Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=3)[O:8][C:4]=2[CH:3]=1.CO.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[NH2:15])[O:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3ccc(Br)cc3o2)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a mixture of 6-bromo-2-(3-nitrophenyl)benzoxazole (Compound of Example 266) (5.96 g), nickel bromide(II) (204 mg), methanol (100 ml), tetrahydrofuran (100 ml) was added sodium borohydride (2.12 g) little by little at 0° C. The mixture was stirred at 0° C. for 10 minutes and at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4 and treated with activated carbon. The solvent was distilled off under reduced pressure, and resulting crystals were collected by filtration to obtain 3-(6-bromobenzoxazol-2-yl)aniline (4.46 g, 83%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14]>>[CH2:3]([N:2]([CH3:1])[S:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][Cl:7])(=[O:15])=[O:14])[CH2:4][CH2:5][CH3:6]
Reactant: O=S(=O)(Cl)CCCCCCl
Reactant: CCCCNC
Product: CCCCN(C)S(=O)(=O)CCCCCCl
Yield: 92.8 %

Procedure:
The reaction was carried out in the same manner as in Preparation Example 11 except for using N-methyl-n-butylamine (5.75g, 66 mmol) in place of diethylamine, and 5-chloropentanesulfonyl chloride (6.15g, 30 mmol) in place of 6-chlorohexanesulfonyl chloride in Preparation Example 11, to give N-n-butyl-N-methyl-5-chloropentanesulfonamide (7.12 g) as a pale yellow oil.
Reaction SMILES: C(NC1C=CC(S([N:14]=[N+:15]=[N-])(=O)=O)=CC=1)(=O)C.C(N(CC)CC)C.[C:24]1(=[O:31])[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]1>ClCCl>[N+:14](=[C:25]1[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:24]1=[O:31])=[N-:15]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=C1CCCC(=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=C1C(=O)CCCC1=O
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of 4-acetamidobenzenesulphonylazide (25 g, 104 mmol) and triethylamine (36 ml, 250 mmol) in dichloromethane maintained at a temperature below 30° C. by external cooling is treated dropwise by a solution of cyclohexane-1,3-dione (13 g, 115 mmol) in 200 ml of dichloromethane. The reaction mixture is stirred for 75 minutes at ambient temperature then filtered on Celite. After concentration to approximately 300 ml, the filtrate is washed with water then dried over sodium sulphate. The brown-yellow solid (14 g; 88%) obtained by evaporation of the solvent under reduced pressure is similar to that obtained in Example 55.1, and is used as it is in the following stage.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CN(C)C=O.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29]>O>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Sc1ccccc1Br
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1SCCN1CCOCC1
Temperature: 100 °C

Procedure:
Potassium carbonate (10.95 g) and 2-chloroethylmorpholine hydrochloride (5.9 g) were mixed with dimethylformamide (50 ml) and 2-bromothiophenol was added before the mixture was heated to 100° C. for 3 days. The mixture was allowed to cool before water (500 ml) was added. The product was extracted into diethyl ether (×3). The combined extracts were dried over sodium sulphate and filtered before evaporation. The product was purified by column chromatography eluting with ethyl acetate/hexane mixtures to give a red/brown oil (6.024 g).
Reaction SMILES: [CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH2:17]Br>>[Cl:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH2:17][N:8]1[C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:7]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Fc1ccc(Cl)c(CBr)c1
Reactant: CC1(C)NN(C2CCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCC2)N1Cc1cc(F)ccc1Cl

