Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[C:17](=[O:18])[N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH:4]2[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:26]1[CH:31]=[N:30][C:29]([CH:32]2[CH2:34][CH2:33]2)=[CH:28][N:27]=1>C(#N)C>[CH:32]1([C:29]2[N:30]=[CH:31][C:26]([O:1][CH:2]3[C:17](=[O:18])[N:5]4[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:9][CH:4]4[CH2:3]3)=[N:27][CH:28]=2)[CH2:34][CH2:33]1
Reactant: Brc1cnc(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)C(O)CC2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN2C(=O)C(Oc3cnc(C4CC4)cn3)CC2C1
Temperature: 50 °C
Reaction time: 48 h
Yield: 63.1 %

Procedure:
To a solution of the product from Example 207B (89 mg, 0.347 mmol) in anhydrous acetonitrile (3.5 mL) was added cesium carbonate (226 mg, 0.695 mmol) and 2-bromo-5-cyclopropylpyrazine (104 mg, 0.521 mmol). The resulting mixture was stirred under N2 at 50° C. for 48 hours. The mixture was allowed to cool to room temperature and partitioned between water and ethyl acetate (3×). The combined organic layers were dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-10% CH3OH in CH2Cl2 to give the title compound (82 mg, 63%).
Reaction SMILES: [Cl:1][SiH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:9][CH2:10][CH:11]=[CH2:12]>>[Cl:1][Si:2]1([CH2:12][CH2:11][CH2:10][CH2:9][C:8]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cl[SiH]1CCCCC1
Reactant: C=CCCC(=O)OCc1ccccc1
Product: O=C(CCCC[Si]1(Cl)CCCCC1)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a mixture of crude 1-chlorosilinane (0.35 g) and benzyl pent-4-enoate (0.50 g; 2.63 mmol) under argon was added two drops of Karstedt's catalyst solution (in xylenes; ˜2% Pt). The reaction vessel was sealed and the mixture was heated to 60° C. for 16 hours. The crude liquid was used without purification.
Reaction SMILES: [N:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH:5]=[N:4][CH:3]=[N:2]1.[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>ClCCl.C(O)CCC>[N:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]32[O:19][CH2:18][CH2:17][O:16]3)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: OCCO
Reactant: O=C1c2ccccc2CCC1n1cncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCO
Solvent: ClCCl
Product: c1ccc2c(c1)CCC(n1cncn1)C21OCCO1

Procedure:
A mixture of 10 g. 3,4-dihydro-2-(1H-1,2,4-triazol-1-yl)-1-(2H)-naphthalenone, 5.8 g. ethylene glycol and 11.5 g. p-toluenesulfonic acid was refluxed in a mixed solvent of 150 ml. toluene and 70 ml. n-butanol under a Dean-Stark [trademark] trap for 48 hours. The solvent was evaporated leaving a slurry which was taken up in dichloromethane and washed twice with 10% aqueous sodium hydroxide and once with water. The extract was dried in sodium sulfate, filtered and evaporated leaving an oily residue which crystallized on cooling to yield 1.5 g. of white crystals. These white crystals were 3',4'-dihydro-2'-(1H-1,2,4-triazole-1-yl)-spiro-[1,3-dioxolane-2,1'(2'H)-naphthalene. This compound had a melting point of 108° C.
Reaction SMILES: C1(C)C=CC=CC=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].Cl[CH2:23][CH2:24][CH2:25][C:26]1([C:39]#[N:40])[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:25]1[C:26]2([CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH2:39][NH:40][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CCCCl)CC1
Agent: COCCO[Al+]OCCOC
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Reaction time: 0.83 h

