Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[CH2:20]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH2:27][CH2:26]1)[CH2:21][CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH2:20]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:39][C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:18][CH3:19])=[CH:17][CH:16]=3)=[CH:37][CH:38]=2)[CH2:29][CH2:30]1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC[C@H](C)CCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(O)cc2)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(OC(=O)c3ccc(OCCCCC[C@@H](C)CC)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (S)-4-(6-methyloctyloxy)benzoyl chloride obtained was dissolved in 20 ml of toluene and then added dropwise to a solution of 0.26 g of 4-[2-(trans-4-pentylcyclohexyl)ethyl]phenol in 2 ml of pyridine. The reaction mixture was stirred at room temperature overnight, then poured into ice-water and extracted with diethyl ether. The extract was washed four times with 25 ml of 3 N hydrochloric acid each time, then washed with 25 ml of 2 N sodium carbonate solution and several times with water, dried over magnesium sulphate and concentrated. Chromatography of the residual oil on silica gel with toluene gave 0.2 g of (S)-4-(6-methyloctyloxy)benzoic acid 4-[2-(trans-4-pentylcyclohexyl)ethyl]phenyl ester. The product was recrystallized several times from ethanol until the phase transition temperatures were constant. M.p. (C-S) 58°, transition S-S*C 58.5° C., transition S*C -Ch 93° C., cl.p. (Ch-I) 140° C.
Reaction SMILES: CC(C)=O.[O-]S([O-])(=O)=O.[Mg+2].[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O[C:25]([CH3:29])([CH3:28])[C:26]#[N:27]>CN(C)C(=O)C>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(O)C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: CC(C)(C#N)N1CCN(Cc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
4.5 ml of acetone, 20 g of dry MgSO4, 10 g of N,N-dimethylacetamide, 10 g of 1-benzylpiperazine and 9.5 ml of 2-hydroxyisobutyronitrile are mixed together and heated at 45° C. for 48 hours with vigorous stirring. The reaction mixture is poured onto ice and left stirring for 30 minutes. The mixture is extracted with ether, the organic phase is washed several times with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 13 g of the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:28]=[N:27][NH:26][C:5]2=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=[C:15]([Cl:17])[CH:16]=1)[O:8][C:7]2=[O:25].Cl.[C:30]1([NH2:36])([CH:33]2[CH2:35][CH2:34]2)[CH2:32][CH2:31]1.C(N(CC)CC)C>CN(C)C=O>[C:30]1([NH:36][C:7]([C:6]2[C:11]([NH:10][C:9]([C:12]3[N:13]([C:18]4[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=4)[N:14]=[C:15]([Cl:17])[CH:16]=3)=[O:8])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:5]=2[NH:26][N:27]=[CH:28]3)=[O:25])([CH:33]2[CH2:35][CH2:34]2)[CH2:32][CH2:31]1
Reactant: NC1(C2CC2)CC1
Reactant: O=c1oc(-c2cc(Cl)nn2-c2ncccc2Cl)nc2c(Cl)cc3cn[nH]c3c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1(C2CC2)CC1)c1c(NC(=O)c2cc(Cl)nn2-c2ncccc2Cl)c(Cl)cc2cn[nH]c12
Temperature: 50 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
To a solution of 400 mg (0.78 mmol) of the above 5-chloro-7-[5-chloro-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 8 mL of N,N-dimethylformamide is added 262 mg (1.96 mmol) of bicyclopropyl-1-ylamine hydrochloride and 273 μL (1.96 mmol) of triethylamine. The reaction is stirred at 50° C. for 16 hours and then concentrated in vacuo. The residue is taken-up with water and tert-butylmethylether. The phases are separated and the aqueous layer is washed twice with tert-butylmethylether. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 1:1 to 1:2, gradient) affords 380 mg (91%) of the product as a white solid; LC/MS:530/532 (M+H)+, m.p.: 173-175° C.
