Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH:20]=2)[C@@H:15]2[C@H:4]([C@H:5]3[C@:12]([CH3:25])([CH2:13][C:14]2=[O:24])[C@@H:8]([C:9](=[O:11])[CH3:10])[CH2:7][CH2:6]3)[CH:3]=1>C(OCC)(=O)C.[Pd]>[CH3:1][C@H:2]1[C@@H:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH2:20]2)[C@@H:15]2[C@H:4]([C@H:5]3[C@:12]([CH3:25])([CH2:13][C:14]2=[O:24])[C@@H:8]([C:9](=[O:11])[CH3:10])[CH2:7][CH2:6]3)[CH2:3]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3C[C@@H](C)[C@H]4CC(=O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 41.9 %

Procedure:
6-Methylpregna-4,6-diene-3,11,20-trione (1.7 g) in ethyl acetate (100 ml) was hydrogenated at atmospheric pressure using 10% palladium on charcoal (500 mg) as catalyst. The catalyst was filtered off and the filtrate evaporated. Crystallisation of the residue from acetonepetroleum ether (b.p. 60°-80°) gave the title compound (720 mg), m.p. 174°-176°, [α]D +106°.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([NH2:8])[CH2:6][NH2:7]>>[CH2:5]([NH2:8])[CH2:6][NH2:7].[C:1]([CH2:2][CH2:3][NH:7][CH2:6][CH2:5][NH2:8])#[N:4]
Reactant: C=CC#N
Solvent: NCCN
Product: N#CCCNCCN
Reaction time: 8 h

Procedure:
In a suitable vessel 79.5 parts (1.5 moles of acrylonitrile was added dropwise with stirring to 270 parts (4.5 moles) of ethylenediamine over 90 minutes. After standing overnight the mixture was distilled under reduced pressure, yielding 184 parts of ethylenediamine, and 100.1 parts of N-cyanoethylethylenediamine. There remained undistilled 43 parts of residue. Boiling point of the N-cyanoethylethylenediamine was 162°-171° C. at 55 mm abs. pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].Br[C:14]([CH3:21])([CH3:20])[C:15](OCC)=[O:16]>>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]2[O:12][C:14]([CH3:21])([CH3:20])[C:15](=[O:16])[NH:1][C:2]=2[CH:7]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Product: CC1(C)Oc2cc([N+](=O)[O-])c(Cl)cc2NC1=O

Procedure:
2-amino-4-chloro-5-nitrophenol (10.0 g) and ethyl α-bromoisobutyrate (7.4 mL) were treated in the same manner as described in Reference Example 1(1) to give 6-chloro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (6.82 g) as a pale brown powder.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[CH2:22](Br)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCc2ccccc2)C1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1-diphenylmethyl)-piperidine (1 g), phenethyl bromide (0.67 g), anhydrous potassium carbonate (1.5 g) and acetonitrile (25 ml) was heated under reflux for 4 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (30% up to 70%) then dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound as colourless rhombs, yield 0.72 g, m.p. 134-138° C., [α]D25 +13.3° (c 1.0, CH2Cl2).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH:3](O)[CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>OS(O)(=O)=O>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: CC(C)C(O)CCNc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCCNc2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 7.8 %

Procedure:
A mixture of 4-methyl-1-(phenylamino)-pentan-3-ol (22 g, 0.11 mol) in 98% H2SO4 (250 mL) was stirred at 50° C. for 30 min. The reaction mixture was poured into ice-water basified with sat. NaOH solution to pH 8 and extracted with CH2Cl2. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (petroleum ether) to afford 5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine as a brown oil (1.5 g, 8%).
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH:8]([C:20]([OH:22])=O)[CH2:7]1)=[O:5])[CH3:2].O[N:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH2:27]>>[CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:7][CH:8]([C:20]2[O:22][N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]=2)[CH2:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=2)[CH2:11]1)=[O:5])[CH3:2]
Reactant: NC(=NO)c1ccccc1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N(C)CC)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4)no3)CN(C(=O)N(C)CC)C2)cc1

Procedure:
64 mg (0.20 mmol) of 1-[ethyl(methyl)carbamoyl]-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 45A) and 30 mg (0.22 mmol, 1.1 eq.) of N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 12 mg (14% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:33])[C:10]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31]C)[CH:26]=1)[N:20]=[CH:19]2)([OH:15])[C:11]([F:14])([F:13])[F:12].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:33])[C:10]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1)[N:20]=[CH:19]2)([OH:15])[C:11]([F:14])([F:13])[F:12]
Reactant: COc1cccc(-n2ncc3cc(C(O)(C(C)c4ccc(Cl)cc4Cl)C(F)(F)F)ccc32)c1
Agent: BrB(Br)Br
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccc2c(cnn2-c2cccc(O)c2)c1)C(F)(F)F

