Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:15]3[CH2:16][CH2:17][O:18][CH:14]3[O:13][N:12]=2)=[C:9]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:24]1(=O)[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]1>ClCCl>[Cl:1][C:2]1[C:10]([C:11]2[CH:15]3[CH2:16][CH2:17][O:18][CH:14]3[O:13][N:12]=2)=[C:9]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=1)=[O:5]
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C1=NOC2OCCC12
Reactant: O=C1CCCC(=O)C1
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)CCC2)c(Cl)c1C1=NOC2OCCC12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.9 g (2.5 mmol) of 2-chloro-4-ethylsulfonyl-3-(3a,4,5,6a-tetrahydrofuro[3,2-d]-isoxazol-3yl)benzoic acid together with 0.31 g (2.8 mmol) of 1,3-cyclohexandione in 50 ml of dichloromethane are treated with 0.53 g (2.8 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimi hydrochloride and 0.1 g of N,N-dimethylaminopyridine. After the mixture has been stirred for 16 hours at room temperature, it is washed with 1 N hydrochloric acid and sodium chloride solution and dried over magnesium sulfate. It is filtered with suction and the filtrate is concentrated. This gives 0.66 g (58% of theory) of crude 3-oxocyclohex-1-enyl 2-chloro-4-ethylsulfonyl-3-(3a ,4,5,6a-tetrahydrofurro[3,2-d]isoxazol-3-yl)benzoate.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])(=O)[NH2:24]>C1(C)C=CC=CC=1>[C:23]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])(=[S:10])[NH2:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: NC(=S)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
Part A. Lawesson's reagent (90 mg, 0.22 mmol) was added to a stirred slurry of benzyl (S)-2-carbamoyl-pyrrolidine-1-carboxylate (100 mg, 0.40 mmol) in toluene (3 mL) at ambient temperature. The reaction mixture was heated to 100° C. for 3 h then the solvents were removed. The residue was purified by flash silica gel chromatography yielding benzyl (S)-2-thiocarbamoylpyrrolidine-1-carboxylate as white solid (108 mg, crude quantative yield): HPLC (method 1) tR=2.55 min, Purity 100%; LCMS (method 4) tR=1.34 min, m/z 287 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[N:4]=1.[C-:27]#[N:28].[Na+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[N:4]=[C:3]2[CH2:2][C:27]#[N:28]
Reactant: [C-]#N
Reactant: COc1ccc(Cn2nc(CCl)c3cc(OC)c(OC)cc32)cc1OC
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Cn2nc(CC#N)c3cc(OC)c(OC)cc32)cc1OC
Temperature: 25 °C
Yield: 60.9 %

Procedure:
3-Chloromethyl-5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazole (187.0 g) was dissolved in dimethyl sulfoxide (1000 ml) and a solution was stirred at room temperature. Then sodium cyanide (134.0 g) which had been ground in a mortar was added thereto. The reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was returned to room temperature, poured into water (15000 ml) and stirred for 1 hour. The solid thus precipitated was collected by filtration, washed with water (1000 ml×3), dissolved in chloroform (5000 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue thus obtained was purified by using silica gel columns (chloroform/ethanol 50/1, silica gel 2 kg, followed by silica gel 2 kg, ethyl acetate/hexane=3:1) to give 111.0 g of a pale brown solid product. This solid product was used in the subsequent reaction without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=1[C:16]([F:17])([F:18])[F:19])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCOc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCOc1ccc(N)cc1C(F)(F)F
Yield: 101.1 %

