Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[F:44][C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:46]=1[CH2:52][CH2:53][O:54][CH2:55][C:56]([NH2:58])=[NH:57]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:58][C:56](=[NH:57])[CH2:55][O:54][CH2:53][CH2:52][C:46]1[CH:47]=[C:48]([F:51])[CH:49]=[CH:50][C:45]=1[F:44])=[O:6]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: N=C(N)COCCc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(COCCc1cc(F)ccc1F)NC(=O)c1cc(Cl)cnc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.2 %

Procedure:
2,5-Dichloronicotinic acid (50 mg, 260 μmol), TBTU (88 mg, 273 μmol) and DIPEA (130 μl, 781 μmol) were added to a solution of 2-[2-(2,5-difluoro-phenyl)-ethoxy]-acetamidine hydrochloride (65 mg, 260 μmol) in DMF (1 ml). The solution was stirred for 72 h at ambient temperature and poured onto ice water/dichloromethane 1/1. The layers were separated, the aqueous layer was extracted two times with dichloromethane, the combined extracts were washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure yielded 2,5-dichloro-N-{2-[2-(2,5-difluoro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide (97 mg, 250 μmol; 96%) as orange oil which was used in the next step without further purification. MS: m/e=388.2 [M+H+].
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11]CC)=O.[N:14]1([CH:20]([CH3:23])[CH2:21][NH2:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([NH:22][CH2:21][CH:20]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH3:23])=[O:11]
Reactant: CCOC(=O)CN1C(=O)CCC1C
Reactant: CC(CN)N1CCCCC1
Product: CC(CNC(=O)CN1C(=O)CCC1C)N1CCCCC1

Procedure:
From 9.3 g. of ethyl 2-methyl-5-oxo-1-pyrrolidineacetate and 10.7 g. of 2-(1-piperidinyl)propylamine (J. Chem. Soc. 1947, 1511), following the procedure of Example 9, there is obtained (±)-2-methyl-5-oxo-N-[2-(1-piperidinyl)propyl]-1-pyrrolidineacetamide; m.p. 111°-112° C. after recrystallization from heptane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]([CH3:30])([OH:29])[CH2:17]OS(C1C=CC=CC=1C)(=O)=O.[OH-].[K+].C(Cl)Cl>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11][CH3:12])=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][C@:16]1([CH3:30])[O:29][CH2:17]1
Reactant: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)COS(=O)(=O)c2ccccc2C)c1C
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: COc1c(C)c(C)c(OC)c(CC[C@@]2(C)CO2)c1C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
177 mg of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1-toluylsulphonyloxy-2-butanol are dissolved in 1 ml of ethanol and treated with 0.3 ml of alcoholic potassium hydroxide solution (1.5N). The mixture is left to stand at room temperature for 10 minutes, 30 ml of methylene chloride are then added and the mixture is dried over anhydrous sodium sulphate and concentrated. There are obtained 105 mg of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-epoxy-butane, m.p. 47°-48° C. [α]D20 +4.91° (c=2.2% in CHCl3).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-])=O.[C:14](O)(=[O:16])[CH3:15]>C(OC(=O)C)(=O)C.[Pd].O=[Pt]=O>[NH:9]1[C:10]2[C:5](=[C:4]([NH:1][C:14](=[O:16])[CH3:15])[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cccc2ncccc12
Agent: O=[Pt]=O
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc2c1CCCN2
Reaction time: 10.4 h

