Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1.[CH3:20][N:21]=[C:22]=[S:23].C(Cl)(Cl)Cl.CO.N>CO>[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:22]([NH:21][CH3:20])=[S:23])[N:11]=1
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: CN=C=S
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNC(=S)NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 3 h

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.3 g.) and methyl isothiocyanate (0.18 g.) in methanol (6 ml.) was allowed to stand at room temperature for 3 hours. The residue obtained on evaporation of the solvent was subjected to preparative thin layer chromatography using chloroform/methanol/ammonia 90:10:0.5 v/v/v for development. The appropriate zone of the chromatogram was isolated and extracted with hot ethanol/chloroform 50:50 v/v (100 ml.). Evaporation of the solvent gave 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-(3-methylthioureido)butyl]thiazole as a straw-coloured gum. The n.m.r. spectrum d6 dimethylsulphoxide using tetramethylsilane as internal standard included the following resonances (δ):- 2.75 (3H, doublet), 4.04 (2H, multiplet) and 6.34 (1H, singlet). On addition of D2O the multiplet at δ4.04 collapsed to a quartet.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][CH2:13][SH:14]>C(N(CC)CC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[NH:11][CH2:12][CH2:13][S:14]2)=[CH:4][CH:3]=1
Reactant: NCCS
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Brc1ccc(C2NCCS2)cc1

Procedure:
The procedure of Example 1 was repeated, except that the reactants consisted of 18.5 g. of 4-bromobenzaldehyde and 27 g. of 2-aminoethanethiol hydrochloride, and the reaction mixture also contained 10 ml. of triethylamine. Since removal of solvent left a solid residue, the material was recrystallized from benzene/hexane to give 2-(4-bromophenyl)thiazolidine, m.p. 105°-7°. The following elemental analysis was obtained:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([CH:9]([OH:16])[C@@H:10]([C:13]([OH:15])=[O:14])[NH:11][CH3:12])=[CH:7][CH:6]=1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[N+:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40]Cl)([O-:33])=[O:32].[OH-].[Na+]>ClCCl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:9]([OH:16])[C@@H:10]([C:13]([OH:15])=[O:14])[N:11]([CH3:12])[S:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N+:31]([O-:33])=[O:32])=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccccc1SCl
Reactant: CN[C@H](C(=O)O)C(O)c1ccc(OCOC)cc1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCOc1ccc(C(O)[C@@H](C(=O)O)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of O-methoxymethyl-N-methyl-β-hydroxytyrosine (15.1 g) and bis(trimethylsilyl)acetamide (25 ml) in dichloromethane (150 ml) was added a solution of 2-nitrophenylsulfenyl chloride (11.2 g) in dichloromethane (50 ml). After stirring for 2 hours at 0° C., bis(trimethylsilyl)acetamide (10 ml) and 2-nitrophenylsulfenyl chloride (5.6 g) was added to the solution. The mixture was stirred for 3 hours at room temperature and added to 1N-sodium hydroxide (200 ml). The organic layer was washed with water (300 ml) and the aqueous solutions were combined. After the aqueous solution was acidified with diluted hydrochloric acid, the product was extracted with ethyl acetate (300 ml) and the extract was washed with water (100 ml×3). After the solution was dried over magnesium sulfate, the solvent was removed in vacuo to give O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-hydroxytyrosine (20.5 g).
Reaction SMILES: C1([O:4][S:5](=O)(=[O:7])[NH2:6])CC1.[CH2:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][O:14][S:5](=[O:7])(=[O:4])[NH2:6]
Reactant: CC(C)(C)CO
Reactant: NS(=O)(=O)OC1CC1
Product: CC(C)(C)COS(N)(=O)=O

Procedure:
Neopenylsulfamate was synthesized according to the method presented in the synthesis of sulfamic acid cyclopropyl ester in Example 1 with the exception of utilizing neopentylalcohol to obtain sulfamic acid 2,2-dimethyl-propyl ester.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)([CH3:8])[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:8][C:2]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)([CH3:1])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(C)c1ccncc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(CO)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 143.8 %

