Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]4[C:18](=[C:19]([C:21]([OH:23])=[O:22])[CH:20]=3)[NH:17][N:16]=[CH:15]4)=[CH:10][NH:9][C:6]2=[CH:7][N:8]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:21]([OH:23])(=[O:22])[CH3:19].[CH2:24]([NH:31][C:21]([C:19]1[CH:20]=[C:12]([C:11]2[C:5]3[C:6](=[CH:7][N:8]=[C:3]([NH2:2])[CH:4]=3)[NH:9][CH:10]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][N:16]=[CH:15]2)=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: Nc1cc2c(-c3cc(C(=O)O)c4[nH]ncc4c3)c[nH]c2cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)O
Product: Nc1cc2c(-c3cc(C(=O)NCc4ccccc4)c4[nH]ncc4c3)c[nH]c2cn1
Reaction time: 1 h
Yield: 45.2 %

Procedure:
A solution of 5-(5-amino-1H-pyrrolo[2,3-c]pyridin-3-yl)-1H-indazole-7-carboxylic acid hydrochloride (Preparation #13, 32.9 mg, 0.10 mmol) and benzylamine (24.0 μL, 0.22 mmol) in DMF (1.0 mL) were treated with o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (38.0 mg, 0.10 mmol) at ambient temperature and the reaction was stirred for about 1 hour. The reaction was concentrated under reduced pressure and the residue was purified by preparative HPLC (Waters Symmetry C8 column (25×100 mm, 7 μm particle size) using a gradient of 10%-100% CH3CN/0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL/min). Product fractions were combined and concentrated to remove organic solvents and then lyophilized to yield N-benzyl 5-(5-amino-1H-pyrrolo[2,3-c]pyridin-3-yl)-1H-indazole-7-carboxamide acetate (10 mg, 23%) as an off-white powder; RP-HPLC (Table 1, Method e) Rt 1.94 min; m/z: (M−H)− 381.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40](=[O:51])[CH2:41][CH2:42][O:43]CC4C=CC=CC=4)=[CH:35][CH:34]=3)[CH:23]=[C:24]([O:26]COCCOC)[CH:25]=2)=[CH:16][CH:15]=1)=[O:12])C1C=CC=CC=1.C1COCC1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(O)(C)C.CCOCC>[OH:26][C:24]1[CH:25]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][C:11](=[O:12])[CH2:10][CH2:9][OH:8])=[CH:15][CH:16]=2)[CH:21]=[C:22]([C:33]2[CH:34]=[CH:35][C:36]([O:39][C:40](=[O:51])[CH2:41][CH2:42][OH:43])=[CH:37][CH:38]=2)[CH:23]=1
Reactant: COCCOCOc1cc(-c2ccc(OC(=O)CCOCc3ccccc3)cc2)cc(-c2ccc(OC(=O)CCOCc3ccccc3)cc2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CCO)Oc1ccc(-c2cc(O)cc(-c3ccc(OC(=O)CCO)cc3)c2)cc1
Temperature: 70 °C
Reaction time: 60 h

Procedure:
5.40 g (7.82 mmol) 3-benzyloxy-propionic acid-4″-(3-benzyloxy-propionyloxy)-5′-(2-methoxy-ethoxymethoxy)-[1,1′;3′,1″]terphenyl-4-yl ester are dissolved in 40 ml isopropanol and 10 ml THF and after addition of 1.97 g (7.82 mmol) pyridiniumtosylate are stirred for 60 h at 70° C. After cooling to RT the mixture is diluted with MTB ether, washed with sat. aq. sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and the residue is hydrogenated in 40 ml THF on Pd/activated charcoal until the reaction is completed. The solvent is removed in vacuo and the crude product is recrystallized from dichloromethane, to give 3-hydroxy-propionic acid-5′-hydroxy-4″-(3-hydroxy-propionyloxy)-[1,1′;3′,1″]terphenyl-4-yl ester as colourless crystals.
Reaction SMILES: [C:1]([O-])(=[O:12])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH3:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH2:1]([OH:12])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCC=CCC=C/C=C/C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCC=CCC=C/C=C/CO
Yield: 78 %