Procedure:
Charge 435 g of toluene then 302.1 g of sodium bis(2-methoxyethoxy)aluminum hydride to R1. Cool the mixture to −5° C.˜5° C. Charge 652.5 g of toluene and 50 g of tert-butyl 4-(3-chloropropyl)-4-cyano-piperidine-1-carboxylate into R2 and stir the mixture until clear. Add the solution of tert-butyl 4-(3-chloropropyl)-4-cyano-piperidine-1-carboxylate in R2 drop-wise to R1, control the temperature below 5° C. Stir the mixture in R1 for 0.5 hour at −5° C.˜5° C. then warm the mixture to 15˜20° C. and stir for 1˜3 hours. Charge 25 g of sodium carbonate to R2 then add 1500 g of water and cool the mixture to 0˜10° C. Add the mixture in R1 drop-wise to R2, controlling the temperature below 10° C. Warm the mixture to 20˜40° C. and stir for 10-20 mins then allow to stand for 40-60 mins Separate the aqueous layer and wash the organic layer with 2×250 g water then 297.5 g of 25% aqueous sodium chloride solution. Concentrate the organic layer to 100 g total weight below 50° C. and then add 273.0 g of acetonitrile. Concentrate the organic layer to 250 g total weight below 50° C. of title compound, tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate, which is stored as a solution: mass spectrum (m/z): 255 (M+H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:64]([N:71]1[CH2:77][CH2:76][CH2:75][N:74]([CH:78]2[CH2:83][CH2:82][CH:81]([NH2:84])[CH2:80][CH2:79]2)[CH2:73][CH2:72]1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C=O)C>[CH2:64]([N:71]1[CH2:77][CH2:76][CH2:75][N:74]([CH:78]2[CH2:83][CH2:82][CH:81]([NH:84][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([NH:21][C:19]4[N:18]=[CH:17][C:8]5[N:9]([CH3:16])[C:10](=[O:15])[C:11]6([CH2:13][CH2:14]6)[CH2:12][N:6]([CH:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)[C:7]=5[N:20]=4)=[C:23]([O:31][CH3:32])[CH:24]=3)[CH2:80][CH2:79]2)[CH2:73][CH2:72]1)[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: NC1CCC(N2CCCN(Cc3ccccc3)CC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCC(N3CCCN(Cc4ccccc4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (66 mg, 0.15 mmol, 1 eq), DIPEA (52 μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) were added to 1 mL DMF and the resulting solution was stirred at rt for 20 min before the addition of 4-(4-benzyl-1,4-diazepan-1-yl)cyclohexanamine (Intermediate 16) (54 mg, 0.19 mmol, 1.27 eq) dissolved in DMF (0.5 mL). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—5) to provide N-(4-(4-benzyl-1,4-diazepan-1-yl)cyclohexyl)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzamide as a mixture cis and trans isomers (off-white solid, 33 mg, 31%).
Reaction SMILES: [H-].[K+].[C:3]1([CH:13]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][N:17]3[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[S:14]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:28](Cl)(=[O:30])[CH3:29]>C1COCC1>[C:28]([O:20][C:19]1[C:18]2=[CH:21][CH:22]=[CH:23][N:17]2[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[S:14][C:13]=1[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: O=C1c2cccn2-c2ccccc2SC1c1cccc2ccccc12
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)OC1=C(c2cccc3ccccc23)Sc2ccccc2-n2cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a suspension of potassium hydride (0.303 g, 2.64 mmol, 35% in oil) in anhydrous THF (5.0 mL) was added the (±)-6-(1-naphthyl)pyrrolo[2,1-d][1,5]benzothiazepin-7(6H)-one (0.9 g, 2.64 mmol) dissolved in anhydrous THF (7 mL). The reaction mixture was stirred at rt for 2 h, and then acetyl chloride (0.239 g, 3.04 mmol) was slowly added. After stirring for 12 h at rt, the solvent was removed in vacuo and the residue was dissolved in chloroform. The organic layer was washed with brine, dried and concentrated. The residue was chromatographed (dichloromethane and hexane 1:1) to give the PBOX-9 in 86% yield. IR (neat) 1762 cm−1; 1HNMR (CDCl3) δ 1.70 (s, 3 H) 6.45 (m, 1 H), 6.63 (m, 1 H), 7.19-7.55 (m, 10 H), 7.78-7.87 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[C:16]([CH3:25])=[N:17][N:18]([CH3:24])[C:19]=1[CH2:20][CH:21]([CH3:23])[CH3:22]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH:14][C:15]2[C:16]([CH3:25])=[N:17][N:18]([CH3:24])[C:19]=2[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Reactant: Cc1nn(C)c(CC(C)C)c1N
Solvent: c1ccncc1
Product: Cc1nn(C)c(CC(C)C)c1NS(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Yield: 23.6 %

