Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[CH2:8][O:9][C:10]1[C:11]([N+:16]([O-:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)(=O)C.O>CO.[OH-].[Na+]>[OH:4][CH2:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[CH2:8][O:9][C:10]1[C:11]([N+:16]([O-:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)OCc1ccccc1COc1cccnc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ncccc1OCc1ccccc1CO
Yield: 62.2 %

Procedure:
A solution of 3-(2-acetoxymethylbenzyloxy)-2nitropyridine (7.8 g) in methanol (39 ml) and 1N aqueous sodium hydroxide (23 ml) was stirred at room temperature for 0.5 hours. To the mixture was added water (50 ml) and the precipitates were collected by filtration to give 3-(2-hydroxymethylbenzyloxy)-2-nitropyridine (4.18 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[OH:38])[CH2:26][CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:38][C:29]3[CH:30]=[CH:31][C:32]([C:34]([F:35])([F:36])[F:37])=[CH:33][C:28]=3[CH2:25][CH2:26][CH3:27])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CCCc1cc(C(F)(F)F)ccc1O
Product: CCCc1cc(C(F)(F)F)ccc1Oc1nc(C(=O)NC(C)c2cc(F)c(NS(C)(=O)=O)c(F)c2)co1
Yield: 56.2 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 2-propyl-4-trifluoromethylphenol (37 mg, 0.18 mmol) to give the title compound (40 mg, 55%) after purification by flash chromatography on silica gel (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[C:10](=[O:19])[C:11]3=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]3[C:13]2=[O:14])=[CH:3][C:2]=1[F:1]
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1c1ccc(CBr)c(F)c1
Yield: 46.2 %

Procedure:
A mixture of the compound (1.0 g) obtained in Example 248, N-bromosuccinimide (698 mg), α,α′-azobis(isobutyronitrile) (catalytic amount) and carbon tetrachloride (20 ml) was heated under reflux for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=8:2) to give 605 mg of the titled compound (yield, 46%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:15]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O1CCCC1>[CH2:15]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
N-t-butyloxycarbonyl-L-alanine (3.8 g, 20 m mole), L-proline benzyl ester hydrochloride (5 g, 20.6 m mole) and 1-hydroxy benzotriazole, which is hereinafter referred to as HOBt (2.7 g, 20 m mole) were suspended in tetrahydrofuran, which is hereinafter referred to as THF (50 ml). N,N'-dimethylaminopropylethylcarbodiimide, which is hereinafter referred to as WSC (3.8 ml) in THF (10 ml) solution was added dropwisely to the above suspended solution while cooling with coolant of -15° C. and stirring. The reaction was carried for 3 hours at a temperature of less than 0° C. and thereafter at room temperature overnight. The solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid, water, 5% aqueous sodium bicarbonate and water in order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized in ether-n-hexan to give N-t-butyloxycarbonyl-L-alanyl-L-proline benzyl ester (6.7 g, yield: 89%) having melting point of 71° to 72° C. This product gave one spot by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method; spraying with 0.1% ninhydrin and heating).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:36][C:37]1[C:38](=[O:55])[C:39]([C:44]2[N:48]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:47]=[CH:46][CH:45]=2)=[N:40][N:41]([CH3:43])[CH:42]=1.[CH3:56][N:57]1[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[N:59]=[C:58]1[CH2:66][CH2:67][CH2:68]O>C1(C)C=CC=CC=1>[CH3:43][N:41]1[CH:42]=[C:37]([O:36][CH2:68][CH2:67][CH2:66][C:58]2[N:57]([CH3:56])[C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=3[N:59]=2)[C:38](=[O:55])[C:39]([C:44]2[N:48]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:47]=[CH:46][CH:45]=2)=[N:40]1
Reactant: Cn1c(CCCO)nc2ccccc21
Reactant: Cn1cc(O)c(=O)c(-c2ccnn2-c2ccccc2)n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1cc(OCCCc2nc3ccccc3n2C)c(=O)c(-c2ccnn2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
Toluene (10 mL) was added to di-tert-butyl diazene-1,2-dicarboxylate (173 mg) and triphenylphosphine (229 mg) and the mixture was stirred at room temperature for 10 min. Then, 5-hydroxy-1-methyl-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (154 mg), 3-(1-methyl-1H-benzimidazol-2-yl)propan-1-ol (143 mg) were further added and the mixture was stirred at room temperature for 22 hr. The crystals precipitated from the reaction mixture were collected by filtration, washed successively with toluene, methanol and diisopropyl ether, and dried to give the title compound (134 mg).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=2)[CH:12]=[C:13]([CH2:15][O:16][CH3:17])[CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:17][O:16][CH2:15][CH:13]1[CH2:12][N:11]2[C:18]([CH3:22])=[C:19]([CH3:21])[N:20]=[C:10]2[C:9](=[O:8])[CH2:14]1
Reactant: [H][H]
Reactant: COCc1cc(OCc2ccccc2)c2nc(C)c(C)n2c1
Agent: [Pd]
Solvent: CO
Product: COCC1CC(=O)c2nc(C)c(C)n2C1

