Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11]O)C.C=[O:14].[C:15]1([CH3:21])C=CC=CC=1>O>[CH2:10]([O:9][CH2:8][CH2:7][O:6][CH:5]([OH:14])[CH3:4])[CH2:11][CH2:15][CH3:21]
Reactant: Cc1ccccc1
Reactant: C=O
Reactant: CCOCCOCCOCCO
Solvent: O
Product: CCCCOCCOC(C)O

Procedure:
A mixture of 400 g triethylene glycol monoethyl ether (2.2 mol), 48 g paraformaldehyde (1.6 mol), 150 ml toluene and 10 g of an acid ion exchange resin was refluxed for 6 hours in a 1 liter flask equipped with a water separator and reflux condenser. Filtration of the product followed by distillation gave a quantitative yield of the desired product.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][CH:8]([CH3:31])[CH:9]([NH:14][C:15]([C:17]1[S:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)[N:21]=1)=[O:16])[C:10]([O:12][CH3:13])=[O:11].[C:32]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([C:20]3[N:21]=[C:17]([C:15]([NH:14][CH:9]([CH:8]([CH3:31])[CH3:7])[C:10]([O:12][CH3:13])=[O:11])=[O:16])[S:18][CH:19]=3)=[CH:23][CH:24]=2)=[O:41])=[CH:43][CH:44]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)cs1)C(C)C
Reaction time: 0.08 h

Procedure:
Pyridine (0.22 ml) was added to methyl-2-(4-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 3, 300 mg) in DCM (4 ml) and the reaction mixture was stirred for 5 minutes. 4-tert-butyl benzoyl chloride (230 mg) was added and reaction mixture was stirred for 16 hours at RT. Organic solvent was concentrated to obtain a sticky solid, which was purified by column chromatography (silica gel, EtOAc-petroleum ether) to obtain title compound as solid. Yield: 235 mg (53%). 1H NMR (DMSO-d6, 300 MHz): δ 10.31 (s, 1H), 8.83 (d, 1H), 8.36 (s, 1H), 8.10 (d, 2H), 7.91 (dd, 4H), 7.56 (d, 2H), 4.38 (t, 1H), 3.68 (s, 3H), 2.35 (m, 1H), 1.31 (s, 9H), 0.98 (t, 6H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:31])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:29][CH3:30])=[C:17]([O:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][CH3:28])[CH2:23][CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[N:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C(#N)C.C(OCC)(=O)C>[Cl:2][C:3]1[C:4]([F:31])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:29][CH3:30])=[C:17]([O:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([N:27]([C:45]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:46])[CH3:28])[CH2:25][CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CN[C@H]1CC[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CC[C@H](N(C)C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2600 mg 4-[(3-chloro-2-fluoro-phenyl)amino]-6-[trans-4-(methylamino)-cyclohexyl-oxy]-7-methoxy-quinazoline-hydrochloride are suspended in 20 ml acetonitrile, then 3.1 ml triethylamine are added and 0.723 ml morpholine-N-carbonyl chloride, dissolved in 5 ml acetonitrile, are added dropwise at <8° C. After stirring overnight at ambient temperature the reaction mixture is diluted with ethyl acetate and the organic phase is extracted with water and saline solution. The organic phase is dried and evaporated down. The residue is stirred out with acetonitrile, the solid is suction filtered and dried.
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[CH:9](=[N:11][OH:12])[CH3:10].[C:13]([C:15]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:26][CH:27]=2)[CH:18]=[CH:17][N:16]=1)#[CH:14].O>CN(C=O)C>[CH3:10][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[N:26][CH:27]=3)[CH:18]=[CH:17][N:16]=2)[O:12][N:11]=1
