Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]#[N:19].[OH-:20].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([NH2:19])=[O:20]
Reactant: [OH-]
Reactant: N#Cc1ccc(-c2ncccc2C(F)(F)F)nc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)nc1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Cool concentrated sulfuric acid (120 mL) in an ice bath under nitrogen atmosphere. Add in portions 6-amino-3′-trifluoromethyl[2,2′]bipyridinyl-5-carbonitrile (19.8 g) over a period of 15 minutes. Stir at room temperature 48 hours. Pour the reaction mixture over ice, adjust the pH to 10 using 10 N aqueous NaOH, filter the solid, wash the solid with water and dry under vacuum to give 6-amino-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carboxylic acid amide as a light pink solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:14](OCC)[O:15]CC)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].C(O)=O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:14]=[O:15])=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:4]
Reactant: CCOC(OCC)c1cc(C(F)(F)F)c(C(=O)OC)s1
Solvent: C1COCCO1
Solvent: O=CO
Product: COC(=O)c1sc(C=O)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
A solution of 5-Diethoxymethyl-3-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (2.72 g, 8.71 mmol) in dioxane (20 ml) was cooled to 0° C. (ice bath). 88% formic acid (25 ml) was added in one portion and the mixture was stirred at 0° C. for 5 min and then at rt for 60 min The reaction mixture was quenched by pouring into EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (2.05 g, 99% yield).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([N:12]1[CH2:17][CH2:16][C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][O:26][CH2:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])=[CH:21][CH:20]=2)(O)[CH:14]([CH2:33][O:34][C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1>[CH2:5]([N:12]1[CH2:17][CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][O:26][CH2:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])=[CH:21][CH:20]=2)[CH:14]([CH2:33][O:34][C:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC[C@H](C)COCc1ccc(C2(O)CCN(Cc3ccccc3)CC2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COC[C@H](C)COCc1ccc(C2=CCN(Cc3ccccc3)CC2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
102.636 mmol of thionyl chloride are slowly added to a solution of 85.53 mmol of 1-benzyl-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-3-(R,S)-trityloxymethyl -piperidin-4-(R,S)-ol in 250 ml of pyridine at 0° C., taking care that the internal temperature stays below 10° C. After 5 minutes, the reaction mixture is quenched by adding 50 ml of 4N NaOH solution and concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution, water and brine, dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf=0.28 (EtOAc-heptane-25% ammonia conc. 100:200:1); Rt=5.64 (gradient I).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([S:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])=[O:23])=[CH:16]2>>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([N:28]2[CH2:29][CH2:30][N:25]([S:22]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][C:13]([Cl:12])=[CH:21][CH:20]=4)(=[O:23])=[O:24])[CH2:26][CH2:27]2)=[O:10])=[N:4][CH:3]=1
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Reactant: O=C(O)c1ncc(Br)cn1
Agent: Cl
Product: O=C(c1ncc(Br)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1

Procedure:
In the same manner as in Referential Example 12, a reaction was effected using 5-bromo-2-pyrimidinecarboxylic acid and 1-[(5-chloroindol-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C@H:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:30][C:31]([CH3:33])=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C@H:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([CH:31]([CH3:33])[CH3:30])[CH2:22][CH2:23]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=C(N[C@@H](COCC1CCNCC1)c1ccccc1)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)N1CCC(COC[C@H](NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)CC1

