Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][S:8][CH:9]1[CH2:30][CH:12]2[N:13]([N:20]=[CH:21][CH:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[OH:23])[C:14](=[O:19])[N:15]([CH2:16][CH2:17][CH3:18])[CH:11]2[CH2:10]1)=[O:4].[OH-].[Li+].Cl.O>CO.O>[C:3]([CH2:5][CH2:6][CH2:7][S:8][CH:9]1[CH2:30][CH:12]2[N:13]([N:20]=[CH:21][CH:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[OH:23])[C:14](=[O:19])[N:15]([CH2:16][CH2:17][CH3:18])[CH:11]2[CH2:10]1)([OH:4])=[O:2]
Reactant: CCCN1C(=O)N(N=CC(O)C2CCCCC2)C2CC(SCCCC(=O)OC)CC21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN1C(=O)N(N=CC(O)C2CCCCC2)C2CC(SCCCC(=O)O)CC21
Temperature: 45 °C
Yield: 84.9 %

Procedure:
The compound of Example 1 (1.4 g) was dissolved in methanol:water (2:1, 10 ml) and to the stirred solution was added lithium hydroxide (0.267 g). The resulting mixture was maintained at 45° C. for one hour. The pH was adjusted to 5.0 with 2N HCl, water (50 ml) was added and the product was extracted into chloroform (50 ml). After drying over anhy. sodium sulphate, the mixture was filtered and the filtrate concentrated in vacuo to give the desired product (1.15 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:12]2([CH2:14][CH2:13]2)[N:11]([C:16]([C:18]2[C:19]3[C:39]([CH3:40])=[N:38][N:37]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[C:20]=3[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30]C4CCCCO4)=[CH:26][CH:25]=3)[CH:23]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:12]2([CH2:13][CH2:14]2)[N:11]([CH2:16][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[N:21]=[C:20]3[N:37]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[N:38]=[C:39]([CH3:40])[C:19]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC34CC4)c12
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(CN3CCN(C(=O)OC(C)(C)C)CC34CC4)c12
Yield: 74 %

Procedure:
To a solution of 272 mg of) 4-{3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carbonyl}-4,7-diaza-spiro[2.5]-octane-7-carboxylic acid tert-butyl ester in 4 ml of dry THF 3.5 ml of borane-dimethyl-sulfide complex (1 M in DCM) was added slowly at r.t., and the reaction was heated to reflux for 60 min. The reaction was quenched by the addition of 2.2 ml of methanol, and the solvents were evaporated. The residue was purified by flash chromatography (silica, heptane/EtOAc gradient) to obtain 170 mg (74%) of the title compound.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[NH2:6][CH2:7][P:8]([OH:11])(=[O:10])[OH:9]>O>[P:8]([CH2:7][NH:6][CH2:2][C:1]([OH:5])=[O:4])([OH:11])([OH:10])=[O:9]
Reactant: NCP(=O)(O)O
Reactant: O=CC(=O)O
Solvent: O
Product: O=C(O)CNCP(=O)(O)O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
29.6 g (0.2 mol) of 50% strength aqueous glyoxylic acid solution were warmed to 40° C. with stirring. 11.1 g (0.1 mol) of aminomethanephosphonic acid were then added in portions at 40°-45° C., whereupon a vigorous evolution of gas commenced. After completion of the addition, the temperature was increased to an internal temperature of 85° C. After about 1 h, the evolution of gas was complete. The mixture was stirred for a further 15 min at 85° C., a little water was added, and the mixture was cooled. 10 g of N-phosphonomethylglycine, m.p.: 321°-323° C. [decomp.], were obtained. After concentration of the mother liquor and digestion of the precipitated crystal slurry using methanol/water, a further 2.5 g were obtained. The total yield was thus 74% of theory.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]([C:22]1[O:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1)([CH3:21])[CH3:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH:19]([CH3:21])[CH3:20])[O:23][C:24]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: CC(C)c1nc(C(=O)O)c(-c2ccccc2)o1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C(C)C)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-isopropyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH3:11])[C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH2:26]Br)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[CH2:24]([O:23][C:21]([CH:20]1[S:1][C:2]2=[N:7][C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=3[C:4](=[O:12])[N:3]2[CH2:26]1)=[O:22])[CH3:25]
Reactant: Cn1ncc2c(=O)[nH]c(S)nc21
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Cn2c(nc3c(cnn3C)c2=O)S1
Temperature: 80 °C
Reaction time: 6 h
Yield: 24.4 %

