Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:44])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][N:38]=2)[CH:32]=1)(C)(C)C>>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:44])[CH2:29][C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[CH:42]=[CH:41][N:40]=[CH:39][N:38]=4)[CH:32]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncn2)c1
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccncn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (160 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K43) (179 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (112 mg).
Reaction SMILES: C1C[NH:6][C:4](=[O:5])[NH:3]C1.C(N(CC)CC)C.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:15][CH2:16][CH2:17][C:18]([NH:3][C:4]([NH2:6])=[O:5])=[O:19]
Reactant: O=C1NCCCN1
Reactant: O=C(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NC(=O)NC(=O)CCCl
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
20.0 g of N,N'-trimethyleneurea are partially dissolved in 1000 ml of toluene under reflux and admixed with 20.2 g of triethylamine and then dropwise, in the course of 90 minutes, with a solution of 25.4 g of 3-chloropropionyl chloride. Subsequent stirring for 30 minutes, cooling down to 5° C., removal of undissolved matter by filtration and evaporating the filtrate in vacuo gives 24 g of chloropropionylurea of the formula ##STR70## as a beige powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.CC[OH:15]>>[NH2:10][C:4]1[C:5]([C:8]([NH2:9])=[O:15])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CCO
Reactant: N#Cc1ncc(Cl)cc1[N+](=O)[O-]
Product: NC(=O)c1ncc(Cl)cc1N
Reaction time: 2.5 h

Procedure:
Raney Nickel (10 g of Aldrich 50% slurry in water) was washed with water (100 mL), 5% AcOH (100 mL), water (100 mL), and 95% EtOH (3×100 mL). The resulting slurry was added to a solution of 5-chloro-3-nitropicolinonitrile (104) (5.0 g, 27 mmol) in 95% EtOH (100 mL). The mixture was hydrogenated at 45 psi for 2.5 h. The mixture was then filtered over a bed of Celite and washed with 95% EtOH (2×100 mL). The red/brown filtrate was rota-evaporated to dryness, leaving the title compound as a light brown solid, 3.8 g (82%), mp 152°-6° C. (Lit., 165°-6° C., McCaustland and Cheng, J. Heterocycl. Chem. 7:467 (1970)); 1H NMR (CDCl3): δ5.42 (bs, 1H), 6.05 (bs, 2H), 7.00 (d, J=1.2 Hz, 1H), 7.71 (bs, 1H), 7.79 (d, J=1.2 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:19][C:20]5([CH2:21][CH2:22][N:23]([C:29]6[N:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=6)[CH2:24][CH2:25]5)[CH2:26]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(c4ncc(C(F)(F)F)cn4)CC3)C2)CC1
Reaction time: 8 h

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and 2-chloro-5-trifluoromethyl-pyrimidine following a procedure analogous to that described for Example 15; the reaction is conducted at 45° C. overnight. LC (method 6): tR=1.09 min; Mass spectrum (ESI+): m/z=536 [M+H]+.
Reaction SMILES: CON(C)[C:4](=[O:26])[CH:5]([OH:25])[CH:6]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl>O1CCCC1>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][C:4](=[O:26])[CH:5]([OH:25])[CH:6]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:34]
Reactant: CON(C)C(=O)C(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [Li]CC(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-4-phenyl-3-[((phenylmethoxy)carbonyl)amino]butanoic acid, N-methoxy-N-methylamide (372 mg, 1.0 mmol) in tetrahydrofuran is cooled to -78° C. and ethyl lithioacetate (72 mg, 3.0 mmol) is added. The solution is stirred at -78° C. for 1 hour, allowed to warm to room temperature, stirred for 1 hour and poured into dilute HCl. The product is extracted by ethyl acetate (3×150 ml) and the combined organic extracts are washed with NaHCO3, dried over Na2SO4 and the solvent removed in vacuo. The crude product is purified by flash chromatography on silica gel.
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)=O.[CH2:14](N(C)C)C1C=CC=CC=1.C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCC>[CH:2]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)=[CH2:14]
Reactant: CN(C)Cc1ccccc1
Reactant: N#CC=Cc1ccc(C(=O)Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: C=Cc1ccc(C=CC#N)cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
2.39 g (12.5 mmols) of 4-chloroformylcinnamonitrile, 1.69 g (12.5 mmols) of N-benzyldimethylamine and 0.0280 g (0.125 mmol) of palladium acetate are added under argon to 25 ml of toluene. The reaction mixture is stirred for 4 hours at 140° C. under an ethylene pressure of 10 bar. The mixture is then extracted by shaking at room temperature with 100 ml of 2N HCl and 100 ml of 2N NaOH and is dried over magnesium sulfate. The solution is then evaporated and the residue is chromatographed over silica gel using methylene dichloride as the migrating agent. The yellow oil thus obtained is dissolved in boiling n-pentane. 0.84 g (44% of theory) of 4-vinylcinnamonitrile are formed at -20° C. in the form of white crystals; melting point 45.8° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S1C=CC=C1[Cl:19]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: Clc1cccs1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1F

