Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[C:5](=[O:20])[NH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])=[N:8][CH:9]=1)(O)=O.CCOCC.C>N1C2C(=CC=CC=2)C=CC=1.C(O)C>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[NH:6][C:5](=[O:20])[CH:4]=[CH:9][N:8]=1)[CH2:18][CH3:19]
Reactant: CCCOc1ccccc1-c1ncc(C(=O)O)c(=O)[nH]1
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Solvent: CCO
Product: CCCOc1ccccc1-c1nccc(=O)[nH]1

Procedure:
5-Carboxy-2-(2-propoxyphenyl)pyrimidin-4(3H)-one (2.03 g, U.S. Pat. No. 4,031,093) in quinoline (10 ml) was heated under reflux under nitrogen for two hours. Ether was added to the cooled reaction mixture which was then extracted with aqueous sodium hydroxide. The basic extract was washed with ether and then acidified with concentrated hydrochloric acid to pH 7. The aqueous mixture was extracted with chloroform and the chloroform extract was washed with aqueous hydrochloric acid, dried and evaporated under reduced pressure to afford a yellow solid. This solid was dissolved in ethanol and the ethanolic solution Was treated with charcoal, filtered and reduced in volume. From this precipitated a yellow solid impurity which was removed by filtration. A small quantity of the crude title compound (0.1 g) precipitated from the filtrate, however this together with another sample of crude title compound (0.54 g) similarly prepared was combined with the filtrate and eluted from a silica column with chloroform. Combined fractions containing product were evaporated under reduced pressure to afford a solid, 270 mg, which was recrystallised from ether to afford the title compound, 170 mg, m.p. 112°-113° C.
Reaction SMILES: C([O:3][C:4](/[C:6](=[C:11](\[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[CH2:7][C:8]([OH:10])=[O:9])=[O:5])C.[OH-].[Na+]>C(O)C.O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22](/[C:11](=[C:6](/[CH2:7][C:8]([OH:10])=[O:9])\[C:4]([OH:5])=[O:3])/[C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][CH:17]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)/C(CC(=O)O)=C(\c1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C(\CC(=O)O)C(=O)O)c2ccc(Cl)cc2)cc1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a suspension of 50 g (0.118 mole) of (Z)-3-ethoxycarbonyl-4-(4-chlorophenyl)-4-(4-methanesulphonylphenyl)-3-butenoic acid, prepared in example 3, in 1000 ml of ethanol is added a solution of 10.4 g (0.26 mole) of sodium hydroxide in 25 ml of water. The mixture is heated under reflux for 6 hours, the precipitate is filtered off and washed with ethanol. The solid is then taken up into 500 ml of a 1N sodium hydroxide solution and the insoluble is filtered off. The aqueous phase is washed with dichloromethane and then acidified with hydrochloric acid to pH=1. After one hour's stirring, the precipitate obtained is filtered under suction, washed with water and dried to give 38.4 g of (Z)-2-[1-(4-chlorophenyl)-1-(4-methanesulphonylphenyl)-methylene]succinic acid in the form of crystals with a melting point of 199-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](I)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][C:18](=[CH2:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>ClCCl.O>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]/[C:18](=[CH:26]\[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])/[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]
Reactant: O=S(=O)(I)c1ccc(Cl)cc1
Reactant: C=C(COCCOC)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCCOC/C(=C\S(=O)(=O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 23 h
Yield: 104.7 %

Procedure:
To a solution of 4-chlorobenzenesulphonyl iodide (4.95 g, 16.4 mmol) in dichloromethane (12 mL) at room temperature was added tert-butyl 2-(2-methoxyethoxymethyl)acrylate (2.36 g, 10.9 mmol). The mixture was stirred at room temperature for 23 hours, cooled to 0° C. and triethylamine (2.9 mL, 21.8 mmol) added dropwise. The reaction was stirred at 0° C. for 1.25 hours, diluted with distilled water (25 mL) and dichloromethane (12 mL) and the layers separated. The aqueous layer was further extracted with dichloromethane (10 mL) and the combined organic extracts were washed with 1.0M aqueous hydrochloric acid solution (25 mL), 5% aqueous sodium thiosulphate solution (25 mL) and distilled water (10 mL). The dichloromethane phase was concentrated under reduced pressure to give a brown oil (4.46 g). The crude product was purifed by chromatography on silica by eluting with hexane/ethyl acetate (3:1) to give, after combination and evaporation of appropriate fractions, the title compound as a oil, (3.50 g, 82%), Rf =0.38 (silica, hexane/ethyl acetate, 2:1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].C(=O)([O-])[O-].[K+].[K+].I[CH:38]([CH3:40])[CH3:39]>CN(C=O)C>[CH:38]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=1)=[O:11])([CH3:40])[CH3:39]
Reactant: O=C(c1ccc(Oc2nccnc2N2CCOCC2)cc1)c1nc2ccccc2[nH]1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)c2ccc(Oc3nccnc3N3CCOCC3)cc2)nc2ccccc21
Reaction time: 8 h

