Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].F[B-](F)(F)F.[F:10][S:11]([F:23])([F:22])([F:21])([F:20])[C:12]1[CH:17]=[CH:16][C:15]([N+]#N)=[CH:14][CH:13]=1>CC#N>[F:10][S:11]([F:20])([F:21])([F:22])([F:23])[C:12]1[CH:13]=[CH:14][C:15]([S:1][C:2]#[N:3])=[CH:16][CH:17]=1
Reactant: N#C[S-]
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: F[B-](F)(F)F
Agent: [NH4+]
Solvent: CC#N
Product: N#CSc1ccc(S(F)(F)(F)(F)F)cc1

Procedure:
A solution of ammonium thiocyanate (7.3 mg, 0.096 mmol) and 1 (10.1 mg, 0.0318 mmol) in 0.29 g of MeCN was heated at 70° C. for 0.5 h. After cooling, the mixture was filtered through SiO2 with CH2Cl2 and the solvent was evaporated to give a pale yellow oil, whose purification by SiO2 column chromatography with 9:1 hexane/CH2Cl2 furnished pure 25c as colorless crystals (2.6 mg, 31%); m.p. 67.2-68.2° C. IR (ATR): {tilde over (v)}=3103, 2162, 1585, 1479, 1402, 1105, 1082, 837 cm-1. MS (GC, EI): m/z=261 [M+], 242 [M+-F], 153, 133. 1H NMR (500 MHz, CDCl3): δ=7.84 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ=154.0 (C), 129.6 (C), 128.7 (2CH), 127.8 (2CH), 108.6 (C) ppm. 19F NMR (470 MHz, CDCl3): δ=82.5 (quint, J=151 Hz, 1 F), 62.9 (d, J=151 Hz, 4 F) ppm.
Reaction SMILES: [CH2:1]([N:3]1[C:16]2[CH:15]=[CH:14][C:13]([CH:17]=O)=[CH:12][C:11]=2[S:10][C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[C:19]1([NH:25][N:26]=[CH:17][C:13]2[CH:14]=[CH:15][C:16]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([S:10][C:11]=3[CH:12]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNc1ccccc1
Reactant: CCN1c2ccccc2Sc2cc(C=O)ccc21
Solvent: CO
Product: CCN1c2ccccc2Sc2cc(C=NNc3ccccc3)ccc21

Procedure:
10-Ethylphenothiazine-3-carbaldehyde (3 g, 0.012 mol) was dissolved in 30 ml of methanol under mild heating. A solution of 1.9 g (0.018 mol) of N-phenylhydrazine in methanol was added to the cooled reaction mixture. Next, the reaction mixture was refluxed for 0.5 hour. The precipitated product was filtered, washed with a large amount of methanol, and then dried. The yield of yellowish crystals of 10-ethylphenothiazine-3-carbaldehyde N-phenylhydrazone (C21H19N3S, FW=345.00) was 3 g (75%).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([S:12](=[O:39])(=[O:38])[NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]=[C:24]3[C:27]3([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH2:30][CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+].O>C(O)C>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:27]2([C:24]3[C:25]4[C:20](=[CH:19][CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:13][S:12]([N:9]5[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]5)(=[O:38])=[O:39])[CH:26]=4)[CH2:21][CH2:22][N:23]=3)[CH2:30][CH2:29][CH2:28]2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)N1CCN(S(=O)(=O)NCCOc2ccc3c(c2)C(C2(c4ccc(Cl)cc4)CCC2)=NCC3)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=S(=O)(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2)N1CCNCC1
Yield: 100 %

Procedure:
4-(2-{1-[1-(4-Chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-yloxy}-ethylsulfamoyl)-piperazine-1-carboxylic acid ethyl ester (450 mg, 0.782 mmol, example 54, procedure 1) and a 10% solution of potassium hydroxid in ethanol (20 ml) were heated under reflux for 15 h. The solvent was reduced and water was added to the residue. The mixture was extracted with dichloromethane. The combined organic layers were washed with sodium chloride, dried with potassium sulphate and evaporated. The residue was purified by column chromatography with silica gel using dichloromethane/methanol 3%->5% as the eluent to give the desired product as a yellow oil (394 mg, 0.782 mmol, 61%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1.[Cl-].[Li+].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].C1(C)C=CC=CC=1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1)[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc2nonc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1ccc2nonc2c1
Temperature: 110 °C

