Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21].[Br:22]Br.O.S(=O)(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][C:6]([Br:22])([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21]
Reactant: BrBr
Reactant: CCCC1Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCC1(Br)Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3
Yield: 78.4 %

Procedure:
A stirred suspension of 4,5-dimethyl-6-oxo-7-propyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid (14 g., 0.00486 mole) in acetic acid (15 ml.) is treated with a solution of bromine (0.8 g., 0.005 mole) in acetic acid (5 ml.) during a three minute period. The reaction mixture is poured into water (100 ml.) containing sodium bisulfate (1 g.), extracted with ether, washed with water, dried over magnesium sulfate and the ether distilled at reduced pressure affording an oil which on trituration with cyclohexane affords 4,5-dimethyl-6-oxo-7-bromo-7-propyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid (1.4 g., 78%) as a white solid which melts at 78°C. and is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([N:26]1[C:38]2[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:24]#[CH:25].C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:25]#[C:24][CH2:23][N:26]3[C:38]4[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=4[C:32]4[C:27]3=[CH:28][CH:29]=[CH:30][CH:31]=4)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCn1c2c(c3ccccc31)CCCC2
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc2n1-c1sc(C#CCn3c4c(c5ccccc53)CCCC4)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was obtained by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 1,2,3,4-tetrahydro-9(2-propynyl)-9H-carbazole under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 8 % (v/v) of ethanol in methylene chloride for elution. The residue obtained after evaporation of the combined clean fractions containing product was crystallized from ethanol to give colorless crystals of 4-(2-chlorophenyl)-2-[3-(1,2,3,4-tetrahydro 9H-carbazol-9-yl)-1-propynyl]-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with m.p. 164°-166°. These crystals contained 0.66 molar amounts of ethanol according to analytical and spectral data.
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=2[C:7](=[O:15])[O:6][C:5]=1[NH:16][C@@H:17]([CH:25]1[CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)(=[O:3])[CH3:2].[OH-:28].[Na+]>O1CCCC1.CO>[CH:25]1([C@H:17]([NH:16][C:5]([CH:4]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=2[C:7]([OH:6])=[O:15])[C:1](=[O:3])[CH3:2])=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:27][CH2:26]1
Reactant: CC(=O)c1c(N[C@H](c2cccc(F)c2)C2CC2)oc(=O)c2c(F)cccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)C(C(=O)N[C@H](c1cccc(F)c1)C1CC1)c1cccc(F)c1C(=O)O
Temperature: 20 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
4-Acetyl-3-{[(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amino}-8-fluoro-2-benzopyran-1-one (14.30 g, 38.72 mmol) was dissolved in a mixture of tetrahydrofuran (50 mL) and methanol (50 mL) and placed on an ice/water bath with stirring. NaOH (1 M in H2O, 100 ml) was added and stirring continued for 1 hour. The cold bath removed and the mixture was allowed to warm to r.t. (20° C.) during 1 hour. The reaction mixture was poured into ice-water mixture (200 g+200 ml), followed by slow addition of 2 M aq. HCl (200 mL) and extracted with ethyl acetate (200 mL), washed with sat. aq. NaCl, dried (Na2SO4), filtered and evaporated to give the title compound (14.65 g, yield 97.7%) as a pale brown foam. The crude product was used in the next step without further purification. LC-MS (m/z) 388.3 (MH+); tR=1.2. 1H NMR (500 MHz, DMSO-d6): a mixture of tautomers and diastereoisomers.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][NH:4][C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(NCCO)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1NCCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(OCc3ccccc3)c21
Reaction time: 0.25 h
Yield: 484.1 %

Procedure:
To a solution mixture of 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-amide (347) (140 mg, 0.28 mmol) and diisopropyl azodicarboxylate (0.28 mL, 1.41 mmol) in dichloromethane (70 mL) was added triphenyl phosphine (443 mg, 1.69 mmol) at room temperature and the reaction mixture was stirred for 15 min at the same temperature. The yellow color disappeared (silica TLC, ethyl acetate 100%; Rf=0.2). The dichloromethane was removed in vacuum to get 9-benzyloxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (348) (650 mg, crude) which was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[CH2:38][NH:39][CH3:40].CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:43]=[CH:42][CH:41]=[C:37]([CH2:38][NH:39][CH3:40])[CH:36]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: CNCc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CNCc1cccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)c1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (89.7 mg, 0.20 mmol), (3-bromo-benzyl)-methyl-amine (43.4 mg, 0.22 mmol), and Pd[P(Ph)3]4 (15.4 mg, 6.7 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. The product was then converted to the HCl salt. After dissolving the product in a minimum amount of acetonitrile and cooling the solution in dry ice, 2.0M HCl in diethyl ether was added until precipitate crashed out of solution. The mixture was centrifuged, and the liquid was decanted. Additional cold diethyl ether was added, and the mixture was again centrifuged and the liquid decanted. The resulting solid was dried to give the HCl salt of the desired product. Yield 5.9 mg. MS: 444.2 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 1.80-2.02 (m, 3H), 2.17-2.35 (m, 1H), 2.53-2.64 (t, 3H), 3.39-3.57 (m, 2H), 4.15-4.23 (t, 2H), 4.33-4.44 (m, 1H), 4.60-5.12 (m, 2H), 7.02-7.76 (m, 12H), 8.06-8.12 (m, 1H), 8.78-8.93 (s, 1H), 10.10-10.25 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][C:4]([NH:13][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCCl)NC1CCCCC1