Procedure:
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (0.35 g, 1.1 mmol) and 4-amino-1,3-dimethyl-5-isobutyl-1H-pyrazole (0.18 g, 1.1 mmol) in pyridine (4 ml) according to the method of intermediate 1, to give the title compound as an orange solid (118 mg, 0.26 mmol, 24%). δH (D-6 DMSO, 300K) 7.67 (2H, s), 6.69 (1H, s), 3.71 (3H, s), 2.45 (2H, d J 7.8 Hz), 1.90 (1H, m), 1.84 (3H, s), 0.91 (6H, d J 6.8 Hz). m/z (ES+, 70V) 456.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N+:5]([O-])=[C:4]([CH3:11])[CH:3]=1.P(Br)(Br)Br>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: COc1c[n+]([O-])c(C)cc1Br
Agent: BrP(Br)Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cnc(C)cc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-bromo-5-methoxy-2-methyl-pyridine 1-oxide (Step AL4) (150 mg, 0.7 mmol) in CHCl3 (2 mL) at 10° C. was added dropwise PBr3 (78 μL, 0.826 mmol). The mixture was stirred at rt for 4 h, then at 50° C. for 1 h. The reaction mixture was dissolved in CH2Cl2 and extracted with a saturated aqueous solution of NaHCO3, washed with brine, dried (Na2SO4), filtered and concentrated. The product was crystallised (CH2Cl2/TBME). ESI-MS: tR=0.69 min, [M+H]+ 202.0/204.0 (LC-MS 1).
Reaction SMILES: C(O[C:4](=[O:12])[C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1)C.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[N:13]1([C:4]([C:5]2[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=2)=[O:12])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1ncccc1O
Product: O=C(c1ncccc1O)N1CCCC1
Reaction time: 24 h

Procedure:
18 g (0.093 moles) of ethyl-3-hydroxypicolinate [J. Heterocyclic Chem. 23, 665, 1986] were cooled at -5° C. and ml 250 of pyrrolidine were added under nitrogen atmosphere. After the addition, the solution was allowed to reach room temperature, stirred 24 h and then evaporated in vacuo to give 15 g of the title compound as a slight yellow oil which crystallized on standing.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:21]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:28])[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Reactant: O=C(Cl)c1cccnc1
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2C(=O)c1cccnc1
Yield: 55 %

Procedure:
Starting from 1,3-dihydro-5(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4 thiadiazin-5-yl)-3,3 dimethyl-2H-indol-2-one (Example 3) and according to the method described in Example 23, but using nicotinoyl chloride instead of isonicotinoyl chloride, afforded the desired compound.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[CH2:19]([OH:23])[CH2:20][CH2:21][CH3:22]>O.C1(C)C=CC=CC=1>[C:19]([O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@@H:2]([C:11]([OH:13])=[O:12])[NH2:1])=[CH:9][CH:8]=1)(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCO
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC(=O)Oc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
18.19 g of tyrosine was suspended in a solution of 9.8 g of concentrated sulfuric acid, 40 mL water, 40 mL of butanol, and 200 mL of toluene in a 500 mL round bottom flask equipped with a condenser and a Dean-Stark apparatus. The resulting solution was heated at reflux temperature until no more water could be distilled. The resulting solution was cooled in an ice bath, which caused the solution to separate into two phases. The upper phase was discarded and the lower phase, an oily syrup, was retained. The syrup was mixed with sufficient 5% aqueous sodium bicarbonate solution to neutralize acidic impurities to provide a solid that was collected by filtration and washed with cold water. The resulting solid was re-crystallized in ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)=[CH:4][C:3]=1[NH:23][C:24](=[O:39])[C:25]1[CH:30]=[C:29]([S:31]([F:36])([F:35])([F:34])([F:33])[F:32])[CH:28]=[C:27]([CH:37]=[O:38])[CH:26]=1.O.P([O-])(O)(O)=[O:42].[Na+].Cl([O-])=O.[Na+]>CS(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)=[CH:4][C:3]=1[NH:23][C:24]([C:25]1[CH:26]=[C:27]([CH:28]=[C:29]([S:31]([F:35])([F:34])([F:33])([F:36])[F:32])[CH:30]=1)[C:37]([OH:42])=[O:38])=[O:39]
Reactant: O=P([O-])(O)O
Reactant: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cc(C=O)cc(S(F)(F)(F)(F)F)c1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 mg (0.142 mmol, 80% pure) of the compound from Example 77A were dissolved in 2 ml of DMSO, and a solution of 48 mg (0.350 mmol) of sodium dihydrogenphosphate hydrate in 0.7 ml of water was added at RT. A solution of 39 mg (0.342 mmol) of sodium chlorite in 0.3 ml of water was then added dropwise. The reaction mixture was stirred at RT for 24 h and then diluted with 100 ml of water and extracted three times with in each case about 100 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and freed from the solvent on a rotary evaporator. The crude product obtained in this manner was purified by preparative HPLC (Method 32). After evaporation of the product fractions, the residue was stirred in a mixture of 2 ml of pentane, 0.5 ml of dichloromethane and 0.5 ml of diisopropyl ether for 10 min. Filtration with suction and drying of the solid under high vacuum gave 43 mg (52% of theory) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][S:10][C:9]1=[S:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10][C:9]1=[S:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=S)N1Cc1ccccc1
Reactant: O=Cc1ccccc1
Solvent: CC#N
Product: O=C1C(=Cc2ccccc2)SC(=S)N1Cc1ccccc1