Procedure:
To a 250 mL flask charged with 5-Bromo-2,1,3-benzoxadiazole (5.0 g, 25 mmol), Palladium Tetrakis (0.87 g, 0.75 mmol), and lithium chloride (2.1 g, 50 mmol) was added Allyl Tri-n-butyltin (10 g, 30 mmol) and toluene (100 mL). The mixture was attached to a reflux condenser, sealed and purged with nitrogen. The reaction was heated to 110° C. for 2 hours. TLC showed good and complete reaction. The reaction was diluted with EtOAc, washed with brine, concentrated and purified by silica gel chromatography.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.[OH-:30].[Na+].OO>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:30])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(CCO)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
To a stirred solution of the obtained methyl 2-benzyloxy-5-vinylbenzoate (1.52 g) in tetrahydrofuran (15 ml) was added dropwise a solution of 9-borabicyclo[3.3.1]nonane (726 mg) in tetrahydrofuran (15 ml) at −20° C., and the mixture was stirred for 17.5 hours at room temperature. After the reaction mixture was cooled to 0° C., 2N aqueous sodium hydroxide solution (8.5 ml) and 30% aqueous hydrogen peroxide solution (6.8 ml) were added to the mixture, and the resulting mixture was stirred for 3 hours at room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2) gave methyl 2-benzyloxy-5-(2-hydroxyethyl)benzoate (1.30 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C@H:8]([CH3:11])[CH2:9][OH:10].C(N(CC)C(C)C)(C)C.[S:21](Cl)(Cl)=[O:22]>ClCCl>[CH3:11][CH:8]1[CH2:9][O:10][S@@:21](=[O:22])[N:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: C[C@H](CO)Nc1ccccn1
Reactant: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CO[S@@](=O)N1c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A solution of (R)-N-(2-pyridyl)-2-aminopropanol (20.0 g, 0.13 moles) and N,N-diisopropylethylamine (33.6 g, 0.13 moles) in dichloromethane (500 ml) was cooled to 5° C. Then thionyl chloride (15.5 g, 0.13 moles) in dichloromethane (100 ml) was added slowly whilst the temperature was kept below 10° C. The mixture was stirred for 0.5 h. and ice cold water (500 ml) was added. The organic phase was separated and washed with water (5×500 ml). The aqueous phase was back-extracted with dichloromethane (2×500 ml), the organic phases were combined, dried (MgSO4) and evaporated in vacuo to give a brown oil. This was purified on a silica column, eluting with diethyl ether to give (R)4-methyl-3-(2-pyridyl)-[1,2,3]oxathiazolidine 2-oxide (15.4 g) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C@@H:23]3[C@@H:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][C:26]4([CH2:28][CH2:27]4)[CH2:25][NH:24]3)=[O:22])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(OCC)(=O)C>[CH3:40][N:24]1[C@H:23]([C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)=[O:22])[C@@H:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][C:26]2([CH2:27][CH2:28]2)[CH2:25]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc(COc2ccc(NC(=O)[C@H]3NCC4(CC4)C[C@@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)OC(C)(C)C)CC4(CC4)CN3C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of tert-butyl (6S,7S)-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate (140 mg, 0.27 mmol) in methanol (3.0 mL) was added formaldehyde (37% solution in water, 0.5 mL) and sodium triacetoxyborohydride (0.25 g, 1.2 mmol). The mixture was then stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate, washed with saturated NaHCO3, water and brine. Dried and concentrated. tert-butyl (6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate (105.0 mg) was obtained by column using CH2Cl2/Methanol (10%). ESI (M+H)+ 516.5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:12][CH2:11][C:10](=[O:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7]2)[CH2:3][CH2:2]1.[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)#[N:19]>C1COCC1>[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:1]2[CH2:6][CH2:5][C:4]3([CH2:12][CH2:11][C:10](=[O:13])[C:9]4[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=4[NH:7]3)[CH2:3][CH2:2]2)=[CH:22][CH:21]=1)#[N:19]
Reactant: O=C1CCC2(CCNCC2)Nc2ccccc21
Reactant: N#Cc1ccc(CBr)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CN2CCC3(CCC(=O)c4ccccc4N3)CC2)cc1
Reaction time: 12 h
Yield: 63.6 %