Procedure:
2-Cyclohexyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-5-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C@@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:30][CH2:29][CH2:28][C@@:19]3([CH2:23][C@@H:22]([O:24]C(=O)C)[CH2:21][CH2:20]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].CO.[OH-].[Na+].Cl>O1CCCC1>[OH:24][C@H:22]1[CH2:21][CH2:20][C@:19]2([CH2:28][CH2:29][CH2:30][C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C@@H:5]([C:6]#[C:7][CH3:8])[CH2:4][C:3]([OH:31])=[O:2])=[CH:14][CH:13]=3)=[CH:18]2)[CH2:23]1
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OCC2=C[C@]3(CCC2)CC[C@H](OC(C)=O)C3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#C[C@@H](CC(=O)O)c1ccc(OCC2=C[C@]3(CCC2)CC[C@H](O)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a solution of (3S)-3-[4-((2S,5R)-2-acetoxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid methyl ester (107 mg) obtained in Step 1 in a mixed solvent of methanol (0.65 mL)-tetrahydrofuran (0.65 mL) was added 2N aqueous sodium hydroxide solution (0.28 mL) under ice-cooling, followed by stirring the mixture at room temperature overnight. To the reaction mixture was added 2N aqueous hydrochloric acid solution (0.28 mL), followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by thin-layer column chromatography on silica gel (acetic acid: methanol:chloroform (volume ratio)=0.1:1:20) to give (3S)-3-[4-((2S,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid (79 mg). Configuration of the structure was determined by NMR spectrum (NOESY, HSQC).
Reaction SMILES: [NH2:1][OH:2].Cl.[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](=O)[CH3:14])=[CH:12][C:7]=2[CH2:6][CH2:5]1.N1C=CC=CC=1>CO>[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](=[N:1][OH:2])[CH3:14])=[CH:12][C:7]=2[CH2:6][CH2:5]1
Reactant: NO
Reactant: CC(=O)c1ccc2c(c1)CCO2
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=NO)c1ccc2c(c1)CCO2
Temperature: 20 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
NH2OH.HCl (7.3 g, 105 mmol) was added to a stirred solution of ketone 191 (14.2 g, 87.7 mmol) and pyridine (9.2 mL, 114 mmol) in MeOH (100 mL) and the mixture stirred at 20° C. for 16 h. The solvent was evaporated and the residue partitioned between brine and EtOAc. The organic fraction was dried and the solvent evaporated to give crude 1-(2,3-dihydro-1-benzofuran-5-yl)ethanone oxime (15.3 g, 99%). HCl gas was bubbled through a solution of the oxime (15.3 g, 86.5 mmol) in Ac2O (16.3 mL, 173 mmol) and HOAc (54 mL, 865 mmol), and the solution stood at 20° C. for 24 h. The precipitate was poured into ice/water, stirred for 2 h, the solid filtered and washed with water and dried. The aqueous fraction was extracted with DCM (2×50 mL), the combined organic extract dried and the solvent evaporated. The slurry was treated with water (20 mL) and evaporated several times to remove Ac2O. The combined solids were purified by chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give acetamide 192 (7.94 g, 52%) as a white solid: mp 92-93° C. [lit. (Blade-Font, A.; de Mas Rocabayera, T. J. Chem. Soc. P1, 1982, 814848) mp 93° C.]; 1H NMR δ 7.47 (br s, 1H, H-4), 7.21 (br s, 1H, NH), 6.99 (dd, J=8.5, 2.1 Hz, 1H, H-6), 6.69 (d, J=8.5 Hz, 1H, H-7), 4.55 (t, J=8.7 Hz, 2H, H-2), 3.18 (br t, J=8.7 Hz, 2H, H-3), 2.13 (s, 3H, CH3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](S(C)=O)[N:3]=1.[CH3:19][C:20]1[C:21]([CH2:26][OH:27])=[N:22][CH:23]=[CH:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([O:27][CH2:26][C:21]2[C:20]([CH3:19])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: Cc1cccnc1CO
Reactant: CS(=O)c1nc(N)nc(-c2cc(Br)co2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccnc1COc1nc(N)nc(-c2cc(Br)co2)c1C#N

Procedure:
From 2-amino-4-(4-bromo-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 3-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 388 (M{81Br}+H+, 100), 386 (M{79Br}+H+, 80).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:18]2[N:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)=[CH:20][CH:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[NH2:29][C:30]1[CH:35]=[C:34]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[CH:33]=[CH:32][C:31]=1[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:18]2[N:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([NH:29][C:30]3[CH:35]=[C:34]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)[CH:33]=[CH:32][C:31]=3[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:28])=[CH:20][CH:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: COc1ccc(-c2ccc(/C=C/C(=O)O)cn2)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccc(/C=C/C(=O)Nc3cc(-c4cccs4)ccc3NC(=O)OC(C)(C)C)cn2)cc1OC
Yield: 100.4 %

