Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[NH:12][CH:11]3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36].[H-].[Li+].[Cl:43][CH2:44][CH2:45][CH2:46]Br.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:46][CH2:45][CH2:44][Cl:43])[CH:11]3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36]
Reactant: ClCCCBr
Reactant: Cc1ccc(F)cc1C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1CC(=O)N(CCCCl)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 8 h
Yield: 24.2 %

Procedure:
Racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.40 g, 0.67 mmol) prepared in example 146a was reacted with LiH (0.13 g, 16.70 mmol) and 1-chloro-3-bromo-propane (0.63 g, 4.01 mmol) in N,N-dimethyl-formamide (3 mL), a catalytic amount of KI. After the solution was stirred overnight, the solution was poured into water. The water layer was extracted with ethyl acetate and the combined organic layers were dried, concentrated to obtain the crude product. The crude product was purified by chromatography to give racemic (2′S,3S,4′R)-6-chloro-1′-(3-chloro-propyl)-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a yellow solid (Yield: 0.11 g, 24%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C1C=CC2N(O)N=NC=2C=1.[CH2:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25]>ClCCl>[CH2:24]([N:26]1[CH2:31][CH2:30][N:29]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[O:8])[CH2:28][CH2:27]1)[CH3:25]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCN1CCN(C(=O)c2ccc(C)c([N+](=O)[O-])c2)CC1
Reaction time: 13 h
Yield: 94.8 %

Procedure:
To 4-methyl-3-nitro-benzoic acid (730 mg, 4.03 mmol), WSCI (930 mg, 4.85 mmol), HOBt (110 mg, 0.674 mmol) and N-ethylpiperazine (608 μl, 4.79 mmol), dichloromethane (8 ml) was added, followed by stirring for 13 hours. The reaction mixture was washed with aqueous ammonium chloride solution, and subsequently dried over sodium sulfate. After filtering sodium sulfate, the filtrate was concentrated under reduced pressure, to obtain (4-ethyl-piperazin-1-yl)-(4-methyl-3-nitro-phenyl)-methanone (1.06 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22]OC(OC)OC>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:14]=[CH:13][C:12]3[NH:15][CH:22]=[N:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1N
Reactant: COC(OC)OC
Solvent: O=CO
Product: Clc1cccc(C(c2ccc3[nH]cnc3c2)n2ccnc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
A mixture of 2.99 parts of 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine, 50 parts of trimethoxymethane and 2.4 parts of formic acid was stirred for 16 hours at room temperature. The reaction mixture was evaporated. The residue was dissolved in hydrochloric acid solution 2N. This solution was treated with ammonia and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (90:5:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 1.8 parts (58.2%) of 5-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1H-benzimidazole; mp. 108.2° C. (compound 93).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[Br:41][C:42]1[S:46][C:45]([S:47](Cl)(=[O:49])=[O:48])=[CH:44][CH:43]=1>O1CCCC1.O>[Br:41][C:42]1[S:46][C:45]([S:47]([N:14]2[C:10]([C:9]3[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=3)=[C:11]([F:25])[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:13]2)(=[O:49])=[O:48])=[CH:44][CH:43]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2ccc(Br)s2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26.0 mg) in tetrahydrofuran (3 mL) was added tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (156 mg) at room temperature, and the mixture was stirred for 10 min. 15-Crown-5 (143 mg) and 5-bromothiophene-2-sulfonyl chloride (196 mg) were added and the mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a colorless oil (yield 248 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][CH2:13][NH:12][C:11]2[N:16]([CH3:31])[N:17]=[C:18]([C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3C(OC(C)(C)C)=O)[C:10]1=2.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][CH2:13][NH:12][C:11]2[N:16]([CH3:31])[N:17]=[C:18]([C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[C:10]1=2
Reactant: Cn1nc([C@@H]2CCCN2C(=O)OC(C)(C)C)c2c1NCCSC2c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc([C@@H]2CCCN2)c2c1NCCSC2c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.6 %

