Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9](=[O:15])[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:4].[Li+].[OH-].Cl>CO.O>[C:11]([NH:10][C:9]([N:6]1[CH2:7][CH2:8][C@H:5]1[C:3]([OH:4])=[O:2])=[O:15])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)[C@@H]1CCN1C(=O)NC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)NC(=O)N1CC[C@H]1C(=O)O
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of (2S)-methyl-1-(N-t-butylcarbamoyl)azetidine-2-carboxylate from Reference Example 5 (211.6 mg, 0.99 mmol) in methanol (5.0 mL) was added 1N LiOH in water (1.8 mL) at about 0° C. The mixture was warmed to about room temperature and stirred under argon overnight. The pH was adjusted to about pH 1 by adding 1N HCl and then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give 211.3 mg (85% yield) of the product as a yellow oil. 1H NMR (CDCl3) δ 1.38 (s, 9H); 2.34-2.46 (m, 1H); 2.61-2.74 (m, 1H) 3.71-3.88 (m, 2H); 4.18-4.26 (br, 1H); 4.82 (t, 1H, J=8.6).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:10]([C@@H:12]1[C@@H:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13]1)[OH:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH:50]1[C:62]2[CH:61]([CH2:63][O:64][C:65](=[O:84])[NH:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][C:77](=[O:83])[NH:78][CH2:79][CH2:80][CH:81]=O)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[Si:18]([O:17][C@H:16]1[C@@H:15]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@H:14]([N:33]2[CH:38]=[CH:37][C:36](=[O:39])[N:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:34]2=[O:49])[O:13][CH:12]1[C@H:10]([OH:11])[C@@H:2]([C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])[NH:1][CH2:81][CH2:80][CH2:79][NH:78][C:77](=[O:83])[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][NH:66][C:65](=[O:84])[O:64][CH2:63][CH:61]1[C:60]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:54]2[C:62]1=[CH:50][CH:51]=[CH:52][CH:53]=2)([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reactant: O=CCCNC(=O)CCCCCCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)CCCCCCCCCCNC(=O)OCC4c5ccccc5-c5ccccc54)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 64.9 %

Procedure:
By using an analogous procedure to that described for Example 1, a solution of tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (125 mg, 0.173 mmol, obtained from Reference Example 6), 9H-fluoren-9-ylmethyl-11-oxo-11-[(3-oxopropyl)amino]undecyl-carbamate (99 mg, 0.208 mmol, obtained from Reference Example 30), acetic acid (2 drops) and sodium triacetoxyborohydride (73 mg, 0.346 mmol) in anhydrous tetrahydrofuran (4 ml) was stirred at room temperature under nitrogen for 5.5 hours. The product was purified by chromatography (flash column, silica gel, ethyl acetate) to provide tert-butyl (21S)-21-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-1-(9H-fluoren-9-yl)-3,15-dioxo-2-oxa-4,16,20-triazadocosan-22-oate (133 mg, 65%) as a white solid.
Reaction SMILES: [O:1]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]2[C@H:20]3[C@H:30]([CH2:31][CH2:32][C@:15]12[CH3:16])[C@:28]1([CH3:29])[C:23](=[CH:24][C:25](=[O:33])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3>CS(C)=O>[OH:1][C@@H:21]1[CH2:22][C:23]2[C@:28]([CH3:29])([CH2:27][CH2:26][C:25](=[O:33])[CH:24]=2)[C@@H:30]2[C@@H:20]1[C@H:17]1[C@@:15]([CH2:32][CH2:31]2)([CH3:16])[C@@H:14]([OH:13])[CH2:19][CH2:18]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CS(C)=O
Product: C[C@]12CC[C@H]3[C@@H]([C@H](O)CC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reaction time: 22 h

