Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]#[N:24]>C(#N)C>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:22][C:23]#[N:24])=[CH:3][CH:2]=1
Reactant: N#CCBr
Reactant: Oc1cccc2[nH]c3ccccc3c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCOc1cccc2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.7 %

Procedure:
To a mixture of 9H-carbazol-4-ol (1.1 g, 6.0 mmol) in acetonitrile (100 mL) is added potassium carbonate (1.66 g, 12 mmol) and bromoacetonitrile (0.42 mL, 6.0 mmol). The mixture is stirred at room temperature for 20 h. The mixture is partitioned between water and CH2Cl2. The layers are separated and the organic layer dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography, silica gel (100 mL), using CH2Cl2 as eluent gave 1.13 g (85%) of the title compound; 1H NMR (DMSO-d6) δ5.4, 6.81, 7.18, 7.36, 7.46, 8.09; Anal. Calcd for C14H10N2O: C, 75.66; H, 4.53; N, 12.60. Found: C, 75.18; H, 4.56; N, 12.54.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].[CH3:14]I>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:14])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc2c(Cl)nc(Cl)nc21
Reaction time: 0.17 h

Procedure:
To a cold solution of 2,6-Dichloro-7H-purine (1 g, 5.29 mmol) in DMF (5 mL) was added 60% NaH (233 mg, 5.8 mmol) under N2. After stirring for 10 min, MeI (910 μL) was added, the reaction mixture was stirred for 30 min at this temperature and then overnight at room temperature, concentrated and co-evaporated with H2O to dryness. The residue was suspended in 2 mL cold water and filtered to the give crude mixture of 7A and 8A in about 1:1 ratio.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]#[N:13])=[CH:9][C:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)=[CH:7]2.B(Br)(Br)Br.CC(N(C(C)C)CCNC(C1N=C(NC(C2C(O)=CC(OC)=C(OC)C=2)=O)SC=1)=O)C.Cl>>[Br:1][C:2]1[C:3]([OH:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]#[N:13])=[CH:9][C:8]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[CH:7]2
Reactant: COc1ccc(-c2cc(C#N)c3c(Br)c(O)ccc3c2)cc1
Agent: BrB(Br)Br
Agent: COc1cc(O)c(C(=O)Nc2nc(C(=O)NCCN(C(C)C)C(C)C)cs2)cc1OC
Agent: Cl
Product: N#Cc1cc(-c2ccc(O)cc2)cc2ccc(O)c(Br)c12

Procedure:
The title compound was prepared by reacting 8-bromo-7-hydroxy-3-(4-methoxyphenyl)-1-naphthonitrile (0.13 g, 0.37 mmol) with boron tribromide (1.1 mL of 1 N solution, 1.1 mmol) according to method D to yield 0.050 g (40%) of an off white solid: mp 204-208° C.(d); 1H NMR (DMSO-d6): δ 6.90 (2H, d, J=8.30 Hz), 7.41 (1H, d, J=8.79 Hz), 7.72 (2H, d, J=8.79 Hz), 8.02 (1H, d, J=9.23 Hz), 8.37 (1H, d, J=1.95 Hz), 8.47 (1H, d, J=2.44 Hz), 9.72 (1H, s), 11.16 (1H, s); MS (ESI) m/z338/340 (M−H).Anal. for C17H10BrNO2
Reaction SMILES: [CH3:1][NH:2][NH2:3].O=[C:5]([CH2:11][C:12](=O)[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(O)C>[CH3:1][N:2]1[C:12]([CH3:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:3]1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: CNN
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(C)n1
Temperature: 0 °C

