Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][OH:18])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].COCCO[AlH2-]OCCOC.[Na+].OS([O-])(=O)=O.[K+]>CCOCC>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:10][CH2:11][C@H:12](/[CH:15]=[CH:16]/[CH2:17][OH:18])[CH2:13][CH2:14]1)[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCO)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](/C=C/CO)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of 4.5 g (16.8 mmol) of trans-[4-(3-Hydroxy-prop-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 180 ml Et2O was cooled (0° C.) and treated slowly with a solution of 13.46 ml (47.1 mmol) of Red-Al (70% in toluene). The solution was stirred 2 h at RT, cooled (0° C.) and treated again with 1.3 ml (4.7 mmol) of Red-Al (70% in toluene). After 2 h at RT, the reaction was cooled (−50° C.) and hydrolyzed with a suspension of 3 g MgSO4.7H2O, 3 g silicagel in 4 ml aqueous 10% KHSO4. The cooling bath was removed, THF was added, the mixture was filtered. After evaporation, the residue was dissolved in CH2Cl2, dried over Na2SO4 and evaporated to yield 3.59 g (quantitative) of trans-(1E)-[4-(3-Hydroxy-propenyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, MS: 270 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][C:13]=3[CH3:20])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:21].B(Br)(Br)Br>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=3[CH3:20])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: COc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)c(C)c1
Agent: BrB(Br)Br
Product: Cc1cc(O)ccc1-c1ccc2c(Cl)c(O)ccc2c1

Procedure:
The title compound was prepared by reacting 1-chloro-6-(4-methoxy-2-methylphenyl)-2-naphthol (400 mg, 1.41 mmol) with boron tribromide (4.0 mL of 1.0 M solution in CH2Cl2, 4.0 mmol) according to method D to yield 310 mg (77%) of a yellowish solid: mp 216–218° C.; 1H NMR (DMDO-d6): δ 2.20 (1H, s), 6.68 (1H, dd, J=8.19 Hz, J=2.42 Hz), 6.72 (1H, d, J=2.13 Hz), 7.10 (1H, d, J=8.16 Hz), 7.29 (1H, d, J=8.89 Hz), 7.29 (1H, d, J=8.89 Hz), 7.53 (1H, dd, J=8.78 Hz, J=1.62 Hz), 7.76 (1H, d, J=1.38 Hz), 7.80 (1H, d, J=8.94 Hz), 8.02 (1H, d, J=8.72 Hz), 9.4 (1H, s), 10.43 (1H, s); 13NMR (DMDO-d6): δ 20.47, 112.20, 112.99, 117.00, 118.66, 121.85, 127.83, 128.09, 128.38, 129.47, 130.00, 130.88, 131.65, 136.09, 136.51, 150.88, 156.62; MS (ESI) m/z 283/285(M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14](O)=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].COCCO[Al+]OCCOC.[Na+].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[OH:15][CH2:14][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: COCCO[Al+]OCCOC
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CSCC[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-D-methionine (12.47 g, 50 mmol) and sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al®) (50 mmol) in dry toluene (125 mL) was stirred at 0° C. for 30 minutes, then at ambient temperature for 1 hour. The mixture was treated with aqueous Rochelle salt and extracted with diethyl ether. The extract was washed sequentially with brine and aqueous NaHCO3, dried (MgSO4), filtered, and concentrated to provide the desired product (9.05 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:6]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:8]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH:2]([C:3]1[CH:8]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:6]=[C:5]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:4]=1)=[O:1]
Reactant: CC(C)(C#N)c1cc(CO)cc(C(C)(C)C#N)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C#N)c1cc(C=O)cc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2,2'-(5-hydroxymethyl-1,3-phenylene)di(2-methylpropiononitrile), (1.9 g), in dichloromethane (20 ml) was treated with pyridinium chlorochromate (2.15 g) and stirred at room temperature for 1.5 h. The reaction mixture was subjected to flash column chromatography, eluting with dichloromethane, to give 2,2'-(5-formyl-1,3-phenylene)di(2-methylpropiononitrile), mp. 145°-147°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:11]=[O:12])=[C:6]2[C:10]=1[O:9][CH:8]=[CH:7]2.Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1>>[CH:11]([C:5]1[C:6]2[CH:7]=[CH:8][O:9][C:10]=2[C:2]([O:1][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=2)=[CH:3][CH:4]=1)=[O:12]
Reactant: O=Cc1ccc(O)c2occc12
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(Oc2ccc(C=O)c3ccoc23)nc1

