Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[N:13]=[N:12]1.[NH2:23][C:24]1[C:25]([O:39][CH3:40])=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1>>[C:30]([C:28]1[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:25]([O:39][CH3:40])=[C:24]([NH:23][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=4)[N:13]=[N:12]3)[CH:4]=2)[CH:29]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cc1ccc(-c2cn(-c3cc(C(=O)O)ccc3C)nn2)cn1
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(C)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 7 was prepared by coupling 4-methyl-3-[4-(6-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as Example 1. ESI MS m/z 547 [C28H32N6O4S+H]+.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]>CCOCC>[NH:1]([C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[NH2:2]
Reactant: NN
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOCC
Product: NNC(=O)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of hydrazine (0.83 mL, 26 mmol) in ether was added phenyl chloroformate (0.92 mL, 7.4 mmol) at −20° C. The solution was stirred for 1 h, removed solid by filtration, and filtrate was concentrated to give phenyl hydrazinecarboxylate. To phenyl hydrazinecarboxylate was added compound 2b (1.2 g, 5.2 mmol), THF (20 mL), and DIPEA (1.5 mL) and the solution was stirred for 1 h. Partitioned reaction between sat. aq. NaHCO3 and CH2Cl2, dried (MgSO4), filtered, and concentrated to yield compound 81a (400 mg, 22%).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([NH2:8])=[O:7])(N)=[O:2].[C:9]1([CH2:17][NH2:18])[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]N)[CH:10]=1>CN1CCCC1=O>[NH:5]1[C:6](=[O:7])[N:8]([CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH2:17][N:18]3[C:6](=[O:7])[NH:5][NH:4][C:1]3=[O:2])[CH:10]=2)[C:1](=[O:2])[NH:4]1
Reactant: NCc1cccc(CN)c1
Reactant: NC(=O)NNC(N)=O
Solvent: CN1CCCC1=O
Product: O=c1[nH][nH]c(=O)n1Cc1cccc(Cn2c(=O)[nH][nH]c2=O)c1

Procedure:
64.2 g of hydrazodicarbonamide and 37 g of m-xylylene diamine in 300 ml of N-methyl pyrrolidone are heated with stirring for 4 hours to 175° C. and for 30 hours to 200° C. The solvent is then distilled off in vacuo and the residue is recrystallised from chloroform, giving 58 g (70% of the theoretical) of 1,3-bis-(1,2,4-triazolidine-3,5-dione-4-yl-methyl)-benzene in the form of colourless crystals melting at 244° to 246° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(=O)([O-])[O-].[K+].[K+].CC1C=CC([C:26]2[C:27]([F:37])=[C:28]([CH:32]=[C:33]([Cl:36])[C:34]=2F)[C:29]([O-:31])=[O:30])=CC=1>CS(C)=O>[Cl:36][C:33]1[C:34]([O:12][C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:11])[F:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:26][C:27]([F:37])=[C:28]([CH:32]=1)[C:29]([O:31][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:2][CH:3]=1)=[O:30]
Reactant: Cc1ccc(-c2c(F)c(Cl)cc(C(=O)[O-])c2F)cc1
Reactant: Oc1ccc(C(F)(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)c(Cl)c3)cc2F)cc1
Reaction time: 0.08 h
Yield: 92.7 %

Procedure:
To a solution of 3-chloro-4-(trifluoromethyl)phenol (Preparation 16, 100 mg, 0.470 mmol) in DMSO (1 mL) was added potassium carbonate (0.84 mg, 0.611 mmol) and the mixture stirred for 5 minutes. 4-methylphenyl-5-chloro-2,4-difluorobenzoate (Preparation 10, 0.133 mg, 0.470 mmol) was then added and the reaction stirred under nitrogen for 3 hours. The reaction was quenched by the addition of water (2 mL) and ethyl acetate (3 ml). The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to afford a white solid that was purified using silica gel column chromatography eluting with ethyl acetate:heptane 3:97 to furnish the title compound (100 mg, 47%).
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[C:14]([CH3:20])=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:21])[C:18]2[C:13](=[C:14]([CH3:20])[N:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(C)nc1C)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(C)nc(C)cc2c1=O
Temperature: 260 °C
Yield: 36 %