Procedure:
A solution of 5-nitroquinoline (50 g, 0.29 mol) in 1 L acetic acid and 30 mL acetic anhydride was treated with 5% Pd/C (3 g) and shaken on a Parr apparatus under a H2 atmosphere (50.8 psi) for 10.4 hours. The reaction was then treated with PtO2 (1 g) and recharged with H2 (50.8 psi) and shaken an additional 2 hours. After removing the catalyst by filtration, the filtrate was evaporated and the residue was separated between methylene chloride and water. The aqueous layer was basified with 50% NaOH and washed with methylene chloride. The combined organic layer was dried over sodium sulfate, filtered, and evaporated. The resulting solid was crystallized from ethyl acetate (23 g, 42%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]=[C:10]([N:13]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][C:22]=3[O:31][CH2:32][CH3:33])[CH2:14][CH:15]([OH:19])[C:16](O)=[O:17])[N:11]=[CH:12][C:3]=12.CN([P+](Br)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:61]([NH2:64])[CH2:62][NH2:63]>CN(C=O)C>[NH2:63][CH2:62][CH2:61][NH:64][C:16](=[O:17])[CH:15]([OH:19])[CH2:14][N:13]([C:10]1[N:11]=[CH:12][C:3]2[C:4]([N:9]=1)=[N:5][C:6]([NH2:8])=[N:7][C:2]=2[NH2:1])[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[O:31][CH2:32][CH3:33]
Reactant: CCOc1ccc2ccccc2c1CN(CC(O)C(=O)O)c1ncc2c(N)nc(N)nc2n1
Reactant: NCCN
Agent: CN(C)[P+](Br)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2ccccc2c1CN(CC(O)C(=O)NCCN)c1ncc2c(N)nc(N)nc2n1
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To 3-[(5,7-diamino-pyrimido[4,5-d]pyrimidin-2-yl)-(2-ethoxy-naphthalen-1-ylmethyl)-amino]-2-hydroxy-propionic acid (200 mg, 0.445 mmol) in dry DMF (2 ml) was added BroP (249 mg, 0.534 mmol). After the mixture was stirred for 30 min, DIEA (126 mg, 0.979 mmol) was added. After stirring for another 20 min, ethylene diamine (53.5 mg, 0.89 mmol) was added. The mixture was then stirred at room temperature for 16 hours and was directly purified by prep HPLC to yield 35 mg (16%) of the title compound: MS m/z (M+H) 492.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C)C=O>[CH3:23][N:14]1[C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]2[CH:10]=[N:9][C:8]([C:5]3[N:4]=[C:3]([CH2:2][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[O:7][N:6]=3)=[C:12]2[CH2:13]1
Reactant: C1CCNC1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CN4CCCC4)n3)ncn2-c2ccccc2C1=O
Yield: 85.4 %

Procedure:
1.5 g (4.5 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 80° for 2 hours in 1.1 ml (14 mmol) of pyrrolidine and 30 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 1.4 g (84%) of 5-methyl-3-[5-(pyrrolidin-1-yl)methyl-1,2,4-oxadiazol-3-yl]-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p 251°-254°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](N(OC)C)=[O:12])=[CH:5]2.[CH2:17]([Li])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:12])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5]2
Reactant: [Li]CCCCCC
Reactant: CON(C)C(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a solution (100 mL) of 5-chloro-N-methoxy-N-methyl-1H-indole-2-carboxamide (9.14 g) synthesized above in tetrahydrofuran was added a 2.3M solution (50.0 mL) of hexyllithium in hexane at −78° C., and the mixture was stirred under nitrogen atmosphere for 1.5 hr. A 2.3M solution (38.3 mL) of hexyllithium in hexane was additionally added, and the mixture was stirred at −78° C. for 2 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to give the title object compound (6.90 g, 68%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14](Br)[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:22]([Cu])#[N:23]>CN(C)C=O.O>[F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([C:22]#[N:23])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C#N)C(C)CN(C(=O)C(F)(F)F)CC2
Yield: 64 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (18 mg, 0.05 mmol) in dimethylformamide (1 mL) was treated with CuCN (20 mg, 0.24 mmol) and the mixture was microwaved at 200° C. for 0.5 hours. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (35% EtOAc in hexane, silica) resulted in 10 mg of a clear oil. MS calculated for C15H15F3N2O2+H: 313, observed: 313.
Reaction SMILES: [CH2:1]1[CH:8]([NH2:9])[C:6](=[O:7])[NH:5][C:3](=[O:4])[CH2:2]1.Cl.Br[CH2:12][C:13]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:14]=1[C:15](OC)=[O:16].C(N(CC)CC)C>CN(C)C=O>[O:16]=[C:15]1[C:14]2[C:13](=[C:22]([CH3:23])[CH:21]=[CH:20][CH:19]=2)[CH2:12][N:9]1[CH:8]1[CH2:1][CH2:2][C:3](=[O:4])[NH:5][C:6]1=[O:7]
Reactant: COC(=O)c1cccc(C)c1CBr
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 16.25 g of 2,6-dioxopiperidin-3-ammonium chloride, and 30.1 g of methyl 2-bromomethyl-3-methylbenzoate, and 12.5 g of triethylamine in 100 mL of dimethylformamide is stirred at room temperature for 15 hours. The mixture is then concentrated in vacuo and the residue mixed with methylene chloride and water. The aqueous layer is separated and back-extracted with methylene chloride. The combined methylene chloride solutions are dried over magnesium sulfate and concentrated in vacuo to give 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:10][C:11]1[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH3:9]>CO>[CH2:6]([O:10][C:11]1[N:12]=[N:13][C:14]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH3:9]
Reactant: C=CCS
Reactant: CCCCOc1ccc(Cl)nn1
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OCCCC)nn1