Procedure:
A solution of 4-Nitro-1-pentyloxy-2-trifluoromethyl-benzene (1.2 g, 4.8 mmole) and 0.1 g of 10% Palladium on activated carbon in 40 mL of ethanol is hydrogenated with hydrogen balloon at room temperature overnight. Filtration and concentration gave a pink oil 1.2 g (100%) of 4-Pentyloxy-3-trifluoromethyl-phenylamine MS: 248 (M+1).
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].[CH3:11][CH2:12][C@:13]12[CH2:29][C@:28]([OH:34])([C:30]([O:32][CH3:33])=[O:31])[N:27]3[C:19]4=[C:20]([CH2:35][CH2:36][N:17]([C@@H:18]14)[CH2:16][CH2:15][CH2:14]2)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=13>CO>[CH3:11][CH2:12][C@:13]12[CH2:29][C@:28]([OH:34])([C:30]([O:32][CH3:33])=[O:31])[N:27]3[C:19]4=[C:20]([CH2:35][CH2:36][N:17]([C@@H:18]14)[CH2:16][CH2:15][CH2:14]2)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=13.[O:1]=[C:2]([CH2:6][CH2:7][C:8]([O-:10])=[O:9])[C:3]([O-:5])=[O:4]
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: CC[C@]12CCCN3CCc4c(n(c5ccccc45)[C@@](O)(C(=O)OC)C1)[C@@H]32
Solvent: CO
Product: O=C([O-])CCC(=O)C(=O)[O-]

Procedure:
12 g. (0.082 mole) of 2-ketoglutaric acid are dissolved in 500 ml. of methanol. The solution is brought to the boil and 22.5 g. (0.0635 mole) of vincamine are added a small amount at a time, with vigorous agitation. When dissolution is complete, the resulting solution is concentrated in a rotary evaporator until its volume is reduced to 200 ml. On cooling, 22 g. of vincamine 2-ketoglutarate are obtained. By adding 500 ml. of ethyl ether to the mother liquors, a further amount of 9.6 g. of the salt are obtained. The total amount of salt obtained is therefore, 29.6 g. (yield 93%). The melting point is 214°-215°C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]3[CH2:17][CH2:16][CH:15]([NH:18][OH:19])[CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.C[Si]([N:26]=[C:27]=[O:28])(C)C.C(O)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]3[CH2:17][CH2:16][CH:15]([N:18]([OH:19])[C:27]([NH2:26])=[O:28])[CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:20][CH:21]=1
Reactant: ONC1C=C(c2cccc(Oc3ccc(F)cc3)c2)CC1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)N(O)C1C=C(c2cccc(Oc3ccc(F)cc3)c2)CC1
Reaction time: 1 h

Procedure:
To a stirred solution of N-[3-[3-(4-fluorophenoxy)phenyl]cyclopent-2-enyl]-N-hydroxylamine (1.07 g; 3.75 mM) in dry THF (10 ml) was added trimethylsilyl isocyanate (0.76 g; 5.63 mM) at room temperature. After stirring for 1 hr, ethanol (10 ml) was added. Volatiles were removed, and the resulting solids were recrystallized from ethyl acetate-n-hexane to give 0.6 g (y. 28%) of the subtitle compound [G] as colorless solids.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.[SH2]=N.[C:15]1([NH:21][C:22](C2C=CC=CC=2C(O)=O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:15]1([NH:21][C:22]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Agent: N=[SH2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NCc1ccccc1)Nc1ccccc1
Temperature: 5 °C
Yield: 87.3 %

Procedure:
A mixture of 1.1 g benzylamine and 5 ml aceton was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 20 ml aceton, under stirring. The reaction mixture was stirred for 35 minutes at room temperature, then diluted with 150 ml water and cooled to 5° C. The precipitated solid product was filtered, washed with water and dried. 1.02 g 1-phenyl-3-benzylurea was obtained with a melting point of from 170° to 172° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([N:15]([CH2:29][CH2:30][OH:31])[C:16](=[O:28])[C@@H:17]([NH:20]C(=O)OC(C)(C)C)[CH2:18][CH3:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:20][C@@H:17]([CH2:18][CH3:19])[C:16]([N:15]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:29][CH2:30][OH:31])=[O:28]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(CCO)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)C(=O)N(CCO)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
TFA(10 mL) was added to (S)-tert-butyl 1-(benzyl(2-hydroxyethyl)amino)-1-oxobutan-2-ylcarbamate (3 g, 8.92 mmol) in CH2Cl2 (50 mL) at 0° C. The mixture was stirred at 0° C. for 1.5 h, followed by solvent removal under reduced pressure. The residue was partitioned between CH2Cl2 (300 mL) and 25% aqueous sodium hydroxide (100 mL). The aqueous fraction was further extracted with CH2Cl2 (2×100 mL), and combined organic fraction was dried (Na2SO4), filtered and concentrated to afford (S)-2-amino-N-benzyl-N-(2-hydroxyethyl)butanamide as a yellow oil (1.84 g, 87%). 1H NMR consistent.
Reaction SMILES: [F:1][C:2]1[CH:12]=[N:11][CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[F:1][C:2]1[CH:12]=[N:11][CH:10]=[CH:9][C:3]=1[CH2:4][OH:5]
Reactant: CCOC(=O)c1ccncc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1ccncc1F