Procedure:
Using the procedure outlined in Preparation 70, 7-hydroxybenzofuran-4-carbaldehyde (preparation 73) and 6-chloronicotinonitrile gave the title compound: RT=3.40 min; m/z (ES+)=265.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]>CO>[O:14]=[C:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: NCCCCCCCCCCCC(=O)O
Solvent: CO
Product: CCCCCCCCCCC(=O)NCCCCCCCCCCCC(=O)O
Yield: 110.4 %

Procedure:
Reaction similar to example 2, of 9.30 g (50.0 mmol) N-hydroxysuccinimide and 12.0 g (58.0 mmol) DCC gave 14.0 g (100%) of the succinimidylester, which was reacted with 12.5 g (58.1 mmol) 12-aminododecanoic acid to yield 12.3 g (65%) colourless crystals, m.p. 102°-104° C. (methanol).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[CH3:12][O:13][C:14](=[O:31])[C:15]1[CH:20]=[C:19]([CH:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[C:18]([C:26]([F:29])([F:28])[F:27])=[CH:17][C:16]=1[NH2:30]>O1CCOCC1>[CH3:12][O:13][C:14](=[O:31])[C:15]1[CH:20]=[C:19]([CH:21]2[CH2:25][CH2:24][O:23][CH2:22]2)[C:18]([C:26]([F:28])([F:29])[F:27])=[CH:17][C:16]=1[NH:30][C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3]
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(C2CCOC2)c(C(F)(F)F)cc1N
Solvent: C1COCCO1
Product: COC(=O)c1cc(C2CCOC2)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4-Chlorophenyl chloroformate (27.3 μL, 1.1 equiv) was added to a solution of 2-amino-5-(tetrahydro-furan-3-yl)-4-trifluoromethyl-benzoic acid methyl ester (51.3 mg, 0.18 mmol) in dioxane (500 μL). The mixture was then stirred for 2 h (TLC control) at 80° C. The mixture was evaporated to dryness. The product was used in the next step without further purification. (rt 6.87 min.)
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:21][OH:22])=[CH:15][CH:14]=1>C(Cl)Cl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:21]=[O:22])=[CH:17][CH:18]=1
Reactant: CC(C)(C)C(CO)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 42.1 %

Procedure:
A mixture of pyridinium chlorochromate (3.8 g) and 3,3-bis-(4-fluorophenyl)-2-(1,1-dimethylethyl)propanol (2.4 g, 7.9 mmol) in 100 mL of methylene chloride was stirred at 25° C. for 64 hours during which time a gummy precipitate separated. The solvent was decanted from the precipitate and the residue rinsed with two 50 mL portions of methylene chloride. The combined methylene chloride solution was concentrated in vacuo. The residue was trituated with three 60 mL portions of hexane. The hexane solution was concentrated in vacuo and the residue crystallized from fresh hexane to give 1.0 g of the title compound; m.p. =49°-51° C. MS(CI): m/e =300 for M+.
Reaction SMILES: C(OC(=O)[C:5]1[C:10]([OH:11])=[CH:9][C:8]([OH:12])=[N:7][C:6]=1[C:13]([F:16])([F:15])[F:14])C.N>Cl>[F:16][C:13]([F:14])([F:15])[C:6]1[N:7]=[C:8]([OH:12])[CH:9]=[C:10]([OH:11])[CH:5]=1
Reactant: CCOC(=O)c1c(O)cc(O)nc1C(F)(F)F
Agent: Cl
Agent: N
Product: Oc1cc(O)nc(C(F)(F)F)c1
Temperature: 115 °C
Reaction time: 72 h
Yield: 84.2 %