Procedure:
β-Chloropropionyl chloride (31.7 g.) is added dropwise to a stirred solution of cyclohexylamine (24.8 g.) and triethylamine (28.2 g.) in toluene (250 ml.). The mixture is cooled and filtered and the filtrate is evaporated to dryness under reduced pressure. There is thus obtained as residue β-chloro-N-cyclohexylpropionamide, m.p. 77°-80° C. β-Chloro-N- 2-furfurylpropionamide may similarly be obtained from furfurylamine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Cl[C:20]1[N:21]=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[N:21]=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Reactant: COc1cnnc(Cl)c1
Product: COc1cnnc(-c2cc(C)c(Cl)c(C)c2)c1

Procedure:
The title compound is prepared from 2-chloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 3-chloro-5-methoxy-pyridazine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 11): tR=0.93 min; Mass spectrum (ESI+): m/z=249/251 (Cl) [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13]C(=O)C(F)(F)F)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C1COCC1>[NH2:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)C(F)(F)F)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S)-1-(tert-butoxycarbonyl)-3-(trifluoro-acetamido)pyrrolidine, as described above in Step A, (2.80 g, 9.5 mmol) in THF (80 mL) and H2O (10 mL) was added 1.0 N aqueous lithium hydroxide (10.5 mL, 10.5 mmol) and the resulting mixture was stirred at ambient temperature for 18 hours, then adjusted to pH 7 with 1.0 N aqueous HCl and concentrated to dryness in vacuo to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.CO[CH:13](OC)[CH2:14][NH2:15]>>[Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[N:15][CH:14]=[CH:13]2
Reactant: Cc1cccc(C=O)c1Cl
Reactant: COC(CN)OC
Product: Cc1ccc2ccncc2c1Cl

Procedure:
8-Chloro-7-methylisoquinoline was prepared from 2-chloro-3-methylbenzaldehyde and 2,2-dimethoxyethylamine by the procedure described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([OH:25])[C@@H:5]([NH:14]C(OCC1C=CC=CC=1)=O)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1>C(O)C>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([OH:25])[C@@H:5]([NH2:14])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1
Reactant: COC(=O)[C@H](O)[C@@H](NC(=O)OCc1ccccc1)c1ccc(F)c(F)c1
Solvent: CCO
Product: COC(=O)[C@H](O)[C@@H](N)c1ccc(F)c(F)c1
Reaction time: 16 h

Procedure:
(2R, 3S)-N-Benzyloxycarbonyl-3-amino-3-(3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester (>12.2 g, 33.3 mmol maximum) was dissolved in 750 mL ethanol. The flask was purged with argon and palladium on carbon (2 g, 10% wt) was added. The suspension was then purged, filled with hydrogen, and stirred 16 h. The suspension was purged with argon, filtered through celite and concentrated in vacuo to give (2R, 3S)-3-amino-3-(3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.O.[NH2:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[NH2:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(Br)ccn1
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc(-c2ccnc(N)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a 100 ml flask was added 4-bromopyridin-2-amine 36.A (432 mg, 2.50 mmol, available from Apollo), 3-aminophenylboronic acid hydrate 36.B (465 mg, 3.00 mmol, available from Oakwood), tetrakis(triphenylphosphine)palladium(0) (288 mg, 0.25 mmol), DMF (5 mL) and saturated aqueous K2CO3 (5 mL). The reaction mixture was stirred at 80° C. overnight. The reaction was then extracted with DCM (2×50 mL), the organic layers combined, washed with brine and dried on MgSO4. The DCM was removed under vacuum, leaving a crude solution of 4-(3-aminophenyl)pyridin-2-amine in DMF to which was added more DMF (10 mL), (S)-2-(tert-butoxycarbonyl)-3-phenylpropanoic acid (662 mg, 2.5 mmol, available from Aldrich), diisopropylethylamine (1.74 mL, 10 mmol) and 2-(1H-Benzotriazole-1-yl)-1,1,3,3-Tetramethyluronium hexafluorophosphate (1.90 g, 5.0 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was then partitioned between water (50 mL) and EtOAc (100 mL). The layers were separated, and the aqueous phase was extracted with additional EtOAc (2×50 mL). The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography to afford tert-butyl (S)-1-(3-(2-aminopyridin-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 36.C (200 mg, 15% yield).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[CH:13]([Mg]Br)([CH3:15])[CH3:14]>C1COCC1>[F:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][CH:13]([CH3:15])[CH3:14])[C:7]=2[CH:8]=1
Reactant: Fc1ccc2scc(CBr)c2c1
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CC(C)Cc1csc2ccc(F)cc12
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 3-bromomethyl-5-fluorobenzothiophene (2.0 g; cf. Raga, Manuel; Palacin, Celia; Castello, Josep Maria; Ortiz, Jose A.; Cuberes, Maria Rosa; Moreno-Manas, Marcial, Eur. J. Med. Chem. (1986), 21(4), 329-32) in THF (30 ml) was added over 5 minutes isopropylmagnesium bromide (1.0 M, 16.6 ml). The reaction mixture was stirred at 50° C. for 5 h, cooled, quenched with ice/water and ammonium chloride solution, and extracted with ethyl acetate. The organic phases were washed with water, dried and concentrated. The residue was chromatographed on silica gel using heptane/methylene chloride as eluent to obtain the title compound (1.35 g) as a yellowish oil. MS (EI): 208.3 (M)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[NH4+]>C(O)(C(F)(F)F)=O.CO.[Pt](=O)=O>[NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[N:2]1
Reactant: c1cnc2cn[nH]c2c1
Agent: O=[Pt]=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: c1n[nH]c2c1NCCC2
Reaction time: 24 h
Yield: 82.7 %

