Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:27]1[C:31]([CH:32]=O)=[CH:30][N:29]=[CH:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:15]([CH2:32][C:31]3[NH:27][CH:28]=[N:29][CH:30]=3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Reactant: O=Cc1cnc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2cnc[nH]2)C2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (134 mg, 0.34 mmol) was dissolved in absolute CH2Cl2 (10 ml), and 1H-imidazole-5-carbaldehyde (65 mg, 0.67 mmol), NaBH(OAc)3 (143 mg, 0.67 mmol) and glacial acetic acid (41 mg, 0.67 mmol) were added. The mixture was stirred at room temperature for 2.5 hours. The mixture was then filtered and the organic phase was extracted by shaking three times with HCl (1 N). The aqueous phase was brought to pH 8 with NaOH (2 N) and extracted by shaking three times with CH2Cl2. The organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified by preparative HPLC (as described under Example 14 in MeOH/H2O/Et2NH 80:20:0.1). MeOH was evaporated off from the product fraction, the aqueous phase was extracted by shaking three times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated. A colorless solid was isolated.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([NH:13][C@H:14]1[C@@:23](C(=O)C2C=CC=CC=2)([OH:24])[C@:22](C(=O)C2C=CC=CC=2)([OH:33])[C@@H:21]([CH2:42]O)[O:20][C@@H:15]1[O:16][CH2:17][CH:18]=[CH2:19])(=[O:12])[CH3:11]>COCCOCCOC.C[O-].[Na+].CO>[C:10]([NH:13][C@H:14]1[C@@H:23]([OH:24])[C@H:22]([OH:33])[C@@H:21]([CH2:42][F:7])[O:20][C@@H:15]1[O:16][CH2:17][CH:18]=[CH2:19])(=[O:12])[CH3:11]
Reactant: C=CCO[C@H]1O[C@H](CO)[C@](O)(C(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@@H]1NC(C)=O
Reactant: CCN(CC)S(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CO
Product: C=CCO[C@H]1O[C@H](CF)[C@@H](O)[C@H](O)[C@@H]1NC(C)=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a stirred solution of (diethylamino)sulfur trifluoride (0.5 mL) in dry diglyme (2mL) was added a solution of allyl 2-acetamido-3,4-di-benzoyl-2-deoxy-α-D-mannopyranoside, prepared as described above, (100 mg) in dry diglyme (3 mL) at room temperature, and the reaction mixture was stirred for one hour at room temperature and three hours at 40° C. After the starting material was consumed, the reaction mixture was poured onto ice-water and extracted with ethyl acetate. The extract was dried, concentrated, and the residue was applied to silica gel chromatography. After the impurity was eluted with hexane, the product was eluted with ether to give the fluorinated product in 89 percent yield. The product was then dissolved in 5 mL of 1N sodium methoxide in methanol to remove benzoyl group. After 20 minutes, Dowex 50W X-8[H+ ] was added to neutralize the reaction mixture. The resin was filtered and the filtrate was concentrated to give allyl 2-acetamido-2,6-dideoxy-6-fluoro-α-D-mannopyranoside in 99 percent yield. The product (50 mg), 1.2 equivalents of palladium (II) acetate, and 2.5 eq of sodium acetate in 95 percent acetic acid (5 mL) were stirred at 50° C. for 18 hours, and the solvent was removed under vacumn. The residue was applied to silica gel chromatography, eluted with ethyl acetate/methanol (2/1) to obtain 2-acetamido-2,6-di-deoxy-6-fluoro-α-D-mannopyranoside in 73 percent yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].BrC1C=NC([Cl:25])=C(C=1)C(O)=O.CN(C)C=O>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([Cl:25])=[O:8]
Reactant: CON(C)C(=O)c1cc(Br)cnc1Cl
Reactant: O=C(O)c1cc(Br)cnc1Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)cnc1Cl
Temperature: 80 °C

Procedure:
5-Bromo-2-chloro-N-methoxy-N-methylnicotinamide. To a mixture of 5-bromo-2-chloronicotinic acid (6 g, 25.5 mmol) in thionyl chloride (30 mL) was added a drop of N,N-dimethylformamide, and the reaction mixture was heated at 80° C. for 2 h. The mixture was cooled to room temperature, and concentrated to give crude 5-bromo-2-chloronicotinoyl chloride. A solution of O,N-dimethyl-hydroxylamine hydrochloride salt (3.45 g, 35.6 mmol) and triethylamine (7.48 g, 74.1 mmol) in dichloromethane (80 mL), and a solution of the above 5-bromo-2-chloronicotinoyl chloride in dichloromethane (20 mL) were added, and the reaction mixture was stirred overnight. The mixture was poured into water, and extracted with dichloromethane (50 mL×3). The combined organic layer was concentrated under reduced pressure, and purified on silica gel column (eluting with 5-10% ethyl acetate in petroleum ether) to give 5-bromo-2-chloro-N-methoxy-N-methylnicotinamide as a solid (6.2 g, 71.4% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.65 (s, 1H), 8.39 (s, 1H), 3.49 (s, 3H), 3.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([O:13]CC)=O)=[N:6][CH:7]=1.C(O)C.O.[NH2:21][NH2:22]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:13])[NH:21][N:22]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(Cl)cn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(Cl)cn2)=NN1
Yield: 81.1 %

