Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.P(Br)(Br)[Br:17]>CCOCC>[Br:17][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: BrP(Br)Br
Reactant: CCCCCC#CCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCC#CCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 202.6 %

Procedure:
A solution of 2-octyne-1-ol (37.8 g) in ether (150 mL) containing pyridine (3 ml) was cooled to -35° and treated with a solution of phosphorous tribromide (28.9 g) over 45 min. The mixture was then stirred at -30° for 2 hours, 3 hours at room temperature and 1/2 hour at 40°. The reaction mixture was then cooled to room temperature, poured onto ice and extracted with ether. The combined ether extracts were washed with aqueous NaHCO3 solution, brine and dried (MgSO4). Removal of the solvents and distillation of the residue yielded 1-bromo-2-octyne (40.9 g), bp, 106°-110° (25 mmHg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH2:32])[CH3:28].C(OCC)(=O)C>[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[O:5])[CH3:2]
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(CCCNCCN(CC)CC)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 25 °C

Procedure:
5-(3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 g (8.24 g, 21 mmol) was dissolved in N,N-diethylethylenediamine (15 ml, 100 mmol) under stirring at room temperature, and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with 100 ml of ethyl acetate and 100 ml of saturated brine, stirred for 5 minutes, and separated into layers. The organic phase was washed with saturated brine (100 ml×4), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain brown oil. The residue was purified by silica gel column chromatography to obtain the title compound 5-[3-(2-diethylamino-ethylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 h (8.2 g, yield 95%) as a colorless oil.
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH:43]2[CH2:45][CH:40]1[CH2:41][NH:42]2)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH:43]2[CH2:45][CH:40]1[CH2:41][N:42]2[C:22]([C:21]1[CH:20]=[N:19][C:18]([NH:17][C:14]2[N:15]=[CH:16][C:11]3[CH:10]=[C:9]([C:27](=[O:31])[N:28]([CH3:29])[CH3:30])[N:8]([CH:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:12]=3[N:13]=2)=[CH:26][CH:25]=1)=[O:24])=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CC4CN5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCCCC1
Yield: 72.6 %

Procedure:
Following general amide formation method 1, 6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (52.5 mg, 0.124 mmol, 1.0 eq) was combined with 2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (32.0 mg, 0.162 mmol, 1.5 eq) which gave 5-[6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (59 mg, 0.09 mmol, 76% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 9.12 (br s, 1H) 8.85 (s, 1H) 8.73 (br s, 1H) 8.61 (br s, 1H) 7.98 (br s, 1H) 6.48 (s, 1H) 4.47-4.65 (m, 2H) 3.72 (br s, 1H) 3.52-3.69 (m, 2H) 3.46 (t, J=8.59 Hz, 1H) 3.18 (s, 6H) 2.58-2.74 (m, 2H) 1.99-2.09 (m, 2H) 1.83-1.99 (m, 5H) 1.65-1.83 (m, 4H) 1.55-1.65 (m, 2H) 1.37-1.55 (m, 9H)
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][C:6]([F:9])([F:8])[CH2:5][CH:4]1[NH:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[N:22]=[CH:21][CH:20]=[N:19]1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:8][C:6]1([F:9])[CH2:5][CH:4]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[N:19]=[CH:20][CH:21]=[N:22]2)[CH:3]([NH:2][C:25]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:7]1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: NC1CC(F)(F)CC1NC(=O)c1ccccc1-n1nccn1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC(F)(F)CC1Nc1ncc(C(F)(F)F)cn1)c1ccccc1-n1nccn1
Temperature: 140 °C

