Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH3:12])=[C:7]([NH2:13])[N:6]=1)=[O:4].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22]([NH:13][C:7]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[N:9][C:8]=1[O:11][CH3:12])(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COC(=O)c1cnc(OC)c(N)n1
Product: COC(=O)c1cnc(OC)c(NS(=O)(=O)c2cccc(Cl)c2Cl)n1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 6-amino-5-methoxypyrazine-2-carboxylic acid methyl ester (Example 201b) (0.3 g) and 2,3-dichlorobenzenesulphonyl chloride (0.4 g). Yield 0.15 g.
Reaction SMILES: [OH-].[Na+].Cl.[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=O>C(Cl)(=O)C>[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]1[CH2:10][C:11](=[O:13])[O:17][C:15](=[O:16])[CH2:14]1
Reactant: O=C(O)CC(CC(=O)O)c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)Cl
Product: O=C1CC(c2cccs2)CC(=O)O1
Temperature: 25 °C

Procedure:
To a solution of commercial 2-thiophen-carboxaldehyde (22.4 g) and ethyl acetoacetate (50.5 ml) in ethanol (40 ml) piperidine (4 ml) was added with stirring at rt. The solution was kept at rt for 3 d to form a precipitate. After cooling in the refrigerator the yellow solid was crushed, collected by suction filtration, and washed with ethanol. Drying in vacuo affords 31 g of a faint yellowish solid (the bis-adduct of acetoacetate to the aldehyde). The powdered solid was added in portions to 40% NaOH (500 g) with stirring. The resulting orange coloured slurry was stirred at reflux for 2 h. After cooling in an ice bath the mixture was acidified by portionwise addition of conc. HCl (440 ml) to give a colourless precipitate. The solid was collected by suction filtration and washed with water. After drying in vacuo 3-(2-thienyl)glutaric acid (9.7 g) was obtained. The suspension of finely divided 3-(2-thienyl)glutaric acid in acetyl chloride (17 ml) was heated to reflux with stirring for 1 h. After cooling to rt precipitation of the product is induced by addition of petrol ether (100 ml). The precipitate is isolated by suction filtration, washed with petrol ether, and dried in vacuo to give 3-(2-thienyl)glutaric anhydride (8.2 g) as colourless crystals.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1Cl
Reactant: c1c[nH]cn1
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3ccccc3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,5-dichloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([CH3:22])(=[O:21])=[O:20])[C:3]=1[CH3:23].[I:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([CH3:35])([CH3:34])[CH2:30][NH:31]2)=[CH:27][CH:26]=1.Cl>CN1C(=O)CCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:31]3[C:32]4[C:28](=[CH:27][CH:26]=[C:25]([I:24])[CH:33]=4)[C:29]([CH3:35])([CH3:34])[CH2:30]3)=[C:3]([CH3:23])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[S:19]([CH3:22])(=[O:21])=[O:20])=[N:5]2)=[CH:10][CH:9]=1
Reactant: CC1(C)CNc2cc(I)ccc21
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(I)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 4-chloro-7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (102 mg, 0.29 mmol) (described herein), 6-iodo-3,3-dimethylindoline (80 mg, 0.29 mmol) (described herein), hydrochloric acid (70 μL, 0.29 mmol), and NMP (0.490 mL). The reaction mixture was heated in a microwave at 150° C. for 150 min. Purification afforded 7-fluoro-4-(6-iodo-3,3-dimethylindolin-1-yl)-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline as a yellow solid. Mass Spectrum (ESI) m/e=587 (M+1).
