Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Br)[N:3]=1.[C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)#[N:18].[OH-].[K+]>>[C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:4]2[N:3]=[C:2]([NH2:1])[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=2)[CH2:21][CH2:20]1)#[N:18]
Reactant: N#CN1CCNCC1
Reactant: COc1cc2nc(Br)nc(N)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2nc(N3CCN(C#N)CC3)nc(N)c2cc1OC

Procedure:
In a flask fitted with stirrer, thermometer, and drying tube is placed 100 ml. of chloroform, 12.0 g. (0.05 mole) of 4-amino-2-bromo-6,7-dimethoxyquinazoline (prepared by the method of U.S. Pat. No. 3,511,836) and 5.8 g. (0.052 mole) of 1-cyanopiperazine. The mixture is maintained at 50° C. for 24 hours after which 2N potassium hydroxide solution is added at room temperature to adjust to pH 9.5. The organic layer is separated and the aqueous phase extracted again with chloroform and the combined extracts are evaporated to dryness to obtain 2-(4-cyanopiperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S@@](C)=O)=[CH:3][CH:2]=1.C([Si](Cl)(Cl)Cl)C=C.[CH3:18][C:19](=[N:28][NH:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][CH:32]=1)[CH2:20][CH2:21][C:22]1C=CC=CC=1>CC(=CC)C.C(Cl)Cl>[CH2:18]([C@@H:19]([NH:28][NH:29][C:30](=[O:39])[C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH3:38])=[CH:35][CH:36]=1)[CH2:20][CH:21]=[CH2:22])[CH2:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCc1ccc(C(=O)NN=C(C)CCc2ccccc2)cc1
Reactant: Cc1ccc([S@@](C)=O)cc1
Agent: C=CC[Si](Cl)(Cl)Cl
Agent: CC=C(C)C
Solvent: ClCCl
Product: C=CC[C@@H](CCc1ccccc1)NNC(=O)c1ccc(CC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.4 %

Procedure:
(R)-(+)-methyl p-tolyl sulfoxide (0.5 g, 3.21 mmoles) and tetrabutylammonium triphenyl-difluorosilicate (TBAT) (0.12 g, 0.214 mmoles) were dissolved in 0.038 mL of 2-methyl-2-butene and 2.4 mL of anhydrous methylene chloride under nitrogen and with magnetic stirring. Allyltrichlorosilane (0.23 mL, 1.61 mmoles) was added at −78° C. and the reaction was stirred for 15 minutes. 4-ethyl-benzoic acid (1-methyl-3-phenyl-propylidene)hydrazide (0.3 g, 1.07 mmoles) was dissolved in 11.6 mL of anhydrous methylene chloride and added to the reaction over a period of 30 minutes. The reaction mixture was stirred for 5 hours under nitrogen and maintained at −78° C. to −70° C., with TLC monitoring. The reaction was quenched with 1.5 mL triethylamine and 3 mL anhydrous methanol at −78° C. Brine was then added and the mixture was allowed to warm to room temperature. The organic layer was removed, combined with three methylene chloride extractions, and dried over sodium sulfate. The solvent was evaporated, and the crude mixture was purified by flash chromatography using a step gradient of 2:1 and 1:1 pentane:ethyl acetate. Purified (R)-4-ethyl-benzoic acid N′-(1-phenethyl-but-3-enyl)-hydrazide was obtained as a clear oil (0.145 g, 41.4% yield, 57.6% ee by chiral HPLC on Chiralcel ADH). Rf=0.50 (1:1 EtOAc:n-hexane); 1H NMR (400 MHz, CDCl3) δ 7.64-7.13 (m, 9H), 5.91 (m, 1H), 5.15 (t, J=28.0 Hz, 2H), 3.12 (m, 1H), 2.76-2.63 (m, 4H), 2.38-2.24 (m, 2H), 1.88-1.74 (m, 2H), 1.23 (t, J=8.0 Hz, 3H).
Reaction SMILES: [OH-].[K+].CI.[Cl:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2[C:20]([Cl:21])=[C:19]([O:22][CH:23]([F:25])[F:24])[N:18]([CH3:26])[N:17]=2)=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].N1C=C[CH:29]=N1>CC(C)=O>[Cl:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2[C:20]([Cl:21])=[C:19]([O:22][CH:23]([F:24])[F:25])[N:18]([CH3:26])[N:17]=2)=[CH:11][C:7]=1[C:8]([O:10][CH3:29])=[O:9]
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: c1cn[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Yield: 48 %