Procedure:
To a solution of N-(2-amino-4,4-difluorocyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 42; 120 mg, 0.39 mmol) in dry DMSO (1.2 ml) was added 2-chloro-5-(trifluoromethyl)pyrimidine (CAS number 69034-12-4; 70 mg, 0.384 mmol) and DIPEA (183 μl, 1.047 mmol). The reaction mixture was heated in a sealed vial at 140° C. for 17 hours then partitioned between ethyl acetate and water. The organics were washed with water, filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) then was chirally separated using SFC (Waters prep30/MS system using 20% Isopropanol, Daicel AD 10 mm id×250 mm long columns at 30 ml/min, 40° C. and 100 bar) to afford the title compound as a single enantiomer.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18]2[C:23]([CH2:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:26][CH3:27])=[N:12][CH:11]=1>C1COCC1.CCOCC>[CH2:26]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH2:24][CH3:25])[C:18]=1[C:13]1[N:12]=[CH:11][C:10]([CH2:9][OH:8])=[C:15]([O:16][CH3:17])[CH:14]=1)[CH3:27]
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1-c1cc(OC)c(CO)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of LiAlH4 (1 M in THF, 15 mL) is added dropwise to a solution of 6-(2,6-diethyl-phenyl)-4-methoxy-nicotinic acid methyl ester (1.5 g, 5 mmol) in THF (10 mL). The reaction mixture is stirred at room temperature for 6 hours, then diluted with ether (10 mL) and quenched with Na2SO4.10H2O (10 g). The resulting mixture is stirred for one hour, filtered through celite and concentrated to give [6-(2,6-diethyl-phenyl)-4-methoxy-pyridin-3-yl]-methanol. 1H NMR (CDCl3) 8.47 (s, 1H), 7.28 (t, 1H), 7.13 (d, 2H), 6.79 (s, 1H), 4.72 (s, 2H), 3.89 (s, 3H), 2.55 (br, 1H), 2.34 (m, 4H), 1.06 (t, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:16])[C:7]2=[O:15].[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:17][O:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:16])[C:7]2=[O:15]
Reactant: O=C([O-])[O-]
Reactant: CN1CCc2c(O)ccc([N+](=O)[O-])c2C1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c2c1CCN(C)C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a stirring solution of 5-Hydroxy-2-methyl-8-nitro-3,4-dihydro-2H-isoquinolin-1-one (444 mg, 2.0 mmol) and in DMF (5 mL) is added potassium carbonate (553 mg, 4.0 mmol.) and the solution cooled to 0° C. Iodomethane (0.25 mL, 4.0 mmol.) is added and the reaction mixture allow to warm to room temperature and then stirred for 1 hour. The mixture is quenched with a cold water and then the precipitate is filtered, washed with water and dried under vacuum to give a white solid corresponding to 5-methoxy-2-methyl-8-nitro-3,4-dihydro-2H-isoquinolin-1-one (336 mg, 71%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:12][CH:11]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:41]1[CH:45]=[CH:44][N:43]=[CH:42]1>CN(C)C=O.[Cu]I>[N:41]1([C:2]2[CH:3]=[CH:4][C:5]([CH3:34])=[C:6]([NH:8][C:9](=[O:33])[C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]4[N:26]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=4)=[CH:12][CH:11]=3)[CH:7]=2)[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(Br)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccnc2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 110 °C
Yield: 16 %

Procedure:
A mixture of N-(5-bromo-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (198 mg, 0.39 mmol), prepared as described in Example 14, copper (I) iodide (90 mg, 0.47 mmol), 1S,2S—N1,N2-dimethylcyclohexane-1,2-diamine (25 mg, 0.17 mmol), cesium carbonate (270 mg, 0.83 mmol) and imidazole (40 mg, 0.59 mmol) in dimethylformamide (400 μL) were combined in a sealed tube under an atmosphere of nitrogen and heated to 110° C. overnight. Upon cooling to rt, the reaction mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. Insoluble material was filtered and the two layers of filtrate were separated. The aqueous phase was further extracted with ethyl acetate, and the combined organic layers were washed with saturated sodium chloride, dried over sodium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by preparative reverse phase HPLC to give N-[5-(1H-imidazol-1-yl)-2-methylphenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (31 mg, 16%). 1H NMR (400 MHz, DMSO-d6): δ 10.37 (s, 1H), 9.88 (s, 1H), 8.26 (s, 1H), 8.20 (d, 2H), 8.02 (d, 2H), 7.90-7.70 (m, 8H), 7.65 (m, 2H), 7.45 (m, 3H), 7.12 (s, 1H), 2.30 (s, 3H). MS (EI) for C31H24N6O: 497.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]1[CH:9]=[C:8]3[C:21]([CH3:29])([CH3:28])[C:22]4[C:27]([C:7]3=[CH:6][C:5]2=1)=[CH:26][CH:25]=[CH:24][CH:23]=4.[Li]CCCC.[B:35](OC)([O:38]C)[O:36]C>C1COCC1>[B:35]([C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]1[CH:9]=[C:8]3[C:21]([CH3:29])([CH3:28])[C:22]4[C:27]([C:7]3=[CH:6][C:5]2=1)=[CH:26][CH:25]=[CH:24][CH:23]=4)([OH:38])[OH:36]
Reactant: CC1(C)c2ccccc2-c2cc3c4cc(Br)ccc4n(-c4ccccc4)c3cc21
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)c2ccccc2-c2cc3c4cc(B(O)O)ccc4n(-c4ccccc4)c3cc21
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 77.8 %