Procedure:
A solution of 42 g of 2-fluoro-5-nitro-benzoic acid [prepared by Chim. et Ind. 1970, p. 892] melting at 139°-140° C. and 120 ml of thienyl chloride was refluxed for two hours and was then distilled at 40° C. under a pressure of 30 to 40 mm Hg. The residue was taken up in benzene and the solution was evaporated to dryness to obtain 44 g of 2-fluoro-5-nitro-benzoyl chloride melting at 59°-60° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH2:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH2:24]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([N:13]2[CH2:12][CH2:11][CH:10]([N:6]3[C:5]4[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=4[NH:8][C:7]3=[O:9])[CH2:15][CH2:14]2)=[O:33])=[CH:35][CH:36]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: O=c1[nH]c2cc(F)ccc2n1C1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1ccc(C(=O)N2CCC(n3c(=O)[nH]c4cc(F)ccc43)CC2)cc1
Reaction time: 8 h
Yield: 12.3 %

Procedure:
To a solution of 5-fluoro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (29.4 mg, 0.125 mmol) in methylene chloride (1 mL) was added pyridine (0.12 μL, 0.15 mmol) and 4-n-butylbenzoyl chloride (26 μL, 0.138 mmol). The reaction mixture was stirred overnight then purified directly by column chromatography on silica gel by eluting with methylene chloride followed by ethyl acetate. The product fractions were combined and concentrated in vacuo to give 1-[1-(4-butyl-benzoyl)-piperidin-4-yl]-5-fluoro-1,3-dihydro-benzoimidazol-2-one (6.1 mg; 12%) was obtained as a glass.
Reaction SMILES: [O:1]([CH3:3])[K].CO.C1(C)C=CC=CC=1.F[C:14]1[CH:19]=[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=3)[N:22]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:21]=2)[CH:17]=[CH:16][N:15]=1>>[CH3:3][O:1][C:14]1[CH:19]=[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=3)[N:22]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:21]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CO[K]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccnc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)ccn1
Temperature: 70 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
In a 250 ml pressure vessel, 3-(2-Fluoro-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole 3BV (5.005 g, 10.0 mmole) was dissolved in 0.1N KOCH3/MeOH/Toluene (Acros, 150 mL, 15.0 mmole) under dry N2 gas. The pressure vessel was tightly sealed and heated under stirring at 70° C. for 24 hours. The pressure vessel was cooled to 0° C. in ice-bath before opening. The contents of the pressure vessel were transferred to 500 ml RBF and evaporated to dryness. The resulting solid was dissolved in CH2Cl2 and washed with saturated NaCl solution and dried over MgSO4. The solvent was evaporated to dryness and dried under high vacuum to yield 4BV as a brown solid (5.12 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C1(P(=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(F)c1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of 3-fluorobenzaldehyde 1-1 (18.16 g, 146 mmol) in dichloromethane (500 mL) was added ethyl (triphenylphosphoranylidene)acetate (61.2 g; 176 mmol), and the resulting solution was stirred at room temperature for 18 hr. After evaporation of the solvent, the residue was swirled with ether/hexane and filtered. The filtrate was concentrated and then purified on a plug of silica gel eluting with hexane/EtOAc 9:1. Removal of the solvent afforded the title compound 1-2 as an oil (~95% trans) which was used without further purification in the next step.
Reaction SMILES: [ClH:1].Cl.[C@H]1(CN2CCC([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])CC2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.N[CH:49]1[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][N:57]2[CH2:62][CH2:61][C@H:60]([OH:63])[C@@H:59]([CH3:64])[CH2:58]2)[CH2:51][CH2:50]1>>[ClH:1].[ClH:1].[OH:63][C@H:60]1[CH2:61][CH2:62][N:57]([CH2:56][CH2:55][N:52]2[CH2:53][CH2:54][CH:49]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:50][CH2:51]2)[CH2:58][C@@H:59]1[CH3:64]
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Reactant: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c2cc1C
Agent: Cl
Product: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)c2cc1C