Procedure:
A KOH powder (0.1 g, 1.8 mmoles) and methyl iodide (0.26 g, 1.8 mmols) were added to a solution of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzoic acid (0.30 g, 0.8 moles) in 20 ml acetone and reacted with this pyrazole derivative under reflux 3 hours. Then the extraction with ethylacetate, washing with water, dehydration, and concentration of the extract solution, and purification of the residue by column chromatography gave the title compound (0.15 g), yield 48%.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:26][C:27]1([CH2:34][CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=3)[N:39]=[CH:38][N:37]=2)[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1>ClCCl>[O:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH2:1][NH:11][CH:30]3[CH2:29][CH2:28][C:27]([CH2:34][CH2:35][C:36]4[C:45]5[C:40](=[CH:41][CH:42]=[C:43]([O:46][CH3:47])[CH:44]=5)[N:39]=[CH:38][N:37]=4)([OH:26])[CH2:32][CH2:31]3)=[CH:3][C:4]=2[O:5][CH2:6]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: COc1ccc2ncnc(CCC3(O)CCC(=O)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2ncnc(CCC3(O)CCC(NCc4ccc5c(c4)OCO5)CC3)c2c1
Reaction time: 8 h

Procedure:
Piperonylamine (0.030 ml, 0.24 mmol) and sodium triacetoxyborohydride (0.08 g, 0.377 mmol) were added to a solution of 4-hydroxy-4-[2-(6-methoxy-quinazolin-4-yl)-ethyl]-cyclohexanone (0.06 g, 0.2 mmol) in dichloromethane (1 ml). The reaction mixture was stirred overnight and then filtered over Hydromatrix (wetted with an NaHCO3 solution, 2 ml) and subsequently washed with dichloromethane. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (dichloromethane:MeOH 9/1 and then dichloromethane:MeOH 9/1 and 2% triethylamine).
Reaction SMILES: [Br:1][CH:2]([CH3:20])[CH:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:15](=[O:17])[OH:16])=[N:10][C:9]=2[C:8]([O:18][CH3:19])=[CH:7][CH:6]=1)[OH:4]>O.C(O)(=O)C>[Br:1][CH:2]([CH3:20])[C:3]([C:5]1[C:13]2[S:12][C:11]([NH:14][C:15](=[O:16])[OH:17])=[N:10][C:9]=2[C:8]([O:18][CH3:19])=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(C(O)C(C)Br)c2sc(NC(=O)O)nc12
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)C(C)Br)c2sc(NC(=O)O)nc12
Temperature: 70 °C

Procedure:
5.0 g of [7-(2-bromo-1-hydroxy-propyl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyll ester 0.0133 Mol) were suspended in water (30 ml) and 2.0 g of CrO3 (0.02 Mol), dissolved in acetic acid (30 ml), were added. The reaction mixture was heated to 70° C. for 2 hrs. and then evaporated to dryness. The residue was taken up in sat. NaHCO3 (200 ml), extracted 4× with ethyl acetate (200 ml each) and the combined organic phases were dried over MgSO4. The title compound was obtained as orange crystals (74%); F.p.: 199-201° C.
Reaction SMILES: [N+]([O:4][C@H:5]([CH2:12][O:13][N+]([O-])=O)[CH2:6][CH2:7][CH2:8][C:9](O)=[O:10])([O-])=O.[N+:17]([O:20][CH:21]([CH2:29][O:30][N+:31]([O-:33])=[O:32])[CH2:22][O:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])([O-:19])=[O:18]>>[N+:17]([O:20][CH:21]([CH2:29][O:30][N+:31]([O-:33])=[O:32])[CH2:22][O:23][CH2:24][CH2:25][C:26]([O:28][C@@H:8]1[CH2:9][O:10][C@@H:6]2[C@H:5]([OH:4])[CH2:12][O:13][C@H:7]12)=[O:27])([O-:19])=[O:18]
Reactant: O=C(O)CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Reactant: O=C(O)CCOCC(CO[N+](=O)[O-])O[N+](=O)[O-]
Product: O=C(CCOCC(CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O

