Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[C:25]([NH2:31])[C:21]=3[C:22](=[O:24])[CH:23]=2)=[CH:14][C:13]=1[F:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br)(=O)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O>CN(C)C=O>[NH2:31][C:25]1[C:21]2[C:22](=[O:24])[CH:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[C:13]([F:32])[CH:14]=3)[O:19][C:20]=2[C:28]([F:29])=[CH:27][C:26]=1[F:30]
Reactant: CC(=O)N(CCCCCCBr)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: C1COCCN1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCCCCN4CCOCC4)c(F)c3)cc(=O)c12
Reaction time: 1.5 h

Procedure:
500 mg (1.07 mmol) of 5-amino-2-[4-(6-bromohexylamino)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 52 was dissolved in 15 ml of dimethylformamide, 0.93 ml of morpholine was added and the mixture was stirred at 50° to 60° C. for 1.5 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol:triethylamine =200:10:1) and recrystallized from ethyl acetate/n-hexane to give Compound 55 which was converted into hydrochloride according to the same manner as that in Example 16 to give 349 mg (62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:21]=1[CH:22]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:21]=1/[CH:22]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(C(F)(F)F)ccc1Cl)C2=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a solution of 6-methoxy-5-morpholino-2, 3-dihydro-1H-inden-1-one 13 (0.120 mg, 0.485 mmol) in toluene (10 mL) was added 2-chloro-5-(trifluoromethyl)benzaldehyde 75 (0.101 mg, 0.485 mmol). PTSA (0.184 mg, 0.971 mmol) was added to the reaction mass, reaction stirred at 100° C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 157 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 15% ethyl acetate in hexane to afford yellow coloured solid (E)-2-(2-chloro-5-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2, 3-dihydro-1H-inden-1-one 157.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)=[CH:4][CH:3]=1.[Cl:25][CH2:26][CH2:27][N:28]=[C:29]=[O:30]>C1(C)C=CC=CC=1.CC(C)=O>[Cl:25][CH2:26][CH2:27][NH:28][C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)=[CH:4][CH:3]=1)=[O:30]
Reactant: CCn1c(C#Cc2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Reactant: O=C=NCCCl
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CCn1c(C#Cc2ccc(NC(=O)NCCCl)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 100 °C
Yield: 54.2 %

Procedure:
2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, is suspended in toluene (600 μL). 2-Chloroethyl isocyanate (32 μL, 0.37 mmol) is added, and the mixture is heated at 100° C. for 5 h. The reaction mixture is then cooled, diluted in acetone, and absorbed onto silica. Purification by column chromatography (5-10% EtOAc in CH2Cl2) yields 1-(2-chloro-ethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea (73 mg, 54%) as a yellow solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[CH:7][N:6]=1.O>CO>[Cl:4][C:5]1[CH:10]=[C:9]([O:2][CH3:1])[N:8]=[CH:7][N:6]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(Cl)ncn1
Temperature: 25 °C
Yield: 100 %

Procedure:
5.8 g sodium methanolate was added to 10 g 4,6-dichloropyrimidine in 150 mL MeOH at 0° C. The reaction was warmed up to RT and stirred over night at RT. Then 3.63 g sodium methanolate was added and the reaction was stirred for 3 h. The mixture was treated with water and extracted with EtOAc. The organic layer was dried over magesiumsulfate and evaporated to give 9.7 g 4-chloro-6-methoxy-pyrimidine.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1)#[N:3].[CH2:20]([OH:22])[CH3:21]>>[ClH:1].[CH2:20]([O:22][N:3]=[CH:2][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1)[CH3:21]
Reactant: CCOC(=O)CNC(=O)Nc1ccc(C#N)cc1
Reactant: CCO
Agent: Cl
Product: CCON=Cc1ccc(NC(=O)NCC(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 30 h