Procedure:
The product of Example 129A and LiAlH4 were processed according to the method of Example 124B to provide the product. MS (ESI+) m/z 128 (M+H)+;
Reaction SMILES: [ClH:1].Cl.[CH3:3][NH:4][C:5]1([CH2:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:6]1.O.[OH-].[Na+].[C:19](=O)([O-])[O-].[Na+].[Na+]>CCOCC.O1CCOCC1>[ClH:1].[CH3:3][N:4]([CH3:19])[C:5]1([CH2:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: CNC1(CCc2cccnc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN(C)C1(CCc2cccnc2)CC1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
1.5 g of the compound of Example 30 are dissolved in 10% aqueous sodium carbonate solution; the mixture is then extracted with ether, dried over sodium sulphate and concentrated to dryness. 1.17 ml of formol and 1.43 g of formic acid at 5° C. are then added to the residue obtained, followed by 0.15 ml of water. The mixture is heated at reflux for 5 hours, cooled to 50° C. and then made alkaline by the addition of 4N sodium hydroxide solution. Extraction with ether, followed by evaporation of the aqueous phase allows a residue to be obtained which is taken up in a mixture of 20 ml of ether and 3 ml of dioxane/4N hydrochloric acid. The mixture obtained is diluted with 50 ml of ether and stirred for 20 hours, and is then filtered and dried, allowing the expected product to be isolated.
Reaction SMILES: [C:1]1([C:7]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[N:24][C:10]3[O:11][CH2:12][C:13]4[N:14]([C:15]([C:18]5[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=5)=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:1]1([C:7]2[C:25]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4([NH2:36])[CH2:35][CH2:34][CH2:33]4)=[CH:30][CH:31]=3)=[N:24][C:10]3[O:11][CH2:12][C:13]4[N:14]([C:15]([C:18]5[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=5)=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccncc3)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccncc3)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 88.2 %