Procedure:
A solution of 1.58 g (7.36 mmol) of ethyl 2-methyl-2-pyrid-4-ylpropionate in 30 mL of THF is cooled to 10° C. When the temperature is reached, 22.08 mL (22.08 mmol) of 1 M diisobutylaluminum hydride solution in toluene are added dropwise. The reaction mixture is allowed to warm to room temperature and is stirred overnight. 1 N hydrochloric acid solution is added to the reaction medium, which is then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness to give 1.60 g of 2-methyl-2-pyrid-4-ylpropan-1-ol, corresponding to the following characteristics:
Reaction SMILES: [Cl:1][CH2:2][C@H:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([OH:16])=[CH:7][C:6]=2[N:5]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([NH:28][C:29](=[O:35])[CH2:30][CH2:31][S:32][S:33][CH3:34])=[CH:23][CH:22]=3)=[O:18])[CH2:4]1.CCN(C(C)C)C(C)C.[C:45]([N:52]1[CH:56]=[CH:55]N=C1)(N1C=CN=C1)=[O:46].C(N(C(C)C)CC)(C)C.N[C:67]1[CH:68]=[C:69]([S:73]([OH:76])(=[O:75])=[O:74])C=C[CH:72]=1>CC(N(C)C)=O>[Cl:1][CH2:2][C@H:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([O:16][C:45]([NH:52][C:56]3[CH:55]=[C:69]([S:73]([OH:76])(=[O:75])=[O:74])[CH:68]=[CH:67][CH:72]=3)=[O:46])=[CH:7][C:6]=2[N:5]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([NH:28][C:29](=[O:35])[CH2:30][CH2:31][S:32][S:33][CH3:34])=[CH:23][CH:22]=3)=[O:18])[CH2:4]1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CSSCCC(=O)Nc1ccc2[nH]c(C(=O)N3C[C@@H](CCl)c4c3cc(O)c3ccccc43)cc2c1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CSSCCC(=O)Nc1ccc2[nH]c(C(=O)N3C[C@@H](CCl)c4c3cc(OC(=O)Nc3cccc(S(=O)(=O)O)c3)c3ccccc43)cc2c1
Reaction time: 0.05 h

Procedure:
To a solution of DC101SMe ((S)—N-(2-(1-(chloromethyl)-5-hydroxy-2,3-dihydro-1H-benzo[e]indole-3-carbonyl)-1H-indol-5-yl)-3-(methyldisulfanyl)propanamide, 100 mg 0.19 mmol) in 10 ml of DMA was added DIPEA (35 μl, 0.20 mmol). After stirred under Ar for 3 min., 32.0 mg (0.20 mmol) of carbonyldiimidazole was added. The mixture was stirred for 2 hours and TLC showed all DC101SMe was consumed, then fresh prepared 3-aminobenzenesulfonate diisopropylethylamine salt (65 mg, 0.21 mmol) was added. The mixture was stirred under Ar for 24 h and HPLC showed the reaction completed to form DC107SMe [(S)-3-((1-(chloromethyl)-3-(5-(3-(methyldisulfanyl)propanamido)-1H-indole-2-carbonyl)-2,3-dihydro-1H-benzo[e]indol-5-yloxy)carbonylamino)benzenesulfonic acid]. The mixture was concentrated to ˜5 ml with oil pump and used directly for next step without further purification.
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]\[C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1)=[O:6])([CH3:4])[CH3:3].[CH3:19][Li]>C1(C)C=CC=CC=1>[CH3:4][C:2]([S:5]([NH:7][C@@H:8]([C:9]1[CH:14]=[N:13][C:12]([C:15]([F:18])([F:17])[F:16])=[N:11][CH:10]=1)[CH3:19])=[O:6])([CH3:1])[CH3:3]
Reactant: CC(C)(C)S(=O)/N=C\c1cnc(C(F)(F)F)nc1
Reactant: [Li]C
Solvent: Cc1ccccc1
Product: C[C@@H](NS(=O)C(C)(C)C)c1cnc(C(F)(F)F)nc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 47.8 %

