Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu]I>[N:11]1([C:2]2[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=[N:12]1
Reactant: C[C@H](N)c1cccc(Br)c1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[C@H](N)c1cccc(-n2cccn2)c1
Temperature: 195 °C
Yield: 58 %

Procedure:
To a solution of (S)-1-(3-bromo-phenyl)-ethylamine (1.5 g, 7.5 mmol) and pyrazole (1.02 g, 15 mmol) in N-methylpyrrolidinone (10 mL) in a quartz tube were added potassium carbonate (2.1 g, 15 mmol), and copper (1) iodide (143 mg, 0.75 mmole), and the resulting mixture was heated at 195° C. for 5 h in a Mars 5 microwave oven (600 W). The reaction mixture was cooled down to room temperature and filtered. The crude product was purified by flash chromatography (10% MeOH/89% EtOAc/1% triethylamine) to provide the title compound (814 mg, 58% yield) as a brown oil.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:48])[C@@H:5]([NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[CH:41]=4)=[O:38])=[C:32]([F:47])[CH:31]=3)[CH:26]=[CH:25][N:24]=2)[NH:20][CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:48])[C@@H:5]([NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[CH:41]=4)=[O:38])=[C:32]([F:47])[CH:31]=3)[CH:26]=[CH:25][N:24]=2)[NH:20][CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)[C@H](CCC(=O)O)NC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl (4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoate (30 mg, 0.046 mmol) in 5 ml of methylene chloride was added 2 ml of TFA. The mixture was stirred at room temperature for 1 hour, and evaporated to dryness. The residue was dissolved in MeOH (3 ml), which was added dropwise into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried to give (4S)-5-(ethylamino)-4-{[(5-{4-[3-fluoro-4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}-5-oxopentanoic acid as white solid. Yield: 20 mg, 74%.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[CH3:10][O:11][C:12](=[O:42])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[C:29]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:28]=[C:27](Br)[CH:26]=2)=[CH:17][C:16]=1[CH3:41]>CN(C=O)C.C(N(CC)CC)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.[Cu]I>[CH3:10][O:11][C:12](=[O:42])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:26]=[C:27]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:28]=[C:29]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:30]=2)=[CH:17][C:16]=1[CH3:41]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCCCC3)c2)cc1C
Reactant: C#CCN1CCCCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCCCC3)cc(C#CCN3CCCCC3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 1-prop-2-ynyl-piperidine (322 mg, 2.62 mmol), (4-{3-[3-bromo-5-(3-piperidin-1-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (204 mg, 0.4 mmol, example 3), Pd(PPh3)4 (50 mg, 0.044 mmol), CuI (23 mg, 0.122 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 30 min at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using ethyl acetate/methanol mixtures to give (4-{3-[3,5-bis-(3-piperidin-1-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester in 138 mg (57%) yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(Cl)Cl>[Pd].CO>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(N2CCCC2)c(F)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(N2CCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of 1-(2-fluoro-4-nitrophenyl)pyrrolidine (1.60 g, 7.62 mmol) in mixed solvents of CH2Cl2 (20 mL) and MeOH (20 mL) was added catalyst Pd/C (0.16 g). The reaction was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V) 5:1) to give the title compound as a white solid (1.20 g, 88%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([C:15]3[O:19][N:18]=[C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:16]=3)[CH2:12][N:11]([C:25]([N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)=[O:26])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([C:15]3[O:19][N:18]=[C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:16]=3)[CH2:12][N:11]([C:25]([N:27]3[CH2:28][CH2:29][S:30](=[O:41])[CH2:31][CH2:32]3)=[O:26])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1ccc(C2CC(c3nc(OCCOC)no3)CN(C(=O)N3CCSCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(OCCOC)no3)CN(C(=O)N3CCS(=O)CC3)C2)cc1
Yield: 25.6 %