Procedure:
22.3 g (51 mmol) of 7-bromo-12,12-dimethyl-10-phenyl-10,12-dihydro-10-azaindeno[2,1-b]fluorene 12 are dissolved in 600 ml of dry THF and cooled to −78° C. At this temperature, 26.2 ml (65.7 mmol/2.5 M in hexane) of n-BuLi are added over the course of about 5 min., and the mixture is subsequently stirred at −78° C. for a further 2.5 h. At this temperature, 7.3 ml (65.7 mmol) of trimethyl borate are added as rapidly as possible, and the reaction is allowed to come slowly to RT (about 18 h). The reaction solution is washed with water, and the precipitated solid and the organic phase are dried azeotropically with toluene. The crude product is washed by stir-ring with toluene/methylene chloride at about 40° C. and filtered off with suction, giving 16 g (82%) of the product as white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[C:5]([CH3:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCCCCC>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[O:22][C:6]1[C:5]([CH3:10])=[CH:4][C:3]([N+:11]([O-:13])=[O:12])=[C:2]([CH3:1])[C:7]=1[Cl:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Cl
Reactant: Cc1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1ccc(Oc2c(C)cc([N+](=O)[O-])c(C)c2Cl)c(C)c1
Yield: 69.6 %

Procedure:
Into a round bottom reaction flask equipped with a magnetic stirrer, condenser, thermometer and nitrogen inlet was added 50.0 grams (0.23 mol) of 2,5-dimethyl-3,4-dichloronitrobenzene, 38.5 grams (0.32 mol) of 2,4-dimethylphenol, 50 grams (0.36 mol) of potassium carbonate and 125 milliliters of dimethylformamide. The reaction mixture was heated to a temperature of 90° C.-100° C. and maintained at this temperature for a period of 72 hours. The reaction mixture was then cooled, filtered and concentrated to give a dark oil. The dark oil was partitioned between toluene (300 milliliters) and 4% sodium hydroxide (250 milliliters) and then separated. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to give a dark oil. The dark oil was trituated with hexane and a solid was formed. The solid was washed with cold hexane and vacuum dried to give 47.8 grams (0.16 mol) of 4-(2,4-dimethylphenoxy) 2,5-dimethyl-3-chloronitrobenzene as a tan powder having a melting point of 78° C.-80° C. Elemental analysis of the tan powder indicated the following:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][N:46]=1>C1COCC1.C(N(C(C)C)C(C)C)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:16][C:49]([C:48]2[CH:47]=[N:46][C:45]([Cl:44])=[CH:53][CH:52]=2)=[O:50])([C:14]#[N:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
To a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (0.527 g, 2.34 mmol, 1.0 equiv; prepared as described in WO 03/104 236 A1 (Bristol-Myers Squibb Company); [CAS RN 331281-25-5]) in anhydrous THF (12 mL) and N-ethyl diisopropylamine (0.48 mL) was added in the presence of (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (1.138 g, 2.58 mmol, 1.1 equiv; BOP reagent) 6-chloro-nicotinic acid (0.369 g, 2.34 mmol, 1.0 equiv) and the reaction mixture stirred at rt for 12 h. The reaction mixture was poured on crashed ice/NH4Cl, extracted with ethyl acetate (2×200 mL) and the combined organic phases washed with a sat. solution of NaCl (2×100 mL) and water (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluting with a mixture of ethyl acetate/triethylamine (97:3) providing 0.63 g (74%) of the title compound as off-white solid. MS (ISP): 365.1 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH2:14].CC(O)=O.[O-:20][C:21]#[N:22].[K+].[O-]C#N>O>[NH2:22][C:21]([NH:14][C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:4]=1[C:3]([O:2][CH3:1])=[O:15])=[O:20]
Reactant: N#C[O-]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(C(=O)OC)c(NC(N)=O)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a 1 L flask charged with 2-aminoterephthalic acid dimethyl ester (29.4 g, 141 mmol) was added AcOH (160 mL) and the suspension heated to 60° C. until a solution was formed. A solution of potassium cyanate (23.4 g, 288 mmol) in water (50 mL) was then added to the stirred solution at 60° C. Effervescence was seen and a white ppt crashed out immediately, hindering stirring. AcOH was added (70 mL) to aid stirring and the suspension was stirred at 75° C. for 7 hrs. Another 1 eq of cyanate added portion wise (dry). More effervescence was seen and the reaction left for 16 hours at 70° C. The reaction was cooled to 0° C. and the product ppt was filtered off, the flask washed with water to get all product out. The material was washed with water (150 mL) and air dried o/n under vacuum. The crude product was suspended in MeOH (300 mL) and stirred under reflux for 1 hour. The suspension was cooled to room temperature and filtered. The product was washed with cold MeOH (300 mL) and ether and dried in vacuo to afford the title compound as a white solid, 31.5 g, 89%. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.71 (1H, s) 8.97 (1H, s) 7.98 (1H, d, J=8.08 Hz) 7.46-7.57 (1H, m) 6.73 (2H, s) 3.88 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH2:18][CH2:17]2)=[CH:3][C:2]=1[NH:1][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1OCc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCN(c2ccc(OCc3ccccc3)c(Nc3ccccc3)c2)CC1
Reaction time: 12 h
Yield: 72.7 %