Procedure:
In analogy to Example 183, 3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-2-[1-(3-methoxy-phenyl)-1H-indazol-5-yl]-butan-2-ol (Example 187) was reacted with BBr3 to give the title compound as a colorless foam. MS (m/e, ISP neg. ion)=479.0 [M−H+].
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](#N)[CH3:10]>>[CH2:5]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])[CH2:6][CH2:1][CH2:2][CH2:3][CH2:4][CH2:9][CH3:10]
Reactant: CC#N
Reactant: Nc1ccccc1N
Product: CCCCCCCCNc1ccccc1N

Procedure:
Into 500 ml of acetonitrile was suspended 50.9 g (0.1 mol) of the phenylenediamine derivative obtained in the foregoing process (2) in an atmosphere of nitrogen. The suspension was cooled with ice to 5° C. or lower where it was then kept. To the suspension was then added 55.8 ml (0.4 mol) of triethylamine. To the reaction mixture was then added dropwise 11.5 g (0.1 mol) of thiophosgene while the temperature of the reaction system was being controlled to lower than 10° C. After completion of the dropwise addition, the temperature of the reaction solution was gradually returned to room temperature. The reaction solution was then allowed to undergo at the same temperature for 2 hours. To the reaction solution was then added a mixture of ethyl acetate and water. The reaction solution was then subjected to separation. The organic phase thus extracted was dried, and then concentrated to obtain 29.4 g of a crude reaction product in the form of oil. The crude reaction product was then purified through a column filled with a 1/5 mixture of ethyl acetate and hexane to obtain 12.6 g (0.048 mol) of the desired benzimidazole (yield: 48%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([O:29]CC)=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27]([OH:29])=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc2c(N[C@@H]3CN(C(=O)OC(C)(C)C)C[C@@H]3C)c(C(N)=O)cnn2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 99.6 %

