Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].B.CSC>C1COCC1>[Br:1][CH2:2][CH:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)[OH:4]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: N#Cc1ccc(C(O)CBr)cc1
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
Following the procedure of Corey et al. (Angew. Chem. Int. Ed., 37:1986-2012 (1998)), a solution of 4-(2-bromoacetyl)benzonitrile (10.00 g, 44.6 mmol) in THF (50 mL) was cooled to 0° C. and treated with (S)-methyl oxazaborolidine (1.0 M in toluene) (8.93 mL, 8.93 mmol) followed by borane-methyl sulfide complex (2.0 M in THF) (13.01 mL, 26.0 mmol) over 10 minutes. The reaction was stirred for 1.5 hours and then quenched by adding MeOH. The reaction was concentrated on a rotary evaporator and then extracted from 1 M HCl using DCM×3 followed by drying over MgSO4, and filtering. The crude material was concentrated in vacuo and purified on a 220 g SiO2 cartridge using 20-80% EtOAc/hexanes gradient over 10 column volumes. The product eluted in fractions 46-60 to afford 9.8 g of 4-(2-bromo-1-hydroxyethyl)-benzonitrile as a clear oil. Chiral HPLC conditions showed 80% e.e. favoring the (S) stereoisomer based on the Corey precedent. The minor (R) stereoisomer was removed by chiral HPLC using multiple runs on a Thar 350 Preparative SFC instrument equipped with a CHIRALPAK® AD-H (25×5 cm, 5 μM). Temp: 35° C.; Flow rate: 280 mL/min; Mobile phase: CO2/iPrOH in 88:12 ratio; Runtime 7.7 min; Retention time=5.1 min to give (S)-4-(2-bromo-1-hydroxyethyl)-benzonitrile in 99.8% d.e. 1H NMR (400 MHz, CDCl3) δ ppm 7.76 (2H, d), 7.56 (2H, d), 5.02 (1H, dd), 3.68 (1H, dd), 3.55 (1H, dd), 3.53 (1H, s).
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:18]=2)=[O:16])=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10]>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:18]=2)=[O:16])=[C:8]([CH:13]=1)[C:9]([O-:11])=[O:10].[Na+:2]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(-c2ccncc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1C(=O)[O-])c1cccc(-c2ccncc2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
20 mL of THF and 2.6 mL of 1N aqueous sodium hydroxide were added to 0.32 g (0.87 mmol) of methyl 5-chloro-2-({[3-(pyridin-4-yl)phenyl]carbonyl}amino)benzoate at room temperature, and the mixture was stirred at 50° C. for 1 hour. After cooling, the solvent was distilled off under reduced pressure, and water was added to the residue, followed by filtration and drying, thereby giving 174 mg of the target sodium 5-chloro-2-({[3-(pyridin-4-yl)phenyl]carbonyl}amino)benzoate (yield: 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:37])[C@@H:11]([N:20]1[C:24](=[O:25])[C@@H:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][OH:35])=[CH:28][CH:27]=2)[NH:22][C:21]1=[O:36])[C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:37])[C@@H:11]([N:20]1[C:24](=[O:25])[C@H:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][OH:35])=[CH:30][CH:31]=2)[NH:22][C:21]1=[O:36])[C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]
Reactant: C[C@@H](c1ccccc1)[C@@H](C(=O)Nc1ccc(I)cc1Cl)N1C(=O)N[C@H](c2ccc(OCCO)cc2)C1=O
Solvent: CO
Product: C[C@@H](c1ccccc1)[C@@H](C(=O)Nc1ccc(I)cc1Cl)N1C(=O)N[C@@H](c2ccc(OCCO)cc2)C1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 29.2 %

Procedure:
A solution of (2S,3S)—N-(2-chloro-4-iodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (prepared as described in example 110) (50 mg, 0.079 mmol) was dissolved in methanol (3 mL) and stirred at ambient temperature for 4 days. The resulting mixture of isomers was concentrated in vacuo and then purified by super-critical fluid chromatography using a Chiracel OJ column eluted with carbon dioxide at 100 bar and 30° C. modified with 35% v/v ethanol in acetonitrile eluted at 2 mL/minute. The first eluted compound was collected and concentrated in vacuo to obtain (2S,3S)—N-(2-chloro-4-iodo-phenyl)-2-{(S)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (14.6 mg, 29%) The compound eluted second was identical with (2S,3S)—N-(2-chloro-4-iodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (18.1 mg, 36%). LC-MS (reverse phase HPLC, C18 column, water/acetonitrile gradient): Rt=2.40 minutes, Obs. Mass (M+Na+), 656. Calcd. Mass, 640 for C27H25CIIN3NaO5+. 1H NMR (DMSO-d6, 300 MHz) OH 9.98 (s, 1H), 8.61 (s, 1H), 4.81 (d, J=11.8 Hz, 1H) ppm (characteristic resonances).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[N:10]([CH:21]1[CH2:23][CH2:22]1)[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[CH:21]1([N:10]([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]2[CH:8]=[C:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])[CH2:23][CH2:22]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
3-[Cyclopropyl-(2,4-dichloro-benzoyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (85 mg, 0.19 mmol) was dissolved in a mixture of THF-MeOH—H2O (3:2:1) (10 mL) and then 1.2 ml of LiOH 1N was added to it. After 60 min of stirring at room temperature, solvent was removed and then partitioned between 15 ml of H2O, 4 ml of KHSO4 5% and 15 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×10 mL). The combined ethyl acetate layer was dried (MgSO4), concentrated and the residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 22 mg (27%) of 3-[Cyclopropyl-(2,4-dichloro-benzoyl)-amino]-5-phenyl-thiophene-2-carboxylic acid. NMR 1H (DMSO, 400 MHz): rotamer: 7.75 ppm (m, 2H, Haro); 7.68 ppm (m Haro, minor rotamer); 7.62-7.55 ppm (m, 2H, Haro); 7.52 ppm (m, Haro, minor rotamer); 7.48-7.27 ppm (m, 5H, Haro); 3.14 ppm (m, minor rotamer); 3.04 ppm (m, 1H, major rotamer); 0.87-0.42 ppm (m, 4H).
Reaction SMILES: C([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5](CO)[C:4]=1[OH:13])O.C(O)(=O)C(O)=O.[C:20]1([C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:23])[OH:21]>O>[CH2:9]([C:7]1[CH:6]=[CH:5][C:4]([OH:13])=[CH:3][CH:8]=1)[CH3:10].[C:20]1([C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[OH:23])[OH:21]
Reactant: CCc1cc(CO)c(O)c(CO)c1
Agent: O=C(O)C(=O)O
Agent: Oc1ccccc1O
Solvent: O
Product: CCc1ccc(O)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a 1 liter, 3 necked round bottomed flask equipped with a paddle stirrer, condenser, thermometer and heating source, were added 150 g (0.81 mole) of the 2,6-dimethylol-4-ethylphenol, followed by 9 g (0.1 moles) of oxalic acid and 181 g (1.64 moles) of catechol. To this was added 400 g of water. The reaction mixture was stirred and heated to 70° C. Solution occurred when the temperature reached approximately 60° C. Then, the reaction mixture was heated to reflux and held for 4 hours. After 1 hour at reflux, the product began to separate.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH:4]([CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH2:5][CH2:6]S([O-])(=O)=O.C(OCC)(=O)C.O.CC#[N:27]>[C-]#N.C([N+](CC)(CC)CC)C>[CH3:1][O:2][CH:3]([O:16][CH3:17])[CH:4]([CH:11]([O:14][CH3:15])[O:12][CH3:13])[CH2:5][C:6]#[N:27]
Reactant: CC#N
Reactant: COC(OC)C(CCS(=O)(=O)[O-])C(OC)OC
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: O
Product: COC(OC)C(CC#N)C(OC)OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Tetraethylammonium cyanide (142.3 g, 910.8 mmol) was added portionwise over 10 minutes to a solution of [2-(dimethoxymethyl)-3,3-dimethoxypropyl]methanesulfonate (124 g, 455.4 mmol) in MeCN (1.24 L). The reaction mixture was stirred at room temperature for 72 h, then portioned between ethyl acetate (1.24 L) and water (1.24 L). The layers were separated and the organic layer was isolated, washed with brine. The organics were dried over MgSO4, filtered and evaporated to give 3-(dimethoxymethyl)-4,4-dimethoxybutanenitrile 11 as a dark brown oil (86.1 g).