Procedure:
A solution of acid 40 (0.10 g, 0.25 mmol), amine 4 (72.7 mg, 0.25 mmol) and BOP reagent (0.133 g, 3.0 mmol) in pyridine (2 mL) was stirred 18 h at room temperature. The reaction mixture was concentrated and the residue was purified by flash chromatography (eluent: 1:1 hexane:AcOEt) to give title compound 41 (0.14 g, 61% yield).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.F[C:22]1[C:27]([CH:28]2[CH2:32][N:31]([CH3:33])[C:30](=[O:34])[CH2:29]2)=[CH:26][CH:25]=[CH:24][N:23]=1>CN1C(=O)CCC1>[CH3:33][N:31]1[CH2:32][CH:28]([C:27]2[C:22]([O:20][C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=4)=[CH:15][CH:16]=3)=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:29][C:30]1=[O:34]
Reactant: CN1CC(c2cccnc2F)CC1=O
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN1CC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1=O
Temperature: 100 °C

Procedure:
To a mixture of cesium carbonate (0.559 g, 1.72 mmol), 4-(pyridin-2-ylamino)phenol (0.320 g, 1.72 mmol), and 4-(2-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one (0.110 g, 0.566 mmol) was added NMP (2 mL). The reaction mixture was degassed and heated to 100° C. for 2 h. The reaction mixture was diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (4×) and the combined organic extracts were washed with 1 M NaOH (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (30% to 100% EtOAc (10% MeOH) in hexanes) gave 1-methyl-4-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)pyrrolidin-2-one as a white solid and a 1:1 mixture of enantiomers. MS (ESI, pos. ion) m/z: 361.1 (M+1). IC50 (uM) 0.01406.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]=1[CH3:12])(=[O:5])[CH3:4].I[CH2:14][CH3:15]>CS(C)=O>[C:3]([C:6]1[S:10][C:9](=[O:11])[N:8]([CH2:14][CH3:15])[C:7]=1[CH3:12])(=[O:5])[CH3:4]
Reactant: CCI
Reactant: CC(=O)c1sc(=O)[nH]c1C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1c(C)c(C(C)=O)sc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
KOH (1.476 g, 26.31 mmol) was added to a solution of 5-acetyl-4-methyl-3H-thiazol-2-one (4.134 g, 26.31 mmol) in DMSO (10 mL), and stirred at room temperature for 30 min. Iodoethane (2.525 mL, 31.57 mmol) was added and the resulting mixture stirred for 72 h. The reaction mixture was extracted into CH2Cl2 (5×30 mL) from H2O (30 mL) and the combined organic layers were dried over MgSO4, before passing through a short SiO2 gel column. Pooling of the desired fractions yielded the title compound (3.104 g, 64%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([NH:18][CH3:19])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([N:18]([CH3:19])[C:2]2[N:11]=[C:10]([N:18]([C:17]3[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=3)[CH3:19])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccc(Cl)cc1
Product: CN(c1ccc(Cl)cc1)c1nc(N(C)c2ccc(Cl)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (60 mg, 0.3.02 mmol) and 4-chloro-N-methylaniline (72 mg, 0.513 mmol) by a procedure similar to Example 1b and was isolated as white powder (50 mg, 83%). 1H NMR (CDCl3): 8.93 (d, J=8.4 Hz, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.47-7.44 (m, 4H), 7.32-7.27 (m, 2H), 7.18-7.14 (m, 2H), 6.95 (t, J=7.5 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 4.02 (s, 3H), 3.25 (s, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([C:16]2[O:17][C:18]3[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:14][CH:13]=[CH:12][N:11]=1>O1CCCC1>[NH2:9][C:10]1[C:15]([C:16]2[O:17][C:18]3[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:14][C:13]([Br:1])=[CH:12][N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cccc2nc(-c3cccnc3N)oc12
Solvent: C1CCOC1
Product: N#Cc1cccc2nc(-c3cc(Br)cnc3N)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
A mixture of 1-bromopyrrolidine-2,5-dione (44.5 mg) and 2-(2-amino-3-pyridyl)-1,3-benzoxazole-7-carbonitrile (59 mg) in tetrahydrofuran (5 ml) was stirred at room temperature for 1 hour. The reaction was incomplete and further 1-bromopyrrolidine-2,5-dione (44.5 mg) was added at room temperature and the reaction mixture was stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration, washed with acetonitrile (2×2 ml) and dried to a constant weight to afford 2-(2-amino-5-bromo-3-pyridyl)-1,3-benzoxazole-7-carbonitrile (70.0 mg) as a pale brown solid. NMR Spectrum: (DMSOd6) 7.61 (dd, 1H), 7.85 (bs, 2H), 7.96 (dd, 1H), 8.20 (dd, 1H), 8.37 (d, 1H), 8.39 (d, 1H); Mass spectrum: M(+CH3CN)+H+ 356-358.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([N:17]1[C:21]2([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[NH:20][CH:19]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18]1=[O:34])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:1]1([NH:7][C:8]([N:24]2[CH2:25][CH2:26][C:21]3([N:17]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:18](=[O:34])[CH:19]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:20]3)[CH2:22][CH2:23]2)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Reactant: S=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1C(Cc2ccccc2)NC2(CCN(C(=S)Nc3ccccc3)CC2)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
Phenyl isothiocyanate (203 mg, 1.50 mmol) was added to a solution of 1,3-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one (505 mg, 1.50 mmol) in toluene (14.3 ml) with stirring under a blanket of nitrogen at RT and the reaction mixture was stirred at 50° C. for 8 h. After removal of the solvent, the desired product 1,3-dibenzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-thiocarboxylic acid phenylamide was obtained by means of preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.O=S(Cl)Cl.[CH3:20][O:21][C:22]([C:24]1[NH:25][CH:26]=[CH:27][CH:28]=1)=[O:23]>ClC(Cl)C>[CH3:20][O:21][C:22]([C:24]1[NH:25][CH:26]=[C:27]([C:13]([C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:15])[CH:28]=1)=[O:23]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: COC(=O)c1ccc[nH]1
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(C(=O)c2c(-c3ccccc3)noc2C)c[nH]1
Temperature: 25 °C

