Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C2C=C(C(O)=O)OC=2C2C=CC=C(C#N)C=2)C=C(F)C=1.[Cl:25][C:26]1[CH:27]=[C:28]([C:33]2[O:37][C:36]([C:38]([O:40]CC)=[O:39])=[CH:35][C:34]=2[C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([Cl:50])[CH:44]=2)[CH:29]=[CH:30][C:31]=1[F:32]>>[Cl:25][C:26]1[CH:27]=[C:28]([C:33]2[O:37][C:36]([C:38]([OH:40])=[O:39])=[CH:35][C:34]=2[C:43]2[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([Cl:50])[CH:44]=2)[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2ccc(F)c(Cl)c2)o1
Agent: N#Cc1cccc(-c2oc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)c1
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2ccc(F)c(Cl)c2)o1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 20A starting with the compound from Example 12A. The crude product obtained after extraction is dried under high vacuum and reacted further without chromatographic purification. 0.65 g (80% of theory) of the title compound with a purity of 75% are obtained.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:15]2=[O:31])=[CH:9][C:8]=1[CH3:32])(C)(C)C.[CH3:35][Si]([N-][Si](C)(C)C)(C)C.[K+].IC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>CN(C=O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:10]2[CH:9]=[C:8]([CH3:32])[C:7]([OH:6])=[C:12]([CH3:13])[CH:11]=2)([CH3:35])[C:15]1=[O:31]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1cc(C2C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(C2(C)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc(C)c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.6 %

Procedure:
Dissolve 3-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1-(2-chloro-benzyl)-1,3-dihydro-indol-2-one (150 mg, 0.31 mmol) in anhydrous DMF (3 mL) under nitrogen and cool in an ice bath. Add a 0.5M solution of potassium bis(trimethylsilyl)amide (0.622 mL, 0.31 mmol) and stir 10 min. Add iodomethane (0.020 mL, 0.31 mmol) and after 30 min remove the ice bath and allow the reaction to warm to room temperature. After 2.5 h treat the reaction with a 1.0M solution of tetrabutylammonium fluoride (0.35 mL, 0.35 mmol) and stir 2 h. Pour the reaction into 1N HCl (20 mL) and extract with ethyl acetate (3×20 mL). Wash the combined organic portions with brine, dry (MgSO4), filter and concentrate in vacuo to obtain a crude orange oil. Purify by flash chromatography (gradient of 5% EtOAc/hexanes to 33% EtOAc/hexanes) to give 70 mg (58%) of the title compound as a pink solid. MS (ES): m/z=392 (M+1), 390 (M−1); 1H NMR(DMSO-d6): δ8.23 (s, 1H), 7.54 (dd, J=1.9, 1.5 Hz, J=7.5, 7.3 Hz, 1H), 7.38-7.20 (m, 4H), 7.09-7.02 (m, 2H), 6.89 (d, J=7.6 Hz, 1H), 6.80 (s, 2H), 5.02 (s, 2H), 2.11 (s, 6H), 1.70 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:16][O:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[N:6]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].[NH3:27]>C1COCC1.CS(C)=O>[CH2:22]([O:21][P:19]([CH2:18][O:17][CH2:16][C:5]1[N:6]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]2[C:3]([N:4]=1)=[C:2]([NH2:27])[N:10]=[CH:9][N:8]=2)([O:24][CH2:25][CH3:26])=[O:20])[CH3:23]
Reactant: N
Reactant: CCOP(=O)(COCc1nc2c(Cl)ncnc2n1CC(C)(C)C)OCC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOP(=O)(COCc1nc2c(N)ncnc2n1CC(C)(C)C)OCC

Procedure:
A solution of 6-chloro-8-diethylphosphonomethoxymethyl-N9-neopentylpurine (1 mmol) in THF-DMSO was treated with liquid ammonia (10 mmol) at 25° C. for 6 h. Extraction and chromatography afforded 8-diethylphosphonomethoxymethyl-N9-neopentyladenine as a white solid. TLC: Rf=0.44, 25% MeOH-EtOAc.
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:5].[Cl-].[NH4+]>>[OH:5][CH:4]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:1]
Reactant: C[Mg]Br
Reactant: O=Cc1nc2ccccc2s1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(O)c1nc2ccccc2s1
Reaction time: 3.5 h
Yield: 66 %

