Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([C:12]2[NH:13][O:14][C:15](=O)[CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>>[C:6]1([C:12]2[CH:16]=[C:15]([Cl:3])[O:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccccc2)[nH]o1
Solvent: CCN(CC)CC
Product: Clc1cc(-c2ccccc2)no1
Reaction time: 8 h

Procedure:
To 84.3 g (0.55 mol) of phosphorus oxychloride, 18.3 g (0.11 mol) of 3-phenyl-5-isoxazolone were added under stirring. While the internal temperature was maintained at 0°-10.C., 11.1 g (0.11 mol) of triethylamine were added further. They were then reacted under heating and stirring at 100°-120° C. for 3 hours. The reaction mixture was allowed to stand overnight at room temperature, and precipitated insoluble matter was filtered off. After the filtrate thus obtained was concentrated under reduced pressure, the residue was transferred into 500 ml of ice water, followed by neutralization with sodium hydrogencarbonate. The solution was extracted with ethyl ether. The organic layer was washed with water and then dried. The solvent was distilled off and the residue was purified by silica gel column chromatography (solvent: hexane/ethyl acetate=20/1), whereby the title compound was obtained as colorless crystals.
Reaction SMILES: C([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@:11]3([OH:27])[CH2:12][CH2:13][C@@H:14]2[CH2:15][C:16]#[N:17])[CH2:6]1)(=O)C.P([O-])(O)(O)=O.[Na+]>CO.O1CCCC1.[OH-].[Na+]>[OH:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@:11]3([OH:27])[CH2:12][CH2:13][C@@H:14]2[CH2:15][C:16]#[N:17])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](CC#N)CC[C@]32O)C1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](CC#N)CC[C@]12O
Yield: 86.2 %

Procedure:
A solution of 11.18 g of 3β-acetoxy-14β-hydroxy-5β-pregnane-21-nitrile in 260 ml of methanol, 260 ml of tetrahydrofuran and 143 ml of 1N NaOH was stirred at room temperature for 20 hrs. The mixture was then neutralized with sodium dihydrogenphosphate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to dryness under reduced pressure to give 8.55 g of 3β,14β-dihydroxy-5β-pregnane-21-nitrile.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)(=[O:5])=[O:4])[CH3:2].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>>[CH2:1]([S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[C:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH:19]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CN1CCC(=O)CC1
Reactant: CCS(=O)(=O)Nc1ccc2[nH]ccc2c1
Product: CCS(=O)(=O)Nc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Yield: 113.3 %

Procedure:
Beginning with 1.45 gm (6.5 mMol) 5-ethanesulfonylamino-1H-indole and 1.03 mL (3.4 mMol) 1-methyl-4-piperidone, 1.23 gm (59.7%) of the title compound were recovered as pale orange crystals.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)=[O:28])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1>>[O:31]1[CH:32]=[CH:33][C:29]([C:27]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[C:25]([C:2]3[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)=[O:7])=[CH:4][N:3]=3)[CH:24]=2)=[O:28])=[CH:30]1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)nc2)cc1

Procedure:
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(4-methoxyphenyl)-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and N-[4-methyl-3 -(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 3.19 min, MH+428. NMR: δH [2H6]-DMSO 10.38, (1H, s), 10.00, (1H, s), 9.19, (1H, s), 8.38, (2H, m), 7.83, (1H, s), 7.80, (1H, s), 7.76, (1H, s), 7.73-7.69, (3H, m), 7.32, (1H, s), 7.01, (1H, s), 6.96, (2H, d), 3.76, (3H, s), 2.34, (3H, s).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[O:1][N:2]=[C:3]([N:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:8][CH2:9]2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2noc(-c3cccs3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
To a cold (0° C.) solution of tert-butyl 4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (8 g, 32.7 mmol) in anhydrous DCM (150 mL) was added thiophene-2-carbonyl chloride (4.8 g, 32.7 mmol) followed by DIEA (7.2 mL, 39.2 mmol). The reaction mixture was stirred at RT for 12 hours and then filtered. The filtrate was evaporated and the residue was refluxed in pyridine (100 mL) for 3 hours. The solvent was removed under vacuum and the residue was dissolved in DCM. The organic layer was washed with a 10% aq. solution of sodium bicarbonate, water, brine and dried. The solvent was concentrated and the residue was purified by chromatography (Pet. Ether/EtOAc 7/3) to give 2.2 g (20%) of The title compound as a solid. TLC-Pet ether/EtOAc (9/1): Rf=0.75. HPLC purity>97%.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:48])[CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[C:23]([N:33]3[CH2:38][CH2:37][CH2:36][CH:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34]3)=[N:22][C:21]=2[N:20]([CH3:47])[C:18]1=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:6]([O:5][C:3]([CH2:2][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:48])[CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[C:23]([N:33]3[CH2:38][CH2:37][CH2:36][CH:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34]3)=[N:22][C:21]=2[N:20]([CH3:47])[C:18]1=[O:19])=[O:4])[CH3:7]
Reactant: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1O)c(=O)n2C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccccc1C(=O)Cn1c(=O)c2c(nc(N3CCCC(NC(=O)OC(C)(C)C)C3)n2CC=C(C)C)n(C)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
63 mg of ethyl bromoacetate are added to a mixture of 200 mg of 1-[2-(2-hydroxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine and 63 mg of potassium carbonate in 3 ml N,N-dimethylformamide. The reaction mixture is stirred for five hours at ambient temperature. For working up it is combined with water and the precipitate formed is suction filtered, washed with water and dried for three hours at 80° C. in the drying cupboard.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:21][CH2:20]1
Reactant: IC1CCCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(C4CCCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 112 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and iodocyclohexane.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:9][N+:10]([O-])=O)([OH:8])[CH2:4][CH2:3]1>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:10][CH2:9][C:5]1([OH:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(O)(C[N+](=O)[O-])CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(O)(CN)CC1
Yield: 106.3 %