Procedure:
To a solution of ethyl trans, trans, trans-2,4,7-undecatrienoate (4.7 g) in dry ether (200 ml) was added with stirring lithium aluminum hydride (1 g) under ice-cooling little by little. The mixture was stirred for an hour at the same temperature. To the resultant mixture was added ether containing water to give insoluble materials, which were removed by filtration. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give colorless oily trans, trans, trans-2,4,7-undecatrien-1-ol (3.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26]C=3)(=[O:22])=[O:21])[CH:16]([CH3:30])[CH2:15]2)[CH:3]=1.C1(S(Cl)(=O)=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=3)(=[O:21])=[O:22])[CH:16]([CH3:30])[CH2:15]2)[CH:3]=1
Reactant: CC1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1S(=O)(=O)Cc1ccccc1
Agent: O=S(=O)(Cl)c1ccccc1
Product: CC1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1S(=O)(=O)c1ccccc1

Procedure:
Prepared by the method of example 30, using the product from example 56 part (a) and is benzenesulfonyl chloride to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C:3]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:11]=2)[C@H:6]1[CH3:23])=[O:4].Br[C:27]1[C:36]([O:37][CH:38]([F:40])[F:39])=[C:35]2[C:30]([C:31](=[O:49])[C:32]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:33][N:34]2[CH:41]2[CH2:43][CH2:42]2)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C.[Pd].CC(C)=O>[CH:41]1([N:34]2[C:35]3[C:30](=[CH:29][CH:28]=[C:27]([C:10]4[CH:11]=[C:12]5[C:7](=[CH:8][CH:9]=4)[C@@H:6]([CH3:23])[N:5]([C:3](=[O:4])[C:2]([CH3:1])([CH3:24])[CH3:25])[CH2:13]5)[C:36]=3[O:37][CH:38]([F:40])[F:39])[C:31](=[O:49])[C:32]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:33]2)[CH2:42][CH2:43]1
Reactant: C[C@@H]1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1C(=O)C(C)(C)C
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(Br)ccc2c1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(-c3ccc4c(c3)CN(C(=O)C(C)(C)C)[C@@H]4C)ccc2c1=O
Yield: 96 %

Procedure:
In 15 ml of ethanol is dissolved 2.5 g of (R)-2-(2,2-dimethylpropanoyl)-1-methyl-5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)isoindoline, and thereto are added 2.8 g of ethyl 7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate and 1.1 g of sodium carbonate. Subsequently, 150 mg of 10% palladium-activated carbon is added to the mixture in a nitrogen atmosphere and thereafter the resulting mixture is heated under reflux for 3 hours in the same atmosphere. The reaction mixture is cooled and thereafter added to a mixed solvent of 15 ml of water and 30 ml of acetone, and the crystals deposited are collected by filtration to obtain 3.6 g of ethyl(R)-1-cyclopropyl-8-difluoromethoxy-7-[2-(2,2-dimethylpropanoyl)-1-methyl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[C:16](#[N:18])[CH3:17]>Cl>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[O:3][C:2]([NH:18][C:16]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:17]=3[CH2:5][CH:4]([OH:3])[CH2:8][CH2:9]4)=[N:6][C:5]=2[CH3:7])=[CH:9][CH:10]=1
Reactant: CC#N
Reactant: COc1ccc(-c2oc(Cl)nc2C)cc1
Agent: Cl
Product: COc1ccc(-c2oc(Nc3cccc4c3CC(O)CC4)nc2C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 9 %