Procedure:
Using alkylation method A, 3-chloro-N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (8.97 mmol) and acetone (6.6 mL, 90 mmol) afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 2.2 g (54%) of the title compound.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[NH2:30][C:31]1[N:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[C:34]([C:40]([O:42][CH3:43])=[O:41])=[C:33]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[C:32]=1[CH:51]=O>O1CCCC1.C(OCC)(=O)C>[NH2:30][C:31]1[C:32]([CH:51]=[CH:2][O:3][CH3:4])=[C:33]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[C:34]([C:40]([O:42][CH3:43])=[O:41])=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=1
Reactant: COC(=O)c1c(C(C)C)nc(N)c(C=O)c1-c1ccc(F)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC=Cc1c(N)nc(C(C)C)c(C(=O)OC)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (methoxymethyl)triphenyl-phosphonium chloride (260 mg, 0.75 mmol) in tetrahydrofuran (0.3 mL) was added, dropwise, a solution of potassium tert-butoxide (0.75 mL, 1.0 M in tetrahydrofuran). After 15 min, a solution of methyl 6-amino-4-(4-fluorophenyl)-5-formyl-2-(1-methylethyl)-3-pyridinecarboxylate (95 mg, 0.3 mmol) in tetrahydrofuran (0.3 mL) was added to the above mixture. The resulting mixture was stirred at room temperature for 2.5 h, diluted with ethyl acetate (15 mL) and washed with brine, dried (Na2SO4) and evaporated. The residue was purified by a silica gel chromatography (45 g column), eluting with 15% to 20% of ethyl acetate in hexanes to provide methyl 6-amino-4-(4-fluorophenyl)-2-(1-methylethyl)-5-(2-methoxyethenyl)nicotinate as a E/Z mixture (80 mg, 77%): LCMS (ESI, pos. ion spectrum) m/z 345 (M+H); HPLC (method 3) tR=2.4 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[N:11]O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1>C(O)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([NH2:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)C(=NO)c1ccccn1
Solvent: CCO
Product: COC(=O)C(N)c1ccccn1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A solution of Hydroxyimino-pyridin-2-yl-acetic acid methyl ester (2.0 g, 11.1 mmol) in ethanol (50 mL) was placed in a round bottom flask. The flask was evacuated under vacuum and filled with Ar2 three times. Then 200 mg of 10% Pd on Carbon was added in one portion. The flask was evacuated again under vacuum and filled with Hydrogen three times. The reaction was stirred at room temperature under a balloon containing H2 for 16 h. The mixture was filtered through a pad of celite and rinsed with DCM three times. The combined organics were concentrated down to give Amino-pyridin-2-yl-acetic acid methyl ester (1.8 g) as a yellow oil which was used immediately in next step without further purification, m/z 167.55 [M+1]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:17]([O:16][C:14](=[O:15])[CH2:13][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of 3-fluoro-4-nitrophenol (1.57 g, 10 mmol) in N,N-dimethylformamide (10 ml) were added tert-butyl bromoacetate (1.95 g, 10 mmol) and potassium carbonate (1.38 g, 10 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue purified by column chromatography on silica gel (50 g, dichloromethane eluant) to afford the product as a pale-yellow solid (2.22 g, 84%).
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>C(O)C>[C:15]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:17][C:18]([NH:21][C:3]2[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=2)=[CH:19][CH:20]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccc(-c3ccccc3)cc2)[nH]c1=O
Temperature: 80 °C
Yield: 40 %

Procedure:
Ethyl 2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (60 mg, 0.233 mmol) was added to 1,1′-biphenyl-4-amine (79 mg, 0.467 mmol) dissolved in ethanol. The solution was heated in an oil bath to 80° C., while stirring, in reflux, for 72 hours. The sample was filtered and dried. 1H-NMR confirmed the structure (31 mg, 40% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[C:33]([O:34][CH3:35])=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:27][CH3:26])=[C:33]([O:34][CH3:35])[CH:32]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cnc1OC
Yield: 54.3 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.2 mmol) in 1,2-dimethoxyethane (2 mL) was added 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (63 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.01 mmol), and 2 M sodium carbonate (0.20 mL, 0.4 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (51 mg, 55%). ESI-MS m/z calc. 469.44. found 470.5 (M+1)+. Retention time 2.03 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:35][CH2:36][O:37][CH3:38])(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:35][CH2:36][O:37][CH3:38])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COCCOS(=O)(=O)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Product: COCCC(C(=O)OC(C)(C)C)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O