Procedure:
The title compound was prepared by following the procedure for the synthesis of EXAMPLE 4, except that in Step F the reagent (S)-5,6-di(nitrooxy)hexanoic acid was replaced by 3-(2,3-bis(nitrooxy)propoxy)propanoic acid obtained as described in Oscar Pamies and Jan-E. Backvall, J. Org. Chem. 2002, 67, 1261-1265) and EXAMPLE 10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:34]3[C:10](=[C:11]4[C:31](=[CH:32][CH:33]=3)[C:15]3[N:16]=[C:17]([C@@H:19]5[CH2:23][CH2:22][CH2:21][N:20]5[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:18][C:14]=3[CH2:13][CH2:12]4)[O:9][CH2:8][C:6]=2[CH:7]=1>ClCCl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:34]3[C:10](=[C:11]4[C:31](=[CH:32][CH:33]=3)[C:15]3[N:16]=[C:17]([C@@H:19]5[CH2:23][CH2:22][CH2:21][N:20]5[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:18][C:14]=3[CH:13]=[CH:12]4)[O:9][CH2:8][C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c([nH]1)CCc1c-2ccc2c1OCc1cc(Cl)ccc1-2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c(ccc3c4c(ccc32)-c2ccc(Cl)cc2CO4)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
To a solution of Intermediate tert-butyl (2S)-2-(9-chloro-3,4,5,7-tetrahydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.43 g, 3.0 mmol) in dichloromethane (30 mL) was added manganese(IV) oxide (15 g, 198 mmol). The mixture was stirred for four hours at room temperature then filtered through Celite. The MnO2 was thoroughly rinsed with dichloromethane and the total filtrate was concentrated to yield tert-butyl (2S)-2-(9-chloro-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.37 g, 96% yield). This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]([C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1)([C:4]#[N:5])[CH3:3]>C(O)C.[Ni].[H][H]>[NH2:1][C:2]([C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1)([CH3:3])[CH2:4][NH2:5]
Reactant: CC(C)(C)OC(=O)C1(C(C)(N)C#N)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(C(C)(N)CN)CC1

Procedure:
To a solution (50 mL) of tert-butyl 1-(1-amino-1-cyanoethyl)-1-cyclopropanecarboxylate (1.12 g, 5.30 mmol) in ethanol was added a suspension (30 mL) of Raney nickel catalyst (R-100 manufactured by Nikko Rica Corporation, 10 mL) in ethanol, and the suspension was vigorously stirred at room temperature for 6 hours in hydrogen gas atmosphere. The catalyst was removed by filtration through celite, and the solvent was removed by distillation under reduced pressure to obtain 0.84 g (3.92 mmol, 74%) of the crude target compound as a colorless transparent oil. The thus obtained crude product was used in the subsequent reaction with no further purification.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[CH3:12].C(N(CC)CC)C.[CH3:20][C:21]1[N:25]([CH2:26][C:27]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]3[S:36][CH:37]=[C:38]([C:40](Cl)=[O:41])[N:39]=3)[CH2:31][CH2:30]2)=[O:28])[N:24]=[C:23]([C:43]([F:46])([F:45])[F:44])[CH:22]=1>ClCCl>[CH3:12][CH:4]1[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]1[N:2]([CH3:1])[C:40]([C:38]1[N:39]=[C:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:27](=[O:28])[CH2:26][N:25]3[C:21]([CH3:20])=[CH:22][C:23]([C:43]([F:44])([F:45])[F:46])=[N:24]3)[CH2:34][CH2:33]2)[S:36][CH:37]=1)=[O:41]
Reactant: CNC1c2ccccc2CC1C
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)C3c4ccccc4CC3C)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.4 %

Procedure:
To a solution of 2,3-dihydro-N,2-dimethyl-1H-inden-1-amine (177 mg, 1.1 mmol) and triethylamine (0.22 mL, 1.6 mmol) in 5 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (421 mg, 1 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with 4 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo to give 215 mg of the title compound, the product of present invention as a white foam.
Reaction SMILES: [CH2:1]([N:8]([C@@H:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][C@H:28]1[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:9]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24](O)=[O:25])[CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([NH2:54])(=[O:53])=[O:52])=[CH:47][CH:46]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([N:8]([C@@H:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][C@H:28]1[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:9](=[O:10])[CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH:54][S:51]([C:48]3[CH:47]=[CH:46][C:45]([F:44])=[CH:50][CH:49]=3)(=[O:52])=[O:53])=[O:25])[CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(F)cc1
Reactant: O=C(O)c1cccc(-c2cccc(CC(=O)N(Cc3ccccc3)[C@@H]3c4ccccc4CC[C@H]3Cc3ccccc3)c2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(F)cc1)c1cccc(-c2cccc(CC(=O)N(Cc3ccccc3)[C@@H]3c4ccccc4CC[C@H]3Cc3ccccc3)c2)c1
Reaction time: 5 h

