Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:17][C:16](=[O:18])[NH:15][C:14]3[CH:19]=[C:20]([Cl:26])[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]=3[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=O.[NH2:27][C:28]([NH2:30])=[S:29]>C1COCC1.CCOC(C)=O>[NH2:30][C:28]1[S:29][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:11]3[CH2:17][C:16](=[O:18])[NH:15][C:14]4[CH:19]=[C:20]([Cl:26])[C:21]([N:23]([CH3:25])[CH3:24])=[CH:22][C:13]=4[N:12]=3)[CH:8]=[CH:9][CH:10]=2)[N:27]=1
Reactant: NC(N)=S
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(C(=O)CBr)c1)=N2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3csc(N)n3)c1)=N2
Temperature: 60 °C
Yield: 20.2 %

Procedure:
A mixture of 4-(3-bromoacetyl-phenyl)-8-chloro-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (0.73 g) (Example 193a) and thiourea (0.13 g) in THF (10 mL) was heated to 60° C. for 15 min. The mixture was diluted with AcOEt and washed with sat. NaHCO3 solution and with brine. The organic layer was dried and evaporated and the residue was stirred with CH2Cl2 to give the title compound (0.14 g) as yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][C:10]=1[NH2:11].[CH:12]1[C:21]2[C:16](=[C:17]([CH2:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>>[CH:12]1[C:21]2[C:16](=[C:17]([CH2:22][C:23]([NH:11][C:10]3[CH:9]=[CH:8][S:7][C:6]=3[C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Nc1ccsc1-c1nccs1
Reactant: O=C(O)Cc1cccc2cnccc12
Product: O=C(Cc1cccc2cnccc12)Nc1ccsc1-c1nccs1

Procedure:
The title compound was prepared from 2-(thiazol-2-yl)thiophen-3-amine and 2-(isoquinolin-5-yl)acetic acid according to protocol A. Preparative HPLC gave 2-(isoquinolin-5-yl)-N-(2-(thiazol-2-yl)thiophen-3-yl)acetamide. Method[7], MS(ESI) 352.1 [M+H], Retention time=2.59 min; 1H-NMR (300 MHz, CDCl3) δ 11.32 (s, 1H), 8.26 (d, J=8.2 Hz, 1H), 8.10-8.09 (m, 1H), 8.07 (s, 1H), 7.94 (t, J=7.7 Hz, 1H), 7.35 (d, J=3.3 Hz, 1H), 7.31-7.24 (m, 4H), 7.10 (d, J=3.3 Hz, 1H), 4.33 (s, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([CH3:14])=[N:10][C:9]=2[C:8]([C:15]2[CH2:19][C:18]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].CO>O1CCCC1.Cl.C(OCC)(=O)C>[Cl:30][C:28]1[CH:29]=[C:24]([C:18]2([C:20]([F:22])([F:21])[F:23])[O:17][N:16]=[C:15]([C:8]3[C:9]4[N:10]=[C:11]([CH3:14])[O:12][C:13]=4[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=3)[CH2:19]2)[CH:25]=[C:26]([Cl:31])[CH:27]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2nc(C)oc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc(C(=O)O)c2o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.4 %