Procedure:
To a dry 200 mL flask equipped with magnetic stirrer, and reflux condenser was charged 3.7 g ethyl 4-(5-chloropyridin-2-yl)-4-oxobutanoate (0.0153 mol), 75 mL ethanol, and 0.8 g of hydrazine hydrate (0.0168 mol). The reaction was heated at reflux for about 2 hours. An aliquot was analyzed by GC which indicated no remaining starting material, and one major product. The reaction was cooled and poured into about 200 mL of water to afford a tan solid which was collected by vacuum filtration, washed with water, hexane, and dried overnight in vacuo at 40° C. Isolated 2.6 g of a tan solid. The NMR data is as follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 2.65 (t, 2H); 3.22 (t, 2H), 7.75 (d, 1H); 8.00 (d, 1H); 8.60 (s, 1H); 8.70 (bs, 1H). The sample was stored in the refrigerator and had 81% isolated yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:27])[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][C:15]=3[N+:24]([O-:26])=[O:25])=[C:11]([C:28]([O:30]CC)=[O:29])[N:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:27])[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][C:15]=3[N+:24]([O-:26])=[O:25])=[C:11]([C:28]([OH:30])=[O:29])[N:10]=[N:9]2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(=O)c1ccc(OCOC)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCOc1ccc(C(=O)c2c(C(=O)O)nnn2Cc2ccc(OC)cc2)c([N+](=O)[O-])c1

Procedure:
In the same manner as above, a solution of ethyl 1-(4-methoxybenzyl)-5-(4-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylate (b-2) (3.16 g, 6.72 mmole) in tetrahydrofuran (50 ml) was hydrolyzed with a 1N aqueous sodium hydroxide solution (13 ml) at room temperature for 3 hours to give 1-(4-methoxybenzyl)-5-(4-methoxymethoxy-2-nitrobenzoyl)-1,2,3-triazole-4-carboxylic acid (c-2':MP) (2.22 g, 75%)
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH2:15].Cl>C(O)CCC>[I:20][C:18]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[S:3][C:4]3[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[C:13]([F:12])[CH:19]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: Nc1ccc(I)cc1F
Agent: Cl
Solvent: CCCCO
Product: Fc1cc(I)ccc1Nc1nc2ccc(Cl)cc2s1
Temperature: 90 °C
Yield: 37.8 %

Procedure:
A mixture of 2,6-dichlorobenzothiazole (1.0 g, 4.9 mmol) and 2-fluoro-4-iodoaniline (2.32 g, 9.8 mmol) in 20 mL BuOH was stirred at 90° C., and then HCl (4 M in dioxane, 1.0 mL) was added. The reaction mixture was stirred with heating at 90° C. overnight, under argon. NMR analysis then showed little 2,6-dichlorobenzothiazole remaining. After BuOH was removed by rotary evaporation, EtOAc (100 mL) and 1 N aqueous HCl (100 mL) were added. The organic layer was separated and washed with 1 N aqueous HCl (100 mL), saturated Na2O2S3 solution (50 mL), water (100 mL), and then dried over Na2SO4. Removal of solvent under reduced pressure afforded a residue, which was triturated with EtOAc (10 mL) and hexanes (40 mL). The solid was filtered and dried in vacuo to a constant weight, to afford the desired product as a light purple solid (0.75 g, 38%). 1H NMR (DMSO-d6) δ 10.45 (s, 1H), 8.35 (t, 1H), 7.95 (s, 1H), 7.70 (d, 1H), 7.58 (d, 2H), 7.30 (d, 1H).
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.N1C=CN=C1.[C:14]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[C:14]([Si:18]([O:8][CH:1]1[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1CCC=CCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CCC=CCC1)(c1ccccc1)c1ccccc1

