Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O=[C:7]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[C:10]2[CH:17]=[CH:18][C:19]([C:21]#[N:22])=[CH:20][C:9]=2[NH:8]1>>[Cl:3][C:7]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[C:10]2[CH:17]=[CH:18][C:19]([C:21]#[N:22])=[CH:20][C:9]=2[N:8]=1
Reactant: N#Cc1ccc2c(c1)[nH]c(=O)c1ccncc12
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2c(c1)nc(Cl)c1ccncc12

Procedure:
Phosphorus oxychloride (2 mL) was added to the 5-oxo-5,6-dihydrobenzo[c][2,6]naphthyridine-8-carbonitrile (150 mg, 0.66 mmol). The mixture was heated reflux for 3 hours at which time LCMS analysis indicated the absence of any starting material. Volatiles were removed under vacuum and the crude product was dissolved in dichloromethane, washed with brine and saturated aqueous sodium bicarbonate and dried over sodium sulfate. After concentrating under vacuum, the crude product was triturated with ethyl acetate and hexanes to give 5-chlorobenzo[c][2,6]naphthyridine-8-carbonitrile (125 mg). LCMS (ESI) 240.3 (M+1)+.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2.C(N(CC)CC)C.[N:25]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:2][N:3]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[CH:9]2)[C:30]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:31]
Reactant: O=C(Cl)N1CCCC1
Reactant: CNc1cccc2cc(-c3nccs3)[nH]c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)N1CCCC1)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
To a solution of N-methyl-2-(1,3-thiazol-2-yl)-1H-indole-7-amine hydrochloride (133 mg) and triethylamine (105 μL) in tetrahydrofuran (5 mL) was added pyrrolidine-1-carbonylchloride (100 mg). The reaction mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give yellow crystals (8.2 mg, yield 5%). melting point 182° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6].[F:14]C1C=C(C=CC=1O)C=O>>[F:14][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: O=Cc1cc(Cl)c(O)c([N+](=O)[O-])c1
Reactant: O=Cc1ccc(O)c(F)c1
Product: O=Cc1cc(F)c(O)c([N+](=O)[O-])c1
Yield: 53 %

Procedure:
Followed procedure described for Intermediate 59, starting with 3-fluoro-4-hydroxybenzaldehyde. Desired product isolated in 53% yield.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(I)cc1
Reactant: OB(O)c1ccc(F)cc1F
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(F)cc2F)cc1
Yield: 87.6 %

Procedure:
(+,−) Trans propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (120 mg, 0.31 mmol, prepared in example 2) and 2,4-difluorophenylboronic acid (60 mg, 0.38 mmol) were treated as described in example 6 to afford 103 mg (89%) of the title compound as a white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1.C([O-])(O)=O.[Na+].[Br:16]Br>ClCCl>[Br:16][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: COc1cccnc1OC
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(Br)cnc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,3-dimethoxypyridine (4-1, 2.5 g, 18.0 mmol, 1.0 equiv) in dichloromethane:saturated NaHCO3 (80 mL: 40 mL) at 0° C. was added bromine (0.93 mL, 18.0 mmol, 1.0 equiv) and the reaction mixture was stirred for 2 h at 25° C. The reaction mixture was quenched with solid Na2SO3 (˜10 g) and the aqueous phase was extracted with dichloromethane (3×100 mL). The organic phase was dried over magnesium sulfate and concentrated. The residue was purified via normal phase chromatography (0 to 20% EtOAc in hexanes, silica) to afford the desired product (4-2) as an oil after concentration. ESI+MS[M+H]+C7H8NO2 calc'd 218.0. found 218.0.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:3][CH2:2]1.S(Cl)([Cl:17])=O.CN(C)C=O>CCOCC>[CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:17])=[O:14])[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCCC1CC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)CCCCCCCCC1CC1