Procedure:
Palladium hydroxide (2.3 g of 20% on carbon) was added to a solution of 1-methyl-4-nitromethylpiperidin-4-ol (11.57 g) in ethanol (120 mL). The mixture was placed under hydrogen pressure (50 psi, 3.4×105 Pa) on a Parr apparatus for 55 hours. The reaction mixture was filtered through a layer of CELITE filter aid and the filter cake was rinsed with methanol (100 mL). The filtrate was concentrated under reduced pressure to provide 10.18 g of 4-aminomethyl-1-methylpiperidin-4-ol as a thick oil.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[N+:14]([O-])=O)(=O)[CH3:2]>CO.Cl.O>[NH2:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[CH2:1][CH3:2])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(C(C)=O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Solvent: O
Product: CCc1ccc(C(=O)OC)cc1N

Procedure:
The method described in Step 2. of Example 1 was applied to a solution of 35 (0.17 g) in methanol (20 mL) and 10% hydrochloric acid/water (5 mL) to prepare the above named compound. NMR (300 MHz, CDCl3) δ 7.40 (1H, d, J=8 Hz), 7.34 (1H, s), 7.10 (1H, d, J=8 Hz), 3.88 (3H, s), 3.71 (2H, b), 2.54 (2H, q, J=8 Hz), 1.26 (3H, t, J=8 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][C:3]=1[N:10]1[N:14]=[C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]2=[N:11]1.[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>CC(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22])=[CH:4][C:3]=1[N:10]1[N:14]=[C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]2=[N:11]1
Reactant: OCCNCCO
Reactant: Oc1ccc(CBr)cc1-n1nc2ccccc2n1
Solvent: CC(C)=O
Product: OCCN(CCO)Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
2-(2′-Hydroxy-5′-bromomethylphenyl)benzotriazole (3.03 g, 0.01 mole), diethanol amine (3.14 g, 0.03 mole) were dissolved in 100 mL of acetone. The reaction mixture was refluxed with constant stirring at 75° C. for 6 h. The solvent was then removed by rotary evaporation. Crude product was purified using silica gel column chromatography. Product was identified by 1H-NMR.
Reaction SMILES: [CH:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:25][C:26]([N:28]([CH:37]([CH3:39])[CH3:38])[C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)=[O:27]>CN(C=O)C.O>[CH:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[N:13]([CH2:25][C:26]([N:28]([CH:37]([CH3:39])[CH3:38])[C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[O:27])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1Cc2nnc(C3CCCCC3)n2-c2ccccc2N1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(C4CCCCC4)n3-c3ccccc32)C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-cyclohexyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(B) (100 mg, 0.354 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in oil, 15 mg, 0.372 mmol). The reaction was stirred at 0° C. for 30 minutes, was cooled to −10° C. and 2-bromo-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide (Preparation 1(B) (107 mg, 0.372 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature for 24 h and was diluted with water. The aqueous solution was washed with EtOAc (3×). The combined organic solutions were dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (1% EtOAc in hexanes to 100% EtOAc) to provide 861.8 mg of 2-(1-cyclohexyl-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CDCl3) δ 8.11-7.48 (m, total 3H), 7.36 (m, 3H), 6.79 (dd, 1H), 4.99 (m, 1H), 4.12 (m, 2H), 3.92 (d, 3H), 3.65 (d) and 3.82 (d, total 1H), 3.46 (dd, 1H), 2.83 (m, 1H), 2.20 (d, 1H), 2.03-1.86 (m, 3H), 1.68 (m, 2H), 1.54 (m, 2H) 1.31-1.41 (m, 2H), 1.07 (m, 6H); MS 489.4 (M+1), 487.4 (M−1).
Reaction SMILES: [I:1]I.[C:3]1([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(O)C>[I:1][C:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: II
Reactant: c1ccc(N2CCCC2)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Ic1ccc(N2CCCC2)cc1
Reaction time: 1 h
Yield: 19.6 %