Procedure:
A solution of the product of Example 8B (1.57 g, 14.05 mmoles), imidazole (1.43 g, 21.08 mmoles), and Tert-butyl-chlorodiphenylsilane (4.76 gm, 17.4 mmoles) in N,N-dimethylformamide (10 mL) was stirred for five hours at 23° C. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine (25 mL), dried with MgSO4, filtered, and solvent evaporated in vacuo. The crude product was purified by flash column chromatography (hexanes:ethyl acetate 100:0 to 90:10) to provide the title compound as an oil.
Reaction SMILES: [C:1]([S:9]/[CH:10]=[CH:11]\[C:12]([OH:14])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>ClCCl>[C:1]([S:9]/[CH:10]=[CH:11]\[C:12]([Cl:23])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C\SC(=O)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)/C=C\SC(=O)c1ccccc1
Yield: 98.5 %

Procedure:
To a mixture of 7.0 g (0.0336 mol) of cis-3-(benzoylthio)propenoic acid and 0.5 ml of N,N-dimethylformamide in 100 ml of dichloromethane under nitrogen was added 2.93 ml (0.0336 mol) of oxalyl chloride. After 12 h the solvents were removed to give 7.5 g (99% yield) of cis-3-(benzoylthio)propenoyl chloride as a pale yellow solid.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([NH2:22])=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>C(O)C>[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([N:22]3[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]3=[O:11])=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2ccc3c(c2)CCC3)C1=O
Yield: 71.7 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 2,3-dihydro-1H-inden-5-amine (0.593 g; 4.36 mmol) in ethanol (3 mL). 1-(2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidine-3-carboxylic acid 0.255 g (71%) was obtained as a white solid.
Reaction SMILES: [OH-].[Na+].C1(S([N:12]2[C:20]3[CH:19]=[CH:18][N:17]=[C:16]([C:21]4[N:22]=[C:23]([N:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)[C:24]5[N:29]=[C:28]([CH2:30][N:31]6[CH2:34][CH:33]([N:35]7[CH2:40][CH2:39][O:38][CH2:37][CH2:36]7)[CH2:32]6)[S:27][C:25]=5[N:26]=4)[C:15]=3[CH:14]=[CH:13]2)(=O)=O)C=CC=CC=1>O1CCOCC1>[O:44]1[CH2:45][CH2:46][N:41]([C:23]2[C:24]3[N:29]=[C:28]([CH2:30][N:31]4[CH2:34][CH:33]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)[CH2:32]4)[S:27][C:25]=3[N:26]=[C:21]([C:16]3[C:15]4[CH:14]=[CH:13][NH:12][C:20]=4[CH:19]=[CH:18][N:17]=3)[N:22]=2)[CH2:42][CH2:43]1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(-c3nc(N4CCOCC4)c4nc(CN5CC(N6CCOCC6)C5)sc4n3)nccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: c1cc2[nH]ccc2c(-c2nc(N3CCOCC3)c3nc(CN4CC(N5CCOCC5)C4)sc3n2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 38 %

Procedure:
A degassed solution of 7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-1-ylmethyl)-5-(tributylstannanyl)thiazolo[5,4-d]pyrimidine (200 mg, 0.30 mmol), 1-benzenesulfonyl-4-bromo-1H-pyrrolo[3,2-c]pyridine (132 mg, 0.39 mmol), PdCl2{PtBu2(Ph-p-Nme2)}2 (22 mg, 0.03 mmol) and copper(I) thiophene-2-carboxylate (12 mg, 0.06 mmol) in 1,4-dioxane (4 mL) was subjected to microwave irradiation at 140° C. for 20 minutes. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated to give 5-(1-benzenesulfonyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-1-ylmethyl)thioazolo[5,4-d]pyrimidine as a crude oil. Aqueous NaOH (12.5 M, 0.5 mL) was added to a solution of 5-(1-benzenesulfonyl-1H-pyrrolo[3,2-c]pyridin-4-yl)-7-morpholin-4-yl-2-(3-morpholin-4-yl-azetidin-1-ylmethyl)-thiazolo[5,4-d]pyrimidine in 1,4-dioxane (4 mL) and IMS (4 mL). The reaction mixture was stirred at ambient temperature for 45 min, then concentrated in vacuo. The residue was dissolved in MeOH then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated to afford a solid. The solid was purified by flash chromatography (Si—PPC, DCM:MeOH, 100:0 to 98:2 to 96:4) to afford 152 as a yellow solid (56 mg, 38%). LCMS (Method E): RT=4.34 min, M+H +=493.2. 1H NMR (CDCl3, 400 MHz) δ 8.72 (bs, 1 H), 8.56 (d, J=5.7 Hz, 1 H), 7.41 (m, 2 H), 7.36 (d, J=3.2 Hz, 1 H), 4.49-4.44 (m, 4 H), 4.02 (s, 2 H), 3.90 (t, J=4.7 Hz, 4 H), 3.74-3.65 (m, 6 H), 3.16-3.07 (m, 3 H), 2.35 (m, 4 H)
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[O:3][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:5]#[CH:6].[CH2:14]([SnH:18]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])/[CH:6]=[CH:5]/[CH:4]([O:3][Si:2]([CH3:12])([CH3:13])[CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(CCCCC)O[Si](C)(C)C
Product: CCCCCC(/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C