Procedure:
To a solution of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl)-2-methyl-benzo[d]oxazole-7-carboxylic acid methyl ester (Example 6.10) (2.75 g) in tetrahydrofuran (50 ml) was added aqueous sodium hydroxide (1M) (8.7 ml) and methanol (5 ml). The reaction mixture was stirred at ambient temperature for 2.5 hours. The reaction mixture was diluted with aqueous hydrochloric acid (1M) (150 ml) and ethyl acetate (200 ml) and the phases separated. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: 1-6% v/v methanol in dichloromethane) to give 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl)-2-methyl-benzo[d]oxazole-7-carboxylic acid (2.12 g) as yellow solid. 1H-NMR (400 MHz, CDCl3): 8.05-7.43 (m, 5H), 4.57 (d, 1H), 4.13 (d, 1H), 2.79 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:8][C:9]1([CH3:21])[S:13][C@@H:12]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:11]2[C@H:10]1[C:18]([OH:20])=[O:19].ClC1C([O:29][C:30](=O)[CH:31]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:32]([O:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=2)=[O:33])=C(Cl)C(Cl)=C(Cl)C=1Cl>ClCCl>[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:42][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][C:38]=1[CH3:41])[O:34][C:32]([CH:31]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:30]([NH:17][CH:14]1[C:15](=[O:16])[N:11]2[CH:10]([C:18]([O-:20])=[O:19])[C:9]([CH3:21])([CH3:8])[S:13][C@H:12]12)=[O:29])=[O:33]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(OC(=O)C(C(=O)Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2Cl)c2ccccc2)cc1C
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Solvent: ClCCl
Product: CC[NH+](CC)CC
Product: Cc1ccc(OC(=O)C(C(=O)NC2C(=O)N3C(C(=O)[O-])C(C)(C)S[C@H]23)c2ccccc2)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.6 ml. (0.026 moles) of triethylamine are added to a suspension of 2.8 g. (0.013 moles) of 6-APA in 50 ml. of dichloromethane, and the mixture is stirred at room temperature until a clear solution is obtained. The solution is cooled to 0° C., 7 g. (0.013 moles) of phenylmalonic acid 3,4-dimethylphenylester pentachlorophenylester are added, and the mixture is stirred at the same temperature for one hour. Thereafter the solvent is evaporated in vacuo, and the residue is admixed with 30 ml. of ethyl acetate. 7.5 g (95%) of 6-(α-[3,4-dimethylphenoxycarbonyl]-phenylacetamido)-2,2-dimethyl-penam-3-carboxylic acid triethylammonium salt separate in the form of a white, crystalline substance. M.p.: 155°-160° C.
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[C:3]([O:12][Si](C)(C)C)[O:4][CH2:5]CO[Si](C)(C)C.[C:18]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:22])[C:19]([CH3:21])=[CH2:20].F[H-]F.CN([S+](N(C)C)N(C)C)C>C1COCC1>[C:3]([O:4][CH3:5])(=[O:12])[C:2]([CH3:17])=[CH2:1].[C:18]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:22])[C:19]([CH3:21])=[CH2:20]
Reactant: CC(C)=C(OCCO[Si](C)(C)C)O[Si](C)(C)C
Agent: C=C(C)C(=O)OCCCC
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: F[H-]F
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC

Procedure:
Following the procedure of Example 46, hydroxy-terminated methyl methacrylate (35%)/n-butyl methacrylate (BMA) (65%) copolymer was prepared using the following amounts of materials: [(2-methyl-1-[2-(trimethylsiloxy)ethoxy]-1-propenyl)oxy]trimethylsilane, 0.51 g (1.85 mmol); MMA, 11 ml (103.7 mmol); BMA, 30 ml (188.5 mmol); tris(dimethylamino)sulfonium bifluoride, 20 mg (0.1 mmol); THF, 100 ml. Upon addition of the monomers the temperature rose to 48.6° from 20.6°. Evaporation of solvents and drying of the resultant residue gave 38.6 g of copolymer. GPC: Mn 22100, Mw 24500, D 1.11 (theor. Mw 20,215).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=4)[O:22][C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]2[O:22][C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:19]=3[N:20]=2)=[CH:28][CH:27]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3oc(-c4ccc(C(C)(C)C)cc4)nc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCNCC4)cccc3o2)cc1

Procedure:
4-[2-(4-tert-butyl-phenyl)-benzooxazol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (900 mg, 2.07 mmol) was stirred in a solution of concentrated trifluoroacetic acid (20 mL) and methylene chloride (20 mL) under N2 at room temperature for 5 h. The solvent was removed in vacuo and the oil was transferred to a separatory funnel with ethyl acetate (150 mL) and washed with 1M aqueous potassium carbonate solution (100 mL×2). The aqueous washings were combined and extracted with ethyl acetate (150 mL). The organic extracts were combined and washed with brine (100 mL), dried (Na2SO4), filtered and the filtrate concentrated to give a clear oil which was concentrated in vacuo with hexane several times to give a waxy material which was placed on a drying pistol overnight to afford the product as an amber colored wax (550 mg, 79%). Mass Spectrum (+ESI): 336 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1O.C(N(CC)CC)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:46][O:47][C:48](=[O:60])[N:49]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]#[CH:59])=[CH:54][CH:53]=1)[CH3:50]>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[C:59]#[C:58][C:55]1[CH:56]=[CH:57][C:52]([CH2:51][N:49]([C:48]([O:47][CH3:46])=[O:60])[CH3:50])=[CH:53][CH:54]=1
Reactant: C#Cc1ccc(CN(C)C(=O)OC)cc1
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C#Cc1ccc(CN(C)C(=O)OC)cc1
Temperature: -8 °C
Reaction time: 2 h
Yield: 156.8 %

