Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:7]2[CH:8]3[CH2:22][CH2:21][CH:20]=[CH:19][C:9]3=[C:10]3[C:18]([CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]3=4)=[C:6]2[C:5](C)([CH3:23])[C:4]([CH3:26])([CH3:25])[C:3]1([CH3:28])[CH3:27].[CH2:30]([Li])CCC.CCCCCC.[CH:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][C:42]=1[C:51]([C:57]1[CH:66]=[CH:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=1)=[C:52]1[CH:56]=[CH:55][CH:54]=[CH:53]1.Cl>O1CCCC1.C(OCC)C>[CH:58]1[C:59]2[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:65]=[CH:66][C:57]=1[C:51]([C:42]1[CH:43]=[CH:44][C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:41]=1)([CH:52]1[CH:56]=[CH:55][CH:54]=[CH:53]1)[C:7]1([CH3:30])[C:6]2[C:5]([CH3:23])([CH:12]3[CH2:13][CH2:14][CH:15]=[CH:16][C:11]3=[C:10]3[C:18]=2[CH2:17][C:19]2[CH:20]=[CH:21][CH:22]=[CH:8][C:9]3=2)[C:4]([CH3:26])([CH3:25])[C:3]([CH3:28])([CH3:27])[C:2]1([CH3:1])[CH3:29]
Reactant: C1=CC(=C(c2ccc3ccccc3c2)c2ccc3ccccc3c2)C=C1
Reactant: CC1(C)C2=C3Cc4ccccc4C3=C3C=CCCC3C2C(C)(C)C(C)(C)C1(C)C
Reactant: [Li]CCCC
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC12C(=C3Cc4ccccc4C3=C3C=CCCC31)C(C)(C(c1ccc3ccccc3c1)(c1ccc3ccccc3c1)C1C=CC=C1)C(C)(C)C(C)(C)C2(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 200-ml two-necked flask equipped with a magnetic stirrer, a three-way cock and a 100-ml dropping funnel was thoroughly purged with nitrogen, and sequentially charged with 1.35 g (3.48 mmol) of octamethyloctahydrodibenzofluorene and 40 mL of tetrahydrofuran. Then, 2.30 ml (3.60 mmol) of a 1.58 mol/l n-butyllithium/hexane solution was gradually added while cooling the mixture in an ice water bath, and then the mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. Subsequently, 1.18 g (3.57 mmol) of 6,6-di-2-naphthylfulvene dissolved in 30 ml of tetrahydrofuran in advance was gradually added over 30 minutes while cooling the mixture in a methanol/dry ice bath. The mixture was gradually warmed to room temperature, and stirred for 20 hours at room temperature under a nitrogen atmosphere. Then, 100 ml of 1 N hydrochloric acid was gradually added, and subsequently 100 ml of diethyl ether was added. The two-layered solution thus obtained was transferred to a 300-ml separatory funnel and the funnel was shaken several times. The aqueous layer was then removed. Subsequently, the organic layer obtained was washed 2 times with 100 ml of water and once with 100 ml of saturated brine, and dried over anhydrous magnesium sulfate for 3 hours. The solids were separated by filtration, and the solvent was distilled off. The residue was purified by separation using silica gel chromatography to obtain a target product (yield 1.28 g (51%)). The target product was identified by 1H-NMR and FD-MS spectroscopy.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl-].[NH4+].[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[CH3:24][S:23][C:20]1[N:21]=[CH:22][C:11]2[C:10](=[O:25])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]4[N:28]=[N:29][NH:30][N:2]=4)[CH:4]=3)[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]=2[N:19]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C#N)c1)C2=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn[nH]n3)c1)C2=O
Temperature: 100 °C
Reaction time: 9.5 h
Yield: 27.4 %

Procedure:
(S)-5-(3-Cyanophenyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (366 mg, 1.04 mol) obtained in Step 1 of Example 71 was dissolved in DMF (7 mL), and the mixture was stirred at 100° C. for 9.5 hours after adding ammonium chloride (222 mg, 4.16 mmol) and sodium azide (176 mg, 2.71 mmol). The mixture was extracted by addition of ethyl acetate and water. The aqueous layer was collected, and the pH was adjusted to 5 with 1 mol/L hydrochloric acid. After extraction with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and reslurried with diethyl ether to give (S)-9-methylthio-5-[3-(2H-tetrazol-5-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (293 mg, 71%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([O:27]CC)=[O:26])[C:17]2=[O:33])=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C1SC(N2CCN(CC3C=C(C=CC=3)C(OC)=O)C2=O)=NC=1C)=O)C1C=CC=CC=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([OH:27])=[O:26])[C:17]2=[O:33])=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(CN2CCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)c1
Agent: COC(=O)c1cccc(CN2CCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)c1
Product: Cc1nc(N2CCN(Cc3cccc(C(=O)O)c3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 85 %