Procedure:
A solution of diamine 11 (5 mg, 0.022 mmol) in anhydrous THF and 4-cyanobenzyl bromide (5 mg, 0.026 mmol) was agitated at room temperature for 16 h, and piperidinomethyl polystyrene N-2-(mercaptoethyl)aminoethyl polystyrene (26 mg, 0.033 mmol) was then added. The reaction was agitated for another 12 h and then filtered. The filtrate was concentrated to yield 24 (5 mg, 0.014 mmol, 66%) as an oil. LRMS: M+=345.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[O:5]([C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=1[NH2:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(N(CC)CC)C.O1CCOCC1>[O:5]([C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=1[NH:14][C:3]([NH:2][CH3:1])=[O:4])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN=C=O
Reactant: Nc1cc(Cl)c(Cl)cc1Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CNC(=O)Nc1cc(Cl)c(Cl)cc1Oc1ccccc1
Reaction time: 15 h

Procedure:
2.0 gm (35 mmols) of methylisocyanate and two drops of triethylamine are added to a solution of 6.35 gm (25 mmols) of 2-phenoxy-4,5-dichloroaniline in 50 ml of anhydrous dioxan. The resulting solution is kept at 50°-60° C. for 15 hours. Then about 40 ml of dioxan are distilled off in vacuo and the residue is stirred with 50 ml of petrol. After cooling to 5°-10° C. for one hour, the crystalline product is suction filtered, washed with 20 ml of petrol and dried.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][NH:12]2)=[C:8]([NH2:15])[N:7]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[CH2:27][P:28]([CH3:33])(=[O:32])[O:29][CH2:30][CH3:31]>CN(C=O)C>[NH2:15][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[CH2:23][C:24]1[CH:25]=[C:26]([CH2:27][P:28]([CH3:33])(=[O:32])[O:29][CH2:30][CH3:31])[CH:34]=[CH:35][CH:36]=1
Reactant: CCOP(C)(=O)Cc1cccc(CBr)c1
Reactant: CCCCNc1nc(N)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2ncn(Cc3cccc(CP(C)(=O)OCC)c3)c2n1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A mixture of 64 (300.0 mg, 1.45 mmol) and K2CO3 (200.0 mg, 1.45 mmol) was dissolved in DMF (5 mL) and to it was added 65 (420.0 mg, 1.45 mmol). The mixture was left to stir over night at room temperature, solvent was evaporated by rotary evaporation. The remaining solid was taken up in water and the product extracted with DCM (3×50 mL). Combined organic layers were washed with water (1×50 mL) and brine (2×50 mL) and dried over Na2SO4. Product was purified by flash column eluting 0-20% methanol in ethyl acetate to give 299.4 mg (50%) 66 as a solid. 1H NMR (300 MHz, CDCl3) δ 0.818 (t, 3H), 1.15 (t, 3H), 1.24 (d, 3H), 1.27 (m, 2H), 1.43 (m, 2H), 2.99 (d, 2H), 3.28 (m, 2H), 3.87 (m, 2H), 4.01 (m, 2H), 5.09 (s, 2H), 7.11 (m, 4H), 7.36 (s, 1H). LCMS: m/z for C20H29N6O2P++H observed 417.3 at 1.76 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:34]([F:35])=[CH:33][C:28]([O:29][CH2:30][CH2:31][OH:32])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(NC(C)C)(C)C>C(Cl)Cl>[CH3:39][S:40]([O:32][CH2:31][CH2:30][O:29][C:28]1[CH:27]=[C:26]([F:36])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:37][CH3:38])[CH:4]=3)([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[C:34]([F:35])[CH:33]=1)(=[O:42])=[O:41]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCOS(C)(=O)=O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.7 %