Procedure:
In 150 ml of dimethylformamide was dissolved 8.42 g (46.2 mmol) of 4,5-dihydro-6-mercapto-1-methylpyrazolo[3,4-d]pyrimidin-4(1H)-one [Helv. Chim. Acta, 42, 349 (1959)], and 12.8 g (92.4 mmol) of potassium carbonate and 18.0 ml (69.3 mmol) of ethyl 2,3-dibromopropionate were added to the solution, followed by stirring at 80° C. for 6 hours. After evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform to give 3.16 g (24%) of Compound 42. The compound was recrystallized from ethanol for purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.[C:34]([Mg]Cl)#[CH:35]>>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[C:34]#[CH:35])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Reactant: C#C[Mg]Cl
Product: C#CC(O)c1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Yield: 97.1 %

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (11B, 250 mg, 0.551 mmol) was added to a oven dried 20 mL microwave vial, charged with THF (10 ml), degassed under nitrogen and cooled to −78° C. To the mixture was added ethynylmagnesium chloride (1.322 ml, 0.661 mmol) dropwise and the reaction was slowly warmed to rt over 30 minutes. The reaction was quenched with saturated ammonium chloride, extracted 3×20 mL EtOAc, washed with brine, dried over sodium sulfate filtered and concentrated in vacuo to provide crude 1-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)prop-2-yn-1-ol (257 mg, 0.535 mmol, 97% yield) which was used without further purification. MS: [M+H]+ m/z 480.
Reaction SMILES: [F:1][C:2]1[C:3]([C:27](O)=[O:28])=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)[N:7]([CH3:25])[C:6]=2[CH:26]=1.C(O)(=O)C.[CH3:34][N:35]([CH3:40])[C:36](=[O:39])[CH2:37][NH2:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:34][N:35]([CH3:40])[C:36]([CH2:37][NH:38][C:27]([C:3]1[C:2]([F:1])=[CH:26][C:6]2[N:7]([CH3:25])[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:22])([F:23])[F:24])[CH:17]=[CH:16][C:14]=4[N:15]=3)=[N:9][C:5]=2[CH:4]=1)=[O:28])=[O:39]
Reactant: CN(C)C(=O)CN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)c(F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CN(C)C(=O)CNC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1F
Yield: 35.6 %

Procedure:
6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (32 mg) was prepared by following General Procedure F starting from 6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), glycine dimethylamide acetate (32 mg), HBTU (80 mg), and DIEA (46 uL). LC/MS: m/z 511.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.19-8.00 (m, 2H), 7.93 (s, 1H), 7.74 (d, 1H), 7.54 (d, 1H), 7.36 (d, 1H), 4.18 (d, 2H), 3.61 (bs, 3H), 3.01 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li].[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.O>O1CCCC1>[CH:17]1([C:16]2[C:15]([CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)=[C:25]([CH2:24][CH3:23])[CH:26]=[CH:27][CH:22]=2)[CH2:18][CH2:19][CH:20]=[CH:21]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cccc(C2C=CCC2)c1C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A solution of 67.8 mmol of lithiumfluorene in 50 cm3 of tetrahydrofuran is added to a solution of 11.4 g (67.8 mmol) of 6-methyl-6-phenyl-fulvene in 40 cm3 of tetrahydrofuran at room temperature. After the mixture had been stirred at room temperature for 2 hours, 60 cm3 of water were added. The substance which precipitated during this procedure was filtered off with suction, washed with diethyl ether and dried under an oil pump vacuum. 19.1 g (84.2%) of 2,2-cyclopentadienyl(9-fluorenyl)-ethylbenzene were obtained (correct elemental analyses; 1H-NMR spectra).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][C@H:23]1[C@@H:27]([CH3:28])[CH2:26][NH:25][CH2:24]1>N1C=CC=CC=1>[NH2:22][C@H:23]1[C@@H:27]([CH3:28])[CH2:26][N:25]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([F:17])[C:10]=2[F:16])[CH2:24]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: C[C@H]1CNC[C@H]1N
Solvent: c1ccncc1
Product: C[C@H]1CN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1N
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
In the same manner as described in Example 5, a mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, cis-3-amino-4-methylpyrrolidine, and pyridine was stirred at 50° C. for 30 minutes to give 7-(cis-3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 264°-265° C.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O-:3])=[O:2].[CH:12](=[O:15])[CH2:13][CH3:14].CC(O)C>CCCCCC>[CH:6]1([C@H:5]([CH2:4][N+:1]([O-:3])=[O:2])[C@H:13]([CH3:14])[CH:12]=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCC=O
Reactant: O=[N+]([O-])/C=C/C1CCCCC1
Solvent: CCCCCC
Solvent: CC(C)O
Product: C[C@H](C=O)[C@@H](C[N+](=O)[O-])C1CCCCC1

