Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>>[CH2:14]([C:4]1[C:3]2[C:8](=[C:9]([C:17](=[O:20])[CH2:18][CH3:19])[C:10]([OH:12])=[CH:11][C:2]=2[OH:1])[O:7][C:6](=[O:13])[CH:5]=1)[CH2:15][CH3:16]
Reactant: CCC(=O)Cl
Reactant: CCCc1cc(=O)oc2cc(O)cc(O)c12
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(O)cc(O)c12

Procedure:
acylating 5,7-dihydroxy-4-propylcoumarin with propionyl chloride in the presence of a Lewis acid to form 4-propyl-5,7-dihydroxy-8-propionylcoumarin;
Reaction SMILES: CC(N)C1C=CC=CC=1.C(OC([NH:20][CH:21]([PH:26](=[O:28])[OH:27])[C:22]([SH:25])([CH3:24])[CH3:23])=O)C1C=CC=CC=1.Cl.Br>O.C(O)(=O)C.C(OCC)C>[NH2:20][CH:21]([PH:26](=[O:27])[OH:28])[C:22]([SH:25])([CH3:24])[CH3:23]
Reactant: CC(C)(S)C(NC(=O)OCc1ccccc1)[PH](=O)O
Agent: Br
Agent: CC(N)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: CC(C)(S)C(N)[PH](=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The (+)-α-methylbenzylamine salt of (-)-(1-benzyloxycarbonylamino-2-mercapto-2-methylpropyl)phosphinic acid [paragraph (c)] was suspended in water, the suspension was acidified to pH 1 with 2N hydrochloric acid and extracted with two 25 ml portions of diethyl ether. The combined ethereal extracts were dried over magnesium sulphate. Removal of the solvent by evaporation gave an oil which was dissolved in 2 ml of glacial acetic acid and treated with 5 ml of 45% hydrogen bromide in acetic acid. The solution was stored at room temperature overnight. 200 ml of diethyl ether were added and the cloudy suspension was cooled at 0° C. for 2 hours. The ethereal layer was decanted off and the residue was dissolved in 15 ml of methanol. 10 ml of acetone were then added. The solution was heated under reflux for 1 hour, cooled and filtered. The filtrate was adjusted to pH 5 by adding propylene oxide. The acetone adduct crystallized out at 0° C. and was collected. The acetone adduct, which melted at 183°-185° C., was dissolved in 5 ml of boiling water, filtered and concentrated to 3 ml by boiling off excess water. 15 ml of isopropanol were added and the mixture was allowed to cool slowly to room temperature. The mixture was then cooled at 0° C. for 16 hours. The resulting crystalline solid was collected and dried, there being obtained (-)-(1-amino-2-mercapto-2-methylpropyl)phosphinic acid of melting point 211°-212° C. (decomposition; [α]D25 =-4.5° (c=1.5% in water).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9]2=[N:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)=[N:17][N:8]2[C:7]1=[O:24])[CH2:2][CH2:3][CH2:4][CH3:5].C(N1C2N=CNC=2C2=NN=C(C3C=CN=CN=3)N2C1=O)CCCC.[Br:49]N1C(=O)CCC1=O>C1COCC1>[Br:49][C:12]1[NH:11][C:10]2[C:9]3=[N:15][C:16]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][N:19]=4)=[N:17][N:8]3[C:7](=[O:24])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: CCCCCn1c(=O)n2nc(-c3ccncn3)nc2c2[nH]cnc21
Reactant: O=C1CCC(=O)N1Br
Agent: CCCCCn1c(=O)n2c(-c3ccncn3)nnc2c2[nH]cnc21
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n2nc(-c3ccncn3)nc2c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-pentyl-8-pyrimidin-4-yl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (14C1) and 6-pentyl-3-pyrimidin-4-yl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purin-5-one (14C2) (25 mg, 0.15 mmol) in THF (5 mL) was added N-bromosuccinimide (19 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 hour, then the reaction was quenched by phenol. After removing the solvent, the residue was purified using preparative LCMS (method B) to yield the pure compound (14D1) and the pure compound 14D2 respectively. LCMS calculated for C15H16BrN8O (M+H): 403.1; found: 403.0, 405.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=2[CH3:12])[N:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+]>O.CO>[CH3:12][C:10]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]([CH3:16])=[C:6]2[C:11]=1[C:2]([O:18][CH3:17])=[CH:3][CH:4]=[N:5]2
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c(Cl)ccnc12
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccnc2c(C)cc([N+](=O)[O-])c(C)c12
Reaction time: 21 h