Procedure:
A mixture of 406 mg (2 mmol) 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (commercially available) and 4 mL SOCl2 was heated to reflux for 3 h. After evaporation of all volatiles the residue was added to a mixture of 206 mg (2 mmol) 1H-pyrrole-2-carboxylic acid methyl ester (commercially available) and 440 mg (3 mmol) AMCl3 in 25 mL dichloroethane and heated to reflux for 3 h. After cooling to room temperature the precipitate was collected and washed with dichloromethane. The residue was purified on silica eluting with a gradient of ethyl acetate and heptane affording 210 mg (37%) of the title compound as white foam. (m/e): 311.0 (MH+; 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][OH:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[Cl-:16].[S:17]([CH2:36][CH2:37][NH:38][C:39](=[O:52])[CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N+:43]([CH3:50])=[C:42]1[CH3:51])[S:18][CH2:19][CH2:20][NH:21][C:22](=[O:35])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N+:26]([CH3:33])=[C:25]1[CH3:34].[Cl-]>C(O)C.N1CCCCC1>[Cl-:16].[S:17]([CH2:36][CH2:37][NH:38][C:39](=[O:52])[CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N+:43]([CH3:50])=[C:42]1[CH:51]=[CH:9][C:8]1[CH:7]=[CH:6][C:5]([N:4]([CH2:3][CH2:2][OH:1])[CH2:13][CH2:14][OH:15])=[CH:12][CH:11]=1)[S:18][CH2:19][CH2:20][NH:21][C:22](=[O:35])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N+:26]([CH3:33])=[C:25]1[CH:34]=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:13][CH2:14][OH:15])[CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=1.[Cl-:16]
Reactant: Cc1n(CC(=O)NCCSSCCNC(=O)Cn2c(C)[n+](C)c3ccccc32)c2ccccc2[n+]1C
Reactant: O=Cc1ccc(N(CCO)CCO)cc1
Agent: [Cl-]
Solvent: C1CCNCC1
Solvent: CCO
Product: C[n+]1c(C=Cc2ccc(N(CCO)CCO)cc2)n(CC(=O)NCCSSCCNC(=O)Cn2c(C=Cc3ccc(N(CCO)CCO)cc3)[n+](C)c3ccccc32)c2ccccc21
Yield: 163.3 %

