Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:76][CH2:77][CH2:78][O:79][CH2:80][CH2:81][O:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][NH2:88]>O1CCCC1>[NH2:88][CH2:87][CH2:86][O:85][CH2:84][CH2:83][O:82][CH2:81][CH2:80][O:79][CH2:78][CH2:77][NH:76][C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:37]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: NCCOCCOCCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCOCCOCCOCCN)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 20 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol), HBTU (61.5 mg, 162 μmol) and Hunig's base (105 mg, 142 μL, 811 μmol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred at room temperature for 30 min. 1,11-Diamino-3,6,9-trioxaundecane (15.6 mg, 15.2 μL, 81.1 μmol) was added. After stirring at room temperature overnight, the reaction mixture was absorbed on small amount of silica gel, loaded on a 24 g pre-packed silica gel column and eluted with ethyl acetate to give (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethylcarbamoyl)-2-methoxy-phenyl]-amide, dimer as white solid (148 mg, 66% yield). LCMS (ES+) m/z calcd. for C70H74Cl4F4N8O9 [(M+H)+]: 1387. found: 1387.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][C:11]([CH3:15])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[O:14])[CH:12]([C:31](=[O:32])[NH:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[C:11]([CH3:15])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2N=C(C)CC2=O)cc1
Reactant: O=C=Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(N2N=C(C)C(C(=O)Nc3ccc(F)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred suspension of 920 g of 1-(p-methoxyphenyl)-3-methyl-2-pyrazolin-5-one in 9,600 ml of toluene 460 g of triethylamine are added during 5 minutes, followed by 618 g of p-fluorophenylisocyanate. The mixture is stirred under nitrogen overnight at room temperature, cooled to 10° and combined with 5,000 ml of 1 N aqueous sodium hydroxide. The mixture is stirred for 15 minutes, the organic phase separated and extracted twice with 2,000 ml of 1 N aqueous sodium hydroxide again. The combined aqueous solutions are washed twice with 2,000 ml of diethyl ether each, cooled to 5° and acidified with 900 ml of concentrated hydrochloride acid during 30 minutes. The resulting suspension is stirred for 1 hour, filtered and the residue washed 6 times with 2,000 ml of water each. 1,364 g thereof are dissolved in 55,000 ml of boiling ethanol, the solution filtered hot and the filtrate stirred under nitrogen overnight at room temperature. The precipitate formed is filtered off, washed twice with 1,000 ml of cold ethanol each and recrystallized from ethanol again, to yield the 1-(p-methoxyphenyl)-3-methyl-4-(p-fluorophenylcarbamoyl)-2-pyrazolin-5-one melting at 255°-257° with decomposition; it is identical with that obtained according to Example 6.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:7]([F:16])=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9](O)=[O:10]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:5][C:6]1[C:7]([F:16])=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([Cl:3])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)c(Cl)c1F

Procedure:
Thionyl chloride is metered at 70° C. to a suspension of 235 g (1.22 mol) of 3-chloro-2,4-difluorobenzoic acid in 800 ml of toluene and 3 ml of dimethylformamide until a clear solution has formed and evolution of gas is no longer observed. The toluene and excess thionyl chloride are then distilled off, and the product is subsequently obtained by distillation.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[S:27](Cl)(=[O:29])=[O:28].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][S:27]([C:23]1[S:22][CH:26]=[CH:25][CH:24]=1)(=[O:29])=[O:28])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: O=S(=O)(Cl)c1cccs1
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNS(=O)(=O)c1cccs1
Yield: 80 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, thiophene-2-sulfonyl chloride (0.218 g, 1.19 mmol) was reacted with 2-azidoethanamine (0.103 g, 1.19 mmol) and triethylamine (0.241 g, 2.39 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)thiophene-2-sulfonamide (0.221 g, 80%). 1H NMR (300 MHz, CDCl3) δ 7.62 (d, 1H), δ 7.59 (d, 1H), 7.08 (t, 1H), 5.52 (s. 1H), 3.41 (t, 2H), 3.17 (q, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 140.6, 132.7, 132.6, 127.9, 50.9, 42.9 ppm; HRMS (ESI) calcd for C6H8N4O2S2 (M+) 232.0089. found 232.0084.
Reaction SMILES: [CH2:1]([O:6][CH2:7][CH:8]([OH:23])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31](Cl)=[O:32])[CH:26]=1>N1C=CC=CC=1>[CH2:1]([O:6][CH2:7][CH:8]([O:23][C:31]([C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1)=[O:32])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOCC(O)/C=C/c1ccc(Cc2ncc[nH]2)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCOCC(/C=C/c1ccc(Cc2ncc[nH]2)cc1)OC(=O)c1cccnc1
Reaction time: 8 h

