Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Clc1nccc2ccc(Br)cc12
Agent: [Zn]
Solvent: CC(=O)O
Product: Brc1ccc2ccncc2c1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A solution of 7-bromo-1-chloroisoquinoline (2.50 g, 10.3 mmol) and activated zinc (1.40 g, 21.65 mmol) in acetic acid (20 mL) was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide 7-bromoisoquinoline (1.86 g): ESI MS m/z 208 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)C(C(C(O)=O)O)O>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of ethyl 6-chloronicotinate (10 g) in 250 mL of THF was slowly added 126 mL of lithium aluminium hydride (1.5 M in toluene). The mixture was stirred at 0° C. for 1 hour. Poured into saturated aqueous tartaric acid (200 mL) and extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes (1:2 to 1:1) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]3[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]#[N:31])=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[BH4-].[Na+]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]#[N:31])=[CH:24][CH:23]=3)[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: N#CC=Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: N#CCCc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
4-(6-Chloronaphthalene-2-sulfonyl)-1-[4-(2-cyano-1-ethenyl)benzoyl]piperazine (699 mg) was dissolved in pyridine (15 ml) and methanol (5 ml), and to the mixture was added sodium borohydride (68 mg). The mixture was stirred at 60° C. for 2 hours and concentrated. To the residue was added diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate aqueous solution and brine in this order, dried and concentrated. The residue was purified with silica gel column chromatography (hexane: ethyl acetate=2:3) to give colorless crystals of the title compound (450 mg).
Reaction SMILES: [Br:1]C1SC(C2C3C(=NSN=3)C(C3SC(Br)=CC=3)=CC=2)=CC=1.S1C=CC=C1C1C2C(=NSN=2)C(C2SC=CC=2)=CC=1.BrC1C2C(=NSN=2)C(Br)=CC=1.[CH2:52]([Sn:56](CCCC)([CH2:62][CH2:63][CH2:64][CH3:65])[C:57]1S[CH:59]=[CH:60][CH:61]=1)[CH2:53][CH2:54][CH3:55]>>[CH2:52]([Sn:56]([Br:1])([CH2:62][CH2:63][CH2:64][CH3:65])[CH2:57][CH2:61][CH2:60][CH3:59])[CH2:53][CH2:54][CH3:55]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Brc1ccc(-c2ccc(-c3ccc(Br)s3)c3nsnc23)s1
Agent: Brc1ccc(Br)c2nsnc12
Agent: c1csc(-c2ccc(-c3cccs3)c3nsnc23)c1
Product: CCCC[Sn](Br)(CCCC)CCCC

Procedure:
The 4,7-bis(5-bromothien-2-yl)-2,1,3-benzothiadiazole is traditionally prepared from 4,7-bis(thien-2-yl)-2,1,3-benzothiadiazole, which in turn is prepared by the Stille coupling reaction of 4,7-dibromo-2,1,3-benzothiadiazole with tributyl(thien-2-yl)stannane as described by Kitamura et al., Chem. Mater., Vol. 8, 1996, pp. 570–578. Unfortunately, tributyl(thien-2-yl) stannane is a highly toxic and costly material that produces a toxic by-product tributyltin bromide. The process is further disadvantaged because the subsequent bromination reaction is carried out in a mixture of N-bromosuccinimide, chloroform, and acetic acid, which requires numerous crystallizations of the product to obtain a suitably pure material in the subsequent copolymerization reaction.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1.Cl>O>[Cl:4][C:3]([C:2](=[C:12]1[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1)[OH:1])([Cl:6])[Cl:5]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: C1=CCCCC1
Agent: Cl
Solvent: O
Product: OC(=C1C=CCCC1)C(Cl)(Cl)Cl
Reaction time: 2 h
Yield: 82.8 %