Procedure:
A mixture of ethyl 4-(((3S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylate (585 mg, 1.356 mmol) and NaOH, 1N (3.39 mL, 3.39 mmol) in THF (14 mL) was stirred at rt for 4 days. At the end of each day, additional NaOH, 1N (3.39 mL, 3.39 mmol) was added, for a total of three additions. The reaction mixture was partitioned between ˜70 ml of EtOAc and 50 ml of water. While stirring the biphasic mixture, the pH was adjusted to ˜2 with saturated KHSO4 solution. The layers were separated and the aqueous layer was extracted with DCM (50 ml). A precipitant began to form in the combined organic layer. The solid was very fine and the suspension was dried over Na2SO4. The supernate was decanted off and the sodium sulfate was thoroughly rinsed with hot EtOAc and hot MeOH. The decanted supernates were concentrated to afford 4-(((3S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (545 mg, 1.351 mmol, 100% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 12.51 (br. s., 1H), 11.23 (br. s., 1H), 8.32 (s, 1H), 8.07 (d, J=1.3 Hz, 1H), 7.19 (d, J=1.3 Hz, 1H), 4.76 (d, J=15.0 Hz, 1H), 3.83-3.51 (m, 2H), 3.40-3.34 (m, 1H), 3.09-2.87 (m, 1H), 2.58 (d, J=7.5 Hz, 1H), 1.37 (d, J=13.2 Hz, 9H), 1.13-0.86 (m, 3H). MS (ES+) m/z: 304.2 (M+H-Boc); LC retention time: 2.533 min (analytical HPLC Method O).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(F)=NC(F)=NC=1[F:19].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10]([F:19])=[O:11])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)F)C(C)(C)C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
To an oven-dried, septaed 25 mL round-bottom flask, cooled under an argon atmosphere, and charged with 24h (170.3 mg, 0.74 mmol) was added 2.0 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15 C and to the flask was added cyanuric fluoride (335 μL, 3.7 mmol). The reaction was stirred at −15 C for 15 minutes then anhydrous pyridine (60 μL, 0.74 mmol) was added. Stirring was maintained at −15 C for 60 minutes. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 112.6 mg of a mixture of 24h and 25h as an off-white solid.
Reaction SMILES: C[Si](C)(C)C[CH2:4][O:5]COC[Sn](CCCC)(CCCC)CCCC.C([Li])CCC.[CH3:29][NH:30][C@H:31]([C:41]([NH:43][C@H:44]([C:49]([N:51]([C@@H:53]([CH:63]([CH3:65])[CH3:64])/[CH:54]=[C:55](\[CH3:62])/[C:56](N(OC)C)=[O:57])[CH3:52])=[O:50])[C:45]([CH3:48])([CH3:47])[CH3:46])=[O:42])[C:32]([CH3:40])([CH3:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[OH:5][CH2:4][C:56](=[O:57])[C:55]([CH3:62])=[CH:54][CH:53]([N:51]([CH3:52])[C:49]([CH:44]([NH:43][C:41](=[O:42])[CH:31]([NH:30][CH3:29])[C:32]([CH3:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:40])[C:45]([CH3:46])([CH3:48])[CH3:47])=[O:50])[CH:63]([CH3:65])[CH3:64]
Reactant: CCCC[Sn](CCCC)(CCCC)COCOCC[Si](C)(C)C
Reactant: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)N(C)OC)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(C(=O)NC(C(=O)N(C)C(C=C(C)C(=O)CO)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
To a solution of trimethyl-(2-tributylstannanylmethoxymethoxy-ethyl)-silane (933 mg, 2.07 mmole, E. Fernandez-Megia and S. V. Ley; Synlett 2000, 4, 455-8) in 6 mL tetrahydrofuran at −78° C. is added dropwise 1.6 M n-butyllithium solution in hexanes (1.25 mL, 2.0 mmole). The resulting yellow solution is stirred for 10 mins at −78° C. Then a solution of N,β,β-trimethyl-L-phenylalanyl-N1{(1S,2E)-1-isopropyl-4-[methoxy(methyl)amino]-3-methyl-4-oxobut-2-enyl}-N1,3-dimethyl-L-valinamide (258 mg, 0.5 mmole, Example 52) in tetrahydrofuan (5 mL) at −78° C. is added dropwise and the reaction mixture stirred at −78° C. for 15 mins and then at −60° C. for 45 mins. The reaction is quenched with a saturated aqueous solution of ammonium chloride (2 mL), warmed to room temperature and partioned between ethyl acetate (50 mL) and saturated aqueous solution of ammonium chloride (50 mL). The aqueous layer is extracted with ethyl acetate (30 mL) and the combined organic layer is washed with water, brine, dried over sodium sulfate, filtered and the residue treated with a mixture of trifluoroacetic acid (10 mL) and dichloromethane (5 mL) at 0° C. and stirred for 1 hour, evaporated and then purified by HPLC to give 52 mg of an off-white solid, MS (ES): m/z 488.4 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.CC(C)(OC([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:25]([NH:26][CH:27]([CH3:29])[CH3:28])=[CH:24][N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=O)C>ClCCl.[OH-].[Na+]>[CH3:29][CH:27]([NH:26][C:25]1[C:20]([N:17]2[CH2:16][CH2:15][NH:14][CH2:19][CH2:18]2)=[N:21][CH:22]=[N:23][CH:24]=1)[CH3:28]
Reactant: CC(C)Nc1cncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Nc1cncnc1N1CCNCC1

Procedure:
Trifluoroacetic acid (5 ml) is added to a solution of 1-[1,1-dimethylethoxy-carbonyl]-4-[5-(1-methylethylamino)-4-pyrimidinyl]piperazine (PREPARATION 11, 0.37 g) in dichloromethane (20 ml) at 78°. The reaction is allowed to warm to 20°-25° overnight, and then diluted with excess aqueous sodium hydroxide solution (10%). The phases are separated. The aqueous phase is extracted twice again with dichloromethane. The combined organic extracts are washed with saline, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound, NMR (CDCl3) 1.25, 1.7, 3.01, 3.21, 3.45, 3.5, 7.86 and 8.34 δ.
Reaction SMILES: OC1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:8]3=[CH:9][CH:10]=2)[O:5][C:4](=O)C=1.[CH2:18](OCC)C>COCCOCCOCCOC.[Pd]>[CH3:4][O:5][C:6]1[C:7]2[C:8](=[C:12]([CH2:16][CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOCC
Reactant: Cc1cccc2c1ccc1c(O)cc(=O)oc12
Agent: [Pd]
Solvent: COCCOCCOCCOC
Product: CCc1cccc2c(OC)cccc12
Yield: 50 %

