Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34]>>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Fc1ccc(OCCCBr)c(F)c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc(F)cc3F)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.796 g of 1-(3-bromopropoxy)-2,4-difluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.13 (1:2 EtOAc-heptane); Rt=5.12.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[C:14]1([N:20]([CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.CO>[C:14]1([N:20]([CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]([C:22]2[CH:27]=[CH:26][C:25]3[N:28]([CH3:29])[C:11]([CH2:10][NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:30][C:24]=3[CH:23]=2)=[O:31])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CNc1ccc(C(=O)N(CCCC(=O)OC(C)(C)C)c2ccccc2)cc1N
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCC(=O)OC(C)(C)C)c3ccccc3)ccc21
Yield: 65 %

Procedure:
Prepared analogously to Example 25c from N-(4-cyanophenyl)glycine and 3-amino-4-methylaminobenzoic acid-N-phenyl-N-(3-tert-butyloxycarbonylpropyl)amide. Yield: 65% of theory; Rf value: 0.17 (silica gel; dichloromethane/methanol=19:1).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: OCCOCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(2,2,2-trifluoroethoxy)ethanol (1 eq.) in DCM (0.2 M) was added p-toluenesulfonyl chloride (1.3 eq.) and triethylamine (1.5 eq.). The reaction was stirred at rt for 18 h. The reaction was quenched with saturated NH4Cl aqueous solution and extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 30% ether in hexane) to afford the title compound as an oil.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH:5]([O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:6])C.[OH-].[Li+].Cl>O1CCOCC1.O>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH:5]([CH3:6])[C:4]([OH:14])=[O:3])[CH:9]=1
Reactant: CCOC(=O)C(C)Oc1cccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(Oc1cccnc1)C(=O)O
Reaction time: 3 h

Procedure:
To a solution of 2-(pyridin-3-yloxy)-propionic acid ethyl ester, 320 mg (1.6 mmol) in 10 mL of dioxane was added a solution of 190 mg (8.0 mmol) of lithium hydroxide in 10 mL of water. The reaction mixture was stirred for three hours, acidified to pH=1 with 5 N HCl and concentrated to dryness to yield the crude desired product which was carried on without further purification. MS (IS) 168.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:11][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH:9]2[CH:8]4[CH:4]13.[CH:12](OCC)=[O:13]>>[CH:12]([NH:1][CH2:2][CH:3]1[CH2:11][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH:9]2[CH:8]4[CH:4]13)=[O:13]
Reactant: NCC1CC2C3CC4C2C4C13
Reactant: CCOC=O
Product: O=CNCC1CC2C3CC4C2C4C13