Procedure:
19.2 g of 8-benzyloxy-6-methoxymethyl-2,3-dimethylimidazo[1,2-a]pyridine, dissolved in 100 ml of methanol, are treated with 1.9 g of palladium (10% strength on activated carbon, Merck) and hydrogenated with hydrogen at 80° C. using a pressure of 50 bar. After absorption of hydrogen is complete, the catalyst is filtered off, washed with methanol and methylene chloride and the combined filtrate is concentrated to dryness in vacuo. After purification on silica gel (eluent: methylene chloride/methanol=13/1), 7.6 g of the title compound of melting point 103-104° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8](B(O)O)[CH:9]=1)[CH3:2].Br[C:15]1[C:20]([CH2:21][CH3:22])=[CH:19][N:18]=[C:17]([C@H:23]2[CH2:27][CH2:26][C@@:25]3([CH2:31][CH2:30][N:29]([CH3:32])[C:28]3=[O:33])[NH:24]2)[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([C:15]2[C:20]([CH2:21][CH3:22])=[CH:19][N:18]=[C:17]([C@H:23]3[CH2:27][CH2:26][C@@:25]4([CH2:31][CH2:30][N:29]([CH3:32])[C:28]4=[O:33])[NH:24]3)[CH:16]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: CCc1cnc([C@H]2CC[C@@]3(CCN(C)C3=O)N2)cc1Br
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(F)c(-c2cc([C@H]3CC[C@@]4(CCN(C)C4=O)N3)ncc2CC)c1
Temperature: 140 °C
Yield: 73.3 %

Procedure:
To a microwave vial containing a solution of (5-ethoxy-2-fluoro-phenyl)boronic acid (54.39 mg, 0.3000 mmol) in MeCN (1 mL) and water (0.2000 mL) was added (2R,5S)-2-(4-bromo-5-ethyl-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Description 122) (80 mg, 0.2400 mmol), sodium carbonate (50.12 mg, 0.4700 mmol) and bis(triphenylphosphine)palladium (II) dichloride (8.2 mg, 0.0100 mmol). The microwave vial was sealed and heated at 140° C. for 15 minutes. The reaction was concentrated in vacuo and loaded onto a silica column (10 g, Biotage SNAP cartridge). The silica column was then eluted with a gradient of (80:20:2 EtOAc:MeOH:0.88M NH3):EtOAc from 0% to 100%. Fractions containing desired product were combined and concentrated in vacuo to give (2R,5S)-2-[4-(5-ethoxy-2-fluoro-phenyl)-5-ethyl-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (69.9 mg, 0.1759 mmol, 74.4% yield) as a colourless oil;
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8]1([NH2:11])[CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:8]1([NH:11][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH2:9]1
Reactant: NC1CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
Ethyl bromoacetate (1 eq.) was added slowly to an ice-cold solution of cyclopropylamine (17.5 mmol, 3 eq.) and K2CO3 (2 eq.) in DMF (25 ml) and the reaction mixture was then stirred at room temperature for 16 h. For working up, the mixture was diluted with an excess of water and extracted with 20% ethyl acetate/hexane solution. The organic phase was washed with water and sat. NaCl solution and dried over Na2SO4. After the solvent had been removed completely, the crude product was employed in the next stage without further purification. Yield: 52%
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH2:26])([CH3:25])[CH3:24])[C:20]([CH2:27][O:28][CH2:29][CH3:30])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH:26][C:38](=[O:40])[CH3:39])([CH3:24])[CH3:25])[C:20]([CH2:27][O:28][CH2:29][CH3:30])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)N
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
2-(7-Benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethylamine (1.88 g, 4.65 mmol), triethylamine (1.3 mL, 9.3 mmol), and dichloromethane (50 mL) were combined and cooled to 0° C. Acetyl chloride (0.36 mL, 5.11 mmol) was added and the reaction was stirred for 30 minutes. The cooling bath was removed and the reaction was stirred for an additional 3.5 hours. Water was added and the layers were separated. The organic fraction was sequentially washed with brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure to provide a tan solid. The solid was purified by flash column chromatography on silica gel (eluting with a gradient of 6-7.5% methanol in dichloromethane) to yield 1.71 g of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide as a cream colored solid.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:4]1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:4]1)=[N+:22]=[N-:23]
Reactant: Clc1ccc(C2CC(CBr)Cc3ccccc32)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1Cc2ccccc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
A mixture of compound 12 (0.293 g, 0.79 mmol) and sodium azide (0.154 g, 2.38 mmol) in DMF (5 ml) was stirred at 60° C. for 24 hours. The reaction mixture was filtered and evaporated in vacuo. The residue was partitioned between water and EtOAc. The organic layer was separated, washed with water, dried over Na2SO4, and evaporated to give compound 13 as a pale yellow oil (mixture of cis and trans diastereomers, ratio=1:1.1, 0.18 g, 68%). The diastereomers were separated using a preparative chiral HPLC procedure (ChiralPak OD column; hexanes:MeOH=98:2; μ=8 ml/min; and λ=225 nm) to give compounds 13a-13d (retention times: 9.8 min, 12.0 min, 14.5 min and 20.1 min, respectively).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:22][CH3:23])[C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11].C([Li])CCC.[CH:29](N1CCOCC1)=[O:30].Cl>C1COCC1.C(OCC)(=O)C>[CH3:23][O:22][C:4]1[CH:3]=[C:2]([CH:19]=[C:6]([CH2:7][O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[C:5]=1[O:20][CH3:21])[CH:29]=[O:30]
Reactant: COc1cc(Br)cc(CO[Si](C(C)C)(C(C)C)C(C)C)c1OC
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=O)cc(CO[Si](C(C)C)(C(C)C)C(C)C)c1OC
Reaction time: 0.25 h