Procedure:
1.15 g(0.05 mol) of metallic sodium was dissolved in 75 ml of absolute methanol and then mixed with 4.98 ml(0.05 mol) of allylmercaptan. To this mixture was added 9.33 g(0.05 mol) of 3-(n-butoxy)-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale yellow oil.
Reaction SMILES: C(NC1SC(S(NC2C=CC(CC([NH:24][C:25]3[C:26](=[O:45])[N:27]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[F:44])[C:28](=[O:36])[N:29](CC4CC4)[C:30]=3[NH2:31])=O)=CC=2)(=O)=O)=C(C)N=1)(=O)C.Cl.CN(C)CCCN=C=NCC.[Cl:58][C:59]1[N:63]([CH3:64])[N:62]=[C:61]([CH3:65])[C:60]=1[S:66]([NH:69][C:70]1[CH:71]=[CH:72][C:73]([CH2:76][C:77]([OH:79])=O)=[N:74][CH:75]=1)(=[O:68])=[O:67].NC1C(=O)N(CC2C=CC=CC=2F)C(=O)NC=1N>CO.C(Cl)(Cl)Cl>[NH2:31][C:30]1[NH:29][C:28](=[O:36])[N:27]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[C:26](=[O:45])[C:25]=1[NH:24][C:77](=[O:79])[CH2:76][C:73]1[CH:72]=[CH:71][C:70]([NH:69][S:66]([C:60]2[C:61]([CH3:65])=[N:62][N:63]([CH3:64])[C:59]=2[Cl:58])(=[O:67])=[O:68])=[CH:75][N:74]=1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Nc2ccc(CC(=O)Nc3c(N)n(CC4CC4)c(=O)n(Cc4ccccc4F)c3=O)cc2)s1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(CC(=O)O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1[nH]c(=O)n(Cc2ccccc2F)c(=O)c1N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(CC(=O)Nc2c(N)[nH]c(=O)n(Cc3ccccc3F)c2=O)nc1
Yield: 42 %

Procedure:
Prepared as for 2-[4-(2-acetylamino-4-methyl-thiazole-5-sulfonylamino)-phenyl]-N-[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetamide (example 10, step 1) except that the coupling was performed using 1 [3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride as the coupling reagent and [5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetic acid and 5,6-diamino-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione were used as the coupling partners. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 10/90 methanol/chloroform) afforded N-[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-[5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetamide (42%) as an off white solid; LRMS for C29H29ClFN7O4S (M+H)+ at m/z=577/579.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:9]([C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:39])[CH2:18][C@H:19]([NH:31]C(=O)OC(C)(C)C)[CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=4)[CH2:12]3)=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.ClCCl.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>CO.CC#N.O>[NH2:31][C@H:19]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)[CH2:18][C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@@H:11]([C:9]2[N:8]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:10]=2)[CH2:12]1)=[O:39].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2cccc(Cl)c21
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc4ccccc4c3)C2)nc2cccc(Cl)c21

Procedure:
tert-Butyl (R)-4-((R)-3-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (0.111 mmol max, crude oil from Step F) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were then added and the resultant solution was allowed to stir under nitrogen for 4 HR. The solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in methanol (3 mL), filtered, and then purified by preparative LC/MS (25-65% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in CH3CN (1 mL) and water (2 mL). The resultant solution was frozen and lyophilized to afford (R)-3-amino-1-((R)-3-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-(naphthalen-2-yl)butan-1-one (97) as its trifluoroacetic acid salt as a white flocculent solid (0.052 mmol, 0.033 g, 47% over 3-steps) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35-1.56 (m, 1H) 1.63-2.14 (m, 5H) 2.60-2.78 (m, 2H) 2.88-3.42 (m, 9H) 3.69-4.01 (m, 3H) 4.00-4.61 (m, 5H) 7.10-7.30 (m, 2H) 7.42-7.60 (m, 4H) 7.73-7.99 (m, 4H) ESI-MS: m/z 519.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([N:14]3[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]3)=[N:11][CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([Cl:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:30][C:26]1[C:27]([CH3:29])=[N:28][C:23]([NH:1][C:2]2[CH:3]=[C:4]([C:9]3[S:13][C:12]([N:14]4[CH2:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[CH2:15]4)=[N:11][CH:10]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=2)=[N:24][CH:25]=1
Reactant: Cc1nc(Cl)ncc1Cl
Reactant: Cc1cc(N)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(Nc2ncc(Cl)c(C)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Temperature: 90 °C
Yield: 50.4 %