Procedure:
100 ml of a nutrient medium, containing 1% cornsteep liquor and 1% glucose, were adjusted to pH 6.5 and, after sterilization, inoculated with the mycelium of IFO 6469. After incubation at 26.5° on the rotary shaking machine during 22 hours, 100 mg of 17β-hydroxy-4-androsten-3-one in 1 ml of dimethyl sulphoxide were added and the incubation was continued at 26.5° for a further 8 days. Thereafter, the fermentation solution was filtered, the filtrate was extracted with ethyl acetate and concentrated to a small volume and under reduced pressure. The concentrate was chromatographed on silicic acid with chloroform-acetone. There were obtained 17.9 mg of 7α,17β-dihydroxy-4-androsten-3-one.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH:18](OCC)[O:17][C:16](=O)[CH2:15]1)[CH:5]=[CH2:6].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[CH2:4]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH:18]=[N:3][NH:2][C:16](=[O:17])[CH2:15]1)[CH:5]=[CH2:6]
Reactant: NN
Reactant: C=CCOc1ccccc1C1CC(=O)OC1OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCOc1ccccc1C1C=NNC(=O)C1

Procedure:
Hydrazine hydrate (2.8 ml) was added to a solution of 4-(2-allyloxyphenyl)-5-ethoxydihydro-2-furanone (9.8 g) in acetic acid (30 ml) and water (27 ml). The solution was refluxed for 90 minutes, poured into aqueous sodium bicarbonate, extracted into diethyl ether, evaporated under reduced pressure and the resultant solid recrystallised from benzene to afford 5-(2-allyloxyphenyl)-4,5-dihydro-3[2H]-pyridazinone (6.5 g) as white crystals, m.p. 93°-95° C.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][CH:14]([CH2:20][CH2:21][CH2:22][CH3:23])[C:15](OCC)=[O:16].C(O)(=O)C>O1CCCC1.CCCCC>[CH3:13][CH:14]([CH2:20][CH2:21][CH2:22][CH3:23])[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(C)C(=O)OCC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCC(C)C(=O)CP(=O)(OC)OC
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 32.6 %

Procedure:
A stirred solution of dimethyl methylphosphonate (54 g.) in dry tetrahydrofuran (390 ml.) at -45° to -50°C. was treated, dropwise during 20 minutes, with a solution of butyl lithium (32 g.) in pentane (250 ml.). Stirring was continued at that temperature for a further 10 minutes, and then the mixture was cooled to -60°C. and treated, dropwise during 15 minutes, with a solution of ethyl 2-methylhexanoate (34.5 g.) in tetrahydrofuran (120 ml.). The mixture was stirred at -60°C. for a further 90 minutes and then at room temperature for 3 hours, and then it was treated with acetic acid (42 ml.), evaporated to dryness in vacuo, and residue treated with water (170 ml.). The mixture was extracted twice with diethyl ether and the combined ethereal extracts washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. The residue was distilled to give dimethyl 3-methyl-2-oxoheptylphosphonate (16.8 g.), b.p. 93-94°C./0.2mm.Hg.
Reaction SMILES: C[N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][CH:12]=1)[C:3](=O)OC(C)(C)C.[H-].[Na+].[C:24]([C:26]1[CH:27]=[C:28]([S:32]([Cl:35])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1)#[N:25]>>[ClH:35].[CH3:3][NH:2][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:13]([S:32]([C:28]2[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=2)[C:24]#[N:25])(=[O:34])=[O:33])[CH:12]=1
Reactant: CN(Cc1c[nH]c(-c2ccccc2)c1)C(=O)OC(C)(C)C
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C#N)c2)c1
Product: Cl
Yield: 57.6 %

