1H), 7.07 (m, 1H), 7.19 (m, 2H), 7.45 (m, 1H), 7.78 (m, 1H), 7.87 (br m, 1H), 8.25 (m, 1H), 8.31 (s, 1H), 10.18 (s, 1H); Mass Spectrum: M+H+ 448.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=C>>[CH3:13][O:12][C:8]([CH2:9][N:1]([CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C:8]([O:12][CH3:13])=[O:11])=[O:11]
Reactant: NCc1cccs1
Reactant: C=CC(=O)OC
Product: COC(=O)CN(CC(=O)OC)Cc1cccs1

Procedure:
2-Aminomethylthiophene and methyl acrylate are reacted in similar manner so that described in Examples 19 to give 2-[N,N-di(methoxycarbonylmethyl)aminomethyl]thiophene. b. 2-[N,N-Di(methoxycarbonylethyl)aminomethyl]thiophene is cyclized and decarboxylated in a similar manner to that described in Example 19 to give N-(2thienylmethyl)-4-piperidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])=[CH:9][C:8]=2[CH:16]=1)([O-:3])=[O:2].[Br:17]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][Br:17])=[CH:9][C:8]=2[CH:16]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=Cc2cc([N+](=O)[O-])ccc2OC1(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C=C1CBr
Yield: 90.5 %

Procedure:
A solution of 6-nitro-2,2,3-trimethyl-2H-1-benzopyran (33.0 g, 0.151 mol) and benzoyl peroxide (0.020 g) in carbon tetrachloride (330 ml) were heated to 50° C. and N-bromo succinimide (26.8 g, 0.15 mol) was added. The mixture was heated at reflux for eighteen hours and then water and aqueous ferrous sulfate were added. The organic phase was separated and evaporated under reduced pressure, and the residue washed with pentane to give 40.45 g of 6-nitro-2,2-dimethyl-3-bromomethyl-2H-1-benzopyran, m.p. 107° C.
Reaction SMILES: [C:1]([NH:9][CH:10]([P:20]([CH2:31][C:32]([N:34]1[CH2:48][CH2:47][CH2:46][C@H:35]1[C:36]([O:38]CC1C=CC=CC=1)=[O:37])=[O:33])([O:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:21])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[C:1]([NH:9][CH:10]([P:20]([CH2:31][C:32]([N:34]1[CH2:48][CH2:47][CH2:46][C@H:35]1[C:36]([OH:38])=[O:37])=[O:33])([O:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:28])([CH3:29])[CH3:27])=[O:21])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(CCCc1ccccc1)NC(=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)OCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)O)C(CCCc1ccccc1)NC(=O)c1ccccc1

Procedure:
A solution of the diester product from part (a) in methanol is added to a 10% palladium on carbon catalyst and the resulting mixture is shaken in a Parr hydrogenation apparatus for several hours. The catalyst is filtered off and the methanol is stripped from the filtrate. The crude product is chromatographed on silica gel to yield (±)-1-[[[1-(benzoylamino)-4-phenylbutyl][(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl]acetyl]-L-proline.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[C:9]([F:18])[C:8]=2[Cl:19])[N:5]=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].NC(N)=O>O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[C:9]([F:18])[C:8]=2[Cl:19])[N:5]=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Reactant: O=[N+]([O-])O
Agent: NC(N)=O
Solvent: O
Product: Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
10 g (0.032 mol) of 5-amino-1-(2,6-dichloro-3-fluoro-4-trifluoromethylphenyl)-pyrazole are introduced in portions into a boiling solution of 2.3 ml (0.034 mol) of 67% strength nitric acid and 0.1 g of urea in 30 ml of water. The suspension is allowed to cool, and the precipitate is filtered off and dried in vacuo at room temperature. The dry precipitate is introduced into 40 ml of 98% strength sulphuric acid at -5° C., and the mixture is stirred for 12 hours at 0°-5° C. Thereafter, the reaction mixture is introduced into 350 ml of water, boiled up for a short time and allowed to cool to room temperature and the precipitate is filtered off. The precipitate is washed neutral with water and dried in vacuo at 40°-50° C. 7.0 g (61% of theory) of 5-amino-1-(2,6-dichloro-3-fluoro-4-trifluoromethylphenyl)-4-nitropyrazole of melting point 156° C. are obtained.