Procedure:
8-Aminomethyltetracyclo[4,3,0,02,4,03,7 ]nonane (1.1 g.) was heated under reflux for 16 hours with ethyl formate. The solvent was removed in vacuo and the residue chromatographed on silica gel with ethyl acetate as eluant to give 8-(N-formylaminomethyl)tetracyclo[4,3,0,02,4,03,7 ]nonane. This product was reduced in ether solution with lithium aluminium hydride as in previous Examples and the resulting amine precipitated as its hydrochloride. There was thus obtained 8-(N-methylaminomethyl)tetracyclo[4,3,0,02,4,03,7 ]nonane hydrochloride, m.p. 225°-226° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:7]1[C:14]([Cl:15])=[N:13][C:11]([Cl:12])=[N:10][C:8]=1Cl.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[Cl:12][C:11]1[N:13]=[C:14]([Cl:15])[N:7]=[C:8]([N:1]2[CH2:6][CH2:5][N:4]([C:8]3[N:7]=[C:14]([Cl:15])[N:13]=[C:11]([Cl:12])[N:10]=3)[CH2:3][CH2:2]2)[N:10]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1nc(Cl)nc(N2CCN(c3nc(Cl)nc(Cl)n3)CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
Piperazine (8.0 g, 92.9 mmol) is added over a 20 minute period to a mixture of 34.3 g (186 mmol) of cyanuric chloride, 19.7 g of sodium carbonate, 80 ml of water and 200 ml of toluene maintained at a temperature of 5°-10° C. The reaction mixture is stirred for 3 hours at ambient temperature. The precipitate is filtered and washed with water and toluene to obtain 26.0 g (73% yield) of N,N'-bis-(2,4-dichloro-1,3,5-triazin-6-yl)piperazine.
Reaction SMILES: Br.[N:2]1([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>O1CCOCC1>[CH:20]1([C:23]([N:5]2[CH2:4][CH2:3][N:2]([NH:8][C:9](=[O:17])[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:7][CH2:6]2)=[O:24])[CH2:22][CH2:21]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(NN1CCNCC1)c1ccc(F)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NN1CCN(C(=O)C2CC2)CC1)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of N-piperazinyl-p-fluorobenzamide hydrobromide (500 mg) in 1N aqueous solution of sodium hydroxide (5 ml) and dioxane (5 ml) was added cyclopropanecarbonyl chloride (0.3 ml) at ambient temperature, and the solution was stirred at (he same temperature for 2 hours. After removal of the solvent in vacuo, the residue was dissolved into ethyl acetate and washed with brine (×2). The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was recrystallized from 20% ethanol-water to give N-(4-cyclopropanecarbonyl-1-piperazinyl)-p-fluorobenzamide (0.20 g).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[N:3]=[N:2]1.[CH3:9][O:10][C:11](=[O:26])[C@H:12]([CH3:25])[NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH3:24].Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:9][O:10][C:11](=[O:26])[C@H:12]([CH3:25])[N:13]([C:6]([C:4]1[N:3]=[N:2][S:1][CH:5]=1)=[O:7])[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH3:24]
Reactant: COC(=O)[C@H](C)Nc1c(C)ccc2ccccc12
Reactant: O=C(Cl)c1csnn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@H](C)N(C(=O)c1csnn1)c1c(C)ccc2ccccc12
Yield: 95.3 %

Procedure:
14 g (0.095 mole) of 1,2,3-thiadiazole-4-carbonyl chloride in 30 ml of toluene were added dropwise to a solution of 22.9 g (0.0945 mole) of N-(2-methyl-1-naphthyl)-alanine methyl ester in 100 ml of dry toluene at from +15° C. to +30° C. The mixture was stirred at 80° C. for 8 hours, during which the hydrogen chloride formed was continuously expelled in a weak stream of nitrogen. The mixture was cooled and stirred with a solution of 5 g of sodium bicarbonate in 100 ml of water. The organic phase was separated off, dried over sodium sulfate, decolorized with charcoal and evaporated under reduced pressure. The oily residue which remained was dried at 50° C. and under 0.1 mbar for 3 hours to give 32 g (95.2% of theory) of N-(1,2,3-thiadiazol-4-yl-carbonyl)-N-(2-methyl-1-naphthyl)-alanine methyl ester as a light-brown resin.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:12][CH2:11]3)=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[CH:18]=1.[N+:19]([O-])([OH:21])=[O:20]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:12][CH2:11]3)=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]=2[CH:18]=1
Reactant: CCOC(=O)c1c(C2CC2)oc2ccc(Br)cc12
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(C2CC2)oc2cc([N+](=O)[O-])c(Br)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of compound ethyl 5-bromo-2-cyclopropylbenzofuran-3-carboxylate (10 g, 34 mmol) in CHCl3 (60 mL), fuming HNO3 (12 mL, 95%) was added dropwise at −20° C. over 90 min and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was added to ice water and extracted with CH2Cl2. The organic layer was washed with NaHCO3 (aq.) and brine. The solvent was removed by distillation to provide the crude product of ethyl 5-bromo-2-cyclopropyl-6-nitrobenzofuran-3-carboxylate (4.5 g, yield: 40%). 1H-NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.95 (s, 1H), 4.46 (q, J=7.2 Hz, 2H), 3.06˜3.10 (m, 1H), 1.46 (t, J=7.2 Hz, 3H), 1.34˜1.36 (m, 2H), 1.28˜1.32 (m, 2H). MS (M+H)+: 354/356.
Reaction SMILES: C.[NH2:2][CH:3]([C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1)CC(C)C.[C:18]([NH:28][C@H:29]([C:34](O)=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(N[C@H](C(N[C@H](C(O)=O)CC(C)C)=O)CC(C)C)(OCC1C=CC=CC=1)=O>>[CH2:21]([O:20][C:18]([NH:28][C@@H:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:34]([NH:2][CH2:3][C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1)=[O:35])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)c1csc(C(N)CC(C)C)n1
Agent: C
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Product: CCOC(=O)c1csc(CNC(=O)[C@H](CC(C)C)NC(=O)OCc2ccccc2)n1

