Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[Br:12]C1(Br)C(=O)NC(=O)NC1=O>C(OCC)C>[Br:12][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])=[O:3]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Solvent: CCOCC
Product: N#Cc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 162.3 %

Procedure:
To a solution of 1.02 g (7.04 mmol) of 3-acetylbenzonitrile in 70 mL of ethylether was added 1.02 g (3.52 mmol, 0.5 equiv) of dibromobarbituric acid. The mixture was allowed to stir at room temperature overnight. The resultant white slurry was filtered and the filtrate was concentrated. Purification by flash chromotography (silica gel, 20% ethyl acetate/hexane) gave 1.28 g (81%) of the title compound as a whim solid: 1H NMR (400 MHz, CDCl3) δ8.26 (t, 1H, J=1.4 Hz), 8.20 (td, 1H, J=1.5, 8.0 Hz), 7.87 (dd, 1H, J=1.3, 7.8 Hz), 7.64 (t, 1H, J=7.9 Hz), 4.40 (s, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]2[O:13][C@@:14]3([CH2:22][N:23]=2)[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]3)[N:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]2[O:13][C@@:14]3([CH2:22][N:23]=2)[CH:19]2[CH2:18][CH2:17][N+:16]([O-:29])([CH2:21][CH2:20]2)[CH2:15]3)[N:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2cc(NC3=NC[C@]4(CN5CCC4CC5)O3)ncc2c1
Product: [O-][N+]12CCC(CC1)[C@@]1(CN=C(Nc3cc4ccccc4cn3)O1)C2
Yield: 83.7 %

Procedure:
By a method similar to that used in Example 1, (S)—N-(isoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (108 mg, 0.350 mmol) and 3-chlorobenzoperoxoic acid (72.5 mg, 0.420 mmol) gave (R)-2-(isoquinolin-3-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (95 mg, 83% yield). 1H NMR (500 MHz, MeOD) δ ppm 9.04 (1H, s), 7.97 (1H, d, J=8.24 Hz), 7.76 (1H, d, J=8.24 Hz), 7.61-7.67 (1H, m), 7.44-7.49 (2H, m), 4.03 (1H, d, J=10.99 Hz), 3.87 (1H, d, J=10.99 Hz), 3.65-3.77 (2H, m), 3.44-3.53 (3H, m), 3.27-3.31 (1H, m), 2.43-2.55 (1H, m), 2.32 (1H, br. s.), 2.04-2.22 (3H, m). LCMS: RT=0.54 min, MH+=325.2 [ Waters Acquity SDS: 2 to 98% B, 1 min gradient; hold 98% B, 0.5 min; flow rate 0.8 mL/min; Solvent A: 100% H2O/0.05% TFA; Solvent B: 100% ACN/0.05% TFA].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][CH2:29][NH2:30])=[CH:24][NH:25]2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([NH:30][CH2:29][CH2:28][C:23]2[C:22]3[C:26](=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[NH:25][CH:24]=2)=[O:13])[CH:7]=1
Reactant: COc1ccc2c(CCN)c[nH]c2c1
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(CCNC(=O)c3cc(Cc4cccc(F)c4)on3)c[nH]c2c1
Yield: 34.6 %

Procedure:
A solution of the 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g; 0.257 mmol), 2-(6-methoxy-1H-indol-3-yl)ethanamine (0.054 g; 0.284 mmol), HATU (0.108 g; 0.284 mmol) and N,N-diisoprpylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.035 g (38%) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[ClH:20]>>[ClH:20].[CH2:16]([N:13]1[CH2:12][CH2:11][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:19])=[O:2])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)[CH2:17][CH3:18]
Reactant: CCCN1CCC(c2ccc(C(=O)OC)cc2)CC1
Agent: Cl
Product: CCCN1CCC(c2ccc(C(=O)O)cc2)CC1
Temperature: 2 °C

