Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[CH2:16]([NH:23][CH2:24][CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:16]([N:23]1[CH2:24][CH2:25][N:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:2][CH:3]1[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Reactant: COC(=O)/C=C/CBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
Methyl 4-bromocrotonate (Aldrich, 5.53 mL, 40 mmol) was added dropwise with stirring to an ice-cooled solution of triethylamine (11.15 mL, 80 mmol) and N,N′-dibenzylethylenediamine (Aldrich, 9.67 mL, 40 mmol) in toluene (200 mL). The solution was stirred with ice cooling for 1 hour, then allowed to warm gradually to room temperature and stirred 25 hours longer. The mixture was filtered through a pad of diatomaceous earth with an ethyl acetate (20 mL) rinse. The filtrate was concentrated to an oil, which was mixed with 10% aqueous HCl (240 mL). After 5 minutes, the mixture was filtered and the cake was rinsed with water (2×10 mL). The filtrate was washed with ethyl acetate (2×80 mL) and the aqueous phase was made basic (pH˜9-10) by portionwise addition of solid K2CO3 (26 g), then 25% aqueous NaOH (10 mL). The turbid mixture was extracted with ethyl acetate (3×120 mL) and the combined extracts were washed with brine (100 mL), dried (MgSO4) and concentrated under vacuum to leave the title compound as an oil (9.78 g): 1H NMR (300 MHz, CDCl3) δ ppm 2.30-2.47 (m, 4H), 2.49-2.73 (m, 4H), 3.06-3.18 (m, 1H), 3.43 (d, J=13.2 Hz, 2H), 3.53 (d, J=13.2 Hz, 1H), 3.60 (s, 3H), 3.76 (d, J=13.6 Hz, 1H), 7.14-7.36 (m, 10H); MS (DCI) m/z 339 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH3:13])[CH:8]([CH3:9])[CH2:7][CH2:6][C:5]([CH2:11][CH3:12])([CH3:10])[NH:4]1)[CH3:2].[CH2:14](Br)[CH:15]=[CH2:16].[OH-].[Na+]>C(C1(C)N=C(CCC)CC(CCC)(C)N1)CC>[CH2:16]([N:4]1[C:5]([CH2:11][CH3:12])([CH3:10])[CH2:6][CH2:7][CH:8]([CH3:9])[C:3]1([CH2:1][CH3:2])[CH3:13])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: CCC1(C)CCC(C)C(C)(CC)N1
Agent: CCCC1=NC(C)(CCC)NC(C)(CCC)C1
Agent: [Na+]
Agent: [OH-]
Product: C=CCN1C(C)(CC)CCC(C)C1(C)CC
Temperature: 75 °C

Procedure:
36.7 g of 2,6-diethyl-2,3,6-trimethylpiperidine and 30 g of allyl bromide are stirred for 7 days with heating at about 75° C. The reaction mixture is made alkaline by addition of 200 ml of 2 n sodium hydroxide and is extracted with ether. The ethereal solution is dried over K2CO3 and evaporated. The residue is purified by fractional distillation yielding 1-allyl-2,6-diethyl-2,3,6-trimethylpiperidine (Compound No. 4) which distills at 132°-135° C./16 mm Hg.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21](=[O:32])[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)([CH3:19])([CH3:18])[CH3:17].CC1(C)C2CCC1(C)[C:36](/[C:38]/2=[C:39](/[C:41](F)(F)F)\[OH:40])=[O:37].CC1(C)C2CCC1(C)[C:53](/C/2=C(/C(F)(F)F)\O)=[O:54].CC1(C)C2CCC1(C)C(/C/2=C(/C(F)(F)F)\O)=[O:71].[Eu]>C1COCC1>[C:16]([O:20][C:21]([CH2:22][N:23]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C:36](=[O:37])[C@@H:38]1[O:40][C@@H:39]1[C:41]([O:54][CH3:53])=[O:71])=[O:32])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC12CCC(/C(=C(/O)C(F)(F)F)C1=O)C2(C)C
Reactant: COc1ccc(NCC(=O)OC(C)(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Eu]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1O[C@H]1C(=O)N(CC(=O)OC(C)(C)C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 188.0 g (0.88 mol) of dicyclohexylcarbodiimide in 300 ml of THF was added dropwise, within 15 minutes, to a solution of 129.0 g (0.88 mol) of monomethyl (2R,2S)-2,3-oxirandicarboxylate and 196.0 g (0.8 mol) of t-butyl-N-(4-methoxyphenyl)glycinate [M. Shiozaki et al., Tetrahedron 40, 1795, (1984)] in 1100 ml of THF. The mixture was subsequently stirred for a further 30 minutes at room temperature, the resultant precipitate was separated off by filtration, and the filtrate solution was evaporated in vacuo. After purification of the product on 1.8 kg of silica gel (toluene:ethyl acetate=7:3), 263.2 g (90% of theory) of the title compound were obtained as crystals, melting point: 89° C. [α]D20 =-21.78° (c=0.435 in CHCl3). The enantiomer ratio, of 3:2, determined in the preparation example was confirmed by NMR-shift experiments using Eu(TFC)3.
