Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([O:27]CC)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].CCO>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=[O:26])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C(=O)NCc2ccc(C)nc2)cc(-c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylate (1.02 g, 2.62 mmol), lithium hydroxide (310 mg, 13 mmol), EtOH (100 mL), and water (10 mL) was stirred at rt overnight. LC-MS indicated completion of the reaction. The solvent was removed in vacuo and the residue was treated with water (50 mL) and acidified with 1N aq. HCl to pH=4. The precipitated solids were collected by filtration, washed with water, and dried to yield a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9].[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>CC(N(C)C)=O.CCOC(C)=O>[S:21]([NH:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])(=[O:24])(=[O:23])[NH2:22]
Reactant: CCCNC(=O)C(C)(C)COc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCNC(=O)C(C)(C)COc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propylpropanamide (16.5 g, 59.92 mmol) (Example 215b) in DMA (50 mL) was added sulfamoyl chloride (13.85 g, 119.84 mmol) at 0° C. under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen for 3 hrs then diluted, with EtOAc, washed successively with NaHCO3, brine, dried over Na2SO4, filtered and evaporated to give the title compound as a off white solid (18.52 g, 87%). 1H NMR (400 MHz, DMSO-d6) δ 0.79 (t, J=7.6 Hz, 3H), 1.20 (s, 6H), 1.38 (m, 2H), 3.01 (q, J=6.5 Hz, 2H), 4.05 (s, 2H), 6.92 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.24 (s, 2H), 7.53 (t, J=8.4 Hz, 1H), 7.55 (t, J=5.6 Hz, 1H), 9.42 (s, 1H). MS 355 (MH+).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-:6])O.[Na+].CS(C)=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:33](=[O:34])[N:32]([CH2:35][C:36]3[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=3[C:38]([O:40][CH3:41])=[O:39])[C:31]([CH3:46])=[N:30][C:29]=2[CH2:47][CH2:48][CH3:49])=[CH:23][CH:22]=1)#[N:14]>C(OCC)(=O)C>[CH3:46][C:31]1[N:32]([CH2:35][C:36]2[CH:45]=[CH:44][CH:43]=[CH:42][C:37]=2[C:38]([O:40][CH3:41])=[O:39])[C:33](=[O:34])[C:28]([CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:13]3[NH:3][C:4](=[O:7])[O:6][N:14]=3)=[CH:26][CH:25]=2)=[C:29]([CH2:47][CH2:48][CH3:49])[N:30]=1
Reactant: CCCc1nc(C)n(Cc2ccccc2C(=O)OC)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(Cc2ccccc2C(=O)OC)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
A mixture of hydroxylammonium chloride (2.44 g), sodium hydrogen carbonate (3.93 g) and dimethyl sulfoxide (30 mL) was stirred at 40° C. for 30 min, methyl 2-({5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl}methyl)benzoate (1.15 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 mL), N,N′-carbonyldiimidazole (0.45 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.39 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.48 g, 37%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.[C:7]1([S:13]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]=O)=[CH:17]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[NH2:32]>CCO>[C:7]1([S:13]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([C:25]3[CH:4]=[C:2]([C:1]([OH:6])=[O:5])[C:33]4[C:31](=[CH:30][C:29]([O:28][CH3:27])=[C:35]([O:36][CH3:37])[CH:34]=4)[N:32]=3)=[CH:17]2)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: CC(=O)C(=O)O
Reactant: COc1ccc(N)cc1OC
Solvent: CCO
Product: COc1cc2nc(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)cc(C(=O)O)c2cc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Pyruvic acid (0.486 ml) is added to a suspension of (2.00 g) of N-phenylsulfonyl-3-indolecarboxaldehyde in 100 ml absolute EtOH. The mixture is heated to reflux and a solution of 3,4-dimethoxyaniline (1.074 g) in 50 ml absolute EtOH is added dropwise. The reaction is then refluxed for approximately three hours and stirred at RT for 72 hours. The yellow precipitate is collected by filtration, washed with EtOH then with ether and the solid collected. This is triturated with EtOAC/EtOH and dried and used directly in the next step.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].O=S(Cl)Cl.N1C=CC=CC=1.[C:32]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]O)=[CH:36][CH:35]=1)#[N:33]>C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([C:32]#[N:33])=[CH:35][CH:36]=3)=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(CC(=O)O)cc2)CC1