Procedure:
Dry HCl gas is introduced with stirring and cooling (0° C.) into a suspension of 2.3 g (9.3 mmol) of ethyl 3-(4-cyanophenyl)ureidoacetate in 50 ml of anhydrous ethanol. After 30 h, the mixture is concentrated in vacuo. The residue is stirred with ether and filtered off.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].CN(C)C=O>C1CCCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[C:12](=[CH:17][N:18]([CH3:20])[CH3:19])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(OC)N(C)C
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 90 °C
Reaction time: 16 h
Yield: 66.8 %

Procedure:
Tert-butyl-4-oxo-1-piperidinecarboxylate (10 g, 50 mmol) and N,N-dimethylformamide dimethyl acetal (7.3 mL, 55 mmol) were added to N,N-dimethylformamide (75 mL) under nitrogen gas and the mixture heated at 90° C. for 8 hours and then stirred for a further 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue partitioned between ethyl acetate (200 mL) and brine (200 mL). The aqueous phase was re-extracted with ethyl acetate (200 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give a brown oil that solidified on standing. Trituration with cyclohexane (20 mL) gave the title compound as a light brown solid (8.5 g, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:10](=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:5]([C:6]([OH:8])=O)[CH:4]=1.[NH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[C:15]2[C:10](=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:5]([C:6]([NH:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[O:8])[CH:4]=1
Reactant: COc1cc(C(=O)O)nc2c([N+](=O)[O-])cccc12
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc2c([N+](=O)[O-])cccc12