Procedure:
Following the procedure of Example 13, except substituting 1-(tert-butoxycarbonyl)amino-1-4-carboethoxythiazol-2-yl)methane for (1S)-1-tert-butoxycarbonyl)amino-1-(4-carboethoxythiazol-2-yl)-3-methylbutane, and N-Cbz-L-leucine for N-Cbz-L-leucinyl-L-leucine, the title compound was prepared (0.120 g, 32%). MS (MH+): 434.2.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](Cl)=[O:21])=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([CH:7]2[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]2=[O:9])=[O:21])=[CH:14][CH:13]=1
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: COc1ccc(CCC(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(CCC(=O)C2C(=O)NC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
To a suspension of barbituric Acid (6.4 g) in 48 ml of pyridine are added dropwise 11 g of 3-(4-Methoxyphenyl)propionyl chloride and the mixture is stirred at room temperature for 18 hours. The reaction mixture is then poured into ice and acidified to pH=1 by adding 6 N hydrochloric acid. A solid precipitates, which is filtered and resuspended in methanol. The suspension is kept under stirring for 15 minutes, then the solid is recovered by filtration to give 12.2 g of the product m.p. 248-250° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH2:35][CH2:36][CH2:37][S:38]([NH2:41])(=[O:40])=[O:39].Cl>C(N(CC)CC)C.O>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH2:32][NH:35][CH2:36][CH2:37][S:38]([NH2:41])(=[O:40])=[O:39])=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCCS(N)(=O)=O
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: NS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Yield: 36.7 %

Procedure:
In an analogous manner to Example 10, 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.200 g, 0.436 mmol) was reacted with 2-aminoethylsulphonamide hydrochloride (0.200 g, 1.245 mmol) and triethylamine (10 drops). On completion of the reaction, the mixture was acidified with dilute HCl and diluted with water, to give the crude product as a precipitate collected by filtration. Treatment with triethylamine followed by purification by silica gel chromatography, eluting with 3-10% MeOH/CHCl3 gave the title compound as a yellow solid (0.085 g, 0.160 mmol, 37%); δH [2H6]DMSO 9.61 (2H, brs), 9.25 (1H,s), 8.58 (1H,s), 8.23 (1H,d), 7.77-7.88 (3H,m), 7.30-7.52 (5H,m), 7.26 (2H,s), 7.20 (1H,d), 7.08 (2H,d), 6.81 (1H,d), 5.14 (2H,s), 4.44 (2H,s), 3.34-3.60 (2H, m), 3.25-3.45 (2H, obscured by water); m/z (M+1+) 530.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.P(Br)(Br)([Br:19])=O>C1(C)C=CC=CC=1.C(#N)C>[Br:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1
Reactant: CCOC(=O)c1cc(O)c2ccccc2n1
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)c2ccccc2n1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-hydroxyquinoline-2-carboxylate (10.0 g, 46.0 mmol) and phosphorus oxybromide (13.2 g, 46.0 mmol) in 100 mL of toluene and 10.0 mL acetonitrile was heated at 75° C. for 1.5 h. The reaction mixture was cooled to room temperature, quenched slowly with water, and extracted with ethyl acetate. The organic fraction was washed with brine, dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 0-50% ethyl acetate in hexanes to afford ethyl 4-bromoquinoline-2-carboxylate that gave a mass ion (ES+) of 280.1 (79Br) for M+H+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: O=C(O)c1cc(Cl)ccc1Br
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(Cl)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
Into a stirred solution of 2-bromo-5-chlorobenzoic acid (11 g, 46.7 mmol, HPLC RT=2.99 min) in methanol (250 mL) at 0° C. was bubbled HCl gas. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo to give an orange oil, which was purified by flash chromatography using hexanes as eluant to give methyl 2-bromo-5-chlorobenzoate as a colorless oil (10.7 g, 92% yield). TLC Rf=0.6 (5% EtOAc-hexanes); HPLC RT=3.48 min, method A; 1H NMR (CDCl3, 400MHz) 7.78 ppm (d, 1H, J=2.6 Hz); 7.59 ppm (d, 1H, J=12.81 Hz); 7.30 ppm (dd, 1H, J=8.6, 2.5 Hz); 3.94 ppm (s, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][N:11]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:4]1)[CH3:2].[CH3:19][N:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[N:22]=[C:21]1S(C)(=O)=O.[H-].[Na+].O>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][N:11]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:21]3[N:20]([CH3:19])[C:24]4=[N:25][CH:26]=[CH:27][CH:28]=[C:23]4[N:22]=3)=[CH:14][CH:13]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccc(O)cc2)c2nccnc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccnc21
Temperature: 150 °C
Yield: 63.4 %