Procedure:
60.0 mg (0.122 mmol) of the compound from Example 59 were reacted according to General Method 2 with 38.0 mg (0.110 mmol) of meta-chloroperbenzoic acid. Enantiomer separation of 33.9 mg of the racemate according to Method 7D gave 15.6 mg of the title compound from Example 60 (enantiomer 1) and 13.4 mg of the title compound from Example 61 (enantiomer 2).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11].[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)C(=O)NC1CCCCC1O
Reactant: N#Cc1c(N)cccc1F
Product: CC(C)C(=O)NC1CCCCC1Oc1cccc(N)c1C#N

Procedure:
Prepared as in Example 22b from N-(2-hydroxycyclohexyl)isobutyramide (Example 39c) and 2-amino-6-fluorobenzonitrile as a brown solid (70%). MS 302 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].CCN(C(C)C)C(C)C.[CH3:24][CH:25]([SH:27])[CH3:26]>>[CH:25]([S:27][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14])([CH3:26])[CH3:24]
Reactant: CC(C)S
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Sc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 39a was used, starting from 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c), DIEA and 2-propanethiol to give 4-isopropylsulfanyl-6-iodo-quinoline-3-carbonitrile. LC-MS m/e 355 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:10][CH2:11][C:12](Cl)=[O:13]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:3]([N:2]([CH3:1])[C:12](=[O:13])[CH2:11][Cl:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C(=O)CCl
Yield: 63.2 %

Procedure:
To a vigorously stirred suspension of N-methylbenzylamine (0.260 mL, 2 mmol) in EtOAc (3 mL) and 3 mL of saturated NaHCO3 solution was added chloroacetyl chloride (0.160 mL, 2 mmol). Effervescence was observed. Once gas production had ceased, the reaction mixture was diluted with hexanes (10 mL). The phases were separated and the organic phase was washed with brine (5 mL), dried and concentrated to yield ˜0.250 g of the title compound as an oil. The crude material was used in the subsequent step without further purification.
Reaction SMILES: C[O:2][C:3]1([O:35]C)[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[C:24](=[O:28])[C:23]([O:31]C)([O:29]C)[C:22]5=[O:33])[CH:14]=3)[CH:9]=2)[C:4]1=[O:34].C(O)(=O)C.Br>O>[OH:31][C:23]1([OH:29])[C:22](=[O:33])[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:8]4[CH:9]=[C:10]5[C:5](=[CH:6][CH:7]=4)[C:4](=[O:34])[C:3]([OH:2])([OH:35])[C:11]5=[O:12])[CH:14]=3)[CH:20]=2)[C:24]1=[O:28]
Reactant: COC1(OC)C(=O)c2ccc(-c3cccc(-c4ccc5c(c4)C(=O)C(OC)(OC)C5=O)c3)cc2C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccc(-c3cccc(-c4ccc5c(c4)C(=O)C(O)(O)C5=O)c3)cc2C(=O)C1(O)O
Temperature: 115 °C
Yield: 54.8 %

Procedure:
1,3-bis(2,2-dimethoxy-1,3-dioxoindan-5-yl)benzene (33) (119 mg, 0.25 mmol) was suspended in a solvent mixture of 3 ml of acetic acid and 3 ml of water, and the suspension was mixed with 3 ml of 47% hydrobromic acid. This mixture was refluxed at 115° C. over night. After it was cooled to room temperature, the reaction solution was filtered to obtain a solid, which was then dried at a reduced pressure, to obtain 59 mg (56%) of 1,3-bis(2,2-dihydroxy-1,3-dioxoindan-5-yl)benzene (34) in the form of a beige solid. The readings for this compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][NH:13][CH:14]1[CH2:18][N:17]([CH3:19])[CH2:16][CH2:15]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:13]([CH3:12])[CH:14]1[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CNC1CCN(C)C1
Solvent: CCOC(C)=O
Product: CN1CCC(N(C)c2ccc([N+](=O)[O-])cc2Cl)C1
Reaction time: 24 h