Procedure:
In a flask is placed 4-chloro-5,8-dimethyl-6-nitroquinoline (1.52 g, 5.4 mmol) with sodium methoxide (2.27 g, 4.2 mmol) and methanol (25 mL). The mixture is refluxed under argon with stirring for 21 hours, diluted with water (100 mL) and methanol (50 mL) and extracted with dichloromethane (2×200 mL). The organic layer is dried over potassium carbonate, filtered and evaporated. The product is purified by flash chromatography (7/3 hexanes/ethyl acetate), yielding 5,8-dimethyl-4-methoxy-6-nitroquinoline.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:10]([CH:11]=[O:12])[C:9]=2[OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:17].[K+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[C:1]1([CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:10]([C:11]([OH:17])=[O:12])[C:9]=2[OH:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cccc(Cc2ccccc2)c1O
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 34.3 %

Procedure:
According to the general method of Sharma et al., 2000, Synth. Commun., 30:397-405, a stirred solution of the 3-(phenylmethyl)salicylaldehyde (1.27 g, 6 mmol) in ethanol (16 ml) was treated dropwise with a solution of silver nitrate (2.0 g, 12 mmol) in water (16 ml). A solution of potassium hydroxide (2.69 g, 48 mmol) was then added dropwise over 40 minutes. The solution was allowed to stir at RT for 6 h. The mixture was filtered through a pad of celite, and the filter pad washed with water (2×10 ml). The filtrate was washed with diethyl ether (2×15 ml) and then acidified with 1N HCl. The milky suspension was extracted with diethyl ether (2×30 ml), and the combined extracts were dried (Na2SO4) and the solvent removed to yield 3-(phenylmethyl)salicylic acid as a tan solid (0.47 g, 34%). 1H-NMR (CDCl3, 400 MHz): δ 4.02 (s, 2H), 6.84 (t, 1H, J=8 Hz), 7.19-7.32 (m, 6H), 7.79 (d, 1H, J=8 Hz), 10.74 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:12])[C:6]=1[NH:7][C:8](=[O:11])[CH2:9][Cl:10].S(Cl)([Cl:16])(=O)=O>C(Cl)Cl>[Cl:16][C:4]1[S:3][C:2]([CH3:1])=[C:6]([NH:7][C:8](=[O:11])[CH2:9][Cl:10])[C:5]=1[CH3:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1csc(C)c1NC(=O)CCl
Solvent: ClCCl
Product: Cc1sc(Cl)c(C)c1NC(=O)CCl