Procedure:
Following the procedure as described in Example 25, making variations as required to replace ethyl 3-((3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate with methyl 3-((3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate, the title compound was obtained as a colorless solid in 85% yield: mp 143-145° C. (methanol/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.55 (t, J=5.9 Hz, 1H), 7.89-7.87 (m, 2H), 7.58-7.46 (m, 2H), 7.37-7.20 (m, 5H), 4.51 (s, 2H), 4.38 (d, J=5.9 Hz, 2H), 4.04-3.98 (m, 2 H), 3.50-3.3.45 (m, 2H), 2.47 (s, 3H); MS (ES+) m/z 451.2 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][NH:6][S:7]([C:10]1[S:14][C:13]([NH:15][C:16]([N:18](CC2CCCC2)[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[O:17])=[N:12][CH:11]=1)(=[O:9])=[O:8])C.[CH:34]1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)[CH2:38][CH2:37][CH2:36][CH2:35]1.F[C:62]1C=C(C=CC=1F)N.C1(C=O)CCCC1.C(OC(=O)CNS(C1SC(N)=NC=1)(=O)=O)C.COC([C@@H]1CCCN1S(C1SC(N)=NC=1)(=O)=O)=O>>[CH:34]1([N:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[C:16](=[O:17])[N:15]([CH3:62])[C:13]2[S:14][C:10]([S:7]([NH:6][CH2:5][C:4]([OH:3])=[O:33])(=[O:9])=[O:8])=[CH:11][N:12]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Reactant: Nc1ccc(F)c(F)c1
Reactant: CCOC(=O)CNS(=O)(=O)c1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)s1
Agent: CCOC(=O)CNS(=O)(=O)c1cnc(N)s1
Agent: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(N)s1
Agent: O=CC1CCCC1
Product: CN(C(=O)N(c1ccc(F)c(F)c1)C1CCCC1)c1ncc(S(=O)(=O)NCC(=O)O)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazole-5-sulfonylamino}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and (2-amino-thiazole-5-sulfonylamino)acetic acid ethyl ester the latter prepared in a similar manner as (S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][C:22]=3[N:28]([CH3:37])[S:29]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)(=[O:31])=[O:30])=O)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:54])=CC=1>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([S:54][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][C:22]=4[N:28]([CH3:37])[S:29]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)(=[O:31])=[O:30])=[N:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN(c1cccc2cc(C(=O)NCC3(O)CCN(Cc4ccccc4)CC3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(c1cccc2cc(C3=NCC4(CCN(Cc5ccccc5)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 4.9 %

Procedure:
To a solution of N-[(1-benzyl-4-hydroxypiperidin-4-yl)methyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.30 g) in a mixed solvent of toluene (60 ml) and tetrahydrofuran (30 ml) was added Lawesson's reagent (1.94 g), and the mixture was heated under reflux for 3 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=5:95-40:60), and recrystallized from ethyl acetate-hexane to give the title compound (0.063 g, yield 5%) as colorless crystals.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH2:24]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]#[CH:26]>>[O:27]([CH2:24][C:25]1[N:3]=[N:2][N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:26]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C#CCOc1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1cc(COc3ccccc3)nn1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and phenyl prop-2-yn-1-yl ether. MS (+ESI) m/z: 403.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[N:4][CH:3]=1.N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])N(C3C4CCCCC=4C(C#N)=CC=3)[C:36]2=[O:38])[CH2:32][CH2:31]1>>[OH:29][C@H:30]1[C@@H:37]2[N:33]([C:34](=[O:51])[N:1]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]([C:12]#[N:13])=[N:4][CH:3]=3)[C:36]2=[O:38])[CH2:32][CH2:31]1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: N#Cc1ncc(N)c2ccccc12
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ncc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2ccccc12

Procedure:
The title compound was synthesized from compound 13D by procedures analogous to those described in Experiment 2E to 2F. HPLC: 97.6% at 1.54 min (retention time) (Conditions: YMC S5 C-18 (4.6×50 mm); Eluted with 0% to 100% B; 4 min gradient; (A=90% H2O—10% MeCN—0.1% TFA and B=10% H2O—90% MeCN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm). LC/MS m/z 309 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13](Cl)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: C=CCN
Reactant: O=C(Cl)N1CC(Sc2ccc(Cl)cc2)C1
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(=O)N1CC(Sc2ccc(Cl)cc2)C1
Reaction time: 3 h