Reaction SMILES: C(OC([N:8]([CH2:27][CH2:28][CH3:29])[CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:15][CH:16]=2)[O:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:27]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:19][S:20]([C:23]([F:25])([F:26])[F:24])(=[O:22])=[O:21])=[CH:15][CH:16]=2)[O:11][CH2:10]1)[CH2:28][CH3:29]
Reactant: CCCN(C(=O)OC(C)(C)C)C1COc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCNC1COc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoro-methanesulfonic acid 3-(tert-butoxycarbonyl-propyl-amino)-chroman-7-yl ester (2.1 g, 4.78 mmol) was dissolved in dichloromethane (30 ml). Trifluoroacetic acid (3 ml) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness. Dichloromethane was added (twice) and the reaction mixture was evaporated to dryness to give the product (2.6 g, 65% purity).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl.CCOC(C)=O>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCOCC1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCC(NC3CCOCC3)CC2)cc1
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
19 g of 4-amino-1-benzylpiperidine are placed in 50 ml of 1,2-dichloroethane under dry nitrogen and 10 g of tetrahydropyran-4-one in 20 ml of 1,2-dichloro-ethane are added; after stirring for 10 minutes, 29.6 g of NaBH(OAc)3 are added and the mixture is then stirred for one day. 10% Na2CO3 solution and EtOAc are added to the reaction medium and the phases are then separated by settling. The organic phase is washed with 10% Na2CO3 solution and then with saturated NaCl solution, and then dried over MgSO4 and evaporated under vacuum. 23.4 g of the expected compound are obtained. m.p.=60° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:24])[C:10]1[C:15]([S:16][CH3:17])=[CH:14][C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=1[O:22][CH3:23].Br[CH2:26][CH:27]([OH:31])[CH2:28][CH2:29]Br>>[OH:31][CH:27]1[CH2:28][CH2:29][N:1]([C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH:8][C:9](=[O:24])[C:10]2[C:15]([S:16][CH3:17])=[CH:14][C:13]([C:18]([F:20])([F:21])[F:19])=[CH:12][C:11]=2[O:22][CH3:23])[CH2:26]1
Reactant: OC(CBr)CCBr
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1CCCC[C@@H]1N1CCC(O)C1

Procedure:
The title compound, light yellow foam, MS: m/e=433.2 [(M+H)+], was prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate I) and 1,4-dibromo-2-butanol. The two diastereomers were not separated.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4](OC)=[O:5].O.[NH2:15][NH2:16]>CCO>[CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH:15][NH2:16])=[O:5]
Reactant: NN
Reactant: COC(=O)C(SC)c1ccccc1
Solvent: CCO
Solvent: O
Product: CSC(C(=O)NN)c1ccccc1
Reaction time: 18 h

Procedure:
To a stirred solution of methyl 2-(methylthio)-2-phenylacetate (0.300 g, 1 equiv) in anhydrous EtOH (5 mL) was added hydrazine hydrate (0.15 mL, 2 equiv) and heated to reflux. Stirring was then continued for 18 hours. The reaction mixture was then cooled and the solvents removed under reduced pressure. The crude oil was diluted with EtOAc and washed with H2O and the organic phase dried over Na2SO4, filtered, and the solvents removed under reduced pressure to yield a yellow oil which was purified by flash chromatography on silica gel using ethyl acetate and hexanes. The purified product was a white solid (193 mg, 66%).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:11]([C@@H:14]1[N:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:18][CH2:17][C:16]([C:26]2[N:27]=[C:28]([SH:31])[S:29][CH:30]=2)=[CH:15]1)([CH3:13])[CH3:12].O(P(OC1C=CC=CC=1)O[C:41]1[C@H:47]([CH3:48])[C@H:46]2[N:43]([C:44](=[O:56])[C@@H:45]2[C@H:49]([O:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH3:50])[C:42]=1[C:57]([O:59][CH2:60][CH:61]=[CH2:62])=[O:58])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:23]([O:22][C:20]([N:19]1[C@@H:14]([CH:11]([CH3:13])[CH3:12])[CH:15]=[C:16]([C:26]2[N:27]=[C:28]([S:31][C:41]3[C@H:47]([CH3:48])[C@H:46]4[N:43]([C:44](=[O:56])[C@@H:45]4[C@H:49]([O:51][Si:52]([CH3:53])([CH3:54])[CH3:55])[CH3:50])[C:42]=3[C:57]([O:59][CH2:60][CH:61]=[CH2:62])=[O:58])[S:29][CH:30]=2)[CH2:17][CH2:18]1)=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)N1CCC(c2csc(S)n2)=C[C@@H]1C(C)C