Procedure:
312 mg (0.75 mmol) of tert-butyl {4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate in the presence of 0.90 ml (0.90 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 312 mg (1.50 mmol, 1.5 eq.) of 2-methoxyethyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 201 mg (purity 91%, 51% of theory)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].ClCCl>>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCC(NS(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NC1CCC(N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound obtained from step A was dissolved in 50% trifluoroacetic acid/dichloromethane and the mixture was stirred at room temperature for 30 minutes. The excess acid was removed under reduced pressure and the residue was triturated with ether to give a white powder, 1.51 g, 90% for two steps. MS(ES) (M+H)+=193.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Br:25]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:25])[N:6]2[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: BrBr
Reactant: Nc1nc(Sc2ccccc2)nc2c1ncn2Cc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(Sc2ccccc2)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 22 %

Procedure:
6-Amino-9-benzyl-2-phenylthiopurine (95 mg, 0.28 mmol) and bromine (0.4 ml) were dissolved in 150 ml of methylene chloride and the solution was stirred at room temperature for 4.5 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtered was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (25 mg, yield 22%).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]3[CH:11]=[C:10]([C:12](OCC)=[O:13])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[CH:12]([C:10]1[N:9]=[C:7]2[N:6]([CH:11]=1)[C:5]1[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][C:4]=1[S:8]2)=[O:13]
Reactant: CCOC(=O)c1cn2c(n1)sc1cc(C)ccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)sc1nc(C=O)cn12
Temperature: -78 °C

Procedure:
To a stirred solution of Ethyl 7-methylimidazo[2,1-b]-benzthiazole-2-carboxylate (4.0 g, 15.38 mmol) in dry THF at −78° C., DIBAL (1M. solution in toluene) (16.0 ml, 16 mmol) was added. The reaction mixture was stirred at −78° C. and slowly elevated to room temperature. The reaction mixture was stirred at room temperature for 30 minutes and quenched with saturated NH4Cl. The reaction mixture was extracted with chloroform and washed well with water. The organic layer was dried over anhydrous MgSO4; filtered and concentrated. The residue was purified bt SiO2 column chromatography by eluting it with chloroform:methanol (20:1). Brown solid; (M+H) 217; Yield: 800 mg (24%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])[N:18]=[CH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:27]=1.[C:28]([Cu])#[N:29]>CN(C=O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]1[C:15]([C:13]2[S:12][C:11]3[C:5]4[CH:4]=[CH:3][C:2]([C:28]#[N:29])=[CH:27][C:6]=4[O:7][CH2:8][CH2:9][C:10]=3[CH:14]=2)=[N:16][CH:17]=[N:18]1
Reactant: N#C[Cu]
Reactant: Clc1ccccc1-n1ncnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)OCCc1cc(-c3ncnn3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedure in Example 53, 5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1-(2-chlorophenyl)-1H-1,2,4-triazole was reacted with CuCN in DMF to give 325 as a colorless solid after purification by reverse phase HPLC. MS: (ESI+) 405.1
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O[C:16]([CH3:27])([CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:17]>CS(O)(=O)=O>[CH3:17][C:16]1([CH3:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(O)CCCc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1(C)CCCc2ccccc21
Temperature: 105 °C
Yield: 89.9 %