Procedure:
9.2 ml of methylhydrazine was added dropwise over 30 minutes to a solution of 25 g of ethyl 2,4-dioxovalerate in 36 ml of ethanol, the temperature of the mixture being kept below 40° C. by cooling in an ice bath. The resulting solution was heated at reflux for 23 hours, poured into 300 ml of ice water and the resulting mixture was extracted with ether. The extract was dried (MgSO4), filtered and stripped of solvent. The residue was chromatographed on silica gel, with a 1:1 v:v mixture of ethyl acetate and hexane as eluent. The middle fractions gave ethyl 1,5-dimethylpyrazole-3-carboxylate (39A), as a yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])[C@@H:3]1O[C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[K+].[Se-]C#N.[K+]>COC(OC)(C)C.C(OCC)(=O)C>[CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])/[CH:3]=[CH:4]/[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#C[Se-]
Agent: O=C([O-])O
Solvent: COC(C)(C)OC
Solvent: CCOC(C)=O
Product: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C/C=C/[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 44.4 %

Procedure:
Pseudomonic acid A (500 mgs) was dissolved in 2,2-dimethoxypropane (50 ml) and treated with p-toluene sulphonic acid (few crystals). After 1 hour the solution was diluted with ethyl acetate, washed with brine and dried (MgSO4). The solution was evaporated in vacuo and the residue redissolved in water-methanol (1:1, 20 ml) and potassium bicarbonate (100 mgs, 1 eq) added. The solvents were removed in vacuo and potassium selenocyanate (432 mgs, 3 eq) and iso-hexylalcoholwater (9:1, 15 ml) added and reaction refluxed for 4 days. After filtering, the reaction mixture was diluted with ethyl acetate (20 ml) and extracted with aqueous sodium bicarbonate (3×20 ml). The aqueous extracts were combined and acidified with acetic acid under a layer of ethylacetate (20 ml). After stirring for ca. 1 hour the organic layer was separated and aqueous layer further extracted with ethylacetate (3×20 ml). The combined extracts were washed with brine, dried (MgSO4) and evaporated to an oil. Chromatography of the oil on silica (5 g) gave pure pseudomonic acid C (215 mgs, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[Br:11]Br.N>>[Br:11][C:3]1[C:4]2[NH:8][CH:7]=[N:6][C:5]=2[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: BrBr
Agent: N
Product: Nc1ccc2nc[nH]c2c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of 5-aminobenzimidazole (3.3 g, 2.3 mmol) in 30 ml of ACOH was added bromine (0.055 ml, 1.1 mmol) in a portion and resulting reaction mixture was stirred for 0.5 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a dark brown solid which was subjected to silica gel column chromatography (NH3 saturated 10% MeOH/EtOAc) to yield 0.22 g (0.97 mmol, 42%) of the desired product.
Reaction SMILES: C([O:4][C@@H:5]1[CH:10]=[CH:9][C@@:8]([OH:17])([C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:7][O:6]1)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[OH:6][CH2:7][C:8]1([C:11]#[C:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[O:17][C@@H:5]([OH:4])[CH:10]=[CH:9]1
Reactant: CC(=O)O[C@@H]1C=C[C@@](O)(C#C[Si](C)(C)C)CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: C[Si](C)(C)C#CC1(CO)C=C[C@H](O)O1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
400 mL of an aqueous solution containing 9.8 g of Lipase PS Amano SD was added to a solution of 98.4 g (387 mmol) of the acetylated form (Compound 5) dissolved in 300 mL of acetonitrile, and agitated at 40° C. overnight. At the end of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, filtrated, and subjected to vacuum concentration to obtain 84.2 g of a crude product (crude yield: 75.8%). The obtained crude product was subjected to column purification (n-Hex:AcOEt=3:1) to obtain 62.3 g of a mixture of Compounds 9 and 10 as a yellow oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.N([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=C=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[CH3:21][CH2:20][CH:19]([C:8]([NH2:7])=[O:10])[CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCCCCCCN=C=O
Agent: O=c1[nH]c2cc(Cl)ccc2s1
Solvent: C1COCCO1
Product: CCCCC(CC)C(N)=O