Procedure:
Tert-butyl (1-(4-(8-phenyl-1-(pyridin-4-yl)-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (14 mg, 0.024 mmol) was dissolved in dichloromethane (1 ml); TFA (0.5 ml) was added at room temperature and the resulting mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexane (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (10 mg, 87% yield). LCMS (Method A) RT=3.66 min, M+H+=474. 1H NMR (500 MHz, CDCl3): 8.77 (2H, d), 8.79 (2H, d), 7.41 (2H, d), 7.33 (1H, s), 7.32 (2H, d), 7.18-7.13 (3H, m), 6.96 (2H, dd), 5.66 (2H, s), 2.70-2.61 (2H, m), 2.52-2.43 (2H, m), 2.19-2.08 (1H, m), 1.92-1.82 (1H, m).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[BH4-].[Na+]>C(O)C>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12]
Reactant: O=Cc1ccc2ncccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc2ncccc2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirbar was charged with Intermediate 4B, 1,5-naphthyridine-2-carbaldehyde (200 mg, 1.265 mmol). Ethanol (12.6 mL) was added to give a solution. To this stirred solution was added, portionwise, sodium borohydride (47.8 mg, 1.265 mmol). The reaction mixture was stirred at ambient temperature for 15 minutes, then quenched with aqueous sodium bicarbonate. Volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous layer was extracted once more with EtOAc, then the combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give (1,5-naphthyridin-2-yl)methanol as a pale yellow solid that was purified by eluting through a plug of silica gel with 100% EtOAc. After evaporation of the solvent under reduced pressure, an off white solid was obtained, which was dried in a vacuum oven at ambient temperature for 3 days to give (1,5-naphthyridin-2-yl)methanol (142 mg, 70%). 1H NMR (300 MHz, methanol-d4) δ 8.94 (dd, J=4.3, 1.6 Hz, 1H), 8.47-8.40 (m, 2H), 7.96 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.6, 4.3 Hz, 1H), 4.91 (s, 2H). MS (DCI—NH3) m/z=161 (M+H)+, m/z=178 (M+NH4)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[N:4]1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([N:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[N:4]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
To a stirred suspension of NaH (53 mg, 1.33 mmol, 60% dispersion in mineral oil) in THF (5 mL), was added dropwise over 3 min a solution of ethyl 1H-pyrazole-4-carboxylate (155 mg, 1.11 mmol). The mixture was stirred at rt for 45 min and then treated with benzyl bromide (neat). After 2 h, the reaction was quenched with saturated solution of NH4Cl and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (Isco CombiFlash) 0-60% EtOAc/heptane provided ethyl 1-benzyl-1H-pyrazole-4-carboxylate (256 mg, 98%). 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (t, J=7.09 Hz, 3H), 4.28 (q, J=7.08 Hz, 2H), 5.31 (s, 2H), 7.24-7.28 (m, 2H), 7.31-7.42 (m, 3H), 7.86 (s, 1H), 7.95 (s, 1H); LCMS-MS (ESI+) 230.80 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32]>>[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2)=[O:32]
Reactant: O=C(O)c1cccc(F)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc(F)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-fluoro-benzoic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:27]=[CH:28][N:29]=[C:2]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:3]=3)=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(N2CCCC2)c1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and pyrrolidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.21 (m, 2H), 7.83 (m, 1H), 7.59 (m, 2H), 7.42 (d, 1H), 7.10 (m, 2H) 7.02 (m, 2H), 4.31 (t, 2H), 3.61 (m, 4H), 3.49 (m, 4H), 2.87 (t, 2H), 2.58 (m, 4H), 1.99 (m, 4H). MS: 447.2 (M+1).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14](=[O:21])[CH2:15][C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17]>ClCCl>[Br:1][CH:15]([C:16]([CH:18]1[CH2:19][CH2:20]1)=[O:17])[C:14]([C:5]1[CH:6]=[CH:7][C:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:9][C:4]=1[Cl:3])=[O:21]
Reactant: CS(=O)(=O)c1ccc(C(=O)CC(=O)C2CC2)c(Cl)c1
Reactant: BrBr
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)C(Br)C(=O)C2CC2)c(Cl)c1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Under an inert atmosphere, bromine (0.24 g) is slowly added dropwise to a solution of (1-[2-chloro-4-(methylsulphonyl)phenyl]-3-(cyclopropyl)propan-1,3-dione (0.43 g) in 25 ml of dichloromethane cooled to 5° C., then the mixture is stirred overnight at room temperature.
Reaction SMILES: Br[C:2]([CH:9]=[O:10])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[N-:11]=[N+:12]=[N-:13].[Na+]>C(COC)OC.O>[N:11]([C:2]([CH:9]=[O:10])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N+:12]=[N-:13]
Reactant: CCOC(=O)C(C)(Br)C=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(C)(C=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl α-bromo-α-formylpropionate (20 g.) in dimethoxyethane (200 ml.) is added a solution of sodium azide (8 g.) in water (40 ml.) and the mixture is stirred at room temperature for 5 hours. The dimethoxy ethane is removed under reduced pressure and the residue is taken up in a mixture of ether and water. The ethereal phase is separated, washed with water, dried over anhydrous sodium sulfate and evaporated yielding ethyl α-azido-α-formylpropionate which is purified by vacuum distillation.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[CH2:8][NH:9][C@@H:10]1[C@@H:15]([OH:16])[C@H:14]([CH2:17][C:18]2[CH:23]=[C:22](F)[C:21]([N+:25]([O-:27])=[O:26])=[C:20]([F:28])[CH:19]=2)[CH2:13][S:12](=[O:30])(=[O:29])[CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]([F:42])([F:41])[C@H:36]([OH:40])[CH2:37][O:38][CH3:39]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[CH2:8][NH:9][C@@H:10]1[C@@H:15]([OH:16])[C@H:14]([CH2:17][C:18]2[CH:23]=[C:22]([O:40][C@H:36]([CH2:37][O:38][CH3:39])[C:35]([F:42])([F:41])[F:34])[C:21]([N+:25]([O-:27])=[O:26])=[C:20]([F:28])[CH:19]=2)[CH2:13][S:12](=[O:29])(=[O:30])[CH2:11]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COC[C@@H](O)C(F)(F)F
Reactant: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3cc(F)c([N+](=O)[O-])c(F)c3)[C@@H]2O)c1
Product: COC[C@@H](Oc1cc(C[C@@H]2CS(=O)(=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F