Procedure:
The nitro compound 8 (47.87 g, 0.223 mol) was dissolved in acetonitrile (240 ml) and cooled to −8° C. Triethylamine (33.8 g, 0.334 mol) was added. A clear dark solution was formed. Triflic anhydride (69.17 g, 0.245 mol) was added slowly and the reaction temperature was maintained at −10° C. 10 minutes after addition was complete, TLC analysis indicate the completion of triflate formation. Cooling bath was removed. Alkyne 5 (47.46 g, 0.234 mol) was added. The solution was degassed 3 times by evacuating the flask and backfilling it with nitrogen. The solution was then transferred into an addition funnel. Into a separate reaction flask was added acetonitrile (240 ml) and triethylamine (22.5 g, 0.223 mol). The solution was degassed 3 times by exposing the reaction flask to vacuum and nitrogen alternatively. Dichlorobis(triphenylphosphine) palladium (II) (3.13 g, 0.0045 mol) was added to the solution and the solution was degassed again 3 times. This solution was heated to 65° C. under protection of nitrogen. Once the temperature reached 65° C., one quarter of the solution of alkyne 5 and triflate in addition funnel was quickly added to the reaction flask. The remaining solution in addition funnel was added over 30 minutes at 65° C. After the addition was complete, the reaction solution was stirred at 65° C. for 2 hours. HPLC analysis indicated the reaction was complete. Reaction mixture was cooled to room temperature. Solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 ml) and washed with water (300 ml). The aqueous phase was separated and back extracted with ethyl acetate (200 ml). The combined organic solution was washed with water (200 ml). It was then concentrated to dryness to provide a dark oil residue (140 g). This crude product was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 2.87 (d, br, 3H), 3.755 (s, 3H), 4.011 (s, 3H), 4.50 (s, br, 2H), 7.21 (s, br, 2H), 7.55 (d, 2H, J=9 Hz), 7.80 (dd, 1H, J=2.7 Hz and J=7.2 Hz), 7.86 (dd, 1H, J=2.7 Hz and J=8.1 Hz).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([CH2:22][CH3:23])([OH:21])[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1.[H][H]>[Pd].CO>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([CH2:22][CH3:23])([OH:21])[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: CCC(O)(c1ccc(OCc2ccccc2)cc1)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CCC(O)(c1ccc(O)cc1)c1cccc(C(F)(F)F)c1

Procedure:
54.1 g. of 3-trifluoromethyl-4'-benzyloxy-α-ethyl-benzhydrol in 541 ml. of methanol are hydrogenated under atmospheric pressure, in the presence of 27.1 g. of a 10% palladium-on-charcoal catalyst. When the uptake of the calculated amount of hydrogen is complete, the catalyst is filtered off, and the solvent is distilled off under reduced pressure. The crude product is decoloured with charcoal in ethyl acetate, and recrystallized from a mixture of ethyl acetate and n-hexane. 30.8 g. of the named compound are obtained, melting at 102.5° to 103° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:26][C:27]1[NH:28][C:29]2[C:34]([C:35]=1[CH3:36])=[CH:33][C:32]([OH:37])=[CH:31][CH:30]=2>>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:37][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:26])=[C:35]2[CH3:36])#[N:13]
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Product: Cc1[nH]c2ccc(Oc3ccnc4cc(OCCCN5CCS(=O)(=O)CC5)c(C#N)cc34)cc2c1C
Yield: 64.8 %

Procedure:
Using an analogous procedure to that described in Example 7, 4chloro-6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (100 mg, 0.26 mmol) was reacted with 2,3-dimethyl-5-hydroxyindole (51 mg, 0.32 mmol), (Arch. Pharm. 1972, 305, 159), to give 6-cyano-4-(2,3-dimethylindol-5-yloxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (85 mg, 64%).
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](Cl)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].[CH:23]([SH:26])([CH3:25])[CH3:24].[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([S:26][CH:23]([CH3:25])[CH3:24])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3]
Reactant: CC(C)S
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)SC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Temperature: 0 °C

