Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:24]2)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[S:24])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Nc1ccc(N2CCCCC2=O)cc1
Solvent: Cc1ccccc1
Product: Nc1ccc(N2CCCCC2=S)cc1
Reaction time: 0.75 h

Procedure:
2.1 15 g (78.8 mmol) of 1-(4-aminophenyl)piperidin-2-one are heated to the boil together with 16.0 g (39.5 mmol) of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) in 100 ml of anhydrous toluene. After 45 minutes, the solvent is evaporated, and the residue is taken up in dichloromethane and 2 N HCl. The aqueous phase is extracted three times with dichloromethane and adjusted to a pH of 12 using conc. NaOH. Extraction with dichloromethane, drying over sodium sulfate and evaporation of the solvent give 1-(4-aminophenyl)piperidine-2-thione as a colourless solid, ESI 207.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH:16][C:17]([NH2:19])=[S:18].[H-].[Na+].[ClH:22]>CS(C)=O.C(OCC)(=O)C.O1CCOCC1>[ClH:22].[ClH:22].[NH2:19][C:17]1[S:18][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=3)=[CH:4][C:3]=2[N:16]=1
Reactant: COc1ccnc(-c2ccc(F)c(NC(N)=S)c2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: COc1ccnc(-c2ccc3sc(N)nc3c2)c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a suspension of N-(2-fluoro-5-(4-methoxypyridin-2-yl)phenyl)-thiourea (0.104 g) in dimethyl sulfoxide (5 ml) was added a sodium hydride (60% dispersion in mineral oil ,15.4 mg), and the mixture was stirred at 100° C. for 5 hours. The mixture was diluted with ethyl acetate and washed with water three times and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 10 g, 5% methanol in dichloromethane). The compound obtained was dissolved in ethyl acetate, and a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml) was added. The precipitate was collected by filtration and dried under reduced pressure to give 2-amino-5-(4-methoxypyridin-2-yl)benzothiazole dihydrochloride (46 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.C([Mg]Br)(C)C.C1(C)C=CC(S([C:26]#[N:27])(=O)=O)=CC=1.O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:26]#[N:27])=[CH:9][N:10]=2)[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: Brc1ccc2ncc(I)n2c1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cnc2ccc(Br)cn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
Method 2) 80 g of 6-bromo-3-iodoimidazo[1,2-a]pyridine (compound in Production Example 49) was dissolved in 500 mL tetrahydrofuran, and 273 mL of 1.0 M isopropyl magnesium bromide in tetrahydrofuran was slowly added dropwise thereto at 0° C. and stirred for 30 minutes, and 380 mL of 68 g 4-toluenesulfonyl cyanide in tetrahydrofuran was added dropwise slowly over 1 hour, and the mixture was stirred for additional 1.5 hours. The reaction solution was poured into iced water, diluted with ethyl acetate and filtered through Celite. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate, and the collected organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate and filtered through NH silica gel. Solid obtained by removing the solvent was triturated with diethyl ether, collected by filtration and washed with hexane to give 39.4 g of the title compound (brown solid).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]([NH2:30])=[O:29])[CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].N>CO.C(Cl)Cl.CN(C=O)C>[CH3:3][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH:25]([C:28]([NH2:30])=[O:29])[CH2:26][CH2:27]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: NC(=O)C1CCN(CCCCl)CC1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CN(C)CC1(c2ccc(OCCCN3CCC(C(N)=O)CC3)cc2)CCOCC1
Yield: 20.4 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 1-(3-chloro-propyl)-piperidine-4-carboxylic acid amide (436 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM:MeOH:NH3) to give the title compound as a white solid (175 mg, 20%). 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.86 (d, 2H), 5.44 (br s, 1H), 5.25 (br s, 1H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.03-2.93 (m, 2H), 2.51 (t, 2H), 2.40 (s, 2H), 2.22-1.66 (m, 13H), 1.97 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][CH2:16][C:13]32[CH2:15][CH2:14]3)=O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>O1CCOCC1>[CH2:15]1[C:13]2([CH2:16][CH2:17][CH2:18][CH2:19][N:12]2[C:10]2[N:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]3=[N:8][N:9]=2)[CH2:14]1
Reactant: O=C(NNc1ccc(F)cn1)N1CCCCC12CC2