Procedure:
4-Methoxy-8-nitroquinaldic acid (3.6 g) (see Example 16) and N,N'-carbonyldiimidazole (2.5 g) in dimethylformamide (70 ml) were heated on a steam bath for 1 hour. 5-Aminotetrazole (2.5 g) was added and the mixture was heated on a steam bath for 1 hour and cooled. 4-Methoxy-8-nitro-N(1H-tetrazol-5-yl)quinaldamide, compound with imidazole, m.p. 238°, was filtered off and was triturated with 2N hydrochloric acid (50 ml). 4-Methoxy-8-nitro-N(1H-tetrazol-5-yl)quinaldamide was collected and dried, m.p. 268° (d).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:21][OH:22])=[C:4]([N:8]2[C:12](=[O:13])[C:11]3[S:14][C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:16][C:10]=3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([O:22][CH2:21][C:3]1[C:4]([N:8]2[C:12](=[O:13])[C:11]3[S:14][C:15]([C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:16][C:10]=3[CH2:9]2)=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:31])[CH3:30]
Reactant: CC(C)(C)c1cc2c(s1)C(=O)N(c1cccc(Br)c1CO)C2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1c(Br)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 114g (240 mg, 0.633 mmol), pyridine (150 mg, 1.90 mmol) and methylene chloride (10 mL). The solution was cooled to 0° C., and acetyl chloride (75 mg, 0.950 mmol) was added. The cooling bath was then removed, and the reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was partitioned between water (5 mL) and methylene chloride (5 mL), and the layers were separated. The aqueous phase was extracted with methylene chloride (2×10 mL), and the combined organic extracts were washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) and brine (10 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 114h in 86% yield (231 mg) as a white solid: mp 172-173° C.; 1H NMR (500 MHz, CDCl3) δ 7.63 (d, 1H, J=8.0 Hz), 7.34-7.21 (m, 2H), 6.87 (s, 1H), 5.21 (s, 2H), 4.64 (s, 2H), 2.05 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [Cl:1][CH:2]([C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=O)C.[BH4-].[Na+]>C(O)C>[Cl:1][CH:2]([CH:8]([OH:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(Cl)C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of ethyl 2-chloro-3-oxo-3-phenylpropionate (CI, 100 g, 0.44 mol) and glacial acetic acid (25 ml, 0.44 mol) in ethanol (1 l) is cooled to −5° and stirred for 10 min. Sodium borohydride pellets (12.54 g, 0.33 mol, diam. 11 mm) are added in portions (4.2 g×3) with vigorous stirring. The reaction temperature is maintained at −5 to 0°. After the addition, the reaction mixture is stirred continuously at 0° for 5 hr and is then poured slowly into ice-water with stirring. The mixture is extracted with ethyl acetate (1 l). The organic phase is washed three times with water (100 ml) and saline (100 ml), dried over magnesium sulfate, and the solvent is removed under reduced pressure to give the title compound as a 1:4 mixture of the anti and syn isomers as determined by NMR, MS (m/z, CI+NH3) 246 (M++17), 228 (M+), 210, 194; “Anti” NMR (500 MHz, CDCl3) 7.60-7.50, 5.33, 4.64, 4.33, 1.33 δ; CMR (300 MHz, CDCl3) 167.9, 138.2, 128.7, 128.5, 126.7, 74.6, 62.9, 62.2 and 13.7 δ; “Syn” NMR (500 MHz, CDCl3) 7.60-7.50, 5.24, 4.58, 4.44 and 1.46 δ; CMR (300 MHz, CDCl3) 168.9, 138.8, 126.7, 126.5, 126.9, 75.2, 62.3, 59.2 and 13.8 δ.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([Cl:15])=[C:12]([OH:14])[CH:13]=1.Cl>CCO>[Cl:15][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:13][C:12]=1[OH:14]
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: Brc1nccs1
Agent: Cl
Solvent: CCO
Product: Oc1cc(Nc2nccs2)ccc1Cl
Temperature: 90 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (0.25 mL, 2.78 mmol), 5-amino-2-chlorophenol (200 mg, 1.39 mmol) and 37% HCl solution (0.24 mL, 2.78 mmol) in 10% aqueous EtOH solution (5 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 69% yield (217 mg).
Reaction SMILES: C(NC(C)C)(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1.CN(C)[CH:20]=[O:21]>O1CCCC1>[Br:8][C:9]1[C:10]([CH:20]=[O:21])=[C:11]([F:17])[C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: COc1ccc(Br)cc1F
Reactant: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(Br)c(C=O)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
A solution of anhydrous tetrahydrofuran (50 mL) and diisopropylamine (11 mL) was cooled to 0° C. and had 1.6 M n-butyl lithium/hexanes (47 mL) added drop wise under nitrogen balloon. The mixture was stirred for 10 minutes at 0° C. and was then cooled to −78° C. with an acetone dry ice bath. A mixture of 4-bromo-2-fluoro-1-methoxybenzene (7.9 mL, 61 mmol) in anhydrous tetrahydrofuran (50 mL) was added drop wise, under nitrogen balloon, to the reaction. The mixture was then allowed to stir for 30 minutes at −78° C. N,N-dimethylformamide (7.5 mL) was added drop wise at −78° C. under a nitrogen balloon. The reaction was stirred for 1 hour at room temperature under a nitrogen balloon. Half of the solvent from the solution was removed under reduced pressure and the solution was extracted using ethyl acetate, water (300 mL), and 1 M HCl (65 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was crystallized by washing with hexanes. The solid was collected via filtration and dried under reduced pressure to give 6-bromo-2-fluoro-3-methoxybenzaldehyde (8.21 g, 58% yield).
Reaction SMILES: [NH2:1][C:2]1[C:10](Br)=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([NH:31][C:32]([C:34]2[CH:38]=[CH:37][S:36][CH:35]=2)=[O:33])[CH:25]=[CH:24]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[NH2:6])=[CH:7][C:8]([CH3:12])=[CH:9][C:10]=1[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([NH:31][C:32]([C:34]1[CH:38]=[CH:37][S:36][CH:35]=1)=[O:33])[CH:25]=[CH:24]2
Reactant: Cc1cc(Br)c(N)c(C(N)=O)c1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(N)=O)c(N)c(-c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)c1
Temperature: 25 °C
Yield: 10 %