Procedure:
To the stirred solution of 5.0 g (0.0245 mol) of N-(2,4-dimethylthien-3-yl)-chloroacetamide in 50 ml of dry CH2Cl2 are added dropwise at 0° 3.3 g (0.0245 mol) of sulfuryl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.N.CC[N:21](C(C)C)C(C)C>C(Cl)Cl.CO.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([NH2:21])=[O:6]
Reactant: O=C(O)c1cc(O)cc(Cl)c1
Reactant: CCN(C(C)C)C(C)C
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1cc(O)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 3-chloro-5-hydroxybenzoic acid (3.22 mmol), oxalyl chloride (6.5 mmol) and catalytic amount of DMF in DCM was heated at reflux for 2 hrs. (bath temperature at 60° C.). Solvent was evaporated in vacuo and the residue was dissolved in 1,4-dioxane. NH3 (0.5 M in 1,4-dioxane, 1.5 eq.) and DIEA (1.5 eq.) were added and the reaction mixture was stirred at RT overnight. The reaction mixture was transferred to a pressure vessel, followed by the addition of 1 mL of 6 M NH3 in MeOH. The pressure vessel was sealed and heated at 90° C. for 2 hrs. The solvents were evaporated to give a crude product, which was purified by chromatography over silica gel (EtOAc) to yield 0.51 g (57%, theoretical yield 0.896 g) of 3-chloro-5-hydroxybenzamide. LCMS (Cond. A) RT 1.05 min., MH+ 172. 1H NMR (500 MHz, CD3OD) δ 7.31 (t, J=1.7 Hz, 1 H), 7.19 (t, J=1.8 Hz, 1 H), 6.94 (t, J=2.1 Hz, 1 H).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)=O.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[N:12]1([CH2:1][C:3]2[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(C(=O)O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1cccc(CN2CCOCC2)n1
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To a solution of 6-formyl-2-pyridinecarboxylic acid (available from Chemstep Product List, 250 mg, 1.65 mmol) in dichloromethane (6.8 ml) was added morpholine (0.377 ml, 4.31 mmol) and acetic acid (0.083 ml). The mixture was stirred at room temperature for 15 min when sodium triacetoxyborohydride (459 mg, 2.17 mmol) was added and the mixture stirred overnight. The crude reaction mixture was diluted with dichloromethane (10 ml) and methanol was added until a clear solution was observed. The mixture was loaded onto an aminopropyl cartridge (5 g) pre-eluted with dichloromethane. The cartridge was eluted with dichloromethane followed by methanol and fractions containing product were combined and blown to dryness under a stream of nitrogen. The crude product was taken up in sodium hydroxide solution (2M, 25 ml) and washed with dichloromethane (2×25 ml). The aqueous layer was acidified to pH7 using hydrochloric acid (5M) and concentrated under vacuum to approximately 25 ml. The solution was loaded onto an Oasis cartridge (6 g), which had been pre-eluted with methanol (1 volume) followed by water (1 volume). The cartridge was eluted with water (1 volume) followed by methanol. Fractions containing product were combined and dried to give the title compound (129 mg).
Reaction SMILES: [CH3:1][CH:2]([S:4][C:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[S:8][C:9]=1[C:10](O)=[O:11])[CH3:3].C1N=C[N:19](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[CH3:1][CH:2]([S:4][C:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[S:8][C:9]=1[C:10]([NH2:19])=[O:11])[CH3:3]
Reactant: CC(C)Sc1c(C(=O)O)sc2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Sc1c(C(N)=O)sc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To 3-[(1-methylethyl)thio]benzo[b]thiophene-2-carboxylic acid (133 mg, 0.53 mmol) [Connor D. T., et al., U.S. Pat. No. 4,703,053 (1987)] in 6 mL of THF is added N,N-carbonyldiimidazole (99 mg, 0.61 mmol). The mixture is heated at reflux for 1.5 hours then cooled slightly. Aqueous NH4OH (1 mL) is added and the reaction mixture is stirred at room temperature for 30 minutes, then partitioned between ethyl acetate and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography eluting with 1:1 hexane:ethyl acetate to provide 3-[(1-methylethyl)thio]benzo[b]thiophene-2-carboxamide in 83% yield; mp=183-185° C.
Reaction SMILES: C(O[C:5](=[O:33])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH2:13][C:14](=[O:32])[NH:15][C:16]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27]C=[C:25]([CH2:29][F:30])[CH:24]=4)[C:20](C)=[CH:19][C:17]=3[N:18]=2)[CH:7]=1)C=C.O.[NH2:35][NH2:36]>CO.O>[F:30][C:29]1[CH:27]=[CH:28][C:23]([C:21]2[CH:20]=[CH:19][C:17]3[N:18]=[C:12]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=4)[C:5]([NH:35][NH2:36])=[O:33])[CH2:13][C:14](=[O:32])[NH:15][C:16]=3[CH:22]=2)=[CH:24][CH:25]=1
Reactant: NN
Reactant: C=CCOC(=O)c1cccc(C2=Nc3cc(C)c(-c4cccc(CF)c4)cc3NC(=O)C2)c1
Solvent: CO
Solvent: O
Product: NNC(=O)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 33 %

Procedure:
To a suspension of 3-[7-(3-fluoromethyl-phenyl)-8-methyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoic acid allyl ester (Starting material 8a-1) (207 mg, 0.5 mmol) in MeOH (3.5 mL) was added hydrazine hydrate (0.25 mL, 5 mmol). The mixture was stirred at 60° C. for 15 h, then cooled to 23° C. and diluted with H2O (35 mL). The precipitate was collected by filtration and dried, and the crude product was purified by chromatography on silica gel using ethyl acetate/hexane (1:1) as eluent. The purified product was crystallized from Et2O/hexane to give the title compound as light yellow solid (64 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:8])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)[CH3:10]
Reactant: O=C(O)c1ccoc1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Product: CCOc1ccc(NC(=O)c2ccoc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 3-furoic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (DMSO-d6): 10.25 (s, 1H), 8.36 (d, J=2.4, 1H), 7.83-7.81 (m, 1H), 7.53-7.47 (m, 2H), 7.35-7.31 (m, 1H), 6.94 (d, J=2.4, 1H), 4.12 (q, J=6.9, 2H), 1.35 (t, J=6.9, 3H).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[O:21][C:20](=[O:22])[C:19]([S:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:18]([OH:35])[CH2:17]2)=[CH:12][CH:11]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:31]([C:25]1[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=1[S:23][C:19]1[C:20](=[O:22])[O:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][OH:6])=[CH:11][CH:12]=2)([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:17][C:18]=1[OH:35])([CH3:34])([CH3:32])[CH3:33]
Reactant: Cc1ccc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccccc3)(c3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)OC2=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccccc3)(c3ccc(OCCO)cc3)OC2=O)c1

