Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])O[C:7](=[O:12])[C:6]=2[CH:13]=1.[C:14]([CH2:16]C(OCC)=O)#[N:15].C(N(CC)CC)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:10][C:9](=[O:11])[C:16]([C:14]#[N:15])=[C:7]2[OH:12]
Reactant: CCOC(=O)CC#N
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1c(O)c2cc(Cl)ccc2[nH]c1=O

Procedure:
A solution of 6-chloro-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione (2 g, 10.1 mmol, Eq: 1.00), ethyl cyanoacetate (1.15 g, 1.08 ml, 10.1 mmol, Eq: 1.00) and triethylamine (14.5 g, 20.0 ml, 143 mmol, Eq: 14.2) in DMF (1.00 ml) was stirred at RT for 65 h. Then 1N HCl was added and the reaction mixture was extracted with ethyl acetate (3×). The combined extracts were washed brine. An off-white solid precipitated and was filtered off (337 mg). MS (ESI): 219.1 (M−H)−.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:13])[N:10]=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14](Br)[CH:15]=[CH2:16]>>[CH2:16]([S:13][C:9]1[N:10]=[N:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: Sc1nncc(-c2ccccc2)n1
Product: C=CCSc1nncc(-c2ccccc2)n1

Procedure:
3-(Allylthio)-5-phenyl-1,2,4-triazine (compound A) is prepared from 5-phenyl-1,2,4-triazine-3-thiol and allyl bromide according to the following synthetic scheme;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[N:46]=[CH:45][N:44]([C:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:43]=2)=[CH:32][CH:31]=1>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[N:46]=[CH:45][N:44]([C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[N:43]=3)=[CH:34][CH:35]=2)[C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: BrCc1ccc(-c2ccccc2-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Examle 1, Step I) and 4-bromomethyl-2'-(1-triphenylmethyl-1,2,4-triazol-3-yl)-1,1'-biphenyl by the procedure described in Example 2, Step E.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:14]C(=O)C)[CH:8]=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: CC(=O)Oc1ccc2cc([N+](=O)[O-])ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=c1ccc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
Compound 46A (210 mg, 0.90 mmol) was dissolved in MeOH (10 mL), K2CO3 was added, and the reaction was stirred at rt for 30 min. The reaction was then concentrated under reduced pressure and subsequently purified by silica gel flash chromatography eluting with 5-10% MeOH/CH2Cl2 (gradient) to give the title compound (162 mg, 94%) as a pink solid. LC/MS m/z 191 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([C:7]1[S:8][C:9]([Br:14])=[C:10]([Br:13])[C:11]=1[Br:12])=[O:6])C.Cl>CC(C)=O.O>[Br:12][C:11]1[C:10]([Br:13])=[C:9]([Br:14])[S:8][C:7]=1[C:5](=[O:6])[C:4]([OH:15])=[O:3]
Reactant: CCOC(=O)C(=O)c1sc(Br)c(Br)c1Br
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C(=O)c1sc(Br)c(Br)c1Br
Temperature: 25 °C

