Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3C=C[N:20]=[CH:19]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1(C(=NO)N)[CH2:27][CH2:26]1>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][N:20]=[C:19]([CH:25]4[CH2:27][CH2:26]4)[N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2cccc(Cl)c2C1=O
Reactant: NC(=NO)C1CC1
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nc(C4CC4)no3)ncn2-c2cccc(Cl)c2C1=O

Procedure:
15 g (43.8 mmol) of 1-[[7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbonyl]imidazole, 6.60 g (65.8 mmol) of cyclopropanecarboxamidoxime and 100 ml of N,N-dimethylformamide are stirred at 70° for 1.5 hours, whereupon the mixture is evaporated to dryness, 100 ml of glacial acetic acid are added to the residue and the solution is heated to 120° for 1.5 hours. The solution is then evaporated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and evaporated. By recrystallization of the residue from methylene chloride and ethyl acetate there is obtained 7-chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 183°-184°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][C:18]3[N:23]=[C:22]([C:24]([OH:26])=O)[CH:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][S:28]([NH:31][C:24]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:17][C:6]2[C:5]3[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=3)[NH:8][C:7]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:23]=1)=[O:26])(=[O:30])=[O:29]
Reactant: Cc1ccc2c(Cc3cccc(C(=O)O)n3)c(-c3ccccc3)[nH]c2c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc2c(Cc3cccc(C(=O)NS(C)(=O)=O)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
Under an argon atmosphere, to a solution of 6-(6-methyl-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylic acid (838 mg) in dichloromethane (17.4 mL) were added methane sulfonamide (279 mg), 4-dimethylaminopyridine (718 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.13 g) successively, and this mixture was stirred at room temperature for 24 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed with 1 mol/L hydrochloric acid, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-dichloromethane) to obtain the title compound (740 mg).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=O>C1COCC1>[F:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[CH:15][C:3]=1[CH2:4][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COc1cccc(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1
Solvent: C1CCOC1
Product: COc1cccc(NCc2cc(-c3cccc(F)c3)ccc2F)c1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To a solution of 2-fluoro-5-(3-fluorophenyl)-N-(3-methoxyphenyl)benzamide (605 mg, 1.80 mmol, 1.0 eq) in THF (3 mL) was added dropwise a solution of BH3 (1 M in THF, 5.3 mL, 5.3 mmol, 2.9 eq) at 0° C. The reaction was heated at reflux overnight, then cooled to room temperature and quenched by addition of methanol and water. The reaction was diluted with EtOAc and water and the aqueous layer extracted further with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was purified by flash chromatography (petroleum ether: EtOAc, 10:1) to give the title compound as a colourless oil (512 mg, 88%).
Reaction SMILES: [F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>>[F:1][CH:2]([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:21][S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(F)F)nc1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)F)nc1
Yield: 81 %

Procedure:
The title compound is prepared in 81% yield (1.24 g, colorless oil) from 1-(6-(2,2-difluoroethoxy)pyridin-3-yl)ethanone (1.0 g, 4.97 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Br)cc2)cc1
Reactant: Oc1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccc(Cl)cc2)NS(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
The procedure described in Example 125 was repeated, except that ((RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (420 mg) was reacted with 4-chlorophenol (191.6 μl) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-3-(4-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl) propanamide (242.12 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.N>S(=O)(=O)(O)O>[Br:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([CH3:1])=[CH:3][N:4]=[CH:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cncc2ccccc12
Agent: N
Agent: O=S(=O)(O)O
Product: Cc1cncc2cccc(Br)c12
Reaction time: 2 h

Procedure:
4-Methylisoquinoline (0.1 ml, synthesized according to the method described in Tetrahedron. Lett. 34, 45, 7239 (1993)) was dissolved in concentrated sulfuric acid (1 ml), then added with N-bromosuccinimide (125 mg) with ice cooling and stirred for 2 hours. The reaction mixture was added with 28% aqueous ammonia (5 ml) and extracted twice with dichloromethane (10 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain the title compound (108 mg).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH:15]=[O:16])=[C:10]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]=[CH:8]2>C(O)(=O)C>[Br:1][C:6]1[C:5]([O:4][CH3:3])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:11]2[CH:15]=[O:16]
Reactant: BrBr
Reactant: COc1ccc2c(C=O)c(OCc3ccccc3)ccc2c1
Solvent: CC(=O)O
Product: COc1ccc2c(C=O)c(OCc3ccccc3)ccc2c1Br
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Bromine (3.22 mL, 62.5 mmol) was dissolved in 60 mL of glacial acetic acid and added, over a 20 minute period, to a soluton of 6-methoxy-2-(phenylmethoxy)-1-naphthalenecarboxaldehyde (17.4 g, 59.5 mmol, described in Example 5) in 270 mL of glacial acetic acid at 45° C. The resulting suspension was allowed to cool for 1 hour, then the precipitate was collected by filtration and washed thoroughly with absolute ethanol. The solid was suspended in 170 mL of toluene and concentrated by distillation at ambient pressure until about 30 mL remained then allowed to stand at room temperature overnight. The precipitate which formed upon cooling was collected by filtration and washed with hexane to give 18.14 g of the title compound as a yellow powder, m.p. 214°-220° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH2:11][CH2:10]1.C(N(CC)CC)C.O=C1N(N(N2CCOC2=O)P(Cl)(Cl)=O)CCO1.[NH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:18]([NH:51][CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)=[O:19])[CH2:11][CH2:10]1
Reactant: NCCN1CCOCC1
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Agent: O=C1OCCN1N(N1CCOC1=O)P(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCC(C(=O)NCCN2CCOCC2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 12.9 %