Procedure:
Deprotection of 1.75 g (2.7 mmol) of 6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl } -3-(2-tert-butyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-phenethyl-5,6-dihydro-pyran-2-one (prepared in the paragraph above) was accomplished as described in General Method 8 using 5.4 mL (5.4 mmol) of 1 M tetrabutylammonium fluoride and 10 mL of THF. Purification by silica gel chromatography, eluting with MeOH:(50% Hexane-50% CH2Cl2) (1:99 to 5:95) gave the title compound, m.p. 154-156° C.
Reaction SMILES: [CH2:1]([O:14][C:15](Cl)=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH:18]1[CH:23]=[C:22]2[NH:24][C:25]([C:27]3[NH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[N:26][C:21]2=[CH:20][CH:19]=1>>[CH2:1]([O:14][C:15]([N:35]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:28]=[C:27]1[C:25]1[N:24]([C:15]([O:14][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:16])[C:22]2[CH:23]=[CH:18][CH:19]=[CH:20][C:21]=2[N:26]=1)=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCOC(=O)Cl
Reactant: c1ccc2[nH]c(-c3nc4ccccc4[nH]3)nc2c1
Product: CCCCCCCCCCCCCOC(=O)n1c(-c2nc3ccccc3n2C(=O)OCCCCCCCCCCCCC)nc2ccccc21

Procedure:
Following the procedure of Example 2, tridecylchloroformate was reacted with 2,2'-bibenzimidazole to give 1,1'-bis(tridecyloxycarbonyl)-2,2'-bibenzimidazole in 86% purity.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH2:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:37][C:38]([F:45])([F:44])[CH2:39][S:40](Cl)(=[O:42])=[O:41]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH:29][S:40]([CH2:39][C:38]([F:45])([F:44])[F:37])(=[O:42])=[O:41])[C:25]([F:26])([F:27])[F:28])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(CC(F)(F)F)NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Yield: 96.4 %

Procedure:
To a mixture of 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (80.0 mg, 0.165 mmol) and triethylamine (0.0460 mL, 0.330 mmol) in tetrahydrofuran (2 mL) was added 2,2,2-trifluoroethanesulfonyl chloride (0.0219 mL, 0.198 mmol) at 0° C. The resultant mixture was stirred at room temperature for 30 min and diluted with aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (100 mg, 0.159 mmol, 96%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9](N)=[O:10])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[OH-:12].[Na+].[ClH:14]>>[ClH:14].[F:1][C:2]1[C:3]([C:9]([OH:10])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: NC(=O)c1ncc(Br)cc1F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ncc(Br)cc1F

Procedure:
A solution of 3-fluoro-5-bromopyridine-2-carboxamide (1.44 g, 6.5 mmol) in conc HCl (aq) (17 mL) was heated to 120° C. for 1.5 h. The reaction was cooled in an ice bath and 48% NaOH was added to slowly until the pH was 5. The solvent was removed in vacuo and toluene (25 mL) was added and then removed in vacuo. The resulting solid was extracted with 4:6 methanol/DCM (×2) and the combined extracts evaporated in vacuo to give crude 3-fluoro-5-bromopyridine carboxylic acid hydrochloride which was used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2Cl.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Clc1nc(Cl)c2cccc(Br)c2n1
Reactant: C1COCCN1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2cccc(Br)c2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.6 %

Procedure:
To an ice cold solution of 8-bromo-2,4-dichloro-quinazoline (5.5 g, 0.0197 mol) in DCM (100 mL), morpholine (3.77 mL, 0.0433 mol) was slowly added and the reaction was continued for 15 min. The solvent was evaporated to dryness to get the crude compound. The crude product was purified, using column chromatography (60-120 silica gel, 5-30% ethyl acetate in hexane) to get the title compound [2.5 g, 39%]. 1H NMR (400 MHz, CDCl3): δ 8.05 (dd, J′=7.8 Hz, J″=1.2 Hz, 1H), 7.81 (dd, J′=8.4 Hz, J″=0.9 Hz, 1H), 7.29 (t, J=8.4 Hz, 1H), 3.89 (s, 8H); LC-MS (ESI): Calculated mass: 326.9; Observed mass: 327.9 [M+H]+ (RT: 1.57 min).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7]CC#N.[OH-:11].[Na+].[O:13]1[CH2:18][CH2:17]OCC1>>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:17][C:18]([OH:13])=[O:11]
Reactant: C1COCCO1
Reactant: N#CCCN1CCCC1=O
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)CCN1CCCC1=O
Yield: 49 %