Procedure:
This compound is synthesized from 4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (127, see example 104) and amine 14 analogously to the method described in example 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[C:4]([CH3:10])[N:3]=1>CCO.O.[Pd]>[Cl:1][C:2]1[N:3]=[C:4]([CH3:10])[C:5]([NH2:9])=[CH:6][N:7]=1
Reactant: Cc1nc(Cl)nc(Cl)c1N
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Cc1nc(Cl)ncc1N
Reaction time: 8 h
Yield: 19.8 %

Procedure:
2,4-Dichloro-6-methylpyrimidin-5-amine (1.0 g, 5.62 mmol) was dissolved in anhydrous EtOH (3.5 mL) and H2O (7.0 mL). MgO (1.40 g, 34.74 mmol) and 10% Pd/C (35 mg) were added to the reaction mixture which was hydrogenated at 1 atm, at room temperature, overnight. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (MeOH/CH2Cl2 gradient, 0-15% MeOH) to afford 2-chloro-4-methylpyrimidin-5-amine as light pink solid (0.16 g, 20%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[CH3:13][O:12][C:10]([C:5]1[C:4]2[CH:3]=[CH:2][N:1]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([O:25][CH2:24][C:15]4[CH:16]=[CH:17][C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:14]=4)=[CH:33][CH:32]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:11]
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COC(=O)c1cccc2[nH]ccc12
Product: COC(=O)c1cccc2c1ccn2Cc1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
This compound was prepared from methyl 4-indole carboxylate and 4-(quinolin-2-ylmethoxy)benzyl chloride (Example 1a by the method described in Example 1b part i), m.p. 128°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:22][CH:23]=1)=O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:16][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[N:22][CH:23]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)cn1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cn1
Temperature: -20 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (70 mg, 287 μmol) and tert-butyl (5-formylpyridine-2-yl)carbamate (159 mg, 717 μmol) in MeOH (3 ml) was stirred at 45° C. for overnight to give a suspension, cooled to −20° C. and was filtered to collect the solid. The solid was re-suspended in MeOH (5 ml), NaBH4 (163 mg, 4.3 mmol) was added in a few portions and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in EtOAc (5 ml) and washed with water (2×4 ml), dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (silica gel, 24 g, 3% to 6% MeOH in DCM) afforded a white solid as desired product (60.8 mg, 47% yield). MS +m/z: 450 (M+H)+
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][Si](C(C)(C)C)(C)C)=[CH:8][C:7](=[O:34])[CH2:6][CH2:5]1.O>C(O)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:8][C:7](=[O:34])[CH2:6][CH2:5]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Solvent: O
Solvent: CC(=O)O
Product: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Yield: 115.1 %

Procedure:
A solution of 23.1 g of 11β-fluoro-7α-{5-tert-butyl-dimethylsilyloxypentyl)-estr-4-ene-3,17-dione in 115 ml of The and 64 ml of water are stirred with 128 ml of glacial acetic acid for 2.5 hours at 50° C. The reaction mixture is concentrated by evaporation in a vacuum, taken up in ethyl acetate, washed with water and dried. 20.4 g of 11β-fluoro-7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione is obtained as foam.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([P:12]([O:17][CH2:18][CH3:19])(=[O:16])[O:13][CH2:14][CH3:15])[N:9]=[C:8](P(OCC)(=O)OCC)[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[CH2:1]([NH:5][C:6]1[N:7]=[C:8]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])[N:9]=[C:10]([P:12]([O:13][CH2:14][CH3:15])(=[O:16])[O:17][CH2:18][CH3:19])[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCNCC
Reactant: CCCCNc1nc(P(=O)(OCC)OCC)nc(P(=O)(OCC)OCC)n1
Product: CCCCNc1nc(N(CC)CC)nc(P(=O)(OCC)OCC)n1