Procedure:
To a solution of 4-(1-ethyl-1H-pyrazolo[3,4-b]pyrazin-3-yl)phenol (100 mg) and 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (88 mg) in DMF (3 mL) was added NaH (60% in oil, 17 mg) at room temperature, and the mixture was heated at 150° C. for 1.5 h under microwave irradiation. The mixture was poured into water and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (98 mg).
Reaction SMILES: C([O:4][CH:5]1[CH2:28][N:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:8]2=[N:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:12]=[C:7]2[CH:6]1[O:40]C(=O)C)(=O)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:4][CH:5]1[CH2:28][N:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:8]2=[N:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[N:12]=[C:7]2[CH:6]1[OH:40]
Reactant: CCOC(=O)CCCCCCN1CC(OC(C)=O)C(OC(C)=O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)CC(O)C3O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of rac-5-(7-ethoxy-7-oxoheptyl)-2,3-dip-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine-7,8-diyl diacetate (step 6) (117 mg, 0.199 mmol) in THF (3 ml) and water (1 ml) was added LiOH (28.6 mg, 1.194 mmol). The mixture was stirred at RT for 18 h followed by heated at 60° C. for 1 h. After cooling to RT, the mixture was acidified to pH 4/5 with 2M HCl and extracted with EtOAc. The combined organic extracts were dried (sodium sulphate), filtered and concentrated in vacuo to afford a mixture of the title products;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:16])([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[CH2:23]([C:27]1[N:28]=[N:29][C:30](Cl)=[CH:31][C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:35][CH:34]=1)[CH2:24][CH2:25][CH3:26]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][O:15][C:30]2[N:29]=[N:28][C:27]([CH2:23][CH2:24][CH2:25][CH3:26])=[C:32]([C:33]3[CH:34]=[CH:35][C:36]([O:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[CH:37][CH:38]=3)[CH:31]=2)([F:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCc1nnc(OCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
To a stirred solution of 4-fluoro-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.5 mmol, 0.116 g) in THF (2 mL) at room temperature was added potassium tert-butoxide (0.5 mmol, 0.5 mL, 1M solution in THF) and continued stirring for 30 min. 3-Butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (Example 14, 0.5 mmol, 0.172 g) was taken THF (1 mL) and added to the reaction and stirred for 10 h at room temperature. The reaction was quenched with slow addition of water (2 mL) and the product was extracted with ethyl acetate (2×5 mL), Organic layer was washed with water (5 mL), brine (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge with 30% ethyl acetate in hexanes to provide 4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (90 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][F:11].[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.[Cl-].[Na+].O.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[C:9](=[N:19]\[S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])/[CH2:10][F:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C(CF)c1cccc(F)c1F
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C(/CF)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.7 %

