Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:61]([CH3:63])[CH3:62])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[C@H:47]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:48]7[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=7)=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:60]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].[CH3:64][O:65][C:66](N[C@@H](C(C)C)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:61]1[CH2:63][CH2:66][O:65][CH2:64][CH2:62]1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[C@H:47]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:48]7[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=7)=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:60]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]4)ccc23)[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]4)ccc23)[nH]1)C1CCOCC1

Procedure:
This compound was made in an analogous manner to methyl (R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate, substituting (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amide coupling. LCMS-ESI+: calculated for C50H52N8O8: 893.00; observed [M+1]+: 894.00.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20].C(N(CC)CC)C>O1CCCC1>[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:20]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([Cl:15])[CH:17]=2)[CH:10]=1
Reactant: NCc1cccc(Cl)c1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a solution of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.5 g) in tetrahydrofuran (10 ml) was added a solution of 3-chlorobenzylamine (0.45 g) (Table 1-1, amine 19) and triethylamine (0.32 g) in tetrahydrofuran (3 ml) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 18 hr. The reaction mixture was concentrated, and the crystals were collected by filtration. The obtained crystals were added to a mixture of dimethylsulfoxide (5 ml)-water (5 ml), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, the residue was purified by preparative HPLC, and the obtained fraction was treated with PL-HCO3MP (200 mg cartridge, Polymer Laboratories) to give the title compound (0.33 g).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][NH2:7].[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1.[OH-].[Na+]>OS(O)(=O)=O.O=S(=O)=O>[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]2[O:14][C:13]([C:12]3[CH:16]=[CH:17][C:9]([NH2:8])=[CH:10][CH:11]=3)=[N:6][N:7]=2)=[CH:11][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: NN
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Na+]
Product: Nc1ccc(-c2nnc(-c3ccc(N)cc3)o2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 63.3 %

Procedure:
60 g (0.46 mole) of hydrazine sulphate was dissolved in 700 ml of oleum with 20% SO3. 137 g (1.0 mol) p-aminobenzoic acid was added at room temperature. The mixture was stirred for 2.5 hours at a temperature of 70° C. to 75° C. and then poured onto 10 liters of ice and neutralized with a concentrated sodium hydroxide solution. The resulting precipitate was filtered off, washed with water, and again filtered off. The yield was 91 g of impure product. This impure product was recrystallized in ethanol. After partial evaporation of the resulting liquid, 73.5 g of pure 2,5-bis-(p-aminophenyl)-1,3,4-oxadiazole were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].Cl.C[O:26][C:27](=[O:52])[CH:28]([NH:41][C:42](=[O:51])[C:43]1[C:48]([Cl:49])=[CH:47][CH:46]=[CH:45][C:44]=1[Cl:50])[CH2:29][C:30]1[O:34][N:33]=[C:32]([CH:35]([NH2:40])[CH2:36][CH:37]([CH3:39])[CH3:38])[CH:31]=1>>[Cl:50][C:44]1[CH:45]=[CH:46][CH:47]=[C:48]([Cl:49])[C:43]=1[C:42]([NH:41][CH:28]([CH2:29][C:30]1[O:34][N:33]=[C:32]([CH:35]([NH:40][C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:36][CH:37]([CH3:39])[CH3:38])[CH:31]=1)[C:27]([OH:52])=[O:26])=[O:51]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)C(Cc1cc(C(N)CC(C)C)no1)NC(=O)c1c(Cl)cccc1Cl
Agent: Cl
Product: COc1cc(CC(=O)NC(CC(C)C)c2cc(CC(NC(=O)c3c(Cl)cccc3Cl)C(=O)O)on2)ccc1NC(=O)Nc1ccccc1C
Yield: 51 %