Procedure:
Under an argon atmosphere, 3-trimethylsilyloxy-1-octyne (47, 2.00 g, 10.08 mmol) and tributyltin hydride (2.70 mL, 10.18 mmol) were irradiated with a 275 W GE sunlamp, without solvent, for 4 h to produce 49: 1H NMR (CDCl3) δ 6.04 (d, J=18.9 Hz, 1H), 5.93 (dd, J1 =18.9 Hz, J2 =5.4 Hz, 1H), 4.04 (q, J1 =6.5 Hz, J2 =5.6 Hz, 1H), 1.52, 1.34 (2m, 26H), 0.91 (m, 12H), 0.11 (s, 9H). 1H NMR analysis revealed that 49 was only ca. 85% pure. Other isomers, presumed to be the cis-vinyl-stannane and the regioisomeric vinylstannane, could be clearly seen in the vinyl region of the NMR spectrum. The production of these impurities in this reaction has been previously described.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[C:14](=O)[C:8]1([CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)[CH2:7][CH2:6]2.C([SiH](CC)CC)C.[ClH:26]>FC(F)(F)C(O)=O.O>[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C:8]1([CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC1(CCCCN1)C2=O
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(c1)CCC1(CCCCN1)C2
Reaction time: 1 h

Procedure:
In 30 ml of trifluoroacetic acid was dissolved 6.57 g of 3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidin]-1-one followed by addition of 8.5 ml of triethylsilane and the mixture was stirred for 1 hour. This reaction mixture was poured portionwise in water. To this was added 1N-hydrochloric acid and the mixture was washed with hexane. The aqueous layer was made basic to 1N-aqueous sodium hydroxide and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate and filtered and the solvent was distilled off. The group was treated with 7.0 ml of 4N-methanolic hydrochloric acid to give a solid. This solid was recrystallized from methanol-ether to provide 5.09 g of white crystals.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(O[C:13](=O)[N:14]([C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:24][CH2:23]2)[CH:19]=[C:18]([C:38]([C:40]2[CH:50]=[C:49]([CH3:51])[C:43]3[N:44]([CH3:48])[C:45](=[O:47])[O:46][C:42]=3[CH:41]=2)=[O:39])[CH:17]=1)C)(C)(C)C>C(Cl)Cl>[CH3:48][N:44]1[C:43]2[C:49]([CH3:51])=[CH:50][C:40]([C:38]([C:18]3[CH:17]=[C:16]([NH:14][CH3:13])[N:21]=[C:20]([N:22]4[CH2:27][CH2:26][CH:25]([N:28]5[C:36]6[C:31](=[N:32][CH:33]=[CH:34][CH:35]=6)[NH:30][C:29]5=[O:37])[CH2:24][CH2:23]4)[CH:19]=3)=[O:39])=[CH:41][C:42]=2[O:46][C:45]1=[O:47]
Reactant: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)nc(N(C)C(=O)OC(C)(C)C)c2)cc2oc(=O)n(C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.00 mL TFA were added to 59 mg (0.096 mmol) tert-butyl[4′-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl]-methyl-carbamate in 5.00 mL DCM and the mixture was stirred for 3 h at RT. Then the reaction mixture was evaporated down, the residue was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.[I:19]I.O>C1COCC1>[I:19][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: II
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2cc(I)ccc2c1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (2.5 M in hexanes, 92 mL, 230 mmol) is added via dropping funnel to a solution of 2-bromo-6-methoxy-naphthalene (49.5 g, 209 mmol) in anhydrous THF (2 L) at −75° C. at such a rate that the temperature is kept below −70° C. (over 45 min). The resulting yellow solution is stirred for 15 min at −75° C. A solution of iodine (58.3 g, 230 mmol) in anhydrous THF (100 mL) is added via a fresh dropping funnel until the red iodine colour persists (addition over 45 min, max. temp. −68° C.). The mixture is warmed to rt. and water (1.3 L) is added. The mixture is extracted with dichloromethane (2 L) with brine (500 mL) being added to aid the separation. The aqueous fraction is back-extracted with dichloromethane (1 L). The combined organic fractions are reduced in vacuo to approx. 1 L, washed with saturated aqueous sodium metabisulphite (100 mL), then brine (200 mL), dried (Na2SO4), filtered and solvent removed in vacuo. The crude residue is recrystalised from IMS (1.9 l) washing with ice-cold IMS (2×150 mL) and dried in a vacuum oven at 70, ° C. to give a light cream crystalline solid. 46.45 g, 78%.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[C:3](=[N:6]\[OH:7])/[S:4][CH3:5].[CH3:10][N:11]=[C:12]=[O:13]>C(N(CC)CC)C>[F:1][C:2]([F:9])([F:8])/[C:3](=[N:6]\[O:7][C:12](=[O:13])[NH:11][CH3:10])/[S:4][CH3:5]
Reactant: CN=C=O
Reactant: CS/C(=N/O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CNC(=O)O/N=C(/SC)C(F)(F)F
Yield: 73.9 %