Procedure:
Iodine (6.09 g) was added slowly to a stirred solution of phenylpyrrolidine (3.21 g) and sodium bicarbonate (2.75 g) in water (30 ml). The reaction was stirred for 1 h and then left to stand overnight. The solid was isolated by filtration, dissolved in ethanol (50 ml) and discoloured with aqueous sodium thiosulfate. The product was then isolated by filtration and recrystalised from ethanol to give the desired product as a brown/red powder (1.17 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[CH2:17]2)[CH:7]=1)=[O:4].[N-:27]=[N+:28]=[N-:29].[Na+]>C(#N)C.C(OCC)(=O)C>[N:27]([CH2:2][C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[CH2:17]2)[CH:7]=1)=[O:4])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)Nc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: [N-]=[N+]=NCC(=O)Nc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
To a solution of 2-chloro-N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]acetamide (70 mg, 0.19 mmol) in acetonitrile (2 mL) was added sodium azide (62 mg, 0.95 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (20 mL), and then washed with water (10 mL). The ethyl acetate fraction was dried over sodium sulfate, and then concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1:4) to give 65 mg of product as a white powder (yield was 91.8%). MS obsd. (ESI+) [(M+H)+] 373.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37]C(C)(C)C)=[O:36])=[C:33]([F:44])[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([OH:37])=[O:36])=[C:33]([F:44])[CH:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:45])=[C:16]([F:22])[CH:17]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)OC(C)(C)C)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 6 h
Yield: 95.3 %

Procedure:
In a 50 mL round-bottomed flask, tert-butyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-fluorobenzoate (170 mg, 257 μmol, Eq: 1.00) was combined with CH2Cl2 (3 mL) to give a colorless solution. TFA (3 ml) was added and the reaction was stirred for 6 hours. The crude reaction mixture was concentrated in vacuum, added DCM and concentrated again. Recrystallization from diethyl ether and hexanes afforded a white solid (148 mg, 93% yield). MS (ES+) m/z Calcd: [(M+H)+]: 604. found: 604.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[C:7]=1[N+:13]([O-:15])=[O:14].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>>[NH2:12][C:8]1[C:7]([N+:13]([O-:15])=[O:14])=[C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([C:33]([F:35])([F:34])[F:36])[CH:26]=3)=[O:32])[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Nc1cc(Oc2ccnc(N)c2[N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Nc1nccc(Oc2cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc(C(F)(F)F)c2)c1[N+](=O)[O-]
Yield: 98 %

Procedure:
Method G was used with 4-(3-amino-5-(trifluoromethyl)phenoxy)-3-nitropyridin-2-amine and 4-chloro-3-trifluoromethylphenyl isocyanate to afford the title compound as a yellow powder (262 mg, 98%). 1H-NMR (δ, ppm, DMSO-d6): 6.17 (d, 1H, HPy,4, J=5.6 Hz), 7.19 (m, 1H, Harom), 7.28 (bs, 2H, NHPy), 7.56 (s, 1H, Harom), 7.61 (d, 1H, Harom, J=8.7 Hz), 7.68 (dd, 1H, Harom, J=8.7 Hz, J=2.1 Hz), 7.80 (s, 1H, Harom), 8.07 (d, 1H, Harom, J=2.3 Hz), 8.08 (d, 1H, HPy,5, J=5.6 Hz), 9.43 (bs, 2H, NHurea). 13C-NMR (δ, ppm, DMSO-d6): 101.5 (C-4); 109.9 (C-11); 111.6 (C-9); 113.0 (C-7); 117.1 (C-15); 117.2 (C-2); 122.2 (C-17); 122.8 (C-16); 123.5 (C-19); 124.4 (C-10); 126.6 (C-20); 131.0 (C-12); 131.9 (C-18); 138.7 (C-14); 142.1 (C-8); 152.2 (C-13); 153.5 (C-5); 153.9 (C-1); 154.4 (C-6); 157.8 (C-3). LC-MS (m/z): 536 (M+H, 100).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11][N:10]=1.[CH2:17]([O:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24])[CH3:18]>O1CCCC1>[CH3:18][CH2:17][O:19][CH2:20][CH2:21][NH:22][C:23]([N:10]1[C:9](=[O:8])[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11]1)=[O:24]
Reactant: CCOCCN=C=O
Reactant: CCOc1nc(O)ns1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOCCNC(=O)n1sc(OCC)nc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
1 ml of triethylamine was added to a solution of 14.6 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 140 ml of tetrahydrofuran and then 23 g of ethoxyethyl isocyanate were added dropwise. The mixture was stirred for 2 hours at 25° C and was concentrated to dryness. The residue was chromatographed over silica gel and elution with a 4-6 benzene-ethyl acetate mixture yielded 14 g of 2-(N-β-ethoxyethylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at <50° C.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[CH:4]=1.[CH3:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:15][N:16]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)[CH2:2][C:3]1[S:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[CH:4]=1
Reactant: O=[N+]([O-])c1ccc2sc(CCl)cc2c1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1cc2cc([N+](=O)[O-])ccc2s1
Reaction time: 20 h