Procedure:
The title compound was prepared from (E)-(2-nitrovinyl)cyclohexane and propionaldehyde according to general procedure. The enantiomeric excess was determined by HPLC with Chiralpak AD-H column at 210 nm (2-propanol:hexane=1:99), 1 mL/min, tmajor=17.0 min, tminor=19.1 min, the diastereomeric ratio was determined by
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:9]([CH2:11][CH3:12])[N:10]=2)[N:7]=1.[CH3:17][O-:18].[Na+].Cl>CO>[CH2:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([O:18][CH3:17])=[N:7][N:6]2[C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14])[CH3:12]
Reactant: C[O-]
Reactant: CCc1nc2ccc(Cl)nn2c1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1nc2ccc(OC)nn2c1S(N)(=O)=O
Temperature: 0 °C

Procedure:
6-Chloro-2-ethylimidazo[1,2-b]pyridazin-3-ylsulfonamide (1.50 g, 5.75 mmol) was suspended in methanol (30.0 ml) and stirred at room temperature, during which sodium methoxide (28%, 3.34 g, 17.3 mmol) was added thereto. The mixture was heated for 5 hours under reflux, and then the reaction solution was poured into ice-water (200 ml) and adjusted to pH 2 with conc. hydrochloric acid. The precipitated crystals were filtered and washed with water, to give the title compound as colorless crystals. The yield was 1.02 g (69.3%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14]Cl.[NH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19]>>[CH2:18]([CH:17]([N:16]1[C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([CH3:12])[C:3]=2[CH2:13][CH2:14]1)[CH2:20][CH3:21])[CH3:19]
Reactant: CCC(N)CC
Reactant: Cc1cc2nc(C)c(CCCl)c(Cl)n2n1
Product: CCC(CC)N1CCc2c(C)nc3cc(C)nn3c21