Procedure:
In 3.9 ml. (0.04M) of chloral 0.1 g. of ferric chloride-hexahydrate is dissolved, and then 3.95 ml. (0.04M) of cyclohexene are added dropwise at 10°-25° C. After stirring for 2 hours 20 ml. of water and 4 ml. of concentrated hydrochloric acid are added. The layers are separated and the aqueous layer is extracted with carbon tetrachloride. The organic layers are combined, dried, filtered and the solvent is distilled off at reduced pressure. 7.6 g. (82.8%) of trichloromethyl-(2-cyclohexenyl-1-yl)-carbinol are obtained.
Reaction SMILES: COC(N[C@@H](C(C)C)C(N1CC(=O)C[C@H]1C(OCC1C=CC=CC=1)=O)=O)=O.Cl.Cl.Cl.[F:31][C:32]1([F:85])[C:44]2[CH:43]=[C:42]([C:45]3[CH:46]=[CH:47][C:48]4[N:52]=[C:51]([C@@H:53]5[C@H:58]6[CH2:59][C@@H:55]([CH2:56][CH2:57]6)[N:54]5[C:60](=[O:73])[C@H:61]([NH:68][C:69](=[O:72])[O:70][CH3:71])[C:62]5[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=5)[NH:50][C:49]=4[CH:74]=3)[CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][C:35]([C:75]1[NH:79][C:78]([C@@H:80]3[CH2:84][CH2:83][CH2:82][NH:81]3)=[N:77][CH:76]=1)=[CH:36][CH:37]=2.[CH3:86][O:87][C:88]([NH:90][C@@H:91]([CH:95]1[CH2:100][CH2:99][O:98][CH2:97][CH2:96]1)[C:92](O)=[O:93])=[O:89].Cl.O=C1CN[C@H](C(OCC2C=CC=CC=2)=O)C1.COC(N[C@@H](C(C)C)C(O)=O)=O>>[CH3:71][O:70][C:69](=[O:72])[NH:68][C@H:61]([C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[C:60]([N:54]1[C@H:53]([C:51]2[NH:50][C:49]3[CH:74]=[C:45]([C:42]4[CH:41]=[CH:40][C:39]5[C:38]6[C:33](=[CH:34][C:35]([C:75]7[NH:79][C:78]([C@@H:80]8[CH2:84][CH2:83][CH2:82][N:81]8[C:92](=[O:93])[C@@H:91]([NH:90][C:88]([O:87][CH3:86])=[O:89])[CH:95]8[CH2:100][CH2:99][O:98][CH2:97][CH2:96]8)=[N:77][CH:76]=7)=[CH:36][CH:37]=6)[C:32]([F:31])([F:85])[C:44]=5[CH:43]=4)[CH:46]=[CH:47][C:48]=3[N:52]=2)[C@H:58]2[CH2:59][C@H:55]1[CH2:56][CH2:57]2)=[O:73]
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: COC(=O)N[C@@H](C(=O)N1[C@@H]2CC[C@H](C2)[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6)[nH]5)ccc3-4)cc2[nH]1)c1ccccc1
Agent: COC(=O)N[C@H](C(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1)C(C)C
Agent: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6[C@@H]7CC[C@H](C7)N6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c5c4)ccc2-3)[nH]1)C1CCOCC1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-benzyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate, except that methyl (R)-2-((1R,3S,4R)-3-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-1-phenylethylcarbamate 3HCl salt and (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid were used instead of (S)-benzyl 4-oxopyrrolidine-2-carboxylate hydrochloride and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. MS (ESI) m/z 939.92 [M+H]+. (34 mg, 23%).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:12]1([C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:10][CH3:11])=[O:9])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COC(=O)CCCCC(=O)[O-]
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 100.4 %

Procedure:
Monomethyl adipate (3.20 g) is dissolved in chloroform (70 ml), and thereto are added morpholine (2.61 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.75 g) and triethylamine (3.04 g) under ice-cooling. The mixture is then stirred at room temperature for 19 hours. Ice-water is added to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine successively and dried over sodium sulfate. The solvent is removed by evaporation under reduced pressure to give methyl 6-morpholin-4-yl-6-oxohexanoate (4.63 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:14]([OH:42])[C@@H:15]([N:25](CC1C=CC=CC=1C)CC1C=CC=CC=1C)[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:14]([OH:42])[C@@H:15]([NH2:25])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: Cc1ccccc1CN(Cc1ccccc1C)[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Yield: 97.9 %

Procedure:
Add 2-(R)-[2-(S)-[bis-(2-methylbenzyl)-amino]-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-piperidine-1-carboxylic acid tert-butyl ester (0.33 g, 0.56 mmol), 20% palladium hydroxide on carbon (230 mg) and methanol (25 mL) and stir under 1 atmosphere of hydrogen gas for 18 h. Add filter agent, filter and concentrate to give the title compound as a foam (0.203 g, 98%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])[CH3:15].[OH-].[Na+]>ClCCl>[C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:7]([CH3:6])[C:3](=[O:4])[CH2:2][Br:1])(=[O:16])[CH3:15]
Reactant: O=C(Br)CBr
Reactant: CNc1ccccc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)c1ccccc1N(C)C(=O)CBr
Reaction time: 0.33 h
Yield: 388.7 %