Procedure:
One drop of triethylamine was added to a mixture of 6.37 g (0.04 mol) of S-methyl (E)-2,2,2-trifluoro-N-hydroxythioacetimidate and 2.28 g (0.04 mol) of methyl isocyanate. An exothermic reaction ensued, and the reaction mixture was cooled in an ice-bath. The reaction mixture solidified on cooling. Recrystallization from ether gave 6.39 g (74% yield) of S-methyl (E)-2,2,2-trifluoro-N-(methylcarbamoyloxy)thioacetimidate as colorless crystals, mp. 83°-85°. Analysis of the isomer prepared in a similar procedure follows:
Reaction SMILES: [C:1]([C:5]#[CH:6])([CH3:4])([CH3:3])[CH3:2].Cl/[C:8](=[N:14]/[OH:15])/[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[Cl-].[Na+]>O1CCCC1>[C:1]([C:5]1[O:15][N:14]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC(C)(C)C
Reactant: CCOC(=O)/C(Cl)=N\O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
5.61 g of t-butylacetylene and 9.09 g of ethyl (2E)-chloro(hydroxyimino)acetate were dissolved in 70 ml of tetrahydrofuran, and 11.4 ml of triethylamine was then added dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature overnight. After aqueous saturated sodium chloride was added, the reaction mixture was separated into layers. The aqueous layer was extracted with methyl-t-butyl ether. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.83 g of ethyl 5-t-butyl-isoxazole-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10](=[O:23])[C:11]3[C:15]=2[C:14](=[O:16])[NH:13][C:12]=3[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH3:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:28][N:13]1[C:14](=[O:16])[C:15]2=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:9][C:10](=[O:23])[C:11]2=[C:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1NC(c2ccccc2)=C2C(=O)OC(c3ccc(Br)cc3)=C12
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C2=C(c3ccc(Br)cc3)OC(=O)C2=C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A mixture of furopyrrole 6 (1.5 g, 4.08 mmol), methyl tosylate (1.14 g, 6.12 mmol), potassium carbonate (1.13 g, 8.16 mmol) and dimethylformamide was stirred at room temperature overnight. Water was then added, and the organic component extracted with DCM. The solvent was removed, and washing with water then methanol gave the methylated compound 7 as a red solid (0.831 g, 53%), m.p. 215-216° C. δH (CDCl3) 8.19 and 7.61 (each 2H, AA′BB′, p-C6H4Br), 7.78-7.73 (2H, m, o-Ph), 7.54-7.50 (3H, m, m/p-Ph) and 3.38 (3H, s, NCH3). λmax (abs) (DCM)/nm 454 (ε 15,878)
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.[C:23](=[S:38])(OC1C=CC=CN=1)OC1C=CC=CN=1>C(Cl)Cl>[N:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:10]2[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:21][CH:20]=1)=[C:23]=[S:38]
Reactant: CSc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClCCl
Product: CSc1nccc(-c2cccnc2Oc2ccc(N=C=S)cc2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A dry 100 ml round bottom flask, under nitrogen, was charged with 4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy) benzenamine (1.72 g, 5.54 mmol), O,O-dipyridin-2-yl carbonothioate (1.35 g, 5.82 mmol), and DCM (37 ml, 0.15 M). The vessel was closed, kept under nitrogen, and mixture stirred at RT for 18 h. The reaction was diluted with 20 ml DCM and washed with water. The organic layer was collected, dried with Na2SO4, filtered, and concentrated to give 4-(2-(4-isothiocyanatophenoxy)pyridin-3-yl)-2-(methylthio)pyrimidine as a yellow solid. MS m/z=353.0 [M+H]+. Calc'd for C17H12N4OS2: 352.43.