Procedure:
A mixture of 0.85 g. of 9-cyclopropylnonanoic acid, 0.45 ml. of thionyl chloride (density 1.656) and 0.10 ml. of dimethylformamide (density 0.945) in 10 ml. ether is stirred overnight at room temperature. The upper layer of the reaction mixture is then separated and the solvent removed by evaporation to yield 9-cyclopropylnonanoyl chloride to which is added at 0° under nitrogen 1.4 g. of 9-octadecen-1-ol and 40 ml. of ether. To this mixture is added dropwise 0.52 ml. of pyridine (density 0.98). The reaction mixture is then stirred 1/2 hour at 0° and overnight at room temperature. The mixture is filtered, 3 equivalents of water are added and then the mixture is stirred for one hour. Ether is added to dilute the reaction mixture which is washed in turn with 2N sulfuric acid (2 × 50 ml.), 10% aqueous sodium carbonate (2 × 50 ml.), water (2 × 50 ml.) saturated aqueous copper sulfate, water (2 × 50 ml.) and saturated aqueous sodium chloride (1 × 50 ml.). The solution is then dried over calcium sulfate and the solvent removed by evaporation to yield 9-octadecenyl 9-cyclopropylnonanoate which is purified by thin layer chromotography (15% ether/hexane solvent).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]Cl)[N:9]=1)(=[O:3])[CH3:2].[CH:12]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][N:28]2[CH2:29][CH2:30][N:25]([CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
A mixture of 2-acetamido-4-chloromethylthiazole (7.6 g), 1-benzhydrylpiperazine (10.0 g) and potassium carbonate (5.5 g) in N,N-dimethylformamide (80 ml) was stirred at 80° C. for 2 hours. After the reaction mixture was poured into ice-water, the precipitated crystals were collected by filtration, washed with water and then crystallized twice from methanol to give white crystals (8.4 g) of 2-acetamido-4-(4-benzhydrylpiperazin-1-ylmethyl)thiazole, mp 178°-179° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:19].[K+].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([OH:19])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(O)cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
39.5 g of the 2-benzyloxy-4-fluoronitrobenzene (0.16 mol) prepared as described in Example 1 are added to a mixture of an aqueous potassium hydroxide solution prepared from 27.2 g of potassium hydroxide (0.48 mol) and 180 ml of distilled water, and 150 ml of dimethyl sulfoxide in a three-neck flask fitted with reflux condenser, stirrer and nitrogen inlet, and the mixture is then heated to 100° C. After 4 hours, the reaction solution is allowed to cool to room temperature, and the residue is filtered off via a fluted filter. The dark-orange solution is then added to 800 ml of water, and concentrated hydrochloric acid is added with vigorous stirring until the mixture is acidic. Within about 1 hour, a white-yellowish, flaky reaction product precipitates; this is filtered off via a Büchner funnel and washed three times with water. The reaction product is recrystallized from ethanol and then dried for 48 hours under nitrogen at 40 ° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.[Cl:29][CH2:30][CH2:31][N:32]=[C:33]=[O:34]>C1C=CC=CC=1>[C:1]([NH:5][C:33]([NH:32][CH2:31][CH2:30][Cl:29])=[O:34])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(N)=O
Reactant: O=C=NCCCl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)NC(=O)NCCCl

Procedure:
A mixture of 71.1 g (1.0 mole) acrylamide, 0.5 g triethylamine, 0.5 g 2,6-ditert-butyl-4-methylphenol and 250 ml benzene is mixed with 110.8 g (1.05 mole) 2-chloroethyl isocyanate and heated in an autoclave over a period of 10 hours to 110° C. The finely crystalline precipitate obtained on cooling is filtered off. 140 g of substance is so obtained. It is recrystallized from 700 ml acetonitrile to yield 115 g (0.65 mole=65% of theory) white crystal needles having a melting point between 156° and 158° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:20][O:21][CH:22]([O:34][CH3:35])[C:23]1[C:28](F)=[C:27]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:25][C:24]=1[F:33]>C1COCC1>[CH3:35][O:34][CH:22]([O:21][CH3:20])[C:23]1[C:24]([F:33])=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1]
Reactant: COC(OC)c1c(F)ccc([N+](=O)[O-])c1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1c(F)ccc([N+](=O)[O-])c1Nc1ccc(I)cc1F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a solution of 2-fluoro-4-iodo-aniline (2.24 g, 9.43 mmol) in anhydrous THF (30 ml) under an atmosphere of nitrogen was added 1M LHMDS in hexanes (18 ml, 1M, 18.0 mmol) keeping the internal temperature below −65° C. After complete addition the reaction mixture was stirred for 30 minutes at −70° C. A solution of 2-dimethoxymethyl-1,3-difluoro-4-nitro-benzene (2.0 g, 8.58 mmol) in anhydrous THF (20 ml) was added to the reaction mixture keeping the internal temperature below −68° C. After complete addition the reaction mixture was stirred for 30 minutes at −70° C. then allowed to warm to room temperature and stirred for 22 hours. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate (200 ml). The organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo to a minimum volume and triturated with cyclohexane to yield the title compound (2.18 g, 56%). LCMS (Method B): RT=4.26 min, [M−H]−=449.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:16]2[CH:17]=[CH:18][C:13]([NH2:12])=[CH:14][CH:15]=2)=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(O)cc1
Reactant: Cn1c(CO)cnc1[N+](=O)[O-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(N)cc2)cnc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 51.5 %

