Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][N:22]3[CH:26]=[N:25][N:24]=[N:23]3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.[OH-].[Na+]>CO.ClCCl.CO>[N:22]1([CH2:21][CH2:20][N:19]2[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=[C:15]2[N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)[CH:26]=[N:25][N:24]=[N:23]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCn2cnnn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1ccc2c(c1)nc(N1CCCNCC1)n2CCn1cnnn1
Reaction time: 4 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (2.06 g) and methanol (15 mL). Add a solution of hydrochloric acid in dioxane (4 mL, 4 M, 16 mmol) and stir. After 4 hours, add a 1 M aqueous solution of sodium hydroxide until the pH is about 14. Concentrate in vacuo to remove most of the methanol and then extract 5 times with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 10% methanol/dichloromethane/0.5% concentrated aqueous ammonia to give 4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.30 (silica gel, 10% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[NH:20][CH2:21][CH2:22][N:23]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[N:23]([C:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])[CH2:22][CH2:21][N:20]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Clc1ccccc1CC1=NCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cccnc1Cl)N1CCN=C1Cc1ccccc1Cl
Reaction time: 2 h

Procedure:
Dissolve 2-chloro-3-pyridinylcarbonyl chloride (4.69g) in dichloromethane (25 ml), and add the solution to a stirred, cooled (ice bath) solution of 2-(2-chlorophenyl)methyl-imidazoline (4.30g) and diisopropylethylamine (7.69 ml) and dichloromethane (25 ml). Allow the resulting solution to stir 2 hours, then wash it with water, 1 M sodium bicarbonate solution, and with water. Dry the dichloromethane solution, using sodium sulfate, then filter and evaporate the solvent. Crystallize the residue from ethyl acetate to obtain 2-[(2-chlorophenyl)methyl]-1-[(2-chloro-3-pyridinyl) carbonyl]-4,5-dihydro-1H-imidazole, mp 128.5°-130° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[S:31]1[C:35]([C:36]([NH:38][NH2:39])=O)=[CH:34][CH:33]=[N:32]1.C(O)CCC>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:36]([C:35]3[S:31][N:32]=[CH:33][CH:34]=3)=[N:38][N:39]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: NNC(=O)c1ccns1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCCCO
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2ccns2)C1
Temperature: 110 °C

Procedure:
A solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37)(244 mg, 0.839 mmol) in dry dichloromethane (DCM) (2098 μl) was stirred at room temperature under an atmosphere of argon. Triethyloxonium tetrafluoroborate (175 mg, 0.923 mmol) was added and the resulting mixture was stirred for ¾ hours. After this time, 5-isothiazolecarbohydrazide (I84) (153 mg, 1.069 mmol) was added and the resulting mixture was stirred at room temperature for 60 hours (over the weekend). 1-Butanol (2098 μl) was added and the reaction mixture was heated to 110° C. for 2 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between DCM (approx 40 ml) and NaHCO3 (saturated aqueous solution approx. 20 ml). The organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to give a pale yellow coloured solid. The solid was purified using MDAP to give a white coloured solid.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH:16]=[CH:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:28][CH:27]=1)=O>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[C:16]([CH2:24][C:26]2[CH:37]=[CH:36][C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:27]=2)=[CH:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc2ccn(C(c3ccccc3)c3ccccc3)c2c1
Reactant: COC(=O)COc1ccc(C=O)cc1
Product: O=C(O)COc1ccc(Cc2cn(C(c3ccccc3)c3ccccc3)c3cc(Cl)ccc23)cc1

Procedure:
This compound was prepared from the 1-benzhydryl-6-chloro-1H-indole and methyl 2-(4-formylphenoxy)acetate according to the procedure in Example 117 Step 1.
Reaction SMILES: [C:1]([CH:5]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([C:20]1C=CC=C[C:21]=1[O-:22])(C)(C)C.[Na+].ClCC(OCC)=O>>[C:1]([CH:5]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([O:22][CH2:21][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1[O-]
Reactant: CC(C)(C)C(Oc1ccccc1)C(=O)Cl
Agent: [Na+]
Solvent: CCOC(=O)CCl
Product: CCOC(=O)C(Oc1ccccc1)C(C)(C)C