Procedure:
The title compound was prepared in the manner described in example 2B using 3-methoxy-4-(3-o-tolyl-ureido)-phenylacetic acid and 3-[3-(1-amino-3-methyl-butyl)-isoxazol-5-yl]-2-(2,6-dichloro-benzoylamino)-propionic acid methyl ester hydrochloride. 51% yield; white solid. MS (m/z) 724.2 and 726.2 (M+1). C. 3-[3-(1-Amino-3-methyl-butyl)-isoxazol-5-yl]-2-(2,6-dichloro-benzoylamino)-propionic acid methyl ester hydrochloride
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCCCCn1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(NCCCCn1ccnc1)c1ccc(Br)cc1
Reaction time: 22 h
Yield: 30.5 %

Procedure:
To a stirred solution of 1.39 g of 1H-imidazole-1-butanamine in 50 ml of dichloromethane at room temperature, covered with an excess of saturated sodium bicarbonate solution was added 2.55 g of 4-bromobenzenesulfonyl chloride. Stirring was continued for 22 hours, then the layers were separated and the organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol. The recrystallized material was dissolved in dichloromethane containing 5% ethanol. The solution was passed through a silica gel column. The column was washed twice with 200 ml portions of ethyl acetate, then three times with 200 ml portions of 10% ethanol/ethyl acetate. The 10% ethanol/ethyl acetate cuts were combined and evaporated in vacuo, the residue was dried in vacuo at 50° C. and gave 1.09 g of the compound of the Example as colorless crystals, mp 158°-159° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:23]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][CH:22]=4)[N:19]=[CH:18][CH:17]=[CH:16]5)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc2ncccc2c1)c1cnc2ccc(-c3ccccc3)nn12

Procedure:
A 48 mL sealed tube was charged with (6-chloroimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.530 g, 1.72 mmol), phenylboronic acid (0.314 g, 2.58 mmol), cesium carbonate (1.68 g, 5.15 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.0701 g, 0.0858 mmol), 1,4-dioxane (6.31 ml, 73.8 mmol), and water (1.11 ml, 61.8 mmol), flushed with argon, sealed, then placed in an 80° C. oil bath for 8 hours. The mixture was concentrated then triturated with water, followed by MeOH/DCM to give (6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone as a reddish brown solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:6])[CH3:5].Cl.[OH-].[Na+].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1>C(O)C>[CH3:5][N:4]([CH2:3][CH2:2][S:17][C:14]1[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][CH:13]=1)[CH3:6]
Reactant: Sc1ccc(Br)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCSc1ccc(Br)cc1
Reaction time: 0.03 h
Yield: 86 %

Procedure:
A solution of 23.5 g of chloroethyldimethylamine.HCl in 75 ml of ethanol was added to 160 ml of sodium hydroxide solution formed by dissolving 20 g of sodium hydroxide pastilles in 500 ml of ethanol. A solution of 30 g of 4-bromothiophenol in 100 ml of ethanol was added to 160 ml of the said sodium hydroxide solution and the first solution was added thereto over 2 minutes at 20° C. The mixture was refluxed for 3 hours and was evaporated to dryness. Water was added to the residue and the mixture was extracted with methylene chloride. The organic phase was washed with aqueous 0.1N sodium hydroxide solution, then with water, dried and evaporated to dryness. The residue was distilled to obtain 35.5 g of 4-(N,N-dimethylaminoethylthio)-bromobenzene boiling at 110° C. at 0.1 mm Hg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].N1C=CC=CC=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([NH:20][C:29](=[O:30])[O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(F)c(N)cc23)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C#Cc1cccc(Nc2ncnc3cc(F)c(NC(=O)Oc4ccccc4)cc23)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
N4-(3-ethynylphenyl)-7-fluoroquinazoline-4,6-diamine (50 mg, 0.18 mmol) was dissolved into DMF (2 mL) containing pyridine (17.5 μL, 0.21 mmol). Phenyl chloroformate (23 μL, 0.18 mmol) was added to the mixture at room temperature and stirred at 70° C. for 1 h to give phenyl 4-(3-ethynylphenylamino)-7-fluoroquinazolin-6-ylcarbamate. N1-(2,2-diethoxyethyl)-N2,N2-diethylethane-1,2-diamine (42 mg, 0.18 mmol) was added and stirred at 70° C. for 2.5 h. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was concentrated and purified with a silica column to give 45 mg (70%) of 1-(2,2-diethoxyethyl)-1-(2-(diethylamino)ethyl)-3-(4-(3-ethynylphenylamino)-7-fluoroquinazolin-6-yl)urea.
Reaction SMILES: II.[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)(=[O:5])[CH3:4].[Li+].[Br-].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1>C1COCC1.CN1C(=O)N(C)CC1.C1COCC1.CN1C(=O)N(C)CC1.[Zn].II>[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)(=[O:5])[CH3:4]
Reactant: BrCCCCCCCCCCCOC1CCCCO1
Reactant: CC(=O)OCCCCCCBr
Agent: II
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Product: CC(=O)OCCCCCCCCCCCCCCCCCOC1CCCCO1
Reaction time: 0.08 h
Yield: 93 %