Procedure:
To tert-butyl (2S)-2-[4-(2,4-dichlorophenyl)-1-methyl-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-3-yl]pyrrolidine-1-carboxylate (0.31 g, 0.64 mmol), was added trifluoroacetic acid in DCM (1:4, 20 mL). The resulting mixture was stirred, for about 18 h, at rt. Subsequently, 5% aqueous sodium bicarbonate (100 mL) and DCM (200 mL) were added. The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate/methanol (9:1) followed by 10% methanol in DCM) to afford 4-(2,4-dichlorophenyl)-1-methyl-3-[(2S)-pyrrolidin-2-yl]-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (38 mg, 0.1 mmol, 32%), as white solid: LC-MS (Table 1, Method a) Rt=1.38 min, m/z 383 (M+H)+; Major diastereomer; 1H NMR (400 MHz, CDCl3 and two drops of TFA) δ ppm 1.22-1.28 (1H, m) 1.85-2.35 (3H, m) 2.50-2.60 (1H, m) 2.68-2.83 (2H, m) 3.35-3.65 (3H, m) 3.75-3.85 (1H, m) 3.87 (3H, s) 4.60-4.70 (1H, br s) 5.32 (1H, s) 6.97 (1H, d, J=8.0 Hz) 7.16 (1H, dd, J=8.3, 2.2 Hz) 7.47 (1H, d, J=2.1 Hz) 9.65 (1H, br s). Minor diastereomer; 1H NMR (400 MHz, CDCl3 and two drops of TFA) δ ppm 1.22-1.28 (1H, m) 1.85-2.35 (4H, m) 2.68-2.83 (2H, m) 3.35-3.65 (3H, m) 3.75-3.85 (1H, m) 3.87 (3H, s) 4.60-4.70 (1H, br s) 5.31 (1H, s) 6.95 (1H, d, J=8.0 Hz) 7.10 (1H, dd, J=8.3, 2.2 Hz) 7.43 (1H, d, J=2.1 Hz) 9.25 (1H, br s).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH:5]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:2][CH2:3][C:4]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6](=[O:14])[CH:5]=3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: O=c1cc(CCBr)c2ccccc2[nH]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(CCN2CCC(c3c[nH]c4ccccc34)CC2)c2ccccc2[nH]1
Temperature: 0 °C
Yield: 45.7 %

Procedure:
A suspension of 4-(2-bromethyl)-2-(1H)-quinolinone (II-2) (500 mg, 1.98 mmol), 3-(4-piperidinyl)-1H-indole (396.5 mg, 1.98 mmol) and sodium hydrogencarbonate (249.5 mg, 2.97 mmol) in dry dimethylformamide (5 ml) was react at 80 ° C. for 5 hours. The reaction mixture was poured into ice-water and the separated solid was filtered by aspiration. The residue was washed with water and recrystallized from methanol/tetrahydrofuran/water to give the desired product (336 mg) (III-2) as pale yellow crystals (mp 259°-260 ° C. (methanol/tetrahydrofuran/water)). Yield 45.7%.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][C:9]([CH3:36])([CH3:35])[C:10]#[C:11][C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[C:14]([N:20]([C@@H:30]([CH3:34])[CH2:31][CH2:32][OH:33])[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])[CH:13]=1.Cl[C:38]1[C:47]2[C:42](=[C:43]([CH3:50])[C:44]([O:48][CH3:49])=[CH:45][CH:46]=2)[N:41]=[C:40]([O:51][CH2:52][CH3:53])[CH:39]=1.C(O[K])(C)(C)C>CS(C)=O>[CH3:36][C:9]([CH3:35])([CH3:8])[C:10]#[C:11][C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[C:14]([N:20]([C@@H:30]([CH3:34])[CH2:31][CH2:32][O:33][C:38]2[C:47]3[C:42](=[C:43]([CH3:50])[C:44]([O:48][CH3:49])=[CH:45][CH:46]=3)[N:41]=[C:40]([O:51][CH2:52][CH3:53])[CH:39]=2)[C:21]([CH:23]2[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])[CH:13]=1
Reactant: CCOc1cc(Cl)c2ccc(OC)c(C)c2n1
Reactant: C[C@@H](CCO)N(c1cc(C#CC(C)(C)C)sc1C(=O)O)C(=O)[C@H]1CC[C@H](C)CC1
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(OCC[C@H](C)N(C(=O)C2CCC(C)CC2)c2cc(C#CC(C)(C)C)sc2C(=O)O)c2ccc(OC)c(C)c2n1
Reaction time: 0.25 h
Yield: 19.1 %