Procedure:
To a solution of the 3.616 g of (5-bromo-2,3-dimethoxybenzyloxy)triisopropylsilane in 60 ml of THF there was added dropwise 3.6 ml of n-butyllithium (2.66 M, hexane solution) at −78° C. under a nitrogen atmosphere. After stirring for 15 minutes, 2 ml of N-formylmorpholine was added and the mixture was stirred at room temperature for 20 minutes. Next, 1N hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (2.605 g) as an oil.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:11][C:10]=2[F:20])[S:6][C:5]=1[NH:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([CH:28]=[C:29]([C:31](OCC)=[O:32])[N:30]=2)[N:27]=1)=[O:3].C[Al](C)C.Cl.[OH:41][CH:42]1[CH2:45][NH:44][CH2:43]1>O1CCCC1>[F:15][C:14]1[CH:13]=[C:12]([C:16]([OH:19])([CH3:18])[CH3:17])[CH:11]=[C:10]([F:20])[C:9]=1[C:7]1[S:6][C:5]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[N:26]([CH:28]=[C:29]([C:31]([N:44]4[CH2:45][CH:42]([OH:41])[CH2:43]4)=[O:32])[N:30]=3)[N:27]=2)=[C:4]([C:2]([NH2:1])=[O:3])[CH:8]=1
Reactant: OC1CNC1
Reactant: CCOC(=O)c1cn2nc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)ccc2n1
Agent: C[Al](C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4nc(C(=O)N5CC(O)C5)cn4n3)s2)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 6-({3-(aminocarbonyl)-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)imidazo[1,2-b]pyridazine-2-carboxylate (33 mg, 0.07 mmol) was taken up in tetrahydrofuran and cooled to 0° C. Trimethylaluminum (0.53 ml, 1.06 mmol) was added dropwise, followed by 3-hydroxyazetidine hydrochloride (7 mg, 0.07 mmol). The reaction was stirred at 0° C. for one hour, warmed to room temperature and allowed to react overnight. The reaction was then quenched slowly with methanol, followed by stirring for 10 minutes at room temperature. The resulting mixture was filtered, washing the solids with ethyl acetate and water. The filtrate was collected, the phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were concentrated under and purified via flash chromatography (0-15% methanol in dichloromethane) to afford the title compound.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:28][N:29]1[CH:33]=[N:32][N:31]=[C:30]1[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:38][C:37]3[CH:36]=[CH:35][C:34]([C:30]4[N:29]([CH3:28])[CH:33]=[N:32][N:31]=4)=[CH:40][CH:39]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cn1cnnc1-c1ccc(N)cc1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cnnc1-c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 100 mg; 0.36 mmol) in DCM (4 ml) was treated with polymer-supported Mukaiyama reagent (400 mg) followed by triethylamine (100 mL; 0.73 mmol) and 4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (Maybridge, 63.2 mg; 0.36 mmol). After stirring at RT for 24 hours the mixture was filtered and washed with saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]4[CH2:20][CH2:19]4)=[O:15])=[CH:10][CH:9]=3)[C:5]([CH3:21])=[CH:4][CH:3]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1ccc(Cl)cc1
Product: Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
4-Chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)benzamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 4-chlorobenzoic acid using method B. LCMS: retention time 3.73 min, MH+419.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:71]1([CH:77]2[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]2)[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1>CN1C(=O)CCC1>[N:71]1([CH:77]2[CH2:82][CH2:81][N:80]([C:32]([C:31]3[CH:30]=[CH:29][C:28]([NH:27][C:26]([NH:25][C:22]4[CH:21]=[CH:20][C:19]([C:9]5[N:10]=[C:11]([N:13]6[CH2:14][CH2:15][O:16][CH2:17][CH2:18]6)[N:12]=[C:7]([N:4]6[CH2:3][CH2:2][O:1][CH2:6][CH2:5]6)[N:8]=5)=[CH:24][CH:23]=4)=[O:37])=[CH:36][CH:35]=3)=[O:33])[CH2:79][CH2:78]2)[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2CCC(N3CCCCC3)CC2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 60.1 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with 1,4′-bipiperidine (67 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product as a white solid (39 mg, 60% yield); MS (ESI) m/z=656.8
Reaction SMILES: [C:1]([CH:4]([NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:26]O>>[C:1]([CH:4]([NH:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:26])=[O:10])(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)C(CCCCC(=O)O)NC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCC(NC(=O)c1ccccc1)C(C)=O