Procedure:
A mixture of 4-[4-(2-methoxyphenyl)piperazin-l-yl]-2-phenylbutanoic acid (3.544 g, 10 mmole), triethylamine (2.024 g, 20 mmole), and N,N-bis(2-oxo-3oxazolidinyl)phosphoramidic chloride (2.545 g. 10 mmole) was stirred in methylene chloride (80 mL) under exclusion of moisture at ambient temperature for 30 minutes, after which 4-(2-aminoethyl)morpholine (1.302 g, 10 mmole) was added. The reaction mixture was stirred at room temperature for 14 hours, washed with water (100 ml), dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. Chromatography on silica gel with methanol/chloroform as eluant, followed by crystallization from ethanol/diethyl ether with addition of ethanolic HCl gave 0.6 g of the title compound as the dihydrochloride, 2.5 hydrate, 0.2 CHCl3 solvate, m.p. 60°-5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)=[N:2]1.[NH2:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1O.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.CCCCCC>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]2[O:16][C:23]3[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=3[N:21]=2)=[N:2]1
Reactant: O=C(O)c1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O
Product: O=[N+]([O-])c1ccc2oc(-c3ccccc3/C=C/c3n[nH]c4ccccc34)nc2c1
Yield: 15 %

Procedure:
In a similar manner to Example 28, (E)-2-[2-(1H-indazol-3-yl)vinyl]benzoic acid (0.30 g, 1.1 mmol) obtained in Step 1 of Example 47, 2-amino-4-nitrophenol (0.19 g, 1.3 mmol), 1-hydroxybenzotriazole monohydrate (52 mg, 0.34 mmol), EDC (0.24 g, 1.3 mmol) and THF/DMF (2/1, 4.5 mL) were reacted. Then, in a similar manner to Step 2 of Example 150, the reaction mixture was treated with p-toluenesulfonic acid monohydrate (0.39 mg, 2.3 mmol) and xylene (10 mL) to obtain Compound 184 (63 mg, 14%).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[NH2:19][CH:20]([CH3:30])[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C>CS(C)=O.O.C(OCC)C>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:4]1[N:3]=[C:2]([NH:19][CH:20]([CH3:30])[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Reactant: CC(N)CNC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(CNC(=O)OC(C)(C)C)Nc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Temperature: 120 °C
Reaction time: 12 h