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].[NH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:21]=[C:20]([C:31](N(OC)C)=[O:32])[CH:19]=2)=[CH:14][CH:13]=1)=[O:8]>C1COCC1>[C:31]([C:20]1[CH:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][NH:9][C:7]([NH2:6])=[O:8])=[CH:17][CH:16]=2)[N:22]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:21]=1)(=[O:32])[CH:1]([CH3:3])[CH3:2]
Reactant: COc1ccc(-n2nc(C(=O)N(C)OC)cc2-c2ccc(CCNC(N)=O)cc2)cc1
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(=O)C(C)C)cc2-c2ccc(CCNC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0.76M solution of isopropylmagnesium bromide in THF (2.0 ml) was added a solution of 5-(4-{2-[(aminocarbonyl)-amino]ethyl}phenyl)-N-methoxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-carboxamide (130 mg) in THF (2 ml) dropwise at at 4° C. The mixture was stirred at ambient temperature overnight. Additional 0.76M solution of isopropylmagnesium bromide in THF (2.0 ml) was added and the mixture was stirred at 50° C. for 5 hours. The reaction mixture was cooled to ambient temperature and was quenched by adding saturated aqueous ammonium chloride solution. The mixture was extracted with AcOEt. The organic layer was washed with 1M HCl, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by MeOH/CHC3 10%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give N-(2-{4-[3-isobutyryl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}ethyl)urea (30 mg) as amorphous powder.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCCC2C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1C(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 87.2 %

Procedure:
1-(1-tert-butoxycarbonylpiperidine-4-carbonyl)-piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (75) (1.41 g; 2.39 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15 mL) is added in a slow stream, and the solution is stirred for 2.25 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.02 g) as an oil. ESMS:MH+ 490.4
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:15][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:17])[CH:14]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a solution of (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (500 mg, 2.1 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (640 mg, 3.2 mmol) and triphenylphosphine (840 mg, 3.2 mmol) in anhydrous tetrahydrofuran (20 ml) was added diethyl azodicarboxylate (0.5 ml, 3.2 mmol) dropwise. After being stirred under an argon atmosphere at room temperature for 4 hours, the mixture was diluted with water (15 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (elution with 20% ethyl acetate in hexanes) to give 4-(7-fluoro-3-methoxycarbonylmethyl-naphthalen-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (740 mg, 84%) as a pale yellow solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH3:16])=[O:14])[C:9]([CH3:18])([CH3:17])[CH2:8]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:17][C:9]1([CH3:18])[CH2:8][CH:7]([O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][CH2:11][CH:10]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C1CCC(O)CC1(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(OS(C)(=O)=O)CC1(C)C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (1.69 mL, 21.7 mmol) was added at −20° C. to a solution of racemic methyl 4-hydroxy-2,2-dimethylcyclohexanecarboxylate (3.11 g, 16.7 mmol) and triethylamine (4.65 mL, 33.4 mmol) in dichloromethane (67 mL). The reaction was stirred for 3 hours. Saturated aqueous sodium bicarbonate was added to the mixture and extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 2,2-dimethyl-4-[(methylsulfonyl)oxy]cyclohexanecarboxylate. 1H NMR (500 MHz, CDCl3) δ 4.92-4.72 (m, 1H), 3.64 (s, 3H), 2.99 (s, 3H), 2.29-2.15 (m, 1H), 2.15-2.00 (m, 1H), 1.99-1.87 (m, 1H), 1.83-1.71 (m, 2H), 1.63-1.59 (m, 1H), 1.49-1.32 (m, 1H), 1.01 (s, 6H).