Procedure:
400 mg (1.3 mmol) of E-4-pentyloxy-1-[4-(1-imidazolylmethyl)phenyl]but-1-en-3-ol (5a) were dissolved in 10 ml of dry pyridine, and 409 mg (1.5 mmol) of 3-pyridinecarbonyl chloride hydrochloride were added. The mixture was stirred at room temp. for 8 h, and the solvent was substantially removed in vacuo, and the residue was partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride. The aqueous phase was extracted twice with methylene chloride. Drying of the combined organic phases with magnesium sulfate and removal of the solvent in vacuo produced, after chromatography on silica gel (ethyl acetate/methanol=10:1, Rf=0.20), 380 mg (0.91 mmol, 70%) of ester 6a as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10]([OH:12])=O)[CH:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])[CH:3]=1
Reactant: CNOC
Reactant: O=C(O)C=Cc1cc(Br)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)C=Cc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.1 %

Procedure:
3-(4-Bromo-pyridin-2-yl)-acrylic acid (6.3 g, 27.6 mmol) prepared in Step 1, N,O-dimethylhydroxylamine hydrochloride (3.0 g, 30.4 mmol), HOBT (7.5 g, 55.3 mmol), EDAC (10.6 g, 55.3 mmol) and triethylamine (11.5 mL, 82.9 mmol) were added to N,N-dimethylformamide (100.0 mL). The reaction mixture was stirred at room temperature for 18 hours, quenched with a saturated solution of ammonium chloride, and then extracted with ethyl acetate. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 2.4 g of the titled compound as a pale yellow solid.
Reaction SMILES: [Xe][F:2].[Cl:3][C:4]1[CH:37]=[CH:36][CH:35]=[CH:34][C:5]=1[CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[CH:9]=[C:8]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:3][C:4]1[CH:37]=[CH:36][CH:35]=[CH:34][C:5]=1[CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[C:9]([F:2])=[C:8]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])[CH2:21]1
Reactant: F[Xe]
Reactant: Cn1c(=O)c2c(cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cn1c(=O)c2c(c(F)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.1 %

Procedure:
Xenon fluoride (56 mg) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.00 g) in acetonitrile (10 ml), and the resulting mixture was stirred overnight at room temperature. After a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, the acetonitrile was distilled off under reduced pressure, and the residue was extracted twice with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a thin-layer silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (8 mg).
Reaction SMILES: C(C1C(C)=NC(C)=C(C=1)C#N)(=[O:3])C.S1C=CN=C1C(=O)C.[CH3:22][C:23]1[N:30]=[C:29]([CH3:31])[C:28]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([CH2:42][CH2:43][N:44]4[CH2:48][CH2:47][CH2:46][C@H:45]4[CH3:49])[CH:38]=3)[N:33]=2)=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:22][C:23]1[N:30]=[C:29]([CH3:31])[C:28]([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([CH2:42][CH2:43][N:44]4[CH2:48][CH2:47][CH2:46][C@H:45]4[CH3:49])[CH:38]=3)[N:33]=2)=[CH:27][C:24]=1[C:25]([NH2:26])=[O:3]
Reactant: CC(=O)c1cc(C#N)c(C)nc1C
Reactant: Cc1nc(C)c(-c2ccc3cc(CCN4CCC[C@H]4C)ccc3n2)cc1C#N
Agent: CC(=O)c1nccs1
Product: Cc1nc(C)c(-c2ccc3cc(CCN4CCC[C@H]4C)ccc3n2)cc1C(N)=O