Procedure:
300 mg (1.37 mmol) of 5-chloro-3H-benzothiazol-2-one were reacted in analogy to Example 1 with 174 mg (1.37 mmol) of 1-isocyanatoheptane in dioxane at 80° C. Yield: 100 mg (19%), M+H+: 327.38.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:11]2([CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:10][CH:9]1[NH:16][C:17]([O:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=1)=[O:18].F[C:32]1[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][N:33]=1>>[Br:38][C:35]1[CH:36]=[CH:37][C:32]([N:13]2[CH2:14][CH2:15][C:11]3([CH2:10][CH:9]([NH:16][C:17]([O:19][CH2:20][C:21]4[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=4)=[O:18])[CH2:8]3)[CH2:12]2)=[N:33][CH:34]=1
Reactant: CCOC(=O)c1cc(COC(=O)NC2CC3(CCNC3)C2)on1
Reactant: Fc1ccc(Br)cn1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(COC(=O)NC2CC3(CCN(c4ccc(Br)cn4)C3)C2)on1

Procedure:
The process is performed according to the procedure described in Example 2 (step 2.6.). Starting with 1.7 g (3.90 mmol) of ethyl 5-(6-azaspiro[3.4]oct-2-ylcarbamoyloxymethyl)isoxazole-3-carboxylate trifluoroacetate (isomer 5) and 0.68 g (3.90 mmol) of 2-fluoro-5-bromopyridine, and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 1.00 g of pure product is thus obtained in the form of a gum.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>ClCCl>[C:1]([NH:5][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([Br:13])[CH:15]=1)(=[O:22])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1cccc(Br)c1
Reaction time: 1 h
Yield: 1248 %

Procedure:
tert-Butylamine (3.14 g, 3.0 mmol, 1.1 eq) and triethylamine (5.94 g, 58.6 mmol, 1.5 eq.) were dissolved in dichloromethane (20 mL) and stirred at room temperature while 3-bromobenzenesulfonyl chloride (10.0 g, 39.1 mmol) was added slowly. The mixture was stirred for 1 hour and then concentrated by evaporation under reduced pressure. The residue was taken up in 5% citric acid and ethyl acetate. The organic layer is washed repeatedly with brine and water, dried over anhydrous magnesium sulfate and concentrated to give N-tert-butyl-3-bromobenzenesulfonamide (10.94 g) as a white powder.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].O>ClCCl>[O:20]([C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a solution of estrone (100 g, 0.37 mole) in 400 ml of dichloromethane, imidazole (50.36 g, 0.74 mole) and t-butyl-dimethylsilyl chloride (61.3 g, 0.41 mole) were added. The solution was stirred at room temperature for 24 hours. Then water (200 ml) was added. The organic layer was partially evaporated and diisopropyl ether added. The white solid formed was collected by filtration and dried. It weighed 135.2 g, yield 95%, mp 172° C.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1.C(Cl)Cl>OS(O)(=O)=O>[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: O=Cc1cc(Br)cs1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: O=Cc1cc(Br)c([N+](=O)[O-])s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A solution of potassium nitrate (110 g, 1.09 mol) in H2SO4 (550 mL, conc.) was added to a solution of 4-bromo-thiophene-2-carbaldehyde (207.6 g, 1.08 mol) in H2SO4 (1.1 L, conc.) at CH2Cl2 (5 mL, anhydrous) at 0° C. over a 45 minute period. The reaction mixture was stirred 0° C. for 2 hrs, then stirred overnight at rt. The reaction mixture was poured over ice, filtered, and washed with water and hexanes. The yellow solid was dried overnight to afford the title compound (251.4 g, 98.6%). 1H-NMR (DMSO-d6): δ 9.90 (s, 1H), 8.56 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:15])([F:14])[CH:11]1[CH2:13][O:12]1>>[CH2:1]([NH:8][CH2:13][CH:11]([OH:12])[C:10]([F:15])([F:14])[F:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)C1CO1
Reactant: NCc1ccccc1
Product: OC(CNCc1ccccc1)C(F)(F)F