Reaction SMILES: [OH-].[K+].F[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1.O>CS(C)=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N+:10]([O-:12])=[O:11])=[N:18][CH:19]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Cl)cn1
Temperature: 20 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
9.9 g potassium hydroxide powder and 5.0 g 1-fluoro-2-nitrobenzene were added little by little in this order to a solution of 5.8 g 5-chloro-2-aminopyridine in dimethyl sulfoxide (100 mL), and the mixture was stirred at 20° C. for 4 hours under nitrogen atmosphere. The reaction solution was poured into iced water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane, to give 6.02 g of the title compound as orange crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:35])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[N:23][C:22]=3[Cl:34])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:36][CH:37](C[AlH]CC(C)C)C.C([Zn]CC)C>C1COCC1.CCOC(C)=O>[Cl:34][C:22]1[N:23]=[CH:24][N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([CH2:36][CH3:37])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:35])=[O:20]
Reactant: CC(C)C[AlH]CC(C)C
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Agent: CC[Zn]CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (112 mg, 0.180 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (7.33 mg, 8.98 μmol) in THF (10 ml) was added DIBAL-H (1.0 M solution in DCM) (2.55 mg, 0.018 mmol), followed by diethylzinc (1.0 M solution in heptane) (22.18 mg, 0.180 mmol). The reaction mixture was stirred for one hour at 60° C., cooled to room temperature, diluted with EtOAc and washed with water. The solvent was removed and the crude material (64 mg) was used directly in the next step without purification. LC-MS (ES+) m/z 572 [M+H].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[N+:8]([O-])([O-:10])=[O:9].[K+]>S(=O)(=O)(O)O>[N+:8]([C:4]1[CH:3]=[C:2]([CH:6]=[O:7])[S:1][CH:5]=1)([O-:10])=[O:9]
Reactant: O=Cc1cccs1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1cc([N+](=O)[O-])cs1

Procedure:
As shown in Scheme 3, 5-Nitro-2-thiophenecarboxaldehyde and 5-nitro-3-thiophene-carboxaldehyde, carboxaldehyde, each of which are commercially available, can be reacted with tris(trimethylsilyl)phosphite to give XII. Thiophene-2-carboxaldehyde is nitrated in sulfuric acid with potassium nitrate to give 4-nitrothiophene-2-carboxaldehyde which in turn is reacted with diethylphosphite on basic alumina and allowed to stand for 2-20 hours. Extraction of the product with methylene chloride gives XV. Treatment of XV with 5-8 equivalents of bromotrimethylsilane in methylene chloride (50-100 mL) gives compound XVI.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N+:38]([O-:40])=[O:39]>CN(C=O)C>[N+:38]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1)([O-:40])=[O:39]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccccc2[N+](=O)[O-])c1
Reaction time: 14 h
Yield: 32.9 %

Procedure:
A solution of [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone (0.15 g, 0.38 mmol), 1-Bromomethyl-2-nitro-benzene (0.10 g, 0.46 mmol) and CsCO3 (0.25 g, 0.76 mmol) in DMF (3 ml) was heated to 60° C. After 14 hr, the reaction was cooled, filtered and concentrated. The crude residue was purified by reverse phase HPLC to provide the desired compound (0.066 g, Yield=33%); MS (ESI) m/z 529;
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Reaction time: 0.5 h

Procedure:
To 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (100 g) in methanol (500 mL) at 50° C. was added p-toluenesulfonic acid monohydrate (6 g). The reaction was stirred for 30 mins, whereupon white solid has crashed fully out of solution. The solid is filtered and collected thru Buchner funnel, rinsed with Methanol and dried under vacuum to get 4-(2-chloro-9H-purin-6-yl)morpholine. Cesium carbonate (200 g) and iodomethane (30 mL) were subsequently added to a stirring solution of 4-(2-chloro-9H-purin-6-yl)morpholine in DMF at 50° C. The reaction was monitored by lc-ms until complete, about 30 minutes, whereupon the solvent was concentrated to dryness. Subsequent suspension of the crude reaction in water precipitated 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine (72 g) as a white solid, which was filtered and dried under vacuum overnight.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=2[CH3:31])[CH2:15][CH2:14]1)[CH:9]1[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:40][N:41]1[C:50]2[NH:49][C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[NH:46][CH2:45][C:44]=2[CH:43]=[N:42]1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH:9]1[CH2:11][CH2:10]1)[CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19](=[O:32])[CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:46]3[CH2:45][C:44]4[CH:43]=[N:42][N:41]([CH3:40])[C:50]=4[NH:49][C:48]4[CH:51]=[CH:52][CH:53]=[CH:54][C:47]3=4)=[O:27])=[CH:24][C:23]=2[CH3:31])[CH2:17][CH2:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)O)ccc1CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)C2CC2)CC1
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
WSCD (1.08 g, 5.6 mmol) and DMAP (343 mg, 2.8 mmol) were added to a solution of 4-(3-{4-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidin-1-yl}-3-oxo-propyl)-3-methyl-benzoic acid from Example E86.2 (1.25 g, 2.8 mmol) in dichloromethane (100 ml) and triethylamine (0.783 ml, 5.6 mmol). The mixture was stirred for 1 h at room temperature then 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (676 mg, 3.4 mmol) was added. The mixture was heated at reflux for 2 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 2% methanol:98% EtOAc to 5% methanol:95% EtOAc) to yield the title compound (1.1 g, 62%).