Procedure:
A mixture of (1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)-phenyl)methanone (115 mg, 286 μmol), potassium carbonate (79.2 mg, 573 μmol) and 2-iodopropane (97.4 mg, 573 μmol) in DMF (2 mL) was stirred overnight. Additional isopropyl iodide was added until the starting material was consumed. The mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate and the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Biotage™, 10-30% acetone/hexanes gradient, to give (1-isopropyl-1H-benzo[d]imidazol-2-yl) (4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 444.1 (M+1). IC50 (uM) ++++.
Reaction SMILES: O1C2=CC3C=[C:9]([C:13]([OH:15])=[O:14])[NH:10]C=3C=C2OC1.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[C:26]([CH3:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O1C2C=CC(C=O)=CC=2OC1>>[CH2:16]([O:23][C:24]1[CH:31]=[C:30]2[C:27]([CH:28]=[C:9]([C:13]([OH:15])=[O:14])[NH:10]2)=[C:26]([CH3:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1C=O
Reactant: O=C(O)c1cc2cc3c(cc2[nH]1)OCO3
Agent: O=Cc1ccc2c(c1)OCO2
Product: Cc1cc(OCc2ccccc2)cc2[nH]c(C(=O)O)cc12

Procedure:
Intermediate I-5a was prepared using procedures analogous to those described above for the synthesis of 5H-[1,3]dioxolo[4,5-f]indole-6-carboxylic acid (I-4c) using 4-(benzyloxy)-2-methylbenzaldehyde (I-4c) as the starting material instead of benzo[d][1,3]dioxole-5-carbaldehyde. ESI MS: m/z 282.24 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:31][CH3:32])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH:21][CH2:22][C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH2:24])[CH:9]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:43](Cl)([O:45]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:31][CH3:32])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]2[CH2:22][C@@H:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:24][C:43]2=[O:45])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNC[C@H](N)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C[C@@H](c2ccccc2)NC1=O
Reaction time: 0.75 h

Procedure:
A solution of (1R)—N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1-phenylethane-1,2-diamine (96.0 mg, 0.22 mmol) in CH2Cl2 (15 mL) was cooled to 0° C. and DIPEA (230 μL, 1.32 mmol) was added followed by triphosgene (32.6 mg, 0.11 mmol). After 45 minutes, the reaction was poured into saturated NaHCO3 (25 mL). The mixture was extracted with EtOAc (75 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 10 to 60% EtOAc/hexanes afforded (4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl)}4-phenylimidazolidin-2-one. The minor enantiomer was removed by chiral HPLC using an AD chiral column and 15% IPA/heptanes to afford enantiomerically pure product. Rf=0.16 (40% EtOAc/hexanes). LCMS=469.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) (atropisomers present in 1:1 ratio, doubling of some peaks observed) δ 7.65 (m, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.21-7.36 (m, 7H), 6.87-6.94 (m, 2H), 4.65-4.77 (m, 2H), 4.10-4.49 (m, 2H), 3.71 & 3.72 (2 singlets, 3H), 3.49-3.53 (m, 1H), 2.94-2.97 (m, 1H), 2.87 (m, 1H), 1.19-1.24 (m, 6H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]=[N:27][OH:28])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[O-]Cl.[Na+].CCN(CC)CC.[CH:43]#[C:44][CH2:45][CH2:46][CH3:47]>C(Cl)Cl.O>[C:9]([O:8][CH2:7][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:43]=[C:44]([CH2:45][CH2:46][CH3:47])[O:28][N:27]=3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: C#CCCC
Reactant: CC(=O)NC(CCc1ccc(-c2ccc(C=NO)cc2)cc1)(COC(C)=O)COC(C)=O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1cc(-c2ccc(-c3ccc(CCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of acetic acid 2-acetoxymethyl-2-acetylamino-4-[4′-(hydroxyimino-methyl)biphenyl-4-yl]butyl ester (0.2 mmol), NaOCl (2 mmol), Et3N (3 mmol) and pentyne (40 mmol) in DCM (4 mL) and H2O (1 mL) is stirred at room temperature for 12 h. It is diluted with DCM (5 mL) and H2O (10 mL) and the organic phase is washed with brine and dried over Na2SO4. After concentrating, the crude product is purified by column chromatography using EtOAc/hexane (1/1) to give the desired product as a white solid. MS: (ES+): 507.2 (M+1)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:17])[NH:10][CH2:11][C@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]([C:20]1[C:21]([F:32])=[CH:22][N:23]=[C:24]2[C:29]=1[N:28]=[C:27]([O:30][CH3:31])[CH:26]=[CH:25]2)=[CH2:19]>CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:17])[NH:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH2:19][CH2:18][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=4)[N:23]=[CH:22][C:21]=3[F:32])[CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NC[C@H]1CCNC1)OCc1ccccc1
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Solvent: CN(C)C=O
Product: COc1ccc2ncc(F)c(CCN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Reaction time: 24 h
Yield: 74.5 %