Procedure:
Starting material: benzylamine and 2-(trifluoromethyl)oxirane
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][C:12]([CH3:14])=[N:11][C:10]([CH3:15])=[C:9]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1.[S].S>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:10]([CH3:15])[N:11]=[C:12]([CH3:14])[N:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C(C)N=C(C)NC1c1ccc(F)cc1
Agent: S
Agent: [S]
Product: CCOC(=O)c1c(C)nc(C)nc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
Ethyl 6-(4-fluorophenyl)-1,6-dihydro-2,4-dimethyl-5-pyrimidinecarboxylate (75.7 g, 0.274 mol) and 9.67 g (0.3 mol) of powdered sulfur were heated together at 130°-150° C. for three and one-half hours. After hydrogen sulfide evolution had ceased, the melt was cooled to room temperature and flash chromatographed on silica gel, eluting with 10% ethyl acetate/hexane, to yield 48.7 g of ethyl 4-(4-fluorophenyl)-2,6-dimethyl-5-pyrimidinecarboxylate.
Reaction SMILES: [S:1]([C:5]1[S:9][C:8]([NH:10]C(=O)C)=[N:7][N:6]=1)(=[O:4])(=[O:3])[NH2:2].Cl>CO>[NH2:10][C:8]1[S:9][C:5]([S:1]([NH2:2])(=[O:4])=[O:3])=[N:6][N:7]=1
Reactant: CC(=O)Nc1nnc(S(N)(=O)=O)s1
Agent: Cl
Solvent: CO
Product: Nc1nnc(S(N)(=O)=O)s1
Yield: 98.7 %

Procedure:
To a solution of N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide (1.0 g, 4.50 mmol) and MeOH (15 mL) was added HCl (2 N, 10 mL). The reaction mixture was heated at reflux for 18 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0-10% MeOH in CMA) to afford the sub-title compound (800 mg, 98%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=4)[N:13]([CH3:24])[CH:12]=3)=[CH:10][C:3]=12.[CH3:35][N:36](C)C(=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][O:22][C:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:24])[CH:12]=[C:11]2[C:9]1[NH:8][C:4]2=[N:5][CH:6]=[CH:7][C:2]([C:35]#[N:36])=[C:3]2[CH:10]=1)=[O:21]
Reactant: CC(=O)N(C)C
Reactant: COC(=O)c1ccc2c(c1)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Product: COC(=O)c1ccc2c(c1)c(-c1cc3c(C#N)ccnc3[nH]1)cn2C
Temperature: 140 °C

Procedure:
A mixture of 3-[4-chloro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-yl]-1-methyl-1H-indole-5-carboxylic acid, methyl ester [0.4 g, Reference Example 2(r)], zinc powder (0.05 g), zinc cyanide (0.117 g), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) complex with dichlroromethane (catalytic) and N,N-dimethylacetamide (8 mL) was heated at 130-150° C. for 5 hours. The reaction mixture was cooled, filtered and the precipitated washed with dimethylformamide (2 mL). The filtrate was diluted with ethyl acetate (120 mL) and the solution extracted with water (2×20 mL). The combined organic layer was evaporated and the residue subjected to flash column chromatography on silica gel eluting with a mixture of heptane and ethyl acetate (7:3 v/v) moving to neat ethyl acetate to give the title compound (0.12 g) as a bright yellow solid. MS: 331 (MH+). HPLC (Method C): RT=4.01 minutes.
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:12]3)C=CC=CC=1>[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]([F:22])([F:20])[F:21])[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:12]2
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1CC(F)(F)F
Agent: [Pd]
Product: CCOC(=O)c1cc2cc(O)ccc2n1CC(F)(F)F
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of ethyl 5-[(phenylmethyl)oxy]-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylate (0.23 g, 0.6 mmol) in EtOAC (5 mL), under N2, was added 5% Pd/C (0.12 g). The mixture was hydrogenated under balloon pressure for 3 h. The catalyst was filtered off and washed with EtOAc. The filtrate was concentrated to afford the title compound (0.15 g, 89% yield): MS (ES) m/z 288 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[NH:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N(C[C@@H]2CCCN2)c2ccccc2C12COc1cc3c(cc12)CCO3
Yield: 88 %

