Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:7]2[CH2:8][CH2:9][C:10]3[O:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: O=C(O)c1ccc(C(=O)c2cccc(Cl)c2)cc1
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(C(=O)N2CCc3occc3C2)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.114 g (0.720 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.175 g (0.67 mmol) of 4-(3-chlorobenzoyl)benzoic acid and 0.4 ml (2.9 mmol) of triethylamine in 30 ml of dichloromethane, 0.18 g (1.1 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. This mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The-resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate/dichloromethane=3/1/1). The resulting purified product was recrystallized from methanol-hexane to yield the desired product.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: Brc1nccs1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3nccs3)CC2)c(Cl)c1Cl
Yield: 60.2 %

Procedure:
3,4-Dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1; 1 g, 3.2 mmol) was dissolved in NMP (10 ml). Bromothiazole (2.65 g; 16 mmol) was added followed by the addition of N,N-diisopropylethylamine (2.75 ml, 16 mmol). Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for a total of 3 h. The mixture was diluted with EtOAc and washed well with water, NaHCO3, brine. The organic phase was dried over Na2SO4 and concentrated in vacuo to give the title compound as a brown solid (692 mg).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:24]([N:6]1[CH2:7][C@H:3]([OH:2])[CH2:4][C@H:5]1[C:8]([O:10][CH3:11])=[O:9])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: CCCCCCCCCCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCN1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A solution of trans-4-hydroxy-L-proline, methyl ester, hydrochloride (4.0 g, 22.02 mmol) and 1-iodododecane (3.04 g, 44.04 mmol) in methanol (30 ml) was treated with potassium carbonate. The mixture was stirred and refluxed for 7 h, cooled to r.t., diluted with ethyl acetate (700 ml), washed with water (400 ml), brine (200 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (petroleum ether/ethyl acetate 60:40 to 40:60) to afford the title compound (3.72 g, 54%) as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:16])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[N+:13]([O-:15])=[O:14])(C)(C)C>C(O)(C(F)(F)F)=O.O.C1(SC)C=CC=CC=1>[N+:13]([C:9]1[N:8]([CH2:7][C:6]([OH:16])=[O:5])[CH:12]=[CH:11][N:10]=1)([O-:15])=[O:14]
Reactant: CC(C)(C)OC(=O)Cn1ccnc1[N+](=O)[O-]
Solvent: CSc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1ccnc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Compound 2 (2.5 g) is dissolved in 20 mL of a cocktail of TFA, water, thioanisole 95-2.5-2.5 and stirred at room temperature for one night. The mixture is then concentrated under vacuum and co-evaporated several times with diethyl ether until formation of a powder. After filtration, the precipitate is washed with dichloromethane and acetonitrile to give quantitatively the expected product. Mp 143° C. (decomposition); 1H NMR (DMSO-d6, 400 MHz) δ 5.21 (s, 2H), 7.21 (d, 1H, J=1.01 Hz), 7.64 (d, 1H, J=1.01 Hz). 13C (DMSO-d6, 101 MHz) δ 50.65, 127.69, 128.44, 168.56, 168.57; MS (ESI+/ESI−) m/z 170.12 [M−H]−, 341.05 [2M−H]−, 194.14 [M+Na]+.
Reaction SMILES: ClCI.[Br:4][C:5]1[CH:6]=[C:7]([C:19]([OH:22])=[CH:20][N:21]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:9].[C:23]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:4][C:5]1[N:21]=[CH:20][C:19]2[O:22][CH2:23][N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[C:8](=[O:9])[C:7]=2[CH:6]=1
Reactant: O=C(NCc1ccc(F)cc1)c1cc(Br)ncc1O
Reactant: O=C([O-])[O-]
Agent: ClCI
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cc(Br)ncc2OCN1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Chloroiodomethane (800 mg, 4.6 mmol) was slowly added to a mixture of 2-bromo-N-(4-fluorobenzyl)-5-hydroxyisonicotinamide (750 mg, 2.3 mmol) and Cs2CO3 (3.0 g, 9.2 mmol) in DMF (20 mL) at 100° C. The mixture was stirred at 100° C. for 2 h. Water was added and the mixture was extracted with EtOAc. After being concentrated, the residue was purified by column chromatography (PE:EtOAc=1:1) to give the product of 6-bromo-3-(4-fluorobenzyl)-2H-pyrido[4,3-e][1,3]oxazin-4(3H)-one (600 mg, yield: 80%). 1H-NMR (Methanol-d4, 400 MHz) δ 8.24 (s, 1H), 7.94 (s, 1H), 7.39 (dd, J=5.6, 8.0 Hz, 2H), 7.09 (t, J=8.8 Hz, 2H), 5.34 (s, 2H), 4.75 (s, 2H). MS (M+H)+: 337/339.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH:7]([CH2:28][N:29](CC1C=CC=CC=1)[CH2:30][CH3:31])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:39])[CH:7]([CH2:28][NH:29][CH2:30][CH3:31])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN(CC)Cc3ccccc3)C(=O)OC(C)(C)C)CCCC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCNCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCC)CC2)CCCC1)C(=O)OC(C)(C)C
Yield: 83.7 %