Procedure:
To a stirred solution of (4-(3-amino-4-(benzyloxy)phenyl)piperazin-1-yl)(phenyl) methanone (1 g, 2.58 mmol) and phenylboronic acid (0.94 g, 7.74 mmol) in DCM (100 mL) was added triethylamine (1.0 mL, 7.74 mmol) and Cu(OAc)2 (0.7 g, 3.87 mmol). The mixture was stirred for 12 h. It was then filtered through celite, evaporated under vacuum. Flash column chromatography gave (4-(4-(benzyloxy)-3-(phenylamino) phenyl) piperazin-1-yl) (phenyl)methanone (0.87 g), 82% yield. 1H NMR (500 MHz, DMSO): δ 3.01 (bs, 2H), 3.16 (bs, 2H), 3.59 (bs, 2H), 3.95 (bs, 2H), 5.10 (s, 2H), 6.20 (s, 1H), 6.42 (dd, J=2.5, 3 Hz 1H), 6.91 (d, J=8.5 Hz, 1H), 7.01 (m, 2H), 7.17 (d, J=8.0 Hz, 2H), 7.32 (m, 2H), 7.37 (m, 10H). HRMS (ESI) calculated for C30H30N3O2: 464.2333, Found: 464.2338.
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:24][OH:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[CH3:26][S:27]([O:25][CH2:24][C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCNC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)COS(C)(=O)=O
Reaction time: 3 h

Procedure:
A solution of Nα-Boc-Nδ-Cbz-ornithinol (363 mg) in dichloromethane (10 ml) at 0° C., under nitrogen atmosphere, was treated sequentially with methanesulfonyl chloride (110 μl, 1.4 eq) and triethylamine (200 μl, 1.4 eq). After 3 hrs, the solution was poured into dichloromethane and worked up as usual. The crude product, which is very pure (400 mg), is a white solid: 1H NMR (400 MHz, CDCl3) δ1.45 (s, 9H), 1.63 (m, 4H), 3.02 (s, 3H), 3.24 (m, 2H), 3.84 (m, 1H), 4.19 (dd, J=9.5; 3.7 Hz, 1H), 4.23 (d, J=9.5 Hz, 1H), 5.14 (s, 2H), and 7.39 (m, 5H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH:3]1[C:14]([O:16][CH3:17])=[O:15].[CH3:18][C:19]1[CH:28]=[C:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](Cl)=[O:40])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:26]2[CH2:25][CH:24]=[CH:23][CH2:22][C:21]=2[N:20]=1>C(Cl)Cl.O>[CH3:18][C:19]1[CH:28]=[C:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39]([NH:1][CH:2]4[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH:3]4[C:14]([O:16][CH3:17])=[O:15])=[O:40])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CC1N
Reactant: Cc1cc(Cn2ccc3cc(C(=O)Cl)ccc32)c2c(n1)CC=CC2
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CC1NC(=O)c1ccc2c(ccn2Cc2cc(C)nc3ccccc23)c1
Reaction time: 3.5 h
Yield: 69.1 %