Procedure:
4-(1-Propyl-piperidin-4-yl)-benzoic acid methyl ester (32 mmol) is dissolved in 4N HCl (45 ml) and heated under reflux for 7 hours. The mixture is cooled in an ice bath to 0-4° C. and the solid material formed is filtered off, washed with cold acetone and dried (vacuum). A brown powder with mp. >270° C., Rf=0.08 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:16]=[N:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22][C:23]1[C:35](=[O:36])[N:34]([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:26]2[N:27]=[C:28](S(C)=O)[N:29]=[CH:30][C:25]=2[C:24]=1[CH3:42].C1(=O)OC(=O)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2[CH:16]=[N:17][C:18]([NH:21][C:28]3[N:29]=[CH:30][C:25]4[C:24]([CH3:42])=[C:23]([Br:22])[C:35](=[O:36])[N:34]([CH:37]5[CH2:38][CH2:39][CH2:40][CH2:41]5)[C:26]=4[N:27]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(N)nc2)CC1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Agent: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(C4CCCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Reaction time: 3 h
Yield: 43.4 %

Procedure:
A solution of 4-(6-amino-pyridin-3-yl)-azepane-1-carboxylic acid tert-butyl ester (614 mg, 2.10 mmol) in toluene (10 mL) was refluxed in a Dean-Stark apparatus for 3 h. The heat was removed and when the reflux subsided 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (700 mg, 1.89 mmol) was added. This mixture was refluxed for 12 h under N2. Succinic anhydride (500 mg) was added and the reflux continued for 3 h. The reaction mixture was cooled and dissolved in ethyl acetate (100 ml) and the organic layer was washed with water (100 mL total). The organic layer was dried over magnesium sulfate and the solvents evaporated. The crude product was subjected to chromatography on silica gel and eluted with a chloroform/2-propanol gradient to give 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-azepane-1-carboxylic acid tert-butyl ester as a yellow powder (414 mg, 0.82 mmol). MS (APCI+) 500, 600 (M+1, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2([OH:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2([OH:45])[CH2:40][CH2:41][N:42]([C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:30])([F:29])[F:31])[C:9]=5[CH:17]=4)[CH:19]=3)=[O:23])[CH2:43][CH2:44]2)=[CH:35][CH:34]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(4-chlorophenyl)-4-hydroxypiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=640.96 (M+H+); retention time=0.95 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][C:2]=1[OH:8].OS(O)(=O)=O.[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:3]1[C:2]([OH:8])=[N:1][CH:6]=[CH:5][C:4]=1[OH:7])([O-:16])=[O:15]
Reactant: Oc1ccnc(O)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(O)ccnc1O
Yield: 90 %

Procedure:
A 100 mL 3-necked round bottom flask was charged with pyridine-2,4-diol (9.0 g, 81 mmol) and concentrated H2SO4 (40 mL). To the above solution was added dropwise fuming HNO3 (40 mL) at 0° C. Work-up: the mixture was poured onto crushed ice and chilled in freezer. The resulting precipitate was collected by filtration, washed with cold water and dried in vacuo, to afford 11.4 g (90%) of the product as a colorless solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][CH:13]([CH3:33])[CH2:14][N:15]1[C:27]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[NH:28][C:29](=[O:32])[O:30][CH3:31]>ClCCl>[CH3:12][CH:13]([CH3:33])[CH2:14][N:15]1[C:27]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:20]([O-:6])=[CH:19][C:18]=2[N:17]=[C:16]1[NH:28][C:29](=[O:32])[O:30][CH3:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Nc1nc2cnc3cccnc3c2n1CC(C)C
Solvent: ClCCl
Product: COC(=O)Nc1nc2c[n+]([O-])c3cccnc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 76 h
Yield: 57 %

Procedure:
3-Chloroperoxybenzoic acid (1.73 g of approximately 75% pure material) was added to a stirred solution of methyl [1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]carbamate (1.5 g, 5.01 mmol) in dichloromethane (40 mL), and the reaction was stirred for 76 hours at room temperature. A precipitate formed and was collected by filtration, washed with a minimal amount of dichloromethane, and dried to provide 0.9 g of methyl [1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]carbamate as a solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:6]2=[N:5][C:4]2[CH2:15][CH2:16][CH2:17][C:3]1=2.S(=O)(=O)(O)O.[CH3:23]O>>[O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:23])=[O:13])[C:6]2=[N:5][C:4]2[CH2:15][CH2:16][CH2:17][C:3]1=2
Reactant: O=C(O)c1cccn2c(=O)c3c(nc12)CCC3
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccn2c(=O)c3c(nc12)CCC3