Procedure:
Tetraethyl 2-n-butylamino-1,3,5-triazine-4,6-diphosphonate prepared as described in Example 17 was dissolved in excess diethylamine and heated at reflux (59°-60° C.) for 6 hours to produce diethyl 2-n-butylamino-4-diethylamino-1,3,5-triazine-6-phosphonate.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][CH:19]=[CH:18][C:17]=3[CH:23]=2)=[CH:9][CH:8]=1>CN(C)C=O>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][C:19]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:18][C:17]=3[CH:23]=2)=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(-c2ccc3c(c2)C=CCCO3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(S(=O)(=O)Cl)CCO3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under ice-cooling, to dimethylformamide (0.2 ml) was added dropwise sulfuryl chloride (0.17 ml), and the mixture was stirred, under nitrogen atmosphere, at room temperature for 10 minutes. To the mixture was added 7-(4-methyl-phenyl)-2,3-dihydro-1-benzoxepine (0.3 g), and the mixture was stirred, under nitrogen atmosphere, at 90° C. for 3 hours. To the mixture was added ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-sulfonylchloride (0.36 g) as pale yellow crystals.
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([N+:24]([O-])=O)[CH:3]=1>C(O)C.C(O)(=O)C.[Fe]>[I:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:13][CH2:14]2)=[O:7])=[C:4]([NH2:24])[CH:3]=1
Reactant: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(I)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(I)ccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Yield: 90.4 %

Procedure:
0.26 g (0.000588 mol) of 1-benzyl-piperidin-4-yl 4-iodo-2-nitro-benzoate was dissolved in 3.3 ml of ethanol, diluted with 3.3 ml of acetic acid and treated with 0.123 g (0.0022 mol) of iron powder. The mixture was boiled at reflux for 4 hrs., the solvent was distilled off, the residue was taken up in ethyl acetate, washed with saturated sodium carbonate solution and sodium chloride solution and the organic phase was dried over sodium sulfate. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:4) as the eluent. 0.232 g (95%) of 1-benzyi-piperidin-4-yl 4-iodo-2-amino-benzoate was obtained as a yellow oil. MS: me/e=437 (C19H22IN2O2 +).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH2:25][CH:24]=[CH2:23])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid (50.0 g) in N,N-dimethylformamide (500 ml) were added potassium carbonate (60.3 g) and allyl bromide (28.3 ml), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water (600 ml), and the mixture was extracted with ethyl acetate (600 ml). The organic layer was sequentially washed with water (600 ml) and saturated aqueous sodium chloride solution (400 ml). The separated aqueous layer was extracted with ethyl acetate (300 ml) again. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the resulting residue in n-hexane/ethyl acetate (4/1, 400 ml) was added silica gel (70 g), and the mixture was stirred at room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the titled compound (62.5 g).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCCC2=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCCN1C1CNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
A mixture of 3-(2-oxopyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (320 mg, 1.33 mmol) and TFA (1.5 mL) in DCM (3 mL) was stirred at room temperature for 4 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM and eluted with 2M NH3/MeOH affording 1-Azetidin-3-ylpyrrolidin-2-one as a white solid (174 mg, 93%). 1H NMR (CDCl3, 300 MHz): δ 5.05 (m, 1 H), 3.85-3.76 (m, 4 H), 3.61 (m, 2 H), 2.41 (m, 2 H) and 2.07 (m, 2 H)
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NCCC1CCOCC1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCOCC3)cc2F)cn1
Yield: 44.3 %

Procedure:
Using a method similar to Example 405, a reaction of 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.0294 g, 0.113 mmol) and 2-(tetrahydropyran-4-yl)ethylamine (0.016 g, 0.124 mmol) gives the title compound (0.0187 g, 44.2%): TOF MS ES+ 374.2 (M+H)+, HRMS calcd for C20H25N3O3F 374.1880 (M+H)+, found 374.1863, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 30-99% over 19 min], tR=5.2 min, 95.2% purity.