Procedure:
2-(N-Benzyl-N-ethylaminomethyl)-3-{1-[(cis-4-ethoxycarbonyl-cyclohexyl)carbamoyl]cyclopentyl}-propanoic acid t-butyl ester (3.38 g, 6.2 mmole) was dissolved in ethanol (70 ml) and hydrogenated at 30 p.s.i. (2 bar) over 20% palladium hydroxide on carbon at room temperature for 16 hours. The catalyst was removed by filtration through an Arbacell pad and the filtrate evaporated under vacuum. The residue was chromatographed on silica eluting with methanol-dichloromethane mixtures to give the title compound as an oil (2.35 g, 83%). Found: C,65.51; H,9.57; N,6.14. C25H44N2O5.0.1 CH2Cl2 requires C,65.37; H,9.66; N,6.08%.
Reaction SMILES: [C:1](=[NH:25])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][C:21]([F:24])([F:23])[F:22])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[OH:26]/[CH:27]=[C:28](/[CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=1)\[C:29](OC)=O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:29]=[C:28]([CH2:33][C:34]4[CH:35]=[N:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=4)[C:27](=[O:26])[N:25]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[O:20][C:21]([F:24])([F:22])[F:23]
Reactant: COC(=O)/C(=C\O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(OC(F)(F)F)c4)cc3)nc2=O)cn1
Reaction time: 4 h
Yield: 15.7 %

Procedure:
The same procedure as E177 from 4-(4-chloro-3-(trifluoromethoxy)phenoxy)phenethyl carbamimidate (100 mg, 0.267 mmol), (Z)-methyl 3-hydroxy-2-((2-methoxypyrimidin-5-yl)methyl)acrylate (180 mg, 0.803 mmol) and Cs2CO3 (260 mg, 0.798 mmol) in 1,4-dioxane (2 mL), except that the reaction temperature was 120° C. and the time was 4 h, to afford the title compound (28 mg, 0.042 mmol, 15.83% yield). LCMS: rt=3.63 min, [M+H+]=549
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:20]=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23]O.C(OC(=O)C)(=O)C.[OH-].[Na+]>O1CCCC1.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:20]#[N:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c[nH]c2ccc(C(=O)OCc3ccccc3)cc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1c[nH]c2ccc(C(=O)OCc3ccccc3)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of 3-formyl-1H-indole-5-carboxylic acid benzyl ester (4.3 g) and pyridine (4.8 g) in tetrahydrofuran (60 ml) was added hydroxylamine hydrochloride (1.6 g) at room temperature and this mixture was stirred at 80° C. overnight. Acetic anhydride was added to reaction mixture at the same temperature and this mixture was stirred for 8 hours. After cooling to ambient temperature, 1 mol/L sodium hydroxide solution (20 mL) was added to this mixture and resulting mixture was extracted with diethyl ether. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and this residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (2.8 g).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH2:12])[CH2:4][CH2:3]1.[CH3:13][N:14]=[C:15]=[O:16]>>[CH3:13][NH:14][C:15]([NH:12][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:16]
Reactant: CN=C=O
Reactant: NC1CCC(O)c2ccccc21
Product: CNC(=O)NC1CCC(O)c2ccccc21