Procedure:
A suspension of 7.0 g. of the product from Example 4, 500 ml of absolute methanol, and 18.4 g. of concentrated sulfuric acid is stirred and heated under reflux for 48 hours. A clear solution forms after that heating period. The solution is concentrated in vacuo, the residue is cooled, dissolved in 200 ml of ether, and the ether solution is washed with saturated aqueous sodium bicarbonate until the washings remain at pH 7.6. The ether solution is dried an concentated to give the named compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:21])[CH:11]3[CH:16]([C:17]=2[O:18]C)[CH:15]2[O:20][CH:12]3[CH2:13][CH2:14]2)=[C:4]([CH3:22])[CH:3]=1.[F-].[Cs+].CN(C)C=O.[CH2:30]([Sn](CCCC)(CCCC)C#CC)[CH2:31][CH2:32]C>O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:8][C:6]1[CH:7]=[C:2]([C:30]#[C:31][CH3:32])[CH:3]=[C:4]([CH3:22])[C:5]=1[CH:9]1[C:10](=[O:21])[CH:11]2[CH:16]([CH:15]3[O:20][CH:12]2[CH2:13][CH2:14]3)[C:17]1=[O:18]
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C2C3CCC(O3)C12
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC#Cc1cc(C)c(C2C(=O)C3C4CCC(O4)C3C2=O)c(C)c1
Temperature: 120 °C

Procedure:
To (1RS,2SR,6RS,7SR)-4-(4-bromo-2,6-dimethylphenyl)-5-methoxy-10-oxa-tricyclo[5.2.1.02,6]dec-4-en-3-one (0.40 g, 1.10 mmol), cesium fluoride (0.34 g, 2.20 mmol), cuprous iodide (0.04 g, 0.22 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.12 g, 0.17 mmol) under nitrogen atmosphere is added anhydrous dimethylformamide (3.8 g, 4 ml, 51 mmol) followed by tributyl(prop-1-ynyl)stannane (1.10 g, 1.0 ml, 3.3 mmol). The mixture is heated at 120°C. under microwave irradiation for 60 minutes then diluted with water (50 ml) and ethyl acetate (50 ml) and filtered through a bed of diatomaceous earth. The residue is washed with ethyl acetate and the crude product is extracted with ethyl acetate (50 ml×2). The combined organic fractions are washed with distilled water then brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash column chromatography to afford (1RS,2SR,6RS,7SR)-4-(2,6-dimethyl-4-prop-1-ynylphenyl)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH:8]=O.Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1/[CH:8]=[N:20]/[NH:19][C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=Cc1c(Br)cncc1Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1ccc(N/N=C/c2c(Br)cncc2Br)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 3,5-dibromo-4-pyridinecarboxaldehyde (30.0 g, 113 mmol) in ethanol (1200 mL) at reflux was added 4-fluorophenylhydrazine hydrochloride (20.0 g, 123 mmol) in several portions followed by a solution of sodium acetate (31.0 g, 228 mmol) in water (200 mL). The mixture turned from a deep red to a bright yellow and over time a yellow solid precipitated. After 20 minutes, the mixture was cooled, diluted with water (1000 mL) and the yellow solid was collected by filtration. The solid was washed with water and dried to afford N-[1-(3,5-dibromopyridin-4-yl)-meth-(E)-ylidene]-N′-(4-fluorophenyl)-hydrazine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([S:26]([NH2:25])(=[O:28])=[O:27])=[CH:30][CH:31]=3)[CH:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(S(N)(=O)=O)cc3)c2)n1

