Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](SC)=[N:7][C:6]=2[CH:17]=1.O.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)=[N:7][C:6]=2[CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CSC1=Nc2cc(O)ccc2Nc2cscc21
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2c(c1)N=C(N1CCN(c3ccccc3)CC1)c1cscc1N2

Procedure:
A solution of 7-hydroxy-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excess N-phenylpiperazine and glacial acetic acid is heated at 140°-160°C. for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([CH:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[N:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[NH4+].[OH-].CO>CCO.CCOC(C)=O>[N:26]1([C:2]2[N:10]=[C:9]3[C:5]([NH:6][CH:7]=[N:8]3)=[C:4]([CH:11]3[CH2:16][NH:15][CH2:14][CH2:13][N:12]3[C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[N:3]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: C[Si](C)(C)CCOC(=O)N1CCNCC1c1nc(Cl)nc2nc[nH]c12
Reactant: C1CNCCN1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOC(=O)N1CCNCC1c1nc(N2CCNCC2)nc2nc[nH]c12
Temperature: 145 °C
Yield: 95.8 %

Procedure:
2-Chloro-6-[N-(trimethylsilylethoxycarbonyl)piperazinyl] purine (17.10 g, 44.66 mmol) and piperazine (23.08 g, 268 mmol) were suspended in EtOH (200 mL) in a bomb reactor. The bomb reactor was heated to 145° C. for 24 hours. The reaction progress was monitored by thin layer chromatography NH4OH:MeOH:EtOAc (5/5/90, v/v/v) which showed disappearance of starting material and formation of a new product spot after 24 hours. The EtOH was evaporated and water (700 mL) was added to the residue. The resulting precipitate was filtered and dried in a vacuum oven at 110° C. for 24 hours to give 18.5 g (96%) of the title compound. 1H NMR (CDCl3): δ 0.02 (s, 9H), 1.01 (t, 2H), 2.99 (bs, 4H), 3.61 (bs, 4H), 3.74 (bs, 6H), 4.23 (bm, 6H), 7.59 (s, 1H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:16][C:10]=2[NH:9][C:8]1=[O:23].Br[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1>>[OH:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:16][C:10]=2[N:9]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][O:33]2)[C:8]1=[O:23]
Reactant: BrCC1CCCO1
Reactant: COc1ccc(COn2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)c(OC)c1
Product: O=c1c2sc(-c3ccccc3)cc2n(CC2CCCO2)c(=O)n1O

Procedure:
3-(2,4-dimethoxy-benzyloxy)-6-phenyl-1H-thieno[3,2-d]pyrimidine-2,4-dione (from previous example) was alkylated with 2-bromomethyl-tetrahydro-furan via general procedure B1. This crude intermediate was deprotected via general procedure D1 to give the title compound which was purified by mass-triggered preparative HPLC. 1H NMR (DMSO-d6) δ 7.80 (d, 2H, J=8.1 Hz), 7.78 (s, 1H), 7.52-7.44 (m, 3H), 4.23-4.06 (m, 3H), 3.74 (dd, 1H, J=7.8, 13.8 Hz), 3.59 (dd, 1H, J=7.5, 13.8 Hz), 2.05-1.58 (m, 4H); Electrospray MS: 345 (M+H); retention time: 2.43 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=4[F:37])=[O:28])=[CH:22][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[NH:10][CH:9]=1)=[O:7].C(N(CC)C(C)C)(C)C.Br[CH2:48][C:49]([O:51][CH3:52])=[O:50].O>CN(C=O)C>[F:37][C:31]1[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=1[NH:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:11]3[NH:10][CH:9]=[C:8]([C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:48][C:49]([O:51][CH3:52])=[O:50])=[O:7])[CH:12]=3)[CH:18]=2)=[CH:25][CH:24]=1)=[O:28]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN)c[nH]4)c3)cc2)c1
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CNCCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of N-(3-aminopropyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (260 mg, 0.52 mmol) and N,N-diisopropylethylamine (134 mg, 1.04 mmol) in 10 ml of anhydrous DMF was added methyl bromoacetate (80 mg, 0.52 mmol). The mixture was stirred at room temperature for 40 minutes and poured into 100 ml of water with vigorous stirring. The precipitates were filtered and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with a gradient of 3˜10% MeOH/CHCl3 to afford methyl [(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)amino]acetate as white solid. Yield: 100 mg, 34%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]2=O.[H-].[Na+].[CH3:23]I.CN(C)[CH:27]=[O:28]>>[CH3:6][C:5]1([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:4][C:3]2[C:7](=[C:8]([O:12][CH3:23])[C:9]([CH3:11])=[CH:10][C:2]=2[CH3:1])[C:27]1=[O:28]
Reactant: CN(C)C=O
Reactant: Cc1cc(C)c2c(c1O)C(=O)C(Cc1ccccc1)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COc1c(C)cc(C)c2c1C(=O)C(C)(Cc1ccccc1)C2
Reaction time: 0.67 h