Procedure:
The synthesis of this product required the preparation of t-butylphenoxyacetyl chloride from sodium t-butylphenoxide and ethyl chloroacetate. The ethyl t-butylphenoxyacetate obtained is cleaved with potassium hydroxide in order to liberate the t-butylphenoxyacetic acid. The acid chloride is obtained by heating this acid in thionyl chloride. After removing the excess thionyl chloride, the t-butylphenoxyacetyl chloride is reacted with deoxyguanosine according to the procedure described by SCHULHOF et al. for 2-N-phenoxyacetyldeoxyguanosine [Nucleic Acids Res., 15(2), p. 397-415, (1987)].
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[C:8](I)=[C:9]([OH:17])[C:10]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:12]=1.C(=O)([O-])O.[Na+].[CH:24]([C:26]1(O)[CH2:29][CH2:28][CH2:27]1)=[CH2:25]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]2[C:8]=1[CH:25]=[CH:24][C:26]1([O:17]2)[CH2:29][CH2:28][CH2:27]1
Reactant: C=CC1(O)CCC1
Reactant: Oc1c(OC(F)F)ccc(Br)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(Br)c2c1OC1(C=C2)CCC1
Temperature: 140 °C
Reaction time: 4 h
Yield: 7 %

Procedure:
To 48 ml of N,N-dimethylformamide solution containing 10.0 g (27.5 mmol) of 3-bromo-6-difluoromethoxy-2-iodophenol obtained in Reference example 12-(f) were added 0.62 g (2.8 mmol) of palladium acetate, 9.2 g (110 mmol) of sodium hydrogencarbonate and 3.23 g (32.9 mmol) of 1-vinylcyclobutanol (see J. Org. Chem., 1977, 42, 300-305) under argon atmosphere, and the mixture was stirred at 140° C. for 4 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.61 g of the title compound as a pale yellowish oil. (Yield: 70%)
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>>[Cl:24][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: CCOC(=O)c1c(N(CC)CC)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)c1nc2ccc(Cl)cc2c(Cc2ccccc2Cl)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 12 step B from a mixture of 6-chloro-4-(2-chloro-benzyl)-2-diethylamino-quinoline-3-carboxylic acid ethyl ester (50 mg, 0.116 mmol) and 1N NaOH. Pale yellow solid (32 mg, 68%). LC-MS (ESI): 403 (M+H)+.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:28][CH3:29])=[C:12]([S:19][CH2:20][CH:21](OCC)OCC)[CH:13]=2)[CH:8]=1)C.ClC1C=CC=CC=1.ClCCl>CO>[CH3:29][O:28][C:11]1[C:12]2[S:19][CH:20]=[CH:21][C:13]=2[C:14]2[CH:15]=[C:16]([O:17][CH3:18])[C:7]3[S:6][CH:5]=[CH:4][C:8]=3[C:9]=2[CH:10]=1
Reactant: CCOC(CSc1cc2cc(OC)c(SCC(OCC)OCC)cc2cc1OC)OCC
Solvent: Clc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c3ccsc3c(OC)cc2c2ccsc12
Temperature: 140 °C
Yield: 64.6 %