Procedure:
To a solution of phenylmethyl[(3S)-3-pyrrolidinylmethyl]carbamate (127 mg, 0.54 mmole) in DMF (1 mL) was added 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (0.10 g, 0.49 mmole). After 24 h at 100° C., the reaction contents were purified on silica gel (CHCl3/MeOH, 9:1, containing 5% NH4OH) to afford the title compound (0.16 g, 77%) as a light yellow oil: LC-MS (ES) m/e 439 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:4].[Na].[CH3:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1>>[CH3:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[N:5]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3](=[O:4])[CH2:2][N:26]1[CH:27]=[CH:28][N:29]=[C:25]1[CH3:24]
Reactant: Cc1cccc(C)c1N(CCCc1cccnc1)C(=O)CCl
Reactant: Cc1ncc[nH]1
Agent: [Na]
Product: Cc1cccc(C)c1N(CCCc1cccnc1)C(=O)Cn1ccnc1C

Procedure:
This material was prepared in an analogous manner as the previous example from 2.9 g of 2-chloro-N-(2,6-dimethylphenyl)-N-[3-(3-pyridinyl)propyl]acetamide and the sodium salt of 2-methyl imidazole. After filtration through silica gel, the residue (3 g) was crystallized from ethyl acetate-hexane to give 2.1 g of analytically pure free base, mp 89°-90° C.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:17]2[NH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[N:14][C:13]=2[C:12]([N+:22]([O-:24])=[O:23])=[CH:11][C:10]=1[N+:25]([O-:27])=[O:26].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCOCC>C1C=CC=CC=1>[N:28]1([C:9]2[C:17]3[NH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[N:14][C:13]=3[C:12]([N+:22]([O-:24])=[O:23])=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1N1CCCCC1

Procedure:
Triethylamine (1.0 gram; 0.00968 mole) was added to 3.0 grams of 4-chloro-5,7-dinitro-2-trifluoromethylbenzimidazole (0.00968 mole) in 200 milliliters of benzene. There was then added dropwise 0.8 gram of piperidine (0.00968 mole) in 10 milliliters of benzene. The resulting reaction mixture was refluxed overnight, cooled, an amount of ether added, and the mixture filtered. The filtrate was evaporated, yielding the desired 4-piperidino-5,7-dinitro-2-trifluoromethylbenzimidazole product as an orange solid. It was recrystallized from benzene as a light brown solid, m.p., 199°-206° C. NMR analysis confirmed the identity but suggested the presence of a small amount of triethylamine.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>C1(C)C=CC=CC=1>[CH2:15]([C:2]1[CH:11]=[C:10]([F:12])[C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1)[CH:14]=[CH2:13]
Reactant: O=C1OCc2cc(Br)cc(F)c21
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1cc(F)c2c(c1)COC2=O