Procedure:
6-Acetyl-6-benzoylaminohexanoic acid (4.35 g) was dissolved in 100 ml of methanol, and 0.5 ml of conc. sulfuric acid was added. The mixture was heated to reflux for 2.5 hours. The reaction solution was cooled, poured into ice-cold water, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated to provide 4.4 g of the objective compound as yellowish crystals. M.p. 59–60° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:8][N:9]([CH3:14])[S:10]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)(=[O:12])=[O:11]
Reactant: c1cn[nH]c1
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cccn1
Reaction time: 0.33 h

Procedure:
Pyrazole (12 g) was dissolved in tetrahydrofuran (200 mL), sodium hydride (60% in oil, 8.46 g) was added at 0° C. with stirring under a nitrogen atmosphere. After 20 min, dimethylsulfamoyl chloride (17 mL) was added dropwise, and the mixture was further stirred at the same temperature for 1 hr, and at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (400 mL), the mixture was extracted with ethyl acetate (400 mL), and the extract was dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the object fraction was concentrated under reduced pressure to give the title compound (25.3 g) as a colorless oil.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH:14]=[O:15])=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[BH4-].[Na+].O>CO>[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][OH:15])=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2cnc(C=O)s2)OCCO1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(c2cnc(CO)s2)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 5-(2-methyl-[1,3]dioxolan-2-yl)-thiazole-2-carbaldehyde (555 mg, 2.79 mmol) was dissolved in MeOH (5 mL). NaBH4 (136 mg, 3.46 mmol) was added portionwise at 0° C. and the reaction mixture stirred at rt for 1 h. Water (10 mL) was added and the mixture extracted with EA (3×20 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (1:1 hept-EA)=0.25. LC-MS-conditions 02: tR=0.64 min [M+H]+=202.48.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:35])[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.O1CCCC1.[Pd]>[C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:22]1[CH2:21][CH2:20][N:19]([C:17](=[O:18])[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[O:35])[CH2:24][CH2:23]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)Nc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)Nc2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.5 %

Procedure:
A mixture of N-[4-(benzyloxy)phenyl]-2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetamide (Example 198, 3.64 g, 7.72 mmol) and palladium (10% on carbon, wetted with ca. 50% water, 300 mg) in ethyl acetate (10 mL) was stirred at room temperature for 24 h under hydrogen. The reaction mixture was diluted with tetrahydrofuran and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.90 g, 98%) as a white solid.