Procedure:
2,6-Bis-(2,2-diethoxy-ethylsulfanyl)-3,7-dimethoxy-naphthalene (5.0 g, 10.3 mmol) and 6.8 g of 84% polyphorphoric acid were added into a 250 mL 3-neck flask equipped with a condenser. The system was flashed with argon for 15 minutes before 50 mL of anhydrous chlorobenzene was added. The mixture was heated at 140° C. for 40 hours before it was cooled down to room temperature. Dichloromethane (100 mL) was added. The organic mixture was washed with saturated NaHCO3 before the solvent was removed under vacuum. Methanol (100 mL) was added before 5,10-dimethoxy-1,6-dithia-dicyclopenta[a,f]naphthalene (2.0 g, ˜66% yield) was collected as a white solid by filtration, washed with methanol and dried in vacuo. 1H NMR (CDCl3, 500 MHz): δ 7.97 (d, 2H, J=5.5 Hz), δ 7.62 (d, 2H, J=5.5 Hz), δ 7.51 (s, 2H), δ 4.18 (s, 6H).
Reaction SMILES: [C:1]1([S:7]([O-:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:12][P+:13]([CH2:18]O)([CH2:16]O)[CH2:14]O.[CH3:20][NH:21][C:22]([NH:24][CH3:25])=[O:23]>C1(C)C=CC=CC=1>[C:1]1([S:7]([O-:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:23]=[C:22]1[N:24]([CH3:25])[CH2:16][P+:13]2([CH2:12][N:24]([CH3:25])[C:22](=[O:23])[N:21]([CH3:20])[CH2:14]2)[CH2:18][N:21]1[CH3:20]
Reactant: CNC(=O)NC
Reactant: OC[P+](CO)(CO)CO
Agent: O=S(=O)([O-])c1ccccc1
Solvent: Cc1ccccc1
Product: CN1C[P+]2(CN(C)C1=O)CN(C)C(=O)N(C)C2
Yield: 111.2 %

Procedure:
Reaction of tetrakis(hydroxymethyl)phosphonium benzenesulfonate (31.23 g, 0.1 mol) with 1,3-dimethylurea (17.62 g, 0.2 mol) in toluene (100 ml), following Example 19, gave 46.30 g of 3,9-dioxo-2,4,8,10-tetramethyl-2,4,8,10-tetraaza-6-phosphoniaspiro [5.5]undecane benzenesulfonate (II, R=R'=CH3, X=SO3C6H5) as a caramel-colored, low-melting solid.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)OC2CCN(C)C(=O)N2c2nnc(C3CC3)s2)cc1

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 4-Methoxybenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(4-methoxybenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[O:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[C:10]=2[C:11]=1[CH3:12].[NH3:15]>>[CH3:1][C:2]1[C:3](=[O:4])[NH:15][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[C:10]=2[C:11]=1[CH3:12]
Reactant: Cc1c2c(oc(=O)c1C)CCCC2=O
Reactant: N
Product: Cc1c2c([nH]c(=O)c1C)CCCC2=O

Procedure:
Prepared from 3,4-dimethyl-5,6,7,8-tetrahydro-cumarin- 5-one (melting point: 109°-111° C., prepared from methyl 2methylacetoacetate and cyclohexan-1,3-dione) and methanolic ammonia for one hour in an autoclave at 150° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.[F:24][C:25](I)([F:27])[F:26]>[Cu].CN(C)C=O>[F:24][C:25]([F:27])([F:26])[C:2]1[CH:3]=[C:4]([C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:9]([F:12])([F:11])[F:10])[CH:18]=2)([C:13]([F:15])([F:14])[F:16])[C:9]([F:10])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)I
Reactant: FC(F)(F)C(c1cccc(I)c1)(c1cccc(I)c1)C(F)(F)F
Agent: [Cu]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(C(c2cccc(C(F)(F)F)c2)(C(F)(F)F)C(F)(F)F)c1
Temperature: 150 °C