Reaction SMILES: [ClH:1].C([N:5]([CH2:15][CH:16]1[O:21][CH2:20][CH2:19][NH:18][CH2:17]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH3:14])(=O)C.Cl.[OH-].[Na+]>>[ClH:1].[CH2:13]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][CH2:15][CH:16]1[O:21][CH2:20][CH2:19][NH:18][CH2:17]1)[CH3:14]
Reactant: CCOc1ccccc1N(CC1CNCCO1)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccccc1NCC1CNCCO1
Temperature: 0 °C

Procedure:
A mixture of 2-(N-acetyl-2-ethoxyanilino)methylmorpholine hydrochloride (2 g.) and concentrated hydrochloric acid is heated under reflux for 24 hours. The solution is cooled, diluted with ice (25 g.), basified with sodium hydroxide solution and extracted with ether (2× 100 ml.). The ether extract is dried (Na2SO4) and treated with ethereal HCl to give 2-(2-ethoxyanilino)methylmorpholine hydrochloride, m.p. 180°-181° C. on recrystallisation from ethanol.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:14]([CH2:16][CH2:17][OH:18])[CH3:15])[CH:10]=2)[CH:5]=1)(=O)[CH3:2].[C:19](#[N:23])[CH2:20][C:21]#[N:22].CCOCC>N1C=CC=CC=1>[C:21]([C:20]([C:19]#[N:23])=[C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:14]([CH2:16][CH2:17][OH:18])[CH3:15])[CH:10]=2)[CH:5]=1)[CH3:2])#[N:22]
Reactant: N#CCC#N
Reactant: CC(=O)c1ccc2cc(N(C)CCO)ccc2c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=C(C#N)C#N)c1ccc2cc(N(C)CCO)ccc2c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
0.51 g (2.1 mmol) of the third compound 3 is dissolved in 3 mL of dry pyridine to be added with 0.63 g (8.3 mmol) of malononitrile (CH2(CN)2). Reaction is processed under nitrogen to be heated at 70° C. with stirring for 4 hrs. After cooling, 50 mL of ether is added with sufficient stirring, where the part insoluble to ether is abandoned. The ether solution is washed with 50 mL of water. After being dried with anhydrous sodium sulfate and concentrated under reduced pressure, an organic phase is separated and purified by liquid chromatography (SiO2, CHCl3:EtOAc=1:1). Thus, a red solid product, 2-(1,1-dicyanopropen-2-yl)-6-[(2-hydroxyethyl)methylamino]naphthalene 4 (hereinafter referred to as fourth compound 4), is obtained, which has a weight of 0.46 g and a yield of 75.3%.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[O:11]C1C=CC=CC=1.O.[NH2:22][NH2:23]>C(O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([NH:22][NH2:23])=[O:11]
Reactant: O=C(Nc1ccccc1C(F)(F)F)Oc1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)Nc1ccccc1C(F)(F)F

Procedure:
Phenyl (2-trifluoromethylphenyl)carbamate (12.1 g) was dissolved in ethanol (150 mL). Hydrazine monohydrate (16.7 mL) was added and the mixture was heated under reflux for 2.25 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (7.5 g).
Reaction SMILES: [I:1][C:2]1[C:10]2[CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][C:5]=2[NH:4][N:3]=1.[CH3:13]C([O-])(C)C.[K+].IC>C1COCC1>[I:1][C:2]1[C:10]2[CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][C:5]=2[N:4]([CH3:13])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)CCc2c(I)n[nH]c2C1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2c1CC(C)(C)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
To a solution of 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (919 mg, 3.33 mmol) in THF (8 mL) at 0° C. was added KOt-Bu (523 mg, 4.66 mmol). The reaction mixture was stirred at 0° C. for 30 min then iodomethane (0.29 mL, 4.66 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then warmed to room temperature and stirred for 1.5 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated. The residue was absorbed onto SiO2 and purified by chromatography with 10% to 20% EtOAc/hexanes to afford 523 mg (54%) of 3-iodo-1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazole as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.72 (s, 3H), 2.33 (t, J=6.4 Hz, 2H), 2.29 (s, 2H), 1.51 (t, J=6.4 Hz, 2H), 1.02 (s, 6H). Also isolated 160 mg (17%) of 3-iodo-2,6,6-trimethyl-4,5,6,7-tetrahydro-2H-indazole as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.87 (s, 3H), 2.41 (s, 2H), 2.36 (t, J=6.6 Hz, 2H), 1.54 (t, J=6.6 Hz, 2H), 1.00 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:25]([NH:24][C:21]4[CH:22]=[CH:23][C:18]([CH3:27])=[CH:19][CH:20]=4)=[O:26])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and p-tolyl isocyanate (32 μL, 0.25 mmol) in CH2Cl2 (5 mL) are reacted according to method C yielding the title product as a colorless solid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:30])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:31][CH2:32][CH2:33]Br>C(O)C>[CH3:3][O:4][C:5](=[O:30])[CH:6]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:33][CH2:32][Br:31])=[CH:10][CH:9]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1cccnc1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1cccnc1
Yield: 28.1 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-((2-nicotinoylphenyl)amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.10 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.40 g, 28.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][C:23]1=[O:28]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NC1CCCNC1=O
Product: O=C(NC1CCCNC1=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 3-aminopiperidin-2-one (11.4 mg, 0.1 mmol). The title compound was obtained as a solid (10.4 mg, 23% yield). MS m/z: 446 [M+H]+.