Procedure:
Similarly, 1,2,3,4-tetrahydro-4-hydroxy-1-naphthylamine is allowed to react with an equivalent amount of methyl isocyanate to afford 1-methyl-3-(1,2,3,4-tetrahydro-4-hydroxy-1-naphthyl)urea, m.p. 172° C. to 180° C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[OH:9].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CN(C)C=O>CC1C=CC(C)=CC=1>[Br-:11].[OH:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]1[N+:2]([CH3:10])([CH3:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CN(C)C1CCCCC1O
Reactant: CCCCCCCCBr
Solvent: CN(C)C=O
Solvent: Cc1ccc(C)cc1
Product: CCCCCCCC[N+](C)(C)C1CCCCC1O
Product: [Br-]

Procedure:
A solution comprising 5 g of 2-dimethylamino-1-cyclohexanol, 10 g of 1-bromooctane and 5 ml of dimethylformamide was heated in a glass pressure bottle at about 95° for 16 hours. p-Xylene (25 ml) was added and the solution was concentrated at 60° using a film evaporator to remove dimethylformamide as its azeotrope with xylene. A second 25 ml portion of p-xylene was added and the azeotrope distilled until the residue was free of volatile material. This residue was dissolved in water, and the aqueous solution was extracted five times with diethyl ether. The aqueous solution was then concentrated under reduced pressure to give (2-hydroxycyclohexyl)(dimethyl)octylammonium bromide, a clear amorphous gum.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[C:4]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:3]=1[C:30](=[O:32])[CH3:31].[C:33](O)(=[O:37])[C@@H:34]([CH3:36])[OH:35].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[C:30]([C:3]1[C:4]([O:23][CH:24]2[CH2:25][CH2:26][N:27]([C:33](=[O:37])[C@H:34]([OH:35])[CH3:36])[CH2:28][CH2:29]2)=[N:5][C:6]2[N:7]([N:8]=[CH:9][C:10]=2[C:11]2[CH:12]=[N:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:2]=1[NH2:1])(=[O:32])[CH3:31]
Reactant: C[C@@H](O)C(=O)O
Reactant: CC(=O)c1c(OC2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1c(OC2CCN(C(=O)[C@@H](C)O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yloxy)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone (211 mg, 0.49 mmoL), D-(−)-lactic acid (53.3 mg, 0.59 mmoL), EDC (189.0 mg, 0.99 mmoL), HOBt (132.0 mg, 0.99 mmoL) and DIEA (514 uL, 2.96 mmoL) in DMF (5 mL) was stirred at room temperature for 2 hr. Purification with prep-LC provided
Reaction SMILES: [CH2:1](Cl)[CH3:2].[N:4]1([CH2:10][CH2:11][CH2:12][O:13][C:14]([N:16]2[N:21]=[C:20]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32](=[O:43])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=3)[CH2:27][CH2:26][CH2:25]4)[CH:19]([CH3:44])[S:18][C:17]2=[O:45])=[O:15])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([N:7]1[CH2:6][CH2:5][N:4]([CH2:10][CH2:11][CH2:12][O:13][C:14]([N:16]2[N:21]=[C:20]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32](=[O:43])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=3)[CH2:27][CH2:26][CH2:25]4)[CH:19]([CH3:44])[S:18][C:17]2=[O:45])=[O:15])[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCCl
Reactant: COc1ccc(C(=O)N2CCCc3cc(C4=NN(C(=O)OCCCN5CCNCC5)C(=O)SC4C)ccc32)cc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN1CCN(CCCOC(=O)N2N=C(c3ccc4c(c3)CCCN4C(=O)c3ccc(OC)c(OC)c3)C(C)SC2=O)CC1