Procedure:
Using tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (250 mg), sodium hydride (60% in oil, 175 mg) and 3-cyanobenzenesulfonyl chloride (528 mg), a procedure as in Example 36 was performed to give the title compound as pale-purple crystals (yield 195 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([Cl:46])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1.Br[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][CH2:55][OH:56]>>[Cl:46][C:41]1[CH:42]=[C:43]([CH3:45])[CH:44]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[CH2:54][CH2:55][OH:56])=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:12][CH:13]=1
Reactant: OCCc1ccccc1Br
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(-c4ccccc4CCO)cc3C)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and commercially available 2-(2-bromophenyl)ethanol as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 75% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:19]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2.[S:28]([O:33]C)([O:31][CH3:32])(=[O:30])=[O:29]>C1(C)C=CC=CC=1>[CH3:32][O:31][S:28]([O-:33])(=[O:30])=[O:29].[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:19]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N+:13]([CH3:32])=[CH:12][CH:11]=[CH:10]2
Reactant: COC1(c2cc(F)cc(OCc3ccc4ncccc4c3)c2)CCOCC1
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: COC1(c2cc(F)cc(OCc3ccc4c(ccc[n+]4C)c3)c2)CCOCC1
Product: COS(=O)(=O)[O-]
Temperature: 60 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A mixture of a toluene solution of 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydo-2H-pyran-4-yl]phenoxy)methyl]quinoline (8% w/v, 115 ml) and dimethyl sulphate (4.75 g) was heated to 60° C. and stirred at this temperature for 4 hours. The mixture wascooled to ambient temperature and the precipitate was filtered off, washed with toluene (30 ml) and dried to give 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl]phenoxy)methyl]-1-methylquinolinium methyl sulphate (10.7 g) in 87% yield.
Reaction SMILES: [N:1]1([CH:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]#[C:16][C:17](O)=[O:18])=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>C1COCC1.ClCCl>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([NH:48][C:17](=[O:18])[C:16]#[C:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[CH:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7][CH2:8]4)=[CH:44][CH:43]=2)=[CH:40][CH:41]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=C(O)C#Cc1ccc2c(c1)CCC2N1CCCC1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(C#Cc1ccc2c(c1)CCC2N1CCCC1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
A solution of 0.1 g (0.39 mmol) of (1-pyrrolidin-1-ylindan-5-yl)propynoic acid and 47 mL (0.43 mmol) of N-methylmorpholine in 5 mL of absolute THF is combined with 56 mL (0.43 mmol) of isobutyl chloroformate at −15° C. and stirred for ten minutes. Then 87 mg (0.43 mmol) of 4′-chlorobiphenyl-4-ylamine are added at ambient temperature and the reaction mixture is stirred for 14 hours. Then 3 mL of dichloromethane are added to the reaction mixture and this is stirred for 48 hours. Then the reaction mixture is filtered, the filtrate is evaporated down, combined with water and extracted with dichloromethane. The organic phase is evaporated down. The purification is carried out by preparative HPLC (eluant: dichloromethane/methanol/ammonia=8:2:0.2). Yield: 9 mg (5.7% of theory); C28H25ClN2O (M=440.97); calc.: molecular ion peak (M+H)+: 441/443; found: molecular ion peak (M+H)+: 441/443.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH:17]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18]2)=[CH:12][CH:11]=1.B(O[O-])=[O:30].[Na+].[OH-:34].[Na+]>S(=O)(=O)(O)O>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH:17]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:18]2)(=[O:30])=[O:34])=[CH:14][CH:15]=1
Reactant: [OH-]
Reactant: Clc1ccc(SC2CCN(Cc3ccccc3)C2)cc1
Reactant: O=BO[O-]
Agent: O=C(O)/C=C\C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(Cc2ccccc2)C1

Procedure:
A mixture of 12.88 g (0.0425 mole) of 3-[(4-chlorophenyl)thio]-1-(phenylmethyl)pyrrolidine maleate and 27 g (0.175 mole) of sodium perborate in 500 ml of 2M sulfuric acid was refluxed for 17 hr. The reaction mixture was poured over ice and the solution made basic with 50% sodium hydroxide solution. The resulting solution was extracted with several portions of methylene chloride. The methylene chloride phase was dried over magnesium sulfate and the solvent was removed in vacuo to give an oil, the free base of the title compound. The maleate salt was prepared and recrystallized from methanol-diethyl ether as in Preparation 2 to give 13.77 g (70.6%) of the product as a white crystalline solid, m.p. 154.5°-155° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH2:7]2)[N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4][NH:3]1.F[C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH3:36][O:35][C:33]([C:32]1[CH:37]=[CH:38][C:29]([N:3]2[C:2](=[O:1])[C:6]3([CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:13])[CH2:10][CH2:11]3)[N:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:4]2)=[CH:30][CH:31]=1)=[O:34]
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Yield: 99.4 %