Procedure:
A 250 mL Parr bottle was charged with a solution of 1H-pyrazolo[4,3-b]pyridine (2 g, 16.8 mmol, obtained from J&W PharmLab, LLC) in TFA (20.0 mL) and platinum(IV) oxide (381 mg, 1.68 mmol). The reaction mixture was evacuated twice with hydrogen and shaken under 55 psi pressure of hydrogen for 24 h. The reaction mixture was filtered over celite, and the filter cake washed with 5% methanol in CH2Cl2. The filtrate was concentrated in vacuo to afford a light brown oil that was dissolved in methanol (20 mL). Concentrated ammonium hydroxide solution was added drop wise until the pH remained basic (pH 8). The mixture was concentrated in vacuo then the residue adsorbed on silica gel and purified by chromatography (silica, 150 g column, 50 μm from Analogix, 0 to 5% of a 9:1 methanol:ammonium hydroxide solution in dichloromethane, 15 min) to give a yellow oil. This oil solidified upon drying under high vacuum to yield 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (1.712 g, 13.9 mmol, 83%) as a yellow solid. 1H NMR (CHLOROFORM-d) d: 7.09 (s, 1H), 3.14-3.25 (m, 2H), 2.76 (t, J=6.6 Hz, 2H), 1.88-2.02 (m, 2H). MS (EI/CI) m/z: 124.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[NH2:23][CH:24]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CO>[C:33]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:34]=[CH:35][C:30]([CH:24]([NH:23][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:31][CH:32]=1
Reactant: COC(=O)CC(N)c1ccc(-c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)CC(Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2,4-dinitrofluorobenzene (247 mg, 847 μmol) in methanol (2 mL) was added N,N-diisopropylethylamine (147 μL, 844 μmol) and methyl 3-amino-3-(1,1′-biphenyl)-4-ylpropanoate (158 mg, 849 μmol). The solution was stirred at room temperature for 72 hours, then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of petroleum ether and dichloromethane (1:1 to 0:1), to afford the title compound, [LCMS (Method B, Mobile Phase I) RT=3.81 min, MH+ 422].
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][O-])[CH2:5][CH2:4][O:3]1.[Na+].[Br:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[Br:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:7]=[C:6]2[CH2:5][CH2:4][O:3][C:2]2=[O:1])[CH:12]=1
Reactant: O=C1OCCC1=C[O-]
Reactant: Nc1cc(Br)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1OCCC1=CNc1cc(Br)ccn1

Procedure:
A solution of sodium (2-oxodihydrofuran-3(2H)-ylidene)methano-late (134 mg, 1 mmol), 4-bromopyridin-2-amine (173 mg, 1.0 mmol) and 4-methylbenzenesulfonic acid (50 mg, 0.29 mmol) in toluene was stirred at 150° C. for 1 hr. After the suspension was diluted with water, the solution was adjusted to pH 8 and extracted with ethyl acetate. Then, the organic layers were dried over Na2SO4 and concentrated to give crude product, which was used for then next reaction without further purification. MS (ESI): 269, 271 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][C:13](O)=O>>[CH3:12][C:13]1[NH:11][S:8](=[O:9])(=[O:10])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CC(=O)O
Product: CC1=Nc2ccccc2S(=O)(=O)N1
Yield: 91 %