Procedure:
1.3 g of ethyl chloride dissolved in 10 ml of toluene are added dropwise with stirring to a solution of 10 g of 3-(3-piperazinopropoxycarbonyl)-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one and 1.8 g of triethylamine in 100 ml of toluene, and the mixture is stirred with heating for one hour. The solvent is removed and the mixture is worked up in the conventional manner to give 3-[3-(1-ethyl-4-piperazinyl)-propoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[C:31]([F:32])=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[C:27]=4[F:35])=[CH:22][C:21]3=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[C:31]([F:32])=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[C:27]=3[F:35])=[CH:22][C:21]2=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: COc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H](O)CO)n3)C2)c1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91 %

Procedure:
A solution of (S)-2-[4-(2,6-difluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (prepared in Example 118, 0.163 g, 0.30 mmol) in tetrahydrofuran (15 mL) was treated with 2N aqueous hydrochloric acid (7.5 mL). The reaction mixture was stirred for 3.5 h at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue purified by ISCO column chromatography (Teledyne Isco RediSep Flash Column 12 g, 30% to 100%, (9:1 dichloromethane:methanol)/hexanes) which afforded (S)-2-[4-(2,6-difluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.135 g, 90%) as an off-white solid: HR-ES-MS m/z calculated for C23H28F2N4O6, [M+H]+ 495.205 observed 495.205; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.4 Hz, 3H), 1.43 (br. s., 1H), 1.49-1.67 (m, 1H), 1.67-1.87 (m, 1H), 3.18-3.32 (m, 2H), 3.69-3.86 (m, 2H), 3.87 (s, 3H), 4.09 (dd, J=13.6, 2.7 Hz, 1H), 4.27 (d, J=18.7 Hz, 1H), 4.63 (d, J=18.7 Hz, 1H), 4.71 (t, J=4.8 Hz, 1H), 4.81-4.91 (m, 1H), 4.94 (d, J=4.8 Hz, 1H), 5.06 (s, 1H), 6.40 (br. s., 1H), 7.09-7.24 (m, 1H), 7.24-7.38 (m, 1H), 7.53 (br. s., 1H), 10.79 (br. s., 1H).
Reaction SMILES: ClC1[C:7]([C:8]([N:10]([CH3:14])[CH2:11][C:12]#[CH:13])=[O:9])=[C:6]([Cl:15])[N:5]=[CH:4]N=1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:15][C:6]1[C:7]2[C:8](=[O:9])[N:10]([CH3:14])[CH2:11][C:12]=2[CH:13]=[CH:4][N:5]=1
Reactant: C#CCN(C)C(=O)c1c(Cl)ncnc1Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: CN1Cc2ccnc(Cl)c2C1=O
Yield: 55.8 %

Procedure:
A solution of 4,6-dichloro-N-methyl-N-(prop-2-yn-1-yl)pyrimidine-5-carboxamide (Compound 310F, 7.6 g, 31 mmol) in Nitrobenzene (76 mL) was evacuated and purged with argon (3×). The reaction mixture was irradiated in the microwave for 1.5 minutes at 250° C. The reaction mixture was filtered through a pad of celite. The nitrobenzene solution was passed through a silica gel plug and washed with DCM to remove the nitrobenzene. The silica was then washed with DCM/MeOH solution (90:10). The filtrated was concentrated under reduced pressure to yield a red solid. The crude material was purified by silica gel chromatography on a combi-flash Rf system using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield an orange solid (3.1598 g, 56%). 1H NMR (DMSO-d6, 400 MHz): δ=8.53 (d, J=5.05 Hz, 1H), 7.70 (d, J=5.05 Hz, 1H), 4.53 (s, 2H), 3.05 (s, 3H). MS (ES+): m/z 183.02 [M+] (TOF, polar).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[S:11][C:10](Cl)=[C:9]([Cl:13])[C:8]=1[Cl:14].CN(C)[CH:17]=[O:18].Cl>O1CCCC1.CCCCCC.C(OCC)(=O)C>[Cl:13][C:9]1[C:8]([Cl:14])=[C:7]([Cl:6])[S:11][C:10]=1[CH:17]=[O:18]
Reactant: CN(C)C=O
Reactant: Clc1sc(Cl)c(Cl)c1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1sc(Cl)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Butyllithium (2.5 molar in tetrahydrofuran, 3.96 mL, 9.9 mmol) is added to a solution of tetrachlorothiophene (2.00 g, 9.01 mmol) in tetrahydrofuran at 0° C. The reaction mixture is stirred at 0° C. for 30 minutes, warmed to room temperature over 45 minutes, treated with N,N-dimethylformamide (0.79 g, 10.8 mmol), stirred for three hours, poured into one molar hydrochloric acid at 4° C. and extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to obtain a brown solid. Flash chromatography of the solid using silica gel and a 5% ethyl acetate in hexane solution gives a beige solid which is recrystallized from ethyl acetate and hexane to obtain the title product as beige needles (1.63 g, 84%, mp 81°-82° C.).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:37])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:36])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)[CH2:10]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:3][S:4]([NH:7][C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[C:28]([NH:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:36])[CH2:10][C:9]2([CH3:37])[CH3:8])=[O:20])(=[O:6])=[O:5]
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cccc(C(=O)Nc3ccccc3)c2)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(C(=O)Nc3ccccc3)c2)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.3 %