Reaction SMILES: C([N:8]1[C:13](=[O:14])[N:12](CC2C=CC=CC=2)[C:11](=[O:22])[N:10]([NH:23][C:24](=[O:47])[C@@H:25]([C@@H:30]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:31][CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][CH:27]([CH3:29])[CH3:28])[C:9]1=[O:48])C1C=CC=CC=1>CO.C(O)(=O)C.[OH-].[Pd+2].[OH-]>[C:43]([O:42][C:40]([C@H:30]([C@@H:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:24]([NH:23][N:10]1[C:11](=[O:22])[NH:12][C:13](=[O:14])[NH:8][C:9]1=[O:48])=[O:47])[CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)C[C@@H](C(=O)Nn1c(=O)n(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O)[C@H](CC=Cc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)Nn1c(=O)[nH]c(=O)[nH]c1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Yield: 97.5 %

Procedure:
A solution of 0.830 g of N-(3,5-dibenzyl-hexahydro-2,4,6-trioxo-1,3,5-triazin-1-yl)-2(R)-[1(S)-(tert-butyloxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleramide in 50 ml of methanol and a few drops of acetic acid was hydrogenated in the presence of 0.08 g of palladium (II) hydroxide for 8 hours. The mixture was filtered and evaporated to give 0.588 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methyl-N-(2,4,6-trioxo-1,3,5-triazin-1-yl)valeramide in the form of white solid.
Reaction SMILES: [C:1]([N:4]([CH2:28][C@@H:29]1[O:33][C:32](=[O:34])[N:31]([C:35]2[CH:40]=[CH:39][C:38]([CH:41]3[CH2:46][CH2:45][S:44](=[O:48])(=[O:47])[CH2:43][CH2:42]3)=[C:37]([F:49])[CH:36]=2)[CH2:30]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:27])[C@@H:11]([NH:19]C(OC(C)(C)C)=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.[ClH:58]>C1COCC1>[ClH:58].[C:1]([N:4]([CH2:28][C@@H:29]1[O:33][C:32](=[O:34])[N:31]([C:35]2[CH:40]=[CH:39][C:38]([CH:41]3[CH2:42][CH2:43][S:44](=[O:47])(=[O:48])[CH2:45][CH2:46]3)=[C:37]([F:49])[CH:36]=2)[CH2:30]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:27])[C@@H:11]([NH2:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: COc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
2(S)-tert-Butoxycarbonylamino-3-phenyl-propionic acid (acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamoyloxy)-methyl ester (12 g) (0.78 g, 1.1 mmol), anisole (0.5 mL) and THF (20 mL) are cooled to 0° C. Hydrogen chloride (4 M in dioxane, 8 mL, 33.1 mmol) is added in a dropwise manner. After complete addition, the ice-bath is removed and the mixture is stirred at RT overnight. Under reduced pressure, the mixture is concentrated to one-half of its original volume. Ether is then added dropwise to the mixture while stirring, resulting in the formation of a solid. The solid is collected via filtration, rinsed with ether and ethyl acetate, and dried under vacuum to give the title compound in 63% yield (0.45 g). 1H NMR (400 MHz, CD3OD): δ 7.50 (dd, 1H), 7.39-7.24 (m, 7H), 6.02 (d, 1H), 5.97 (d, 1H), 4.86 (m, 1H), 4.50 (dd, 1H), 4.18 (m, 2H), 4.09 (dd, 1H), 3.83 (dd, 1H), 3.35 (m, 3H), 3.21 (m, 2H), 3.11 (m, 2H), 2.53 (s, 3H), 2.34 (m, 2H), 2.16 (m, 2H). MS-APCI (m/z+): 341, 385, 606.