Procedure:
To a solution of 1-(2,3-difluorophenyl)-2-fluoroethanone (18.9 g, 109 mmol) in THF (400 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (26.3 g, 217 mmol) followed by tetraisopropoxytitanium (93 g, 326 mmol). The reaction was heated to reflux for 2 h. The mixture was allowed to cool to room temperature and then treated with brine (400 ml). The resulted suspension was stirred for 15 min and filtered through a pad of celite. The filter cake was washed with EtOAc. The filtrate was extracted with EtOAc (2×). The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-20% EtOAc/hexane) to afford (R,E)-N-(1-(2,3-difluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (12.3 g, 44.4 mmol, 40.9% yield) as yellow oil, MS m/z=278.0 [M+H]+. calculated for C12H14F3NOS: 277.3
Reaction SMILES: [OH:1][C:2]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[C:9]([F:12])[CH:10]=2)[N:5]([C:14]([NH2:16])=[O:15])[C:4]1=[O:17].[CH3:23][N:24]([CH3:35])[C:25](=[O:34])[CH2:26][O:27][C:28]([O:30][CH:31](I)[CH3:32])=[O:29]>CC(C)=O>[C:14]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([F:12])=[C:8]([Cl:13])[CH:7]=2)[C:3](=[C:2]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[O:1][CH:31]([O:30][C:28]([O:27][CH2:26][C:25]([N:24]([CH3:23])[CH3:35])=[O:34])=[O:29])[CH3:32])[C:4]1=[O:17])(=[O:15])[NH2:16]
Reactant: CC(I)OC(=O)OCC(=O)N(C)C
Reactant: NC(=O)N1C(=O)C(=C(O)c2cccs2)c2cc(F)c(Cl)cc21
Solvent: CC(C)=O
Product: CC(OC(=O)OCC(=O)N(C)C)OC(=C1C(=O)N(C(N)=O)c2cc(Cl)c(F)cc21)c1cccs1
Reaction time: 90 h
Yield: 8.7 %

Procedure:
The tetrabutylammonium salt of 3-[hydroxy-(2-thienyl)methylene]-6-chloro-5-fluoro-2,3-dihydro-2-oxo-1H-indole-1-carboxamide (6.25 g) and N, N-dimethyl-(1-iodoethoxy)carbonyloxyacetamide (5.55 g) were combined in 60 mL of acetone, and the solution stirred for 90 hr. at 20° C. The precipitate present was removed by filtration and dried in vacuo. The solids were chromatographed on silica gel, eluting with 90:10 chloroform:acetone. Fractions containing the title product were combined and evaporated. The residue was slurried with a small amount of ethyl ether and filtered to give 820 mg of yellow solid, mp 194.5°-195.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:18])[C@H:12]([C@H:14]([CH2:16][CH3:17])[CH3:15])[NH2:13])[CH3:9].C(OC(=O)[C@H]([C@H](CC)C)N)C.C(N)C1C=CC=CC=1.[CH3:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH2:50][C:51](Cl)=[O:52].COCCCCCCCCCCCC(Cl)=O>>[CH3:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][CH2:50][C:51]([NH:13][C@H:12]([C:11]([O:10][CH2:8][CH3:9])=[O:18])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:52]
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)CC
Reactant: COCCCCCCCOCCCC(=O)Cl
Agent: COCCCCCCCCCCCC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: NCc1ccccc1
Product: CCOC(=O)[C@@H](NC(=O)CCCOCCCCCCCOC)[C@@H](C)CC

Procedure:
The title compound is prepared by the method of Example 14 using L-isoleucine ethyl ester trifluoroacetate [the title product of Example 44] as a reactant instead of benzylamine, and using an equivalent amount of 4-[(7-methoxyheptyl)oxy]butanoyl chloride [the title product of Example 100] instead of 12-methoxy-1-docecanoyl chloride [the title product of Example 11].