Procedure:
To 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethanol (270 mg, 0.48 mmol, 1.0 eq) in DCM (2.5 mL) was added methanesulfonyl chloride (0.1 mL, 1.44 mmol, 3.0 eq), followed by diisopropylamine (0.25 mL, 1.44 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 45 min at which time LCMS showed complete consumption of starting material. Aqueous work up (EtOAc and water) followed by purification (column chromatography, 0 to 80% EtOAc/Hex) provided 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethyl methanesulfonate (230 mg, 75%) as a white foam. MS (EI) m/z 462 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH2:5]O.S(Cl)([Cl:13])=O>C(Cl)Cl>[Cl:13][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[C:8]([CH3:10])[CH:7]=1)[NH2:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(N)cc(CO)c1
Solvent: ClCCl
Product: Cc1cc(N)cc(CCl)c1
Yield: 142.6 %

Procedure:
To a stirred solution of 3-amino-5-methyl-benzyl alcohol (6.32 g; 42.8 mmol; GL Syntech LLC, Hatfield, Pa.) in DCM (140 mL) at 0° C. was added dropwise thionylchloride (9.4 mL; 128 mmol). The mixture was allowed to react at room temperature overnight. Then, the mixture was concentrated under reduced pressure. The resulting material was dissolved in DCM again and evaporated to dryness to give crude 3-(chloromethyl)-5-methylaniline (9.5 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH2:12][C:13]([O:15]CC)=O)=[CH:4][CH:3]=1>CC(O)=O.CCOC(C)=O.[Fe]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:12][C:13](=[O:15])[NH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1COc2ccc(Br)nc2N1
Temperature: 90 °C

Procedure:
Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90° C. for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52%); MS (ES) m/z 229.0 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:40][C:41]1[C:42](=[O:49])[N:43]([CH3:48])[CH:44]=[C:45]([Br:47])[CH:46]=1>C(Cl)Cl>[Br:47][C:45]1[CH:46]=[C:41]([NH:40][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:6])[C:42](=[O:49])[N:43]([CH3:48])[CH:44]=1
Reactant: O=C(O)C1CC1
Reactant: Cn1cc(Br)cc(N)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(Br)cc(NC(=O)C2CC2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
To a mixture of cyclopropanecarboxylic acid (180 mg, 2.0 mmol), HATU (570 mg, 1.5 mmol) and DIPEA (390 mg, 3.0 mmol) in DCM (8 mL) was added 3-amino-5-bromo-1-methylpyridin-2(1H)-one (230 mg, 1.12 mmol). The reaction mixture was stirred at 25° C. for 5 hours. The resulting mixture was evaporated under reduced pressure and the residue was purified on a silica-gel column chromatography eluting with 20:1 DCM/methanol to afford the 102a (220 mg, 72%). MS-ESI: [M+H]+ 270.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.Br[CH2:25][CH:26]1[CH2:31][CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28][CH2:27]1.COC1C=CC(C2NC(C(N)=O)=C(C3C=CC(OC)=CC=3)N=2)=CC=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(O)cc1
Reactant: O=C(OCc1ccccc1)N1CCC(CBr)CC1
Agent: [Pd]
Agent: COc1ccc(-c2nc(-c3ccc(OC)cc3)c(C(N)=O)[nH]2)cc1
Solvent: CO
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCC2CCNCC2)cc1

Procedure:
The title compound was prepared by alkylation of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide with benzyl 4-(bromomethyl)piperidine-1-carboxylate according to the procedure described in example S-1, step b, followed by subsequent deprotection using the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1 ml/min, 20° C., 0.05M in MeOH). NMR (DMSO) δ 1.30-1.50 (2H, m), 1.85 (2H, d), 1.90-2.10 (1H, m), 2.71-2.81 (2H, m), 3.21 (2H, d), 3.92 (2H, d), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.21-8.30 (2H, m). LCMS (2) 3.13 min; m/z (ES+) 414.
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:22]([OH:25])[C:23]#[CH:24].CC(O[K])=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:25][CH2:22][C:23]#[C:24][C:2]1[C:3]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=S(=O)(Nc1nccnc1Cl)c1ccccc1C(F)(F)F
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)O[K]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccnc1C#CCO)c1ccccc1C(F)(F)F
Temperature: 100 °C
Yield: 48 %