Procedure:
A solution of benzyl 6-(1-hydroxyethyl)-3-chloro-1-azabicyclo[3.2.0]hept-2-ene-7-one-2-carboxylate (32 mg) in anhydrous dimethylformamide (DMF, 2 ml) is cooled to -40° C. and stirred under a nitrogen atmosphere. A solution of isopropylmercaptan (8 mg) in anhydrous DMF (1 ml) containing 57% sodium hydride (4.4 mg) is added dropwise over 10 mins. The resulting solution is stirred for 2 hrs, with gradual warming to 0° C. The solution is diluted with ethyl acetate (20 ml), washed with water (5×10 ml) and brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue is purified by plc on silica gel GF to yield benzyl 6-(1-hydroxyethyl)-3-isopropylthio-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: C(=NC(=O)O[NH:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[N:8]=1)=S.Cl.[NH2:19]O.C([N:24]([CH:27](C)C)CC)(C)C>C(O)C>[NH2:19][C:27]1[N:6]=[C:7]2[N:8]=[C:9]([O:15][CH3:16])[CH:10]=[C:11]([O:13][CH3:14])[N:12]2[N:24]=1
Reactant: COc1cc(OC)nc(NOC(=O)N=C=S)n1
Reactant: NO
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CCO
Product: COc1cc(OC)n2nc(N)nc2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
Ethyl [(4,6-dimethoxypyrimidin-2-yl)amino carbonothioylcarbamate (0.50 g, 1.7 mmol) was mixed with ethanol (5 mL). To this mixture was added hydroxylamine hydrochloride (0.12 g, 1.7 mmol) and diisopropylethyl-amine (0.30 mL, 1.7 mmol). The resulting mixture was allowed to stir at room temperature. After 2.5 hours, additional diisopropylethylamine (0.30 mL, 1.7 mmol) was added to the mixture. After 48 hours the ethanol was removed in vacuo and the residue was partitioned between H2O and Et2O to give a powder. The powder was filtered and dried to afford the product as a tan powder (0.27 g, 82%). mp 215-220° C. Anal: Cacld for C7H9N5O2: C, 43.08; H, 4.65; N, 35.88; O, 16.39; found: C, 39.88; H, 4.22; N, 32.00; O, 16.35. 1H NMR (DMSO-d6): δ 6.04 (s, 1H); 5.97 (br, 2H); 4.04 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[C:18](O)=[O:19].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18]([C@@H:14]3[CH2:15][CH2:16][CH2:17][O:13]3)=[O:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 7 h
Yield: 70.8 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol), (S)-tetrahydrofuran-2-carboxylic acid (252 mg, 2.17 mmol), triethylamine (606 μL, 4.35 mmol), and BOP-Cl (203 mg, 2.17 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 7 hours. 2M LiOH (5 mL) was added then to the mixture and stirred at room temperature for 30 minutes. Water (25 mL) was then added and stirred for an additional 30 minutes. The solid formed was filtered, washed with water (3×5 mL) and dried to provide (S)-N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydro furan-2-carboxamide (202 mg, 70.8% yield) as a solid. LCMS (APCI+) m/z 327.9, 329.9 (M+H)+; Retention time=2.80 minutes (Method 2).
Reaction SMILES: [OH:1][CH:2]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:3][CH2:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:8]([O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[C:7]([CH3:19])[CH:6]=1.O.[CH3:32]O>>[CH3:32][O:1][CH:2]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:22][CH:21]=1)[CH2:3][CH2:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:8]([O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[C:7]([CH3:19])[CH:6]=1
Reactant: Cc1cc(CCC(O)c2ccc(OC(F)(F)F)cc2)cc(C)c1OC(C)(C)C(=O)O
Reactant: CO
Solvent: O
Product: COC(CCc1cc(C)c(OC(C)(C)C(=O)O)c(C)c1)c1ccc(OC(F)(F)F)cc1