Procedure:
The title compound was prepared from 2′-chloro-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.28) (0.150 g, 0.430 mmol) and commercially available (4-aminosulfonylphenyl)boronic acid [CAS-No. 613660-87-0] (0.146 g, 0.516 mmol) according to the general procedure VI. Obtained as a white solid (0.075 g, 37%). MS (ISP) 470.3 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[C:16]2=[O:31])=[C:12]2[C:8]([C:9]([CH3:34])=[C:10]([CH3:33])[N:11]2[CH3:32])=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>O1CCOCC1.O>[CH3:1][O:2][C:3]([C:5]1[C:13]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:16]2=[O:31])=[C:12]2[C:8]([C:9]([CH3:34])=[C:10]([CH3:33])[N:11]2[CH3:32])=[CH:7][CH:6]=1)=[O:4]
Reactant: CCOC(=O)CCn1c(=O)n(Cc2c(C(=O)OC)ccc3c(C)c(C)n(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C)c(C)n(C)c2c1Cn1c(=O)n(CCC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
To a solution of 7-[3-(2-Ethoxycarbonyl-ethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl]-1,2,3-trimethyl-1H-indole-6-carboxylic acid methyl ester (60 mg, 0.13 mmol) in 1,4-dioxane (5 mL) and H2O (2 mL) was added LiOH (6.4 mg). The solution was stirred at room temperature for 5 hours. The solution was concentrated and the residue was purified by CombiFlash with 10% MeOH in CH2Cl2 as the eluent to afford the desirable product 7-[3-(2-Carboxy-ethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl]-1,2,3-trimethyl-1H-indole-6-carboxylic acid methyl ester (10 mg, 17%) as a white solid. LC-MS (M+): 435.36.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[I:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>ClCCl>[N:1]1([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([I:16])=[CH:18][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCc1ccc(I)cc1
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Ic1ccc(CN2CCCCC2)cc1
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a mixture of 0.31 g of piperidine (3.6 mmol) and 0.47 g of N,N-diisopropylethylamine 3.6 mmol) in 10 mL of dichloromethane was added 0.90 g of 4-iodobenzylbromide (3 mmol). The mixture was allowed to stir for 16 h and partitioned between 50 mL of EtOAc and 50 mL of water. The layers were separated and the EtOAc was washed with 25 mL of brine, dried (MgSO4) and concentrated in vacuo to give 0.90 g of 4-(N-piperidinylmethyl)iodobenzene. The product was used without further purification.
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C@H:17]3[CH2:22][CH2:21][C@@H:20]([C:23]([F:26])([F:25])[F:24])[CH2:19][CH2:18]3)[CH:12]=2)[CH:7]=1)([CH3:5])[CH2:3][OH:4].C[C@@]1(C2C=CC3C(=CC=C(O[C@H]4CC[C@H](C(F)(F)F)CC4)C=3)C=2)COC(=O)N1>>[NH2:1][C@@:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([C:23]([F:24])([F:25])[F:26])[CH2:19][CH2:18]3)[CH:12]=2)[CH:7]=1)([CH3:5])[CH2:3][OH:4]
Reactant: C[C@](N)(CO)c1ccc2cc(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1
Agent: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@H](C(F)(F)F)CC4)ccc3c2)COC(=O)N1
Product: C[C@](N)(CO)c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1

Procedure:
(R)-2-Amino-2-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol was synthesized as per (R)-2-amino-2-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol (Example 259) in 83% yield using (R)-4-Methyl-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one as the starting material. MS: m/z=351.20 [M-NH2]+. 1H NMR (400 MHz, METHANOL-d4) δ ppm: 7.86 (d, J=2.0 Hz, 1H), 7.73-7.80 (m, 2H), 7.57 (dd, J=8.8, 2.0 Hz, 1H), 7.26 (d, J=2.5 Hz, 1H), 7.12 (dd, J=8.9, 2.4 Hz, 1H), 4.39-4.49 (m, 1H), 3.74 (d, J=11.0 Hz, 1H), 3.67-3.72 (m, 1H), 2.29-2.38 (m, 2H), 2.19-2.30 (m, 1H), 2.03-2.11 (m, 2H), 1.46-1.66 (m, 7H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:12]2[C:13](=[O:17])[NH:14][CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH3:27])[N:21]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:12]2[C:13](=[O:17])[N:14]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH3:27])[N:21]=3)[CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCn2nc(OCc3ccccc3)cc21
Reactant: COc1nccc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COc1nccc(N2CCn3nc(OCc4ccccc4)cc3C2=O)n1
Temperature: 100 °C
Reaction time: 24 h
Yield: 35.4 %