Procedure:
A mixture of Example 14D (0.840 g, 3.76 mmol) and Example 1A (1.04 g, 3.76 mmol) in acetonitrile (19 mL) was heated in a microwave reactor at 150° C. for 20 minutes. Two drops of aqueous concentrated HCl were added and the reaction was reheated in the microwave to 150° C. for 20 min. The volatiles were evaporated and the crude material was dissolved in tetrahydrofuran (20 mL), followed by addition of 10 mL 6N HCl. The mixture was stirred overnight at ambient temperature, then diluted with ethyl acetate. The organic phase was washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by chromatography on silica gel using methanol/CH2Cl2 as eluent (2% to 20%), followed by triturating with diethyl ether to afford 122 mg (9% yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.60 (d, J=7.93 Hz, 1H), 7.42 (d, J=9.12 Hz, 2H), 7.04 (m, 3H), 6.81 (d, J=7.54 Hz, 1H), 4.80 (d, J=3.97 Hz, 1H), 3.92 (bs, 1H), 3.78 (s, 3H), 2.90 (m, 2H), 2.75 (m, 1H), 2.22 (s, 3H), 1.87 (bs, 1H), 1.62 (bs, 1H). MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: F[C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([CH3:21])[C:5]([C:19]#[N:20])=[C:6]2[C:10]=1[O:9][C:8]([N:11]([CH3:18])[CH2:12][C:13]1[NH:17][N:16]=[CH:15][N:14]=1)=[N:7]2.C(N(CC)CC)C.[CH3:35][N:36]([CH3:42])[C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>CS(C)=O.ClCCl>[CH3:35][N:36]([CH3:42])[C@H:37]1[CH2:41][CH2:40][N:39]([C:2]2[C:3]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:4]([CH3:21])[C:5]([C:19]#[N:20])=[C:6]3[C:10]=2[O:9][C:8]([N:11]([CH3:18])[CH2:12][C:13]2[NH:17][N:16]=[CH:15][N:14]=2)=[N:7]3)[CH2:38]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N(C)Cc3ncn[nH]3)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N(C)Cc3ncn[nH]3)nc2c1C#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 43.1 %

Procedure:
7-Fluoro-5-methyl-2-[methyl(1H-1,2,4-triazol-5-ylmethyl)amino]-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-165) (0.24 g, 0.66 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (0.19 ml, 1.37 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.17 ml, 1.34 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours. This was diluted with dichloromethane, and washed with water and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1), then diisopropyl ether was added and the insoluble matter was collected by filtration to obtain a beige solid (0.13 g, 42%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21](C)P(N(C)C)(N(C)C)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1([C:20]#[N:21])[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: Brc1ccc(OCc2ccccc2)c2c1CCCC2
Solvent: ClCCl
Product: N#CC1(OCc2ccccc2)CC=CC2=C1CCCC2

Procedure:
1-Benzyloxy-4-bromo-5,6,7,8-tetrahydronaphthalene (4.5 g, 14.2 mM), cuprous cyanide (1.71 g, 8.67 mM) pyridine (1 ml) and hexamethylphosphoramide (0.25 ml) was stirred at 170° C. for 16 hours. The resultant viscous mixture was dissolved in methylene chloride and washed with ammonium hydroxide solution, saturated brine solution, dried (sodium sulphate) and evaporated to give an oil (4.6 g). This oil was chromatographed on alumina (eluted with methylene chloride:petroleum ether, 1:1) to give the nitrile (5) as a solid (2.4 g) m pt 74°-75° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[C:18]([O:19][CH3:20])=[CH:17][C:16]2[NH:15][C:14]3[CH:13]=[CH:12][C:11]4[C:21](=[O:24])[CH2:22][CH2:23][C:10]=4[C:9]=3[C:8]=2[CH:7]=1)(=[O:5])[CH3:4].[H][H].Cl.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32]Cl.Cl>C(Cl)Cl>[C:3]([C:6]1[C:18]([O:19][CH3:20])=[CH:17][C:16]2[N:15]([CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])[C:14]3[CH:13]=[CH:12][C:11]4[C:21](=[O:24])[CH2:22][CH2:23][C:10]=4[C:9]=3[C:8]=2[CH:7]=1)(=[O:5])[CH3:4]
Reactant: COc1cc2[nH]c3ccc4c(c3c2cc1C(C)=O)CCC4=O
Reactant: [H][H]
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(cc1C(C)=O)c1c3c(ccc1n2CCCN(C)C)C(=O)CC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
NaH (6.88 g of 60%, 171.95 mmol, 2.5 eq) was added to a suspension of 9-acetyl-8-methoxy-1,2-dihydro-6H-cyclopenta[c]carbazole-3-one (83) (26 g, 68.78 mmol, 1 eq) in dry CH2Cl2 (300 mL), and the mixture was stirred at room temperature for 20-30 min until the evolution of hydrogen ceased. 3-Dimethylaminopropylchloride hydrochloride (16.3 g, 103.16 mmol, 1.5 eq) was added portionwise under nitrogen. The reaction mixture was stirred for 30 min at room temperature, then at 60° C. for 24 h and poured into ice water (4 L). The aqueous solution was acidified to pH about 2 with conc. HCl and the unreacted starting material extracted with EtOAc/THF=3/1 mixture. Upon adjusting the pH of the water layer to about 9, the product was extracted with 1:1 EtOAc:THF mixture (10×500 mL). The combined extracts were washed with brine, dried over Na2SO4 and solvent evaporated out to afford 22 g (68%) of crude carbazole (84), reasonable pure by LC/MS. It was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:7][CH:6]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])[CH2:18][CH2:17]1>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]([OH:13])[CH2:12][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:27][CH2:26][CH2:25][NH:24][C:23]3=[O:28])[CH2:18][CH2:17]2)=[CH:7][CH:6]=1
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: COCCc1ccc(OCC2CO2)cc1
Solvent: CCO
Product: COCCc1ccc(OCC(O)CN2CCC(N3CCCNC3=O)CC2)cc1