Procedure:
A 500 mL autoclave was charged with 44.5 g (80.0 mmol) of 2,2-bis[3-iodophenyl]-1,1,1,3,3,3-hexafluoropropane, 40.09 (204 mmol) of trifluoromethyl iodide, 150 mL of dry N,N-dimethylformamide and copper powder (catalyst), and the mixture was heated at a temperature of 150° C. for 24 hours with stirring. After being cooled, the reaction mixture was filtered to remove the copper powder, and the filtrate was fractionally distillated under a reduced pressure to obtain the aimed compound 2Aa.
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([N:46]2[CH:50]=[C:49]([NH:51][C:52]3[N:57]=[C:56]([CH2:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=4[CH2:66][C:67]([OH:69])=O)[C:55]([CH3:70])=[CH:54][N:53]=3)[CH:48]=[N:47]2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C=O)C>[NH2:7][C:67](=[O:69])[CH2:66][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=1[CH2:59][CH2:58][C:56]1[C:55]([CH3:70])=[CH:54][N:53]=[C:52]([NH:51][C:49]2[CH:48]=[N:47][N:46]([CH:43]3[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:39])[CH2:41][CH2:42]3)[CH:50]=2)[N:57]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1cnc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1CCc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HOBt (0.051 g, 0.379 mmol), EDCl.HCl (0.081 g, 0.42 mmol) and DIPEA (0.11 mL, 0.65 mmol) were added to a solution of 2-(2-(2-(2-((1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-ylethyl)phenyl)acetic acid (A127) (0.068 g, 0.131 mmol) in dry DMF (5 mL) under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (0.126 g, 1.31 mmol) was added in one portion and the resulting mixture stirred for 18 hours at room temperature. Additional HOBt (0.051 g, 0.38 mmol), EDCl.HCl (0.081 g, 0.42 mmol), DIPEA (0.11 mL, 0.65 mmol) and ammonium carbonate (0.126 g, 1.31 mmol) were added to the reaction mixture and the mixture stirred for 12 days at room temperature. The volatiles were removed in vacuo then the residue diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine (25 mL) and dried over Na2SO4. The solvent was removed in vacuo to afford a yellow oil that was purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. followed by 0-30% MeOH in EtOAc) to give the title compound A127 as an off white solid (0.044 g, 65%); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.85 (s, 1H), 7.50 (d, J=0.5 Hz, 1H), 7.26-7.17 (m, 5H), 5.79 (s, 1H), 5.62 (s, 1H), 4.26-4.19 (m, 3H), 3.65 (s, 2H), 3.07 (dd, J=9.5, 6.2 Hz, 2H), 2.93-2.82 (m, 4H), 2.15-2.08 (m, 2H), 2.04 (s, 3H), 1.91 (qd, J=12.3, 4.3 Hz, 2H), 1.46 (s, 9H). LCMS-A: rt 5.178 min; m/z 520 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])=[O:5])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:4]([OH:5])[CH:1]1[CH2:3][CH2:2]1
Reactant: Nc1ccccc1C(=O)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccccc1C(O)C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a solution of o-aminophenyl cyclopropyl ketone (7.78 g, 48.3 mmol) in tetrahydrofuran at 0° C. is added 29 mL of a 1.0M lithium aluminum hydride solution in tetrahydrofuran. The reaction mixture is stirred at 0° C. for 2 hours, warmed to and stirred at room temperature for 16 hours, quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and 30% to 50% ethyl acetate in hexanes solutions gives the title product as a yellow solid (5.02 g, 64%, mp 76°-79° C.) which is identified by 1HNMR and MS spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](N)[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18].[ClH:19].N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:19])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:10]1=[O:18]
Reactant: Cl
Reactant: CC1(C)CC(=O)C(c2ccc(N)cc2Cl)C(=O)C1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(=O)C(c2ccc(Cl)cc2Cl)C(=O)C1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
A suspension of 5.00 g (0.0188 mol) of 2-(2'-chloro-4'-aminophenyl)-5,5-dimethyl-1, 3-cyclohexanedione in 75 ml of water containing 4.0 ml of concentrated HCl was stirred and heated almost to boiling for 10 min., then cooled to 10° C. and an additional 7 ml of conc. HCl added and the solution cooled to 0°-5° C. A solution of 2.00 g (0.0282 mol) of sodium nitrite in 6.0 ml of water was added dropwise to the amine hydrochloride solution while maintaining the temperature at 0°-5° C. When all the NaNO2 solution had been added, the diazonium salt solution was stirred for 30 min. at 0° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][C:34]([F:37])([F:36])[F:35])[CH2:22][CH2:21]1.NCCCN1CCN(C2C=CC(F)=CC=2OCC(F)(F)F)CC1>>[C:5]1([C:8]2[C:12]([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][N:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH2:33][C:34]([F:36])([F:37])[F:35])[CH2:24][CH2:25]3)=[O:15])=[CH:11][O:10][N:9]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1
Reactant: O=C(O)c1conc1-c1ccc(F)cc1
Agent: NCCCN1CCN(c2ccc(F)cc2OCC(F)(F)F)CC1
Product: O=C(NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1)c1conc1-c1ccccc1
Yield: 88 %