Procedure:
404 mg (2 mmol) of bromoacetyl bromide were added to a stirred, ice-cooled solution of 298 mg (2 mmol) of 2′-(methylamino)acetophenone in 5 ml of dichloromethane. The mixture was stirred for 20 minutes then 2 ml of 1M sodium hydroxide solution were added and stirring was continued for a further 15 minutes. The resulting solution was washed with 2M hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated to dryness to give 2.1 g of 2′-acetyl-2-bromo-N-methylacetanilide as a viscous gum. 1H NMR (400 MHz CDCl3) δ: 2.54 (3H,s), 3.16 (3H,s), 3.45-3.52 (2H,q), 7.34 (1H,dd), 7.48 (1H,dt), 7.56 (1H,dt), 7.77 (1H,dd).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6].C(N(CC)CC)C.[C:18](Cl)(Cl)=[S:19]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][N:6]=[C:18]=[S:19]
Reactant: S=C(Cl)Cl
Reactant: NCc1cc(F)cc(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1cc(F)cc(CN=C=S)c1
Temperature: -10 °C
Reaction time: 2.75 h
Yield: 86.4 %

Procedure:
A solution of 3,5-difluorobenzylamine (6.5 g, 0.05 mole) and triethylamine (15.4 ml, 0.11 mole) in 50 ml of tetrahydrofuran was added dropwise to a solution of thiophosgene (4.2 ml, 0.055 mole) in 50 ml of tetrahydrofuran with cooling to -10° C. over a period of twenty minutes. The mixture was stirred at 25° C. for 2.75 hours and then filtered. The filtrate was treated with charcoal, filtered, and evaporated to an oil. The oil was diluted with hexane:ethyl acetate (90:10) and purified on a flash silica column eluted with hexane:ethyl acetate (90:10) to yield 8.0 g (62%) of 3,5-difluorobenzyl isothiocyanate as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[C:11]3[C:15]([CH:16]=[C:17](B4OC(C)(C)CC(C)(C)O4)[CH:18]=2)=[N:14][N:13](C2CCCCO2)[CH:12]=3)=[O:8])[N:6]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:42]1[CH:43]=[C:44]([NH:49][S:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[CH3:59])(=[O:52])=[O:51])[C:45]([Cl:48])=[N:46][CH:47]=1.O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CO.O>[Cl:48][C:45]1[N:46]=[CH:47][C:42]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][NH:14]3)=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH:18]=2)=[CH:43][C:44]=1[NH:49][S:50]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH3:59])(=[O:52])=[O:51]
Reactant: Cc1ccccc1S(=O)(=O)Nc1cc(Br)cnc1Cl
Reactant: Cc1nc(C(=O)Nc2cc(B3OC(C)(C)CC(C)(C)O3)cc3nn(C4CCCCO4)cc23)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nc(C(=O)Nc2cc(-c3cnc(Cl)c(NS(=O)(=O)c4ccccc4C)c3)cc3[nH]ncc23)cs1
Temperature: 140 °C
Yield: 32.2 %

Procedure:
2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg), Pd(dppf)Cl2 (7.6 mg) and sodium carbonate (44 mg) were added to a 0.5-2 ml microwave vial. N-(5-Bromo-2-chloro-3-pyridinyl)-2-methylbenzenesulfonamide (37.5 mg) was added followed by 1,4-dioxane (0.5 ml) and water (0.5 ml). The reaction was heated at 140° C. for 20 min. The material was passed though a 1 g silica cartridge with DCM/methanol, then evaporated to dryness. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v), passed through a 1 g C18 cartridge, washing with acetonitrile and then evaporated in the blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v) and purified by MDAP (method F). Pure fractions were combined, blown down, suspended in ca. 3 ml dioxane:water (1:1, v/v) and freeze-dried to give title compound (18 mg)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([O:9]C)=[O:8].CO.O.[Li+].[OH-]>C1COCC1>[NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C1COCCN1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1COCCN1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A solution of 4-([4-2-butynyloxy)phenyl]sulfonyl}-morpholine-3-carboxylic acid, methyl ester (0.1 g, 0.28 mmol) in 2.4 mL of THF:methanol:water [4:1:1] was cooled in an ice bath and 2N LiOH (0.3 mL, 0.59 mmol) was added. The reaction was stirred at 0° C. for 30 minutes and at room temperature for 2 hours. After evaporating the solvent, the residue was diluted with ether and filtered. The solid was dissolved in water, neutralized with 1N HCl to pH˜3 and extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to give 0.06 g of 4-[4-(2-butynyloxy)phenyl]sulfonyl}-morpholine-3-carboxylic acid. Yield˜69.8%. mp 40-42° C. Electrospray Mass Spec 338.1(M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:13][C:14](=[O:16])[CH3:15].F[B-](F)(F)F.[O:22]=[N+:23]=[O:24].O>C(#N)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[C:4]([N+:23]([O-:24])=[O:22])=[CH:5][CH:6]=[C:7]2[NH:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Nc1cccc2c(Br)ccc(C)c12
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1ccc([N+](=O)[O-])c2c(Br)ccc(C)c12