Procedure:
A solution of (3,4,5-tribromothiophen-2-yl)-oxo-acetic acid ethyl ester (0.4 g, 0.95 mmol) in acetone (10 ml), water (2 ml), and conc. HCl (8 ml) was stirred under reflux for 1.5 hours. The reaction mixture was allowed to cool to ambient temperature and concentrated in vacuo to remove acetone which gave rise to solids which were collected, washed with water and dried. (3,4,5-tribromothiophen-2-yl)-oxo-acetic acid was thus obtained as a light yellow solid (0.17 g, 49%). MS (M−H)−: 392.75; 13C NMR (75 MHz, CDCl3) δ124.19, 117.80, 113.26, 111.72. IR (KBr) cm−1 3477.9, 3107.1, 2922.5, 1715.9, 1681.5, 1666.0, 1484.5, 1306.5, 1268.9.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC(=O)[NH:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[CH:20]=1)(C)(C)C>C(OCC)(=O)C>[CH3:26][N:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:19]1[CH:20]=[C:15]([NH2:14])[CH:16]=[N:17][CH:18]=1.[ClH:1]
Reactant: Cn1cccc1-c1cncc(NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1cccc1-c1cncc(N)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4M hydrogen chloride/1,4-dioxane (1 ml) was added to an ethyl acetate (2 ml) solution containing tert-butyl(5-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl)carbamate (80 mg) obtained in the 1st step, followed by stirring at room temperature for 15 hours. An insoluble precipitate was collected by filtration, and a light brown solid of 5-(1-methyl-1H-pyrrol-2-yl)pyridin-3-amine•hydrochloride (42 mg) was thus obtained.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12]Cl)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH:25]([CH3:29])[C:26]([OH:28])=[O:27])[CH:19]=[CH:18]2>>[CH3:29][CH:25]([C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH2:12][C:10]3[N:11]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[S:8][CH:9]=3)[CH:16]=2)[CH:21]=1)[C:26]([OH:28])=[O:27]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: ClCc1csc(-c2ccccc2)n1
Product: CC(C(=O)O)c1ccc2cc(OCc3csc(-c4ccccc4)n3)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 2-phenyl-4-(chloromethyl)thiazole and racemic 6-hydroxy-α-methyl-2-naphthalene acetic acid. White crystals are obtained having a melting point of 163°-164° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:27])=[CH:4][C:5]([OH:26])=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(OCCO)C>[C:14]1([C:12]2[N:11]=[C:10]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:9]=[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[C:3]([O:27][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:4][C:5]=3[OH:26])[N:13]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Oc1cc(O)c(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1Cl
Reactant: CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCCO
Product: CCCCCCOc1cc(O)c(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1Cl
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a 350 mL sulfonation flask equipped with a mechanical stirrer, condenser, dropping funnel and a nitrogen atmosphere are charged 26.3 g (70 mmol) of the product of Example 54, 10.6 g (77 mmol) of potassium carbonate, 50 mg of potassium iodide, and 50 mL of 2-ethoxyethanol. The suspension is warmed to 110° C., and 10.8 g (77 mmol) of 1-bromohexane are added dropwise over 30 minutes. After 8 hours, the reaction mixture is cooled to room temperature, the precipitate is removed by filtration, washed with water to pH 6, rinsed with methanol and dried at 70° C. under vacuum. The crude beige product (26.9 g) is recrystallized twice from 600 mL of 2-ethoxyethanol to give the title compound in a yield of 18.6 g as a yellow solid melting at 147°-149° C., purity 98.7% (DSC assay).
Reaction SMILES: IC1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]([F:35])([F:34])[F:33])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[CH:36]=1.[CH:37]([Mg]Br)(C)C.[CH3:42][C:43]([CH3:45])=[O:44]>C1COCC1.CCOCC>[F:18][C:16]([F:17])([F:19])[C:13]1[CH:14]=[CH:15][C:9]2[CH2:8][N:7]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4([C:32]([F:35])([F:34])[F:33])[CH2:31][CH2:30]4)=[CH:27][CH:28]=3)(=[O:21])=[O:22])[C:6]3[CH:36]=[C:42]([C:43]([OH:44])([CH3:37])[CH3:45])[CH:3]=[CH:4][C:5]=3[NH:11][C:10]=2[N:12]=1
Reactant: O=S(=O)(c1ccc(C2(C(F)(F)F)CC2)cc1)N1Cc2ccc(C(F)(F)F)nc2Nc2ccc(I)cc21
Reactant: CC(C)=O
Reactant: CC(C)[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(C3(C(F)(F)F)CC3)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of 8-iodo-2-(trifluoromethyl)-6-({4-[1-(trifluoromethyl)-cyclopropyl]phenyl}sulfonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 59, 150 mg, 0.235 mmol) in THF (1.5 mL) at 0° C. was added isopropylmagnesium bromide (1.89 mmol of a 2M solution in ether). After stirred at 0° C. for 40 min, acetone (204 mg, 3.52 mmol) was added dropwise and the reaction mixture was gradually brought to rt. The reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined extracts were washed with water, brine, dried over MgSO4 and concentrated. Purification of the residue via SiO2 column chromatography provided the title compound. LC/MS: m/e 572.0 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.65 (1H, d, J=2.1 Hz), 7.56 (1H, d, J=7.5 Hz), 7.44 (1H, dd, J=8.5, 1.6 Hz), 7.21 (2H, d, J=8.3 Hz), 7.05 (1H, d, J=7.3 Hz), 7.02 (2H, d, J=8.5 Hz), 6.77 (1H, s), 6.74 (1H, J=8.2 Hz), 4.70-4.90 (2H, s, br), 1.64 (6H, s), 1.35-1.42 (4H, m), 1.26-1.30 (4H, m).
Reaction SMILES: [CH3:1][S:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[NH:4][CH3:5].C(N(CC)CC)C.[Cl:17][C:18]([Cl:22])([Cl:21])[S:19]Cl.Cl>CN(C=O)C>[CH3:1][S:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[N:4]([CH3:5])[S:19][C:18]([Cl:22])([Cl:21])[Cl:17]
Reactant: CNC(=N[N+](=O)[O-])SC
Reactant: ClSC(Cl)(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSC(=N[N+](=O)[O-])N(C)SC(Cl)(Cl)Cl
Yield: 57.1 %

