Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCCC1.[Cu]I>[Br:1][C:2]1[O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: Oc1ccccc1C=C(Br)Br
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cc2ccccc2o1
Temperature: 80 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
To a solution of 2-(2,2-dibromovinyl)phenol (2.8 g, 10 mmol) in tetrahydrofuran (30 mL) was added copper (I) iodide (0.1 g, 0.5 mmol) and potassium phosphate (4.2 g, 20 mmol). The reaction mixture was stirred at 80° C. under nitrogen atmosphere for 12 hours. After the reaction, the mixture was poured into water (200 mL) and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:20) to give the pure product 2-bromobenzofuran (1.8 g, 92%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:13][C:12](=[O:14])[O:11][C:9](=O)[C:8]=12)[CH3:2].[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1C(O)=O>CS(C)=O>[CH2:1]([C:3]1[C:8]2[C:9](=[O:11])[N:15]3[CH2:22][CH2:21][CH2:20][C@H:16]3[C:12](=[O:14])[NH:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCc1cccc2[nH]c(=O)oc(=O)c12
Solvent: CS(C)=O
Product: CCc1cccc2c1C(=O)N1CCC[C@H]1C(=O)N2

Procedure:
7.65 g (0.04 mol) of 6-ethylisatoic acid anhydride and 4.6 g (0.04 mol) of L-proline are suspended in 40 ml of dimethyl sulphoxide, heated to 70° for 2.5 hours, the solvent is removed in a high vacuum and the oil obtained is heated to 170° for 15 minutes. The crude product is purified by chromatography on silica gel using chloroform for the elution. There is obtained amorphous (S)-6-ethyl-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione.
Reaction SMILES: Cl.C([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#N.[OH-].[K+].C1(C)C=CC=CC=1>O>[C:10]1([CH:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(C2CCNCC2)cc1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
4-Cyano-4-phenylpiperidine hydrochloride (10.0 g, 45.0 mmol) was combined with KOH pellets and stirred vigorously under Ar at 160° C. for 4 h. The reaction mix was cooled to RT and dissolved into toluene (100 ml) and H2O (100 ml). After separation of the layers, the aqueous layer was back-extracted two times with toluene. The combined organic layer was dried over Na2SO4, concentrated in vacuo, and dried under high vacuum, yielding a white solid.
Reaction SMILES: [C:1](#[N:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Li].[CH2:14]([NH2:17])[CH2:15]C>C(N)CN>[CH2:2]([C:1]1[NH:12][CH2:15][CH2:14][N:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCC#N
Reactant: CCCN
Agent: [Li]
Solvent: NCCN
Product: CCCCCCCCCCC1=NCCN1
Reaction time: 0.33 h
Yield: 22 %

Procedure:
Reduction of undecanenitrile in n-propylamine and ethylene-diamine. Lithium, (0.21 g, 30 mmol) in small pieces, was added to a stirred solution of undecanenitrile (0.84 g, 5 mmol) in n-propylamine and ethylenediamine (1.0 mL). The temperature began to rise after 20 min and reached 32° after 30 min and the reaction mixture turned blue. An aliquot of the reaction mixture showed no nitrile by glpc. The reaction mixture was poured over crushed ice and extracted with ethyl acetate (2×50 mL). After distillation of the ethyl acetate the residue deposited crystals. The crystals were collected and dried to give 2-(n-decyl)imidazoline (0.23 g, 22%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20].Cl>O1CCOCC1>[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:21])[CH:19]=[CH2:20])=[CH:3][CH:4]=1)(=[O:9])(=[O:10])[NH2:11]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: C=CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-aminobenzenesulfonamide (1.00 g) and pyridine (1.41 mL) were added to 1,4-dioxane (30 mL). Acryloyl chloride (0.49 mL) was added dropwise and the solution was stirred for 3 hours at room temperature. 1M HCl was added, and the solution extracted with ethyl acetate. The extracts were dried using brine and anhydrous sodium sulfate and the solvent was removed to afford crude product of sufficient purity for subsequent use.
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=O)[CH:11]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[C:22](OCC)=[O:23])[CH2:10]3)[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.C([O-])(=O)C.[NH4+:37]>C(O)(=O)C>[C:4]1(=[O:27])[N:5]([CH2:6][C:7]2[CH:15]=[CH:14][C:13]3[C:12]4[NH:37][C:22](=[O:23])[C:18]5[N:17]([CH:21]=[CH:20][N:19]=5)[C:11]=4[CH2:10][C:9]=3[CH:8]=2)[C:1](=[O:32])[C:2]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:3]12
Reactant: [NH4+]
Reactant: CCOC(=O)c1nccn1C1Cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2C1=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Temperature: 20 °C
Yield: 66.1 %