Procedure:
To a solution of the product of Example 1 (82.0 mg, 0.145 mmol), 4-fluorobenzene sulfonamide (27.9 mg, 0.160 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP, 74.4 mg, 0.160 mmol), and methylene chloride (12 mL) was added diisopropylethyl amine (0.126 mL, 0.725 mmol). After stirring for 5 h, the reaction was concentrated to dryness and then diluted with ethyl acetate (25 mL). This was then washed with 0.1 N HCl (2×20 mL) and brine (25 mL), dried (magnesium sulfate), and concentrated. The title compound was isolated in quantitative yield as a foam following chromatography on silica gel with ethyl acetate/hexane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([O:15][CH2:16][CH3:17])=[C:4]([CH:18](O)[CH3:19])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:28])=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([O:15][CH2:16][CH3:17])=[C:4]([CH:18]([Cl:28])[CH3:19])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOc1c(C(C)O)cc(Cl)c(C#N)c1N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1N1CCCC1
Reaction time: 2 h
Yield: 102.2 %

Procedure:
The 6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-pyrrolidin-1-ylbenzonitrile (0.045 g, 0.15 mmol) was taken up in methylene chloride (3.0 mL) and N,N-dimethylformamide (0.002 mL, 0.03 mmol) and cooled in an ice bath. The thionyl chloride (0.017 mL, 0.23 mmol) was added and the reaction was monitored by LC/MS. After stirring for 2 hrs the reaction was complete. The reaction was then taken up in ethyl acetate, washed with sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give crude 6-chloro-4-(1-chloroethyl)-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile as a yellow oil (0.048 g, 100%). LCMS calculated for C15H19Cl2N2O (M+H)+: m/z=313.1; found 313.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:16]([O:18]C(C)(C)C)=[O:17])[C:11](=[O:30])[CH:10]=1.C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:16]([OH:18])=[O:17])[C:11](=[O:30])[CH:10]=1
Reactant: CC(C)(C)OC(=O)C(Cc1cccnc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(Cc1cccnc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O

Procedure:
274 mg (purity 88%, 0.49 mmol) of tert-butyl 2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-3-yl)propanoate (racemate) were hydrolysed with TFA according to General Method 6A. Yield: 244 mg (purity 57%, 65% of theory)
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:23](=[C:24]3[CH2:29][CH2:28][N:27](C)[CH2:26][CH2:25]3)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH2:16][CH2:15][C:14]=2[CH:31]=1)#[N:9].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(N(CC)CC)C>[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:23](=[C:24]3[CH2:29][CH2:28][N:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:26][CH2:25]3)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH2:16][CH2:15][C:14]=2[CH:31]=1)#[N:9]
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Yield: 75.2 %

Procedure:
Toluene (40 ml) was added to 1 g of 8-cyano-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine to dissolve the latter, followed by the addition of 0.52 g of triethylamine and 1.92 g of ethyl chloroformate. The resulting mixture was refluxed for 2.5 hours. The mixture was cooled and washed with water. The organic layer was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column. The substance eluted with chloroform was recrystallized from n-hexane, whereby 0.89 g of 8-cyano-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine was obtained (yield: 75%).
Reaction SMILES: [CH:1]1([C@@H:4]2[O:12][CH2:11][C:7]3=[N:8][O:9][CH2:10][C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1.C(=O)=O.CO>>[CH:1]1([C@H:4]2[O:12][CH2:11][C:7]3=[N:8][O:9][CH2:10][C@H:6]3[CH2:5]2)[CH2:3][CH2:2]1
Reactant: C1O[C@@H](C2CC2)C[C@H]2CON=C12
Agent: O=C=O
Solvent: CO
Product: C1O[C@H](C2CC2)C[C@@H]2CON=C12

