Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([O:12]P(N3CCOCC3)(N3CCOCC3)=O)[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1.[CH3:34][O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([O:12][CH3:34])[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1
Reactant: O=P(OC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)(N1CCOCC1)N1CCOCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 8 h

Procedure:
To a solution of 24.5 mg. (0.5 mmoles) of 7-chloro-2-di-(morpholino)phosphinyloxy-5-phenyl-3H-1,4-benzodiazepine in 5 ml. of methanol at room temperature was added 82 mg. (1.5 mmoles) of sodium methoxide. The mixture was left at room temperature overnight. Methanol was evaporated and the residue was slurried with ether. Insoluble salts were removed by filtration. The clear ether solution was evaporated. Crystallization of the residue from petroleum ether yielded a final product having a m.p. of 94°-97°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C@H:25]([NH2:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[CH3:29][C:30]1[NH:34][N:33]=[C:32]([C:35](O)=[O:36])[CH:31]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C@H:25]([NH:26][C:35]([C:32]4[CH:31]=[C:30]([CH3:29])[NH:34][N:33]=4)=[O:36])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)n[nH]1
Reactant: CC1(C)C[C@@H](N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N[C@@H]2CC(C)(C)Oc3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc(Cl)cc4)cc32)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the product of Step B (300 mg, 0.69 mmol), 5-methylpyrazole-3-carboxylic acid (105 mg, 0.83 mmol), PyBOP (540 mg, 1.04 mmol), and NEt3 (0.19 mL, 1.38 mmol) in 20 mL of CH2Cl2 was stirred at rt. After 16 h, the reaction mixture was diluted with Et2O (50 mL), washed with saturated aq NaHCO3 (3×50 mL) and brine (3×50 mL). The organic layer was separated, dried over MgSO4 and concentrated. Chromatography on a Biotage 40+S cartridge using 1:1 v/v EtOAc/Hexanes as the eluant afforded the title compound: 1H NMR δ 1.44 (s, 3H), 1.51 (s, 3H), 1.94 (t, J=12.5, 1H), 2.26-2.30 (m, 4H), 5.62 (m, 1H), 6.58 (s, 1H), 6.96 (d, J=8.5, 2H), 7.12-7.29 (m, 5H), 7.69 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:9]3[CH2:15][CH2:14][CH2:13][CH:10]32)=C(OS(C(F)(F)F)(=O)=O)[CH:4]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.[C:63]([O:66][CH2:67]C)(=[O:65])[CH3:64]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:67][O:66][C:63]([C:64]1[C:6]2[CH2:7][CH:8]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH:9]3[CH2:15][CH2:14][CH2:13][CH:10]3[C:11]=2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:65]
Reactant: CCOC(C)=O
Reactant: COc1ccc(C2Cc3c(OS(=O)(=O)C(F)(F)F)cc(OC)cc3C3CCCC23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COC(=O)c1cc(OC)cc2c1CC(c1ccc(OC)cc1)C1CCCC21
Yield: 88 %

Procedure:
Combine trifluoro-methanesulfonic acid 8-methoxy-4-(4-methoxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-6-yl ester (0.1 g, 0.22 mmol), palladium acetate (0.0393 g, 0.18 mmol), 1,3-bis(diphenylphosphino)-propane (0.0723 g, 0.18 mmol), with dDMSO (6 ml) and methanol (2 m), and heat at 80-85° C. for 12 hours under an atmosphere of carbon monoxide. Remove solvent in vacuo, take in ethyl acetate and wash 5× with water. Dry over anhydrous sodium sulfate and chromatograph the residue on silica gel with 10% ethyl acetate in hexanes to yield the titled compound (0.07 g, 88%). 1H NMR (CDCl3): 7.21 (d, J=7.9, Hz, 2H), 7.19 (s, 1H), 6.9(s, 1H), 6.86 (d, J=7.9 Hz, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 3.8 (s, 3H), 3.45 (m, 1H), 3.22 (m, 1H), 3.1 (m, 2H), 2.58 (m, 1H), 2.2 (m, 1H), 1.6-1.3 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:21][CH:22]=[C:23]([Cl:26])[CH2:24]Cl>O>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH2:24][C:23]([Cl:26])=[CH:22][Cl:21])[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClC=C(Cl)CCl
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Cl)c(Cl)cnn1CC(Cl)=CCl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.5 %