Procedure:
8-Phthalimidomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one can be obtained in the following way: a mixture of 17 g of ethyl 1-(5-phthalimidomethyl-1oxoindan-2yl)imidazole-2-carboxylate and 153 g of ammonium acetate in 355 ml of glacial acetic acid is heated at reflux for 16 hours. The reaction mixture is cooled to a temperature in the region of 20° C. The precipitate is filtered on sintered glass, rinsed with distilled water to neutral pH and then washed with acetone. After drying under vacuum (1 mbar) at 80° C., 10 g of 8-phthalimidomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of a brown solid (1H NMR spectrum in d6-DMSO, T=300K, δ in ppm: 4.00 (2H, s, CH2), 4.83 (2H, s, NCH2), 7.47 (1H, d, J=7 Hz, arom. CH), 7.55 (2H, d, J=7 Hz, arom. CH), 7.80 (1H, d, J=7 Hz, arom. CH), between 7.85 and 8.00 (4H, m, phthal. H), 12.30 (1H, broad s, NH)).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[K].[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20]>CC(N(C)C)=O>[CH3:10][C:4]1[CH:3]=[C:2]([O:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[Cl:12])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1cc(Cl)ccc1C#N
Reactant: Oc1ccc(F)cc1Cl
Agent: [K]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccc(F)cc2Cl)ccc1C#N
Yield: 96.8 %

Procedure:
A stirred solution of 4-chloro-2-methylbenzonitrile (4.7 g., 0.03 mole) and the potassium salt of 2-chloro-4-fluorophenol (5.54 g., 0.03 mole) in 40 ml of dimethyl acetamide was heated for 48 hours at 150° C. The cooled reaction mixture was diluted with 200 ml. of water to precipitate a brown oil. An ether extract yielded 7.6 g of 2-methyl-4-(2'-chloro-4'-fluorophenoxy)benzonitrile as a brown oil in about 90% purity.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.C1C(=O)N([Cl:18])C(=O)C1>CN(C=O)C>[Cl:18][C:10]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7][NH:8][CH:9]=1
Reactant: c1csc(-c2cc[nH]n2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Clc1c[nH]nc1-c1cccs1

Procedure:
Following protocol L, 3-thiophen-2-yl-1H-pyrazole was treated with NCS in DMF, to yield title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[CH:12][O:13][C:14]=2[CH3:15])=[CH:4][C:3]=1[O:16][CH3:17].CON(C)[C:21](=[O:37])[CH:22]([O:35][CH3:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[C:12]([C:21](=[O:37])[CH:22]([O:35][CH3:36])[C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[CH:27][CH:28]=3)[O:13][C:14]=2[CH3:15])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(-c2ncoc2C)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Product: COc1cc(-c2nc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)oc2C)cc(OC)c1Br

Procedure:
1-(4-(4-Bromo-3,5-dimethoxyphenyl)-5-methyloxazol-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone was prepared from 4-(4-bromo-3,5-dimethoxyphenyl)-5-methyloxazole and N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (40% EtOAc-hexanes) gave the product as a yellow solid (0.048 g, 13% yield). MS: m/z 531.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](Cl)=[N:12][C:11]([O:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([OH:28])[CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([N:8]1[C:13]([O:28][C:21]2[CH:20]=[CH:19][C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=2)=[N:12][C:11]([O:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC1=NS(=O)(=O)N(Cc2ccccc2)C(Cl)=N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1=NS(=O)(=O)N(Cc2ccccc2)C(Oc2ccc([N+](=O)[O-])cc2)=N1