Reactant: N#Cc1ccc(CO)cc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(CC(=O)OCc3ccc(C#N)cc3)cc2)CC1
Reaction time: 2 h

Procedure:
28.8 g of p-(trans-4-pentylcyclohexyl)-phenylacetic acid is boiled for 1 hour with 24 g of SOCl2 ; the mixture is evaporated; the crude acid chloride obtained is dissolved in 150 ml of toluene, 8 ml of pyridine and 13.3 g of p-cyanobenzyl alcohol are added; and the mixture is boiled for 2 hours. Cooling and working up in a customary manner give p-cyanobenzyl p-(trans-4-pentylcyclohexyl)-phenylacetate, m.p. 85°, c.p. 30°.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][OH:51]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:48][C:49]([CH3:53])([CH3:52])[CH2:50][OH:51])=[O:43])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: CC(C)(N)CO
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(C)CO)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-amino-2-methyl-propan-1-ol (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H51Cl2N6O4 [(M+H)+] 737.3344, observed 737.3342.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14]4[CH:24]=[CH:25][C:26]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:13]=4[N:12]=3)=[N:9][N:8]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:49]2[CH:50]=[C:51]([CH:55]=[O:56])[CH:52]=[N:53][CH:54]=2)O1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C(Cl)Cl.O.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>[F:30][C:29]([F:31])([F:32])[O:28][C:26]1[CH:25]=[CH:24][C:14]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:49]5[CH:50]=[C:51]([CH:55]=[O:56])[CH:52]=[N:53][CH:54]=5)[CH:3]=4)[N:8]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:9]=3)=[N:12][C:13]=2[CH:27]=1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1nc(-c2nc3cc(OC(F)(F)F)ccc3n2COCC[Si](C)(C)C)c2cc(Br)cnc21
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: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1nc(-c2nc3cc(OC(F)(F)F)ccc3n2COCC[Si](C)(C)C)c2cc(-c3cncc(C=O)c3)cnc21
Temperature: 100 °C

Procedure:
5-bromo-3-[5-trifluoromethoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine Compound 16e (0.12 g, 0.18 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-3-carbaldehyde Compound 15b (0.063 g, 0.27 mmol) and 2M Na2CO3 (5 drops) were mixed in DME (10 mL) in a reaction tube. The resulting yellowish clear solution was degassed with nitrogen for 15 minutes, then tetrakis(triphenylphosphine)palladium(0) (0.021 g, 0.018 mmol) was added and the reaction tube was sealed and heated at 100° C. overnight. The sealed tube was cooled and opened and the contents was diluted with DCM and H2O, then filtered through Celite. The solvent was evaporated to dryness to provide 5-[3-[5-trifluoromethoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-pyridine-3-carbaldehyde Compound 17a (0.241 g) as a brown semi-solid which was used directly in the next step without further purification. LCMS single peak, 4.614 min, MS (ESI) m/z 685.2 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>CO.C1COCC1>[CH3:32][C:29]([CH3:30])([CH3:31])[C:28](=[O:33])[CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]([C:12]2[CH:13]=[CH:14][C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:10][C:9]=3[CH:11]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:21][C:22]=1[CH3:34]
Reactant: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of 6-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carboxylic acid ethyl ester (0.89 g, 1.86 mmol) in MeOH (5.0 mL) and THF (5.0 mL) and is treated with NaOH (2.0 M, 10.0 mL). The resulting mixture is stirred at RT for 2 h. The mixture is concentrated, acidified with HCl (1 N) until pH˜3, and extracted with EtOAc (2×50 mL). The organic layer is dried over Na2SO4, concentrated, and purified using silica gel column chromatography (50% EtOAc/Hex) to afford the title compound (840 mg, 99%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:17]=[C:18]=[S:19])[CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:17]([CH:15]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)[CH3:16])[C:18]1=[S:19])[CH3:2]
Reactant: CC(N=C=S)c1ccc(F)cc1