Procedure:
In a 50-ml flask, zinc powder (98 mg, 1.5 mmol) was dried at 70° C. under high vacuum for 30 min. After back-filling with nitrogen, DMI (25 ml) was added followed by solid I2 (380 mg, 1.53 mmol) for Zn activation. The iodine color disappeared after stirring for 5 min. Neat 6-bromohexyl acetate (6.83 g, 30.61 mmol) was added and the mixture was stirred at 65-80° C. for 2-14 h, cooled to the room temperature, excess zinc was allowed to settle, and the organozinc solution 46 was transferred via cannula into a solution of anhydrous LiBr (5.32 g, 61, 23 mmol) in THF (50 ml). The solution of organozinc reagent in DMI-THF mixture was cooled to 0° C. and solution of PEPPSI-IPr (130 mg, 0.191 mmol) in DMI (3 ml) was added followed by a rapid addition of neat Br(CH2)11OTHP 47 (6.42 g, 19.13 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for 9 h. Reaction mixture was quenched with aqueous NH4Cl solution (250 ml) and extracted with EtOAc (250 ml). The extract was washed with aqueous NH4Cl solution, dried over Na2SO4 and concentrated under reduced pressure. The crude product was chromatographed on silica gel in hexane-EtOAc (97:3) to give the compound 39 (7.09 g, 93%).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[O:13])=[CH:8][C:7]=1[N+:23]([O-:25])=[O:24])([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O.C(OCC)(=O)C>[N+:23]([C:7]1[CH:8]=[C:9]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([O:18][CH2:12][C:9]2[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=2)=[O:17])=[O:13])[CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][C:1](=[O:3])[O:2][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O-:25])=[O:24]
Reactant: O=C(O)CNc1ccc(C(=O)c2ccccc2C(=O)O)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(C(=O)c2ccccc2C(=O)OCc2ccccc2)cc1[N+](=O)[O-])OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 165.6 %

Procedure:
To a solution of 2-({4-[(carboxymethyl)amino]-3-nitrophenyl}carbonyl)benzoic acid (0.26 g, 0.76 mmol) in N,N-dimethyl formamide (5.0 mL), potassium carbonate (0.52 g, 3.80 mmol) was added, followed by the addition of benzyl bromide (0.22 mL, 1.82 mmol). The reaction mixture was stirred for 15 hours at room temperature. It was poured into ice water and diluted with ethyl acetate (50 mL). The organic layer was separated and it was washed with water, 2M aqueous hydrochloric acid and brine. It was dried over anhydrous sodium sulfate. Evaporating the solvent, followed by purification of the crude product by silica gel flash chromatography (hexane:ethyl acetate 4:1 to 3:2 eluent) resulted in phenylmethyl 2-{[3-nitro-4-({2-oxo-2-[(phenylmethyl)oxy]ethyl}amino)phenyl]carbonyl}benzoate (0.33 g, 82% yield) as an amorphous residue. MS (EI) for C30H24N2O7: 524 (MH+).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[N:5]2[CH:4]=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21]([O-])([O-])=O.[K+].[K+].CI>CN(C)C=O>[CH3:21][N:9]1[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[N:6]2[C:2](=[O:1])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][N:5]2[C:10]1=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cn2c(=O)[nH]c3ccccc3n2c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(=O)n(C)c3ccccc3n2c1=O
Reaction time: 20 h