Procedure:
A solution of 2-oxo-1-pyrrolidinepropionitrile (22.4 g, 16.2 mmol), 15% NaOH solution (40 mL) and dioxane (40 mL) was heated under reflux for 5 h under N2. The reaction mixture was extracted with EtOAc. The aqueous layer was made acidic with 6N HCl amd extracted with CH2Cl2 (5×50 mL). The organic layers were dried over Na2SO4 and concentrated to give the title compound as a cream solid (12.4 g, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O>CCO.C1COCC1.[Pd]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[NH2:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccc(N)c(N)c1
Reaction time: 12 h
Yield: 96.5 %

Procedure:
To a mixed solution of 4-amino-3-nitrobenzonitrile (8 g) in EtOH/THF (40 ml/40 ml) was added Pd—C (50% wet) (0.8 g), followed by stirring under an H2 atmosphere for 12 hours. The reaction solution was filtered through celite, and concentrated. The residue was powdered/washed with a mixed solvent of IPE and IPA, and collected by filtration to obtain 3,4-diaminobenzonitrile (6.3 g) as orange powders.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][S:24][CH2:25][CH2:26][O:27][C:28]([NH:30][C:31]1[NH:32][C:33](=[O:44])[C:34]2[N:35]=[CH:36][N:37]([CH2:40][C:41](O)=[O:42])[C:38]=2[N:39]=1)=[O:29]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:41](=[O:42])[CH2:40][N:37]1[CH:36]=[N:35][C:34]2[C:33](=[O:44])[NH:32][C:31]([NH:30][C:28]([O:27][CH2:26][CH2:25][S:24][CH3:23])=[O:29])=[N:39][C:38]1=2)[CH3:2]
Reactant: CSCCOC(=O)Nc1nc2c(ncn2CC(=O)O)c(=O)[nH]1
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OCCSC)nc21
Yield: 81.8 %

Procedure:
The title compound (2.67 g, 75%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [2-N-(2-methylthioethoxycarbonyl)-guanin-9-yl]-acetic acid (1.64 g, 5 mmol) as per the procedure of Example 20.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[F:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:5]([OH:18])=[CH:4][CH:3]=1.[C:19]([O-])([O-])=O.[Cs+].[Cs+].ClCI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH2:19][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]([F:17])=[C:8]3[C:6]=2[N:7]=1
Reactant: Oc1ccc(Cl)nc1-c1[nH]c2ccccc2c1F
Reactant: O=C([O-])[O-]
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1c2n(c3ccccc13)COc1ccc(Cl)nc1-2
Yield: 47.5 %

Procedure:
A solution of 6-chloro-2-(3-fluoro-1H-indol-2-yl)pyridin-3-ol (120 mg, 0.46 mmol) and Cs2CO3 (452 mg, 1.39 mmol) in DMF (6 mL) was stirred at 100° C. (internal temperature), then chloroiodomethane (173 mg, 0.92 mmol) in DMF (1 mL) was added dropwise. After the reaction was completed according to TLC, the mixture was filtered and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=4:1) to provide 2-chloro-12-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (60 mg, yield: 47.6%). 1H-NMR (CDCl3, 400 MHz) δ 7.63 (d, J=8.0 Hz, 2H), 7.06˜7.28 (m, 4H), 5.76 (s, 2H). MS (M+H)+: 275/277.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][C:21]([CH2:45][C:46]#[N:47])([N:23]2[CH:27]=[C:26]([C:28]3[C:29]4[CH:36]=[CH:35][N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:30]=4[N:31]=[CH:32][N:33]=3)[CH:25]=[N:24]2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[OH-].[Na+]>C(O)C.O>[OH:18][CH:19]1[CH2:22][C:21]([CH2:45][C:46]#[N:47])([N:23]2[CH:27]=[C:26]([C:28]3[C:29]4[CH:36]=[CH:35][N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[C:30]=4[N:31]=[CH:32][N:33]=3)[CH:25]=[N:24]2)[CH2:20]1
Reactant: CC(C)(C)[Si](OC1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(O)C4)c3)ncnc21
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To {3-{[tert-butyl(diphenyl)silyl]oxy}-1-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile (2.85 g, 4.30 mmol) in ethanol (120 mL) was added 5.0M sodium hydroxide in water (29 mL, 150 mmol). The reaction was stirred for 3 hours and diluted with water. The ethanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate three times. The combine organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified with silica gel column eluting with a gradient from 0-10% MeOH/DCM to give of the product (1.62 g, 88%) as .off-white foam. LCMS (M+H)+: 425.2.