Reactant: CCNCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(C(C)c2ccc(F)cc2)C1=S
Yield: 33.1 %

Procedure:
A mixture of the crude N-ethyl glycine (18.4 g), 1-(4-fluorophenyl)-ethyl-isothiocyanate (18.1 g), triethyl amine (20.2 g) and chloroform (300 mL) was heated at reflux for 18 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 1N HCl (2×300 mL), then evaporated to dryness. Crystallization from ethyl acetate afforded the title compound (8.8 g) as a light yellow solid, m.p. 93°-95° C. Anal. Calcd. for. C13H15F N2O S: C, 58.63; H, 5.68; N, 10.52. Found: C, 58.69; H, 5.64; N, 10.58. Mass spectrum (EI, M.+) m/z 266.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:14][CH3:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:16]([OH:20])(=O)[CH2:17]O>>[OH:20][CH2:16][C:17]1[N:14]([CH3:15])[C:3]2=[N:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:7]=[C:2]2[N:1]=1
Reactant: CNc1nc(-c2ccccc2)ccc1N
Reactant: O=C(O)CO
Product: Cn1c(CO)nc2ccc(-c3ccccc3)nc21
Yield: 15.3 %

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 4.9 g of 3-amino-2-methylamino-6-phenylpyridine (prepared as described in Preparation 109) and 5.6 g of glycolic acid were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and ethanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 0.9 g of the title compound, melting at 174-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([N:17]3[C:21]([CH:22]([CH3:24])[CH3:23])=[N:20][N:19]=[N:18]3)[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.[CH3:25][C:26]1[N:27]=[CH:28][C:29]([CH2:32][NH2:33])=[N:30][CH:31]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([N:17]3[C:21]([CH:22]([CH3:23])[CH3:24])=[N:20][N:19]=[N:18]3)[CH:16]=2)[C:11]([NH:33][CH2:32][C:29]2[CH:28]=[N:27][C:26]([CH3:25])=[CH:31][N:30]=2)=[O:13])=[N:6][CH:7]=1
Reactant: CC(C)c1nnnn1-c1cc(C(=O)O)cc(-c2ccc(Cl)cn2)c1
Reactant: Cc1cnc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(CNC(=O)c2cc(-c3ccc(Cl)cn3)cc(-n3nnnc3C(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
3-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid (650 mg, 1.89 mmol), C-(5-methyl-pyrazin-2-yl)-methylamine (233 mg, 1.89 mmol), EDCI (362 mg, 1.89 mmol), HOBt (255 mg, 1.89 mmol) and Et3N (1.32 mL, 9.45 mmol) were added to 10 mL methylene chloride. The reaction mixture was stirred at room temperature for 18 hours, then was partitioned between water and methylene chloride. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (80-100% EtOAc/hexanes) to give 492 mg of 3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-benzamide, MS (M+H)=449.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][CH:4]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[N:11]=1)=[O:9])CC.[OH-:28].[Na+].CN1CC[CH2:33][C:32]1=O>>[CH2:32]([C:3]1([CH2:2][OH:28])[O:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[N:11]=2)[N:7]=[CH:4]1)[CH3:33]
Reactant: CCC(C=C(Cl)Cl)NC(=O)c1nn(Cc2ccccc2F)c2ccccc12
Reactant: [OH-]
Reactant: CN1CCCC1=O
Agent: [Na+]
Product: CCC1(CO)C=NC(c2nn(Cc3ccccc3F)c3ccccc23)O1
Yield: 52 %

Procedure:
1.05 g of 1,1-dichloro-3-[1-(2-fluorobenzyl)indazole-3-carboxamido]-pent-1-ene (2.58 mmol) and 5.20 ml of NaOH, 1N (5.20 mmol) were stirred in 15 ml of N-methylpyrrolidone at 50° C. under argon for 2 days. After cooling, the mixture was poured onto ice-water and extracted several times with ethyl acetate. The organic phase was dried (sodium sulphate) and concentrated (N-methylpyrrolidone stripped off under a high vacuum). The residue was purified by column chromatography (aluminium oxide, cyclohexane/ethyl acetate 2:1). 470 mg (52%) of 5-ethyl-2-[1-(2-fluorobenzyl)-indazol-3-yl]-5-hydroxymethyl-oxazole were obtained as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].Br[CH:23]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26].O>CN(C=O)C>[C:12]([O:11][C:9](=[O:10])[CH:8]([CH:23]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCCC(Br)c1ccc(C(=O)OC)cc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(c1ccc(C(=O)OC)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