Procedure:
5-Methoxy-1-tetralone (5) (4 g, 22.6 mmol) was dissolved in 50 mL anhydrous diethyl ether, stirred, and cooled down on ice to 0° C. Ethylmagnesium bromide (19 mL, 56.8 mmol) was added dropwise to the solution, producing copious precipitation. The mixture was then heated to reflux and stirred for 10 h. After cooling, cold water was added slowly to the reaction mixture, which was then extracted with diethyl ether three times. The organic layer was evaporated to afford crude product 6. Without purification, zinc chloride (15 g, 114 mmol) was added to a solution of 6 in benzene (35 mL), then concentrated hydrochloride acid (12 mL) was added to the solution at room temperature. The reaction mixture was heated to reflux for 5 h, cooled, extracted with diethyl ether three times, and the organic layer was evaporated to afford crude product. Purification by column chromatography gave 7 (2 g). To a solution of 7 (2 g) in triglyme (15 mL) was added 10% Pd/C (2 g) and the mixture was heated to reflux for 3 days. After cooling, diethyl ether was added to the mixture and it was filtered on Celite, then washed with diethyl ether to provide compound 8. 50% yield; 1H NMR δ 1.37 (3H, t, J=7.8 Hz, CH3CH2—), 3.10 (2H, q, J=7.8 Hz, CH3CH2—), 4.01 (3H, s, OCH3), 6.82 (1H, d, J=7.8 Hz, H-2), 7.36-7.44 (3H, m, H-3, 6, 7), 7.64 (1H, d, J=8.7 Hz, H-4), 815 (1H, d, J=8.4 Hz, H-8).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>CO>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: CO
Product: O=C1CCC(c2ccc(F)cc2)CC1
Yield: 87 %

Procedure:
Hydrochloric acid (0.75 ml) was added to a solution 8-(4-fluorophenyl)-1,4-dioxaspiro[4,5]decane (10 mmole) in 66% methanol (100 ml). After stirring for 2 hr the methanol was removed in in vacuo and the residue extracted with methylene chloride. Removal of the methylene chloride in vacuo gave the product as an oil (87%).
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=2)[CH2:3][CH2:2]1.[CH3:12][NH:13][CH2:14][CH2:15][CH:16]=[O:17]>C1C=CC=CC=1>[CH3:12][N:13]([CH2:14][CH2:15][CH:16]=[O:17])[C:10]([NH:9][C:7]1[S:8][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=1)=[O:11]
Reactant: CNCCC=O
Reactant: O=C=Nc1nnc(C2CC2)s1
Solvent: c1ccccc1
Product: CN(CCC=O)C(=O)Nc1nnc(C2CC2)s1

Procedure:
A mixture of 5-cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-methylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-methyl-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:51]([S:53][CH2:54][CH3:55])[CH3:52].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([O:29][CH:51]([S:53][CH2:54][CH3:55])[CH3:52])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Reactant: CCSCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCSC(C)O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Yield: 75 %

Procedure:
To a solution of the compound of Example 1 (0.50 g, 0.69 mmol) and ethyl sulfide (1.9 mL) in acetonitrile (5 mL) at 0° C. was added benzoyl peroxide (0.84 g) in three portions over 3 hours. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel, eluting with a gradient of 50-100% ethyl acetate in chloroform to give the title compound (0.42 g, 75% yield).
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=O.O>O1CCCC1>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:26]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: O=Cc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(/C=C/c1ccccn1)OCC
Reaction time: 0.33 h
Yield: 93.3 %

Procedure:
A solution of tetraethyl methylenediphosphonate (3.7 g, 13 mmol) in tetrahydrofuran (5 ml) was added dropwise to a mixture of sodium hydride (60% in oil, 750 mg, 18 mmol) and tetrahydrofuran (15 ml) at 0° C., and the mixture was stirred at the same temperature for 20 minutes. Successively, a solution of 2-pyridinecarbaldehyde (1.3 g, 12 mmol) in tetrahydrofuran (5 ml) was added dropwise to the mixture at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (20:1, v/v) were collected and concentrated to give the titled compound (2.7 g, 94%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[F:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]=1CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:5][CH2:1][C:8]1[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:10][CH:11]=[CH:12][C:7]=1[F:6]
Reactant: CC(C)(C)OC(=O)Nc1nccc(F)c1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(F)c1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
CBr4 (531 mg, 1.6 mmol) was added to a solution of the product of Step B (242 mg, 1 mmol) in THF (3 mL). Then a solution of triphenylphosphine in THF (1 mL) was added dropwise and the mixture was stirred at room temperature for 3 hours. The mixture was loaded onto a silica gel column. Elution with (EtOAc:PE=1:3) to afford the title compound (160 mg, 52%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 8.38-8.35 (m, 1H), 7.09 (s, 1H), 6.90-6.86 (m, 1H), 4.61 (s, 2H), 1.54 (s, 9H) ppm MS: M/e 305 (M+1)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:17])[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:17])[CH2:15][CH2:14][CH:13]([N:18]4[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=5)=[O:24])[CH2:19]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1CCC(O)(c2ccc3c(c2)OCO3)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc4c(c3)OCO4)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-benzo[1,3]dioxol-5-yl-4-hydroxy-cyclohexanone (as prepared in Example 1, Step B) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.