Procedure:
To a stirring solution of 4-[bis(2-hydroxyethyl)-amino]benzaldehyde (1.7 g, 8.1 mmol) and 1,1′-{disulfanediylbis[ethane-2,1-diylimino(2-oxoethane-2,1-diyl)]}bis(2,3-dimethyl-1H-benzimidazol-3-ium) chloride (1.2 g, 2 mmol) in 35 ml of ethanol, 0.5 ml of piperidine was added as a catalyst. The reaction mixture was heated to reflux for 7 h. After cooling, the resulting orange solids were collected by filtration and then washed with dichloromethane and methanol. The drying afforded 1.6 g of a orange solid. Analyses were in accordance with the expected structure.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)#[CH:15].C1COCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[CH3:11][Si:10]([C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[CH:3][CH:4]=1)([CH3:13])[CH3:12]
Reactant: C#Cc1ccc(N)cc1
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(C#Cc2ccc(N)cc2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
Following a general coupling procedure, (4-iodo-phenylethynyl)-trimethyl-silane (Maya et al., Chem. Mater., 2004, 16:2987-2997) (0.75 g, 2.50 mmol) was coupled to 4-ethynyl-phenylamine (Fan et al., J. Am. Chem. Soc., 2002, 124:5550) (0.35 g, 3.00 mmol) using PdCl2(PPh3)2 (0.09 g, 0.13 mmol), CuI (0.05 g, 0.25 mmol), TEA (3 mL), and THF (10 mL). The reaction was stirred at 40° C. overnight. The mixture was poured into H2O and extracted (3×) with CH2Cl2, dried using anhydrous MgSO4, and concentrated in vacuo. Column chromatography, silica gel (CH2Cl2) afforded 4-(4-trimethylsilanylethynyl-phenylethynyl)-phenylamine as a yellow solid (0.64 g). Following the general deprotection of TMS-protected alkynes, 4-(4-trimethylsilanylethynyl-phenylethynyl)-phenylamine (0.64 g, 2.21 mmol) was dissolved in a mixture of CH2Cl2 (15 mL), MeOH (15 mL), and K2CO3 (1.53 g, 11.05 mmol). The product 6, was afforded without additional purification as an orange solid (0.47 g, 87%, 2 steps). 1H NMR (400 MHz, (CD3)2CO) δ 7.45 (m, 4H), 7.25 (d, J=6.7 Hz, 2H), 6.68 (d, J=6.7 Hz, 2H), 5.09 (s, 2H), 3.77 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4](Cl)[N:3]=1.[OH-].[NH4+:12]>>[Cl:8][C:6]1[N:7]=[C:2]([CH3:1])[N:3]=[C:4]([NH2:12])[C:5]=1[NH2:9]
Reactant: [NH4+]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Agent: [OH-]
Product: Cc1nc(N)c(N)c(Cl)n1
Temperature: 120 °C
Reaction time: 0.42 h

Procedure:
2-Methyl-4,6-dichloro-5-aminopyrimidine (Aldrich, 1.05 g) and ammonium hydroxide (3.0 mL, J. T. Baker, Phillipsburg, N.J., 28.0%-30.0%) were placed in a microwave vial. The vial was sealed and heated in a CEM microwave reactor (CEM Corporation, Matthews, N.C.) at 120° C. and 40 Watts for 25 minutes. The reaction was cooled to room temperature. This procedure was repeated a total of nine times using the following amounts of 2-methyl-4,6-dichloro-5-aminopyrimidine under the same reaction conditions:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>>[Cl:15][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: O=S(Cl)Cl
Product: Fc1ccc2c(Cl)ncnc2c1

Procedure:
7-Fluoro-3H-quinazolin-4-one (8.2 g, 50 mmol) is heated at reflux in thionyl chloride (80 mL). Concentration affords the expected 4-Chloro-7-fluoro-quinazoline (9.1 g, ˜quant).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=O)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:27]([NH2:29])[CH3:28].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:24]=[N:29]/[O:27][CH3:28])[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(C=O)c2s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(/C=N/OC)c2s1
Temperature: 105 °C
Yield: 70.4 %

Procedure:
1-(5-(Benzyloxy)-7-formylbenzo[d]thiazol-2-yl)-3-ethylurea (425 mg, 1.20 mmol), methoxylamine hydrochloride (105.2 mg, 1.26 mmol) and N,N′-diisopropylethylamine (0.77 g, 1.05 ml) were stirred in DMF degassed with N2. The reaction was purged with N2, sealed and heated to 105° C. for 18 h. LCMS after indicated complete consumption of starting material. The solvents were removed under reduced pressure and the resulting residue absorbed onto silica and purified by flash column chromatography eluting with 0 to 100% EtOAc in petroleum-ether to afford the product as a white solid 325 mg (70%) which was used directly in the next step.