Procedure:
A solution of 7-chloro-6-(2-chloroethyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine (4.0 g, 16 mmol), 3-aminopentane (40 mL) in acetonitryl (120 mL) was heated under reflux for nine hours. After evaporating, the residue was purified by silica gel column chromatography (20% ethyl acetate/hexane), to give the title compound (3.7 g) as white crystals.
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)#[N:4].[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:24]1[CH2:25][CH2:26][N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH:23]=1)#[N:4]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2[nH]cc(C3=CCN(Cc4ccccc4)CC3)c2c1
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a solution of 5.02 gm (89.0 mMol) potassium hydroxide in 50 mL methanol were added 5.00 gm (35.17 mMol) 5-cyano-1H-indole and 7.8 mL (42.08 mMol) 1-benzyl-4-piperidone. The reaction mixture was stirred for 16 hours at reflux and then was allowed to cool. The reaction mixture was then concentrated under reduced pressure. The resultant residue was subjected to flash chromatography, eluting with dichloromethane containing 5% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to give 11.0 gm of the title compound of sufficient purity to be used in subsequent reactions.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C@@H:3]([O:17][CH3:18])[CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[N:27][C:22]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][C@H:3]([O:17][CH3:18])[C:2]([F:1])([F:19])[F:20])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:23][CH:24]=1
Reactant: CO[C@@H](CN1CCc2ccc(N)cc2CC1)C(F)(F)F
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(C[C@H](OC)C(F)(F)F)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-((S)-3,3,3-trifluoro-2-methoxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide was prepared from 3-((S)-3,3,3-trifluoro-2-methoxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 328c. Product isolated as a yellow solid (57 mg, 26%). m.p.=160-162° C.; LCMS (m/e) 549 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.08 (s, 1H), 8.68 (d, 1H, J=8.5 Hz), 8.11 (s, 1H), 7.50 (d, 1H, J=7.9 Hz), 7.48-7.42 (m, 1H), 7.36 (s, 1H), 7.30-7.25 (m, 1H), 7.13-7.07 (m, 1H), 7.04 (d, 1H, J=8.0 Hz), 3.76-3.67 (m, 1H), 3.62 (s, 3H), 3.06 (d, 3H, J=4.7 Hz), 2.94-2.86 (m, 4H), 2.86-2.82 (m, 2H), 2.79-2.73 (m, 4H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:28][CH2:27][C:13]2([N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[NH:16][C:15](=[O:26])[CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:29]([O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)[CH:30]([CH3:32])[CH3:31]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:28][CH2:27][C:13]2([N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:16]([CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:35][CH:36]=3)[C:15](=[O:26])[CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)NN2Cc1ccc(F)cc1
Reactant: CC(C)COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(CN2C(=O)CC3(CCN(C(=O)OC(C)(C)C)CC3)N2Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
NaH (24 mg, 0.50 mmol) was added slowly to a solution of 84AF84-19 (0.149 g, 0.41 mmol) in dry DMF (5 mL) and the mixture stirred at rt for 30 min. A solution of 4-isobutoxybenzyl bromide 69NLS69 (117 mg, 0.48 mmol) in dry DMF (1 mL) was added dropwise to the mixture. After 1 h stirring at rt the mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with a stepwise gradient of 3-6% methanol in dichloromethane, followed by preparative reversed phase HPLC (C18) afforded the desired compound (109 mg, 50%).
Reaction SMILES: N1C=CC=CC=1.[SH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:14][C:15](=[CH:19][C:20]1[CH:25]=[C:24]([C:26]2[C:30]([Cl:31])=[C:29]([O:32][CH:33]([F:35])[F:34])[N:28]([CH3:36])[N:27]=2)[C:23]([Cl:37])=[CH:22][C:21]=1[Cl:38])[C:16](Cl)=[O:17]>O1CCCC1>[Cl:14][C:15](=[CH:19][C:20]1[CH:25]=[C:24]([C:26]2[C:30]([Cl:31])=[C:29]([O:32][CH:33]([F:35])[F:34])[N:28]([CH3:36])[N:27]=2)[C:23]([Cl:37])=[CH:22][C:21]=1[Cl:38])[C:16]([S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:17]
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)Cl)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: CCOC(=O)CS
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CSC(=O)C(Cl)=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(Cl)cc1Cl
Reaction time: 8 h

Procedure:
0.95 g (7.3 mmol) of pyridine and 0.88 g (7.3 mmol) of ethyl mercaptoacetate were added to a solution of 3.3 g (6.7 mmol) of 2-chloro-3-(2,4-dichloro-5-{4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)phenyl)propenoyl chloride in 70 ml of tetrahydrofuran. The reaction mixture was stirred for 8 hours and then concentrated. The crude product was purified by chromatography on silica gel (eluent: hexane/ethyl acetate =1:1). Yield: 2.1 g.
Reaction SMILES: [ClH:1].O1CCOCC1.[OH:8][C@@H:9]1[C@H:13]2[N:14]([C:18](=[O:32])[C@@H:19]([NH:24]C(=O)OC(C)(C)C)[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][C@@H:16]([CH3:17])[C@H:12]2[O:11][CH2:10]1>>[ClH:1].[NH2:24][C@@H:19]([C:20]([CH3:21])([CH3:23])[CH3:22])[C:18]([N:14]1[CH2:15][C@@H:16]([CH3:17])[C@H:12]2[O:11][CH2:10][C@H:9]([OH:8])[C@@H:13]12)=[O:32]
Reactant: C[C@@H]1CN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CN(C(=O)[C@@H](N)C(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 1.5 h