Procedure:
A solution of 10.4 g of 1-[p-(2-methyoxyethyl)-phenoxy]-2,3-epoxy-propane and 9.15 g of 1-(4-piperidyl)-2-oxo-hexahydropyrimidine in 7 ml of abs. ethanol is heated for 5 hours to 95° C and then evaporated in vacuo. The residue is recrystallised from ethyl acetate/petroleum ether to yield the 1-[3-(p-(2-methoxyethyl)-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 113°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2ylmethyl)-4-carboxybenzamide, pyrrolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.43 minutes; C20H18Cl2N4O2 (417.29); mass spectrum: (M+H)+=417.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[OH:24][C:25]([C:28]1[S:29][C:30]([C:33](O)=[O:34])=[CH:31][N:32]=1)([CH3:27])[CH3:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:33]([C:30]5[S:29][C:28]([C:25]([OH:24])([CH3:26])[CH3:27])=[N:32][CH:31]=5)=[O:34])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)(O)c1ncc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(O)c1ncc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)s1
Yield: 42.2 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol), 2-(1-hydroxy-1-methylethyl)-1,3-thiazole-5-carboxylic acid (96 mg, 0.51 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (95 mg, 0.50 mmol), 1-hydroxybenzotriazole (67 mg, 0.50 mmol) and N,N-dimethylformamide (8.0 mL) as starting materials and in the same manner as in Example 318, the title compound (99 mg, 43%) was obtained as a white powder.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.C([O-])(=O)C.[Na+].[Br:22]Br>C(O)(=O)C.O>[ClH:1].[Br:22][C:10]1[CH:9]=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: COc1cccc(N2CCNCC2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N2CCNCC2)ccc1Br
Reaction time: 1 h

Procedure:
To a solution of 2.33 g (8.8 mmol) of 1-(3-Methoxyphenyl)piperazine dihydrochloride and 756 mg (9.7 mmol) sodium acetate in 70 mL of acetic acid and 15 mL of water at 0° C. was added 1.55 g (9.7 mmol) bromine. After 1 hour, the reaction was concentrated to an oil in vacuo, and the oil was partitioned between ethyl acetate and 1M NaOH. The phases were separated, and the ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to an oil in vacuo. The oil was dissolved in a minimum volume of methanol, and the solution was acidified with 2M HCl in ether. The product was isolated by filtration. 1H NMR (D2O, 400 MHz) 7.36 (d, 1H), 6.73 (s, 1H), 6.50 (d, 1H), 3.75 (s, 3H), 3.32 (m, 8H) ppm.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.Br[CH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([O:24][CH3:25])[N:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)(Cl)Cl>[NH2:2][CH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([O:24][CH3:25])[N:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CCOC(=O)c1cc(CBr)nc(OC)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(CN)nc(OC)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
6.72 g (47.9 mmol) of hexamethylenetetramine (urotropin) were initially introduced in 250 ml of chloroform and a solution of 10.95 g (39.95 mmol) of ethyl 2-bromomethyl-6-methoxyisonicotinate (20c) in chloroform was added dropwise at 0° C. The mixture was stirred at RT for 4.5 hours and after this a further 3.36 g (24.0 mmol) of hexamethylenetetramine (urotropin) was added. After standing at RT for a further 60 hours, the solvent was distilled off under reduced pressure and the residue was dissolved in 500 ml of ethanol. 50 ml of concentrated HCl were added and the mixture was stirred at RT for two hours. After addition of a further 30 ml of concentrated HCl and stirring at RT overnight, it was freed from the solvent under reduced pressure. The residue was taken up in DCM and carefully treated with K2CO3 until evolution of gas was no longer observed. Subsequently, it was washed twice with saturated K2CO3 solution, and the organic phase was dried with MgSO4 and concentrated. The crude product thus obtained (7.60 g) was reacted further without further purification. LCMS-Rt: 0.74 min [M+H+]: 211.2
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])=[O:25])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[Cl:15])=[O:7].O[Li].O.C(O)(=O)C>C1COCC1.O>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([NH:5][C@H:4]([C:3]([OH:34])=[O:2])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])=[O:25])=[CH:21][CH:22]=2)=[O:7])=[C:9]([Cl:15])[CH:10]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(N)cc1Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
A solution of N-[(4-amino-2-chlorophenyl)carbonyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (66 mg, 0.126 mmol) in THF (3 mL) was treated with a solution of LiOH.H2O (20 mg, 0.48 mmol) in water (0.5 mL) and the mixture was stirred over night at room temperature. Acetic acid (0.5 mL) was added and the mixture was purified directly by RP-HPLC (5-95-35-214) to give 40 mg of a white solid. HRMS: (C23H18Cl3N3O4): Obs. Mass 506.0461. Calcd. Mass 506.0441 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[Si:12]([CH3:15])([CH3:14])[CH3:13])[CH3:2].[CH3:19]I>>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4](=[O:16])[C:5]1[C:6]([Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:8]([CH3:11])=[CH:9][C:10]=1[CH3:19])[CH3:18]
Reactant: CCN(CC)C(=O)c1ccc(C)cc1[Si](C)(C)C
Reactant: CI
Product: CCN(CC)C(=O)c1c(C)cc(C)cc1[Si](C)(C)C