Procedure:
A mixture of the product of part (A) above (3.20 g), N-methyl-4-nitrophenethylamine (2.52 g), anhydrous potassium carbonate (4.0 g) and acetonitrile (40 ml) was heated under reflux with stirring for 20 hours and then cooled and filtered. The residue was washed with acetonitrile, and the combined filtrate and washings were evaporated to give an oil which was chromarographed on silica gel. Elution with dichloromethane first gave impurity followed by pure product. The Product-containing fractions were evaporated to give the title compound (4.17 g), m.p. 76°-78° (from isopropanol).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[C:6]([OH:14])[CH:5]=1.[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[C:21]([Cl:26])[CH:20]=1)(=[O:18])=[O:17]>CN(C=O)C>[Cl:26][C:21]1[CH:20]=[C:19]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:24]=[CH:23][C:22]=1[O:14][C:6]1[CH:5]=[C:4]([F:3])[CH:9]=[CH:8][C:7]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1ccc(F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(F)ccc2CC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% wt. disp. oil, 0.176 g) was added to a solution of the product from step (vi) (0.34 g) in dry DMF (10 ml) and stirred at RT for 1 h before adding the product from example 3 step (vii) (0.416 g). The mixture was heated at 80° C. for 1 h, then partitioned between 2M hydrochloric acid/ethyl acetate. The organics were dried, evaporated under reduced pressure and the residue purified by reverse phase HPLC. Yield 0.064 g
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4](=O)[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Cl:14])[CH2:10][C:9]([CH2:16][CH3:17])([CH3:15])[CH2:8]2.[H][H]>CO.S(=O)(=O)(O)O.[Pt](=O)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Cl:14])[CH2:10][C:9]([CH2:16][CH3:17])([CH3:15])[CH2:8]2
Reactant: CCC1(C)Cc2cc(Cl)c(C(=O)C(=O)OC)cc2C1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCC1(C)Cc2cc(Cl)c(CC(=O)OC)cc2C1

Procedure:
A solution of 5.2 g of 2-ethyl-6-chloro-2-methyl-α-oxo-5-indanacetic acid methyl ester in 100 cc of methanol and 10 cc of concentrated sulphuric acid is hydrogenated at 45° and a hydrogen pressure of 5 atmospheres with the addition of 1.0 g of platinum(IV) oxide. After the take up of the theoretic amount of hydrogen the catalyst is filtered off, the solution is diluted with a 5% sodium bicarbonate solution and extracted with ether. The extract is washed with water, dried over sodium sulphate and concentrated by evaporation. The resulting title compound is purified by chromatography. Thin layer chromatogram: Rf value 0.60 (adsorbent: silica gel, eluant: chloroform).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:23]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:12]=2[C:13]=1[CH3:14]>N1C=CC=CC=1>[CH3:6][N:7]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:24][CH:23]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:18]=[CH:17][C:16]([NH:19][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:15][C:12]=2[C:13]=1[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(CN(C)CCc2ccc(NS(C)(=O)=O)cc2)oc2ccc(N)cc12
Solvent: c1ccncc1
Product: Cc1c(CN(C)CCc2ccc(NS(C)(=O)=O)cc2)oc2ccc(NS(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Methanesulphonyl chloride (0.21 g, 1.85 mmole) was added dropwise to a solution of N-methyl-N-(3-methyl-5-aminobenzofur-2-ylmethyl)-4-methanesulphonamidophenethylamine (see Preparation 10B--0.78 g, 1.68 mmole) in pyridine (7 ml) and the solution was then stirred at room temperature for 60 hours. The solvent was evaporated and the residue triturated with toluene. The toluene was decanted, the residue stirred with aqueous sodium bicarbonate, and the precipitate collected by filtration and recrystallised from methanol to give the title compound, yield 0.38 g, m.p. 142°-143.5°.