Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[S:20](N)([NH2:23])(=[O:22])=[O:21]>O1CCOCC1>[N:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:20]([NH2:23])(=[O:22])=[O:21])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: NS(N)(=O)=O
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Solvent: C1COCCO1
Product: NS(=O)(=O)Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 16.8 %

Procedure:
A solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (0.50 g) and sulphamide (1.90 g) in dioxan (30 ml) was heated under reflux for 1 hour and then evaporated. The residue was triturated with water and the mixture was filtered. The solid was crystallised from a mixture of N,N-dimethylformamide and water to give the title compound (0.11 g), m.p. 216°-219° C. Found: C,54.03; H,5.59; N,20.68. C15H19N5O2S requires: C,54.05; H,5.75; N,21.01%.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH2:24]([N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:21])[CH2:19][CH3:20])[CH3:25]
Reactant: CCI
Reactant: CCC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)N(CC)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 6.1 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]propanamide in 200 ml of dry dimethylformamide under argon, was added 1.1 g of sodium hydride (50% in oil). The mixture was stirred for one hour, then 1.86 ml of ethyl iodide was added. This mixture was stirred overnight and then treated as described in Example 1. The chromatography fractions containing the product were combined and the solid recrystallized as described in Example 1, giving 4.37 g of the desired product, mp 145°-148° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:12])[CH3:11])[N:5]=1)(=[O:3])C.[BH4-].[Na+].[CH:15](O)(C)C>>[CH3:15][C:10]([CH3:11])([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][OH:3])[N:5]=1)[OH:12]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: CC(C)O
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(O)c1cccc(CO)n1

Procedure:
A 250 mL three-necked round bottom flask fitted with magnetic stirrer and nitrogen inlet was charged with 5.0 g (30.6 mmol) of 2,6-diacetylpyridine and 60 mL of anhydrous isopropyl alcohol. To the stirred solution was added 1.16 g (3.06 mmol) of sodium borohydride in three equal portions. The initially colorless solution became yellow and warmed then slowly returned to pale yellow.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:18])[CH2:10][N:9]([CH2:11][CH2:12][N+:13]([CH3:16])([CH3:15])[CH3:14])[C:8](=[O:17])[NH:7]1.C(O[Cl:24])(C)(C)C>CO>[C:1]([O-:4])(=[O:3])[CH3:2].[Cl:24][N:7]1[C:6]([CH3:18])([CH3:5])[CH2:10][N:9]([CH2:11][CH2:12][N+:13]([CH3:16])([CH3:15])[CH3:14])[C:8]1=[O:17]
Reactant: CC(C)(C)OCl
Reactant: CC1(C)CN(CC[N+](C)(C)C)C(=O)N1
Agent: CC(=O)[O-]
Solvent: CO
Product: CC1(C)CN(CC[N+](C)(C)C)C(=O)N1Cl
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
A solution of 2-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-N,N,N-trimethylethanaminium acetate (0.428 mmol) in MeOH (2 ml) was cooled to 0° C. tert-Butylhypochlorite (100 ul, 0.84 mmol) was added, causing a white precipitate to form. The solution was stirred for 15 min, and another portion of tert-butylhypochlorite (100 ul, 0.84 mmol) was added. The solution was stirred for an additional 15 min, then concentrated in vacuo. The residue was purified by RP-HPLC (H2O/CH3CN) to afford the title compound as a white powder (74.7 mg, 0.276 mmol, 65%). 1H NMR (D2O, 400 MHz) δ 1.24 (s, 6H), 1.85 (s, 3H), 3.11 (s, 9H), 3.37 (s, 2H), 3.50 (m, 2H), 3.68 (m, 2H). 13C NMR (D2O, 100 MHz) δ 22.32, 27.01, 39.24, 55.38, 57.82, 62.40, 161.31, 180.46. ESI/APCI (pos) expected for C10H21ClN3O+: 234.14. Found: 234.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH2:19][OH:20])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:30][C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:30][C:31]([O:20][CH2:19][C@H:10]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:33]
Reactant: OC[C@@H](COCc1ccccc1)OCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)OC[C@@H](COCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 200 %