Procedure:
To a mixture of 10.8 g of 4,5-dichloro-3(2H)-pyridazinone and 9.5 g of anhydrous potassium carbonate were added 65 ml of N,N-dimethylformamide and stirred for 10 minutes at room temperature. Then, 10.0 g of 1,2,3-trichloro-1-propene (mixture of E-from and Z-form) were added to the mixture solution and were stirred for 6 hours at 40° C. The solution was poured into a large quantity of water and extracted with benzene, and freed of solvent by distillation under reduced pressure to give 6.0 g of the intended compound (mixture of E-form and Z-form). The compound thus obtained was separated into isomer (m.p.: 93.7°-94.6° C., 112.8°-114.8° C.) by means of column chromatography (on silica gel, eluting with benzene).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.Br[CH2:15][C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[C:16]([CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)#[N:17]
Reactant: N#CCBr
Reactant: COC(=O)c1ccc(O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC#N)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
Methyl 4-hydroxy-2-methoxy-benzoate (0.790 g, 4.34 mmol), 2-bromoacetonitrile (361 μL, 5.42 mmol), and potassium carbonate (900 mg, 6.51 mmol) were combined in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of ethyl acetate and 25 mL of water. The layers were separated and the water layer was extracted with 50 mL of ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium chloride (2×). The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness to yield methyl 4-(cyanomethoxy)-2-methoxy-benzoate (99%) as a brown oil. ESI-MS m/z calc 221.1. found 222.1 (M+1)+. Retention time: 1.08 minutes (3 min run).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=2[CH:23]=1.[Br:24][C:25]1[C:26](F)=[N:27][CH:28]=[C:29]([F:31])[CH:30]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CN(C=O)C>[Br:24][C:25]1[C:26]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=3[CH:23]=2)=[N:27][CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: Fc1cnc(F)c(Br)c1
Reactant: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncc(F)cc4Br)cc3n2C)c1
Yield: 54.1 %

Procedure:
The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (2.28 g, 7.30 mmol), 3-bromo-2,5-difluoropyridine produced in Example (8a) (1.56 g, 8.03 mmol), copper iodide (0.14 g, 0.73 mmol), 1,10-phenanthroline (0.13 g, 0.73 mmol), cesium carbonate (7.14 g, 21.9 mmol) and DMF (40 mL) to obtain the title compound (1.92 g, 54%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)=[O:4].[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)=[O:4])=[CH:15][CH:16]=1
Reactant: OCc1ccc(O)cc1
Reactant: COc1cccc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(C(=O)COc2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a stirring solution of 2-bromo-3′-methoxyacetophenone (3.00 g, 13.1 mmol; Supplier=Kalexsyn; Lot=803-TTP-145) in acetone (30 ml) was added 4-hydroxybenzylalcohol (1.69 g, 13.6 mmol) and potassium carbonate (1.88 g, 13.6 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The product was analyzed on a large Biotage column eluting with 50% EtOAc/hexanes. Fractions containing product were combined and evaporated in vacuo to give 2.98 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: COC(=O)Cc1nc(N)sc1C
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: COC(=O)Cc1nc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)sc1C