Procedure:
28.3 Grams of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-benzyl-1H-inden-1-one was dissolved in 350 ml of dimethylformamide, then 5.2 g of 60%-sodium hydride was added thereto at 55°-60° C. and the mixture was stirred for 40 minutes. Next 8 ml of methyl iodide was added thereto, and the whole mixture was heated to the same temperature for 1 hour. Followed by 5.2 g of 60%-sodium hydride was added and stirred for 40 minutes at the same temperature. Next, 8 ml of methyl iodide was further added and heated for 10 minutes at the same temperature. Furthermore, 5.2 g of 60%-sodium hydride was added to the reaction mixture and stirred for 55 minutes at the same temperature, and 8 ml of methyl iodide was added to the reaction mixture and heated to the same temperature for 3 hours and 20 minutes. After the reaction was completed, dimethylformamide was removed under a reduced pressure and the residue obtained was extracted with ethyl acetate. The extract was washed with water and with an aqueous solution saturated with sodium chloride in this order, then the solvent was removed under a reduced pressure to obtain the residue. The residue was purified by means of a silica gel column chromtagraphy (eluent: n-hexane: ethyl acetate) to obtain 23.0 g of 2,3-dihydro-2,4,6-trimethyl-7 -methoxy-2-benzyl-1H-inden-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:23](=[O:24])[N:22]([CH3:25])[C:13]2[N:14]([CH3:21])[C:15]3[C:20]([C:12]=2[CH:11]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3.[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:21])[C:13]1[N:22]([CH3:25])[C:23](=[O:24])[C:10]([C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[Cl:1])=[CH:11][C:12]2=1)(=[O:28])[CH3:27]
Reactant: COc1ccc(-c2cc3c4ccccc4n(C)c3n(C)c2=O)c(Cl)c1
Reactant: CC(=O)Cl
Product: COc1ccc(-c2cc3c4cc(C(C)=O)ccc4n(C)c3n(C)c2=O)c(Cl)c1

Procedure:
The process is carried out as indicated in Example 60 above, using compound B: 3-(2-chloro-4-methoxyphenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and acetyl chloride.
Reaction SMILES: [CH2:1]1[N:3]([CH2:4][CH:5]([OH:15])[CH2:6][N:7]2[C:11]([N+:12]([O-:14])=[O:13])=[N:10][CH:9]=[CH:8]2)[CH2:2]1.[C:16]([OH:19])(=[O:18])[CH3:17].C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:12]([C:11]1[N:7]([CH2:6][CH:5]([OH:15])[CH2:4][NH:3][CH2:1][CH2:2][O:19][C:16](=[O:18])[CH3:17])[CH:8]=[CH:9][N:10]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1nccn1CC(O)CN1CC1
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OCCNCC(O)Cn1ccnc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 58 %