Procedure:
A stirred solution of 2.6 g (0.01 mole) of 3-[(4-chlorophenyl)thio]-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was cooled in a water bath and treated with 2.2 g (0.02 mole) of 2-propenylamine. After stirring for 3 hr, the reaction mixture was diluted with 200 ml of water and the product separated as a yellow oil. The oil slowly solidified to yield a dull orange-red waxy material. After decanting the water and allowing the residue to air dry, the residue was triturated 5 times with boiling isopropyl ether and the decanted solutions upon cooling yielded 5 solid fractions, from white to pale beige color. The fractions were all consistent with the expected product by mass spectral analysis and TLC showed only a single product. All five fractions were combined to give 1.7 g (60.3%), m.p. 88°-89° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH:33]([C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1)[OH:34]>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH:33]([OH:34])[C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCC(O)c1cccc(O)c1
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCC(O)c3cccc(O)c3)n2)c1

Procedure:
Intermediate 4 was coupled with 3-(2-Amino-1-hydroxy-ethyl)-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 472. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 2H) 7.9 (m, 1H) 7.6 (m, 1H) 7.5 (m, 1H) 7.3 (m, 1H) 7.0 (m, 1H) 6.8 (m, 2H) 6.6 (m, 1H) 4.8 (m, 1H) 4.4 (s, 2H) 3.8 (m, 2H) 3.3 (m, 2H) 2.9 (s, 3H) 2.7 (m, 2H) 1.7 (m, 2H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.[C:19]([O:23][C:24](=[O:43])[N:25]([CH2:27][C:28]1[CH:32]=[C:31](Br)[N:30]([S:34]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH:29]=1)[CH3:26])([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][N:25]([CH2:27][C:28]1[CH:32]=[C:31]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[N:30]([S:34]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH:29]=1)[C:24](=[O:43])[O:23][C:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(Cc1cc(-c2cccs2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of crude tributyl(2-thienyl)stannane (1.1 g) and tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg) in toluene was added tetrakis(triphenylphosphine)palladium (116 mg), and the mixture was stirred under a nitrogen atmosphere at 120° C. for 1 hr. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give the title compound as a pale-yellow oil (yield 315 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[Cl:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[CH:19]=[CH:20][C:21](O)=O>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(Cl)c3)nc2n(CC)c1=O
Yield: 42.1 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 3.50 g (17.7 mmol) of 5,6-diamino-1,3-diethyluracil and 3.55 g (19.4 mmol) of 3-chlorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.57 g (yield 42%) of Compound 131 as white plates.
Reaction SMILES: [CH2:1](Cl)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[S-:11][C:12]#[N:13].[Na+].[CH3:15][O:16][C:17](=[O:28])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[NH2:19]>C(O)C>[OH:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C@H:18]([NH:19][C:12]2[S:11][CH:1]=[C:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:13]=2)[C:17]([O:16][CH3:15])=[O:28])=[CH:26][CH:25]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(CCl)c1ccccc1
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1nc(-c2ccccc2)cs1
Reaction time: 12 h

Procedure:
15.40 g (0.1 mol) of phenacyl chloride and 8.66 g (0.107 mol) of dry sodium thiocyanate in ethanol (200 ml) were stirred for 3 h at 50° C. The solution of 19.51 g (0.1 mol) of (S)-tyrosine methyl ester in ethanol (100 ml) was added in one portion and the reaction mixture was stirred for 12 h. After removing ethanol by distillation, water and ethyl acetate were added. Aqueous phase was extracted twice with ethyl acetate, combined organic phases were dried over sodium sulfate, and the solvent was evaporated. The product was purified by chromatography. The yield was 20.54 g (58%). MS (ES) 354 (M+, 100%)
Reaction SMILES: S=[C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[NH:3]1.[OH-].[Na+].OO.[CH2:29](N)[CH:30]([CH3:32])[CH3:31]>CN(C)C=O>[CH3:29][CH:30]([CH3:32])[CH2:31][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1
Reactant: O=c1[nH]c(=S)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2
Reactant: CC(C)CN
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)Cc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 500 mg of 4,5-dihydro-5-thioxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (prepared as described in Example 8) in 10.0 ml of N,N-dimethylformamide was added 1.5 ml of 1N sodium hydroxide. The reaction mixture was cooled to 0° C. in an ice bath, then 0.5 ml of 30% hydrogen peroxide was added to the mixture dropwise. The reaction mixture was stirred at 0° C. for 30 minutes, then 1.0 ml of isobutylamine was added in one portion and the mixture was allowed to warm to room temperature, then was stirred for 2 hours. The solid was collected by filtration and washed with water, then ether to give 223 mg of the product of the example as a white solid, m.p. 266°-268° C. Following the procedure of Example 14 and reacting, 4,5-dihydro-5-thioxo-8-[3-(trifluoromethyl)phenyl]3H ,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one with the appropriate primary aliphatic amine or cyclic secondary amine, the products of Examples 15-27 were obtained as set forth in Table III.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:3]=1[NH2:16].[C:17](OCC)(OCC)(OCC)[CH2:18][CH3:19].C(S(O)(=O)=O)C>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:16]=[C:17]([CH2:18][CH3:19])[N:8]2[C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1
Reactant: CCOC(CC)(OCC)OCC
Reactant: Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1
Agent: CCS(=O)(=O)O
Product: CCc1nc2c(Cl)ncnc2n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.6 %