Procedure:
A mixture consisting of 0.50 ml (1.98 mmol) of (S)-(−)-1,2-dibenzylglycerol and 0.69 ml (3.96 mmol) of N,N-diisopropylethylamine was dissolved in 5 ml of dichloromethane. The obtained solution was added dropwise to 5 ml of a dichloromethane solution containing 294 mg (0.99 mmol) of triphosgene under cooling on ice. The obtained mixture was stirred at a room temperature for 30 minutes. Thereafter, the reaction solution was concentrated, and the concentrate was then dissolved in 5 ml of dichloromethane, so as to obtain a dichloromethane solution of (R)-2,3-bis-benzyloxy-propyl chloroformate (1.98 mmol/5 ml).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[SH:10].[CH2:11]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[F:8][C:7]1[C:2]2[N:1]=[C:21]([C:20]3[CH:23]=[CH:24][C:17]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=3)[S:10][C:3]=2[CH:4]=[CH:5][C:6]=1[F:9]
Reactant: Nc1c(S)ccc(F)c1F
Reactant: CCCCCCc1ccc(C=O)cc1
Product: CCCCCCc1ccc(-c2nc3c(F)c(F)ccc3s2)cc1

Procedure:
2-Amino-3,4-difluorothiophenol [131105-92-5] is reacted analogously to Reference 1 with 4-hexylbenzaldehyde (commercially available, [49763-69-1]) to give 4,5-difluoro-2-(4-hexylphenyl)benzothiazoline, which is converted into 4,5-difluoro-2-(4-hexylphenyl)benzothiazole using barium permanganate by the method described in the cited literature. a-Lithiation (by means of lithium diisopropylamide analogously to J. Chem. Soc. Perkin Trans. II 1989, 2048) and quenching with hexyl bromide gives the target compound, which can be purified by chromatography and by recrystallization from acetonitrile.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][N:19]1[CH2:36][C:37](O)=[O:38].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:11]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH3:10])[CH2:8][NH:9][C:37](=[O:38])[CH2:36][N:19]2[CH2:20][CH2:21][CH2:22][C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]2=[O:17])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(CN)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(CNC(=O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2-diphenylpropan-1-amine (0.10 g, 0.5 mmol) in dichloromethane (10 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.16 g, 0.50 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.19 g, 1.00 mmol) and N,N-dimethylpyridin-4-amine (6 mg, 0.05 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:3) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.05-7.35 (m, 20H), 6.0-6.1 (m, 1H), 3.98 (s, 2H), 3.95 (s, 2H), 3.2-3.4 (m, 2H), 2.4-2.5 (m, 2H), 1.65-1.75 (m, 2H), 1.5 (s, 3H); MS (ESI+) m/z 503 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]3[CH2:12][CH:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]([NH:13][NH2:14])=[N:4][N:3]=1.[C:15](O)(=O)[CH3:16]>>[Cl:1][C:2]1[C:11]2[CH:10]3[CH2:12][CH:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]2=[N:13][N:14]=[C:15]([CH3:16])[N:4]2[N:3]=1
Reactant: CC(=O)O
Reactant: NNc1nnc(Cl)c2c1C1CCC2C1
Product: Cc1nnc2c3c(c(Cl)nn12)C1CCC3C1
Yield: 84 %

Procedure:
In a procedure similar to that of Example 5, 1-chloro-4-hydrazino-5,6,7,8-tetrahydro-5,8-methanophthalazine (25.0 grams, 0.119 mol) was mixed with 150 milliliters of acetic acid, and the mixture was heated at the boiling temperature under reflux for two hours. The reaction mixture was concentrated and the residue taken up in aqueous sodium bicarbonate. The resulting precipitate was collected, washed with water and air-dried to yield 23.4 grams (84 percent yield) of 6-chloro-7,8,9,10-tetrahydro-3-methyl-7,10-methano(1,2,4)triazolo[3,4-a]phthalazine. After recrystallization from benzene-hexane this product melted at 137°-138° C. Infrared spectroscopy and elemental analysis were consistent with the named structure.
Reaction SMILES: O[C:2]1[C:3]2[S:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.P(Cl)(Cl)([Cl:15])=O.CN(C)C1C=CC=CC=1>C(#N)C>[Cl:15][C:2]1[C:3]2[S:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(O)c2sccc2n1
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CSc1nc(Cl)c2sccc2n1
Yield: 90.5 %