Procedure:
To a solution of 2-methyl-N-{(1Z)-[2-(trifluoromethyl)pyrimidin-5-yl]methylene}propane-2-sulfinamide (14.3 g, 51.2 mmol) in toluene (260 mL) at −70° C. was added methyllithium (1.6 M; 35.0 mL, 56.0 mmol). The mixture was stirred at −70° C. for 15 min. The mixture was quenched with sat. NH4Cl and the reaction was allowed to warm to ambient temperature. The mixture was extracted with dichloromethane (3×). The combined organic extracts was dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→35% hexanes/ethyl acetate then 100% ethyl acetate→94% ethyl acetate/methanol) gave the title compound (7.23 g). MS 240.0 [(M+1)-56].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([C:8](=[O:22])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH:7]=1.[OH-].[Na+]>CCO.O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:23][CH:10]([C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:15][CH:16]=1)[CH2:9][C:8]2=[O:22]
Reactant: O=C(/C=C/c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CC(c2ccc(OC(F)(F)F)cc2)Oc2ccc(Br)cc21
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of (E)-1-(5-bromo-2-hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one (8 g, 20 mmol) in EtOH (144 mL) and H2O (432 mL) was added NaOH (800 mg, 20 mmol). The reaction mixture was stirred overnight. The mixture was filtered to give a solid residue. The solid residue was dissolved in EtOAc. The resulting solution was dried over Na2SO4 and then concentrated in vacuo to give 6-bromo-2-(4-(trifluoromethoxy)phenyl)chroman-4-one (6 g, 80%). 1H-NMR (CDCl3): 2.91 (d, 1H), 3.04 (m, 1H), 5.49 (dd, 1H), 6.94 (m, 1H), 7.31 (d, 2H), 7.50 (d, 2H), 7.59 (m, 1H), 8.03 (s, 1H).
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]1([C:15]2[C:23]([CH:24]=[CH:25][C:26](O)=[O:27])=[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[CH2:36]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][NH:39]1)[CH3:37]>C(Cl)Cl.O1CCCC1>[C:9]1([C:15]2[C:23]([CH:24]=[CH:25][C:26]([N:39]3[CH2:40][CH2:41][CH2:42][CH2:43][CH:38]3[CH2:36][CH3:37])=[O:27])=[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C=Cc1c(-c2ccccc2)nn2ccccc12
Reactant: CCC1CCCCN1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: 25 °C
Yield: 47.8 %