Procedure:
A mixture of P2O5 (55.3 g, 0.390 mol) in 400 ml of methanesulfonic acid was heated to 105° C. under argon until all of the solid had dissolved. The resulting solution was cooled to room temperature and 2-hydroxy-2-methyl-5-phenylpentane (63.0 g, 0.354 mol) added slowly with stirring. After 4 hours the reaction was quenched by carefully pouring the solution onto 1 L of ice. The resulting mixture was extracted with Et2O (4×125 ml)and the combined organic layers washed with water, saturated aqueous NaHCO3, water, and saturated aqueous NaCl before being dried over MgSO4. Concentration of the solution under reduced pressure, followed by distillation afforded 51.0 g (90%) of the product as a clear colorless oil, bp. 65-67° C./1.1 mmHg. 1H NMR (CDCl3): δ 7.32 (1H, d, J=7.4 Hz), 7.16-7.05 (3H, m), 2.77 (2H, t, J=6.3 Hz), 1.80 (2H, m), 1.66 (2H, m), 1.28 (6H, s).
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:16])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:14]([O:13][C:11]([C:10]1[C:9]([CH3:16])=[N:8][N:7]2[C:2]([O:1][CH2:21][C:20]3[C:23]([F:27])=[CH:24][CH:25]=[CH:26][C:19]=3[Cl:18])=[CH:3][C:4]([CH3:17])=[CH:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1c(C)nn2c(O)cc(C)cc12
Reactant: OCc1c(F)cccc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3Cl)cc(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 180 mg (0.76 mmol) of 7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (Example 8A) in 7 ml of tetrahydrofuran was admixed with 247 mg (1.52 mmol) of 2-chloro-6-fluorobenzyl alcohol, 419 mg (1.60 mmol) of triphenylphosphine and 0.32 ml (1.60 mmol) of diisopropyl azodicarboxylate. The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (mobile phase: cyclohexane-ethyl acetate, gradient 10% to 30%), which gave 280 mg (84% yield, 84% pure) of the target compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH:20][C:21]([C:23]1[N:24]=[C:25]([N:28]2[CH2:31][CH:30]([OH:32])[CH2:29]2)[S:26][CH:27]=1)=[O:22])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]([NH:20][C:21]([C:23]1[N:24]=[C:25]([N:28]2[CH2:31][CH:30]([O:32][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:29]2)[S:26][CH:27]=1)=[O:22])[CH2:11][O:12][Si:13]([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106.3 %

Procedure:
To a solution of 1-{4-[2-(t-butyldimethylsilyloxy)-1-(t-butyldimethylsilyloxymethyl)ethylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (1.27 g, 2.53 mmol) (obtained as described in Reference Example 39(5)) in methylene chloride (64 ml) were added methanesulfonyl chloride (587 μl, 7.59 mmol) and triethylamine (1.06 ml, 7.59 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:2) as the eluant to afford 1-{4-[2-(t-butyldimethylsilyloxy)-1-(t-butyldimethylsilyloxymethyl)ethylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.56 g, yield 100%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:27]=[CH:28][C:29]([Cl:41])=[C:30]3[C:34]=2[N:33]([CH3:35])[N:32]=[C:31]3[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:5]([C@@H:8]([NH:18]C(=O)OC(C)(C)C)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[OH:48][C:42]([C:44]([F:47])([F:46])[F:45])=[O:43].[NH2:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:27]=[CH:28][C:29]([Cl:41])=[C:30]3[C:34]=2[N:33]([CH3:35])[N:32]=[C:31]3[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:5]([C@@H:8]([NH2:18])[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)cnc3[C@@H](N)Cc3cc(F)cc(F)c3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 49A (60 mg) was dissolved in 2 mL of DCM and to it was added 0.3 mL of TFA. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed to afford the title product. MS (m/z): 507.00 [M+H]+.
Reaction SMILES: [CH:1]([C@@H:3]1[C@:11]2([CH3:12])[C@@:6]([OH:19])([CH2:7][C@@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)[CH2:5][CH2:4]1)=O.C(=O)(O)O.[NH2:24][NH:25][C:26]([NH2:28])=[NH:27]>Cl.O1CCOCC1>[NH:25](/[N:24]=[CH:1]/[C@@H:3]1[C@:11]2([CH3:12])[C@@:6]([OH:19])([CH2:7][C@@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)[CH2:5][CH2:4]1)[C:26]([NH2:28])=[NH:27]
Reactant: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O)CC[C@@H]2C=O
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: C1COCCO1
Product: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O)CC[C@@H]2/C=N/NC(=N)N
Yield: 69.2 %

Procedure:
A solution of 0.57 g of (1S,3aS,5S,7aR)-1-formyl-5-phenyl-7a-methylperhydroinden-3a-ol and 1.50 g of aminoguanidine hydrogencarbonate in 30 ml of 0.01N hydrochloric acid and 80 ml of dioxane was kept at room temperature for 3 days and then evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 78/20/2 as the eluant. The fractions containing the title compound were collected and evaporated to dryness. The residue was triturated with ethanol/ethyl acetate to give 0.48 g of the title compound (I-aa) as a white solid.