Procedure:
A solution of 1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol (2.12 g, 10.0 mmol) in acetone (20 cm3) prepared as described in Example 1(a) was treated with ethanoic acid (2.5 mol equivalents) at 25° C. then warmed to 50° C. for 15 minutes. The resulting mixture was cooled to 20° C., stirred with a decolourising charcoal (0.3 g) and excess anhydrous potassium carbonate for 30 minutes, filtered and concentrated under reduced pressure to give 1-(2-nitro-1-imidazolyl)-3-(2-acetoxyethylamino)-2-propanol (1.58 g, 58.0%) in the form of a pale yellow crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16](=O)[CH2:17][C:18](=[O:20])[CH3:19].[NH2:22][C:23]([CH3:33])=[CH:24][C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:26].C(O)(=O)C>C(O)(C)C>[C:18]([C:17]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:24]([C:25]([O:27][CH2:28][C:29]([F:30])([F:32])[F:31])=[O:26])=[C:23]([CH3:33])[NH:22][C:16]=1[CH3:15])(=[O:20])[CH3:19]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(=O)CC(C)=O
Reactant: CC(N)=CC(=O)OCC(F)(F)F
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)OCC(F)(F)F)C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 93.1 mg (0.93 mmol) of 2,4-pentanedione, 97 mg (0.53 mmol) of 2,2,2-trifluoroethyl 3-aminobut-2-enoate and 32 μl (0.55 mmol) of acetic acid in 5 ml of isopropanol and heated under reflux under argon for 10 h. The solvent is then removed in vacuo, and the residue is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol 95:5). 28 mg (12% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[C:34](=[N:36]O)[NH2:35]>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[C:34]1[N:36]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:35]=1
Reactant: NC(=NO)c1cc(Cl)ccc1Cl
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cc(Cl)ccc4Cl)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 45 mg (0.22 mmol, 1.1 eq.) of 2,5-dichloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 28 mg (27% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][N:3]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)=[CH:4][N:3]=1
Reactant: OCc1ccc(Br)nc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Brc1ccc(COC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
To a solution of 2-bromo-5-hydroxymethylpyridine (4 Scheme 27, 7.3 g, 38.8 mmol) and 3,4-dihydro-2H-pyran (3.6 g, 42.7 mmol) in dichloromethane (150 mL) was added p-TsOH (200 mg) and the mixture was stirred for 5 h at room temperature. The reaction mixture was concentrated and purified by column chromatography (1:5 ethyl acetate/hexanes) to give the desired compound as a liquid (10 g, 95%); 1H NMR (300 MHz, CDCl3) δ 1.42-1.81 (6 H), 3.48 (m, 1 H), 3.80 (m, 1 H), 4.43 (m, 1 H), 4.62-4.73 (2 H), 7.42 (m, 1 H), 7.53 (m, 1 H), 8.30 (m, 1 H); 13C NMR (75 MHz, CDCl3) 19.5, 25.5, 30.6, 62.5, 65.8, 98.3, 128.0, 133.5, 138.4, 141.3, 149.7. HRMS (EI) calcd for C11H14BrNO2 271.0208 and 273.0187, found 271.0207 and 273.0171.
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].C(O)(=O)C.[BH4-].[Na+].[OH-].[Na+]>O1CCCC1.CO>[C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)CC#N
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CC(O)CC(O)CC#N

Procedure:
Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate (about 150 moles) from Step (1) is dissolved in the first distillate from Step (a) along with 50 L of tetrahydrofuran, cooled to −75° C.±20° C., and optionally diluted with 25 L of methanol, and 10 kg of acetic acid. Sodium borohydride (8 kg) as a solution in methanol and aqueous sodium hydroxide is added slowly. After the addition, the reaction mixture is warmed to 0° C.±25° C. The reaction mixture is quenched by the addition of 10 kg of acetic acid and 20 L of methanol and concentrated by vacuum distillation. The residue is dissolved in methanol and acetic acid, optionally diluted with water, and concentrated by vacuum distillation. The residue is dissolved in methanol and concentrated by vacuum distillation. The residue is dissolved in a mixture of water and ethyl acetate, and the aqueous layer separated. The organic layer is concentrated by vacuum distillation. The residue is dissolved in methanol and acetic acid and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation affording crude [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.
Reaction SMILES: O[CH2:2][C@@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:13][N:10]1[CH:11]=[CH:12][C:8]([N:7]2[C:5](=[O:6])[CH2:4][C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:2]2)=[N:9]1
Reactant: Cn1ccc(NC(=O)C[C@@H](CO)NC(=O)OC(C)(C)C)n1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1ccc(N2C[C@@H](NC(=O)OC(C)(C)C)CC2=O)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of tert-butyl ((2S)-1-hydroxy-4-((1-methyl-1H-pyrazol-3-yl)amino)-4-oxobutan-2-yl)carbamate (553.0 mg) and tri-n-butylphosphine (0.924 mL) in a mixed solvent of toluene (9 mL)/THF (3 mL) was added 40% diethyl azodicarboxylate toluene solution (0.954 mL) under ice-cooling, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (358 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18](S(C)(=O)=O)[N:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.[NH2:26][CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30].C(N(C(C)C)CC)(C)C>CS(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:26][CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30])[N:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3occn23)n1
Reactant: CC(C)(CN)CO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(CO)CNc1nccc(-c2c(-c3ccc(F)cc3)nc3occn23)n1
Temperature: 100 °C
Yield: 86.1 %