Procedure:
The title compound was prepared in analogous manner as described for example 24j) from (3R,4S,5S)-3-(3-tert-butyl-benzylamino)-5-(3,5-difluoro-4-nitro-benzyl)-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-ol (example 24i) and (R)-1,1,1-trifluoro-3-methoxy-propan-2-ol to yield the title compound as a colorless foam: TLC (EtOAc-MeOH 19:1) Rf=0.47; HPLC RtA=2.13 min; ESIMS [M+H]+=607; 1H NMR (600 MHz, DMSO-d6): δ 7.34 (s, 1H), 7.28 (s, 1H), 7.24 (m, 2H), 7.143 (d, 1H), 7.10 (d, 1H), 5.59 (m, 1H), 5.30 (d, 1H), 3.80 (m, 2H), 3.70 (dd, 1H), 3.64 (d, 1H), 3.40 (dt, 1H), 3.29 (s, 3H), 3.21 (m, 1H), 3.12 (dd, 1H), 3.03 (m, 2H), 2.81 (m, 1H), 2.62 (dd, 1H), 2.42 (m, 1H), 2.14 (m, 1H), 1.27 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:14][CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)([OH:21])[C:17]([F:20])([F:19])[F:18])[CH3:13]>>[CH2:12]([N:14]([CH2:15][C:16]([CH2:22][NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:33]1[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=1)([OH:21])[C:17]([F:19])([F:20])[F:18])[C:4](=[O:5])[C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[F:11])[CH3:13]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(F)cccc1F

Procedure:
Prepared similarly to Example 48 from 2,6-difluorobenzoyl chloride and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[O:5][CH:6]=1.C([Li])(C)(C)C.[CH2:20]([Sn:24]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])Cl)[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:4]2[O:5][CH:6]=[C:2]([Sn:24]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=2)[CH2:9][CH2:10]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CN1CCN(Cc2cc(Br)co2)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1coc(CN2CCN(C)CC2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.3 %

Procedure:
A stirred mixture of 1-((4-bromofuran-2-yl)methyl)-4-methylpiperazine (2.10 g, 8.10 mmol) and THF (50 mL) was cooled to −78° C. in a dry ice/acetone bath. tert-Butyllithium (7.60 mL, 12.2 mmol; 1.6 M in pentane) was added and the reaction mixture was stirred for 30 minutes. Next, tributylchlorostannane (2.09 ml, 7.70 mmol) was added and the reaction mixture was stirred for 30 minutes. The reaction was quenched by addition of pH 7 phosphate buffer (20 mL) and warming to room temperature. The mixture was extracted with diethyl ether, dried over sodium sulfate, filtered and concentrated. The crude material was purified on a Biotage 40S column, eluting with 1:1 EtOAc/hexanes (500 mL), 2:1 EtOAc/hexanes (500 mL), then EtOAc (1 L) to provide a product mixture as a light yellow oil (0.77 g, 86:14 ratio of 1-((4-bromo-5-(tributylstannyl)furan-2-yl)methyl)-4-methylpiperazine to 1-methyl-4-((4-(tributylstannyl)furan-2-yl)methyl)piperazine by 1H-NMR). The mixture was carried forward without separation at this step.