Procedure:
A suspension of 30 g of 1-methyl-2-nitroimidazole-5-methanol, 22 g of 4-aminophenol and 55 g of triphenylphosphane in 600 ml of anhydrous tetrahydrofuran was treated dropwise with vigorous stirring within 20 minutes with a solution of 42.5 g of diisopropyl azodicarboxylate in 300 ml of anhydrous tetrahydrofuran. The mixture was maintained at a temperature of 20°-24° C. by external cooling. After 2 hours, the clear solution obtained was evaporated under reduced pressure and the residue was boiled briefly with a mixture of 125 ml of methylene chloride and 125 ml of ethyl acetate to yield 24.4 g (52%) of crystalline α-(1-methyl-2-nitroimidazol-5-yl)-p-anisidine, m.p. 168°-170° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][C@H:6]1[CH2:23][O:24][Si](C(C)(C)C)(C)C)(=[O:4])=[O:3].[OH:32]O.Cl.O>CO>[CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:32])[CH2:7][C@H:6]1[CH2:23][OH:24])(=[O:4])=[O:3]
Reactant: OO
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](P(c2ccccc2)c2ccccc2)CN1S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: O
Product: CS(=O)(=O)N1C[C@@H](P(=O)(c2ccccc2)c2ccccc2)C[C@H]1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 180 ml of methanol was dissolved 8.39 g (0.0176 mol) of 2S,4S)-N-methanesulfonyl-2 -tert-butyldimethlysilyloxymethyl-4-di-phosphinopyrrolidine [VI], and 11.85 g (0.0348 mol) of 10% hydrogen peroxide was added dropwise to the solution under ice-cooling. The mixture was stirred at 0° C. for one hour and then at room temperature for one hour. To the mixture was then slowly added dropwise a liquid mixture of 8.6 g of 35% hydrochloric acid, 52.7 g of water and 38.7 g of methanol, and the mixture was stirred for 2 hours at room temperature. Any insoluble matter was removed from the mixture by filtration and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in 50 ml of water and the aqueous solution was extracted three times with 100 ml of methylene chloride in each case. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure whereby white crystals were obtained which were then recrystallized from a mixture of ethanol and isopropyl alcohol. Yield 5.3 g (80%), melting point: 138°-139° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([N+:23]([O-])=O)=[CH:6][C:7]([CH3:22])=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)[CH:9]=1)[CH3:2]>CCOC(C)=O.CO.[Pt]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:15]2)[C:7]([CH3:22])=[CH:6][C:5]=1[NH2:23])[CH3:2]
Reactant: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1N
Yield: 89.9 %

Procedure:
To 1-[5-(ethyloxy)-2-methyl-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperidine (33.1 g, 89.0 mmol) in EtOAc (800 mL) and MeOH (200 mL) was added platinum on carbon (sulfided) (17.5 g, 4.47 mmol). The mixture was stirred under H2 (1 atm.) over the weekend. The mixture was filtered through Celite®, washed with DCM, and rotovapped down. The resultant solid was triturated with diethyl ether to provide the title compound of Step G (27.3 g, 80 mmol, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ 6.54 (s, 1H), 6.44 (s, 1H), 4.28 (s, 2H), 3.94 (q, J=6.9 Hz, 2H), 3.11-3.22 (m, 2H), 2.97 (s, 3H), 2.87 (d, J=11.5 Hz, 2H), 2.44-2.56 (m, 2H), 2.06 (s, 3H), 1.59-1.80 (m, 4H), 1.43 (ddd, J=14.2, 7.0, 3.5 Hz, 1H), 1.21-1.36 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5]O[C:3]=1[CH3:9].[CH3:10][NH2:11].C>O>[CH3:10][N:11]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:9]
Reactant: Cc1occc(=O)c1O
Reactant: CN
Solvent: O
Product: Cc1c(O)c(=O)ccn1C
Reaction time: 0.5 h

Procedure:
In particular, 3-hydroxy-2-methyl-4-pyrone (10 g) was refluxed for 6.5 hours with three equivalents of aqueous methylamine (40%) in 200 ml of water. The reaction mixture was allowed to cool after which decolorizing charcoal was added to the solution, and the mixture was stirred for 0.5 hours. After filtration, the solvent was evaporated under reduced pressure, and the solid residue recrystallized three times from water to yield 1,2-dimethyl-3-hydroxypyrid-4-one (HK-1, L1, CP20, DMHP) as fine white needles.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH:10]([C:17]#[N:18])[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[SH2:26]>N1C=CC=CC=1>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH:10]([C:17](=[S:26])[NH2:18])[C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CCCc2ccc(-c3ccccc3)nc21
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)C1CCCc2ccc(-c3ccccc3)nc21
Reaction time: 12 h