Procedure:
2-[(2,6-Dimethyl-pyridin-3-ylamino)-methylene]-malonic acid diethyl ester, prepared in step (i) and diphenyl ether (DPE) were placed in a round bottom flask and this mixture was heated to 260° C. for 1 h. The reaction was then cooled to RT and the content was purified by column chromatography over 100-200 mesh silica gel, eluted with 8% methanol in chloroform, to give the product as a brown solid (36%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]([CH3:14])=[N:3]1.NN.O>C(O)C.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([CH3:14])=[N:3]1
Reactant: Cc1nn(C)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nn(C)c2ccc(N)cc12
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
To a solution of 307a (crude, 2.5 mmol) in ethanol (95%, 30 mL) was added NH2NH2.water (1.25 g, 25.0 mmol), Pd/C (100 mg) under nitrogen protection. The mixture was stirred at 50° C. for 1.5 h. It was then cooled to room temperature and filtered through a pad of CELITE®. The filtrate was concentrated under reduced pressure and the residue was recrystallized from anhydrous ethanol (5 mL) to afford 307b as white solid (340 mg, 84% over two steps). MS-ESI: [M+H]+ 162.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][C@@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:29])[N:9]=2)[CH:7]=1.C1([C@@H](N)C)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][C@H:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:29])[N:9]=2)[CH:7]=1
Reactant: C[C@@H](NCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)c1ccccc1
Agent: C[C@H](N)c1ccccc1
Product: C[C@H](NCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)c1ccccc1

Procedure:
Using synthetic method analoguous to that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(1R)-1-phenylethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from (1S)-1-phenylethan-1-amine. LCMS (Method 25) [M+H]+=552.1, RT=1.15 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.72 (s, 1H), 9.33 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m, 2H), 8.34 (s, 1H), 7.60 (dd, 1H, J=2.9, 8.9 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.43 (d, 1H, J=8.7 Hz), 7.31-7.16 (m, 6H), 6.98 (t, 1H, J=73.2 Hz), 4.18 (t, 2H, J=6.0 Hz), 3.70 (q, 1H, J=6.6 Hz), 2.83-2.73 (m, 2H), 1.22 (d, 3H, J=6.6 Hz).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:1]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Product: C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 94.2 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (36.3 g, 101.6 mmol, 1.35 equiv) in ether (dry, 300 mL) was added potassium t-butoxide (11 g, 98 mmol, 1.3 equiv) in one portion at 0° C. under nitrogen balloon. The mixture was then stirred at reflux for 2 hrs. The hot reaction mixture was cooled to 0° C. with an external ice-bath and then a solution of tert-butyl 4-oxopiperidine-1-carboxylate (15 g, 75.3 mmol, 1.0 equiv) in ether (60 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The mixture was then stirred at reflux overnight (16 h). The mixture was cooled to room temperature and hexane (300 mL) was added. The mixture was stirred for 10 min, filtered and eluted with Hexane/EtOAc (100/100 mL). The combined organic solution was concentrated to give the residue which was purified by CombiFlash (100 g silica gel column, EtOAc/Hex=0-30%) to afford 14 g (yield 94%) of tert-butyl 4-methylenepiperidine-1-carboxylate as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)=[O:14])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1
Yield: 86 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylfuran-2-carboxylic acid (60 mg, 0.306 mmol) was condensed with ethyl 4-aminophenylacetate, and the resultant was purified by silica gel chromatography [hexane-ethyl acetate (4:1)] to obtain ethyl 4-[(4,5-diisopropylfuran-2-carbonyl)amino]phenylacetate (94 mg, 86%) as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]#[N:8])=[N:4][O:5][N:6]=1.O.[NH2:10][NH2:11]>C(#N)C>[NH2:1][C:2]1[C:3]([C:7]([NH:10][NH2:11])=[NH:8])=[N:4][O:5][N:6]=1
Reactant: NN
Reactant: N#Cc1nonc1N
Solvent: O
Solvent: CC#N
Product: N=C(NN)c1nonc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of 4-amino-furazan-3-carbonitrile (0.50 g, 4.50 mmol) in acetonitrile (7.0 mL) was added hydrazine monohydrate (0.28 mL) dropwise. The solution was stirred at ambient temperature for 3 hours after which time a white solid precipitated. The solid was washed with acetonitrile and dried in vacuo to afford the title compound (0.60 g, 94%) as a white, fluffy solid. HPLC Method A Rt 0.18 min, m/z (ES+) (M+H)+ 143.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][N:4]=1)#[N:2].S(=O)(=O)(O)[OH:19].[OH-].[Na+]>>[CH2:13]([O:12][P:10]([CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:19])[CH:8]=1)([O:15][CH2:16][CH3:17])=[O:11])[CH3:14]
Reactant: O=S(=O)(O)O
Reactant: CCOP(=O)(Cc1ccnc(C#N)c1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOP(=O)(Cc1ccnc(C(N)=O)c1)OCC