Procedure:
Palladium (II) acetate (2.8 mg, 0.012 mmol) was added to a stirred suspension of 2-(benzyloxy)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.1 g, 0.41 mmol), 4-chloro-2-methoxy-pyrimidine (0.120 g, 0.82 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (17.7 mg, 0.037 mmol) and Cs2CO3 (0.19 g, 0.58 mmol) in 1,4-dioxane (2 mL). The mixture was stirred at 100° C. for 24 hours. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in MeOH in DCM 0/100 to 95/5). The desired fractions were collected, the solvents evaporated in vacuo and the residue triturated with diethyl ether to yield 2-(benzyloxy)-5-(2-methoxypyrimidin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (51 mg, 35% yield) as a white solid. C18H12N5O3. 1H NMR (500 MHz, CDCl3) δ ppm 4.03 (s, 3H), 4.33 (dd, J=6.6, 5.2 Hz, 2H), 4.64 (dd, J=6.6, 5.2 Hz, 2H), 5.23 (s, 2H), 6.40 (s, 1H), 7.31-7.36 (m, 1H), 7.39 (t, J=7.4 Hz, 2H), 7.42-7.48 (m, 2H), 7.89 (d, J=5.8 Hz, 1H), 8.44 (d, J=5.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].[CH:13](Br)([CH3:15])[CH3:14]>>[Cl:1][C:2]1[C:10]([O:11][CH:2]([CH3:10])[CH3:3])=[CH:9][C:5]([C:6]([O:8][CH:13]([CH3:15])[CH3:14])=[O:7])=[CH:4][C:3]=1[O:12][CH:5]([CH3:6])[CH3:4]
Reactant: O=C(O)c1cc(O)c(Cl)c(O)c1
Reactant: CC(C)Br
Product: CC(C)OC(=O)c1cc(OC(C)C)c(Cl)c(OC(C)C)c1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Isopropyl 4-chloro-3,5-diisopropoxybenzoate (4) (43 mg, 0.12 mmol) was prepared from 4-chloro-3,5-dihydroxybenzoic acid (3) (72 mg, 0.38 mmol) using a procedure essentially the same as in step (i) for AAA-001 except that isopropyl bromide (8 eq.) was used instead of cyclopentyl bromide and the mixture was stirred at 50° C. for 20 h: 1H NMR (400 MHz, CDCl3) δ: 7.25 (2H, s), 5.23 (1H, sep), 4.63 (2H, sep), 1.38 (18H, m).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C:24](=O)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH:24]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Nc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)C1
Yield: 70 %

Procedure:
Intermediate 6 was coupled with 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester following procedure J. The product was purified on silica gel using 1:1 ethyl acetate:hexanes as eluent. Yield: 70%. LC-MS showed the product had the expected M+H+ of 375.
Reaction SMILES: CC1[N:3]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[N:13]([CH3:19])[C:12]=3[CH:20]=2)C(C)=CC=1.Cl.NO.C(N(CC)CC)C>C(O)C.O>[NH2:3][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[N:13]([CH3:19])[C:12]=2[CH:20]=1
Reactant: Cc1ccc(C)n1-c1ccc2c(c1)N(C)C(=O)CCC2
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CN1C(=O)CCCc2ccc(N)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 889.6 %

Procedure:
8-(2,5-Dimethyl-pyrrol-1-yl)-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (175 mgs, 0.065 mmol) was treated with hydroxylamine hydrochloride (20 eq), triethylamine (10 eq) in ethanol/water (4:1, 6 mL) and heated to 80° C. overnight. The mixture was concentrated, partitioned between EtOAc and water, dried (MgSO4) filtered and concentrated. The mixture was stirred 2 h with excess 1N HCl, neutralized to pH 7 with 1 NaOH, partitioned between EtOAc and water, dried (MgSO4) filtered and concentrated to give 8-Amino-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (110 mgs, 58%). 6.95 (d, J=7.8 Hz, 1H), 6.50-6.47 (m, 2H), 3.67 (br s, 2H), 3.30 (s, 3H), 2.61-2.57 (m, 2H), 2.32-2.28 (m, 2H), 2.11-2.08 (m, 2H).
Reaction SMILES: [CH2:1]([NH2:11])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[Cl-].[CH3:13][O:14][C:15](=[O:19])[C:16](O)=[O:17]>>[CH3:13][O:14][C:15](=[O:19])[C:16]([NH:11][CH2:1]/[CH:2]=[C:3](\[CH3:4])/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[O:17]
Reactant: CC(C)=CCC/C(C)=C/CN
Reactant: COC(=O)C(=O)O
Agent: [Cl-]
Product: COC(=O)C(=O)NC/C=C(\C)CCC=C(C)C

Procedure:
Said substance is manufactured according to AAV 1, by converting geranylamine and oxalic acid monomethylester chloride with each other and the product is purified by column chromatography (pentane/diethyl ether=1/1).