Procedure:
Benzyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.50 g, 1.37 mmol), methyl 4-fluorobenzoate (0.21 g, 1.37 mmol), and potassium carbonate (0.38 g, 2.74 mmol) in dimethyl sulfoxide were stirred at 100° C. for 3 days. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by Biotage flash chromatography (gradient from 0 to 30% ethyl acetate/hexanes) to give product as an oil (0.68 g, 21%); 1H NMR (DMSO-d6); δ1.90 (d, 15.6 hz, 2H); 2.25-2.34 (m, 2H); 3.56 (m, 2H); 3.98-4.02 (m, 2H); 5.13 (m, 2H); 5.24 (s, 2H); 6.92 (t, J=8.4 hz, 1H); 6.98 (d, J=8.8 hz, 2H); 7.26-7.39 (m, 7H); 8.02 (dd, J=10 Hz and 17.6 Hz, 4H); MS for C29H29N3O5 m/z 500 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:26]=1[CH:27]1[CH2:29][CH2:28]1)=O)(=O)OC.O.[NH2:35][NH2:36]>>[C:30]([N:25]1[C:26]([CH:27]2[CH2:29][CH2:28]2)=[C:22]([C:20]2[CH:19]=[C:4]3[C:3]([C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]3[CH2:6][CH2:7]4)=[N:36][N:35]=2)[CH:23]=[N:24]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COP(=O)(CC(=O)c1cnn(C(C)(C)C)c1C1CC1)OC
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Reactant: NN
Solvent: O
Product: CC(C)(C)n1ncc(-c2cc3c(nn2)[C@@]2(C)CC[C@@H]3C2(C)C)c1C1CC1

Procedure:
yellow solid. MS (ESI): 351.2 (MH+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [2-(1-tert-Butyl-5-cyclopropyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH2:19][C:20]#[C:21][CH3:22])[C:8](=[N:16][C:17]#[N:18])OC1C=CC=CC=1)=[O:5])[CH3:2].[C:23]([O:27][C:28]([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:23]([O:27][C:28]([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:8]([N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:19][C:20]#[C:21][CH3:22])=[N:16][C:17]#[N:18])[CH2:32]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: CC#CCN(CC(=O)OCC)C(=NC#N)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCN(CC(=O)OCC)C(=NC#N)N1CCCC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10.0 g 1-ethoxycarbonylmethyl-1-(but-2-ynyl)-3-cyano-2-phenyl-isourea are added to a mixture of 10.0 g 3-tert-butoxycarbonylaminopiperidine and 4.8 g potassium carbonate in 50 ml of dimethylformamide. The reaction mixture is stirred for 1 d at ambient temperature and then a further 1.6 g potassium carbonate and 3.0 g 3-tert-butoxycarbonylaminopiperidine are added. After another 3 d at ambient temperature water is added and the mixture is extracted with ethyl acetate. The organic extracts are dried over sodium sulphate, the solvent is removed, and the residue is purified on silica gel (cyclohexane/ethyl acetate 5:1->1:2).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][CH2:17][NH:18][C:19]1[C:20](=[O:30])[N:21]([CH2:26][C:27]([OH:29])=O)[C:22]([CH3:25])=[CH:23][N:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([CH2:44][NH2:45])[CH:42]=2)[NH:37][CH:36]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN1CCOCC1>CN(C)C=O>[CH3:25][C:22]1[N:21]([CH2:26][C:27]([NH:45][CH2:44][C:41]2[CH:42]=[C:43]3[C:38](=[CH:39][CH:40]=2)[NH:37][CH:36]=[C:35]3[CH3:34])=[O:29])[C:20](=[O:30])[C:19]([NH:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([CH:33]=[CH:32][CH:31]=2)[CH2:12][O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[N:24][CH:23]=1
Reactant: Cc1cnc(NCCc2cccc(COCCNC(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)O
Reactant: Cc1c[nH]c2ccc(CN)cc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NCCc4cccc(COCCNC(=O)OC(C)(C)C)c4)c3=O)cc12
Yield: 96.1 %