Procedure:
A mixture of 3-benzylrhodanine (0.50 g, 2.2 mmol), benzaldehyde (0.23 mL, 2.3 mmol) and TEA (0.68 mL, 4.9 mmol) in MeCN (5 mL, anhyd) was heated at reflux. After 2 h the reaction mixture was cooled. Precipitated solids were collected by filtration, triturated with MeCN-Hex and dried under vacuum to yield 3-benzyl-5-benzylidene-2-thioxothiazolidin-4-one, which was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>CO>[C:14]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:13][C:6]=2[CH2:7][CH2:8][CH2:9][C:10]1=[O:12])(=[O:16])[CH3:15]
Reactant: O=C1CCCc2cc(I)ccc2N1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)N1C(=O)CCCc2cc(I)ccc21

Procedure:
10 gms. of the 7-iodo-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine from part (a) of this example are refluxed for 6 hours with 160 ml. of acetic anhydride. The solution is evaporated under vacuum following which a thick oil is obtained, which when admixed with methanol gives crystalline N-acetyl-7-iodo-2 oxo-2,3,4,5-tetrahydro-1-H-1-benzazepine with a melting point of 116° to 117° C. Yield 9.5 gm.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1(C)C=CC=CC=1.[CH3:39][O:40][C@H:41]1[C@@H:45]2[CH2:46][C@H:47]3[C@H:52]([C:53](=O)[C@@H:44]2[C@@H:43]([CH3:55])[O:42]1)[CH2:51][CH2:50][CH2:49][CH2:48]3>>[CH3:39][O:40][C@H:41]1[C@@H:45]2[CH2:46][C@H:47]3[C@H:52]([C:53](=[CH2:2])[C@@H:44]2[C@@H:43]([CH3:55])[O:42]1)[CH2:51][CH2:50][CH2:49][CH2:48]3
Reactant: CO[C@@H]1O[C@H](C)[C@H]2C(=O)[C@@H]3CCCC[C@H]3C[C@@H]12
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C1[C@H]2[C@@H](C[C@@H]3CCCC[C@@H]13)[C@H](OC)O[C@@H]2C
Yield: 87.7 %