Procedure:
4-Hydroxy-2-methylthiothiopheno[3,2-d ]pyrimidine (15.4 g, 78 mmol) was combined with 50 mL of dry acetonitrile and 29 mL (312 mmol) of phosphoryl chloride and 10 mL (78 mmol) of N,N-dimethylaniline were added with stirring. The mixture was heated to reflux with stirring for 2 hours. It was then allowed to cool and most of the acetonitrile was removed by evaporation under reduced pressure. The residue was poured slowly into 200 mL of cold water with cooling and agitation. The resulting mixture was extracted with 4×500 mL of ether and the combined ethereal extracts were dried over magnesium sulfate and concentrated by evaporation under reduced pressure. The 15.3 g of tan solid title compound obtained melted at 115°-118° C. and had a proton NMR spectrum consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH3:20])[OH:4].Br[CH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=1.[H-].[Na+].O>CN(C)C=O>[F:33][C:27]1[CH:26]=[C:25]([CH2:24][O:4][CH:3]([C:5]2[S:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH3:20])[C:2]([F:1])([F:21])[F:22])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(F)(F)F
Reactant: N#Cc1ccc(CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(OCc1ccc(C#N)c(F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
1.30 g 2,2,2-Trifluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol and 815 mg 4-Bromomethyl-2-fluoro-benzonitrile were dissolved in 40 ml dimethylformamide. 192 mg sodium hydride were added and the mixture stirred at room temperature for one hour. Then 15 ml water were added and the mixture extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed in vacuo. The residue was purified by reversed phase HPLC to obtain 840 mg 2-Fluoro-4-{2,2,2-trifluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxymethyl}-benzonitrile as an oil.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH2:10][OH:11].[CH2:12](Br)[CH2:13][CH2:14][CH3:15]>C(O)C>[CH2:12]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH2:10][OH:11])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCBr
Reactant: OCCC1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN1CCCCC1CCO
Yield: 5.9 %

Procedure:
A! A solution of 1N sodium hydroxide (156 ml, 0.156 mole) was added to a mixture of 2-piperidine-ethanol (20 ml, 0.156 mole) and butyl bromide (21 ml, 0.187 mole) in ethanol (200 ml). The reaction mixture was refluxed for 4 hours, then the solvent was evaporated under vacuum. The aqueous solution was acidified with HCl and washed with ethyl ether, then it was treated with a 32% solution of sodium hydroxide until pH-12 and extracted with ethyl ether. The combined organic phases were anhydrified over sodium sulfate and the solvent was evaporated under vacuum. The resulting crude was purified by distillation yielding 1.7 g of N-butyl-2-piperidine-ethanol (b.p.: 88°-99° C./0mmHg) (yield: 40%).
Reaction SMILES: C([O-])(=O)C.[NH4+].[F:6][C:7]1[CH:8]=[C:9]([C:17]2[C:25]3[CH2:24][CH2:23][C:22](=O)[C:21]=3[CH:20]=[N:19][CH:18]=2)[CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14].C([BH3-])#[N:28].[Na+]>CO.C(O)C>[F:6][C:7]1[CH:8]=[C:9]([C:17]2[C:25]3[CH2:24][CH2:23][CH:22]([NH2:28])[C:21]=3[CH:20]=[N:19][CH:18]=2)[CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14]
Reactant: O=C1CCc2c1cncc2-c1ccc(C(F)(F)F)c(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: NC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ammonium acetate (117 mg, 1.52 mmol) in MeOH (1 mL) was treated with 4-(3-fluoro-4-trifluoromethyl-phenyl)-5,6-dihydro-[2]pyrindin-7-one (intermediate A-14 [C1]) (15 mg, 0.051 mmol) dissolved in ethanol (0.5 mL) and the reaction mixture stirred at room temperature for 1 h. Sodium cyanoborohydride (11.2 mg, 0.18 mmol) was added and stirring continued at room temperature. After 15 min, the reaction mixture was heated to reflux for 30 min. The solvent was removed under reduced pressure, a sat. aq. solution of ammonium chloride (2 mL) and a 1 M solution of HCl (1 mL) were added and the aq. phase washed with dichloromethane (3×5 mL). To the aq. phase was added a 1 M solution of NaOH (2 mL) and extracted with dichloromethane (3×5 mL). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The title compound was isolated as light brown solid (3.8 mg, 25%). MS: 297.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([P:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][CH:12]=2)OCC[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:2]([C:7]1[CH:8]=[C:9]([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:3])[CH3:1]
Reactant: CC1(c2cccc(P(c3ccccc3)c3ccccc3)c2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cccc(P(c2ccccc2)c2ccccc2)c1
Yield: 70 %