Procedure:
Isobutyl chloroformate (1.04 g) was added dropwise to a mixture of 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid (trans isomer) (2.0 g) and triethylamine (0.766 g) in methylene chloride (40 ml) and tetrahydrofuran (10 ml) at -20° C. with stirring. After being stirred at the same temperature for 30 minutes, a solution of 2-ethylpiperidine (0.942 g) in tetrahydrofuran (10 ml) was added thereto dropwise at -20° C. and the mixture was stirred at -20° C. to 10° C. for 2 hours. The mixture was warmed to room temperature and evaporated in vacuo. A saturated sodium bicarbonate solution was added to the residue and extracted twice with chloroform (50 ml). The combined extract was washed with saturated brine (50 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (40 g) with chloroform as an eluent. The fractions containing the object compound were combined and evaporated in vacuo to give 1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-ethylpiperidine (trans isomer) (1.30 g) as an oil.
Reaction SMILES: C[O-].[Na+].[OH:4][CH2:5][CH:6]([N:20]1[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[N:22]=[CH:21]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](OCC)=[O:16])[CH:10]=1.O.C([NH2:31])=O>>[C:15]([C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH:6]([N:20]2[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[N:22]=[CH:21]2)[CH2:5][OH:4])[CH:14]=[CH:13][CH:12]=1)(=[O:16])[NH2:31]
Reactant: NC=O
Reactant: CCOC(=O)c1cccc(CCC(CO)n2cnc(C(N)=O)c2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cccc(CCC(CO)n2cnc(C(N)=O)c2)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
Sodium methoxide (39 mg, 0.72 mmol) was added to a stirred solution of 1-{1-hydroxy-4-[3-(ethoxycarbonyl)phenyl]-2-butyl}-imidazole-4-carboxamide (obtained in Example 10(1))(60 mg, 0.18 mmol) in formamide (1.5 ml), and the reaction mixture was stirred at 110° C. for 3 h. After cooling, the reaction mixture was poured into water (5 ml). The residue was purified by HP-20 (16 cc) column chromatography eluting with water/2-propanol (9:1) and lyophilized to give 1[4-(3-carbamoylphenyl)-1-hydroxy-2-butyl]imidazole-4-carboxamide (39.2 mg, 71.6%) as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[C:23]3[CH2:22][CH2:21][CH2:20][C:19]4[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:18]=4[C:17]=3[N:16]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:15]=2)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:43][NH2:44]>ClC1C=CC=CC=1.ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([C:14]2[C:23]3[CH2:22][CH2:21][CH2:20][C:19]4[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:18]=4[C:17]=3[N:16]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:15]=2)[NH:44][CH3:43])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)cc1)c1nn(-c2ccc(Cl)cc2Cl)c2c1CCCc1cc(Cl)ccc1-2
Reactant: CN
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CNC(=NS(=O)(=O)c1ccc(Cl)cc1)c1nn(-c2ccc(Cl)cc2Cl)c2c1CCCc1cc(Cl)ccc1-2
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
4-Chloro-N-{8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2-diaza-benzo [e] azulene-3-carbonyl}-benzene-sulfonamide (2.0 g, 3.44 mmol) and PCl5 (1.56 g, 6.88 mmol) in chlorobenzene (20 mL) were refluxed at ca. 120° C. over a period of 3.0 h. The solvents were evaporated under reduced pressure to afford yellow gummy solid. The gummy solid was taken in dichloromethane (15 mL) and cooled to 0-5° C. To this cooled solution, 40% aq. monomethyl amine solution (5.0 mL) was added and stirred at ca. 29° C. over a period of 1 h. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford yellow oil. The oil was purified through column chromatography to afford 4-Chloro-N-{[8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2-diaza-benzo [e] azulene-3-yl]-methylamino-methylene}-benzene sulfonamide (0.175 g, 0.294 mmol) as title compound 1, a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24].O>CN(C)C=O>[C:23]([NH:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1)(=[O:25])[CH3:24]
Reactant: NCCSc1cccc2nccn12
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NCCSc1cccc2nccn12
Yield: 66.7 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine dihydrochloride (2.66 g, 10 mmoles) and triethylamine (4.32 ml, 31 mmoles) in N,N-dimethylformamide (24 ml) was added acetyl chloride (0.71 ml, 10 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:3) to obtain 1.57 g of the desired product (66.8%, colorless crystals).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:13]1[O:17][N:16]=[C:15]([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([OH:26])[CH2:23][NH:22]2)=[O:20])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10].Cl.C(N(C(C)C)CC)(C)C>C(O)C>[C:9]([C:13]1[O:17][N:16]=[C:15]([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([OH:26])[CH2:23][N:22]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[O:20])[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2)no1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2c2ccnc(Cl)n2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dichloropyrimidine (33.2 mg, 0.223 mmol) is added to the solution of (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (66 mg, 0.223 mmol) and diisopropylethylamine (0.078 mL, 0.446 mmol) in ethanol (2 mL). The reaction is stirred at room temperature overnight. The reaction is quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with methanol/dichloromethane provides the title compound. ESI m/z 366 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.C(=O)=O.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>O1CCCC1.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16]([B:29]([OH:34])[OH:30])=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccccc1-c1ccccc1OCc1ccccc1
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)=O
Product: OB(O)c1ccccc1-c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 2′-benzyloxy-2-bromobiphenyl (2.41 g, 7.09 mmol) in tetrahydrofuran (50 ml) was stirred under nitrogen and cooled to −100° C. (diethyl ether/liquid nitrogen). 1.6M nButyllithium in hexanes (4.87 ml, 7.80 mmol) was added over 15 mins. at −100° C. and the mixture warmed to −78° C. (acetone/Drikold) and stirred for 1 h. Triisopropyl borate (4.00 g (5.02 ml, 21.30 mmol) was added at −78° C. and the reaction allowed to warm to room temperature with stirring over 1.5 h. 1M Hydrochloric acid (50 ml) was added and the mixture stirred vigorously for 1 h. The organic layer was separated and the aqueous layer extracted with diethyl ether (50 ml). The combined organic phase were washed with water, dried (MgSO4) and the solvent removed in vacuo. The yellow oil was flash chromatographed (silica gel, 10-20% EtOAc-isohexane) to give the title compound as a clear oil (1.74 g, 80%). LC/MS RT=3.28 min [(2M−H2O)H−]=589.3
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5](Cl)=[N:4][N:3]=1.[NH2:13][NH2:14].O.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([NH:13][NH2:14])=[N:4][N:3]=1
Reactant: NN
Reactant: Clc1nnc(Cl)c2c1CCCC2
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: NNc1nnc(Cl)c2c1CCCC2
Temperature: 60 °C
Yield: 55.9 %