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C(C)C)N(C(=O)OCC=C)CC3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
A solution of lithium hexamethyldisilazide in THF (1M, 0.62 ml, 0.62 mmol) was added at 0–5° C. to a solution of allyl (6S)-6-isopropyl-4-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (202 mg, 0.62 mmol) in THF (11.0 ml) and the mixture was stirred for 15 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 2.37 g, 1.2 mmol) and the solution was allowed to stand in a refrigerator for 16 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate: 1/5→1/3) to give allyl (4R,5S,6S)-3-[(4-{(6S)-1-[(allyloxy)carbonyl]-6-isopropyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.24 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[CH:15]=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1.OS(O)(=O)=O.[N+:29]([O-])([O-:31])=[O:30].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]([N+:29]([O-:31])=[O:30])=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2cc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c([N+](=O)[O-])c1O
Yield: 78 %

Procedure:
The title compound was prepared following the procedure described for step-3 of intermediate-55 using methyl 2-[(2-chloro-6-fluorophenyl)amino]-6-hydroxy-1H-benzimidazole-5-carboxylate (0.380 g, 1.134 mmol), conc. H2SO4 (1.2 mL) and KNO3 (0.109 g, 1.077 mmol) to afford 0.320 g of the desired product. 1HNMR (DMSO-d6): δ 3.92 (s, 3H), 7.40-7.47 (m, 3H), 7.72 (s, 1H), 9.98 (m, 1H), 11.00-12.00 (s, 2H); MS [M+H]+: 381.03.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]([CH3:13])[CH2:9][C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>CC(O)C>[OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:8]([CH3:13])[CH2:9][C:10](=[O:11])[NH:17][N:18]=2)=[CH:4][CH:3]=1
Reactant: CC(CC(=O)O)C(=O)c1ccc(O)cc1
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: CC1CC(=O)NN=C1c1ccc(O)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A 1 1 three-necked round-bottomed flask equipped with a condenser connected to a gas inlet, a glass rod air driven stirrer and a thermometer was charged with 63.8 g, (306 mmol) of (±)-3-(4'-hydroxybenzoyl)-3-methylpropanoic acid from Example H and 2-propanol (400 ml) at 40° C. The solution was placed under an atmosphere of nitrogen and heated to 65° C. Then hydrazine monohydrate (45 ml, 2.2 mol) was added dropwise over 10 min. The reaction mixture was heated to 80-81° C. (reflux), stirred for 1 hour then slowly cooled to 3° C. over 1 hour with gentle stirring. The formed precipitate was collected by suction filtration, triturated in a 1 L beaker with deionized water (300 ml) at 23° C. for 2 hrs and collected by suction filtration. The solids were dried to constant weight in an air oven (90° C.) to provide 51.9 g (83.5%) of pure (±)-4,5-dihydro-6-(4'-hydroxyphenyl)-5-methyl-3(2H)-pyridazinone, m.p. 268°-273° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC>[CH2:15]([NH:22][C:4]1[N:3]=[C:2]([Cl:1])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCc1ccccc1
Solvent: CCCCO
Product: CC(C)n1cnc2c(NCc3ccccc3)nc(Cl)nc21
Yield: 85 %

Procedure:
2,6-dichloro-9-isopropylpurine (1 mmol) and benzylamine (3.5 mmol) were heated with stirring in 3 ml of n-butanol (3 hour, 110° C.). The reaction mixture (after evaporation of n-butanol) was worked up as above for the compound 2, yield 85-90%.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([CH:6]=[CH2:7])=[CH2:5].[CH2:10]([NH:12][CH2:13][CH2:14][CH3:15])[CH3:11].B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH2:10]([N:12]1[CH2:7][CH2:6][C:4](=[O:5])[CH2:3][CH:13]1[CH2:14][CH3:15])[CH3:11]