Procedure:
5-Chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine (Example 6A) (800 mg, 2.7 mmol), tert-butyl (2-aminopropyl)carbamate (700 mg, 4.0 mmol) and N,N-diisopropylethylamine (1.00 g, 8.0 mmol) are dissolved in DMSO (13 ml) and stirred at 120° C. under argon for 12 hours. The reaction mixture is diluted with water (100 ml) and extracted with ethyl acetate (3×75 ml). The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. Removal of the solvent results in a foam which is taken up in diethyl ether. The product precipitates as solid from the diethyl ether solution and is filtered off with suction and dried. 800 mg (68% of theory) of the product are obtained as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[S:17])[NH:4][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.Cl[C:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[N+:31]([O-:33])=[O:32])=O.O.CC1(C)[C@@H]2CC[C@@]1(CS(O)(=O)=O)C(=O)C2>C1(C)C=CC=CC=1.CCOC(C)=O>[N+:31]([C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:21]=1[C:19]1[S:17][C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[C:5]([C:8]1([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][CH2:9]1)[N:4]=2)[C:25]([O:27][CH3:28])=[O:26])([O-:33])=[O:32]
Reactant: COC(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A slurry of 3-amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (1.00 g, 4.13 mmol) and methyl 4-(chlorocarbonyl)-3-nitrobenzoate (1.11 g, 4.54 mmol) in 10 mL toluene was heated under nitrogen with a water cooled reflux condenser was heated in a 120° C. oil bath. After bubbling had subsided, ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid (0.479 g, 2.06 mmol) was added through the condenser and heating continued for 30 min. The slurry was treated with 5 mL toluene to and heating continued overnight to give a dark brown solution. The reaction mixture was cooled to ambient temperature, then diluted with EtOAc, washed with water, sat'd aq. Bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. Purification by silica gel chromatography, 40 g, 0-30% EA/hexanes gave methyl 3-nitro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoate as a light brown solid. MS (ESI) m/z: Calculated: 431.1; Observed: 432.0 (M++1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]([O:8][CH3:9])=[O:7])=[O:2].[N+:18]([O-])([OH:20])=[O:19]>O>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:18]([O-:20])=[O:19])[C:12]=1[NH:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:6]([O:8][CH3:9])=[O:7])=[O:2]
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)c(C=O)c1
Reactant: O=[N+]([O-])O
Solvent: O
Product: COC(=O)c1cc(C=O)c(NS(C)(=O)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Methyl 3-formyl-4-[(methylsulfonyl)amino]benzoate (3.85 g, 0.015 mol) was added portionwise to fuming nitric acid (45 mL) at 5°-10° C. over 0.25 h. The mixture was further stirred for 1.0 h at room temperature and then poured into cold water (200 mL). The yellow precipitate was collected by filtration and washed several times with cold water. The cake was recrystallized from ethyl acetate-hexane to give 2.5 g (55.3%) of methyl 3-formyl-4-[(methylsulfonyl)amino]-5-nitrobenzoate as light yellow needles, mp 158°-160° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[N:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=1.[Cl:21][C:22]1[CH:42]=[CH:41][C:25]2[CH:26]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:27]3[C:32]([CH2:33][S:34][C:24]=2[CH:23]=1)=[CH:31][CH:30]=[CH:29][N:28]=3.CN1CCOCC1>CN(C=O)C.CCOC(C)=O.O>[Cl:21][C:22]1[CH:42]=[CH:41][C:25]2[CH:26]([N:35]3[CH2:36][CH2:37][N:38]([C:18](=[O:20])[CH2:17][C:14]4[CH:13]=[CH:12][N:11]=[CH:16][CH:15]=4)[CH2:39][CH2:40]3)[C:27]3[C:32]([CH2:33][S:34][C:24]=2[CH:23]=1)=[CH:31][CH:30]=[CH:29][N:28]=3
Reactant: O=C(O)Cc1ccncc1
Reactant: Clc1ccc2c(c1)SCc1cccnc1C2N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccncc1)N1CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 63 %