Procedure:
2-amino-3-bromo-5-methylbenzamide (31.8 mg, 0.139 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (122 mg, 0.370 mmol), Fibercat palladium catalyst (Johnson-Matthey, 68.2 mg), and K2CO3 (2 M in water, 0.51 ml, 1.0 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (1.5 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C for 20 minutes. The reaction was then cooled to room temperature, diluted with water (5 ml), and extracted with EtOAc (4×10 ml). The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified via silica gel (Biotage instrument, 13%->50%->100% EtOAc/hexanes) to afford title compound (5.6 mg, 10%). MS (ESI pos. ion) m/z: 402 (M+H). Calc'd Exact Mass for C23H19N3O2S: 401.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:26])[N:20]([CH2:22][C:23](O)=[O:24])[N:21]=[C:8]2[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:6]=1[CH3:37])=[O:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][NH:72][CH2:73][CH2:74][N:75]([CH3:77])[CH3:76]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:26])[N:20]([CH2:22][C:23](=[O:24])[N:72]([CH2:73][CH2:74][N:75]([CH3:77])[CH3:76])[CH3:71])[N:21]=[C:8]2[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=2)[C:6]=1[CH3:37])=[O:4]
Reactant: CNCCN(C)C
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)O)c(=O)n2C1c1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)N(C)CCN(C)C)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
Intermediate 17 (48 mg, 0.09 mmol) was dissolved in DMF (1 mL), and then diisopropylethylamine (48 μL, 0.28 mmol) and HATU (39 mg, 0.10 mmol) were added. The reaction mixture was stirred at RT for 30 minutes and then N,N,N-trimethylethylenediamine (36 μL, 0.28 mmol) was added. After 3 hours of stirring at RT, another portion of HATU was added (10 mg, 0.03 mmol), and stirring was continued for 1 hour. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-10% (2M NH3 in MeOH) in DCM to give the title compound as a white solid (40 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1.[NH4+].[OH-]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([CH3:24])=[O:33])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)c1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
The product of Step 3 (2.55 g) in CH2Cl2 (30 mL) was cooled to 0° C. and treated with mCPBA (60%, 2.16 g) and stirred for 1 h. The reaction mixture was treated with ice (20 g), saturated NH4OH solution (20 mL) and stirred for 10 minutes. The organic layer was separated and the aqueous layer re-extracted with CH2Cl2 (2×30 mL). The combined organic portions were dried over MgSO4, filtered and evaporated to give a gum. Silica gel chromatography, eluting with EtOAc/CH2Cl2 mixtures, gave 1-benzyloxycarbonyl-4-(2-methylsulfinylphenyl)piperidine (0.5 g).
Reaction SMILES: [CH2:1]([Al](CC)CC)[CH3:2].Br[C:9]1[CH:10]=[C:11]2[CH:17]=[N:16][NH:15][C:12]2=[CH:13][N:14]=1.[NH4+].[Cl-]>C1COCC1.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>[CH2:1]([C:9]1[CH:10]=[C:11]2[CH:17]=[N:16][NH:15][C:12]2=[CH:13][N:14]=1)[CH3:2]
Reactant: Brc1cc2cn[nH]c2cn1
Reactant: CC[Al](CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1cc2cn[nH]c2cn1
Temperature: 65 °C
Reaction time: 60 h