Reactant: C#Cc1cc(Oc2ccc(NC(=O)OC(C)(C)C)nc2)ccn1
Reactant: CC=NO
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(Oc3ccc(NC(=O)OC(C)(C)C)nc3)ccn2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A solution of NCS (0.36 g, 2.70 mmol) in DMF (2 mL) was treated with acetaldoxime (0.16 g, 2.70 mmol), stirred at RT for 0.5 h, added to a solution of tert-butyl (5-((2-ethynylpyridin-4-yl)oxy)pyridin-2-yl)carbamate (0.28 g, 0.90 mmol) and TEA (2 mL) in DMF (2 mL) and heated at 60° C. for 2 h. The mixture was treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford tert-butyl (5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamate (250 mg, 75%). MS (ESI) m/z: 369.1 (M+H+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[SH:30][CH2:31][C:32]([NH2:34])=[O:33]>>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([S:30][CH2:31][C:32]([NH2:34])=[O:33])=[N:3][C:4]=1[O:28][CH3:29])(=[O:10])=[O:11]
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: NC(=O)CS
Product: COc1nc(SCC(N)=O)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.2 g) and 2-mercaptoacetamide (0.05 g). The intermediate product containing the SEM group was purified by silica gel chromatography eluting with ethyl acetate/iso-hexane mixtures. Deprotection as for Example 101b gave the title compound. Yield 0.03 g.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](=[CH2:13])[CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][O:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>C(Cl)(Cl)Cl.O>[Si:1]([O:8][CH2:9][C:10](=[CH2:13])[CH2:11][NH:31][CH2:30][C:29]1[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:28]=1[O:27][CH3:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C(CO)CO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(CN)c(OC)c1
Agent: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(CNCc1ccc(OC)cc1OC)CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 2-(tert-butyldimethylsilanyloxymethyl)-2-propen-1-ol (1.58 g) in chloroform (16 ml) were sequentially added triethylamine (2.2 ml) and methanesulfonyl chloride (0.73 ml) at 0° C., and then the mixture was stirred for 2 hours. To this reaction solution were sequentially added triethylamine (1.2 ml) and 2,4-dimethoxybenzylamine (1.3 ml), and then the mixture was stirred at room temperature for 15 hours. To this reaction mixture was added water, and an organic layer was separated from the mixture, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to give the titled compound (1.14 g).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:42]1[N:43]=[C:44]([NH:47]C=O)[S:45][CH:46]=1)[C:12]([NH:14][CH:15]1[C:40](=[O:41])[N:17]2[C:18]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:19]([CH:22]=[CH2:23])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+].C(OC(C)C)(C)C>CO.O>[NH2:47][C:44]1[S:45][CH:46]=[C:42]([C:11](=[N:10][O:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:12]([NH:14][CH:15]2[C:40](=[O:41])[N:17]3[C:18]([C:24]([O:26][CH:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:25])=[C:19]([CH:22]=[CH2:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:43]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)OC(C)C
Solvent: O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.9 %