Procedure:
A solution of 2-benzyl-3-chloro-5-methoxy-2H-1,2,4,6-thiatriazine-1,1-dioxide (3.8 g) in methylene chloride (10 ml) is added dropwise to a stirred mixture of p-nitrophenol (1.7 g) and pyridine (2.4 g) in methylene chloride (20 ml). The reaction mixture is heated to reflux for 3 hours, cooled, washed with 3N aq. HCl and sat'd aq. Na2CO3. The methylene chloride layer is dried, filtered and evaporated in vacuo yielding the desired product as an oil.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:3](=[O:24])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[C:13]([C:17]4[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=4)=[N:14][O:15][CH:16]=3)=[N:6][CH:5]=2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Product: O=C(NC1CC1)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 28 %

Procedure:
As described for example 324, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.61 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (60 mg, 28%) which was obtained as a white solid. MS: m/e=343.4 [M+H]+.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].I[CH2:10][CH2:11][CH2:12][CH3:13]>CCOCC>[CH2:7]([O:6][C:1](=[O:5])[CH:2]([O:3][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:4])[CH3:8]
Reactant: CCCCI
Reactant: CCOC(=O)[C@H](C)O
Solvent: CCOCC
Product: CCCCOC(C)C(=O)OCC
Reaction time: 15 h
Yield: 49.5 %

Procedure:
31.5 g of ethyl L-(+)-lactate and 107.3 g of 1-iodobutane were mixed into a four-necked flask, and freshly synthesized Ag2O was added in 2 hours. After left standing at room temperature for 15 hours, the mixture was diluted with 200 ml of ether, filtered and then ether was evaporated. The residue was washed with 100 ml of an aqueous 5% KOH, dried over anhydrous Na2SO4 and subjected to vacuum distillation. The fractions at 110° C./54 mmHg were collected to give 23 g of (-)-ethyl-2-butoxypropionate. Optical rotation [α]d24° =-73°
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH2:10])=[CH:5][CH:4]=1)[CH3:2].[O:17]=[CH:18][C@@H:19]([C@H:21]([C@@H:23]([C@@H:25]([CH2:27][OH:28])[OH:26])[OH:24])[OH:22])O.[Cl-].[NH4+]>CO>[CH2:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH:10][C@@H:27]2[O:28][C@H:19]([CH2:18][OH:17])[C@@H:21]([OH:22])[C@H:23]([OH:24])[C@H:25]2[OH:26])=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCc1ccc(Cc2ccccc2N)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCc1ccc(Cc2ccccc2N[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 56 %

Procedure:
2-(4-Ethylbenzyl)aniline 1 (500 mg) was dissolved in methanol (5 ml), and thereto are added D-(+)-glucose 2 (516 mg) and ammonium chloride (25 mg), and the mixture was heated under reflux for 2 hours. Methanol was evaporated under reduced pressure, and water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1-20:1) to give the desired 2-(4-ethylbenzyl)-N-(β-D-glucopyranosyl)aniline 3 (495 mg) as colorless crystals. APCI-Mass m/Z 374 (M+H).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:17]2[C:9]3=[N:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15][C@H:16]2[C:18]([F:20])([F:21])[F:19])=[CH:25][CH:24]=1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: Fc1ccc(I)cc1
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2c1ccc(F)cc1