Procedure:
A sealed tube was charged with a stir bar, 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (Intermediate XX, 75 mg, 0.25 mmol), 2,5-dichloro-4-methylpyrimidine (40 mg, 0.25 mmol), potassium carbonate (69 mg, 0.50 mmol), Pd2(dba)3 (23 mg, 0.025 mmol), and XPhos (59 mg, 0.124 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed t-amyl alcohol (0.83 ml) was added and the tube was sealed and heated at 90° C. for overnight. The resulting slurry was diluted with methanol, absorbed onto 1.5 g of silica, and purified via silica gel chromatography (0-20% methanol in ethyl acetate) to afford 54 mg (0.126 mmol, 51% yield) of 4-(5-{3-[(5-Chloro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)-1,4-diazepan-2-one as a yellow solid. MS APCI: [M+H]+ m/z 429.1. 1H NMR (500 MHz, dmso) δ 9.73 (s, 1H), 8.42 (s, 1H), 7.74 (s, 1H), 7.59 (t, J=5.0 Hz, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 6.91 (s, 1H), 4.16 (s, 2H), 3.78 (m, 2H), 3.21 (m, 2H), 2.44 (s, 3H), 2.26 (s, 3H), 1.78 (m, 2H). rhSyk=+++
Reaction SMILES: [CH2:1]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][C:11]2[O:12][CH:13]=[C:14]([OH:18])[C:15](=[O:17])[CH:16]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=O.C(=O)(O)O.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]([OH:35])[CH2:33][NH2:34])[CH:29]=[CH:30][CH:31]=1>C1C=CC=CC=1>[Cl:25][C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=1)[CH:32]([OH:35])[CH2:33][NH:34][CH:2]([CH3:4])[CH2:1][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][C:11]2[O:12][CH:13]=[C:14]([OH:18])[C:15](=[O:17])[CH:16]=2)=[CH:7][CH:6]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)Cc1ccc(OCc2cc(=O)c(O)co2)cc1
Agent: O=C(O)O
Solvent: c1ccccc1
Product: CC(Cc1ccc(OCc2cc(=O)c(O)co2)cc1)NCC(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.5 %

Procedure:
A solution of 2-(4-acetonylphenoxymethyl)-5-hydroxy-4H-pyran-4-one (0.7 g) and 2-(3-chlorophenyl)-2-hydroxyethylamine carbonate 0.52 g in benzene was heated under reflux for 2.5 h using a Dean and Stark head. The reaction mixture was allowed to cool and the solvent removed in vacuo. The residue was taken up in methanol, treated with sodium cyanoborohydride (0.2 g) and stirred at ambient temperature for 18 h. The solvent was evaporated under reduced pressure, the residue dissolved in ethyl acetate, washed with water (2×50 ml), brine(1×50 ml) and dried (magnesium sulphate). After filtration and evaporation of solvent the residue was purified by column chromatography on silica using methanol:chloroform (3:97) as eluent, followed by crystallisation from acetone to give 2-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]-5-hydroxy-4H-pyran-4-one, (0.1 g), as a (35:65) mixture of diastereoisomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:16][C:15]([CH3:17])=[N:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:16][C:15]([CH3:17])=[N:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(-c2nnc(C)[nH]2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(-c2nnc(C)[nH]2)ccc1N

Procedure:
was prepared by hydrogenating 100 mg of 3-(3-methoxy-4-nitrophenyl)-5-methyl-4H-[1,2,4]triazole in the presence of Pd/C in THF and used further without further purification.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[N:7][C:6]=1[NH:12][NH2:13])([CH3:3])[CH3:2].C(NC1C=C([Cl:23])N=NC=1NN)C>>[ClH:11].[ClH:23].[CH:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[N:7][C:6]=1[NH:12][NH2:13])([CH3:3])[CH3:2]
Reactant: CCNc1cc(Cl)nnc1NN
Agent: CC(C)Nc1cc(Cl)nnc1NN
Product: Cl