Procedure:
3-Chloro-4-fluoronitrobenzene (1.0 g) and N,N'-dimethyl-3-aminopyrrolidine (1.72 g) are combined and stirred for approximately 24 hours. The mixture is then diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (pure ethyl acetate followed by pure methanol is used as the eluants) to provide the desired product as a yellow oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:31][OH:32].C(N(CC)CC)C>C(O)C>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[N:31][OH:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCCCC2=O)c(O[Si](C)(C)C(C)(C)C)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCCCC2=NO)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added 4-{2,4-bis [tert-butyl(dimethyl)silyloxy]phenyl cyclohexanone (100 mg, 0.23 mmol) and ethanol (5 ml). To the stirred suspension was added hydroxylamine hydrochloride (32 mg, 0.46 mmol) and triethylamine (103 μl, 0.74 mmol), then the solution was heated under reflux temperature for 2.5 hr. The solution was allowed to cool to room temperature then evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate (20 ml) and water (10 ml) and the layers separated. The aqueous layer was extracted with ethyl acetate (3×20 ml) and the combined organic layers washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The title compound was isolated (103 mg, 100%) as a white. δH (CDCl3) 0.19 (6H, s), 0.24 (6H, s), 0.95 (9H, s), 1.02 (9H, s), 1.43-1.62 (2H, m), 1.77-1.87 (1H, m), 1.93-2.04 (2H, m), 2.18-2.24 (1H, m), 2.46-2.53 (1H, m), 3.05-3.15 (1H, m), 3.41-3.50 (1H, m), 6.30 (1H, d), 6.40 (1H, dd), 6.79 (1H, br), 6.92 (1H, d).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[OH:11])[CH3:5])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)=[O:11])[CH3:5])[CH3:2]
Reactant: CCOC(C)OCC#CC(O)c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(C)OCC#CC(=O)c1ccc(F)cc1
Reaction time: 0.17 h

Procedure:
A solution of 9.3 g (37 mmol) of 4-(1-ethoxyethoxy)-1-(4-fluorophenyl)-2-butyn-l-ol in 50 ml of methylene chloride was added dropwise at 0° to a suspension of 95 g (1.1 mol) of manganese dioxide in 150 ml of methylene chloride. The reaction mixture was stirred at 0° for 10 minutes, filtered over magnesium sulphate and concentrated. Chromatography of the residue on 300 g of silica gel (elution agent ether/hexane 1:1) yielded 4 -(1-ethoxyethoxy)- 1-(4-fluorophenyl)-2-butyn- 1-one as an oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[CH3:6][CH:1]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:11]=[C:2]1[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=Cc2ccccc2C1C
Yield: 74 %

Procedure:
A 200 ml four-necked flask equipped with a reflux tube, a thermometer and a dropping funnel was thoroughly purged with nitrogen and dried. To the flask, methylmagnesium bromide (3.0 mol/l ether solution) (16.9 ml, 50.7 mmol) and dehydrated ether (50 ml) were introduced. To the flask, a solution of 2-methyl-1-indanon (3.70 g, 25.3 mmol) in dehydrate ether (20 ml) was dropwise added at room temperature with stirring. Then, the reaction mixture was stirred for 2 hours and poured into cold water. The resultant mixture was introduced into a separatory funnel to separate an organic phase. The aqueous phase was extracted by ether (100 ml×3) and a combined organic phase was washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 1,2-dimethyl-1-hydroxy-indene. The compound thus obtained was dissolved in toluene (30 ml) and, thereto, 0.1 g of p-toluenesulphonic acid was added. The reaction mixture was refluxed for 3 hours to remove water. The organic phase thus obtained was introduced into a separatory funnel and washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After removing a solvent, it was purified by column chromatography (developer; hexane) to obtain 2.70 g (GC 94%) of a pale yellow solution (yield: 74%).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]1([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[NH:23][S:22]2(=[O:31])=[O:30])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:32][CH2:33][CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:32][CH2:33][CH2:34][N:23]1[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[S:22]1(=[O:30])=[O:31]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1
Reactant: OCCBr
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S1(=O)N(CCBr)c2ccccc2N1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Diisopropyl azodicarboxylate (0.47 mL, 2.4 mmol, 1.2 equiv.) was added dropwise to a solution of 1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared in an analogous manner as described in general procedure I, 493 mg, 2.00 mmol), 2-bromoethanol (275 mg, 2.20 mmol, 1.1 equiv.) and triphenylphosphine (630 mg, 2.40 mmol, 1.2 equiv.) in dry THF (10 mL) at 0° C. under nitrogen. The solution was stirred overnight while warming to room temperature. Solvent was removed and the oil residue was pre-adsorbed onto Florisil and purified via Isco flash column chromatography (40-g redisep silica gel column, 0-30% ethyl acetate/hexane) to give 706 mg (86%) of 1-(2-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as a viscous, colorless liquid. HRMS: calculated for C14H13BrN2O2S+Na+, 374.9773; found (ESI, [M+H]+), 374.9780.
Reaction SMILES: [CH2:1]([S:5]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)=[O:26])=[CH:20][CH:19]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[SH2:44]>C(N(CC)CC)C>[CH2:1]([S:5]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([C:35](=[S:44])[NH2:36])=[CH:31][CH:30]=2)=[O:26])=[CH:20][CH:19]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)N[C@@H](Cc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1)C(=O)OC(C)(C)C
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)N[C@@H](Cc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)cc1)C(=O)OC(C)(C)C