Procedure:
DEC (464 mg, 2.42 mmol), HOBT (327 mg, 2.42 mmol), and 4-pyridine-acetic acid (332 mg, 2.42 mmol) were added to 1-(8-chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-piperazine (400 mg, 1.21 mmol) and NMM (5.3 ml) in DMF (8 ml), and the mixture was stirred at room temperature for 19 hours. Water (30 ml) and EtOAc (50 ml) were added, and the layers were mixed and separated. The aqueous layer was extracted with EtOAc (3×40 ml). The aqueous layer was basified with saturated NaHCO3 and was extracted with CH2Cl2 (2×20 ml). The organic layers were combined, washed with brine, dried (Na2SO4), decanted and concentrated; the crude product (659 mg) was purified by flash chromatography (30%acetone/CH2Cl2 to 5%MeOH/CH2Cl2) and obtained as a white solid (344 mg, 63%); MS (FAB, M+H)=451; HRMS: calc.: 451.1359; found: 451.1355.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[C:7]([O:23][CH3:24])=[C:8]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]([CH2:16][CH3:17])[CH:10]=[C:9]2[CH2:18][C:19]([NH:21][CH3:22])=[O:20].[CH3:26]O>[Pd]>[CH3:22][N:21]([CH3:26])[C:19](=[O:20])[CH2:18][C:9]1[C:8]2[C:12](=[C:13]([F:15])[CH:14]=[C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:25])[C:7]=2[O:23][CH3:24])[N:11]([CH2:16][CH3:17])[CH:10]=1
Reactant: CO
Reactant: CCn1cc(CC(=O)NC)c2c(OC)c(/C=C/C(=O)OC)cc(F)c21
Agent: [Pd]
Product: CCn1cc(CC(=O)N(C)C)c2c(OC)c(CCC(=O)OC)cc(F)c21
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 27-1 (200 mg, 0.57 mmol) in 20 mL of MeOH was added 0.1 g of Pd/C (10%). The mixture was stirred over night under H2 atmosphere at room temperature. The mixture was filtered and the filtrate was to afford 27-2 (150 mg, 0.42 mmol, 74%) as a white solid. LRMS: calc 364.1 and found: 365.1 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][C:23](O)=[O:24])[CH:20]=3)[N:15]([C:26]3[C:27]4[C@H:34]([CH3:35])[CH2:33][CH2:32][C:28]=4[N:29]=[CH:30][N:31]=3)[CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:38](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-]>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[NH2:38][C:23](=[O:24])[CH2:22][C:19]1[CH:20]=[C:21]2[C:11]3([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[CH2:14][N:15]([C:26]3[C:27]4[C@H:34]([CH3:35])[CH2:33][CH2:32][C:28]=4[N:29]=[CH:30][N:31]=3)[C:16]2=[CH:17][CH:18]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(CC(=O)O)ccc43)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(CC(N)=O)ccc43)c21
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a stirred solution of (R)-2-(1′-(tert-butoxycarbonyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-5-yl)acetic acid (0.020 g, 0.042 mmol), DIEA (0.023 ml, 0.13 mmol), and HBTU (0.017 g, 0.046 mmol) in 1:1 mixture of DCM/DMF (0.2 mL) was added NH4Cl (0.0067 g, 0.13 mmol). The reaction was stirred at about room temperature overnight. An additional equivalent of DIEA and NH4Cl were added and the reaction stirred at about room temperature overnight. The reaction was diluted with DCM, washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by column chromatography (3-5% MeOH/DCM) to yield (R)-tert-butyl 5-(2-amino-2-oxoethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.012 g, 60%). LCMS (APCI+) m/z 478.3 [M+H]+; Rt=3.05 min.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])=[CH:10][C:11](C4C=CC5OCCNC=5N=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:33]1[N:34]=[N:35][C:36]([N:39]2[CH2:44][CH2:43][N:42]([CH:45]3[CH2:48][O:47][CH2:46]3)[CH2:41][CH2:40]2)=[CH:37][CH:38]=1>>[CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])=[CH:10][C:11]([C:33]4[N:34]=[N:35][C:36]([N:39]5[CH2:44][CH2:43][N:42]([CH:45]6[CH2:48][O:47][CH2:46]6)[CH2:41][CH2:40]5)=[CH:37][CH:38]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1cc(-c2ccc3c(n2)NCCO3)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: Brc1ccc(N2CCN(C3COC3)CC2)nn1
Product: C[C@@H](Oc1cc(-c2ccc(N3CCN(C4COC4)CC3)nn2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Yield: 61 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((1-cyclopropyl-5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:, using instead 3-bromo-6-(4-(oxetan-3-yl)piperazin-1-yl)pyridazine as a starting material to afford 52.7 mg (61%) of (R)-4-((R)-1-((1-cyclopropyl-5-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyridazin-3-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, d6-DMSO) δ 8.12 (s, 1H), 8.04 (d, J=9.9 Hz, 1H), 7.80 (d, J=1.1 Hz, 1H), 7.62 (m, 2H), 7.35 (d, J=9.9 Hz, 1H), 4.81 (m, 1H), 4.52 (m, 4H), 3.69 (m, 5H), 3.41 (m, 2H), 3.20 (m, 1H), 2.54 (m, 1H), 2.37 (m, 6H), 1.34 (d, J=6.3 Hz, 3H), 1.09 (m, 4H). MS (ESI+) m/z 504.3 (M+H).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[CH2:7]([O:9][C:10]([Sn](CCCC)(CCCC)CCCC)=[CH2:11])[CH3:8].[F-].[K+]>CN(C=O)C.O.C(OCC)C>[CH2:10]([O:9][C:7]([C:2]1[S:6][CH:5]=[N:4][CH:3]=1)=[CH2:8])[CH3:11]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cncs1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: C=C(OCC)c1cncs1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 83.1 %

Procedure:
A mixture of 3.28 g (20.0 mmol) of 5-bromothiazole (for synthesis see H. C. Beyerman, P. H. Berben, J. S. Bontekoe, Rec. Trav. Chim. 1954, 73, 325), 7.43 mL (22.0 mmol) of (1-ethoxyvinyl)tributyltin, and 284 mg (0.404 mmol) of PdCl2 (PPh3)2 in 40 mL of DMF was heated at 70° C. for 30 h. The reaction mixture was cooled to 0° C. and 40 mL of a solution of potassium fluoride in water and 40 mL of diethyl ether were added. After stirring for 40 min the precipitate was faltered off and the aqueous and organic phases separated. The aqueous phase was re-extracted with 4×40 mL of diethyl ether. The combined ether phases were washed with 2×75 mL of water, 1×100 mL of brine, dried (MgSO4) and the solvent removed in vacuo. Flash chromatography (silica gel, 20% ethyl acetate-hexanes) afforded 2.58 g (83%) of the title compound as a yellow oil: 1H NMR (400 MHz, CDCl3) δ8.65 (s, 1H), 7.80 (s, 1H), 4.61 (d, 1H, J=3 Hz), 4.24 (d, 1H, J=3 Hz), 3.91 (q, 2H, J=7 Hz), 13.9 (t, 3H, J=7 Hz).