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Fc1ccc2nnc(N3CCCCC34CC4)n2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of Intermediate 148b (587 mg, 2.22 mmol), triphenyl phosphine (1.17 g, 4.44 mmol) and triethylamine (1.24 mL, 8.88 mmol) in dioxane (25 mL) at RT was added hexachloroethane (1.05 g, 4.44 mmol). The resulting opaque solution was stirred at RT for 30 min, and at reflux for 16 h. The cooled solution was filtered, and the filter-cake washed with THF (5 mL). The combined organics were applied to an SCX-2 cartridge, which was washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo left a brown oil. Flash chromatography (silica 40 g, 1.5-4.5% MeOH in DCM) gave the title compound as a brown gum (82%). LCMS (Method 3): Rt 2.92 min, m/z 247 [MH+].
Reaction SMILES: [O:1]1[CH2:5][CH:4]([OH:6])[CH:3]([OH:7])[CH2:2]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][CH:3]1[CH:4]([O:6][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:5][O:1][CH2:2]1)(=[O:18])=[O:17]
Reactant: OC1COCC1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1COCC1OS(C)(=O)=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Into a round-bottom flask, was placed a solution of tetrahydrofuran-3,4-diol (500 mg, 4.80 mmol, 1.00 equiv) and triethylamine (1.45 g, 14.3 mmol, 3.00 equiv) in dichloromethane (8 mL). The mixture was cooled to 0-5° C. and a solution of methanesulfonyl chloride (1.40 g, 12.2 mmol, 2.50 equiv) in dichloromethane (2 mL) was added drop-wise. The solution was stirred at room temperature for 2 h, and then diluted with dichloromethane (100 mL). The solution was washed with aqueous NH4Cl (2×30 mL) then brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuum to obtain the title compound as a brown solid (1.00 g, 72%).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][N:4]([CH3:25])[C:5]1[N:10]=[C:9]([S:11][CH3:12])[N:8]=[C:7]([NH:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([NH:19][CH3:20])=[O:18])[CH:6]=1.C(=O)(O)[O-].[Na+].[Br:33]Br.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.C(OCC)(=O)C>[Br:33][C:6]1[C:7]([NH:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:17]([NH:19][CH3:20])=[O:18])=[N:8][C:9]([S:11][CH3:12])=[N:10][C:5]=1[N:4]([CH2:3][C:2]([CH3:27])([CH3:26])[CH3:1])[CH3:25]
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(N(C)CC(C)(C)C)nc(SC)n2)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C)c(Nc2nc(SC)nc(N(C)CC(C)(C)C)c2Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-{6-[(2,2-dimethyl-propyl)-methyl-amino]-2-methylsulfanyl-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (0.10 g) in methylene chloride (2 mL), was added sat. aq. sodium bicarbonate (0.05 mL) and bromine (0.013 mL). The resulting mixture was stirred at room temperature for 30 minutes, and ethyl acetate (30 mL) and magnesium sulfate (1 g) was added. After filtration and concentration, the residue was purified by silica gel column chromatography to afford the product (61.9 mg). MS (m/z): 466 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:16]1[N:25]=[CH:24][C:23]2[CH2:22][CH2:21][C:20]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:19]=3[C:18]=2[N:17]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]2[CH2:11][CH2:12][N:13]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:14][CH2:15]2)=[CH:4][C:3]=1[C:16]1[N:25]=[CH:24][C:23]2[CH2:22][CH2:21][C:20]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:19]=3[C:18]=2[N:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCNCC4)ccc3Cl)ncc1CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCN(S(C)(=O)=O)CC4)ccc3Cl)ncc1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 50 mg (0.11 mmol) N-[8-(2-chloro-5-piperidin-4-ylethynyl-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide, 65 μL triethylamine and 15 μL methanesulphonic acid chloride in 1 mL dichloromethane is stirred for three hours at ambient temperature. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution and the organic phase is evaporated down. The residue remaining is purified by RP-HPLC. Yield: 23 mg yellow solid (MH+=542; RT=3.07; Method A)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.[OH-].[Na+].[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[CH2:15]>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:15][CH:14]([CH3:16])[C:13]([OH:18])=[O:17])=[CH:5][CH:4]=1
Reactant: C=C(C)C(=O)O
Reactant: COc1ccc(CS)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CSCC(C)C(=O)O)cc1
Temperature: 82 °C