Procedure:
A mixture of 1.10 g of 2-cyano-4-(diethylphosphonomethyl)pyridine and 4.5 ml of concentrated sulfuric acid is heated at 90° for 5 minutes. The reaction mixture is poured onto ice and neutralized with 10% sodium hydroxide. The resulting precipitate is collected to afford 4-(di-ethylphosphonomethyl)-2-pyridinecarboxamide melting at 140°-142°.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[N:17][CH:18]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=[O:6].[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)=[CH:29][CH:28]=2)=[O:6])[N:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[N:17][CH:18]=2)[N:11]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: Nc1ccc(OCc2ccncc2)c2ccccc12
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccncc3)c3ccccc23)cn1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-(2-methylpyridin-5-yl)pyrazole (26 mmol), 1-amino-4-(pyridin-4-ylmethoxy)naphthalene (26 mmol), diisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH:19][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][Cl:21])[CH:16]=[C:6]([C:7]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])=[O:8])[CH:5]=1
Reactant: CCCN(CCC)C(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: O=C(Cl)CCCCCl
Product: CCCN(CCC)C(=O)c1cc(NC(=O)CCCCCl)cc(C(=O)OC)c1

Procedure:
Description 90 was prepared in an analogous manner to Description 89 from 5-amino-N,N-dipropyl-isophthalamic acid methyl ester (D88) and 5-chlorovaleryl chloride.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]4)[N:12]=3)=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:28].[C:29](#[N:32])[CH:30]=[CH2:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:28][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1/[CH:31]=[CH:30]/[C:29]#[N:32])[NH:8][CH:7]=[C:6]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[N:12]=1
Reactant: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(Cl)c(F)cc34)n2)CC(C)(C)N1
Reactant: C=CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(/C=C/C#N)c(F)cc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared by the general Heck procedure described in Example 256, using the SEM-protected intermediate of Example 253 and acrylonitrile, followed by TBAF deprotection of the SEM group.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[C@H:10]([OH:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S(=O)(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:32])[CH3:33])[N:28]=[CH:29][N:30]=2)[N:19]=4)[C:10](=[O:36])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3O)cc1OCC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(C(=O)OC(C)(C)C)CC3=O)cc1OCC2
Temperature: 5 °C
Reaction time: 7 h
Yield: 26.9 %

Procedure:
Racemic-trans-3-Hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester from Example 328 (containing approx. 24% of 4-hydroxypiperidine isomer, 0.32 g, 0.65 mmol) was dissolved in DCM (15 mL) and cooled in an ice-bath. Dess-Martin periodinane (0.3 M in DCM, 4.33 mL, 1.3 mmol) was added dropwise, the mixture was stirred at 0-10° C. for 7 h, then refrigerated for 16 h. Aqueous sodium bisulphate and sodium bicarbonate (10 mL each) were added and the mixture was stirred at room temperature for 15 min. The phases were separated and the aqueous phase was extracted twice with DCM. Combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-5% methanol in DCM) then trituration with ether to give 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (86 mg). Additional product was recovered from the trituration liquor (59 mg). Total yield 145 mg (45%). LCMS RT=3.53, [M+H]+=493, [M+H+ MeOH]+=525.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][NH2:13].[CH2:14](OC(OCC)OCC)C>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][N:6]3[CH:14]=[N:13][N:12]=[C:5]3[C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1ncnc2ccc(Cl)cc12
Product: Clc1ccc2ncn3cnnc3c2c1
Reaction time: 48 h

Procedure:
A mixture of 155.7 gms. of 6-chloro-4-hydrazinoquinazoline and 3000 ml. of triethoxy methane is refluxed with stirring for 48 hours, and after filtering off the insoluble material, the filtrate is evaporated in vacuo to dryness and the residue recrystallized from ether to obtain 9-chloro-1,2,4-triazolo[4,3-c]quinazoline, m.p. 179°-182° C.
Reaction SMILES: CCCCCON=O.[Br:9][C:10]1[CH:16]=[CH:15][C:13](N)=[C:12]([O:17][CH3:18])[CH:11]=1.[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br:9][C:10]1[CH:16]=[CH:15][C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([O:17][CH3:18])[CH:11]=1
Reactant: COc1cc(Br)ccc1N
Reactant: c1ccccc1
Agent: CCCCCON=O
Product: COc1cc(Br)ccc1-c1ccccc1
Temperature: 25 °C