Procedure:
A mixture of benzhydryl 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (19.0 g) and conc. hydrochloric acid (11.6 g) in methanol (380 ml) was stirred at ambient temperature for 15 minutes. After addition of water (200 ml), the reaction mixture was neutralized with sodium bicarbonate, followed by removing the methanol under reduced pressure. The resultant aqueous solution was extracted three times with ethyl acetate, and the combined extract was washed with water and an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent gave an oil, which was pulverized with diisopropyl ether to obtain benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (15.3 g).
Reaction SMILES: I[C:2]1[N:3]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:4]2[C:9]([CH:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[CH:7]=[CH:6][CH:5]=2.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.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>[C:33]1([C:2]2[N:3]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:25])=[O:26])[C:4]3[C:9]([CH:10]=2)=[C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]2)[CH:7]=[CH:6][CH:5]=3)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2cc(I)n3S(=O)(=O)c2ccccc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2cc(-c2ccccc2)n3S(=O)(=O)c2ccccc2)CC1

Procedure:
tert-Butyl 4-[2-iodo-1-(phenylsulfonyl)-1H-indol-4-yl]-1-piperazinecarboxylate(40 mg, 0.07 mmol), phenyl boronic acid (12 mg, 0.1 mmol), Pd(PPh3)4 (2 mg, 0.002 mmol) and a 2M aqueous solution of K2CO3 (0.075 mL) were stirred for 3 days at 80° C. in dimethoxyethane (2 mL). After evaporation of the solvent, the crude was purified by column chromatography (SiO2) and led to 30 mg of the desired compound (80%). 1H NMR (270 MHz, DMSO-d6) δ 8.02 (d, J=8 Hz, 1 H), 7.55–7.20 (in, 11 H), 6.78 (t, J=8 Hz, 1 H), 7.57 (s, 1 H), 3.58 (in, 4 H), 3.02 (in, 4 H), 1.48 (in, 9 H). MS (ESI+) for m/z 518 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=[C:6](Br)[CH:7]=1.[Li]CCCC.B(OC)(OC)[O:20]C.C(O)(=O)C.OO.O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([OH:20])[CH:5]=[C:4]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:3]=1
Reactant: Brc1cc(Br)cc(C2OCCO2)c1
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Oc1cc(Br)cc(C2OCCO2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(3,5-dibromo-phenyl)-[1,3]dioxolane (20.25 g, 65.75 mmol, 1.0 equiv) in anhydrous THF (200 mL) was added n-BuLi (45.2 mL, 72.33 mmol, 1.1 equiv, 1.6 M solution in hexane) at −78° C. under Ar. After stirring the reaction mixture for 30 min, trimethyl borate (7.33 mL, 6.83 g, 65.75 mmol, 1.0 equiv) was added rapidly and the reaction allowed to come to 0° C. over a time period of 4 h. A solution of conc. acetic acid (5.64 mL, 5.92 g, 98.63 mmol, 1.5 equiv) was slowly added followed by addition of a solution of 35% hydrogen peroxide in water (6.3 mL, 7.03 g, 72.33 mmol, 1.1 equiv) and the reaction mixture kept at 0° C. for 30 min. After stirring at rt for an additional 4 h, the reaction was extracted with ethyl actetate (3×200 mL), the combined organic phases washed with water, dried over MgSO4 and concentrated by evaporation under reduced pressure. The title compound was obtained in quantitative yield (16.1 g). MS (EI): 245.0 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[F:11][C:12]1[CH:13]=[C:14]([C:22]2[S:26][C:25]([NH2:27])=[N:24][C:23]=2[CH3:28])[CH:15]=[CH:16][C:17]=1[S:18]([CH3:21])(=[O:20])=[O:19]>>[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[NH:27][C:25]1[S:26][C:22]([C:14]2[CH:15]=[CH:16][C:17]([S:18]([CH3:21])(=[O:19])=[O:20])=[C:12]([F:11])[CH:13]=2)=[C:23]([CH3:28])[N:24]=1
Reactant: COC(=O)CCCC(=O)Cl
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Product: COC(=O)CCCC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Temperature: 60 °C

Procedure:
Methyl-4-(chloroformyl)butyrate (4.0 mmol) is added to a stirred solution of 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) (0.77 g, 2.69 mmol) and heated to 60° C. for 1.5 hours. The reaction mixture is allowed to cool to room temperature and the solvent removed in vacuo. The residue is washed with saturated sodium bicarbonate solution (2×50 ml) and water (1×50 ml). The product is extracted with ethyl acetate (2×50 ml) and the combined organic extracts dried (MgSO4). Removal of the solvent followed by recrystallisation from ethyl acetate affords the titled compound.
Reaction SMILES: Cl.[OH:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:6]=2[N:5]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:4]1=[O:33].C(Cl)(Cl)[Cl:35].CO.[C:40](O)(=[O:42])[CH3:41]>C(OC(=O)C)(=O)C>[ClH:35].[C:40]([O:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[CH:18]=[C:19]([C:22]([F:24])([F:23])[F:25])[CH:20]=[CH:21][C:6]=2[N:5]([CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:4]1=[O:33])(=[O:42])[CH3:41]
Reactant: COc1ccc([C@H]2Cc3cc(C(F)(F)F)ccc3N(CCN3CCCC3)C(=O)[C@H]2O)cc1
Reactant: CC(=O)O
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: COc1ccc([C@H]2Cc3cc(C(F)(F)F)ccc3N(CCN3CCCC3)C(=O)[C@H]2OC(C)=O)cc1