Procedure:
The title compound was prepared using the procedure described in Example 57 using 5-acetyl-2,6-dimethylnicotinonitrile for 1-(1,3-thiazol-2-yl)ethanone providing the product from Example 67 which eluted first and the title compound which eluted second. 1H NMR (CDCl3) δ ppm 1.18 (d, J=5.43 Hz, 3 H), 1.53 (m, 1 H), 1.80 (m, 2 H), 1.98 (m, 1 H), 2.2-2.6 (m, 3 H), 2.65 (s, 3 H), 2.78 (s, 3 H), 3.09 (m, 2 H), 3.19 (m, 1 H), 3.33 (m, 1 H), 5.75 (s, 1 H), 5.90 (s, 1 H), 7.52 (d, J=8.48 Hz, 1 H), 7.66 (dd, J=8.65, 1.87 Hz, 1 H), 7.71 (s, 1 H), 7.94 (s, 1 H), 8.06 (d, J=8.82 Hz, 1 H), 8.19 (d, J=8.14 Hz, 1 H). MS (DCI-NH3) [M+H]+ at 389.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[I:13]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(Cl)c(O)c(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Methyl 3-chloro-4-hydroxybenzoate (12.31 g) was dissolved in dichloromethane (100 mL) and methanol (12 mL), and N-iodosuccinimide (15.59 g) and trifluoromethanesulfonic acid (2 mL) were added to the solution, and then the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the obtained residue was'washed with water (100 mL) to obtain the title compound (20.52 g) as a colorless crystal.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=O)[CH2:12][C:11](=[O:15])[N:10]([CH:16]3[CH2:18][CH2:17]3)[C:9]2=[O:19])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.BrC1C=CC(N2C(=O)C=C(Cl)N(C3CC3)C2=O)=CC=1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([Cl:22])=[CH:12][C:11](=[O:15])[N:10]([CH:16]3[CH2:18][CH2:17]3)[C:9]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1CC(=O)N(C2CC2)C(=O)N1c1ccc(Br)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=c1cc(Cl)n(C2CC2)c(=O)n1-c1ccc(Br)cc1
Solvent: O
Product: O=c1cc(Cl)n(-c2ccc(Br)cc2)c(=O)n1C1CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
To 1-(4-bromo-phenyl)-3-cyclopropyl-pyrimidine-2,4,6-trione 32 (11.8 g) obtained in Step 2 was added water (1.31 ml) and phosphorus oxychloride (17.0 ml) was added dropwise with stirring at room temperature. After the completion of the dropwise addition, the mixture was stirred at 110° C. for 3 hrs. After allowing to cool to room temperature, the reaction mixture was added to ice water by small portions and the mixture was stirred. The mixture was stirred at room temperature and extracted with chloroform. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=2:1→chloroform:acetone=30:1) to give a 1:1.4 mixture (11.6 g, yield 93%) of 1-(4-bromo-phenyl)-6-chloro-3-cyclopropyl-1H-pyrimidine-2,4-dione 33 and 3-(4-bromo-phenyl)-6-chloro-1-cyclopropyl-1H-pyrimidine-2,4-dione 34 as a pale-yellow foamy oil.
Reaction SMILES: Br.[CH2:2]([O:6][CH:7]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:8]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:9]([O:11]CC)=O)[CH2:3][CH2:4][CH3:5].[O-:31][C:32]#[N:33].[K+].Cl>C(O)C.O>[CH2:27]([O:26][CH:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])[CH:8]1[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:32](=[O:31])[NH:33][C:9]1=[O:11])[CH2:28][CH2:29][CH3:30]
Reactant: N#C[O-]
Reactant: CCCCOC(OCCCC)C(NCCCCCCC(=O)OCC)C(=O)OCC
Agent: Br
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCOC(OCCCC)C1C(=O)NC(=O)N1CCCCCCC(=O)OCC
Temperature: 100 °C
Reaction time: 22 h
Yield: 107.8 %