Procedure:
To a cold (-5° C.) suspension of 4.45 g (16.00 mmol) of compound (19) in 25 ml acetonitrile was added dropwise a suspension of 2.60 g (16.64 mmol) of nitronium tetrafluoroborate in 5 ml of acetonitrile. After ten minutes, the homogenous, light-yellow reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated NaCl solution and then dried over anhydrous MgSO4. The solvent was then removed under reduced pressure, and the crude residue was recrystallized from methanol to give N-(5-bromo-8-methyl-4-nitro-naphthalen-1-yl)-acetamide (20) as a light-yellow solid, m.p. 216°-217° C. Another 0.80 g of compound (20) was obtained from the concentrated mother liquors after flash chromatography on silica, eluting hexanes:ethyl acetate (1:1). The overall yield was 2.00 g (39%).
Reaction SMILES: O1CCCC1.C([O:8][C:9](=O)[CH2:10][S:11]([NH:14][C:15]1[CH:20]=[C:19]([CH:21]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:18]([Cl:40])=[CH:17][N:16]=1)(=[O:13])=[O:12])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>CCCCCC.CCOCC>[Cl:40][C:18]1[C:19]([CH:21]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])=[CH:20][C:15]([NH:14][S:11]([CH2:10][CH2:9][OH:8])(=[O:13])=[O:12])=[N:16][CH:17]=1
Reactant: CCOC(=O)CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(CCO)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 0 °C
Yield: 62.9 %

Procedure:
To a tetrahydrofuran (5 ml) solution of ethyl[[[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]sulfonyl]acetate (67 mg, 0.116 mmol) was added an ether solution (0.18 ml) of 1M lithium aluminum hydride at 0° C. The resulting mixture was stirred at 0° C. After the termination of the reaction was confirmed by TLC, a saturated aqueous solution of ammonium chloride was added to the reaction mixture. The resulting mixture was filtered through Celite. The filtrate was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure to give the title compound (39 mg, 0.073 mmol, 63%) as a white solid.
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH2:16][CH:15]3[CH2:17][CH:11]([CH2:12][NH:13][CH2:14]3)[CH:10]=2)[CH:4]=1.[CH:18](O)=O>C=O>[ClH:1].[ClH:1].[CH3:18][N:13]1[CH2:14][CH:15]2[CH2:17][CH:11]([CH2:10][C:9]([C:5]3[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=3)=[CH:16]2)[CH2:12]1
Reactant: O=CO
Reactant: C1=C(c2cccnc2)CC2CNCC1C2
Agent: C=O
Agent: Cl
Product: CN1CC2C=C(c3cccnc3)CC(C2)C1

Procedure:
7-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene dihydrochloride (90 mg, 0.33 mmol) was dissolved in 37% aqueous formaldehyde (3 ml), and 98% formic acid (10 ml) was added. This mixture was refluxed for 1 h. The reaction was then cooled, concentrated by rotary evaporation, and treated with saturated sodium bicarbonate solution (15 ml). It was then extracted with chloroform (3×15 ml), and the extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation. Concentrated HCl (5 drops) was added to a solution of the free base in ethanol (10 ml). The excess HCl and residual water were removed by repeated azeotropic rotary evaporation with ethanol. 3-Methyl-7-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene dihydrochloride was isolated as a white, hygroscopic solid (116 mg, >100% due to moisture content).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:3]=1.[NH2:20][CH2:21][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:23][O:24][CH3:25].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:29]([O:28][C:27]([NH:26][C@@H:22]([CH2:23][O:24][CH3:25])[CH2:21][NH:20][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:3]=1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1-c1cnn(C)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H](CNc1cc(C#N)c(C(=O)OC)c(-c2cnn(C)c2)n1)NC(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 12 h