Procedure:
5.22 g 5,6-dihydro-1,5-dioxo-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester, made as in Example 1, 2.76 g K2CO3 and 50 mM CH3I are dissolved in 100 ml dimethylformamide and stirred for 20 hours. The crystalline 5,6-dihydro-6-methyl-1,5-dioxo-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester is isolated after filtration and recrystallized from dimethylformamide/ethanol. The yield is 4.7 g as white needles with a melting point of 243°-244° C.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:21]=[O:22])[N:11]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[CH:15][C:14]=2[Cl:20])[CH:12]=1.CC(C)=[O:25].[OH-].[Na+]>O>[Br:7][C:8]1[CH:9]=[C:10]([C:21]([OH:25])=[O:22])[N:11]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[CH:15][C:14]=2[Cl:20])[CH:12]=1
Reactant: CC(C)=O
Reactant: O=Cc1cc(Br)cn1-c1c(Cl)cncc1Cl
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Br)cn1-c1c(Cl)cncc1Cl
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 2.9 g of potassium permanganate in 15 ml of water was added dropwise to a mixture of 2.86 g of 4-bromo-1-(3,5-dichloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde and 30 ml of acetone while the mixture was maintained at 40° C. The mixture was stirred at 40° C. for 2 hours. A precipitate was filtered off to obtain a filtrate. The filtrate was adjusted to pH 10-12 by an addition of a 2N aqueous sodium hydroxide solution, and then washed with chloroform two times. The aqueous layer was adjusted to around pH 3 by an addition of 2N hydrochloric acid. A deposited precipitate was collected by filtration to obtain 2.08 g of 4-bromo-1-(3,5-dichloro-4-pyridinyl)-1H-pyrrole-2-carboxylic acid of the formula:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].CCOCC.N#N.C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C.Cl>C1COCC1>[C:5]([C:4]1[CH:3]=[C:2]([B:26]([OH:27])[OH:25])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
3-Bromobenzonitrile (10.0 g, 55 mmol) was dissolved in dry THF (100 mL) and cooled to −100° C. (Et2O/N2). n-Butyllithium (24.2 mL, 2.5 M in hexane) was added over 30 minutes, maintaining the internal temp under −90°. After 20 minutes, triisopropylborate (18.0 mL) was added over 15 minutes, again maintaining the internal temperature. After the addition was complete, the reaction was allowed to warm slowly to room temperature over 1.5 hours. The reaction was stirred at room temp for 16 hours, then cooled to 15° C., after which 6 M HCl (25 mL) was added. After stirring vigorously for 3.5 hours, the reaction was partitioned between water and EtOAc. After extracting a second time with EtOAc, the combined organics were washed with 2 M NaOH. The aqueous extract was neutralized with 6 M HCl. The white precipitate was filtered, yielding the desired product (4.80 g, 60%). 1H NMR (DMSO-d6): δ8.37 (s, 2H), 8.10 (s, 1H), 8.03 (dt, 1H, J=7.3, J′=1.1), 7.83 (dt, 1H, J=7.6, J′=1.4), 7.53 (t, 1H, J=7.7).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([CH3:26])[NH:7][C:8](=[O:25])[C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[CH:27]([O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([CH3:29])[CH3:28].C(N(CC)CC)C.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH:1]1([C:4]2[N:5]=[C:6]([CH3:26])[N:7]([C:34]3[CH:35]=[CH:36][C:31]([O:30][CH:27]([CH3:29])[CH3:28])=[CH:32][CH:33]=3)[C:8](=[O:25])[C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:2][CH2:3]1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: Cc1nc(C2CC2)c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nc(C2CC2)c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n1-c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.4 %