The product of Step A (1.80 g, 7.94 mmol) was added to a suspension of KOtBu (980 mg, 8.73 mmol) in anhydrous DMF (15 mL) at 0° C. After stirring for two minutes, a solution of methyl 4-(1-bromobutyl)benzoate in DMF (5 mL) was added dropwise. The mixture was allowed to warm to room temperature. After stirring for 20 minutes, water was added then the solution was extracted with CH2Cl2 (2×100 mL). The combined organic layers were washed with saturated NH4Cl (aq) (20 mL) then saturated NaCl (aq) (20 mL), dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 2% EtOAc/petroleum ether to afford the title compound: 1H NMR (CD3OD, 300 MHz) δ 7.98-8.02 (m, 2H), 7.77-7.81 (m, 2H), 7.38-7.44 (m, 2H), 7.09-7.13 (m, 2H), 3.91 (s, 3H), 3.79-3.81 (m, 1H), 3.34-3.40 (m, 1H), 1.20-1.30 (m, 2H), 1.03 (s, 9H), 0.91-1.02 (m, 2H), 0.68 (t, J=7.4 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[I-].[C:13]([CH2:15][P+](C)(C)C)#[N:14].C(#N)CC.C(N(C(C)C)CC)(C)C>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][CH2:15][C:13]#[N:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[P+](C)(C)CC#N
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#CCCc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
To a mixture of 4-nitrobenzyl alcohol (37) (1 g, 6.53 mmol) and (cyanomethyl)trimethylphosphonium iodide (36) (4 g, 16.32 mmol) were added propionitrile (32 mL) and diisopropylethylamine (2.5 g, 19.58 mmol) at room temperature. The mixture was heated at ˜100° C. for 24 hours. The reaction was quenched with water (1 mL), followed by addition of concentrated HCl (5 mL). The resulting reaction mixture was extracted with ethyl acetate (3×100 mL), washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a dark brown solid. The crude solid product was purified by flash column chromatography (silica gel, ethyl acetate: hexanes 1:1) to give 740 mg of 3-(4-nitrophenyl)propionitrile (38) as a light orange solid. 1H NMR (DMSO-d6): δ 8.20-8.17 (dd, J=8.7 Hz, 2H), 7.59-7.56 (d, J=9.0 Hz, 2H), and 3.06-3.01 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:30]([O:32]C)=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.O.[NH2:35][NH2:36]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:18]3)(=[O:15])=[O:16])=[CH:10][CH:9]=2)=[N:4][C:3]=1[C:30]([NH:35][NH2:36])=[O:32]
Reactant: COC(=O)c1nc(-c2ccc(S(=O)(=O)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnc1N
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(-c3cnc(N)c(C(=O)NN)n3)cc2)C1
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 94.5 %

Procedure:
methyl 3-amino-6-[4-[(1-tert-butoxycarbonyl-3-piperidyl)sulfonyl]phenyl]pyrazine-2-carboxylate (1.65 g, 3.462 mmol) in dioxane (16.50 mL) was treated with hydrazine hydrate (866.5 mg, 842.1 μL, 17.31 mmol) and stirred at 65° C. for 2.5 hours. The reaction mixture was concentrated in vacuo. The residue was treated with water and stirred for 1 hour, filtered and washed with water, and dried overnight under high vacuum giving tert-butyl 3-[4-[5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl]phenyl]sulfonylpiperidine-1-carboxylate (1.572 g, 3.272 mmol, 93.77%) as a pale yellow powder. LC/MS m/z 421.1 [M−56+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:46]=[CH:45][C:39](/[CH:40]=[CH:41]/B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](/[CH:41]=[CH:40]/[C:39]2[CH:45]=[CH:46][C:36]([F:35])=[CH:37][CH:38]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)/C=C/c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(/C=C/c2ccc(F)cc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), (E)-4-fluorostyrylboronic acid (49.9 mg, 0.301 mmol) and PdCl2(PPh3)2 (42.2 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 2 hours. The reaction mixture was subsequently diluted with water (5 mL) and was extracted into EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-4-((E)-4-fluorostyryl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was treated with TFA (4 mL) for 1.5 hours to remove the protecting groups. TFA was subsequently evaporated from the reaction mixture. The residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 10-30% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a tan solid (58 mg, 50%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-1.92 (m, 8H), 3.74 (br s, 1H), 4.40 (d, J=2.53 Hz, 2H), 4.51 (br s, 1H), 6.86 (d, J=6.57 Hz, 1H), 7.27 (t, J=8.84 Hz, 1H), 7.56-7.73 (m, 3H), 7.82 (br s, 3H), 8.14 (d, J=15.92 Hz, 1H), 8.49 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C21H22F2N4O, 385. found, 385.