Reaction SMILES: [CH2:1]([C:7]1[C:8]2[S:17][CH:16]=[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:9]=2[S:10][C:11]=1C(O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C2C(=CC=CC=2)C=CC=1.C(=O)=O>[Cu].CCCCCC>[CH2:18]([C:15]1[C:9]2[S:10][CH:11]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]=2[S:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCc1csc2c(CCCCCC)c(C(=O)O)sc12
Agent: [Cu]
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: CCCCCCc1csc2c(CCCCCC)csc12
Temperature: 262 °C
Yield: 68.6 %

Procedure:
A mixture of compound 55 (30 g, 0.085 mol), copper powder (3.76 g) and quinoline (80 mL) is heated at 264-260° C. in a Woods metal bath. When no further bubbles of carbon dioxide gas are detected (about 2 hours), the mixture is allowed to cool to room temperature and hexane (200 mL) is added. This mixture is washed repeatedly with HCl (1-2 M in water) to remove the quinoline. The remaining organic layer is dried over MgSO4 and concentrated by evaporation, leaving a residue, which is purified by column chromatography (SiO2/hexanes) to yield compound 57 (18 g, 68.4%). m.p. 57.5-59.1° C., 1H NMR (CD2Cl2): δ6.97 (s, 2H), 2.70 (t, 4H), 1.73 (m, 4H), 1.37 (m, 12H), 0.88 (t, 6H). 13C NMR: 136.56, 134.96, 109.80, 31.94, 29.31, 29.28, 28.47, 22.96, 14.22.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18]([CH3:22])([CH3:21])[C:19]#[N:20])=[C:12]([N+:23]([O-])=O)[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C(OCCCN2CCCC2)=CC([N+]([O-])=O)=C(C2(C#N)CCC2)C=1>>[CH:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:13]([C:18]([CH3:22])([CH3:21])[C:19]([NH2:20])=[N:23]3)=[CH:14][C:15]=2[O:16][CH3:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(C)(C)C#N)c([N+](=O)[O-])cc1OCCCC1CCCC1
Agent: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1OCCCN1CCCC1
Product: COc1cc2c(cc1OCCCC1CCCC1)N=C(N)C2(C)C
Yield: 37.2 %

Procedure:
2-(4-(3-cyclopentylpropoxy)-5-methoxy-2-nitrophenyl)-2-methylpropanenitrile (0.126 g, 0.365 mmol), from Step 3, was treated in a manner analogous to that described for 1-(5-methoxy-2-nitro-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)cyclobutanecarbonitrile in Step 5 of Example 7. Purification of the crude product by flash chromatography (silica gel, 10-30% MeOH/DCM) afforded 43 mg (37%) of 6-(3-cyclopentylpropoxy)-5-methoxy-3,3-dimethyl-3H-indol-2-amine 1H NMR (400 MHz, DMSO) δ 7.20 (s, 1H), 6.80 (s, 1H), 3.93 (t, J=6.5 Hz, 2H), 3.75 (s, 3H), 1.84-1.67 (m, 6H), 1.62-1.54 (m, 2H), 1.53-1.48 (m, 2H), 1.48-1.44 (m, 5H), 1.43-1.40 (m, 2H), 1.14-1.02 (m, 2H). MS (ESI) m/z 317 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([CH:9]1[CH2:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[ClH:12].[NH3:13]>C(O)C>[ClH:12].[CH:9]1([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:1]([NH2:13])=[NH:2])[CH2:10][CH2:11]1
Reactant: N
Reactant: CCOC(=O)C(C#N)C1CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C(=N)N)C1CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Into a stirred solution of 38.72 g (0.253 mol) of ethyl 2-cyano-2-cyclopropylacetate (preparation described by R. W. J. Carney and J. Wojtkunski, Org. Prep. Proced. Int., 5, 25 (1973)) in 17.7 mL (0.303 mol) of anhydrous ethanol under a dry N2 atmosphere was introduced 10.0 g (0.274 mol) of gaseous hydrogen chloride with ice cooling. The mixture was allowed to warm to room temperature and stand for 72 hours. The reaction was diluted with 100 mL of anhydrous ethanol, 70 mL of ammonia in ethanol (4.17M) was added slowly at room temperature and the reaction was stirred for 3 hours. The reaction mixture was filtered to remove the ammonium chloride, and the solvent was removed to afford the title compound as a viscous off-white oil, which was taken directly to the next step.