Procedure:
A stirred solution of (cis)-3-hydroxy-1-[2-(1-pyrrolidinyl)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride (3.3 g, 0.0056 mmol) in 80 ml of acetic anhydride under argon was heated in an oil bath at 114°-119° C. for 4.5 hours. The bulk of acetic anhydride was removed on a rotary evaporator at 0.2 mm and the solid residue (12 g) was suspended in 30 ml of ethyl acetate, diluted with 60 ml of ether, cooled for 1 hour, filtered, washed with ether, and dried in vacuo overnight; yield, 2.60 g; melting point 228°-230° C. (dec.); s, 225° C. TLC: Rf =0.48 (8:1:1, chloroform-methanol-acetic acid).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:31][C:32](=[N:44]O)[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:35]([F:43])[CH:34]=1>C1(C)C=CC=CC=1>[F:43][C:35]1[CH:34]=[C:33]([C:32]2[N:31]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:44]=2)[CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COCc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
Intermediate 28 (4 g; 15.61 mmol) was dissolved in dry Toluene (60 mL) under N2 at RT, then oxalyl chloride (1.98 mL; 23.41 mmol) was added in one portion and then DMF (24.02 μl) was added. The reaction mixture was stirred at RT for 3 hours. The reaction mixture was concentrated to afford a yellow liquid. To a flask containing Intermediate 1 (3.31 g; 15.61 mmol) in Py (20 mL; 5 V) and toluene (20 mL) at RT and under N2 was added dropwise the yellow liquid obtained previously in toluene (40 mL), the addition took 15 min. The reaction mixture was stirred at RT for 12 hours. Then the mixture was refluxed for 24 hours. The reaction mixture was cooled to RT and concentrated affording a beige solid which was washed with MeOH (40 mL). The suspension was filtered affording the title compound as a beige solid (5.58 g, 82%). 1H NMR (DMSO-d6, 300 MHz) δ 8.33 (m, 1H), 8.19-7.98 (m, 4H), 7.44-7.28 (m, 4H), 7.16-7.13 (m, 1H), 4.24-4.14 (m, 2H), 3.91 (s, 3H), 3.25 (s, 3H), 2.03 (s, 3H). LC/MS (Method B): 433.1 (M+H)+ HPLC: Rt 5.94 min (Purity: 94.9%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[I:15]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:15][C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:14])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COC(=O)CCc1ccc(OC)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)CCc1ccc(OC)c(I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A 3-neck 5 L RBF equipped with mechanical stirrer, thermometer, and a nitrogen bubbler, was charged with 3-(4-methoxyphenyl)propionic acid methyl ester (100 g, 515 mmol), silver sulfate (161 g, 515 mmol) and iodine (131 g, 515 mmol) in methanol (2 L). The reaction mixture was stirred vigorously at room temperature for 1 hour. The reaction was filtered through Solka-Floc® (ethyl acetate wash). The filtrate was concentrated and the residue was taken up in ethyl acetate (4 L). The organic was washed with water, saturated aq. NaHSO3 (50 mL), and brine (50 mL) before drying over Na2SO4, filtering, and concentrating to dryness. The crude reaction was purified by column chromatography to yield methyl 3-(3-iodo-4-methoxyphenyl)propanoate (155 g, 484 mmol) as a clear oil. MS ESI calc'd. for C11H14IO3 [M+H]+ 321.0. found 321.0.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-])=[C:4]([CH3:10])[CH:3]=1.C(OP([C:19]#[N:20])(OCC)=O)C.C(N(CC)CC)C>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[N:5]=[C:6]([C:19]#[N:20])[C:7]=1[CH3:8]
Reactant: Cc1c[n+]([O-])c(C)cc1Br
Reactant: CCOP(=O)(C#N)OCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Br)c(C)c(C#N)n1
Temperature: 80 °C
Yield: 69.8 %