Procedure:
When 4-isopropylamino-6-chloro-3-hydrazino pyridazine is substituted for 4-ethylamino-6-chloro-3-hydrazino pyridazine in the preceeding process, 4-isopropylamino-6-chloro-3-hydrazino pyridazine dihydrochloride (m.p. 209° to 212°C.) is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH2:27])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2SC)=[CH:13][CH:12]=1)=[O:5])[CH3:2].C(OC(C1SC(N)=C([C:45]#[N:46])C=1C1C=CC(I)=CC=1)=O)C.C(C1C=CC=CC=1B(O)O)#N>>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([NH2:27])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:45]#[N:46])=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(-c2ccccc2SC)cc1
Reactant: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(I)cc1
Agent: N#Cc1ccccc1B(O)O
Product: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(-c2ccccc2C#N)cc1

Procedure:
Using a method substantially in accordance with the method of 5-amino-4-cyano-3-(2′methylsulfanyl-biphenyl-4-yl)-thiophene-2-carboxylic acid ethyl ester starting with the compound 5-amino-4-cyano-3(4-iodo-phenyl)-thiophene-2-carboxylic acid ethyl ester and 2-(cyano)phenylboronic acid gives the title compound: 1H NMR (400 MHz, CDCl3) δ 7.81-7.44 (m, 8H), 5.29 (s, 2H), 4.16 (q, 2H, J=7.2 Hz), 1.17 (t, 3H, J=7.3 Hz), MS found (M−1) 372.0 and (M+1)+NH3 391.0.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH3:9])[OH:4].NC[C@H]([C@@H](NC(=O)OC(C)(C)C)CCCC)O.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41](Cl)(=[O:43])=[O:42]>ClCCl.C(=O)(O)[O-].[Na+]>[OH:4][CH:3]([C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][NH:1][S:41]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=1)(=[O:43])=[O:42]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(O)CNS(=O)(=O)c1ccccn1
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a biphasic mixture of 4.93 g (20 mmol) of tert-butyl (1S)-1-[(1S)-2-amino-1-hydroxyethyl]pentylcarbamate & tert-butyl (1S)-1-[(1R)-2-amino-1-hydroxyethyl]pentylcarbamate in 32 mL dichloromethane and 15 mL saturated sodium bicarbonate was added 24 mL (24 mmol) of 1 M 2-pyridinesulfonyl chloride in dichloromethane. The reaction mixture was stirred overnight and then extracted with dichloromethane. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexanes (6:4) to afford 5.00 g (65%) of tert-butyl (1S)-1-{(1SR)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate & tert-butyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate. 1H-NMR (300 MHz, DMSO-d6): δ 8.73 (d, J=4 Hz, 1H), 8.09 (t, J=8 Hz, 1H), 7.93 (dd, J=8 Hz, J=4 Hz, 1H), 7.68 (m, 1H), 7.60 and 7.54 ((t, J=6 Hz), (t, J=6 Hz), 1H), 6.55 and 6.36 ((d, J=9 Hz), (d, J=9 Hz), 1H), 4.78 (m, 1H), 3.50–2.70 (m, 4H), 1.61 (m, 1H), 1.37-1.05 (m, 14H), 0.86 (t, J=7 Hz, 3H); ES-LCMS m/z 410 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[H-].[Na+].CN(C)C=O.[CH3:17][O:18][C:19](=[O:22])[CH2:20]Br>O>[CH3:17][O:18][C:19](=[O:22])[CH2:20][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(Br)ccc1O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-bromo-2-methylphenol (1.0 g, 5.35 mmol), sodium hydride (0.26 g, 6.42 mmol, 60% mineral oil), N,N-dimethylformamide (10 mL), and methyl-2-bromoacetate (0.56 mL, 5.88 mmol) is stirred at room temperature 18 hr. The mixture is diluted with water (50 mL) and the product extracted to ethyl acetate (3×50 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered, concentrated and purified via silica chromatography eluting with 8:2 hexanes:ethyl acetate to afford title compound as a colorless oil, 1.03 g, 74%. MS M+ 259. The structure is confirmed by 1H NMR spectroscopy.