Procedure:
To a flask charged with 5-bromo-7-fluoro-2-benzofuran-1 (3H)-one (300 mg, 1.3 mmol) and a stir bar was added allyl tri-n-butyltin (0.6 mL, 2.0 mmol), palladium tetrakis triphenylphosphine (230 mg, 0.19 mmol), lithium chloride (170 mg, 3.9 mmol), and toluene (5 mL). The mixture was purged three times with nitrogen, and heated to reflux for 4 hours. LC showed formation of the desired product, which was purified by silica gel chromatography to deliver 5-allyl-7-fluoro-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 193 [M+1]+;
Reaction SMILES: Br[CH2:2][C:3]#[C:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[Cl:9][C:10]1[C:18]([Cl:19])=[C:17]2[C:13]([CH2:14][CH:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]2=[O:20])=[CH:12][C:11]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].Cl>CCOCC.CN(C)C=O>[Cl:9][C:10]1[C:18]([Cl:19])=[C:17]2[C:13]([CH2:14][C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:2][C:3]#[C:4][Si:5]([CH3:8])([CH3:7])[CH3:6])[C:16]2=[O:20])=[CH:12][C:11]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: C[Si](C)(C)C#CCBr
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC#C[Si](C)(C)C)(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of 1-bromo-3-(trimethylsilyl)-2-propyne (2.87 g., 15.0 mmol) prepared according to methods of Corey, Tet. Lett., 3963 (1973) and Miller, Syn. Comun., 2, 267 (1972) in 50 ml. of dimethylformamide is added to a mixture of ethyl (6,7-dichloro-1-oxo-2-phenyl-5-indanyloxy)acetate (2.9 g., 7.65 mmol) and powdered potassium carbonate (2.65 g., 19.2 mmol) under an argon atmosphere. After stirring at 60° for a period of 2 hr. and cooling to room temperature, ether is added to the reaction mixture followed by dilute hydrochloric acid. The acidified solution is extracted with ether and the ethereal extract sequentially washed with water and brine, and then dried over magnesium sulfate. Removal of solvent under reduced pressure affords 4.72 g. of tan solid. Crystallization of this material from cyclohexane provides 3.26 g., (87% yield) of ethyl [6,7-dichloro-1-oxo-2-phenyl-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate, m.p. 111.5°-113° (corr.).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8](O)=[O:9])=[N:6][N:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:12]=2)[C:4]2[N:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.C(Cl)(=O)OC(C)C.[CH:35]1([NH2:38])[CH2:37][CH2:36]1>C(Cl)Cl>[CH:35]1([NH:38][C:8]([C:7]2[C:2](=[O:1])[C:3]3[CH:27]=[CH:26][CH:25]=[N:24][C:4]=3[N:5]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([S:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:12]=3)[N:6]=2)=[O:9])[CH2:37][CH2:36]1
Reactant: O=C(O)c1nn(-c2cccc(Sc3cccnc3)c2)c2ncccc2c1=O
Reactant: NC1CC1
Agent: CC(C)OC(=O)Cl
Solvent: ClCCl
Product: O=C(NC1CC1)c1nn(-c2cccc(Sc3cccnc3)c2)c2ncccc2c1=O
Yield: 6.3 %

Procedure:
4-oxo-1-(3-(pyridin-3-ylthio)phenyl)-1,4-dihydropyridino[2,3-c]pyridazine-3-carboxylic acid (200 mg, 0.53 mmol) was dissolved in 100 ml of DCM, the following were added dropwise at −15° C. in order: TEA (133.8 mg, 1.325 mmol), isopropyl chlorocarbonate (97 mg, 0.792 mmol), and reacted at −15° C. for 0.5 h, then cyclopropylamine (36 mg, 0.631 mmol) was added dropwise, reacted at room temperature for 3 h. The reaction solution was washed with water, the organic phase was dried, concentrated and crystallized to obtain an object product 13.78 mg.
Reaction SMILES: C(OC([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([C:21]([O:23][CH3:24])=[O:22])[CH2:12]1)=O)C1C=CC=CC=1.C([N-]C(C)C)(C)C.[Li+].Cl[C:34]([O:36][CH3:37])=[O:35].Cl>O1CCCC1.[Pd]>[CH3:37][O:36][C:34]([C:13]1([C:21]([O:23][CH3:24])=[O:22])[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:11][CH2:12]1)=[O:35]
Reactant: COC(=O)C1Cc2ccccc2N(C(=O)OCc2ccccc2)C1
Reactant: COC(=O)Cl
Agent: [Pd]
Agent: CC(C)[N-]C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)CNc2ccccc2C1
Reaction time: 0.5 h