Procedure:
To a Smith microwave vial was added 4-bromo-2,5-dimethyl-1-oxido-pyridin-1-ium (which may be prepared as described in Description 136), (300 mg, 1.48 mmol), diethoxyphosphorylformonitrile (0.9 mL, 5.94 mmol) and triethylamine (0.41 mL, 2.97 mmol) in anhydrous MeCN (1 mL). The reaction mixture was heated by microwave at 80° C. for 1 h. The reaction mixture was evaporated and the crude dark oil was purified on silica gel chromatography (10 g SiO2) eluting with ethyl acetate in iso-hexane (0-80%). Evaporation of desired fractions gave 4-bromo-3,6-dimethyl-pyridine-2-carbonitrile (D137) (218 mg, 1.0329 mmol, 69.6% yield) as colourless solid;
Reaction SMILES: CC1C=CC(S(N[C@H](C[C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])C)(=O)=O)=CC=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:30][N@@:29]2[S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)(=[O:33])=[O:32])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([NH:29][S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)(=[O:33])=[O:32])[CH2:30][C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)CC#C[Si](C)(C)C)cc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)[N@]1CC1c1ccc(F)cc1
Agent: O=S(=O)(c1cccc(C(F)(F)F)c1)[N@@]1CC1c1ccc(F)cc1
Product: C[Si](C)(C)C#CC[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1

Procedure:
Proceeding as described for (51), but using (S)-2-(4-fluorophenyl)-1-(3-(trifluoro-methyl)benzenesulfonyl)aziridine afforded (R)—N-(1-(4-fluorophenyl)-4-(trimethylsilyl)but-3-ynyl)-3-(trifluoromethyl)benzenesulfonamide (53). MS (m/z): 444.3 (M+H) (Calc'd for C20H21F4NO2SSi: 443.54).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([OH:10])[N:4]=[C:3]1[S:11][CH3:12].[C:13]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].[H-].[Na+].O>CN(C)P(=O)(N(C)C)N(C)C>[C:13]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:10][C:5]2[N:4]=[C:3]([S:11][CH3:12])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=2[CH3:9])=[CH:23][CH:24]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CSc1nc(O)c(C)c(=O)n1C
Reactant: CC(C)(C)c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CSc1nc(OCc2ccc(C(C)(C)C)cc2)c(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.8 %

Procedure:
In 10 ml of hexamethyl phosphoric triamide were dissolved 1 g of 3,5-dimethyl-6-hydroxy-2-methylthio-4(3H)-pyrimidinone and 1 g of 4-t-butylbenzyl chloride, and thereto was added 0.3 g of sodium hydride (55% in mineral oil). The mixture was stirred for 15 hours at room temperature. The resulting solution was poured into 50 ml of water and then extracted twice with 30 ml of ethyl ether. The ethyl ether layer was dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure to give 1.9 g of a crude product. The product was purified by means of column chromatography (on silica gel, eluting with benzene) and then washed with a mixture of hexane and ethyl ether (10:1) to give 0.8 g of the intended product.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6]CO)=[N+:2]=[N-:3].S(Cl)(C)(=O)=O.[CH3:14][S:15]([O:18][CH2:19]CN=[N+]=[N-])(=[O:17])=[O:16]>>[CH3:14][S:15]([O:18][CH2:19][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:5][CH3:6])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCCCO
Agent: CS(=O)(=O)Cl
Product: CCC(COS(C)(=O)=O)N=[N+]=[N-]

Procedure:
Reaction of 4-azidobutanol (0.80 g, 6.95 mmol) and mesyl chloride (1.48 mL, 10.43 mmol) within 3 h as described for synthesis of 156a gave compound 156c (1.33 g) as a crude colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>CN(C=O)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:10][CH:11]=1
Reactant: c1cn[nH]c1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(-n2cccn2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
Pyrazole (2.05 g, 30.11 mol) was added in portions to sodium hydride (60% in oil, 1.20 g, 30.00 mmol) in DMF (40 mL) and the resulting mixture was stirred for 1 h at RT. 2,5-Dibromopyridine (4.75 g, 20.05 mmol) was added and the mixture was heated to 100° C. for 2 h. Ice-water (100 mL) was added to the cooled reaction mixture and the precipitated solids were removed by filtration and allowed to air-dry. Recrystallization from hexane provided 3.31 g (74%) of the title compound as a tan solid. MS 224 (M+H)+.