Procedure:
25.7 g (73.9 mmol) of [3-(2-methyl-1,3-dioxolane-2-yl)phenyl]diphenylphosphane are dissolved under cover gas in 240 mL of a THF/water mixture (1:1) and mixed with 0.9 g of 4-toluenesulphonic acid. The mixture is boiled under reflux until the original compound is completely reacted. After the addition of 50 mL of a degassed 0.5 M NaHCO3 solution it is washed and after extraction with degassed toluene, the organic phase is separated off and dried over anhydrous MgSO4. The solvent is removed at the rotary evaporator and the residue is purified by column chromatography. The product is obtained in a yield above 70% as colorless oil (purity: >98%, GC). C20H17OP.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1CCCCC1>C(O)C>[CH3:1][N:2]1[C:7](/[CH:8]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: Cc1c([N+](=O)[O-])c(=O)n(C)c(=O)n1C
Reactant: O=Cc1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cn1c(/C=C/c2ccccc2)c([N+](=O)[O-])c(=O)n(C)c1=O
Yield: 60.3 %

Procedure:
A mixture of 1,3,6-trimethyl-5-nitro-1H-pyrimidine-2,4dione (3.00 g, 15.06 mmol), benzaldehyde (1.58 ml, 15.56 mmol), piperidine (1.41 ml, 15.56 mmol) and a 3 Å molecular sieve (6.00 g) in ethanol (70 ml) was refluxed for 4 hours, filtered and the solid was treated with a mixture of chloroform and methanol. The resulting suspension was filtered again and the filtrates were evaporated. The residue was triturated with diethyl ether and the precipitate collected by filtration and dried under vacuum to yield 1,3-dimethyl-5-nitro-6-((E)styryl)-1H-pyrimidine-2,4-dione (2.61 g, 60%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH:13]3[C:17]([OH:19])([CH3:18])[CH:16]([OH:20])[CH:15]([CH2:21][OH:22])[O:14]3)[C:4]=2[N:5]=[CH:6][N:7]=1.S([CH2:33][N+:34]#[C-:35])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[C:3]2[C:10]([C:11]3[O:12][CH:35]=[N:34][CH:33]=3)=[CH:9][N:8]([CH:13]3[C:17]([CH3:18])([OH:19])[CH:16]([OH:20])[CH:15]([CH2:21][OH:22])[O:14]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC1(O)C(O)C(CO)OC1n1cc(C=O)c2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(O)C(O)C(CO)OC1n1cc(-c2cnco2)c2c(Cl)ncnc21

Procedure:
To the compound from Step 1 is added tosylmethyl isocyanide (1 eq.) in MeoH containing K2CO3 (1 eq.) and the mixture is heated to reflux until starting material is consumed. The solvent is removed in vacuo and the crude mixture purified by RP HPLC on a Phenominex column (250×20 mm) using a gradient of acetonitrile in water from 0 to 30% over 30 minutes at 10 mL/minute.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[C:6]([N:7]=[CH:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:18])=O.CCCCCC>C(OCC)(=O)C>[Cl:18][C:9]1[CH:8]=[N:7][C:6]2[C:11](=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc2ncc(=O)[nH]c2c1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc2ncc(Cl)nc2c1OC
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A solution of 7,8-dimethoxy-quinoxalin-2-one (5.0 g, 24.25 mmol, 1.0 eq) in phosphorus oxychloride (25 mL, 268.21 mmol, 11.06 eq) is heated under reflux for 1 hour. Then the reaction mixture is cooled down to room temperature and the solvent is evaporated. The residue is poured into ice water, the resulting mixture is neutralized with saturated sodium hydrogen carbonate and extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: hexane:ethyl acetate, 2:1 to 1:1, v/v) to afford 2-chloro-7,8-dimethoxy-quinoxaline as a light yellow solid (4.2 g, 77% yield).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:31][S:32]([CH2:35][CH2:36][CH2:37][CH3:38])(=[O:34])=[O:33])[CH2:5][NH:6][C:7]([C:9]1[O:13][N:12]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:10]=1)=[O:8].O[Li].O.O.OS([O-])(=O)=O.[Na+]>C1COCC1>[C:24]([N:21]1[CH2:20][CH2:19][CH:18]([CH2:17][CH2:16][CH2:15][O:14][C:11]2[CH:10]=[C:9]([C:7]([NH:6][CH2:5][C@H:4]([NH:31][S:32]([CH2:35][CH2:36][CH2:37][CH3:38])(=[O:34])=[O:33])[C:3]([OH:39])=[O:2])=[O:8])[O:13][N:12]=2)[CH2:23][CH2:22]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CCCCS(=O)(=O)N[C@@H](CNC(=O)c1cc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1)C(=O)OC
Agent: O=S(=O)([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCS(=O)(=O)N[C@@H](CNC(=O)c1cc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1)C(=O)O