Procedure:
To a suspension of 60% sodium hydride (198 mg, 4.95 mmol) in N,N-dimethylformamide (2 mL) was added methanesulfonamide (475 mg, 5 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A20. A solution of 4,4-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (400 mg, 1 mmol) and 1,1′-carbonyldiimidazole (324 mg, 2 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B20. Solution B20 was added to Solution A20 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3-(6-methanesulfonylaminocarbonyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-N-phenyl-benzamide (35 mg, 7%) as a white solid: MS (ESI) M+1=478.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[C:3]1=[O:18].CN1C2C(=CC=CC=2)C(C2[C:30](=[O:35])NCCN=2)=C1.[H-].[Na+].S(OC)(OC)(=O)=O>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:30]=[O:35])[CH:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[C:3]1=[O:18]
Reactant: Cn1cc(C2=NCCNC2=O)c2ccccc21
Reactant: CN1CCN=C(c2cn(C)c3ccccc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CN1CCN(C=O)C(c2cn(C)c3ccccc23)C1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
The 1-methyl-3-(1-methylindol-3-yl)-5,6-dihydro-2(1H)-pyrazinone required as the starting material is prepared as follows: 45.5 g (0.2 mol) of 3-(1-methylindol-3-yl)-5,6-dihydro-2(1H)-pyrazinone, prepared in accordance with Example 33, are dissolved in 400 ml of dimethylformamide, 5.3 g (0.22 mol) of sodium hydride are introduced, the mixture is stirred for 4 hours at 60° C., 27.8 g (0.22 mol) of dimethyl sulphate are added dropwise and the mixture is stirred for 20 hours at 60° C. The compound which is precipitated by dilution with water is recrystallised from methanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH2:25]([N:27](CC)CC)C.N#CBr>C(#N)C>[C:25]([N:21]1[CH2:20][CH2:19][N:18]([C@H:16]([CH3:17])[C@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:24])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH2:23][CH2:22]1)#[N:27]
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCN(CC)CC
Agent: N#CBr
Solvent: CC#N
Product: C[C@@H](N1CCN(C#N)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.9 %

Procedure:
To a cooled (0° C.) mixture of (2R,3R)-2-(2,4-difluorophenyl)-3-(piperazin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol 2 (250 mg, 0.74 mmol) and triethylamine (0.42 ml, 3 mmol) in acetonitrile (15 ml) was added cyanogen bromide (160 mg, 1.5 mmol) in acetonitrile (0.5 ml). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. To the resulting residue water was added and extracted with ethyl acetate (3×20 ml). The combined organic extract was washed with water, brine and dried over magnesium sulphate. The solvent was removed and the product was purified on a column of silica gel (hexane/EtOAc, 1:1) to give the title compound as a colorless solid (150 mg, 56%).