Procedure:
The 1-tert-butyl 3-methyl 4-amino-1,3-pyrrolidinedicarboxylate (0.10 g, 0.41 mmol) was combined with the acid chloride from step (501b) (0.10 g, 0.32 mmol) in methylene chloride (15 mL) and water saturated sodium bicarbonate (15 mL). The reaction was stirred for 3.5 h, partitioned between methylene chloride and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give a solid. This was purified by flash chromatography on silica gel eluting hexane: ethyl acetate (30:60, v:v) to give the 1-tert-butyl 3-methyl 4-[({1-[(2-methyl-4-quinolinyl)methyl]-1H-indol-5-yl}carbonyl)amino]-1,3-pyrrolidinedicarboxylate (0.120 g, 70%) as a solid, MS (M+H)+=543.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][O:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:4][C:3]=1[CH:31]([NH:33]C(=O)OC(C)(C)C)[CH3:32]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][O:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:4][C:3]=1[CH:31]([NH2:33])[CH3:32]
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(C)NC(=O)OC(C)(C)C)c(Cl)c5)nn34)ccnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(C)N)c(Cl)c5)nn34)ccnc2c1

Procedure:
A solution of tert-butyl 1-(2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamate (100 mg, 178 μmol) in DCM (2 mL) and TFA (2 mL) was stirred for 30 min at 23° C. Solvents removed under reduced pressure (not-toluene azeotroping is suggested!) and residue dissolved in CHCl3/IPA (10 mL). Solution stirred as a suspension with Si-Carbonate (1.3 g; 1 mmol) for 30 min. Suspension filtered and filtrate reduced to an amber film (150 mg). Product purified on silica (12 g) eluting with 4-7% of 2M NH3 in MeOH/DCM. MS (ESI pos. ion) m/z: 461 (MH+). Calc'd exact mass for C24H21ClN6O2: 460.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:28])[N:4]([CH2:14][C:15]([NH:17][CH:18]([CH:25]([CH3:27])[CH3:26])[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])=[O:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.[C:39](O)(=[O:43])[C:40]([CH3:42])=[O:41].COC1C=CC(CC(O)=O)=CC=1>CN(C)C1C=CN=CC=1.ClCCl.O1CCCC1>[O:28]=[C:3]1[C:2]([NH:1][C:39](=[O:43])[C:40]([CH3:42])=[O:41])=[CH:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]1[CH2:14][C:15]([NH:17][CH:18]([CH:25]([CH3:26])[CH3:27])[C:19](=[O:24])[C:20]([F:22])([F:23])[F:21])=[O:16]
Reactant: CC(=O)C(=O)O
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: COc1ccc(CC(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)C(=O)Nc1ccc(-c2ccccc2)n(CC(=O)NC(C(=O)C(F)(F)F)C(C)C)c1=O
Reaction time: 72 h

Procedure:
2-(3-Amino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide was subjected to procedure similar to Acylation Method B, but substituting: dichloromethane for tetrahydrofuran, 4-dimethylaminopyridine for 1-hydroxybenzotriazole, and pyruvic acid for 4-methoxyphenyl acetic acid. After 72 h, dichloromethane was added and the mixture was washed (water, brine), dried (magnesium sulfate) and evaporated. Chromatography, eluting with dichloromethane:methanol (gradient, 99.5:0.5, 99:1), gave the title compound as a pale yellow solid; TLC: Rf =0.44, dichloromethane:methanol (98:2); MS: m/z=466(M+1).