Procedure:
The product is prepared according to the procedure described in Example 12, using 140 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) and 0.66 ml of 1-fluoro-4-iodobenzene. After purification by silica chromatography (gradient of 5% to 15% of the eluent CH2Cl2/MeOH/NH4OH 28% 38/17/2 in dichloromethane), 125 mg of (8S)-9-(4-fluorophenyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are the following:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([NH:22][C@H:23]2[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24]2)=[N:17]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:32]1([CH2:35][NH2:36])[CH2:34][CH2:33]1>>[CH:32]1([CH2:35][NH:36][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[CH:15][C:16]([NH:22][C@H:23]3[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:25][CH2:24]3)=[N:17]4)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:34][CH2:33]1
Reactant: NCC1CC1
Reactant: O=S(=O)(Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)c1ccc(F)cc1
Product: O=S(=O)(Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)c1ccc(NCC2CC2)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
4-Fluoro-N-[2-((R)-indan-1-ylamino)-quinolin-5-yl]-benzenesulfonamide (product example 1, 0.175 g, 0.404 mmol) was suspended in 2 mL cyclopropanemethylamine. The reaction mixture was stirred in a sealed tube at 120° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (heptan/ethyl acetate 100:0->50:50 gradient). The title compound was obtained as a white solid (46 mg, 24%), MS: m/e=485.5 (M+H+).
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[Na].[CH2:8](Br)[CH2:9][CH3:10]>C(O)C>[CH2:8]([S:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1)[CH2:9][CH3:10]
Reactant: CCCBr
Reactant: Sc1nc[nH]n1
Agent: [Na]
Solvent: CCO
Product: CCCSc1nc[nH]n1
Temperature: 25 °C

Procedure:
20.2 g. of 3-mercapto-1,2,4-triazole was added to a solution of 4.8 g. sodium in 150 ml. absolute ethanol. When dissolution was complete 24.6 g. propyl bromide was added. The stirred mixture was gradually heated to boiling under reflux, refluxed for 1 hour, cooled to room temperature and filtered. The filtrate was distilled to dryness under reduced pressure and the residue dissolved in ether. The resulting solution was filtered, dried over anhydrous sodium sulphate and distilled under reduced pressure to give 3-propylthio-1,2,4-triazole, b.p. 143° - 144°C./1 mm. This product solidified, m.p. 53° - 56°C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH3:14][N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18](=[O:23])[CH2:19]2>C(OCC)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:18]2([OH:23])[CH2:19][CH:20]3[N:15]([CH3:14])[CH:16]([CH2:22][CH2:21]3)[CH2:17]2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CN1C2CCC1CC(=O)C2
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN1C2CCC1CC(O)(c1ccc(Cl)cc1)C2
Reaction time: 0.33 h
Yield: 76 %

Procedure:
2.5 M n-butyl lithium (17.96 mL, 40.90 mmol) was added to -70 ° C diethyl ether (35 mL) and 4-bromochlorobenzene (9.03 g, 47.15 mmol) in diethyl ether (20mL) was added dropwise over 20 minutes. The mixture was stirred in the cold for 20 minutes then 8-Methyl-8-aza-bicyclo[3.2.1]octan-3-one (5 g, 35.92 mmol) in diethyl ether (12 mL) was added dropwise over 5 minutes. Cooling bath was removed and when internal temperature of −20° C. was reached the solution was quenched with 1N hydrochloric acid (200 mL). The aqueous layer was raised to pH=10 with ammonium hydroxide and extracted with diethyl ether (three times, 200 mL each). The combined organic layers were washed with brine (100 mL), dried with magnesium sulfate and concentrated to yield racemic3-(4-Chloro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-ol (6.87 g, contains 9% 8-Methyl-8-aza-bicyclo[3.2.1]octan-3-one) as a white solid. Solid was used without further purification.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][CH2:2][CH2:3][C:4]2=[O:11])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCOc2ccccc21
Product: O=C1CCOc2ccc([N+](=O)[O-])cc21

Procedure:
At −35° C., 60 g of 4-chromanone are added in small portions to 385 ml of 90% nitric acid. The whole is poured onto ice and then extracted with dichloromethane. The organic phase is washed with a saturated solution of sodium hydrogen carbonate and dried over magnesium sulphate and then the solvent is evaporated off.
Reaction SMILES: [I:1]I.[CH2:3]([O:10][C@H:11]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:13][C@@H:12]1[CH2:42][Hg]Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl>[CH2:26]([O:25][C@H:15]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@@H:12]([CH2:42][I:1])[O:13][C@@H:14]1[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cl[Hg]C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: II
Solvent: ClCCl
Product: IC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.2 %