Procedure:
2-Phenyl-8-cyano-5,6,7,8-tetrahydroquinoline (2 g.) was dissolved in pyridine (5 ml.) and triethylamine (1.3 ml.) and the solution treated with H2S gas for 6 hours and the reaction mixture allowed to stand at room temperature for 12 hours. The solvent was removed and the residual oil dissolved in dilute HCl, extracted with ether (2 × 50 ml.) and the extracts discarded. The aqueous solution was made basic and extracted into chloroform (3 × 50 ml.). The combined extracts were dried and evaporated in vacuo to give 2-phenyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide which was dissolved in ethanol (5 ml.), diluted with ether (25 ml.) and the solution saturated with HCl gas. The solvent was removed in vacuo and the residual solid recrystallised from methanol-ether giving hydrochloride of the title compound as colourless needles mpt. 211° C. Found: C, 63.41; H, 5.70; N, 8.94%. C16H16N2S. HCl requires: C, 63.04; H, 5.62; N, 9.19 %.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[O:17])[CH2:3]1.C1COCC1.C(O)C>C(O)C.[Pd]>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[O:17])[CH2:3]1
Reactant: CN1CC(=O)Nc2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CC(=O)Nc2ccc(N)cc2C1=O
Reaction time: 3 h
Yield: 29.8 %

Procedure:
Intermediate 1 (3.48 g, 15 mmol, preparation described in Example 1) was suspended in a 120 mL of 1:1 solution of THF/Ethanol. The suspension was treated with nitrogen followed by vacuum, before adding Pd/C 10% (0.7 g), suspended in ethanol. The reaction vessel was then fitted onto the Parr hydrogenator and left under hydrogen pressure (20 psi) for about 3 hours with stirring. The excess hydrogen gas was removed using vacuum and then nitrogen was purged through the solution. The catalyst was filtered off using celite and the filtrate was evaporated to the minimum amount of ethanol. A white precipitate formed which was separated by filtration and dried under vacuum to afford 918 mg of desired material 3 in 30% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH: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])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][O:34][C:35]([C:37]1([NH2:40])[CH2:39][CH2:38]1)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:33][O:34][C:35]([C:37]1([NH:40][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[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]2)=[O:29])[CH2:39][CH2:38]1)=[O:36]
Reactant: COC(=O)C1(N)CC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 1-amino-cyclopropanecarboxylic acid methyl ester hydrochloride (100 mg, 0.86 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.22 mL, 1.2 mmol) in CH2Cl2 (20 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-1-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-cyclopropanecarboxylic acid methyl ester as a white powder (120 mg, 49.6%). HRMS (ES+) m/z Calcd for C28H29Cl2F2N3O3+H [(M+H)+]: 564.1627. found: 564.1627.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Br[CH2:24][CH:25]1[CH2:28][CH2:27][CH2:26]1>>[CH:25]1([CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ccc(O)cn2)cc1
Reactant: BrCC1CCC1
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OCC3CCC3)cn2)cc1

Procedure:
N-{3-[4-(5-Hydroxypyridin-2-yloxy)phenyl]-1-methylpropyl}acetamide was reacted with bromomethylcyclobutane in analogy to example 10b.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8].[C:15]([O:18][CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1)(=[O:17])[CH3:16]>ClCCl>[C:15]([O:18][CH2:19][CH2:20][N:21]1[CH:22]=[CH:23][CH:24]=[C:25]1[C:7](=[O:8])[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:17])[CH3:16]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(=O)OCCn1cccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1cccn1CCOC(C)=O

Procedure:
In the next step, a solution of pyridine in anhydrous dichloromethane is added to a stirred and cooled solution of ethoxalyl chloride in anhydrous dichloromethane so that the reaction temperature remains at about -20° to -25° C. Upon completion of this addition an approximately equimolar amount of 1-(2-acetoxyethyl)pyrrole of Formula (III) in anhydrous dichloromethane is added while the temperature is maintained at temperatures of about 0° to -20° C. Washing with water, drying, removal of the solvent and purification gives ethyl 1-(2-acetoxyethyl)pyrrole-2-glyoxylate.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][N:15]([C:19](=[O:23])[CH2:20][CH2:21]Cl)[C:14]=3[CH:24]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:25][CH3:26]>>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][N:15]([C:19](=[O:23])[CH2:20][CH2:21][NH:25][CH3:26])[C:14]=3[CH:24]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: O=C(CCCl)N1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21
Product: CNCCC(=O)N1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21
Reaction time: 0.13 h
Yield: 93 %

Procedure:
A solution of 1-(6-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-3-chloro-propan-1-one (0.100 g., 0.273 mmol) in 4 mL of 2 M methanolic H2NMe was heated in a microwave reactor in a sealed reaction vessel at 80° C. for 2 minutes, then at 130° C. for 8 minutes. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (24:1:0.1 of CH2Cl2:MeOH:NH4OH) to give 0.092 g (93%) of 1-(6-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-3-methylamino-propan-1-one as a clear oil. MS: 361 (M+H)+, mp: 208.3-214.7° C. (as hydrochloride).