Procedure:
A solution of 4N HCl in 1,4-dioxan (20 mL, 80 mmol) was added to tert-butyl (S)-1-((3R,3aR,6R,6aR)-3-hydroxy-6-methyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6 aH)-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (1.43 g, assuming 4.0 mmol). The solution was stirred for 90 minutes then the solvents were removed in vacuo and the residue azeotroped with TBME (3×25 mL) to leave (S)-2-amino-1-((3R,3aR,6R,6aR)-3-hydroxy-6-methyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethylbutan-1-one, hydrochloride as a purple crystalline solid which was used without further purification. HPLC-MS 257.2 [M+H]+.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[O:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][NH2:45].NN>CCO.O>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:45][CH2:44][CH:40]2[CH2:41][CH2:42][CH2:43][O:39]2)=[O:34])[C:15]1=[O:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: NCC1CCCO1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.252 g, 0.49 mmol) in EtOH (15 mL) under nitrogen was treated with 1-(tetrahydro-2-furanyl)methanamine (0.252 mL, 2.44 mmol) for 15 min.@150° C. in a microwave vessel. The reaction was transferred to a test tube, diluted with EtOH (30 mL), and treated with hydrazine (0.4 mL, 13 mmol)@50° C. overnight. After the reaction was cooled to ambient temperature the resulting suspension was diluted with water (120 mL) and refrigerated overnight. The resulting suspension was filtered, washed with 2:1 water:EtOH and thoroughly dried under high vacuum to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.49-1.61 (m, 1H), 1.80-2.00 (m, 3H), 2.78 (t, J=6.46 Hz, 2H), 3.25-3.41 (m, 1H), 3.49-3.59 (m, 1H), 3.68 (t, J=6.81 Hz, 1H), 3.75-3.86 (m, 1H), 3.95-4.05 (m, 1H), 4.16 (s, 2H), 4.18-4.26 (m, 2H), 7.14 (ddd, J=8.95, 6.91, 1.82 Hz, 2H), 7.35-7.43 (m, 2H), 8.15 (d, J=1.40 Hz, 1H), 8.51 (s, 1H), 10.44-10.53 (m, 1H); ES+ MS: 441 (M+H+).
Reaction SMILES: [C:1]1([C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:4]=[C:3]([C:11](OC)=[O:12])[CH:2]=1.[BH4-].[Na+].CO>C1COCC1>[OH:12][CH2:11][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:6]=[C:1]([CH:2]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(CO)cc(C(=O)OC)c1
Yield: 61.2 %

Procedure:
Trimethyl 1,3,5-benzenetricarboxylate (5.02 g, 19.9 mmol) was dissolved in THF (15 mL). The air was evacuated from the reaction system, and then Ar was charged therein. To the solution were added NaBH4 (901 mg, 23.8 mmol), and then a mixed solution of THF:MeOH (12.5 mL:3.7 mL) slowly dropwise. The reaction mixture was refluxed for 30 minutes. TLC was used to confirm the progress of the reaction. Then, the reaction was quenched with HCl (1 N, 20 mL). The mixture was extracted with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc=4:1 to 3:1) to isolate dimethyl 5-hydroxymethylisophthalate (32) (2.73 g, 61%) as white crystals.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH:13](OCC)=[O:14].O>C1(C)C=CC=CC=1>[OH:14][CH:13]=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10]
Reactant: O=C1CCc2ccccc21
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C(=CO)Cc2ccccc21
Reaction time: 17 h

Procedure:
1-Indanone (Aldrich) (5.0 g, 37.8 mmol) in toluene (25 cm3) was added dropwise, to a stirring solution of sodium hydride (Aldrich) (1.8 g, 45.4 mmol 60% w/w dispersion in oil), ethyl formate (Aldrich) (5.6 g, 75.6 mmol) and toluene (50 cm3), under nitrogen, at 0° C. The reaction was stirred for 17 hours before adding water (50 cm3). The organic layer was washed with water and 2M NaOH. The combined aqueous extracts were acidified with 10 M HCl and the precipitate extracted with dichloromethane. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford a yellow-orange solid. An analytically pure sample was obtained by Kugelrohr distillation (0.01 mmHg/100° C.) to give a yellow solid m.p. 110-112° C.