Procedure:
A solution of tert-butyl (2S)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]pyrrolidine-1-carboxylate (0.74 g, 1.60 mmol) and trifluoroacetic acid (1.6 mL) in dichloromethane (8 mL) was stirred at ambient temperature for 80 h. The reaction was made basic with 1 M sodium hydroxide (30 mL) and was extracted with dichloromethane (3×25 mL). The combined organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 1′-[(2S)-pyrrolidin-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.51 g, 89%) as a pale yellow solid: mp 83-86° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.29 (dd, J=7.8, 7.5 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.07-6.99 (m, 2H), 6.52, 6.46 (s, 1H), 6.40 (s, 1H), 4.95, 4.91 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.7 Hz, 2H), 3.91-3.71 (m, 2H), 3.69-3.60 (m, 1H), 3.14-2.90 (m, 5H), 1.98-1.70 (m, 3H), 1.66-1.51 (m, 1H); MS (ES+) m/z 363.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1.C([Li])CCC.CCCCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[S:10][C:9]([CH:31]=[O:32])=[N:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2scnc2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 (1.75 g, 6.85 mmol) in dry THF (40 mL) at −78° C. was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 μL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield 5-chloro-7-morpholinothiazolo[4,5-d]pyrimidine-2-carbaldehyde 43.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.O.NN>C(O)C>[Cl:12][C:4]1[N:3]=[CH:2][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Clc1cc2ccccc2c(Cl)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: Clc1cc2ccccc2cn1
Temperature: 25 °C
Yield: 42.6 %

Procedure:
A mixture of 1,3-dichloroisoquinoline (9.94 g, 50.2 mmol) and hydrazine hydrate (12.2 ml, 251 mmol) in ethanol (150 ml) was heated at reflux for 1.5 hours. The reaction was then cooled to room temperature and the ethanol evaporated. The residue was suspended in chloroform and manganese dioxide (20 g) was added in portions over 30 minutes. Gas evolution was observed. After this had subsided, the mixture was heated to reflux for 2 hours, then filtered and evaporated. Purification of the residue by flash column chromatography using dichloromethane as eluant gave the title compound (3.5 g).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:13]=[N+:14]=[N-].[Na+]>C(O)(C(F)(F)F)=O.O>[N:6]([C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[N+:13]=[N-:14]
Reactant: Nc1ccc(I)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccc(I)cc1
Temperature: 0 °C
Yield: 99 %

Procedure:
4-Iodoaniline (32, 6.00 g, 27.4 mmol) was dissolved in 25 mL TFA and stirred in ice bath. Solid NaNO2 (2.07 g, 30.1 mmol) was added in small portions. The resulting mixture was stirred for 30 min in the ice bath. Sodium azide (1.87 g, 28.8 mmol) was dissolved in 10 mL water and chilled in ice bath. This cold solution was then added to the TFA solution in three portions. The mixture was stirred in ice bath for 1 hr and concentrated in vacuo to remove TFA. The residue was taken into 600 mL DCM and washed with water three times. The organic phase was dried using MgSO4 and concentrated in vacuo to afford 1-azido-4-iodobenzene 33 as a brownish waxy solid in >99% yield. In the mean time, 5-chlorothiophene-2-carboxylic acid (4, 9.13 g, 56 mmol) was dissolved in 200 mL dry DCM along with 0.5 mL dry DMF. To the vigorously stirred solution was carefully added oxalyl chloride (14.7 mL, 169 mmol) dropwise. The resulting solution was stirred for 3 hrs at RT and concentrated in vacuo. The residue was pumped to dryness and then dissolved in 300 mL dry DCM. To this solution was added propargylamine (5.8 mL, 84 mmol) dropwise. The mixture was stirred at RT for overnight and a lot of solid precipitated out. To this mixture was added 600 mL hexane. The mixture was vigorously stirred for a few hours and filtered for the solid (product 34). The solid (9.47 g, 85%) was washed with hexane and was pure enough for direct use without further purification. MS found for C8H6ClNOS as (M+H)+ 200.0, 202.0.