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (d) (2.32 g), pyridine (88 ml), triethylamine (13 ml) and H2S gas were reacted to give t-butyl (2S)-2-(n-butylsulphonylamino)-3-[4-[3-(4-thiocarbamoylbenzoyl)ureido]phenyl]propionate (2.4 g) as a yellow solid: NMR Spectrum (DMSO-d6) 0.79 (3H, t), 1.22 (2H, m), 1.38 (11H, m), 2.70 (2H, t), 2.79 (1H, m), 2.95 (1H, m), 3.95 (1H, m), 7.27 (2H, d), 7.53 (2H, d), 7.68 (1H, d), 7.96 (2H, d), 8.03 (2H, d), 9.66 (1H, br s), 10.05 (1H, br s), 10.74 (1H, s), 11.10 (1H, s); Mass Spectrum m/Z 563 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.[Cl:14][C:15]([F:20])([F:19])[C:16](Cl)=[O:17].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:16](=[O:17])[C:15]([Cl:14])([F:20])[F:19])=[C:7]([CH3:12])[CH:6]=1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Reactant: O=C(Cl)C(F)(F)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CNC(=O)Oc1ccc(NC(=O)C(F)(F)Cl)c(C)c1

Procedure:
According to general procedures outlined above, 3-methyl-4-aminophenyl N-methylcarbamate (2.3g., 0.0128 mole) was reacted with chlorodifluoroacetyl chloride (2.1g., 0.014 mole) in the presence of triethylamine (1.4g., 0.014 mole) and benzene. The product was a light tan solid (1.6g., m.p. 156°-58.5° C.).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:18]=[C:17]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[N:16]=[CH:15][C:14]=3[N:27]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[CH:31]1([CH2:30][O:10][C:9]2[CH:8]=[CH:7][C:6]([C:11]3[O:12][C:13]4[CH:18]=[C:17]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[N:16]=[CH:15][C:14]=4[N:27]=3)=[CH:5][C:4]=2[O:3][CH:2]([F:1])[F:28])[CH2:33][CH2:32]1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)c(OC(F)F)c3)nc2cn1
Reactant: BrCC1CC1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4CC4)c(OC(F)F)c3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(3-(difluoromethoxy)-4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (bromomethyl)cyclopropane, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Br[CH2:14][CH2:15][OH:16].[OH-].[K+]>CN(C)C=O.O>[OH:16][CH2:15][CH2:14][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1
Reactant: OCCBr
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: OCCOc1ccc2cc(Br)ccc2c1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of 6-bromo-2-naphthol (15.1 g, 67.7 mmol), 2-bromoethanol (10.11 g, 80.9 mmol) in N,N-dimethylformamide (60 ml) was added a solution of KOH (5.41 g, 81.9 mmol) and KI (0.37 g, 2.20 mmol) in water (10 ml). Upon stirring at 85° C. for 4 hours, the reaction mixture was filtered. The filtrate was shaken with diethyl ether (400 ml) and water (400 ml). The organic layer was washed with 2% KOH (100 ml water). The solvent was evaporated off to obtain crude product. Recrystallization from a mixed solvent of methanol (20 ml) and water (200 ml) yielded (h) in 10.0 g (55%). Proton-NMR spectral data (CDCl3), δ (ppm): 2.16 (t, HOCH2, 1H), 4.10 (m, HOCH2CH2, 2H), 4.22 (t, ArOCH2CH2,2H), 7.10-7.95 (m, aromatic, 6H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[N:7][C:6]=2[N:5]([CH2:12][CH3:13])[CH:4]=[C:3]1[C:14]([O:16]CC)=[O:15].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[O:1]=[C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[N:7][C:6]=2[N:5]([CH2:12][CH3:13])[CH:4]=[C:3]1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cn(CC)c2ncncc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cncnc21