Procedure:
To a cooled, stirred mixture of S,N-dimethyl-N'-nitroisothiourea (1.0 g), triethylamine (0.68 g) and DMF (10 ml) was added 1.2 g of trichloromethanesulfenyl chloride dropwise at 3°-7° C. After stirring at the same temperature for 1 hour, the mixture was poured into 50 ml of 2N hydrochloric acid and the resulting mixture was extracted with toluene (50 ml). The toluene layer was washed with water (50 ml), dried over MgSO4 and concentrated in vacuo. The resulting residue was applied to column chromatography on silica gel. The column was eluted with hexane-AcOEt (8:1). The fractions containing the desired product were concentrated to afford 1.1 g of S,N-dimethyl-N'-nitro-N-trichloromethanesulfenylisothiourea as a pale yellow crystal, m.p. 75°-78° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>CN(C=O)C>[N:13]1([CH2:12][CH2:11][O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ccc(O)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1ccc(OCCN2CCCC2)cc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
A mixture of 4-aminophenol (4.0 g, 37.4 mmol), 1-(2-chloroethyl)-pyrrolidine hydrochloride (7.6 g, 44.9 mmol, 1.2 equiv), NaOH (3.7 g, 93.5 mmol, 2.5 equiv) in DMF (64 mL) is stirred for 2 h at 75° C., under an argon atmosphere. The mixture is allowed to cool to RT and then filtered through a glass sintered funnel. The filtrate is diluted with CH2Cl2 (200 mL), washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel (260 g) column chromatography (CH2Cl2/MeOH, 70/30→50/50) to afford the title compound as a dark brown oil: ES-MS: 207.1 [M+H]+; Rf=0.18 (CH2Cl2/MeOH, 50/50).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].CS(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][F:27]>[I-].[K+].O>[F:27][CH2:26][CH2:25][O:12][C:11]1[C:2]([OH:1])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[OH:13]
Reactant: FCCBr
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(O)c(OCCF)c(O)c1
Reaction time: 18 h
Yield: 18.1 %

Procedure:
To a 100 mL round bottom flask was added methyl 3,4,5-trihydroxybenzoate (7.00 g, 88.0 mmol) followed by 25 mL of dimethyl sulfoxide. Potassium Carbonate (7.88 g, 57.0 mmol), potassium iodide (31.6 mg, 0.19 mmol) and 1-bromo-2-fluoroethane (5.79 g, 45.6 mmol) were successively added followed by 25 mL more of dimethyl sulfoxide. The reaction mixture was stirred for 18 h after which it was diluted by adding water (100 mL). The mixture was poured into a separatory funnel and extracted with DCM (3×40 mL). The organic layer was then washed with water (4×120 mL) and brine, and dried over magnesium sulfate. The organic layer was then concentrated to obtain an oil. The crude oil was purified using silica gel flash chromatography (DCM/ether 39:1) to obtain 1.9 g (22%) of the title compound (Rf˜0.17 in 19:1 DCM/ether). 1H NMR (600 MHz, CDCl3): δ 7.25 (s, 2H), 5.96 (s, 2H), 4.7 (t of d, 2H, J=48, 1.2 Hz), 4.37 (t of d, 2H, J=24, 1.2 Hz), 3.87 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 166.8, 149, 136.8, 126.4, 109.8, 82.16 (d, J=334 Hz), 72.6 (d, J=37.5), 52.3. MS (ESI): 231.4 (M+H, 100); FIRMS: Calc'd for C10H11FO5 (M+H): 231.06633; Found: 231.0664.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH:20]([CH3:22])[CH3:21])[N:12]=2)=[O:10])[CH2:5][N:4]1C(OC(C)(C)C)=O.Cl>CO>[OH:1][CH2:2][C@H:3]1[NH:4][CH2:5][C@@H:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH:20]([CH3:22])[CH3:21])[N:12]=2)=[O:10])[CH2:7]1
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CO)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Agent: Cl
Solvent: CO
Product: CC(C)n1nc(C(=O)N[C@@H]2CN[C@H](CO)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.4 %