Procedure:
The title compound was prepared from the compound of Example 58 and MeI (4.0 eq) according to General Method A. Purification by HPLC with 3:17 ethyl acetate/hexanes gave 1.4 g of the title compound as a clear oil, an 83% yield.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1.C([BH3-])#N.[Na+].[CH3:30][C:31]([CH3:33])=O.C(#N)C>C(Cl)(Cl)Cl.[B].C(O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][C@@H:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:10][C@@H:2]3[NH:1][CH:31]([CH3:33])[CH3:30])=[CH:13][CH:14]=2)=[CH:20][CH:21]=1
Reactant: CC(C)=O
Reactant: N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Oc2ccc(F)cc2)cc1
Agent: [BH3-]C#N
Agent: [B]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CC#N
Product: CC(C)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Oc2ccc(F)cc2)cc1
Yield: 53 %

Procedure:
The title compound was prepared in a similar manner to Example 31 from (±) cis-2-amino-1-[4-(4-fluorophenoxy)phenoxy]indane (70 mg, 0.2 mmol), sodium cyanoborohydride (25 mg, 0.4 mmol), acetone (0.29 ml, 4 mmol) and acetonitrile (10 ml). After subjecting the crude product to column chromatography on silica gel eluting with 5% ethanol in chloroform, residual boron impurities were removed by dissolving the product in hexanes and filtering. Removal of the hexanes in vacuo afforded the title compound (40 mg) as a colourless oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][CH2:9][C:10]([N:12]1[CH2:16][C@H:15]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C@H:13]1[C:26]([OH:28])=[O:27])=[O:11]>C(O)=O>[C:18]([NH:17][C@H:15]1[CH2:16][N:12]([C:10](=[O:11])[CH2:9][NH:8][CH:1]=[O:3])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:14]1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Solvent: O=CO
Product: O=CNCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.6 %

Procedure:
Acetic anhydride (Acros) (0.32 mL, 3.4 mmol, 10 equivalents) was added dropwise to a solution of (2S4R) 1-(2-Amino-acetyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid (Compound 2, 0.1 g, 0.34 mmol, 1 equivalent) in formic acid (J. T. Baker) (1 mL) at 0° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred an additional 24 hours. The reaction mixture was monitored by TLC and LCMS. An additional amount of acetic anhydride (0.32 mL, 3.4 mmol, 10 equivalents) was added and the reaction mixture stirred for 24 hours at room temperature. Ice-water (1 mL) was added and the volatiles were removed in vacuo to yield an oily crude product that was further purified by HPLC (column: Waters Atlantis 19×150 mm) using 0.1% formic acid in H2O/MeOH 20-40% MeOH over 15 minute gradient to afford 0.031 g (29%) of the desired product.