Procedure:
The title compound was prepared according to the procedure described in Example 8, but substituting compound 15B for Compound 8D and Compound 12B for Compound 8B. Purification by flash chromatography (ethyl acetate-2 N ammonia in methanol 95:5) yielded the title product (88%). M.p. 94.5-95.6° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:29][CH:28]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)o2)c1

Procedure:
The methyl ester (16) (100 mg, 0.30 mmol) was coupled to 4-(trifluoromethoxy)-phenylboronic acid (67 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:14]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][N:21]=[C:22]=[O:23].CC(C)=O.CO.C(Cl)Cl>CCOC(C)=O.[Cu]Cl>[CH3:20][NH:21][C:22](=[O:23])[O:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][N:11]=[C:10]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:14]=2[CH:15]=1
Reactant: CN=C=O
Reactant: Oc1ccc2onc(NCCN3CCOCC3)c2c1
Agent: Cl[Cu]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)=O
Product: CNC(=O)Oc1ccc2onc(NCCN3CCOCC3)c2c1
Yield: 32.9 %

Procedure:
To a stirred solution of 3-[[2-(4-morpholinyl)ethyl]-amino]-1,2-benzisoxazol-5-ol (1 g) and a catalytic amount of copper(I)chloride (0.05 g) in EtOAc (100 ml) was added methyl isocyanate (0.26 g). After 24 hours TLC (silica gel, 1:1:20 acetone/MeOH/DCM) showed no starting material. The reaction was filtered through neutral alumina during with EtOAc (1 l) and the filtrate was concentrated in vacuo. The residue was further purified by flash chromatography (silica gel) eluting with 1:1:20 acetone/MeOH/DCM to yield 0.4 g of the product, m.p. 135°-136° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:12][CH2:13][CH:14](C)[C:15]([NH2:17])=[O:16])[CH2:10][CH3:11])=[C:5]([F:19])[C:4]=1[C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21].[OH-].[Na+].C([NH2:34])(=O)C=C.Cl>C(O)C.O.C(Cl)Cl>[NH2:34][C:25]1[N:24]=[CH:23][C:22]([C:20]([C:4]2[C:5]([F:19])=[C:6]([C@H:9]([NH:12][CH2:13][CH2:14][C:15]([NH2:17])=[O:16])[CH2:10][CH3:11])[CH:7]=[CH:8][C:3]=2[Cl:2])=[O:21])=[CH:27][CH:26]=1
Reactant: C=CC(N)=O
Reactant: CC[C@@H](NCC(C)C(N)=O)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC[C@@H](NCCC(N)=O)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
Example 1 (200 mg, 0.58 mmol) was partitioned between DCM (5 mL) and water (3 mL) basified to pH 12 with 5M NaOH. The organic phase was isolated by phase separator and blown down into a microwave vial. Acrylamide (41 mg, 0.58 mmol, 1 eq.) and MnCl2.4H2O (57 mg, 0.29 mmol, 0.5 eq.) was heated in ethanol (0.9 mL) and water (0.1 mL) in the microwave at 100 degC for 30 min. Only partial reaction, so further acrylamide and MnCl2 (same amounts) were added and the reaction heated for 30 min at 100° C. Still not complete so reaction heated as is for another 30 min at 100° C. The mixture then partitioned between EtOAc (15 mL) and water (10 mL) (plus drop of 5M NaOH) and then the aqueous extracted with further EtOAc (15 mL). Combined organics were washed with water (10 mL) and brine (10 mL) and then dried (MgSO+), filtered and concentrated. Purified by chiral HPLC normal phase, eluting EtOH and heptane. Concentrated and then dissolved in DCM (2 mL) and 1.1 eq. 2M HCl in Et2O added. Concentrated and dried in a vacuum oven to give 3-{[(1R)-1-{3-[(6-aminopyridin-3-yl)carbonyl]-4-chloro-2-fluorophenyl}propyl]amino}-propanamide (56 mg, 0.15 mmol, 25%) as an HCl salt and white solid.