Procedure:
The mixture of tert-butyl (2S,4S)-2-(hydroxymethyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidine-1-carboxylate (115 mg, 0.286 mmol, step 2 of Example 7) and 10% hydrochloric acid in methanol (5 mL) was stirred at room temperature for 14 h and concentrated under reduced pressure. The resulting residue was basified with saturated sodium hydrogencarbonate aqueous solution, extracted with dichloromethane (100 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was recrystallized from isopropyl ether to give 79 mg (91%) of the title compound as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[N:25]1([CH2:30][C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([CH2:30][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)[CH:32]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12
Reactant: Nc1cccc(CN2CCCC2)c1
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Product: O=c1c2cnc(Nc3cccc(CN4CCCC4)c3)nc2n2ccnc2n1-c1ccccc1Cl

Procedure:
A mixture of Example 1E (50.0 mg, 0.139 mmol) and 3-(pyrrolidin-1-ylmethyl)aniline (49.0 mg, 0.278 mmol) was heated in a capped vial at 110° C. for 1 hour. The crude material was purified by HPLC as described in Example 1F to provide the tile compound as a trifluoroacetic acid salt. 1H NMR (400 MHz, CD3OD) δ ppm 1.96-2.10 (m, 2H), 2.14-2.31 (m, 2H), 3.18-3.28 (m, 2H), 3.49-3.65 (m, 2H), 4.44 (s, 2H), 7.07 (d, J=1.83 Hz, 1H), 7.31 (d, J=7.32 Hz, 1H), 7.50-7.63 (m, 4H), 7.66-7.73 (m, 1H), 7.83-8.08 (m, 3H), 8.01 (s, 1H), 9.21 (s, 1H). MS (ESI+) m/z 472.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].I[CH2:14][CH2:15][CH3:16]>CN(C=O)C.C(OCC)(=O)C>[OH:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:14][CH2:15][CH3:16]
Reactant: CCCI
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 143.2 %

Procedure:
3,4-Dihydroxybenzaldehyde (0.5 g, 3.62 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.087 g, 3.62 mmol) was added. The reaction mixture was stirred at rt for 10 min. Iodopropane (0.35 mL, 0.62 mmol) was added and the reaction was stirred at 80° C. for 2.5 h. The reaction was diluted with ethyl acetate and washed with 2N HCl and water. Silica gel chromatography eluting with 35% ethyl acetate/hexane yielded 0.16 g of desired product: ESI-MS 181 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([O:21]C)=[O:20])=[O:12].B(Br)(Br)Br>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([OH:21])=[O:20])=[O:12]
Reactant: COC(=O)c1sccc1NC(=O)c1cnc2ccccc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1ccsc1C(=O)O)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
Methyl 3-[(2-quinoxalinylcarbonyl)amino]-2-thiophenecarboxylate (0.5 g, 1.6 mmol) was dissolved in CH2Cl2 (100 mL) at 0° C. and BBr3 (4.8 mL, 1M solution in CH2Cl2) was added dropwise. The solution was stirred at room temperature overnight. The reaction was quenched with NH4Cl at 0° C. The organic layer washed with NaHCO3 and separated. The resulting organic layer was treated slowly with dil HCl until the solution became acidic. The mixture was concentrated and redissolved in EtOAc. This solution washed with water, The solvent was removed under reduced pressure and the crude product was re-crystallized from methanol to give the desired product (0.2 g, 42%). HPLC/MS: (M+H)+ 300.1 m/z. Retention time (LC-MS)=2.65 min. 1H NMR (DMSO-D6): 13.75 (s, 1H, broad); 12.43(s, 1H); 9.61(s, 1H); 8.26(m, 2H); 8.17(m, 1H); 8.07(m, 2H); 7.99(d, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[C:9]2=[O:37])=[N:4][CH:3]=1.[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:38].[CH3:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:16][C:12]=3[C:11](=[O:23])[N:10]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:9]2=[O:37])=[N:4][CH:3]=1
Reactant: Cc1cnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-{1-[(5-methyl-1,3-thiazol-2-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (980 mg; compound B12) in DCM (5 ml) and 1,4-dioxane (20 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (2.3 ml, 4.0 M) under stirring at RT. After 1 h and after 2.5 h additional amounts of a solution of hydrogen chloride in 1,4-dioxane (4.6 ml and 2.3 ml) are added and the reaction mixture is stirred for another 10 min. All volatiles are removed under reduced pressure and the resulting residue is treated with diethyl ether. Removal of the solvent under reduced pressure gives the title compound as a solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:17](Cl)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:32]=1)([CH3:3])[CH3:2].[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1.NC1C=C(O)C(C)=CC=1>CO>[C:38]([C:37]1[CH:40]=[CH:41][C:34]([NH:33][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([S:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[C:14]([NH:13][C:12]3[C:7]4[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[N:32][C:8]=4[N:9]=[CH:10][N:11]=3)[CH:15]=2)=[CH:35][CH:36]=1)#[N:39]
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Cc1ccc(N)cc1O
Solvent: CO
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccc(C#N)cc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1