Procedure:
The title compound was prepared from methyl 2-(2-amino-5-methyl-1,3-thiazol-4-yl)acetate and 4-biphenylsulfonyl chloride as described in the synthetic METHOD B to give a white solid (22:1 mg) with purity >90%. LCMS (pos) m/z 403.0.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl[CH2:32][C:33]1[CH:48]=[CH:47][C:36]([C:37]([N:39]2[CH2:44][CH2:43][N:42]([CH:45]=[O:46])[CH2:41][CH2:40]2)=[O:38])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:32][C:33]3[CH:48]=[CH:47][C:36]([C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH:45]=[O:46])[CH2:41][CH2:40]4)=[O:38])=[CH:35][CH:34]=3)=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Reactant: O=CN1CCN(C(=O)c2ccc(CCl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCc5ccc(C(=O)N6CCN(C=O)CC6)cc5)cc4)cc3)n(C)c(=O)c12
Yield: 49.7 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (402 mg), 1-(4-chloromethylbenzoyl)-4-formylpiperazine (354 mg) and potassium carbonate (261 mg) in DMF (5 ml) was stirred at room temperature for 24 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to provide the title compound as colorless solid (310 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8])=O.C(N(CC)CC)C.ClC(OCC)=O>CC(C)=O>[Cl:1][CH2:2][C:3]1[O:8][C:7](=[O:9])[C:6]([CH3:11])([CH3:10])[N:5]=1
Reactant: CC(C)(NC(=O)CCl)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)N=C(CCl)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a stirring mixture of 2-(2-chloro-acetylamino)-2-methyl propionic acid (18.0 g; 0.10 mol), triethylamine (11.1 g; 0.11 mol) and 100 mL acetone, cooled with an ice bath, was added ethyl chloroformate (10.5 mL; 0.11 mol) over a period of 10 minutes. The reaction mixture was then allowed to warm to room temperature and was stirred for 2 hours. The mixture was then filtered, and the filtrate was concentrated under vacuum. Hexane (200 mL) was added to the residue, and the mixture was filtered. After removal of the solvent under vacuum, the filtrate residue was distilled under reduced pressure (59-60° C.; 7 mmHg) to give 13.2 g (82%) of a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]3[CH:23]=[CH:24][C:19]([CH3:30])=[CH:20][CH:21]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: Cc1ccc(/C=C/C(=O)O)cc1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3ccc(C)cc3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-p-tolyl-acrylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1cccc(CCl)c1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(OCc3cccc(OC)c3)ccc2S(=O)(=O)CC1
Temperature: 60 °C
Reaction time: 13 h
Yield: 79.3 %

Procedure:
Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 3-methoxybenzyl chloride (350 mg) and potassium carbonate (412 mg) were suspended in DMF (15 ml), and the resulting suspension was stirred at 60° C. for 13 hours. The reaction mixture was diluted with ethyl acetate and washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the residue was subjected to purification using silica gel column chromatography (hexane:ethyl acetate=4:1-hexane:ethyl acetate=3:1) to obtain methyl 7-(3-methoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (459 mg) as a light yellow, amorphous substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23](O)=[O:24])=[C:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:31]1[CH2:34][CH:33]([C:35]2[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=2)[CH2:32]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:39]([C:38]1[CH:37]=[CH:36][C:35]([CH:33]2[CH2:32][N:31]([C:23]([C:22]3[CH:26]=[CH:27][C:28]([CH3:29])=[C:20]([C:16]4[N:15]=[C:14]([CH:11]5[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]5)[NH:18][C:17]=4[CH3:19])[CH:21]=3)=[O:24])[CH2:34]2)=[CH:42][CH:41]=1)#[N:40]
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
A mixture of 3-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 182.2, 506 mg), 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 296 mg, 1.52 mmol), EDCI (315 mg, 1.65 mmol), HOBt (107 mg, 0.64 mmol) and DIEA (877 μL, 5.08 mmol) in DMF (25 mL) was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure, diluted with saturated NaHCO3 (20 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine (3×10 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative TLC with 8% methanol in dichloromethane to give 476 mg (69%) of the title compound as a foam. m/z (ES+) 540 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][N:5]=1>C(O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][N:5]=1
Reactant: CCOC(=O)C=Cc1ccc(Cl)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Cl)nc1
Yield: 79.9 %