Procedure:
5.0 ml of methylmagnesium bromide were added dropwise to a solution of 0.61 g of 2-formylbenzothiazole [prepared as described in step (a) above] which was cooled in an acetone-dry ice bath. The reaction vessel was transferred to an ice-water bath and the reaction mixture was stirred for 3.5 hours. At the end of this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.44 g (yield 66%) of the title compound as a solid having a melting point of 59° to 60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:22])=[C:6]2[C:11]=1[C:10]1=[N:12][CH:13]=[C:14]([C:17]([O:19]CC)=[O:18])[C:15](=[O:16])[N:9]1[CH:8]=[CH:7]2>C(O)(=O)C.Cl.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:22])=[C:6]2[C:11]=1[C:10]1=[N:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[C:15](=[O:16])[N:9]1[CH:8]=[CH:7]2
Reactant: CCOC(=O)c1cnc2c3c(N)ccc(Br)c3ccn2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Br)c2ccn3c(=O)c(C(=O)O)cnc3c12
Temperature: 80 °C
Yield: 39 %

Procedure:
A suspension of ethyl 11-amino-8-bromo-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (500 mg), in a mixture of acetic acid (25 ml) and 36% hydrochloric acid (5 ml) was heated at 80° C. for 3 hours. The mixture was cooled and diluted with water. The precipitated solid obtained was collected and dissolved into N,N-dimethylformamide (30 ml). The solution was added to an aqueous sodium bicarbonate solution (15 ml). The resulting precipitate was collected, and then dissolved in N,N-dimethylformamide (130 ml). The solution was filtered for removal of insoluble materials. The filtrate obtained was acidified with acetic acid to give 11-amino-8-bromo-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (180 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11](NC(C3CC3)=O)[CH:10]=2)[C:5](=[O:21])[N:4]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=C(F)C=3)([CH3:26])[NH:23][C:24](=O)[C:3]=12.C(N(CC)CC)C.Cl.[CH3:42][O:43][NH2:44]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][N:14]=2)[C:5](=[O:21])[N:4]2[C:22]3([CH2:26][CH2:30][CH2:31][CH2:32][CH2:27]3)[NH:23][C:24](=[N:44][O:43][CH3:42])[C:3]=12
Reactant: CON
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CON=C1NC2(CCCCC2)n2c1c(Cl)cc(Nc1ccncn1)c2=O
Temperature: 25 °C

Procedure:
To a solution of 8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (1, 1 g, 2.89 mmol) in chloroform (30 mL) was added triethylamine (1.21 mL, 8.67 mmol) and O-methylhydroxylamine hydrochloride (241 mg, 2.89 mmol). The reaction was stirred at reflux overnight. The resulting mixture was cooled to room temperature and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude was purified via flash column chromatography to afford 8′-chloro-1′-(methoxyimino)-6′-(pyrimidin-4-ylamino)-1′,2′-dihydro-5′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-5′-one (Cpd. No. 132).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.O[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Reactant: OCCN1CCCC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCN1CCCC1
Yield: 11.5 %

Procedure:
Using an analogous procedure to that described in Example 15, 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), was reacted with 1-(2-hydroxyethyl)pyrrolidine (0.11 ml, 0.9 mmol) to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)cinnoline (30 mg, 12%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:9][C:10]1[CH:11]=[N:12][CH:13]=[N:14][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: Nc1cncnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Brc1cncc(Nc2cncnc2)c1
Temperature: 100 °C
Yield: 55.3 %

Procedure:
3,5-Dibromopyridine (0.30 g, 1.3 mmol, 1.0 eq), 5-aminopyrimidine (120 mg, 1.26 mmol, 1.00 eq), Cs2CO3 (578 mg, 1.77 mmol, 1.40 eq), Pd2(dba)3 (58 mg, 0.10 mmol, 0.080 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (88 mg, 0.15 mmol, 0.12 eq) and toluene (4.2 mL) were added to a microwave vial. The vial was purged with argon, capped and heated at 100° C. for 18 h. After cooling the reaction was filtered over a plug of celite and the plug was washed with 5% MeOH/CH2Cl2. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 175 mg (55%) of the title compound as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.95 (bs, 1H), 8.76 (s, 1H), 8.64 (s, 2H), 8.37 (d, J=2.4 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.73 (t, J=2.2 Hz, 1H); [M+1]+: 251.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=Cc1ccccn1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccccn3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with 2-pyridinecarboxaldehyde to provide 44 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[NH:26])[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1C=C(C[F:38])C=CC=1CBr)#N>>[CH:1]1([CH2:7][CH:8]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][C:21]([F:38])=[CH:22][CH:23]=3)[C:18]2=[NH:26])[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cc(CF)ccc1CBr
Reactant: N=C1c2ccccc2CN1C(CC1CCCCC1)C(=O)Nc1nccs1
Product: N=C1c2cc(F)ccc2CN1C(CC1CCCCC1)C(=O)Nc1nccs1