Procedure:
6-chloro-N4-(4-chlorophenyl)pyrimidine-4,5-diamine obtained in step 1 (1.5 g, 5.88 mmol) was dissolved in triethyl ortho propionate (11.8 ml, 58.8 mmol) at room temperature. Ethanesulfonic acid (0.48 mL, 5.88 mmol) was added slowly to the resulting solution at 0 r and warmed to room temperature. The reaction mixture thus obtained was stirred for 6 hours at 50° C. The resulting mixture was filtered with NaHCO3(aq)/H2O. The collected solid was dried under reduced pressure to obtain the title compound (1.39 g, 81%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:31][C:30]=2[O:42][CH3:43])[C:25]([Cl:44])=[CH:24][N:23]=1>>[Cl:44][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:31][C:30]=2[O:42][CH3:43])=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)cc3OC)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.031 g, 37%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.26-8.22 (m, 1H), 8.11 (s, 1H), 8.02-8.00 (m, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 6.63 (s, 1H), 6.57-6.55 (m, 1H), 6.54-6.50 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.27 (s, 2H), 3.23-3.18 (m, 4H), 3.15 (s, 3H), 2.98 (s, 3H), 2.91-2.82 (m, 4H), 2.72-2.65 (m, 4H), 2.64-2.58 (m, 4H), 2.37 (s, 3H). MS: 609 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[O:10][C:4]=2[CH:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[C:15]1([C:2]2[N:7]=[CH:6][C:5]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[O:10][C:4]=3[CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1cc2oc3ccccc3c2cn1
Reactant: OB(O)c1ccccc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2cc3oc4ccccc4c3cn2)cc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
3-chlorobenzofuro[3,2-c]pyridine (2.89 g, 14 mmol), phenylboronic acid (2.56 g, 21 mmol), potassium phosphate (9.6 g, 42 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.45 g, 1.12 mmol) and Pd2(bda)3 (0.256 g, 0.28 mmol) were to toluene (100 mL) and water (10 mL). Nitrogen was bubbled through the solution for 30 minutes and then the solution was refluxed for overnight in an atmosphere of nitrogen. The reaction was then allowed to cool to room temperature and the organic phase was separated from the aqueous phase. The aqueous phase was washed with ethyl acetate and the organic fractions were combined and dried over sodium sulfate and the solvent removed under vacuum. The product was chromatographed using silica gel with ethyl acetate and hexanes as the eluent. The solvent was removed to give 2.77 g of title compound.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]2[C:15]([CH3:17])([CH3:16])[O:14][C:13]([NH:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[CH3:20])=[N:12][S:11]2(=[O:29])=[O:28])[CH:5]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C@@H:19]([NH:18][C:13]1[O:14][C:15]([CH3:16])([CH3:17])[CH:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:30])=[O:2])[S:11](=[O:28])(=[O:29])[N:12]=1)[CH3:20]
Reactant: COC(=O)c1cccc(C2C(C)(C)OC(N[C@@H](C)c3ccccc3F)=NS2(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC1=NS(=O)(=O)C(c2cccc(C(=O)O)c2)C(C)(C)O1)c1ccccc1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 33493 %

Procedure:
To a solution of 3-{2-[(S)-1-(2-fluorophenyl)ethylamino]-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl}benzoic acid methyl ester (1.7 mg) in dioxane (15 ml) were added water (5 ml) and sulfuric acid (0.3 ml), and the mixture was stirred at 100° C. for 16 h. The mixture was alkalized with sodium carbonate solution, diluted with water and washed with ethyl acetate. The aqueous phase was acidified, extracted with ethyl acetate, dried over magnesium sulfate and concentrated. This gave the product (551 mg) with a molecular weight of 420.5 g/mol (C20H21FN2O5S).