Procedure:
To a solution of 6-(4-fluorophenyl)-5-[2-(methylsulfonyl)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazole (F) (0.5 g, 1.4 mmol) in dimethylsulfoxide is added 3-amino-2,2-dimethyl propanol (0.430 mg, 3.8 mmol) followed by the addition of diisopropylethylamine (0.631 g, 5.0 mmol). The mixture is heated at 100° C. overnight. After cooling to room temperature the reaction is diluted with water and extracted with dichloromethane (2×50 ml). The combined organic phase is dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The residue is purified by silica gel column chromatography eluting with ethyl acetate/hexane (3:1) to provide 3-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)-2,2-dimethylpropan-1-ol (G) (0.46 g, 86%), m.p. 149° C.;
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].CC1(C)C(C)(C)OB([C:36]2[C:40]([CH3:41])=[CH:39][S:38][CH:37]=2)O1>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][C:11]2[C:12]3[C:13]([C:36]4[C:40]([CH3:41])=[CH:39][S:38][CH:37]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:26][CH:25]=1
Reactant: Cc1cscc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Product: Cc1cscc1-c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and 4,4,5,5-tetramethyl-2-(4-methylthien-3-yl)-1,3,2-dioxaborolane, the title compound was synthesized following the procedures described Example 108.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.[CH3:13][S:14][C:15](SC)=[C:16]([C:19]#[N:20])[C:17]#[N:18].O1CCOCC1.[H-].[Na+]>C(O)(=O)C>[C:17]([C:16]([C:19]#[N:20])=[C:15]([C:2]1[CH:3]=[C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:6][N:1]=1)[S:14][CH3:13])#[N:18]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: CCOC(=O)Cc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccnc(C(SC)=C(C#N)C#N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
To a mixture of ethyl 4-pyridylacetate (46.7 g, 0.28 mol), 3,3-bis(methylthio)-2-cyanoacrylonitrile (47.6 g, 0.28 mol) and p-dioxane (300 ml) cooled in an ice bath was added 60% NaH (11.2 g, 0.28 mol) over 30 minutes. The mixture was slowly warmed to room temperature over 2 hours and was stirred at ambient temperature for 4 hours. The mixture was poured into ice-water, acidified with acetic acid and the resulting precipitate was collected by filtration and washed with water. The product was recrystallized from cyclohexane and dried at 70°-75° C. in high vacuum to afford 40.3 g (50%) of ethyl 2-(2,2-dicyano-1-methylthioethenyl)-4-pyridylacetate as orange crystals, m.p. 148°-152° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]([C:20]3[S:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[CH:21]=3)=[CH:18][C:17](=[O:29])[C:13]([C:14]([OH:16])=[O:15])=[CH:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:43]1[C:51]2[C:46](=[CH:47][C:48](O)=[CH:49][CH:50]=2)[CH2:45][CH2:44]1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]([C:20]3[S:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[CH:21]=3)=[CH:18][C:17](=[O:29])[C:13]([C:14]([O:16][CH:43]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44]3)=[O:15])=[CH:12]2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-n2cc(C(=O)O)c(=O)cc2-c2cc3ccccc3s2)cc1
Reactant: Oc1ccc2c(c1)CCC2
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-n2cc(C(=O)OC3CCc4ccccc43)c(=O)cc2-c2cc3ccccc3s2)cc1
Temperature: -40 °C
Yield: 54 %