Procedure:
A solution of 3-8 (1.86 mg, 0.32 mmol), LiOH.H2O (67 mg, 1.6 mmol), H2O (2 mL), and THF (8 mL) was stirred at ambient temperature for 1.0 h. The solution was acidified with 1M NaHSO4 followed by evaporation of THF. The residue was partitioned between EtOAc and brine. The EtOAc layer was then dried (MgSO4) and concentrated to give 3-9 as a pale yellow solid. Rf 0.40 (silica, 9/.0.5/0.5 CH2Cl2 :CH3OH:HOAc).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]#[C:4][C:5]#[C:6][Sn](CCCC)(CCCC)CCCC.[O-:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].C([I+:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)#N>>[O-:25][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22].[CH3:21][C:2]([CH3:1])([CH3:20])[C:3]#[C:4][C:5]#[C:6][I+:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N#C[I+]c1ccccc1
Reactant: CCCC[Sn](C#CC#CC(C)(C)C)(CCCC)CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Product: CC(C)(C)C#CC#C[I+]c1ccccc1
Yield: 84 %

Procedure:
(5,5-dimethyl-1,3-hexadiynyl)tri-n-butylstannane was reacted with cyano(phenyliodonium) triflate as described in the preceding paragraph, with the product workup according to procedure 1) producing an 84% yield of 5,5-dimethyl-1,3-hexadiynyl(phenyliodonium) triflate.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]#[N:16])=[CH:10][CH:9]=2)=[O:5])C.C(O)C.[OH-].[K+].Cl>O>[C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)#[N:16]
Reactant: CCOC(=O)c1cc2cc(C#N)ccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc2[nH]c(C(=O)O)cc2c1

Procedure:
5-Cyano-1H-indole-2-carboxylic acid ethyl ester (1.71 g, 8.0 mmol) was added to a solution of ethanol (10 mL) and potassium hydroxide (2 g) and the resulting mixture heated at reflux for 1 hour. Water was added to dissolve the precipitate, and 6N HCl was added to bring the pH to 1. A precipitate formed. The mixture was cooled in an ice bath, filtered, and the resulting colorless solid washed with cold water and dried (1.51 g). A portion (1.4 g) was suspended in hot acetic acid (40 mL) and cooled giving a solid which was filtered, washed with cold ethyl acetate and dried: Yield 980 mg (70%); HPLC (60/40) 3.09 minutes (97%).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][O:4][S:5]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C@:21]3([CH3:33])[C:27]([F:29])([F:28])[C:26]([CH3:31])([CH3:30])[O:25][CH2:24][C:23](=O)[NH:22]3)[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>O1CCOCC1>[CH3:1][C:2]([CH3:34])([CH3:35])[CH2:3][O:4][S:5]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C@:21]3([CH3:33])[C:27]([F:28])([F:29])[C:26]([CH3:31])([CH3:30])[O:25][CH2:24][C:23](=[S:45])[NH:22]3)[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)(=[O:6])=[O:7]
Reactant: CC(C)(C)COS(=O)(=O)c1cccc(-c2ccc(F)c([C@@]3(C)NC(=O)COC(C)(C)C3(F)F)c2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)COS(=O)(=O)c1cccc(-c2ccc(F)c([C@@]3(C)NC(=S)COC(C)(C)C3(F)F)c2)c1
Yield: 90 %

Procedure:
The reaction of 3′-((R)-6,6-difluoro-5,7,7-trimethyl-3-oxo-[1,4]oxazepan-5-yl)-4′-fluoro-biphenyl-3-sulfonic acid 2,2-dimethyl-propyl ester (124 mg, 241 μmol with Lawesson's reagent (97.7 mg, 241 μmol) in 1,4-dioxane (10 ml) yielded the 3′-((R)-6,6-difluoro-5,7,7-trimethyl-3-thioxo-[1,4]oxazepan-5-yl)-4′-fluoro-biphenyl-3-sulfonic acid 2,2-dimethyl-propyl ester (115 mg, 90%) as a white foam. MS (ISP): m/z=530.2 [M+H]+.