Procedure:
The title compound was synthesized according to the method described in connection with Compound 11, except that 2-cyano-4-fluoromethylbenzyl bromide was used. 1H NMR (400 MHz, MeOH-d4) δ: 7.99 (dd, J=2.4, 8.0 Hz, 1H), 7.76-7.82 (m, 1H), 7.58-7.66 (m, 1H), 7.44 (d, J=0.6 Hz, 1H), 7.13 (d, J=0.6 Hz, 1H), 5.11-5.21 (m, 2H), 4.96 (d, J=20.0 Hz, 1H), 2.03-2.24 (m, 2H), 1.70-1.90 (m, 5H), 1.0-138 (m, 6H). [M+H] calc'd for C20H23FN4OS, 387. found, 387.
Reaction SMILES: [I-].[CH3:2][O:3][N:4]=[C:5]([C:8]1[CH:9]=[N+:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[C:6]#[N:7].[BH4-].[Na+]>CO>[CH3:2][O:3][N:4]=[C:5]([C:8]1[CH2:9][N:10]([CH3:14])[CH2:11][CH2:12][CH:13]=1)[C:6]#[N:7]
Reactant: CON=C(C#N)c1ccc[n+](C)c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CON=C(C#N)C1=CCCN(C)C1
Temperature: 0 °C
Yield: 22.3 %

Procedure:
α-(Methoxyimino)-α-(1-methylpyridinium-3-yl)acetonitrile iodide (D6) (0.3 g, 0.001 mol) was dissolved in methanol (10 ml) and cooled to 0° C. Sodium borohydride (0.114 g, 0.003 mol) was added in three equal portions at 15 minute intervals. The mixture was allowed to warm to room temperature over 1 h and then evaporated to dryness. The residue was partitioned between saturated aqueous potassium carbonate solution (50 ml) and chloroform (3×75 ml). The organic layers were separated and dried (Na2SO4) then filtered and evaporated to dryness. The residue was subjected to column chromatography on silica gel eluting with 0-1% methanol/chloroform. This gave the title compound (D7) as an oil (0.04 g, 23%). A portion of this material was converted to the oxalate salt and crystallised from ethanol/diethyl ether to give a white crystalline solid m.p. 157°-158° C.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH3:18])=[C:8]([CH:11]=1)[CH:9]=[O:10]>CO.[NH4+].[Cl-]>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH3:18])=[C:8]([CH2:9][OH:10])[CH:11]=1
Reactant: CC1CCCCN1c1ccc(Br)cc1C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC1CCCCN1c1ccc(Br)cc1CO
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Sodium borohydride (2.2 g, 57.8 mmol) was added portion-wise into a solution of 5-bromo-2-(2-methylpiperidin-1-yl)benzaldehyde (16.3 g, 57.8 mmol) in MeOH (300 mL) cooled at 5° C. After 30 min, the reaction mixture was diluted with a saturated aqueous solution of NH4Cl (300 mL) and extracted with EtOAc (600 mL+300 mL). The organic layers were washed with a saturated aqueous solution of NH4Cl (150 mL) and brine (300 mL). The organic layers were combined, dried (MgSO4) and the solvents were removed under reduced pressure to give the title compound as a yellow oil (15.9 g, 97%) used without further purification in the next step. HPLC (Method A), Rt 2.1 min (Purity: 94.9%). UPLC/MS, M+(ESI): 284.1, 286.0. 1H NMR (CDCl3, 300 MHz) δ 7.38 (dd, J=8.5, 2.4 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.40 (brs, 1H), 4.86 (d, J=13.9 Hz, 1H), 4.67 (d, J=13.9 Hz, 1H), 3.06-2.88 (m, 2H), 2.61 (td, J=11.4, 3.2 Hz, 1H), 1.88-1.58 (m, 4H), 1.53-1.32 (m, 2H), 0.90 (d, J=6.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:12]#[N:13])=[CH:5][NH:6]2.ClC1C=CC=C2C=1C=CN2.ClS([N:28]=[C:29]=[O:30])(=O)=O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:12]#[N:13])=[CH:5][N:6]2[C:29]([NH2:28])=[O:30]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: N#CCc1c[nH]c2cccc(Cl)c12
Agent: Clc1cccc2[nH]ccc12
Solvent: ClCCl
Product: N#CCc1cn(C(N)=O)c2cccc(Cl)c12
Reaction time: 1.5 h
Yield: 62 %