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: CCCNCC
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCC1CC(=O)CCN1CC

Procedure:
To 100 mL of methylene chloride cooled to 0° C. is added 2-(trimethylsilyloxy)-1,3-butadiene (14.2 g, 0.1 mol), 8.5 g (0.1 mol) of N-ethyl-propanamine, and 14.2 g (0.1 mol) of borontrifluoride etherate. Monitor the reaction by thinlayer chromatography. Upon completion add 1N HCl until gas evolution ceases. Separate the aqueous layer and make it alkaline with 1N NaOH. Extract twice with 100 mL ether and dry over Na2SO4. Filter the drying agent and evaporated the solvent in vacuo to obtain the title compound.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.CON(C)[C:23]([C:25]1[CH:30]=[CH:29][N:28]=[N:27][CH:26]=1)=[O:24].CC#N.C(=O)=O>C1COCC1>[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:23]([C:25]1[CH:30]=[CH:29][N:28]=[N:27][CH:26]=1)=[O:24]
Reactant: Cn1ccnc1
Reactant: CON(C)C(=O)c1ccnnc1
Agent: CC[Si](Cl)(CC)CC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC#N
Solvent: C1CCOC1
Product: Cn1ccnc1C(=O)c1ccnnc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-BuLi (1.6 M in hexane, 3.65 mL, 5.84 mmol) was added to a solution of 1-methylimidazole (0.452 mL, 5.7 mmol) in THF (30 mL) at −78° C. The mixture was stirred at −78° C. for 15 min. Chlorotriethylsilane (0.955 mL, 5.7 mmol) was added slowly. The mixture was removed from the dry ice/acetone bath and was stirred for 30 min. The mixture was again cooled in a dry ice/acetone bath before addition of a second portion of n-BuLi (1.6 M in hexane, 3.65 mL, 5.84 mmol). The mixture was stirred at −78° C. for 1 hour, then transferred to an ice bath and stirred 10 min. The mixture was again cooled in a dry ice/acetone bath before addition of a solution of N-methoxy-N-methylpyridazine-4-carboxamide (793 mg, 4.74 mmol, Intermediate 29, step a) in THF (15 mL) via cannula. The reaction mixture was stirred at −78° C. for 30 min, then was transferred to a slurry of CH3CN/dry ice and stirred for 15 min. The reaction was quenched by addition of water (50 mL) and the mixture was extracted with EtOAc three times. The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, gradient 0-4% MeOH-DCM first column, 75-100% EtOAc-heptanes second column) to afford the title compound.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:30][OH:31].O.O.O.C([O-])(=O)C.[Na+]>CCO.O>[C:1]1(/[C:7](/[C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])=[N:30]\[OH:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O/N=C(\c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
Phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (Example 1, 0.128 g, 0.339 mmol) was taken into EtOH/H2O (7 mL, 7:3 mixture) along with hydroxylamine hydrochloride (0.028 g, 0.407 mmol) and sodium acetate trihydrate (0.061 g, 0.447 mmol) and this mixture was refluxed for 1.5 hours. TLC and LC-MS showed no reaction. Therefore, excess quantities of hydroxylamine hydrochloride and sodium acetate trihydrate were added and refluxing was continued overnight. The reaction was concentrated and the resulting material was taken up into CH2Cl2/H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over sodium sulfate and concentrated. The product was purified via column chromatography using 15% ethyl acetate in hexane as the eluent to afford 0.100 g of desired product as a white solid. MS (ESI) m/z 393 ([M+H]+);
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[CH2:5]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12])[CH:6]=[CH2:7].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:5]([O:8][CH2:9][CH:10]1[CH2:11][O:12][C:2]([CH3:4])([CH3:1])[O:13]1)[CH:6]=[CH2:7]
Reactant: C=CCOCC(O)CO
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C=CCOCC1COC(C)(C)O1