Procedure:
To 1,4-dichloro-5,6,7,8-tetrahydrophthalazine (406 mg, 2.0 mmol) in 2 mL THF was added hydrazine (704 uL, 704 mm, 12 mmol) and the mixture heated at 60° C. for 5.5 hours. To the mixture was added 3 mL of water and 10 mL EtOAc. The resulting suspension was filtered, washed with water (3×5 mL) and concentrated to provide Compound 29A as a pale tan powder (222 mg, 56%). LC/MS (m/z)=199.7 (M+H)+.
Reaction SMILES: [Na].[CH3:2]CN(C(C)C)C(C)C.[OH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[F:18][C:19]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:20]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[N:29]=[C:30]3[CH2:41][CH2:40][NH:39][CH2:38][C:31]3=[N:32][C:33]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:24][CH2:23]1.C=O>CO>[F:18][C:19]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:20]=1[O:21][CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[N:29]=[C:30]3[CH2:41][CH2:40][N:39]([CH3:2])[CH2:38][C:31]3=[N:32][C:33]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:26][CH2:27]1.[C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])=[O:11]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: CCN(C(C)C)C(C)C
Agent: C=O
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C)C2
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyhydroborate (9.9 mg, 0.047 mmol) was added to a solution of DIPEA (8 μL, 0.047 mmol), 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (12.1 mg, 0.023 mmol) and formaldehyde (2 μL, 0.023 mmol) in MeOH (230 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (8.9 mg, 71.6%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.3 Hz, 6H), 1.90-2.00 (m, 2H), 2.08-2.17 (m, 2H), 2.95-3.06 (m, 3H), 3.12 (br s, 4H), 3.35-3.53 (m, 3H), 3.76 (br s, 1H), 4.15 (dt, J=13.1, 6.5, 6.5 Hz, 1H), 4.19-4.38 (m, 2H), 4.48 (tt, J=7.3, 3.7 Hz, 1H), 6.85-6.92 (m, 1H), 6.99 (ddd, J=11.4, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 418.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[C:12]([NH2:14])[NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](=O)[CH2:25][C:26](OCC)=[O:27])=[CH:23][C:18]=2[N:17]=[N:16]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[NH:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[NH:14][C:12]4[N:11]([N:10]=[C:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)[N:13]=4)[C:26](=[O:27])[CH:25]=3)=[CH:23][C:18]=2[N:17]=[N:16]1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Reactant: Nc1nc(-c2ccc(Cl)c(Cl)c2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: O=c1cc(-c2ccc3[nH]nnc3c2)[nH]c2nc(-c3ccc(Cl)c(Cl)c3)nn12
Temperature: 130 °C
Reaction time: 24 h
Yield: 40.1 %

Procedure:
To a solution of 3-(3,4-dichlorophenyl)-1H-1,2,4-triazol-5-amine (100 mg, 0.44 mmol) in n-BuOH (1 ml) was added ethyl 3-(1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropanoate (300 mg, 1.28 mmol) and TsOH (5 mg, 0.03 mmol), and the resulting mixture was stirred for 24 h at 130° C. The solids were collected by filtration and washed with methanol (10 ml) to afford 5-(1H-benzo[d][1,2,3]triazol-5-yl)-2-(3,4-dichlorophenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a light yellow solid (70.2 mg, 40%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C@@H:4]2[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>ClCCl>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C@@H:2]2[CH2:17][N:5]3[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:9][C@@H:4]3[CH2:3]2)=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](N)C[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](NC(=O)c3ccc(F)cc3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (7S,8aS)-tert-butyl 7-aminohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (0.241 g, 1 mmol) in dichloromethane (6 mL) was added sodium carbonate (0.127 g, 1.2 mmol) and 4-fluorobenzoyl chloride (0.174 g, 1.1 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then ethyl acetate/methanol=10:1) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.40 (m, 1H), 1.47 (s, 9H), 1.63 (m, 2H), 2.05-2.20 (m, 2H), 2.50-2.65 (m, 2H), 3.00 (m, 2H), 4.20 (m, 2H), 4.70 (m, 1H), 6.68 (m, 1H), 7.10 (m, 2H), 7.80 (m, 2H); MS (ESI) m/z 364 (M+H)+.