Procedure:
4,6-dihydroxy-2-trifluoromethyl-nicotinic acid ethyl ester (15 g, 59.7 mmol) was dissolved in 250 mL of concentrated HCl and the mixture was stirred at 115° C. for 3 days. The mixture was cooled down to 0° C. and 0.88 ammonia was added until pH˜7. The solid formed was filtered, washed with water, azeotroped with toluene and dried in vacuo to give 9 g of the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].Cl.[N+:4]([C:7]1[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5].C(O)(=O)C.[CH:19](=O)[CH2:20][CH3:21]>C(O)C>[N+:4]([C:7]1[CH:8]=[C:9]([NH:13]/[N:14]=[CH:19]/[CH2:20][CH3:21])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: CCC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC/C=N/Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydroxide solution (10%, 15 mL) was added slowly to a stirred suspension of (3-nitrophenyl)hydrazine hydrochloride (1.89 g, 10 mmol) in ethanol (20 mL) until pH 6. Acetic acid (5 mL) was added to the mixture followed by propionaldehyde (0.7 g, 12 mmol). After stirring for 3 h at room temperature, the mixture was poured into ice-water and the resulting precipitate was isolated by filtration, washed with water and dried in air to obtain (E)-1-(3-nitrophenyl)-2-propylidenehydrazine, which was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH2:24]1[CH2:33][C@H:32]2[N:27]([CH2:28][CH2:29][CH2:30][C@H:31]2[CH2:34]O)[CH2:26][CH2:25]1.[I-].C(C[P+](C)(C)C)#N>C(#N)CC>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:34][C@H:31]2[C@@H:32]3[N:27]([CH2:26][CH2:25][CH2:24][CH2:33]3)[CH2:28][CH2:29][CH2:30]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC[C@@H]1CCCN2CCCC[C@H]12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Temperature: 120 °C
Reaction time: 22 h
Yield: 108.1 %

Procedure:
3 (3 g, 15 mmol) is dissolved in 150 ml of propionitril. Ethyldiisopropylamine (10.2 ml, 60 mmol), (−)-lupinine (2.5 g, 15 mmol) and cyanomethyl-trimethyl-phosphonium iodide (Zaragoza reagent, 7.3 g, 30 mmol) are added. The reaction mixture is heated to 120° C. and stirred for 22 hours. Then the mixture is evaporated under reduced pressure. The residue is dissolved with ethyl acetate, washed 10% K2CO3- and NaCl-solution, and dried over Na2SO4. Evaporation gave 5.7 g of a brown oil. The crude product is purified by Flash-chromatography (ethyl acetate, then methanol/ethyl acetate (4:6), silicagel).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:37])[N:7]([C:14]1([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:37])[N:7]([C:14]1([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13]
Reactant: [H][H]
Reactant: O=C1CCC(CCCCNC(=O)OCc2ccccc2)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)N1
Agent: [Ni]
Solvent: CCO
Product: Nc1cccc2c1C(=O)N(C1(CCCCNC(=O)OCc3ccccc3)CCC(=O)NC1=O)C2=O
Reaction time: 1.5 h
Yield: 0 %

Procedure:
To a suspension of 5 (0.24 g, 0.472 mmol) in ethanol (15 mL) was added Raney Nickel (W.R. Grace and Co. Raney® 4200, slurry, in H2O) under argon. The mixture was subsequently saturated with hydrogen using a hydrogen balloon. After 1.5 h, the mixture was flushed with argon, filtered using EtOH and concentrated. Purification by flash chromatography (95:5 DCM:MeOH) afforded 6 (0.112 mg, 49%) as a bright yellow solid. Rf=0.38 (95:5 DCM:MeOH). 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.09 (s, 1H), 9.04 (s, 1H), 7.71-7.52 (m, 2H), 7.49-7.18 (m, 5H), 7.10 (m, 1H), 5.07-4.85 (m, 2H), 2.96 (m, 2H), 2.55 (m, 2H), 2.44 (m, 1H), 2.22 (m, 2H), 2.02 (m, 1H), 1.40 (m, 2H), 1.22 (m, 2H). MS (ESI) m/z calcd for C25H27N4O6 [M+H]+ 479.5, found 479.9.
Reaction SMILES: C(OC(=O)CCSC1SC(NC([C:16]2[C:24]3[C:19](=[CH:20][C:21](C)=[CH:22][CH:23]=3)[N:18](CC3CC3)[CH:17]=2)=O)=NC=1)C.C1(CN2C3C(=CC=C(F)C=3)C(C(NC3SC=C(SCC(O)=O)N=3)=O)=C2)CC1>>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: CCOC(=O)CCSc1cnc(NC(=O)c2cn(CC3CC3)c3cc(C)ccc23)s1
Agent: O=C(O)CSc1csc(NC(=O)c2cn(CC3CC3)c3cc(F)ccc23)n1
Product: c1ccc2[nH]ccc2c1