Procedure:
To a 25 mL three-necked reaction flask, 4.2 mL (0.03 mole) of p-methoxy-α-toluenethiol, 0.58 g (1.5×10-3 mole) of benzyltriphenyl phosphonium chloride and 15 mL (0.03 mole) of 2N NaOH solution were added. The resulting solution was heated to 82° C. with agitation for one hour. Thereafter, 2.56 mL (0.03 mole) of methacrylic acid were added dropwise to the preheated mixture over a 30 minute period, and the reaction mixture was heated to 125° C. and maintained under reflux for 18 hours.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.[CH3:14][C:15]([OH:32])([CH3:31])[CH2:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O>[CH3:14][C:15]([OH:32])([CH3:31])[CH2:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:3]=[CH:4][C:5]3[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=3[N:13]=2)[CH:19]=[N:18]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CSc1ncc2ccc(Cl)nc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CSc1ncc2ccc(-c3cnn(CC(C)(C)O)c3)nc2n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
A suspension of 7-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (Preparation 57, 50.6 mg, 0.239 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (Preparation 124, 63.6 mg, 0.239 mmol), Pd(dppf)C2•DCM (20.2 mg, 0.024 mmol), Na2CO3 (2M, 0.24 mL, 0.48 mmol) in DME (4 mL) was stirred at 140° C. under microwave irradiation for 60 minutes. The reaction mixture was diluted with EtOAc and dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with 25-80% EtOAc/cyclohexane to give the title compound as orange semi-solid (21 mg, 28%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH:18]([CH3:20])[CH3:19])[C:9]=2[S:8][CH:7]=1)=[O:5])[CH3:2].[C:21]1([N:27]2[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN1CCCN(C)C1=O.[Li+].CC([N-]C(C)C)C>C1COCC1.O.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH:18]([CH3:19])[CH3:20])[C:9]=2[S:8][C:7]=1[CH:32]([OH:33])[C:30]1[CH:29]=[N:28][N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:31]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc2c1c(=O)n(C)c(=O)n2C(C)C
Reactant: O=Cc1cnn(-c2ccccc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C(O)c2cnn(-c3ccccc3)c2)sc2c1c(=O)n(C)c(=O)n2C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (2.0 g), 1-phenyl-1H-pyrazole-4-carboxaldehyde (1.39 g) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.63 ml) in anhydrous THF (35 ml) was added a 2.0M solution of LDA (3.72 ml) at −78° C. under nitrogen and the resulting mixture stirred for 3 hr. Glacial acetic acid (1.5 ml) was added, the mixture allowed to warm to room temperature, diluted with water and extracted with ethyl acetate, the organic extracts washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with i-hexane/ethyl acetate (4:1) followed by i-hexane/ethyl acetate (1:1) to give the sub-title compound (2.32 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([N-]C(C)C)(C)C.[Li+].[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br>O1CCCC1.CCCCCCC>[CH3:21][C:22]1[CH:23]=[C:24]([CH2:25][CH2:1][C:2]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc(CBr)c1
Reactant: Cc1cc(C)c(C(=O)O)cc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1cccc(CCc2cc(C)c(C)cc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the product of step (i)(36.7 g) in tetrahydrofuran (300 ml) was added dropwise to a stirred solution of lithium diisopropylamide (235 ml of a 2.0M solution in heptane) at 10-20° C. The mixture was allowed to warm to room temperature and stirred for 30 minutes then cooled to -20° C. A solution of 3-methylbenzylbromide (36.2 ml) in tetrahydrofuran (100 ml) was added dropwise over 20 minutes. The mixture was allowed to warm to room temperature and stirred for 45 minutes before quenching with 2M HCl and adding ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and concentrated under reduced pressure to 200 ml. Isohexane (200 ml) was added and the crystallised unreacted starting material filtered off. The filtrate was evaporated and the residue partitioned between 2M sodium hydroxide and isohexane. The aqueous phase was acidified to pH 1 with 2M HCl and extracted with dichloromethane. The extract was dried (MgSO4) and evaporated under reduced pressure. Used directly in the next step.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][NH:19][NH2:20])=[CH:16][CH:15]=1>>[NH2:10][C:6]1[NH:20][N:19]([CH2:18][C:17]2[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[C:4](=[O:3])[CH:5]=1
Reactant: COc1ccc(CNN)cc1
Reactant: CCOC(=O)C=C(N)OCC
Product: COc1ccc(Cn2[nH]c(N)cc2=O)cc1