Procedure:
Similarly to Example 7, 6665.6 mg(5 equivalents) of methyltriphenylphosphonium iodide and 16.5 ml(5 equivalents) of sodium bis(trimethylsilyl)amide-toluene solution(1M) were reacted with 786.0 mg of (1R,3R,3aS,4aR,8aS,9aR)-1-methoxy-3-methyl-4-oxo-dodecahydronaphtho[2,3-c]furan to obtain 683.5 mg of (1R,3R,3aR,4aR,8aS,9aR)-1-methoxy-3-methyl-4-methylene-dodecahydronaphtho[2,3-c]furan(yield 88%).
Reaction SMILES: [Cl:1][CH:2]([Cl:24])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([Sn](C)(C)C)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:23])[CH3:22])=[O:4].Br[C:26]1[CH:27]=[CH:28][C:29]([CH2:32][NH:33][S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])=[N:30][CH:31]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1CCCC1=O.C(OC(=O)C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][CH:2]([Cl:24])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:26]3[CH:27]=[CH:28][C:29]([CH2:32][NH:33][S:34]([CH2:37][CH3:38])(=[O:35])=[O:36])=[N:30][CH:31]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:23])[CH3:22])=[O:4]
Reactant: CCS(=O)(=O)NCc1ccc(Br)cn1
Reactant: CC1(C)O[C@H](c2ccc([Sn](C)(C)C)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(Cl)Cl)[C@@H]3CF)cc2)cn1
Temperature: 80 °C
Yield: 43.1 %

Procedure:
2,2-dichloro-1-((4S,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(trimethylstannyl)-phenyl)-oxazolidin-3-yl)ethanone (281 mg, 0.66 mmol) and N-((5-bromopyridin-2-yl)methyl)ethanesulfonamide (155 mg, 0.56 mmol) are dissolved in N-Methyl-2-pyrrolidone (40 mL) and purged with nitrogen gas. Pd2(dba)3 (51 mg, 0.055 mmol) and tri-2-furylphosphine (27 mg, 0.11 mmol) are added; the resulting mixture is heated to 80° C. for 18 hours. The reaction mixture is cooled, diluted with ethylacetate, and washed with water. The organic phase is dried (Na2SO4) and concentrated under vacuum. The crude material is chromatographed (24 g Redi-Sep column) eluting from 100% hexanes to 90:10 ethylacetate:hexanes to afford the title compound (125 mg): m/z (Cl) M+H 518.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[OH:9])[O:5][C:6]=1[CH3:7]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[O:9])[O:5][C:6]=1[CH3:7]
Reactant: COc1ccc(C(O)c2cc(C)c(C)o2)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)c2cc(C)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(6-methoxypyridin-3-yl)-methanol (1.24 g) was dissolved in chloroform (30 ml) to prepare a solution. Manganese dioxide (4.63 g) was added to the solution, and the mixture was stirred at room temperature overnight. Manganese dioxide (4.63 g) was then added to the reaction solution, and the mixture was stirred for 6 hr. The reaction solution was filtered through Celite, and the solvent was removed from the filtrate by distillation under the reduced pressure to give (4,5-dimethylfuran-2-yl)-(6-methoxypyridin-3-yl)-methanone (655 mg, yield 53%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([NH:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: Nc1nc(NC2CCCCC2)nc2c1ncn2Cc1ccccc1
Yield: 46.3 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and cyclohexylamine (764 mg, 7.70 mmol) in 1-butanol (10 ml) were refluxed on heating for 60 hours. The reaction mixture was condensed in vacuo. To the residue was added 5N aqueous sodium hydroxide and the solution was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (115 mg, yield 46%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:10]=3[S:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][O:18][C:15]1[CH:16]=[CH:17][C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[C:12]([CH3:13])[S:11][C:10]=2[CH:14]=1
Reactant: Cc1sc2cc(O)ccc2c1-c1ccc(Br)cc1
Reactant: BrCCCCBr
Product: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1

Procedure:
In analogy to example 27.1, 3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophen-6-ol and 1,4-dibromobutane were converted to yield 6-(4-bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene as colorless oil, MS: 452 (M, 2Br).
Reaction SMILES: Br.Cl[C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.CN(C=O)C.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>O>[CH2:19]([N:21]([CH2:22][CH3:23])[C:3]1[CH:4]=[C:5]([CH3:13])[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1)[CH3:20]
Reactant: CCNCC
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)c1cc(C)c2nnc(N)n2n1
Reaction time: 264 h

Procedure:
6-Chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 250 mg) was dissolved in abs. DMF (2 ml) and admixed with diethylamine (7 ml). Thereafter, the reaction mixture was placed into a heating block at 80° C. with stirring for 11 days. The solvent was then drawn off and the residue was admixed with a little water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC (met. A), and the clean product fractions were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated potassium carbonate solution and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 100 mg of the title compound were obtained.