Procedure:
3-{2-[(1-Cyclopropylmethyl-6-methyl-1H-indole-3-carbonyl)-amino]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester was hydrolysed according to the procedure given in the procedure for the synthesis of {2-[(1-cyclopropylmethyl-6-fluoro-1H-indole-3-carbonyl)-amino]-thiazol-4-ylsulfanyl}-acetic acid
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:12](=[CH2:22])[O:11][C@H:10]1[N:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25][C:24]1=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][CH2:32][O:33][P:34]([O:38][CH2:39][CH3:40])([CH2:36][OH:37])=[O:35].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClC(Cl)C>[CH2:32]([O:33][P:34]([CH2:36][O:37][C@:12]1([CH3:22])[C@@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C@H:10]([N:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[N:25][C:24]2=[O:30])[O:11]1)(=[O:35])[O:38][CH2:39][CH3:40])[CH3:31]
Reactant: C=C1O[C@@H](n2ccc(N)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CCOP(=O)(CO)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(Cl)Cl
Product: CCOP(=O)(CO[C@@]1(C)O[C@@H](n2ccc(N)nc2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C)OCC
Temperature: 60 °C
Yield: 25.1 %

Procedure:
To a solution of compound 30.3 (840 mg, 1.85 mmol) in dichloroethane (20 mL) was added diethyl (hydroxymethyl) phosphonate (0.41 mL, 2.87 mmol) and pyridinium p-toluene sulfonate (0.23 g, 0.92 mmol). The mixture was heated to 60° C. for 1 h and then concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 10% MeOH in CH2Cl2 to give compound 30.4 (289 mg, 24% yield). 1H NMR (300 MHz, CDCl3): δ0.04 (s, 3H), 0.08 (s, 3H), 0.10 (s, 6H), 0.89 (s, 9H), 0.92 (s, 9H), 1.38 (m, 6H), 1.49 (s, 3H), 3.93 (m, 1H), 4.14 (m, 2H), 4.20 (m, 1H), 4.38 (m, 1H), 5.83 (d, 1H, J=7.7), 6.08 (d, 1H, J=4.0), 7.99 (d, 1H, J=7.3). LRMS (ESI) MH+ C26H52N3O8PSi2 requires 622.9. Found 622.1.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[N:10]([O-])=O.[Na+].[Sn](Cl)Cl.[OH-].[Na+]>Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:10])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Cc1cc(Br)ccc1NN
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
4-bromo-2-methylaniline (2.0 g) was dissolved in conc. HCl (10 mL) and heated to 80° C. for 30 minutes. The reaction was cooled to 5° C. and a solution of sodium nitrite (781.0 mg in 4.0 mL of water) was added over 10 minutes. The resulting mixture was then stirred at 5° C. for 30 minutes. A solution of tin(II)chloride (15.3 g in 8 mL of concentrated HCl) was added over 10 minutes, and the resulting solution was stirred at room temperature for 45 minutes. The reaction was made basic with 50% NaOH solution and a white precipitate formed. The solid was filtered and the filtrate extracted with dichloromethane. The organic extract was dried over magnesium sulfate, filtered and concentrated to yield 1.08 g (50%) of 1-(4-bromo-2-methylphenyl)hydrazine as a white solid. LC-MS @ 201.1 (M+1)
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]=[O:27])[C:20]4=[N:19][C:18]=3[CH3:28])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[C:29]([Mg]Br)([CH3:32])([CH3:31])[CH3:30]>>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]([OH:27])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:20]4=[N:19][C:18]=3[CH3:28])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC(C)(C)[Mg]Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C=O)cccn34)c(C)nc12
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(O)C(C)(C)C)cccn34)c(C)nc12
Yield: 39.6 %