Procedure:
To a screw-top vial was added methyl 6-chloro-4-cyano-2-(1-methyl-1H-pyrazol-4-yl)nicotinate (115 mg, 0.416 mmol), (R)-tert-butyl 1-amino-3-methoxypropan-2-ylcarbamate (93 mg, 0.457 mmol), and DIPEA (87 μL, 0.499 mmol) in DMF (308 μL). The resulting yellow solution was stirred for 12 h at 45° C. and then at 50° C. for 6 h. The reaction mixture was diluted with EtOAc (20 mL) and was washed with water (10 mL) and brine (20 mL). The organic layer was collected and dried over Na2SO4 and was concentrated to a yellow oil. The concentrate was purified via standard phase column chromatography eluting with EtOAc and hexanes (50-100% EtOAc gradient) to give the title compound as a light yellow residue (36.5 mg, 20%). [M+H] calc'd for C21H28N6O5, 445. found, 445.
Reaction SMILES: I.[NH2:2][NH:3][C:4]([NH:7][CH3:8])=[N:5][CH3:6].Cl.[C:10](Cl)(=O)[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:8][NH:7][C:4]1[N:5]([CH3:6])[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:2][N:3]=1
Reactant: CN=C(NC)NN
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: I
Solvent: c1ccncc1
Product: CNc1nnc(-c2ccncc2)n1C
Temperature: 160 °C
Yield: 26.2 %

Procedure:
A mixture of 1000 mg (4.35 mmol) N-amino-N′,N″-dimethyl-guanidine hydriodide (Henry; Smith; J.Amer.Chem.Soc.; 73; 1951; 1858) and 774 mg (4.35 mmol) isonicotinoyl chloride hydrochloride in 3 ml of pyridine was heated with microwaves for 5 min at 160° C. K2CO3(sat) was added and the mixture was extracted 4 times with CHCl3. The organic phase was dried and concentrated. Recrystallization from ethanol, water and EtOAc gave 216 mg (26%) of a yellow white solid. 1H NMR (DMSO), d (ppm): 2.85 (d, 3 H) 3.45 (s, 3 H) 6.25 (d, 1 H) 7.65 (m, 2 H) 8.67 (m, 2 H).
Reaction SMILES: Cl.NC1NC2C=C(NC(C3C=CC=CC=3C(O)=O)=O)C=CC=2N=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[N:32]=[C:31]([N:33](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[N:30](C(OC(C)(C)C)=O)[C:29]=2[CH:55]=1.[Cl:56][C:57]1[C:65]([Cl:66])=[C:64]([Cl:67])[C:63]([Cl:68])=[C:62]2[C:58]=1[C:59](=[O:70])[O:60][C:61]2=[O:69]>>[ClH:56].[NH2:33][C:31]1[NH:30][C:29]2[CH:55]=[C:25]([NH:24][C:61]([C:62]3[C:63]([Cl:68])=[C:64]([Cl:67])[C:65]([Cl:66])=[C:57]([Cl:56])[C:58]=3[C:59]([OH:70])=[O:60])=[O:69])[CH:26]=[CH:27][C:28]=2[N:32]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2ccc(N)cc2n1C(=O)OC(C)(C)C
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: Cl
Agent: Nc1nc2ccc(NC(=O)c3ccccc3C(=O)O)cc2[nH]1
Product: Nc1nc2ccc(NC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c3C(=O)O)cc2[nH]1
Yield: 154.4 %

Procedure:
Following the same procedure to synthesize 2-(2-amino-1H-benzo[d]imidazol-6-ylcarbamoyl)benzoic acid hydrochloride, tert-butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate (0.100 g, 0.223 mmol) was reacted with 4,5,6,7-tetrachloroisobenzofuran-1,3-dione (0.064 g, 0.223 mmol) to give the title compound (0.081 g, 77% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.32 (s, 2H), δ 7.12 (s, 1H) ppm; 13C NMR (75 MHz, CD3OD) δ 198.8, 165.5, 152.2, 134.7, 133.5, 130.6, 130.2, 129.6, 126.5, 118.5, 112.5, 106.7 ppm; HRMS (ESI) Calcd for C15H8Cl4N4O3 (M+) 431.9351. Found 431.9359.