Procedure:
2-Aminobenzenesulfonamide (17.2 g; 100 mmol) was refluxed in AcOH for 5 days. The precipitate formed was isolated by filtration and washed with water to give 17.8 g (91%) of 3-methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide. 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was transformed by Method A (using dimethylamine as amine). M.p. 260-261° C.
Reaction SMILES: CS(O[CH2:6][CH:7]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:8][CH2:9][CH2:10][CH3:11])(=O)=O.[C-:19]#[N:20].[Na+].O>CN(C)C=O>[CH:13]1([CH2:12][CH:7]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:6][C:19]#[N:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: [C-]#N
Reactant: CCCCC(COS(C)(=O)=O)CC1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(CC#N)CC1CCCCC1
Temperature: 80 °C

Procedure:
2-(Cyclohexylmethyl)hexyl methanesulfonate (2.0 g) in a few ml of dimethylformamide (DMF) was added to a cooled stirred suspension of anhydrous sodium cyanide (0.53 g) in 5 ml of dry DMF. The mixture was heated overnight at 80° C., poured into water (100 ml) and the product extracted with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated to give 3-(cyclohexylmethyl)heptanenitrile, used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3](N2CC[C@@H](O)C2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH2:28]1[C:31]2([CH2:35][CH2:34][NH:33][CH2:32]2)[CH2:30][O:29]1>>[Br:1][C:2]1[C:3]([N:33]2[CH2:34][CH2:35][C:31]3([CH2:30][O:29][CH2:28]3)[CH2:32]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=1)=[O:8]
Reactant: C1CC2(CN1)COC2
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC3(COC3)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 12.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35) and 2-oxa-6-azaspiro[3,4]octane to afford white needles. UPLC-MS (condition 1) tR=2.93 min, m/z=471.9/473.9 [M+H]+, m/z=469.9/471.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.20 (t, J=6.85 Hz, 2H) 3.73 (t, J=6.97 Hz, 2H) 3.95 (s, 2H) 4.51 (d, J=5.87 Hz, 2H) 4.60 (d, J=5.87 Hz, 2H) 7.35 (d, J=8.31 Hz, 2H) 7.82-7.88 (m, 2H) 8.36 (d, J=2.20 Hz, 1H) 8.69 (d, J=1.96 Hz, 1H) 10.24 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([S:5]([N:7]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH2:9][CH:10]=[CH2:11])=[O:6])([CH3:4])[CH3:3].[C:33]([O:37][CH3:38])(=[O:36])C=C>>[C:2]([S:5]([N:7]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=1)[CH:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH2:9]/[CH:10]=[CH:11]/[C:33]([O:37][CH3:38])=[O:36])=[O:6])([CH3:1])([CH3:3])[CH3:4]
Reactant: C=CC(=O)OC
Reactant: C=CCC(c1ccc(C(F)(F)F)cc1)N(Cc1ccc(C(F)(F)F)cc1)S(=O)C(C)(C)C
Product: COC(=O)/C=C/CC(c1ccc(C(F)(F)F)cc1)N(Cc1ccc(C(F)(F)F)cc1)S(=O)C(C)(C)C
Reaction time: 0.5 h

Procedure:
The alkene from Step 2 (800 mg, 1.67 mmol) was dissolved in methyl acrylate (1.5 mL) and Zhan I catalyst (110 mg) was added. This mixture was stirred for 30 min and TLC indicated all starting material had reacted. The mixture was evaporated and purified by chromatography on silica using 10-25% ethyl acetate in iso-hexane to give the product (500 mg) as a mixture of isomers:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:15]=3[N:14]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1C(=O)N([Br:31])C(=O)C1>CN(C=O)C>[Br:31][C:5]1[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[C:3]=2[CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:15]=3[N:14]=2)[NH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Solvent: CN(C)C=O
Product: Cc1cc(C)c2[nH]cc(Br)c2c1Cc1nc2cc(C#N)ccc2[nH]1
Reaction time: 1 h

Procedure:
2-((5,7-Dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 58-C) (61 mg, 0.203 mmol) was dissolved in DMF (2 mL) and NBS (40.1 mg, 0.225 mmol) was added at 0° C. and the reaction stirred for 1 hour. The reaction was then quenched with saturated aq. sodium thiosulfate and saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic phase was dried over MgSO4, concentrated and purified by flash column chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.33 (br. s., 1H) 11.39 (br. s., 1H) 7.97 (s, 1H) 7.83 (s, 1H) 7.41-7.64 (m, 2H) 6.86 (s, 1H) 4.82 (d, J=4.55 Hz, 2H) 2.43 (s, 3H) 2.21 (s, 3H). HRMS calcd. for C19H15BrN4 (M+H)+ 379.0553. found 379.0557.