Reaction SMILES: [CH2:1]([C@@H:4]([C@H:12]([CH2:17][N:18]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:13]([O:15][CH3:16])=[O:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH:2]=C.[O:36]=[O+][O-].CSC>ClCCl>[CH2:29]([N:18]([CH2:17][C@@H:12]([C@H:4]([CH2:1][CH:2]=[O:36])[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:13]([O:15][CH3:16])=[O:14])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C=CC[C@H](C(=O)OC(C)(C)C)[C@H](CN(Cc1ccccc1)C(=O)OCc1ccccc1)C(=O)OC
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)[C@@H](CN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@H](CC=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirred solution of 4-methyl 1-tert-butyl(2S,3R)-2-allyl-3-({benzyl[(benzyloxy)cabonyl]amino}methyl)butanedioate (2.336 g, 4.851 mmol) in dichloromethane (97 mL) at −78° C. was bubbled ozone. After the solution turned blue, ozone bubbling continued for additional 15 min. Nitrogen was then bubbled into the mixture until the blue color disappeared. The reaction was quenched with dimethyl sulfide (1.78 mL, 24.26 mmol) and the solution was stirred at rt for 2 h. The solvent was removed under reduced pressure and the residue was purified by Combiflash (15-25% EtOAc/hexane) to provide 1.853 g (79%) of 1-methyl 4-tert-butyl(2R,3S)-2-({benzyl[(benzyloxy)cabonyl]amino}methyl)-3-(2-oxoethyl)butanedioate as a colorless viscous oil (1.853 g, 79% in yield). MS (ESI): 506.1 (M+Na+).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:19][S:20]([O:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CC1(CO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1(COS(C)(=O)=O)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
253 mg of compound 14b and 225 μl triethylamine were dissolved in 10 ml dichloromethane and cooled to −50° C. 140 μl methanesulfonylchloride was added and the mixture was stirred for one hour allowing the temperature to increase to 0° C. Saturated aqueous sodium bicarbonate was added and the mixture was extracted twice with dichloromethane. The organic extracts were combined and dried with sodium sulfate. Evaporation of the solvent gave 308 mg of the title compound as an almost colorless liquid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[C:27]([N:30]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:31])(=[O:29])[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[C:27]([N:30]([C:32]1[CH:38]=[CH:37][C:35]([NH:36]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:34][CH:33]=1)[CH3:31])(=[O:29])[CH3:28]
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(N-acetyl-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[F:13].[F:14][C:15]([F:23])([F:22])[C:16]1([C:19](O)=[O:20])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH2:6][NH:7][C:19]([C:16]2([C:15]([F:23])([F:22])[F:14])[CH2:18][CH2:17]2)=[O:20])=[CH:4][C:3]=1[F:13]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: NCc1cc(F)c(Cl)c([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1cc(F)c(Cl)c([N+](=O)[O-])c1)C1(C(F)(F)F)CC1

Procedure:
The sub-title compound was prepared in analogy to the procedure in Example 94, step (c) using 4-chloro-3-fluoro-5-nitro-benzylamine (761 mg; 3.72 mmol), 1-trifluoromethyl-cyclopropanecarboxylic acid (573 mg; 3.72 mmol), HBTU (1.41 g; 3.72 mmol), TEA (753 mg; 7.44 mmol) and DMF (10 mL).