Procedure:
N-(3-chloropyrazin-2-yl)-2-(trifluoromethyl)benzenesulfonamide (1.35 g; 4.0 mmol; 1.00 eq.) and 2-propyn-1-ol (336 mg; 6.0 mmol; 1.5 eq.) were dissolved in 10 mL of DMF under nitrogen atmosphere. To the reaction mixture was added CH3COOK (588 mg; 6.0 mmol; 1.5 eq.) and Pd(PPh3)4 (232 mg; 0.2 mmol) under nitrogen. The reaction mixture was then heated at 100° C. under nitrogen for 2 hours. After removal of the solvent by distillation in vacuo, the residue was triturated with water (40 mL) and extracted with diethyl ether (3×30 mL). The organic layer was dried over MgSO4 and evaporated down. The crude product was purified by silica gel column chromatography using a mixture of hexane and AcOEt to give pure N-[3-(3-hydroxyprop-1-yn-1-yl)pyrazin-2-yl]-2-(trifluoromethyl)benzenesulfonamide as a yellowish solid (686 mg, 48% yield, 98% HPLC purity).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1([C:6]2[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=2)[CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[NH:5][NH:4]1.O.NN.FC(F)(F)C1(C2C=C(CN)C=CC=2)N=N1>C(O)C>[F:25][C:2]([F:1])([F:24])[C:3]1([C:6]2[CH:7]=[C:8]([CH2:9][NH2:10])[CH:21]=[CH:22][CH:23]=2)[NH:4][NH:5]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(C2(C(F)(F)F)NN2)c1
Agent: NCc1cccc(C2(C(F)(F)F)N=N2)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cccc(C2(C(F)(F)F)NN2)c1
Reaction time: 3.5 h
Yield: 53.5 %

Procedure:
A stirred solution of intermediate 65, 2-[3-(3-trifluoromethyl-diaziridin-3-yl)-benzyl]-isoindole-1,3-dione, (150 mg, 0.43 mmol) in ethanol (2 mL) was treated with hydrazine hydrate (0.4 mL) at room temperature and the solution stirred for 3.5 hrs. After removing ethanol in vacuo, the residue was partitioned between CH2Cl2 and water. The aqueous phase was acidified with dilute HCl, and washed with CH2Cl2. The aqueous phase was basified with dilute NaOH, and extracted with CH2Cl2. The organic extract was dried (MgSO4), filtered, and concentrated to obtain 50 mg (Yield 54%) of (3-(3-(trifluoromethyl)diaziridin-3-yl)phenyl)methanamine and (3-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)methanamine as a 1:1 mixture; 1H NMR (300 MHz, CDCl3) δ ppm: 3.85 (2H, s) 3.88 (2H, s) 7.08 (2H, s) 7.31–7.40 (4H, m) 7.43–7.50 (1H, m, J=6.2 Hz) 7.54 (1H, s); LC/MS m/z 216 (M+H for diazirine) and 218 (M+H for diaziridine).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22].C([N+](CCCC)(CCCC)CCCC)CCC>CC(C)CC(=O)C>[Cl:3][C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:19][CH2:20][CH2:21][Cl:22])[C:6]=2[CH:5]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Reactant: ClCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)CC(C)C
Product: ClCCCN1c2ccccc2Sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
40 ml of a sodium hydroxide solution (50% by weight) are added to a solution of 2.34 g (10 mmol) of 2-chloropheno-thiazine, 4.73 g (30 mmol) of 1-bromo-3-chloropropane and 0.34 g (1 mmol) of tetrabutylammonium hydrogenosulfate in 40 ml of 4-methylpentan-2-one. The mixture is stirred at ambient temperature for 48 hours. After customary treatment of the organic phase, drying over sodium sulfate, evaporation of the solvent and purification by chromatography on silica gel, 2.17 g of pure product are obtained (eluant: petroleum ether).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[CH:3]=1.IC.[C:17](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:17])[CH:5]=[C:4]([C:9]([NH:11][CH2:12][CH2:13][OH:14])=[O:10])[CH:3]=1
Reactant: O=C(NCCO)c1c[nH]c(=O)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: Cn1cc(C(=O)NCCO)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-N-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (400 mg, 1.532 mmol), iodomethane (0.114 mL, 1.839 mmol), and potassium carbonate (212 mg, 1.532 mmol) in DMSO (5 mL) was stirred at room temperature overnight. The reaction mixture was subsequently filtered and purified via preparative HPLC, eluting with a gradient of 1-30% ACN in H2O (containing 10 mM NH4HCO3) to give the title compound.