Procedure:
This compound was prepared following the general procedure E, using a solution of 2-(4-(3-hydroxy-3-(4-(trifluoromethoxy)phenyl)propyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid in a ⅓:⅔ mixture of water/methanol.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][CH2:30][CH3:31].[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl.C(=O)(O)[O-].[Na+].C(#N)C>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH2:29][CH2:30][CH3:31])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:10]([O:9][CH3:8])[C:32](=[O:34])[CH3:33])[C:27]=2[C:26]2[N:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CCCc1nc2c(N)nc3cccnc3c2n1CCCCNOC
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1nc2c(N)nc3cccnc3c2n1CCCCN(OC)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
Triethylamine (0.24 mL, 1.69 mmol, 1.2 eq) was added to 1-[4-(methoxyamino)butyl]-2-propyl-1H-imidazo[4,5-c]-1,5-naphthyridin-4-amine (0.46 g, 1.41 mmol, 1.0 eq) in dichloromethane (6 mL) and cooled to 0° C. Acetic anhydride (0.13 mL, 1.41 mmol, 1.0 eq) was added dropwise and the reaction mixture was stirred for 1 hour. The reaction was then diluted with dichloromethane (40 mL) and saturated aqueous sodium bicarbonate (30 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (20 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated to afford a yellow solid, which was purified by HPFC (silica gel eluting with 0-25% CMA in chloroform) to afford 0.49 g of a pale yellow substance. The material was dissolved in acetonitrile (10 mL), sonicated for 2 minutes, filtered, and dried under vacuum at 100° C. for 24 hours to afford 0.278 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N-methoxyacetamide as off-white needles, mp 155-156° C. Anal. calcd for C19H26N6O2: C, 61.60; H, 7.07; N, 22.69. Found: C, 61.58; H, 7.31; N, 22.64.
Reaction SMILES: C([O:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)C.[N+:12]([C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([CH3:21])[CH:20]=1)([O-:14])=[O:13].C(N(CC)C(C)C)(C)C>CS(C)=O>[OH:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][C:19]=2[CH3:21])[CH2:10][CH2:11]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCOCCN1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([N+](=O)[O-])ccc1N1CCN(CCO)CC1

Procedure:
In the same manner as in Production Example 5-1, but using 4-(2-ethoxyethyl)piperazine in place of N-ethylpiperazine used in Production Example 5-1, using 5-nitro-2-fluorotoluene in place of 2-fluoro-5-nitrobenzyl alcohol, using N,N-diisopropylethylamine in place of potassium carbonate, and using dimethylsulfoxide in place of N-methylpyrrolidone, the entitled compound was obtained as a yellow solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[CH2:4]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=3)[CH2:4]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(N)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(C)cc1)C2
Reaction time: 20 h

Procedure:
6.0 g (21.1 mmol) of methyl 4-(2-amino-indan-5-yl)-4-oxobutyrate hydrochloride are suspended in 60 ml of chloroform and 5.0 g (25.3 mmol) of p-toluenesulphonyl chloride are added. 5.1 g (50 mmol) of triethylamine are added, with vigorous stirring, a clear solution being formed. After 20 hours at room temperature, the mixture is washed with water, the chloroform solution is evaporated and the residue is recrystallised from methanol.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O.[NH:49]1[C:57]2[C:52](=[CH:53][C:54](O)=[CH:55][CH:56]=2)[CH:51]=[N:50]1>O1CCCC1>[CH:1]1([O:7][C:54]2[CH:53]=[C:52]3[C:57](=[CH:56][CH:55]=2)[NH:49][N:50]=[CH:51]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: Oc1ccc2[nH]ncc2c1
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc2[nH]ncc2cc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
Cyclohexanol (0.315 ml, 2.98 mmol), triphenylphosphine (442 mg, 1.64 mmol) and dibenzyl azodicarboxylate (534 mg, 1.17 mmol) were added at 0° C. to a solution of the 1H-indazol-5-ol (200 mg, 1.49 mmol) obtained in Reference Example 4 in tetrahydrofuran (16 ml). After 30 minutes, the mixture thus obtained was warmed up to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure and a-1M aqueous sodium hydroxide solution (20 ml) was added to the resulting residue, followed by extraction with ethyl acetate (20 ml×2). The organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol, hexane/ethyl acetate) to obtain 5-(cyclohexyloxy)-1H-indazole (140 mg, 43%).