Reaction SMILES: [CH2:1](Br)[C:2]#[C:3][CH3:4].[CH2:6]([O:8][C:9]([CH2:11][NH:12][C:13](=[N:21][C:22]#[N:23])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:6]([O:8][C:9]([CH2:11][N:12]([CH2:1][C:2]#[C:3][CH3:4])[C:13](=[N:21][C:22]#[N:23])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)CNC(=NC#N)Oc1ccccc1
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCN(CC(=O)OCC)C(=NC#N)Oc1ccccc1

Procedure:
11 ml but-2-ynylbromide are added to a mixture of 30.2 g 1-ethoxycarbonylmethyl-3-cyano-2-phenyl-isourea and 20.0 g potassium carbonate in 200 ml acetone. After 1 d (day) stirring at ambient temperature a further 6.5 g potassium carbonate and 3.5 ml but-2-ynylbromide are added. After another 20 h at ambient temperature the solvent is removed and ethyl acetate is added. The organic phase is washed with water, dried over sodium sulphate and evaporated to dryness.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][O:14][C@@H:15]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[O:20][C@H:17]([O:18][CH3:19])[C:16]1=[O:33].O>CCOCC>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][O:14][C@@H:15]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[O:20][C@H:17]([O:18][CH3:19])[C@:16]1([CH2:2][CH3:1])[OH:33]
Reactant: CC[Mg+]
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)C1=O
Agent: [Br-]
Solvent: O
Solvent: CCOCC
Product: CC[C@]1(O)[C@@H](OC)O[C@H](COCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To diethyl ether (300 mL) at −78° C. was slowly added EtMgBr (3.0 M, 16.6 mL) and then dropwise the compound from Step B of Example 2 (4.80 g, 10.0 mmol) in anhydrous Et2O (100 mL). The reaction mixture was stirred at −78° C. for 15 min, allowed to warm to −15° C. and stirred for another 2 h, and then poured into a stirred mixture of water (300 mL) and Et2O (600 mL). The organic phase was separated, dried (MgSO4), and evaporated in vacuo. The crude product was purified on silica gel using ethyl acetate/hexane (1:2) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (3.87 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[CH2:8][CH2:7][C:6]([CH2:11][OH:12])([CH2:9][OH:10])[CH2:5][CH2:4]1.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>N1C=CC=CC=1.CCOC(C)=O>[CH3:22][C:21]1[CH:23]=[CH:24][C:18]([S:15]([O:12][CH2:11][C:6]2([CH2:9][O:10][S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:5][CH2:4][C:3]([O:2][CH3:1])([O:13][CH3:14])[CH2:8][CH2:7]2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC1(OC)CCC(CO)(CO)CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC1(OC)CCC(COS(=O)(=O)c2ccc(C)cc2)(COS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
To a solution of (4,4-dimethoxycyclohexane-1,1-diyl)dimethanol (3.6 g, 17.62 mmol) in pyridine (20 mL) was added tosyl chloride (7.39 mL, 38.8 mmol). The reaction mixture was stirred at rt for 18 h and then diluted with EtOAc (50 mL). The organic mixture and washed with 10% aq. citric acid, dried (Na2SO4) and concentrated in vacuo to afford the title compound (5.4 g, 60% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J=8.3 Hz, 4H), 7.35 (d, J=8.2 Hz, 4H), 3.84 (s, 4H), 3.09 (s, 6H), 2.45 (s, 6H), 1.54-1.45 (m, 4H), 1.42-1.34 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[Cs+].[Cs+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2Cl)CC1
Temperature: 80 °C
Yield: 83.2 %

Procedure:
To a stirred solution of 2-chlorobenzenethiol (2.5 g, 0.017 mole) in DMF (20 mL) was added cesium carbonate (6.77 g, 0.0208 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (4.8 g, 0.0173 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 4.64 g (82%) of 4-(2-chloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 328.11 (M+1)+, 95.12%. A solution of 4-(2-chloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (4 g, 0.0122 mole) in dioxane.HCl (7 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 3.75 g (99%) of 4-(2-chloro-phenylsulfanyl)-piperidine hydrochloride. LCMS: 228.05 (M+1)+, 92.02%.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:40]2[CH2:41][CH2:42][N:37]([C:29]3[N:28]([CH3:27])[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=3)[CH2:38][CH2:39]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Cn1c(N2CCNCC2)nc2ccccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 1e from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 1-methyl-2-(piperazin-1-yl)-benzimidazole.
Reaction SMILES: O1CCOCC1.C([NH:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[O:19][C:18]([CH3:21])([CH3:20])[CH:17]3[O:22][CH:16]3[C:15]=2[CH:23]=1)(=O)C.[OH-].[Na+].Cl>O>[NH2:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[O:19][C:18]([CH3:21])([CH3:20])[CH:17]3[O:22][CH:16]3[C:15]=2[CH:23]=1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)C1OC21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2C2OC21
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
A mixed solution of a 1,4-dioxane (152 mL) and water (76 mL) in which a 6-acetoamido-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (synthesized according to the method of Evans, J. M., et al., J. Med. Chem. 1984, 27, 1127) (7.6 g, 27 mmol) and sodium hydroxide (5.6 g, 5.0 eq.) were dissolved was stirred at room temperature for four hours. After the mixture was neutoralized with hydrochloric acid, the resulting product was diluted by a saturated saline water, extracted with an ethyl acetate and then, dried over a sodium sulfate anhydride. After the solvent was distilled off, the resulting product was recrystallized from a mixed solvent of ethanol and hexane to obtain a 6-amino-3,4-epoxy-3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran (1.4 g, 22%) as orange crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[O:30][C:29]([CH2:34][O:35][CH3:36])([CH2:31][O:32][CH3:33])[C:28]3=[N:37][N:38]=[N:39][N:27]3[C:26]=2[CH:40]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(O)(C)C>[CH3:33][O:32][CH2:31][C:29]1([CH2:34][O:35][CH3:36])[C:28]2=[N:37][N:38]=[N:39][N:27]2[C:26]2[CH:40]=[C:22]([NH:21][C:2]3[N:7]=[C:6]([NH:8][C@@H:9]4[CH2:17][C@H:16]5[N:12]([CH2:13][CH2:14][CH2:15]5)[C:11]([CH3:19])([CH3:18])[CH2:10]4)[C:5]([F:20])=[CH:4][N:3]=3)[CH:23]=[CH:24][C:25]=2[O:30]1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Reactant: COCC1(COC)Oc2ccc(N)cc2-n2nnnc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COCC1(COC)Oc2ccc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)cc2-n2nnnc21
Temperature: 100 °C

Procedure:
A mixture of (7R,8aS)-N-(2-choro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (36 mg, 0.12 mmol, 1 equiv), 8-amino-4,4-bis(methoxymethyl)-4H-tetrazolo[5,1-c]-[1,4]-benzoxazine (40 mg, 0.14 mmol, 1.2 equiv) and pTsOH.H2O (46 mg, 0.24 mmol, 2.0 equiv) in isopropanol (1.0 mL) was heated at 100° C. overnight in a sealed vial. After allowing to cool to room temperature, the solvent was removed and the residue was purified by column chromatography using a mixture of DCM/2N NH3 in MeOH (95:5) to give the product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:38]/[O:39][C:40]([CH3:49])([CH3:48])[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][NH:24][CH2:25][C@H:26]([OH:37])[CH2:27][O:28][CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:55](N2C=NC=C2)=[O:56])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:38]/[O:39][C:40]([CH3:49])([CH3:48])[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])/[C:15](=[O:16])[NH:17][C@H:18]2[C@@H:19]([CH2:23][N:24]3[CH2:25][C@@H:26]([CH2:27][O:28][CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[O:37][C:55]3=[O:56])[NH:20][C:21]2=[O:22])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNC[C@H](O)COCOCC[Si](C)(C)C)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN2C[C@@H](COCOCC[Si](C)(C)C)OC2=O)cs1
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of tert-butyl 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((S)-9-hydroxy-2,2-dimethyl-5,7-dioxa-11-aza-2-siladodecan-12-yl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (155 mg, 0.21 mmol) in DCM (10 mL) at 0° C. was added CDI (62 mg, 0.38 mmol). After stirring at <15° C. for 2 h, the reaction mixture was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 3-5%) to afford the title compound (130 mg, 81%). LCMS: m/z=755.3 (M−1).
Reaction SMILES: [Na].[F:2][C:3]([F:18])([F:17])[S:4]([NH:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([F:16])[N:9]=1)(=[O:6])=[O:5].[F:19]F>C(#N)C>[F:18][C:3]([F:17])([F:2])[S:4]([N:7]([F:19])[C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([F:16])[N:9]=1)(=[O:6])=[O:5]
Reactant: O=S(=O)(Nc1nc(F)nc(F)c1F)C(F)(F)F
Reactant: FF
Agent: [Na]
Solvent: CC#N
Product: O=S(=O)(N(F)c1nc(F)nc(F)c1F)C(F)(F)F
Reaction time: 3 h

Procedure:
A cold (-35° C.), efficiently stirred solution of the sodium salt of perfluoro-[N-(4-pyrimidinyl)methanesulphonamide] (1.22 g) in dry acetonitrile (200 cm3) was treated with neat fluorine at 10-15 mmHg (1.3 to 2.0 kPa) pressure until uptake of the halogen appeared to cease (this took nearly 3 hours). The product solution was filtered (to remove sodium fluoride) and the filtrate evaporated, leaving a colourless oily sample (about 1 g) of perfluoro-[N-fluoro-N-(4-pyrimidinyl)methanesulphonamide], shown by 19F n.m.r. spectroscopy to be contaminated with perfluoro-[N-(4-pyrimidinyl)methanesulphonamide] and its sodium salt. This impure product showed NF absorption at 47.5 p.p.m. in its 19F n.m.r. spectrum [solution in CH3CN; external CF3CO2H reference (computed chemical shift relative to CFCl3 =-29.05 p.p.m.)], and rapidly liberated iodine from aqueous potassium iodide solution. Examination of the filtered iodimetric test solution by 19F n.m.r. spectroscopy revealed only absorptions assignable to perfluoro-[N-(4-pyrimidinyl)methanesulphonamide] [δF 30.1 (m; 2-F), 2.0 (s; CF3SO2), -0.8 (m; 6-F), and -88.2 (m; 5-F) p.p.m. (CF3CO2H ext. ref)]. Examination by 19F n.m.r. spectroscopy of the solution prepared by addition of an excess of heat anisole to the impure perfluoro-[N-fluoro-N-(4-pyrimidinyl)methanesulphonamide] revealed the rapid formation at room temperature of an about 1:1 mixture of o- and p-fluoroanisole, accompanied by complete consumption of the N-fluoro-compound.