Procedure:
In 18 ml of anhydrous methylene chloride was dissolved 0.36 g of 1-(4-acetoxyphenyl)-6-(2-benzo[b]thienyl)-4-oxo-1,4-dihydronicotinic acid, and to this solution was added 0.137 ml of triethylamine at room temperature. The reaction mixture thus obtained was cooled to -40° C., and 0.094 ml of ethyl chlorocarbonate was added thereto. The resulting mixture was subjected to reaction at the same temperature for 1 hour. This reaction mixture was then mixed with 0.14 g of 5-indanol. The mixture was subjected to reaction for 1 hour, and elevated to room temperature. After completion of the reaction, the reaction mixture was washed successively with 15 ml of water and a saturated aqueous solution of sodium chloride, and then dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform) to obtain 0.25 g of indanyl 1-(4-acetoxyphenyl)-6-(2-benzo[b]thienyl)-4 -oxo-1,4-dihydronicotinate having a melting point of 234°-236° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1.OC1C=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][CH2:16]2.C(I)C>>[CH2:11]([O:10][C:9]1[CH:8]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][CH2:16]2)[CH3:7]
Reactant: C1CCOC1
Reactant: CN1C(=O)CCc2cc(O)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCI
Product: CCOc1ccc2c(c1)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
1.0M potassium t-butoxide/THF (5.65 ml, 5.65 mmol) was added to 6-Hydroxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (200 mg, 1.13 mmol) followed by the addition of ethyl iodide (452 μl, 5.65 mmol). The reaction mixture was stirred at room temperature for 2 hours and heated to 45° C. for an overnight. The salts were filtered off, rinsed with ethyl acetate and the combined filtrate was concentrated down to a residue. This was chromatographed using 1:1 ethylacetate/hexane to yield the title compound as a white solid (76 mg, 33% yield). 1H NMR (400 MHz, CDCl3) δ 1.36 (3H, t, J=6.9 Hz), 2.58 (2H, m), 2.82 (2H, m), 3.29 (3H, s), 3.96 (2H, q, J=7.0 Hz), 6.71 (2H, m), 6.84 (1H, d, J=8.7 Hz). m/z (APCI+) 206 (M+1). HPLC (aqueous 200 Mm ammonium acetate buffer/acetonitrile gradient, 3.0 ml/min, Hewlett Packard ODS Hypersil 5 μM, 125×4 mm column), 4.453 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1C(=NO)C.S(Cl)(Cl)=O.C(C1C(O)=CC(O)=[C:29]([C:31](=[N:33]O)C)C=1)(C)(C)C.P(Cl)(Cl)(Cl)=[O:38]>>[CH3:29][C:31]1([OH:38])[NH:33][C:7]2[CH:6]=[C:5]([OH:8])[C:4]([C:9]([CH3:10])([CH3:11])[CH3:12])=[CH:3][C:2]=2[O:1]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=NO)c1c(O)ccc(O)c1C(C)(C)C
Reactant: CC(=NO)c1cc(C(C)(C)C)c(O)cc1O
Solvent: O=S(Cl)Cl
Product: CC1(O)Nc2cc(O)c(C(C)(C)C)cc2O1
Yield: 83 %

Procedure:
In the same manner as described in Example 1 except that 2',5'-dihydroxy-6'-t-butylacetophenone oxime and thionyl chloride were used instead of 5'-t-butyl-2',4'-dihydroxyacetophenone oxime and phosphorus oxychloride, respectively, the desired 2-methyl-5-hydroxy-6-t-butylbenzoxazolol was obtained. Yield 83% (light brown needles), Melting Point 203° to 205° C.
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@H:8]([NH2:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>ClCCl>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][C:21](=[O:22])[NH:10][C@H:8]([CH3:9])[CH2:7][O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:12])[CH3:11])=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: C[C@@H](N)CO[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of (R)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethylamine (693 mg, 3,66 mmol) (from Example 38a supra) and triethylamine (0.77 mL, 5.5 mmol) (Allied Signal) in dichloromethane was treated with 4-nitrophenyl chloroformate (885 mg, 4.39 mmol) (Aldrich) at room temperature for 30 minutes. The reaction was quenched with 1 N aqueous hydrochloric acid and then extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution followed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (15% ethyl acetate in hexanes) to give (R)-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-carbamic acid 4-nitro-phenyl ester as a colorless oil that solidified upon standing. (Yield 0.49 g, 38%).