Procedure:
The 5-(3,3-dimethyl-but-1-ynyl)-3-[(3-hydroxy-1-(S)-methyl-propyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid TFA salt (100 mg, 0.239 mmol) and 4-chloro-7-methoxy-2-ethoxy-8-methyl-quinoline (301 mg, 1.195 mmol) were dissolved in DMSO (3 mL). To this solution tBuOK (107 mg, 0.956 mmol) was added in one portion at rt. The reaction was run at it for 15 min and then cooled in an ice bath. The reaction was quenched with a 20% (v/v) solution of acetic acid in water. The reaction was partitioned between water and EtOAc. The phases were separated and the organic phase was extracted with brine. The organic phase was extracted with brine and then concentrated. The residue was suspended in MeOH and remaining solids were removed by filtration. The filtrate was concentrated, suspended in MeOH and filtered again. The filtrate was clarified with a small amount of EtOAc and 5-(3,3-dimethyl-but-1-ynyl)-3-[[3-(2-ethoxy-7-methoxy-8-methyl-quinolin-4-yloxy)-1-(S)-methyl-propyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (29 mg, 16%) was isolated as the TFA salt by reverse phase HPLC.
Reaction SMILES: [CH:1]([C:4]1[N:13]=[C:7]2[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[CH2:14]([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH3:27])[C:23]=1[C:24](O)=[O:25])=[O:18])[CH3:15].CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH:1]([C:4]1[N:13]=[C:7]2[CH:8]=[C:9]([NH:12][C:24]([C:23]3[N:22]([CH3:27])[N:21]=[CH:20][C:19]=3[C:17]([O:16][CH2:14][CH3:15])=[O:18])=[O:25])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2cc(N)ccn2n1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(C(C)C)nc2c1
Reaction time: 1 h
Yield: 103.3 %

Procedure:
A mixture of 2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine (159 mg, 902 μmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (215 mg, 1.08 mmol), propylphosphonic anhydride (50% in ethyl acetate, 1.33 ml, 2.26 mmol) and diisopropylethylamine (473 μl, 2.71 mmol) in tetrahydrofurane (7 ml) is refluxed for 18 hours. The solvent is evaporated and the residue stirred for 1 hr with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed with water and dried affording ethyl 5-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylate (332 mg, 103%) as a white solid. Mp.: 175-7° C. MS: m/z=357.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:28]Br>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:10][C:11]([C:15]#[N:16])=[C:12]([O:14][CH2:28][C:27]2[CH:30]=[CH:31][C:32]([F:33])=[C:25]([F:24])[CH:26]=2)[N:13]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 75 °C

Procedure:
To the product of Step C (0.500 g, 1.465 mmol) was added Ag2CO3 (0.606 g, 2.198 mmol), DMF (8 mL), and 3,4-difluorobenzyl bromide (0.28 mL, 2.198 mmol). The reaction was heated to 75° C. for 75 min before cooling and filtering through Celite®545 diatomaceous earth. The solution was concentrated and the residue was purified by flash chromatography (silica gel) eluting with a gradient of 15 to 46% ethyl acetate/hexane affording the product. MS (electrospray) m/e 467.0 MH+ (Rt=4.7 min LC/MS).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][OH:17])=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2=[N:29][N:30]=[C:31]([C:32]3[CH:36]=[C:35]([CH3:37])[O:34][N:33]=3)[N:21]2[N:20]=1.C1C2C(=CC=CC=2)C=NN=1>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][O:17][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]3=[N:29][N:30]=[C:31]([C:32]4[CH:36]=[C:35]([CH3:37])[O:34][N:33]=4)[N:21]3[N:20]=2)=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CO)nc1
Agent: c1ccc2cnncc2c1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CO[Si](C)(C)C(C)(C)C)cn4)nn23)no1