Procedure:
1.00 g of N-benzyloxycarbonyl-3(R,S)-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (Example 1s)) are deprotonated in 10 ml of tetrahydrofuran with excess lithium diisopropylamide (1.5 equivalents) under customary reaction conditions, and 0.80 ml of methyl chloroformate is then added at -70° C. After 30 min, the mixture is poured onto 0.1N hydrochloric acid and extracted with methylene chloride. The crude product obtained after customary further working up is dissolved in 30 ml of tetrahydrofuran and hydrogenated in the presence of 1.00 g of palladium-on-charcoal (10% of Pd) until the reaction has ended. After purification of the product over 100 g of silica gel (mobile phase B), 3,3-bis(methoxycarbonyl)-1,2,3,4-tetrahydroquinoline is obtained: Rf (B)=0.50.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[F:19][C:17]1[CH:18]=[C:13](/[C:10](=[N:11]/[OH:12])/[CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:3][CH:4]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH:14]=[C:15]([F:20])[CH:16]=1
Reactant: Cc1ccccc1C(C/C(=N\O)c1cc(F)cc(F)c1)c1ccc(Br)cc1
Reactant: OB(O)c1cncnc1
Product: Cc1ccccc1C(C/C(=N\O)c1cc(F)cc(F)c1)c1ccc(-c2cncnc2)cc1

Procedure:
In analogy to example 22, from (E)-3-(4-bromo-phenyl)-1-(3,5-difluoro-phenyl)-3-o-tolyl-propan-1-one oxime (example 53) and pyrimidine-5-boronic acid was prepared the title compound as a white foam, MS (ESI+): m/z=430.3 ([M+H]+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7].[C:34]([N:37]1[CH2:42][CH2:41][CH:40](C(O)=O)[CH2:39][CH2:38]1)(=[O:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:34]([N:37]1[CH2:42][CH2:41][CH:40]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]2)=[O:7])[CH2:39][CH2:38]1)(=[O:36])[CH3:35]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(C)(C)CC1NC(C(=O)NCCCN)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(NCCCNC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3)C2c2cccc(Cl)c2)CC1
Yield: 70.6 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide prepared in Example 29 (0.18 g, 0.37 mmol) was reacted with 1-acetylpiperidine-4-carboxylic acid (Lancaster) (0.7 g, 0.58 mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.5 g, 3.9 mmol) in CH2Cl2 (20 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1-acetyl-piperidin-4-ylamino)-propyl]-amide as a white solid (0.16 g, 67%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][CH:13]([SH:17])[CH:14]([SH:16])[CH3:15].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O>C1CCCCC1>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]1[S:17][CH:13]([CH3:12])[CH:14]([CH3:15])[S:16]1
Reactant: CC(S)C(C)S
Reactant: O=Cc1ccco1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC1SC(c2ccco2)SC1C
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Into a 100 ml reaction flask equipped with magnetic stirring bar, thermometer and reflux condenser and hot plate with magnetic stirring apparatus is placed 0.5 grams para-toluenesulfonic acid, 5 ml cyclohexane and 6.1 grams (0.05 moles) of 2,3-butanedithiol. Over a period of 35 minutes, 4.8 grams (0.05 moles) of 2-furaldehyde is added to the reaction mass with stirring. The reaction mass is then heated to reflux and refluxed for a period of 7.5 hours with stirring while removing water of reaction. After the refluxing period, the reaction mass is cooled to room temperature and transferred to a separatory funnel. The reaction mass is then washed with one 50 ml portion of saturated sodium chloride solution and dried over anhydrous sodium sulfate and filtered. The resulting filtrate is distilled using a Microvigreux column yielding the following fractions:
Reaction SMILES: O[N:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1.N>C(O)C>[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)Cc1ccc(CC2CCCCC2=NO)cc1
Agent: N
Solvent: CCO
Product: CCOC(=O)Cc1ccc(CC2CCCCC2N)cc1
Yield: 39.1 %

Procedure:
Obtained by operating as in example 1b from 15.5 g (56.7 mmoles) of ethyl 4-[(2-hydroxyiminocyclohexyl)methyl]benzeneacetate in ethanol saturated with NH3. After treatment, 6.1 g (yield=39.1%) of a yellow-green oil is isolated which is used without any other purification.