Procedure:
0.6 g. of this ester and 10 cm3 of a 10% solution of Na2CO3 are heated under reflux for 20 minutes. After cooling, the solution is acidified by means of acetic acid. The precipitate (0.5 g.) is filtered off and recrystallised from water. 0.2 g. of 5-oxo-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine-6-carboxylic acid is obtained, melting point 225° C. (decomposition).
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[C:13]([CH3:14])=[CH:12][S:11][CH:10]=2)[O:3]1.O>CC(C)=O>[CH3:14][C:13]1[C:9]([B:4]([OH:5])[OH:3])=[CH:10][S:11][CH:12]=1
Reactant: Cc1cscc1B1OC(C)(C)C(C)(C)O1
Solvent: O
Solvent: CC(C)=O
Product: Cc1cscc1B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
A solution of 4,4,5,5-tetramethyl-2-(4-methyl-thiophen-3-yl)-[1,3,2]dioxaborolane (3.69 g, 16.47 mmol) in acetone (30 mL) is treated with H2O (30 mL), followed by NaIO4 (7.05 g, 32.95 mmol). The resulting mixture is stirred at rt overnight. The organic solvent is removed in vacuo. The residue is diluted with H2O (50 mL), extracted with EtOAc ((2×100 mL). The organic extracts are combined, dried with Na2SO4, filtered and concentrated. Purification of the crude material by chromatography gives the title compound (0.82 g, 5.78 mmol, 35%). 1H NMR (CDCl3): δ 1.33 (s, 3H), 2.64-2.66 (m, 2H), 7.00-7.02 (m, 1H), 8.27 (d, J=3.0 Hz, 1H). ES-MS (m/z): calcd for C5H7BO2S (M−H)−: 141.0; found: 141.1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[N:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]([O:28]C)=[O:27])[CH:23]=[CH:22][CH:21]=3)[O:17][N:16]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[N:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)[O:17][N:16]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2nc(C(=O)CCCCCCc3ccccc3)no2)n1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(-c2nc(C(=O)CCCCCCc3ccccc3)no2)n1
Yield: 98.8 %

Procedure:
The title compound was prepared from 10f (5.2 mg, 0.008 mmol) following general procedure A. Flash chromatography (SiO2, 0.5×6 cm, 0-2% AcOH-EtOAc) afforded the title compound (3 mg, 99%) as a white solid: NMR (acetone-d6+0.1% TFA, 500 MHz) δ 8.58 (dd, 1H, J=1.0, 7.7 Hz), 8.44 (dd, 1H, J=1.1, 7.8 Hz), 8.38 (t, 1H, J=7.7 Hz), 7.25 (t, 2H, J=7.5 Hz), 7.20 (d, 2H, J=6.9 Hz), 7.14 (t, 1H, J=7.2 Hz), 3.18 (t, 2H, J=7.3 Hz), 2.63 (t, 2H, J=7.7 Hz), 1.78 (m, 2H), 1.65 (m, 2H), 1.44 (m, 4H); 13C NMR (acetone-d6+0.1% TFA, 150 MHz) δ 192.7, 176.7, 168.3, 166.2, 150.7, 144.7, 144.6, 141.8, 130.2, 130.1, 129.7, 129.6, 127.4, 42.4, 37.5, 33.2, 31.3, 30.5, 24.9; HRMS-ESI-TOF m/z 380.1601 ([M+H]+, C21H21N3O4 requires 380.1605).