Procedure:
The reaction was carried out as described in Example 1, Step 4 using 5-(tert-butyldimethylsilyloxymethyl)-2-(hydroxymethyl)pyridine (1.0 g, 3.95 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (1.12 g, 3.95 mmol) to give, after column chromatography on silica using 2-3% MeOH/CH2Cl2 as eluent, the title phthalazine (1.4 g, 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH2:15]OS(C)(=O)=O)[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-:22].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH2:15][F:22])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCc2ccccc2)co1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=c1cc(CF)occ1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice/salt cooled solution of the sulfonate ester obtained in step 1 above ester (20.0 g, 64.4 mmol) in acetonitrile (120 mL) was added a mixture of a 75 wt % solution of tetrabutylammonium fluoride (35 g, 96.6 mmol) and 40 mL of acetonitrile. Additional tetrabutylammonium fluoride solution (35 g, 96.6 mmol) was added after 2.5 hrs and the reaction mixture was allowed to stir at room temperature for overnight. The reaction was concentrated in vacuo to give a dark red oil. The residue was diluted with 700 mL of ethyl acetate and washed 5 times with 120 mL of a 10% sodium hydrogen carbonate solution and twice with 120 mL of brine. The organic layer was dried over sodium sulfate, and concentrated to give a dark red oil. The crude product was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexanes (1/1, v/v) as the eluant to give 5-benzyloxy-2-fluoromethyl-pyran-4-one as a waxy-like solid (10.0 g, 66% yield). 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.69 (s, 1H), 7.42-7.37 (m, 5H, H—Ar)), 6.57 (s, 1H), 5.36 (d, J=46.5 Hz, 2H, CFH2), 4.97 (m, 2H, OCH2).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([OH:13])[C:10]2[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:16][NH:17][CH3:18]>C1COCC1>[CH3:16][N:17]([CH2:2][C:3]1[N:12]=[C:11]([OH:13])[C:10]2[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7][CH2:6][C:5]=2[N:4]=1)[CH3:18]
Reactant: CC1(C)CCc2nc(CCl)nc(O)c2C1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1nc(O)c2c(n1)CCC(C)(C)C2
Temperature: 60 °C

Procedure:
To a solution of 2-(chloromethyl)-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-ol (2.5 g, 11 mmol) in THF (10 mL) was added dimethyl amine (2M in THF, 16.5 mL, 33 mmol). The reaction mixture was heated (60° C.) for two hours and then partitioned between ethyl acetate and sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to provide 2-((dimethylamino)methyl)-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-ol, which was used in step 3 without further purification. MS (ES) for C13H21N3O: 236 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([F:38])([F:37])[F:36].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O>[Cl:8][C:6]1[CH:7]=[C:2]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([F:37])([F:38])[F:36])=[C:29]([Cl:28])[CH:30]=2)[N:3]=[CH:4][N:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)c(Cl)c1
Reactant: Clc1cc(Cl)ncn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.7 %

Procedure:
To a solution of CH3CN and water (75:25 mL) that has been degassed by bubbling N2 into the solvent were added 4,6-dichloro-pyrimidine (3.63 g, 22.7 mmol) and Ph3P (840 mg, 2.2 mmol). De-gassing was continued for an additional 15 min before adding 3-chloro-4-trifluoromethylphenyl boronic acid (5 g, 22 mmol), Pd (OAc)2 (250 mg, 1.11 mmol) and K3PO4 (9.4 g, 44.3 mmol). The resulting mixture was stirred at rt for 2 h before diluting with water and extracting with EtOAc. The organic layer was dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound (2.3 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([OH:17])CO)[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.I(O)(=O)(=O)=O>O1CCCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)[CH:14]=[O:17]
Reactant: OCC(O)c1ccc(C2CCCCC2)c(Cl)c1
Agent: [O-][I+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ccc(C2CCCCC2)c(Cl)c1
Reaction time: 8 h