Procedure:
From 17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 15.2 g of 4-methoxybenzylhydrazine, analogously to the procedure described in Example 45, 9.7 g of the compound identified above, as colorless crystals of melting point 161°, corresponding to 44% of theory, are obtained.
Reaction SMILES: O=[C:2]([CH2:16][CH2:17][C:18]([O-:20])=[O:19])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].S(Cl)([Cl:23])=O>ClCCCl>[Cl:23][C:2]1([C:3]([O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[O:4])[CH2:16][CH2:17][C:18](=[O:19])[O:20]1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=C1CCC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)O1

Procedure:
In 16 ml of 1,2-dichloroethane was dissolved 0.40 g of the Compound (1) obtained in Example 1. To the solution was added 0.88 ml of thionyl chloride. The mixture was heated for 10 hours under reflux. The solvent was evaporated off, and the residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (3:1) to give 0.36 g of the subject Compound (15) as colorless oil.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([OH:19])=[O:18].[OH-].[K+:21]>CO>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([O-:19])=[O:18].[K+:21]
Reactant: O=C(O)Cc1ccc2c(c1)CCc1ccccc1S2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])Cc1ccc2c(c1)CCc1ccccc1S2

Procedure:
A solution of 350 mg. of 10,11-dihydrodibenzo[b.f]-thiepin-2-acetic acid in five ml. of methanol is treated with 1.1 molar equivalents of 1N methanolic potassium hydroxide. The solvent is evaporated under reduced pressure and the residue taken up in 2 ml. of methanol, followed by precipitation with ether, to yield potassium 10,11-dihydrodibenzo[b.f]thiepin-2-acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:15](=O)[CH3:16])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([CH3:16])[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=2)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26])[CH3:10]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: Nc1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(Br)c2)c1-c1ccccc1

Procedure:
m-Bromoaniline (5 mmol, 0.9 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid were combined in ethanol, then heated under reflux. The resulting oil was resuspended in methylene chloride, then washed with water, 5% sodium bicarbonate and brine. The organic layer was dried over MgSO4, then the solids were separated and the solvents evaporated under vacuum. The crude product was recrystallized from ethanol to yield the named product (m.p. 117.5° C.-119.2° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:9][CH:8]=[CH:7][CH:6]=2.[C:23](OC)(OC)(OC)[CH2:24][CH2:25][CH2:26][CH3:27].C1(C)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:24]([C:23]1[N:12]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cccnc12
Reactant: CCCCC(OC)(OC)OC
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3cccnc3c2n1CCNC(=O)OC(C)(C)C
Yield: 47.4 %

Procedure:
1,1-Dimethylethyl N-{2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate 0.6 g, 2 mmol), trimethyl orthovalerate (0.35 g, 2.1 mmol), and toluene (25 mL) were combined and heated at reflux for 2 hours. Additional trimethyl orthovalerate (1 eq.) was added and the reaction mixture was heated at reflux overnight. Xylene was added and the toluene was distilled off. The reaction was heated at reflux for an additional 8 hours. The bulk of the xylene was distilled off leaving a volume of about 5 mL. The reaction mixture was allowed to cool. The resulting precipitate was isolated by filtration, washed with heptane and dried to provide 0.35 g of 1,1-dimethylethyl N-[2-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]carbamate as an ivory powder, m.p. 198-199° C. Analysis: Calculated for C20H27N5O2: %C, 65.01; %H, 7.36; %N, 18.95. Found: %C, 64.75; %N, 7.57; %N, 19.09.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[CH2:14]1[CH2:20][CH:19](Cl)[C:17](=[O:18])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][CH:16]1[CH2:15][CH2:14][CH2:20][CH2:19][C:17]1=[O:18]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: O=C1CCCCC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OC2CCCCC2=O)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 3-hydroxy-4-methoxybenzoate (2.47 g), α-chlorocyclohexanone (2.33 ml), potassium carbonate (3.76 g), and DMF (25 ml) was stirred at 90° C. for 2 hours. α-Chlorocyclohexanone (2.0 ml) was further added to the mixture, followed by stirring at 90° C. for one hour. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ether. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and then with a saturated saline, and dried over sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (silica gel, hexane:ethyl acetate=2:1) to give Compound IIm-a (3.16 g, 83%) as an oily substance.
Reaction SMILES: Cl.[OH:2][NH2:3].C(=O)([O-])[O-].[Na+].[Na+].[O:10]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:13][CH2:12][C@@H:11]1[CH:20]=O>O.C1COCC1>[O:10]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:13][CH2:12][C@@H:11]1[CH:20]=[N:3][OH:2]
Reactant: O=C[C@H]1COC2(CCCCC2)O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: ON=C[C@H]1COC2(CCCCC2)O1
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
In 1000 mL of DI water was added hydroxyl amine hydrochloride (51.0 g, 734 mmol) and the reaction was stirred for 5 minutes. Sodium carbonate (38.1 g, 360 mmol) was added in 3 large portions and the reaction was stirred for 15 minutes. THF (700 mL) was added to the reaction and (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734 mmol) was added in 1 portion in 800 mL of THF. The reaction was stirred for 4 hours and poured into a 4 L separatory funnel and the layers separated. The aqueous layer was extracted twice with MTBE (3000 mL total). The combined organic layers were washed with water (700 mL) and brine (300 mL), dried over MgSO4 and concentrated in vacuo to afford (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%) as a clear viscous oil.