Procedure:
The 4-allyloxymethyl-2,2-dimethyl-1,3-dioxolane was prepared by mixing acetone, 225 parts, 3-allyloxy-1,2propanediol, 195 parts and toluene, 480 parts in a flask fitted with a magnetic stirring bar and a water trap mounted with a reflux condenser. Concentrated sulfuric acid, 4 parts, was added to the flask and the mixture was heated to reflux. The first 170 parts of distillate were removed via the water trap, after which reflux was conducted and water was collected in the water trap. After 13 hours the reaction mixture was cooled, neutralized with solid sodium bicarbonate, distilled to remove water and toluene and then distilled under vacuum to give 161 parts of 4-allyloxymethyl-2,2-dimethyl-1,3-dioxolane having a boiling point of 57° to 58° at 4.5 Torr.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][O:12][CH3:13])[N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[C:18]([F:21])=[N:19][CH:20]=1.C([O-])(=O)C.[K+]>O1CCOCC1.Cl[Pd]Cl>[Cl:14][C:15]1[CH:16]=[C:17]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][O:12][CH3:13])[N:3]=2)[C:18]([F:21])=[N:19][CH:20]=1
Reactant: COCCNc1nc(C)nc(Cl)n1
Reactant: OB(O)c1cc(Cl)cnc1F
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COCCNc1nc(C)nc(-c2cc(Cl)cnc2F)n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 29.5 %

Procedure:
A mixture of 4-chloro-N-(2-methoxyethyl)-6-methyl-1,3,5-triazin-2-amine (300 mg, 1.480 mmol), 5-chloro-2-fluoropyridin-3-ylboronic acid (320 mg, 1.825 mmol), potassium acetate (298 mg, 3.04 mmol), and Am-phos PdCl2 (47 mg, 0.066 mmol) in dioxane (10 mL) was heated at 100° C. under nitrogen. After 6 h, the mixture was cooled to rt and partitioned between water (10 mL) and EtOAc (20 mL). The organic layer was dried over Na2SO4 and concentrated. The oil was purified on silica using EtOAc in hexane (10-80%) to give the product as a yellow solid (130 mg). LCMS (ES, pos.): calcd for C12H13ClFN5O: 297.1. found: 298.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.55 (ddd, J=16.24, 7.92, 2.64 Hz, 1H); 8.27 (br. s., 1H); 5.91 (br. s., 1H); 3.72 (quin, J=5.62 Hz, 2H); 3.59 (t, J=5.09 Hz, 2H); 3.40 (2s, 3H); 2.51 (2s, 3H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[N:40]([CH3:44])[CH:41]=[CH:42][N:43]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[N:40]([CH3:44])[CH:41]=[CH:42][N:43]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: Cn1ccnc1C1(O)CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccnc1C1(O)CCC(N2CC(NC(=O)CNc3nn(C)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-(1-methyl-1H-imidazol-2-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [N:1]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28](O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:41][C@@H:42]([C:53]([NH:55][C@H:56]([C:61]([N:63]([CH3:72])[C@H:64]([C:69]([NH2:71])=[O:70])[CH2:65][CH2:66][S:67][CH3:68])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1.FC(C(O)=O)(F)F.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>>[N:1]1([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:33][CH2:32][CH2:31][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:41][C@@H:42]([C:53]([NH:55][C@H:56]([C:61]([N:63]([CH3:72])[C@H:64]([C:69]([NH2:71])=[O:70])[CH2:65][CH2:66][S:67][CH3:68])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[NH:46][CH:45]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CSCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 60 %

Procedure:
Condensation of BocPro-DTrp-PheOH (Example 33, 1.49 g.) and HDTrp-Leu-MeMetNH2 trifluoroacetate salt (1.25 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-Phe-DTrp-Leu-MeMetNH2 in 60% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DTrp-Leu-MeMetNH2 (1.50 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DTrp-Leu-MeMetNH2, which was isolated as the amorphous white solid phosphate (1:2) salt dihydrate in 57% yield.