Procedure:
To 115 g. of 1-(3-chloro-4-cyclohexylphenyl)-1,2-ethanediol in tetrahydrofuran (800 ml.) is added a solution of periodic acid (102 g.) in ether (750 ml.). The reaction mixture is stirred under nitrogen overnight. The reaction mixture is filtered and the filtrate is washed with water (3×200 ml) and placed over sodium sulfate. Removal of solvent gives a liquid residue which is then distilled to give 3-chloro-4-cyclohexylbenzaldehyde.
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])([O:3][CH3:4])=[O:2].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=1>C(#N)C.CCOCC>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][C:14]([NH:13][S:10]([C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:1]([O:3][CH3:4])=[O:2])(=[O:11])=[O:12])=[O:15])[N:19]=1
Reactant: COC(=O)C1=C(S(=O)(=O)N=C=O)CCC1
Reactant: COc1cc(C)nc(N)n1
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)C1=C(S(=O)(=O)NC(=O)Nc2nc(C)cc(OC)n2)CCC1

Procedure:
The sulfonyl isocyanate product (5 g) of Example 3 was diluted to a concentration of 1.5M with dry acetonitrile and 2.0 ml of this solution was added to a stirred suspension of 0.31 g 4-methoxy-6-methylpyrimidine-2-amine in 4.0 ml of dry acetonitrile under a nitrogen atmosphere at room temperature. After stirring several hours, the mixture was diluted with ether to precipitate the product which was collected by filtration and dried; m.p. 161°-163°. An infrared spectrum (nujol) exhibited absorptions at 1730 and 1700 cm-1, and an NMR (90 MHz) in CDCl3 solution exhibited absorptions at 2.1 (CH2), 2.45 (CH3), 3.0 (CH2 ×2), 3.75 (CH3O), 3.95 (CH3O), 6.3 (CH), 7.9 (NH), 13.8 (NH), ppm indicating the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][O:8][CH3:9].CC([O-])(C)C.[K+].CS[C:18](SC)=[CH:19][N+:20]([O-:22])=[O:21]>C(O)C>[CH3:9][O:8][N:7]1[CH2:6][CH2:5][CH2:4][NH:3][C:18]1=[CH:19][N+:20]([O-:22])=[O:21]
Reactant: CONCCCN
Reactant: CSC(=C[N+](=O)[O-])SC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CON1CCCNC1=C[N+](=O)[O-]

Procedure:
2.0 g (0.011 mol) of 1-amino-3-methoxyaminopropane dihydrochloride and 2.53 g (0.023 mol) of potassium tert-butylate are refluxed in 120 ml of ethanol for 1 hour. Subsequently, 1.86 g (0.011 mol) of 1,1-bis(methylthio)-2-nitroethylene is added and the mixture is refluxed for a further 6 hours until no more gas evolves. The salts are separated off by filtration and the solvent is removed. The crude product is purified by flash chromatography using toluene/ethanol as developer. The desired product is obtained as slightly yellowish crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH:20](O)=[O:21].C(OC(=O)C)(=O)C>O>[NH:1]([CH:20]=[O:21])[C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=CO
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=CN[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
444.7 g (1.67 mole) of commercially available H—Orn(Z)—OH was dissolved in 3.5 L (93 moles) of formic acid. The solution was cooled in an ice bath, and 1.17 L (12 moles) of acetic anhydride was subsequently added in dropwise fashion over two hours while the temperature of the reaction mixture was maintained between about 5° and 15° C. The resultant reaction mixture was stirred at room temperature for about two hours after the addition was completed, and the reaction vessel was refrigerated overnight. 1.5 L of cold water was then added, and the solution was concentrated to dryness under reduced pressure. The residual, light yellow syrup was taken up into EtOAc, washed with water and then with saturated NaCl, and then dried overnight over sodium sulfate. After filtration and evaporation to dryness, the residual syrup was dissolved in 5 L of ethyl ether. The solution was cooled in a dry ice bath and seeded. The resulting crystalline product was filtered, washed with ethyl ether, air dried for two hours and finally dried in a lyophilizer. 431.6 g (1.47 mole, 88%) of For—Orn(Z)—OH was obtained.