Procedure:
A suspension of 0.84 g (1 eq) of Te powder and 0.6 g (2 eq) of NaBH4 in 32 ml of ethanol was heated under nitrogen until it became a homogeneous purple solution. To the above hot solution was added ethyl β-(2-chloropyridin-5yl)acrylate (1.38 g, 6.5 mmol) and the mixture was refluxed for 4 h. The crude product was purified by flash chromatography (silica gel; hexane/ethyl acetate, 3:1) to afford 1.11 g (84,6%) of ethyl 3-(2-chloropyridin-5-yl)propionate.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:42])[C@@H:10]([NH:25][S:26]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([N:39]([CH3:41])[CH3:40])[CH:35]=2)[CH:30]=1)(=[O:28])=[O:27])[CH2:11][CH2:12][CH2:13][NH:14]C(=O)OCC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[NH2:14][CH2:13][CH2:12][CH2:11][C@H:10]([NH:25][S:26]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([N:39]([CH3:41])[CH3:40])[CH:35]=2)[CH:30]=1)(=[O:28])=[O:27])[C:9]([NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:42]
Reactant: CN(C)c1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=O)OCc3ccccc3)C(=O)NCc3ccccc3)ccc2c1
Agent: [Pd]
Solvent: CO
Product: CN(C)c1ccc2cc(S(=O)(=O)N[C@@H](CCCN)C(=O)NCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of (S)-benzyl 5-(benzylamino)-4-(6-(dimethylamino)naphthalene-2-sulfonamido)-5-oxopentylcarbamate (23 mg, 0.039 mmol) in methanol (5 ml) of was added Pd/C (10%) 5 mg. The reaction mixture was stirred under H2 balloon for 8 h at rt. After filtration the filtrate was evaporated in vacuo and the residue was triturated with ether repeatedly to provide (S)-5-amino-N-benzyl-2-(6-(dimethylamino)naphthalene-2-sulfonamido)pentanamide as colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].Cl.[NH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][CH2:22]1)[N:14]=2)[C:5]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:6]
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CCOC(=O)CCCN
Agent: Cl
Product: CCOC(=O)CCCNC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoic acid (0.080 g, 0.20 mmol) and ethyl 4-aminobutyrate hydrochloride, according to Reference S and the general procedure for amide formation afforded ethyl 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzamido)butanoate. MS (ESI) m/z: Calculated: 503.2; Observed: 504.1 (M++1).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N:20]4[C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].O.Cl[C:39]([CH3:42])([CH3:41])[CH3:40]>>[C:39]([C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N:20]4[C:21]5[CH:22]=[CH:23][C:24]([C:5]([CH3:6])([CH3:13])[CH3:4])=[CH:25][C:26]=5[C:27]5[C:32]4=[CH:31][CH:30]=[C:29]([C:26]([CH3:27])([CH3:21])[CH3:25])[CH:28]=5)[CH:15]=3)[C:13]3[C:5]([C:6]=2[CH:7]=1)=[CH:4][C:3]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:2][CH:1]=3)([CH3:42])([CH3:41])[CH3:40]
Reactant: c1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)c1cc(C(C)(C)C)ccc1n2-c1cccc(-n2c3ccc(C(C)(C)C)cc3c3cc(C(C)(C)C)ccc32)c1
Reaction time: 0.08 h

Procedure:
To a solution of 1,3-di(carbazol-9-yl)benzene (1.0 g, 2.45 mmol) in 2-chloro-2-methylpropane (10.0 ml) was added aluminum trichloride (0.32 g, 2.40 mmol) at room temperature under nitrogen atmosphere and stirring. After the addition of AlCl3, insoluble 1,3-di(carbazol-9-yl)benzene disappeared within minutes. The green solid appeared after 5 minutes of reacting at room temperature. The reaction was carried out at room temperature for another 10 minutes. TLC showed that the reaction was finished. After which, water (20.0 ml) was added and the green solid became white. The solid product was collected with filtration and washed with methanol. The product was purified by recrystallization from acetone/THF/methanol to yield a white solid in the amount of 1.23 g (79.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: Cc1cnnc2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1cnnc2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 174.7 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.218 g) and aminoguanidine hydrochloride (94 mg) were added ethanol (5 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was refluxed for 1.5 hours and cooled. Precipitated crystals were filtered, washed with ethanol and dried to give 7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 129) (0.255 g) as crystals.
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][NH:15][CH2:16]3)=[CH:11][CH:10]=2)[O:3]1>Cl>[CH2:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([B:4]([OH:5])[OH:3])[CH:18]=2)[CH2:13][CH2:14][NH:15]1
Reactant: CC1(C)OB(c2ccc3c(c2)CNCC3)OC1(C)C
Agent: Cl
Product: OB(O)c1ccc2c(c1)CNCC2
Yield: 85.2 %

Procedure:
7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (CXXI) (0.3 g, 1.15 mmol) was dissolved in 6 N aqueous HCl (20 mL) and refluxed overnight. The solvent was evaporated to dryness and the residue was crystallized from MeOH/Et2O to give 1,2,3,4-tetrahydroisoquinolin-7-ylboronic acid (CXXII) as a brown solid (0.21 g, 0.98 mmol, 87% yield). 1H NMR (DMSO-d6) δ ppm 2.92-3.07 (m, 2H), 3.36 (brs, 2H), 4.22 (brs, 2H), 7.18 (d, J=7.56 Hz, 1H), 7.59 (s, 1H), 7.67 (d, J=6.87 Hz, 1H), 8.08 (brs, 1H), 9.66 (brs, 2H); ESIMS found for C9H12BNO2 m/z 178 (M+H).