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[C:22](=[O:23])[C:14]3=[CH:15][N:16]4[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]4)=[C:13]3[CH:12]=[N:11]2)[N:5]=[CH:4][CH:3]=1.C([CH:26]1[CH2:31][N:30]([CH:32]2[CH2:35][O:34][CH2:33]2)[CH2:29][CH2:28][N:27]1[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]2[C:44](=[O:59])[N:45]([CH3:58])[CH:46]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:48]=2)=[N:40][CH:41]=1)C.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>O>[CH3:58][N:45]1[C:44](=[O:59])[C:43]([NH:42][C:39]2[CH:38]=[CH:37][C:36]([N:27]3[CH2:28][CH2:29][N:30]([CH:32]4[CH2:33][O:34][CH2:35]4)[CH2:31][CH2:26]3)=[CH:41][N:40]=2)=[CH:48][C:47]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[C:22](=[O:23])[C:14]4=[CH:15][N:16]5[C:21]([CH2:20][CH2:19][CH2:18][CH2:17]5)=[C:13]4[CH:12]=[N:11]3)[N:5]=[CH:4][CH:3]=2)=[CH:46]1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3n(cc2c1=O)CCCC3
Reactant: CCC1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccnc(-n3ncc4c5n(cc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 50 °C
Yield: 40.8 %

Procedure:
A 50-mL round bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-(4-oxo-7,8,9,10-tetrahydropyridazino[4,5-a]indolizin-3(4H)-yl)nicotinaldehyde 192c (118 mg, 0.36 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl-amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (171 mg, 0.36 mmol), Na2CO3 (78 mg, 0.72 mmol), Pd (dppf)Cl2 (30 mg, 0.036 mmol), DMF (10 mL), and water (1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 50° C. for 10 hours under N2 protection. It was then cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 198a (93 mg, 40%) as a brown solid. MS-ESI: [M+H]+ 634.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N:14]1([C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[N:15]1>C(#N)C>[N:14]1([C:19]2[N:24]=[C:23]([NH:25][C:2]3[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=3[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: Nc1cccc(-n2cccn2)n1
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(-n2cccn2)n1
Yield: 24.8 %

Procedure:
A solution of ethyl 4,6-dichloropyridazine-3-carboxylate (230 mg, 1.04 mmol) and 6-(1H-pyrazol-1-yl)pyridin-2-amine (332.3 mg, 2.07 mmol) in acetonitrile (11.8 mL) was heated at 130° C. in a sealed tube for 48 h, then cooled concentrated in vacuo and then purified by chromatography (silica, Analogix 24 g RediSep Gold column 0 to 20% acetone in dichloromethane, 20 min) to give ethyl 4-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (107 mg, 258 μmol, 25%) as a white solid. This material was 83% pure and was used directly in the next step without further purification. MS (EI/CI) m/z: 345.1 [M+H].
Reaction SMILES: [C:1]([C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]>[Ni]>[NH2:2][CH2:1][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)(C)C#N
Agent: [Ni]
Product: CCOC(=O)C(C)(C)CN
Reaction time: 72 h
Yield: 99.9 %

Procedure:
According to the procedure described in the synthesis method of Compound XIV-3 with the modification that the reaction was carried out for 3 days, ethyl 2-cyano-2-methylpropanoate (2.91 ml, 20 mmol) was hydrogenated with raney nickel (600 mg) to obtain the title compound (2.90 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[C:17]([NH2:24])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:25])[N:11]=[C:10]([F:26])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[Cl:25][C:12]1[N:11]=[C:10]([F:26])[C:9]2[O:8][C:5]3[C:4]([C@:15]4([C:23]5[C:18](=[N:19][CH:20]=[CH:21][CH:22]=5)[C:17]([NH2:24])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:27]1[C:29]([F:32])=[N:11][CH:10]=[CH:9][CH:14]=1)=[CH:7][CH:6]=3