Procedure:
Triethylaluminum (21.7 mL, 40.4 mmol, 25 wt % solution in toluene) was added to a vigorously stirred solution of 5-bromo-1H-pyrazolo[3,4-c]pyridine [929617-35-6] (4.00 g, 20.2 mmol) and Pd(PPh3)4 (1.17 g, 1.01 mmol) in THF (100 mL) under argon. The reaction mixture was stirred at 65° C. for 60 h. The mixture was cooled to RT and poured into sat. aq. NH4Cl. The resulting suspension was filtered, the solid was washed with water and discarded. The filtrate and combined washings were extracted with EtOAc (3×). The combined organic extracts were washed with brine, then dried (Phase separator) and concentrated under reduced pressure. The residual oil was purified by flash column chromatography on silica gel (EtOAc/c-hexane 50:50, then 75:25, then 100:0). TLC, Rf (c-hexane/EtOAc 1:3)=0.22; MS (LC-MS): 148 [M+H]+, tR (HPLC conditions k): 0.71 min.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:17][CH2:16][C:13]2([CH2:15][CH2:14]2)[C@@H:12]([O:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH:32]=4)[N:27]([C:41](OC(C)(C)C)=O)[N:26]=3)[CH:22]=[N:21][CH:20]=2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:49]>C1COCC1.CCOC(C)=O>[CH:38]([O:37][C:35](=[O:36])[CH:34]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH3:41])[N:26]=[C:25]2[C:23]1[N:24]=[C:19]([O:18][C@H:12]2[CH2:11][N:10]([C:8]([O:7][C:3]([CH3:5])([CH3:4])[CH3:6])=[O:9])[CH2:17][CH2:16][C:13]32[CH2:14][CH2:15]3)[CH:20]=[N:21][CH:22]=1)[CH3:49])([CH3:39])[CH3:40]
Reactant: CI
Reactant: CC(C)OC(=O)Cc1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)OC(=O)C(C)c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
NaH in mineral oil (7.72 mg, 0.193 mmol) was added to a solution of (R)-tert-butyl 3-(6-((6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octan-4-yl)oxy)pyrazin-2-yl)-5-(2-isopropoxy-2-oxoethyl)-1H-indazole-1-carboxylate (40 mg, 0.064 mmol) in THF (643 μl) at 0° C.; this was stirred for 15 min before iodomethane (12.04 μl, 0.193 mmol) was added. After 1 h at 0° C.; the mixture was warmed to RT and stirred for 1.5 h. The mixture was diluted with EtOAc (100 ml), added to a separatory funnel, and washed with saturated aqueous NH4Cl (2×75 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 4% MeOH/DCM to give (4R)-tert-butyl 4-((6-(5-(1-isopropoxy-1-oxopropan-2-yl)-1-methyl-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (30 mg, 0.055 mmol, 85% yield) as a yellow oil. MS (ESI, pos. ion) m/z: 550.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH2:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22](=O)[CH3:23])=[CH:16][CH:15]=1)[C:10](=[O:25])[CH:9]=3.Cl.[CH3:29][NH:30][CH3:31].C(B)#N.[Na]>C(O)C>[F:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH2:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([N:30]([CH3:31])[CH3:29])[CH3:23])=[CH:16][CH:15]=1)[C:10](=[O:25])[CH:9]=3
Reactant: CNC
Reactant: CC(=O)COc1ccc(-n2nc3c(cc2=O)CCc2ccc(F)cc2-3)cc1
Agent: BC#N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(COc1ccc(-n2nc3c(cc2=O)CCc2ccc(F)cc2-3)cc1)N(C)C

Procedure:
To a mixture of 37 g of 9-fluoro-2-[4-(2-oxopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one, 33 g of dimethylamine hydrochloride and 700 ml of ethanol is added dropwise 200 ml of an ethanol solution of 10 g of sodium cyanoboron hydride while stirring under heating and reflux over the period of 2 hours. After the completion of the dropwise addition, the reaction is concentrated under reduced pressure. To the residue is added 200 ml of water, and then conc. hydrochloric acid is added thereto under ice-cooling. After the mixture is stirred at room temperature for 1 hour, it is rendered alkaline with potassium carbonate and extracted with ethyl acetate. After the extract is washed with water and dried over magnesium sulfate, the solvent is distilled off under reduced pressure Ethanol is added to the thus obtained oily substance and further fumaric acid is added thereto to convert into its salt. The resultant crystals are recrystallized from hydrous ethanol to give 9-fluoro-2-[4-(2-dimethylaminopropoxy)phenyl]-5,6 -dihydrobenzo[h]cinnolin-3(2H)-one.fumarate.