Procedure:
Iodine (0.36 g, 14.4 mmol, 1.1 equiv) dissolved in dry DCM (20 mL) was added to a solution of (((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)mercury(II) chloride (1.0 g, 12.9 mmol, 1.0 equiv) in dry DCM (30 mL). The reaction mixture was stirred at room temperature for 16 hours and then quenched with saturated aqueous sodium thiosulfate solution (50 mL). The biphasic mixture was separated and then the organic layer was washed with saturated aqueous sodium chloride solution (10 mL) and then with water (10 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material thus obtained was purified by silica gel chromatography, eluting with 30% EtOAc in petroleum ether, to give (2R,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(iodomethyl)tetrahydro-2H-pyran as a colorless oil (0.7 g, 82%). 1H NMR (300 MHz, CDCl3) δ 7.44-7.22 (m, 18H), 7.17 (dd, J=6.6, 3.0 Hz, 2H), 5.09 (d, J=11.3 Hz, 1H), 4.92-4.67 (m, 4H), 4.67-4.47 (m, 3H), 4.21 (dd, J=2.8, 1.1 Hz, 1H), 3.90 (t, J=9.5 Hz, 1H), 3.76 (dd, J=11.0, 1.9 Hz, 1H), 3.71-3.60 (m, 2H), 3.57 (t, J=6.9 Hz, 1H), 3.53-3.45 (m, 1H), 3.35-3.24 (m, 2H). ESI (M+H2O) 682.2; calc for C35H37IO5 664.2.
Reaction SMILES: Cl.N([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([CH3:31])[CH:25]=1>CN(C)C=O>[ClH:23].[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[C:26]([CH3:31])[CH:25]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ccc(Cl)cc2C)c2c(ccc3nc[nH]c32)n1

Procedure:
A solution of 22 g. (0.1 m.) of the compound of Example I, C. and 14 g. (0.1 m.) of 4-chloro-2-methylaniline in 200 ml. of dimethylformamide was heated under reflux for 17 hours and filtered hot. The crystalline product which separated on cooling was filtered, washed with cold dimethylformamide, then ether and air-dried, giving 22 g. of straw-colored product. Recrystallization from 550 ml. of ethanol gave 14 g. m.p. 199°-206°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][C:5]2=[O:12].[C:13](Cl)([Cl:15])=[O:14]>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:13]([Cl:15])=[O:14])[CH2:7][CH2:6][C:5]2=[O:12]
Reactant: O=C(Cl)Cl
Reactant: O=C1CCNc2ccc(F)cc21
Solvent: C1COCCO1
Product: O=C1CCN(C(=O)Cl)c2ccc(F)cc21
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
33.0 parts of 6-fluoro-4-oxo-1,2,3,4-tetrahydroquinoline and 200 parts of dioxane were mixed, and 39.6 parts of phosgene were introduced to the stirred mixture over about 30 minutes while the temperature was maintained at 20°-25° C. After the introduction, the temperature was raised gradually, and the reaction was effected at 40°-45° C. for 2.5 hours, after which the temperature was further raised to 70° C., nitrogen gas was passed through the mixture, and the solvent (dioxane) was distilled off under reduced pressure. Petroleum ether was added to the residue followed by filtration, washing and drying, and there was obtained 43.7 parts of 6-fluoro-4-oxo-1-chloroformyl-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[S:34][C:35]([CH2:38][CH3:39])=[CH:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([C:35]1[S:34][C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])=[CH:37][CH:36]=1)[CH3:39]
Reactant: CCc1ccc(CCl)s1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (1.20 g, compound B50) and 2-(chloromethyl)-5-ethylthiophene (480 mg, compound D27) in dry DMF (15 ml) is added potassium carbonate (778 mg). The mixture is stirred for 1 h at 100° C. and subsequently poured into ice-cold water. After stirring for 5 min the resulting precipitate is filtered off and dried in vacuo. The residue is purified by flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 5/1 (v/v)] to afford the title compound as a solid.