Reactant: NC1=N[C@@]2(c3cc(Br)ccc3Oc3c2cc(Cl)nc3F)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(Cl)nc3F)c2cccnc21

Procedure:
The titled compound was synthesized by procedures and steps analogous to those described in Example 5 above, but using (R)-7-bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,5′-pyrrolo[3,4-b]pyridin]-7′-amine (17c-1) in step 3. MS m/z=447.5 [M+H]+. Calculated for C23H12ClF2N5OC2HF3O2: 561.85 (TFA salt). 1H NMR (400 MHz, MeOH) ppm 6.67 (s, 1H) 6.86 (d, J=2.35 Hz, 1H) 7.33 (d, J=8.80 Hz, 1H) 7.42 (dd, J=7.82, 4.89 Hz, 1H) 7.52 (dd, J=8.80, 2.54 Hz, 1H) 7.64 (dd, J=7.73, 1.27 Hz, 1H) 8.74 (dd, J=4.79, 1.27 Hz, 1H)
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10]3[C:11](=[C:16]4[C:20]([C:9]=3[CH:8]([CH3:21])[CH:7]=1)=[CH:19][N:18]=[N:17]4)[CH:12]=[CH:13][CH:14]=2)=O)C.C1(=O)C2=C3C(=CC=C2)C=CC=C3C1.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[CH3:50][S:51]([CH3:53])=[O:52]>O1CCCC1>[CH3:21][CH:8]1[CH:7]=[C:6]([C:4](=[O:3])[CH2:50][S:51]([CH3:53])=[O:52])[C:15]2[C:10]3[C:11](=[C:16]4[C:20]([C:9]1=3)=[CH:19][N:18]=[N:17]4)[CH:12]=[CH:13][CH:14]=2
Reactant: CCOC(=O)C1=CC(C)C2=c3c1cccc3=C1N=NC=C12
Reactant: CS(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C1Cc2cccc3cccc1c23
Agent: [H-]
Solvent: C1CCOC1
Product: CC1C=C(C(=O)CS(C)=O)c2cccc3c2=C1C1=CN=NC=31
Temperature: 0 °C

Procedure:
3-Ethoxycarbonyl-1-methyl-1H-acenaphthyleno[1,2-c]pyrazole (2g), mp 107°-109° C., prepared according to Example 1 starting from acenaphthen-1-one, is dissolved in anhydrous tetrahydrofuran (45 ml) and added dropwise, under stirring, at a temperature varying between 10° C. and 20° C., to a solution of methylsulfinyl carbanion, obtained by reacting 50% sodium hydride (0.7 g) with anhydrous dimethylsulfoxide (30 ml) at 70° C. for 1 hour. The reaction mixture is kept under stirring at room temperature for 1 hour, then is diluted with ice water and acidified with citric acid to pH 4. The precipitate is extracted with ethyl acetate and the organic solution evaporated to dryness in vacuo. The residue is purified over a flash column using toluene/ethanol/diethylamine 100/10/1.5 as eluent. Washings with ethanol give 0.45 g of 1-methyl-3-methylsulfinylacetyl-1H-acenaphthyleno[1,2-c]pyrazole, mp 220°-230° C. dec., NMR (DMSOd6) δppm: 2.76 (s)(3H, --SOCH3), 4.16 (s)(3H, =N--CH3), 4.57 (s)(2H, --COCH2SO--), 7.5-8.70 (m) (6H, phenyl protons).
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:21]=4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[N:3]=1.[CH2:32]([Sn](CCCC)(CCCC)C=C)[CH2:33]CC.C1(C)C=CC=CC=1>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>[O:29]1[CH2:30][CH2:31][N:26]([C:22]2[CH:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([N:4]5[CH:5]=[N:6][C:2]([CH:32]=[CH2:33])=[N:3]5)=[CH:8][CH:9]=4)[N:19]=3)[CH:25]=[CH:24][CH:23]=2)[CH2:27][CH2:28]1
Reactant: Brc1ncn(-c2ccc(Nc3nccc(-c4cccc(N5CCOCC5)c4)n3)cc2)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=Cc1ncn(-c2ccc(Nc3nccc(-c4cccc(N5CCOCC5)c4)n3)cc2)n1
Temperature: 120 °C

Procedure:
A mixture of N-(4-(3-bromo-1H-1,2,4-triazol-1-yl)phenyl)-4-(3-morpholinophenyl)pyrimidin-2-amine (0.024 g, 0.05 mmol), tributyl(vinyl)stannane (0.032 g, 0.10 mmol), Pd(PPh3)4 (0.012 g, 0.01 mmol), toluene (0.4 mL) and DMF (0.1 mL) was heated in a sealed tube at 120° C. with microwave irradiation for 1 h. The reaction mixture was cooled down to room temperature. Purification of this material by column chromatography on silica gel (40% EtOAc/hexane) provided the desired product as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.43 (d, 1H), 8.36 (s, 1H), 7.80 (d, 2H), 7.59 (d, 2H), 7.37 (m, 4H), 7.14 (d, 1H), 7.01 (dd, 1H), 6.75 (dd, 1H), 6.27 (d, 1H), 5.51 (d, 1H), 3.84 (m, 4H), 3.20 (m, 4H). MS (ESI) 426.29 (M+H).