Procedure:
A mixture of 2-[3-{[3-({2-[(tert-butoxycarbonyl)amino]ethoxy}methyl)phenethyl]amino)6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 107) (174 mg, 0.38 mmol), (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (67 mg, 0.42 mmol), HOBT (77 mg, 0.57 mmol), WSCDI.HCl (91 mg, 0.47 mmol) and N-methylmorpholine (124 ml, 1.13 mmol) in N,N-dimethylformamide (5 ml), was stirred at room temperature for 20 hrs. The reaction mixture was partitioned between ethyl acetate and water and the .phases separated. The organic layer was dried over MgSO4 and evaporated under reduced pressure to give the title compound as a white solid, (220 mg, 96%).
Reaction SMILES: [Li].[F:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.[F:18][C:19]([F:24])([F:23])[C:20]([CH3:22])=O>O1CCCC1.CCCCCC.[Cl-].[Cl-].[Cl-].[Ti+3]>[F:18][C:19]([F:24])([F:23])[C:20]([CH3:22])=[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6]1[CH:16]=[CH:17][C:3]([F:2])=[CH:4][CH:5]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(=O)C(F)(F)F
Agent: [Ti+3]
Agent: [Cl-]
Agent: [Li]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 23.5 %

Procedure:
Lithium (1.94 g, 280 mmol) was added to a suspension of titanium trichloride (12.3 g, 80 mmol) in 250 mL tetrahydrofuran. After the initial exothermic reaction had subsided, the mixture was heated at reflux for 2 hours. After cooling to 25° C. a solution of 4,4'-difluorobenzophenone (2.18 g, 10 mmol) and 1,1,1-trifluoroacetone (4.48 g, 40 mmol) in 30 mL tetrahydrofuran was added and the mixture stirred for 2 hours. The mixture was then refluxed for 20 hours. The mixture was cooled and diluted with 30 mL of hexane and the insolubles removed by filtration through diatomaceous earth. The solution was concentrated in vacuo and the residue purified by chromatography on silica eluting with hexane to give 0.7 g of the title compound as an oil. MS(CI): m/e =298 for M+ of C16H11F5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH2:10])[CH:3]=1.[N:11]([O-])=O.[Na+].O.O.Cl[Sn]Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([NH:10][NH2:11])[CH:3]=1
Reactant: O=N[O-]
Reactant: COc1ccc(F)cc1N
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(F)cc1NN
Yield: 31.4 %

Procedure:
The title compound was prepared by the general procedure described above for Preparations 2a-i using 4-fluoro-2-aminoanisole (14.11 g), NaNO2 (7.59 g) and SnCl2.2H2O (49.64 g). Workup gave 4.9 g (31%) of (5-fluoro-2-methoxyphenyl)hydrazine. MS (M−H)+: 157.00; 1H NMR (300 MHz, CDCl3) δ6.71 (1H, dd, J=10.5, 3.0 Hz), 6.32 (1H, dd, J=7.5, 4.9 Hz), 6.38 (1H, dt, J=8.4, 3.0 Hz), 3.78 (3H, s).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:37]([O:39][C:40](=[O:43])[CH2:41]Br)[CH3:38]>CN(C=O)C>[CH2:37]([O:39][C:40](=[O:43])[CH2:41][N:25]1[CH2:24][CH2:23][C:22]([OH:28])([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:14]=[N:15][C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:29])[F:30])=[CH:4][CH:5]=4)=[CH:11][CH:12]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)[CH3:38]
Reactant: OC1(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CCNCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(O)(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Reaction time: 18 h

Procedure:
4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridin-3-yl]-phenyl}-piperidin-4-ol (153 mg, 0.37 mmol, prepared by analogous procedures described above) was dissolved in DMF (2 mL) and to it was added K2CO3 (128 mg, 0.93 mmol) followed by bromo-acetic acid ethyl ester (0.050 mL, 0.44 mmol) added dropwise, and the reaction was stirred for 18 hours. The reaction mixture was partitioned between 40% EtOAc/hexanes and water, washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation to obtain the title compound, as a crude oil, which was taken to the next step without purification: MS (M+H)+ 499.4.