Procedure:
n-Amyl nitrite (8.1 ml, 60 mmol) was slowly added to a stirred mixture of 4-bromo-2-methoxyaniline (J.Med.Chem., 1989, 32, 1936; 8.1 g, 60 mmol) and benzene (175 ml), under nitrogen, at about 50° C. When the addition was complete, the reaction mixture was heated under reflux for about 3 hours, then allowed to cool to room temperature and evaporated under reduced pressure. The residue was azeotroped with tetrahydrofuran, then with ethyl acetate, and purified by flash chromatography, using an elution gradient of hexane:ethyl acetate (100:0 to 95:5) to give the title compound (1.66 g) as a colourless solid, m.p. 50-52° C. δ(CDCl3): 3.77 (s,3H), 7.08 (s,1H), 7.14 (s,2H), 7.30 (m,1H), 7.36-7.41 (m,2H), 7.41-7.49 (m,2H).
Reaction SMILES: I[CH:2]1[CH:8]2[CH2:9][CH:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[OH-].[Na+].[CH2:13]([OH:15])[CH3:14]>>[CH:3]12[O:15][CH:13]1[CH2:14][CH2:9][CH:5]([C:6]([O:7][CH2:8][CH3:2])=[O:10])[CH2:4]2
Reactant: CCO
Reactant: O=C1OC2CC1CCC2I
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C1CCC2OC2C1
Yield: 52 %

Procedure:
To a suspension of Racemate-4-iodo-6-oxa-bicyclo[3.2.1]octan-7-one (45.0 g, 180 mmol) in ethanol (400 mL) was added 2 N aqueous sodium hydroxide (110 mL, 220 mmol) at room temperature while being stirred, and the resulting mixture was stirred for 3 hours. The reaction mixture was concentrated in a bath at a temperature of 35° C. under reduced pressure. Water (500 mL) was added to the resultant oily matter, and the resulting mixture was extracted with ethyl acetate (500 mL). The organic layer was washed with water (500 mL), dried over anhydrous sodium sulfate, filtered and followed by concentration under reduced pressure. The resultant oily matter was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:10˜1:5), to thereby give the tile compound (15.9 g, 52%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[N:20]=[CH:19]4)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].[OH-].[Na+:33]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH2:25][CH2:26][C:27]([O-:29])=[O:28])[N:20]=[CH:19]4)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].[Na+:33]
Reactant: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OCC)c(Cl)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(-c2nc(-c3ccc4c(cnn4CCC(=O)[O-])c3)no2)cc1Cl
Temperature: 50 °C

Procedure:
Ethyl 3-(5-{5-[3-chloro-4-(ethyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indazol-1-yl)propanoate (D57) (77 mg, 0.17 mmol) was suspended in 2M aq. NaOH (2 ml) and ethanol (2 ml). The mixture was heated at 50° C. until dissolved then cooled. The ethanol was removed in vacuo and the resultant solid was filtered, washed with ethanol, water and diethyl ether then dried under high vacuum to afford the title compound (63.6 mg) as a pink solid. δH (methanol-d4, 400 MHz) 1.49 (3H, t), 2.77 (2H, t), 4.25 (2H, q), 4.71 (2H, t), 7.27 (1H, d), 7.82 (1H, d), 8.09-8.25 (4H, m), 8.55 (1H, s). MS (ES): C20H1735ClN4O4 requires; 412 found (MH+) 413.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]1=[O:19].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[Li+].[OH-]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]1=[O:19]
Reactant: O=C1N(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCC12CCCCC2
Reactant: C1COCCN1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1N(Cc2c(Cl)cc(N3CCOCC3)cc2Cl)CCC12CCCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
Heat a solution of trifluoro-methanesulfonic acid 3,5-dichloro-4-(1-oxo-2-aza-spiro[4.5]dec-2-ylmethyl)-phenyl ester (0.15 g, 0.32 mmol) and morpholine (0.099 g, 1.13 mmol) in 1-methyl-2-pyrrolidine (2.5 mL) to 201° C. for 1.5 hours in a microwave reactor. Cool the reaction to room temperature and treat with 2M LiOH (1 mL) and stir 16 hours at room temperature. Dilute the reaction with ethyl acetate and wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify on silica isocratically using 5% methyl t-butyl ether in chloroform to afford 0.064 g (50%) of the titled product. Rf=0.22 (9:1 chloroform:methyl t-butyl ether). MS (m/z): 397 (M+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@@H:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:48]([N:42]1[CH2:43][CH2:44][CH2:45][C@@H:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41]1)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=C(C[C@@H]1CCCNC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCCN(C(=O)c2ccccc2)C1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 71 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide bis(trifluoroacetate) and benzoyl chloride as the starting materials in 71% yield. LCMS for C32H32ClN6O2 (M+H)+: m/z=567.0.