Procedure:
A mixture of 2-(dibutoxymethyl)glycine ethyl ester (2.0 g) with ethyl 7-bromoheptanoate (1.82 g) was heated under nitrogen in a bath at 100° C. for 3 hours. to give crude ethyl 7-((2,2-dibutoxy-1-ethoxycarbonylethyl)amino)heptanoate hydrobromide. A stirred solution of 3.28 g of this hydrobromide in ethanol (13 ml) was cooled in ice-water and treated with a solution of potassium cyanate (1.34 g) in water (4 ml), followed by 2 N-aqueous hydrochloric acid (3.63 ml); the cooling bath was removed and stirring was continued at room temperature for 22 hours. The ethanol was evaported in vacuo, the residue was shaken with water and ether, and the ethereal solution was separated, washed with water and dried over magnesium sulphate (MgSO4); removal of the ether left an oil which was heated under nitrogen at 100° C. for 3 hours, to give 5-dibutoxymethyl-1-(6-ethoxycarbonylhexyl)hydantoin (2.94 g). This was stirred in ether (6 ml) with water (48 ml) and N-aqueous sodium hydroxide (24.9 ml) at room temperature for 11/2 hours and, after the addition of more ether (50 ml), the aqueous phase was separated, cooled (ice-H2O), stirred with fresh ether and acidified to Congo Red with N-aqueous hydrochloric acid. The ethereal solution of carboxylic acid was thrice washed with water, dried (MgSO4), and evaporated, to leave 1-(6-carboxyhexyl)5-dibutoxymethylhydantoin (2.15 g) as a gum. When 1.89 g of the latter were cooled in ice-water and stirred with concentrated aqueous hydrochloric acid (8.5 ml), the resulting solution gave place spontaneously to a suspension of colourless crystals. The suspension was set at room temperature for 11/2 hours, diluted with water (10 ml) and set aside for 15 minutes; the crystals were then collected, washed with water, dried in vacuo, suspended in ether (3 ml), and collected again, to give 1-(6-carboxyhexyl)hydantoin-5-carboxaldehyde (0.74 g), m.p. 223.5°-225° C. (Found: C. 51.86; H, 6.66; N, 10.62. C11H16N2O5 required, C, 51.56; H, 6.29; N, 10.93%). In dimethyl sulphoxide-d6, this compound exists predominantly as the masked aldehyde, 1-(6-carboxyhexyl)-5-hydroxymethylenehydantoin.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCCC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCN1CCCC1
Yield: 84.5 %

Procedure:
A solution of the product from step c (4.32 g, 15.9 mmol) and hydrazine hydrate (3.85 ml, 79.4 mmol) in ethanol (75 ml) was heated at reflux for 1.5 h. The resultant white suspension was diluted with further ethanol (50 ml) and the solid removed by filtration. The filtrate was evaporated at reduced pressure and the residue was suspended in chloroform (50 ml). The solid was removed by filtration and the filtrate evaporated at reduced pressure to afford the title compound (1.91 g, 85%). 1H NMR 2.74-2.69 (2H, m), 2.52-2.42 (6H, m), 1.83-1.75 (4H, m), 1.64-1.46 (6H, m).
Reaction SMILES: [NH2-].[Na+].N.[CH:4]([N:7]([CH:19]([CH3:21])[CH3:20])[CH2:8][CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:11]#[N:12])([CH3:6])[CH3:5].[CH3:22][C:23]([CH3:27])=[CH:24][C:25]#[N:26]>CCOCC.O>[CH:19]([N:7]([CH:4]([CH3:6])[CH3:5])[CH2:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)([C:23]([CH3:27])([CH3:22])[CH2:24][C:25]#[N:26])[C:11]#[N:12])([CH3:21])[CH3:20]
Reactant: CC(C)=CC#N
Reactant: CC(C)N(CCC(C#N)c1ccccn1)C(C)C
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)N(CCC(C#N)(c1ccccn1)C(C)(C)CC#N)C(C)C
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
The mixture of 4.7 g of sodium amide and 400 ml of liquid ammonia is cooled to -40° C., then the solution of 24.5 g of 4-diisopropylamino 2-(2-pyridyl) butane nitrile (Example 1a) in 30 ml of anhydrous ether is added, the temperature being maintained between -40° C. and -33° C. The mixture is stirred for 15 mins. at this temperature then the solution of 9 g of 3,3-dimethyl acrylonitrile in 40 ml of ether is added, still at the same temperature. The temperature is allowed to rise slowly up to ambient temperature (duration: about 5 hrs.). 200 ml of ether are added then water is added drop by drop. The ethereal phase is separated and the aqueous phase is re-extracted with ether. The ethereal extracts are collected and dried over sodium sulfate. The solvent is evaporated to dryness and the residue is chromatographed over a column of alumina with the eluting ethyl acetate-pentane (2.5-100) vol/vol mixture.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].[C:6]([N:10]=[N:11][C:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])([CH3:8])[CH3:7].[N-]=C=O>O>[C:6]([N:10]=[N:11][C:12]1([NH:18][C:19]([O:3][CH2:1][CH3:2])=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Reactant: CCO
Agent: [H-]
Agent: [N-]=C=O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 50 ml of ethanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer, was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. After the temperature came back to 25° C., 10.5 grams (0.05 moles) of 1-t-butylazo-1-isocyanatocyclohexane was added dropwise over 5 minutes. After the addition was complete, the reaction was stirred an additional 30 minutes at room temperature. Gas chromatography indicated that the 1-t-butylazo-1-isocyanatocyclohexane had reacted almost immediately. The reaction mixture was poured into 300 ml water and the product extracted with 100 ml pentane. The pentane extract was separated, washed with water, 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave 10.3 grams (80.5% crude yield) of a yellow liquid. The product had a strong carbonyl band at 1730 cm-1 and a sharp NH band at 3400 cm-1 in its infrared spectrum and the isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[O:16].Cl>O1CCCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:15]([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[OH:16])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=Cc1cccs1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1cccs1
Yield: 108 %