Procedure:
The product from Example 137B was reacted with 4-aminobenzonitrile according to the procedure from Example 137C substituting 4-aminobenzyonitrile for 5-amino-o-cresol to provide the title compound as an off white solid after trituration of the reaction product from methanol (20 mg, 23%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 10.63 (s, 1 H), 8.92 (s, 1 H), 8.69 (s, 1 H), 7.96 (d, J=8.82 Hz, 2 H), 7.66-7.90 (m, 4 H), 7.35-7.46 (m, 3 H), 6.95-7.11 (m, 3 H), 6.55-6.64 (m, 1 H), 3.77 (s, 3 H), 3.18-3.30 (m, 1 H), 1.35 (d, J=6.99 Hz, 6 H); MS (ESI+) m/z 547.3 (M+H)+, (ESI−) m/z 545.3 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.C(N(CC)CC)C.[C:17](Cl)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>ClCCl>[C:17]([O:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)(=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC1(CO)COC(=O)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OCC1(C)COC(=O)N1
Yield: 69.1 %

Procedure:
A solution of 10.5 g of 2-amino-2-methyl-1,3-propanediol and 12.3 g of diethyl carbonate, 0.5 g of sodium ethoxide in 100 ml of toluene was refluxed for 20 hours, cooled and concentrated at reduced pressure to give 13.6 g of crude product. Recrystallization from ethanol gave 9.23 g (67%) of4-hydroxymethyl-4-methyloxazolidin-2-one, m.p. 115 C. To a solution of 2.62 g of 4-hydroxymethyl-4-methyloxazolidin-2-one and 5 ml of triethylamine in 100 ml of dichloromethane was added dropwise 4.6 g of dodecanoyl chloride in 10 ml of dichloromethane. After 3 hours at room temperature the reaction mixture was concentrated, the residue was taken up in ether and washed with aqueous sodium bicarbonate. The ether layer was dried and concentrated to give 4.33 g (69%) of a thick yellow oil. Recrystallization from dichloromethane/hexane (1:10) gave 2.73 g (45%) of white crystals, m.p. 53-55 C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N:11]([CH3:13])[CH3:12])[CH:10]=1)[O:6][CH2+:7].[O:14]1[CH2:16][C@@H:15]1[C@@H:17]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:13][N:11]([CH3:12])[C:9]1[CH:10]=[C:3]([CH:4]=[C:5]([O:6][CH3:7])[CH:8]=1)[CH2:2][NH:1][CH2:16][C@@H:15]([OH:14])[C@@H:17]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: [CH2+]Oc1cc(CN)cc(N(C)C)c1
Solvent: ClCCl
Product: COc1cc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc(N(C)C)c1
Temperature: 50 °C
Yield: 54.5 %

Procedure:
(3-(aminomethyl)-5-(dimethylamino)phenoxy)methylium (0.0361 g, 0.2 mmol, 1.2 eq) was dissolved in the minimum amount of anhydrous CH2Cl2 under Ar. tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (0.0439 g, 0.167 mmol, 1 eq) was added with stirring. Anhydrous CH2Cl2 was added dropwise until all of the epoxide had dissolved. The reaction was heated to 50° C. After heating overnight all of the solvent was gone leaving a solid in the flask. Purification via flash chromatography yielded 0.0405 g, (0.091 mmol, 54% yield) of the product.