Procedure:
Racemic rel-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C18) (20 g, 0.12 mol) was separated into its enantiomers using supercritical fluid chromatography (Column: ChiralPAK® AS-H, 5 μm; Eluent: 9:1 carbon dioxide/methanol). The first-eluting enantiomer provided (3aS,5S)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C75) as a pale yellow solid. The indicated absolute stereochemistry was assigned to compound C75 on the basis of the biological activity of this compound's final targets, which proved to have very poor activity (see Examples 17-18, Table 3); the final targets of its enantiomer C76 (below) proved active (see Examples 9-16, Table 3). Yield: 8.97 g, 0.053 mol, 44%. GCMS m/z 167 [M+]. 1H NMR (400 MHz, CDCl3) δ 4.69 (d, J=13.5 Hz, 1H), 4.57 (ddd, J=10.2, 7.9, 0.7 Hz, 1H), 4.14 (dt, J=13.4, 1.0 Hz, 1H), 3.77 (dd, J=11.8, 7.7 Hz, 1H), 3.39 (qd, J=11.1, 6.7, 1H), 2.81 (ddd, J=10.3, 8.7, 1.4 Hz, 1H), 2.28 (ddd, J=13.1, 6.5, 1.6 Hz, 1H), 1.64 (ddd, J=12.8, 11.4, 11.3 Hz, 1H), 0.86-0.95 (m, 1H), 0.49-0.61 (m, 2H), 0.36-0.42 (m, 1H), 0.19-0.25 (m, 1H).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[CH:27][CH:26]=1>>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:27][CH:26]=3)=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)CCc1ccc(O)c2ccccc12
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c3ccccc23)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting from (3-(4-ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate following Step 5 and 6 using ethyl 3-(4-hydroxynaphthalen-1-yl)propanoate as coupling agent to afford the desired product as an off-white solid. 1H-NMR (300 MHz, CDCl3) δ 8.22 (d, J=8.1 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.58 (t, J=7.5 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.22 (d, J=8.1 Hz, 3H), 6.77 (d, J=7.8 Hz, 1H), 5.22 (s, 2H), 3.39 (t, J=7.8 Hz, 2H), 2.82 (t, J=8.1 Hz, 2H), 2.65 (q, J1=15.5 Hz, J2=7.5 Hz, 2H), 1.20 (t, J=7.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C26H22F3NO3S, 486.1 (M+H). found 486.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].[CH2:19](I)[CH3:20].O>CN(C)C=O>[CH2:19]([O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:2]([NH2:1])[CH:7]=1)[CH3:20]
Reactant: Nc1cc(CC(=O)[O-])ccc1-c1ccccc1
Reactant: CCI
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2ccccc2)c(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium 2-amino-4-biphenylacetate is dissolved in dimethylformamide and the solution treated with ethyliodide. The solution is stirred at room temperature for about 3 hours, the solution added to water and the mixture extracted several times with benzene. The combined benzene extracts are washed with dilute base and water, dried over sodium sulfate, concentrated and crystallized to give ethyl-2-amino-4-biphenylacetate.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[S:3]1.C(N(CC)CC)C.C(Cl)(=O)OCC.[N+:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1)([O-:35])=[O:34]>C(Cl)Cl>[N+:33]([C:36]1[CH:37]=[CH:38][C:39]([CH2:40][NH:41][C:14](=[O:16])[C:13]2[CH:17]=[C:9]([CH2:8][CH:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])[CH:10]=[CH:11][C:12]=2[O:18][CH3:19])=[CH:42][CH:43]=1)([O-:35])=[O:34]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CC2SC(=O)NC2=O)cc1C(=O)NCc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 75.7 %

Procedure:
5-[(2,4-Dioxothiazolidin-5-yl)methyl]-2-methoxybenzoic acid (422 mg, 1.50 mmol), triethylamine (0.732 mL, 5.25 mmol) and methylene chloride (7 mL) were mixed and ethyl chlorocarbonate (0.158 mL, 1.50 mmol) was added under cooling with ice and stirring. After stirring for 10 minutes under cooling with ice, 4-nitrobenzylamine (283 mg, 1.50 mmol) was added. The mixture was stirred for 2 hours at room temperature, and then allowed to stand overnight. After washed with water, the reaction mixture was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved into water (20 mL), which was made acidic with 10% hydrochloric acid and stirred for 2 hours. The precipitated crystals were collected by filtration, washed with water and dried, then they were recrystallized from ethanol to obtain 472 mg (75%) of the title compound as pale yellow prisms.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)=[CH:8][N:7]=[C:6]([S:22][CH3:23])[N:5]=1)[CH3:2].CCN(CC)CC.[C:31](Cl)(Cl)=[O:32]>C(Cl)Cl.O.C(OCC)(=O)C>[CH2:1]([N:3]1[C:4]2=[N:5][C:6]([S:22][CH3:23])=[N:7][CH:8]=[C:9]2[CH2:10][N:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=2)[C:31]1=[O:32])[CH3:2]
Reactant: CCNc1nc(SC)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCN1C(=O)N(c2ccc(F)c([N+](=O)[O-])c2)Cc2cnc(SC)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of N-ethyl-5-((4-fluoro-3-nitrophenylamino)methyl)-2-(methylthio)pyrimidin-4-amine (2.20 g, 6.5 mmol) in CH2Cl2 (25 mL) was added Et3N (2.7 mL, 20 mmol) followed by phosgene (20% solution in toluene, 4.3 mL, 7.8 mmol). The reaction mixture was stirred for 2 h at RT and then diluted with water. The organic layer was separated and washed with brine, dried (MgSO4) and concentrated to provide an orange yellow solid, which on stirring in ethyl acetate followed by filtration provided 1-ethyl-3-(4-fluoro-3-nitrophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a light yellow solid.