Procedure:
To a stirred Grignard complex, previously prepared from 17.5 g (0.10 mol) 1-bromo-4-fluorobenzene and 2.43 g (0.10 mol) magnesium turnings in 50 ml tetrahydrofuran, 8.97 g (0.080 mol) thiophene-2-carboxaldehyde, dissolved in 30 ml tetrahydrofuran, was added dropwise. Upon complete addition the reaction mixture was refluxed for 1 h and then poured on a mixture of ice and 6N hydrochloric acid. Subsequent extraction with toluene, washing of the organic layer and evaporation in vacuo, gave 18 g of the desired (4-fluorophenyl)(2-thienyl)methanol as a brown oil. This was directly converted to the corresponding (4-fluorophenyl)(2-thienyl)methyl chloride with thionyl chloride by a procedure known to the art.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=3[C:9](=[O:17])[N:8]([CH3:18])[CH2:7][C:6]=12.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>C(NCC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:16][C:15]1[C:10]2[C:9](=[O:17])[N:8]([CH3:18])[CH2:7][C:6]3[N:5]([CH:4]=[N:3][C:2]=3[C:23]#[C:22][C:20]([OH:24])([CH3:21])[CH3:19])[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CN1Cc2c(Br)ncn2-c2cccc(Cl)c2C1=O
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: CN1Cc2c(C#CC(C)(C)O)ncn2-c2cccc(Cl)c2C1=O

Procedure:
3.26 g (10 mmol) of 3-bromo-7-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux overnight with 1.10 g (12 mmol) of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 20 ml of diethylamine and 15 ml of methylene chloride. The reaction mixture was evaporated and the residue was dissolved in methylene chloride. After chromatography of the solution on silica gel while eluting with ethyl acetate and crystallization from ethyl acetate there was obtained 7-chloro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 194°-195°.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:10][CH2:9][C@@H:8]2[N:4]1[C:5](=[O:19])[C@H:6]([NH:11]C(=O)OC(C)(C)C)[CH2:7]2)#[N:2].C1(SC)C=CC=CC=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[NH2:11][C@@H:6]1[CH2:7][C@H:8]2[N:4]([C@H:3]([C:1]#[N:2])[CH2:10][CH2:9]2)[C:5]1=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H]2CC[C@@H](C#N)N2C1=O
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@@H]1CC[C@H]2C[C@@H](N)C(=O)N21

Procedure:
80 mg of tert-butyl ((2R,5S,7aS)-5-cyano-3-oxohexahydropyrrolizin-2-yl)carbamate were C reacted with 10% thioanisole in 1 ml of trifluoroacetic acid for 30 min. The solvents were then removed in vacuo, and the residue was stirred with diusopropyl ether.