Procedure:
A mixture of 4′-[(4-cyclopropyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.02 g), (4-isopropoxyphenyl)boronic acid (1.08 g), molecular sieves 4 A (0.51 g), triethylamine (2.1 mL), pyridine (1.0 mL), copper(II) acetate (1.09 g) and methylene chloride (20 mL) was stirred at room temperature for 24 hr. Ethyl acetate was added to the reaction mixture, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.39 g, 27%).
Reaction SMILES: CS(O)(=O)=O.Cl[CH2:7][C:8](=[O:37])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@H:18]([OH:36])[C@@H:19]([N:28]4[CH2:33][CH2:32][O:31][C:30]([CH3:35])([CH3:34])[CH2:29]4)[CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1.[S-:38][C:39]#[N:40].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[OH:36][C@@H:18]1[C@@H:19]([N:28]2[CH2:33][CH2:32][O:31][C:30]([CH3:35])([CH3:34])[CH2:29]2)[CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C:8](=[O:37])[CH2:7][S:38][C:39]#[N:40])[CH2:17]1
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](C(=O)CCl)CC[C@@H]43)C[C@@H]2O)CCO1
Reactant: N#C[S-]
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](C(=O)CSC#N)CC[C@@H]43)C[C@@H]2O)CCO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of (2β,3α,5α)-21-chloro-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnan-20-one methanesulfonate (1:1) salt (1.5 g) in methanol (63 ml) was added a solution of potassium thiocyanate (5.14 g) in water (32 ml). The resulting solution was stirred at room temperature for 72 h, then poured into water and sodium carbonate was added until the pH exceeded 9. The precipitated solid was filtered off, washed with water and dissolved in dichloromethane. The solution was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel and the purified product was crystallised from methanol and then from diethyl ether to give (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-21-thiocyanatopregnan-20-one (497 mg). m.p. 165.5°-166.5° C.; [α]D +121.1° (c 1.3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:17][CH2:18][CH3:19])[CH2:10][N:11]([CH:15]=O)[NH:12][CH:13]=O.C([NH2:22])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:17][CH2:18][CH3:19])[CH2:10][N:11]1[CH:15]=[N:22][CH:13]=[N:12]1
Reactant: CCCC(CN(C=O)NC=O)c1ccc(Cl)cc1Cl
Reactant: NC=O
Product: CCCC(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
6.2 g of the 1-[2-(2,4-dichlorophenyl)-pentyl-1,2-diformylhydrazine obtained according to Example 14 are heated, without purification, in 50 ml of formamide at 170° C. for 6 hours. Chromatography of the product obtained yields 1-[2-(2,4-dichlorophenyl)-pentyl]-1H-1,2,4-triazole, the 1H-NMR spectrum of which agrees with the 1H-NMR spectrum of the same compound described in Example 12.
Reaction SMILES: [CH:1]([N:4]([CH:12]([CH3:32])[CH2:13][C:14]1[C:15](=[O:31])[NH:16][CH2:17][CH2:18][CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29]C)[CH:25]=3)[C:20]=12)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:3])[CH3:2].B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH:1]([N:4]([CH:12]([CH3:32])[CH2:13][C:14]1[C:15](=[O:31])[NH:16][CH2:17][CH2:18][CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([OH:29])[CH:25]=3)[C:20]=12)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:2])[CH3:3]
Reactant: CCCCCCCN(C(C)C)C(C)CC1=C2c3ccc(OC)cc3CCC2CCNC1=O
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCN(C(C)C)C(C)CC1=C2c3ccc(O)cc3CCC2CCNC1=O

Procedure:
The solution of 2.2 g of 1-[2-(N-isopropyl-N-heptylamino)propyl]-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one, RR racemate in 18 ml of methylene chloride, precooled in a dry ice-acetone bath, is added to 31.3 ml of a similarly cooled 10% solution of boron tribromide in methylene chloride. The mixture is allowed to reach room temperature and is stirred at said temperature overnight. It is cooled in an ice bath, neutralized to pH=9 with 75 ml of saturated aqueous sodium carbonate and stirred at room temperature for 3.5 hours. The methylene chloride layer is separated, washed with water, dried and evaporated. The residue is suspended in diethyl ether, the crystallized material is collected and recrystallized from ethyl acetate to give the 1-[2-(N-isopropyl-N-heptylamino)propyl]-9-hydroxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one, RR racemate melting at 144°-146°.