Procedure:
Using a procedure analogous to Example 41, 3-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-2-methyl-imidazo[1,2-a]pyridine-8-carbaldehyde (0.20 g, 0.53 mmol) and t-BuMgBr (2.0 M, 0.32 mL, 0.64 mmol) give the title compound (91.9 mg, 0.21 mmol, 66%). 1H NMR (CDCl3): δ 0.87-0.95 (m, 6H), 1.06 (s, 4.5H), 1.07 (s, 4.5H), 1.79-1.94 (m, 4H), 2.38 (s, 3H), 2.42 (s, 3H), 2.46 (s, 3H), 3.30-3.41 (m, 1H), 4.65-5.80 (m, 1H), 6.69-6.76 (m, 2H), 7.05 (bs, 1H), 7.43 (dd, J=13.7, 7.1 Hz, 1H) ppm. ES-MS (m/z): calcd for C26H35N5O (M+1)+: 434.6. found: 434.5.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:18][C@@H:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@H:20]1[NH:25]C(=O)OC(C)(C)C.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.[ClH:49]>CCCCO.C(Cl)Cl.CO.CCOCC>[ClH:49].[NH2:25][C@H:20]1[C@H:19]([CH3:18])[CH2:24][CH2:23][N:22]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[C:4]=23)[CH2:21]1
Reactant: C[C@@H]1CCNC[C@H]1NC(=O)OC(C)(C)C
Reactant: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](C)[C@H](N)C3)c12
Temperature: 146 °C
Reaction time: 24 h
Yield: 4 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (0.20 g, 0.67 mmol; Example 15, Step A), tert-butyl trans-4-methylpiperidin-3-ylcarbamate (0.43 g, 2.00 mmol; Example I) and DIEA (0.35 mL, 2.00 mmol) in n-BuOH (3 mL) was stirred at 146° C. (bath) for 24 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 10-80% CH3CN/water, 30 CV). The product isolated was dissolved in DCM (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 12M+, 0-80% CH3CN/water gradient, 20 CV). The product isolated was dissolved in MeOH (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected to give N-(4-(trans-3-amino-4-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride (0.011 g, 4%) as a solid. 1H NMR (400 MHz, D2O) δ 8.20 (s, 1H), 7.27 (s, 1H), 3.72 (m, 1H), 3.26 (m, 1H), 3.19 (m, 3H), 2.63 (m, 1H), 1.76 (m, 1H), 1.68 (m, 1H), 1.41 (m, 1H), 1.10 (t, 6H), 1.00 (d, 3H). LCMS (APCI+) m/z 394 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:12][C:13]([C:15]1[N:16]=[C:17]([CH2:36][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=1)=[CH:20][CH:19]=2)=[O:14])[CH2:5][C:6]1[S:7][C:8](Br)=[CH:9][CH:10]=1.[CH2:43]([Sn](CCCC)(CCCC)C(C)=C)[CH2:44][CH2:45]C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:12][C:13]([C:15]1[N:16]=[C:17]([CH2:36][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=1)=[CH:20][CH:19]=2)=[O:14])[CH2:5][C:6]1[S:7][C:8]([C:44]([CH3:45])=[CH2:43])=[CH:9][CH:10]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)s1)NC(=O)c1cc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2c(CC2CCCC2)n1
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=C(C)c1ccc(C[C@H](NC(=O)c2cc3cc(Oc4ccc(C(C)(C)C)cc4)ccc3c(CC3CCCC3)n2)C(=O)OC)s1

Procedure:
3-(5-Bromo-thiophen-2-yl)-2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid methyl ester (prepared in Example 38) was treated with tributyl-isopropenyl-stannane and Pd(PPh3)4 as described in the general procedure M to afford 2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropenyl-thiophen-2-yl)-propionic acid methyl ester. This was treated with Pd/C and H2 (1 atm) by the general procedure N to afford 2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid methyl ester. This ester was hydrolyzed by the general procedure C to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[O:5][CH:6]([CH2:10][O:11][CH3:12])[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.ClC1C=C(C(COC)C(Cl)=O)C=C(Cl)C=1.Cl.[NH2:39][C:40]([CH3:45])([CH3:44])[C:41]#[C:42][CH3:43].Cl>ClCCl.O.C(OCC)(=O)C.CCCCCC.C(N(CC)CC)C>[Cl:16][C:14]1[CH:13]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:15]=1)[O:5][CH:6]([CH2:10][O:11][CH3:12])[C:7]([NH:39][C:40]([CH3:45])([CH3:44])[C:41]#[C:42][CH3:43])=[O:9]
Reactant: COCC(Oc1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: CC#CC(C)(C)N
Agent: COCC(C(=O)Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CC(C)(C)NC(=O)C(COC)Oc1cc(Cl)cc(Cl)c1

Procedure:
The product from Stage 3 (0.44 g) was dissolved in dry dichloromethane (10 ml) with stirring and oxalyl chloride (0.212 g) was added. When no further gas was evolved the mixture was evaporated under reduced pressure to give a pale yellow oil which contained 2-(3,5-dichlorophenyl)-3-methoxypropionic acid chloride. The acid chloride was dissolved in dry dichloromethane (5 ml) and 4-amino-4-methylpent-2-yne hydrochloride (prepared as described below; 0.222 g) was added. The suspension was stirred at ambient temperature whilst triethylamine (0.48 ml) was added dropwise. The mixture was stirred for 3 hours, diluted with water, acidified with dilute aqueous hydrochloric acid (2M) then extracted with further dichloromethane. The organic extract was separated, washed with brine then dried over magnesium sulphate and evaporated under reduced pressure to give a gum. The gum was fractionated by chromatography (silica; hexane:ethyl acetate, 3:1 by volume) to give the required product as a colourless solid, 0.28 g, mp 107-110° C.