Procedure:
The (4-chloro-1H-indol-3-yl)-acetonitrile used in step 1 was prepared from commercially obtained 4-chloro-1H-indole (Aldrich Chemical Co. Cat. No. 24,622-0) using the procedure of steps 4 and 5 of Example 1. To (4-chloro-1H-indol-3-yl)-acetonitrile (500 mg, 2.62 mmol) dissolved in anhydrous dichloromethane (10 mL) was added chlorosulfonyl isocyanate (0.92 mL, 10.50 mmol). After 1.5 hours, the reaction was filtered and the resulting solid was washed with dichloromethane. The solid was then dissolved in acetone and water (2.5 mL) was added. The reaction mixture was concentrated to dryness to yield 4-Chloro-3-cyanomethyl-indole-1-carboxylic acid amide as a pale pink solid (377 mg, 62%). 1H NMR (DMSO-d6) δ: 4.27 (br s, 2H), 7.28 (m, 2H), 7.78 (br s, 2H), 7.98 (s, 1H), 8.28 (m, 1H); M+233.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29]C)=[O:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.O>CC1(C)NC=NC1=O>[C:3]1([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2nccc(Br)c2c1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CC1(C)NC=NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2nccc(Oc3ccc(-c4ccccc4)cc3)c2c1
Reaction time: 3 h
Yield: 56.9 %

Procedure:
60% Sodium hydride (38 mg) was suspended in dimethylimidazolinone (1 ml). 4-Phenylphenol (160 mg) was added while stirring under water-cooling, and the mixture was stirred under water-cooling for 0.5 hr. Methyl 4-bromo-6-quinolinecarboxylate (100 mg) was added under water-cooling and the mixture was stirred at 100° C. for 5 hr, and then at 140° C. for 3 hr. Water (10 ml) was added to the reaction mixture and the mixture was extracted once with ethyl acetate. The aqueous layer was made adjusted to pH 4 with 1N hydrochloric acid and the resulting solid was collected by filtration to give the object compound (73 mg) as a pale brown powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][CH:38]=1)[O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH:27]=[C:28]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[N:29]=2)[N:26]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[CH:33]1([C:31]([NH:30][C:28]2[N:29]=[C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]4[CH:18]=[C:17]([NH:16][C:7]([C:4]5[CH:3]=[C:2]([CH3:1])[O:6][N:5]=5)=[O:9])[CH:38]=[CH:37][CH:36]=4)=[N:26][N:25]3[CH:27]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: Cc1cc(C(=O)O)no1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)no1
Yield: 57.5 %

Procedure:
Using 5-methylisoxazole-3-carboxylic acid (87 mg, 0.679 mmol), N,N-dimethylformamide (1 drop), oxalyl chloride (75.8 μL, 0.88 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (140 mg, 0.453 mmol), triethylamine (138 mg, 1.36 mmol) and tetrahydrofuran (15 mL) as starting materials and in the same manner as in Example 109, the title compound (109 mg, 58%) was obtained as a white powder.
Reaction SMILES: [Br:1][C@@H:2]([CH3:6])[C:3](O)=[O:4].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.ClCCl>O1CCCC1>[Br:1][C@@H:2]([CH3:6])[C:3]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)=[O:4]
Reactant: Cc1cccc(N)c1
Reactant: C[C@H](Br)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(NC(=O)[C@H](C)Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-(−)-2-bromopropionic acid (0.25 mL, 2.77 mmol), m-toluidine (0.30 mL, 2.77 mmol) and 1-hydroxybenzotriazole hydrate (560 mg, 4.16 mmol) in tetrahydrofuran (25 mL) was added a 1M solution of 1,3-dicyclohexylcarbodiimide in dichloromethane (5.54 mL, 5.54 mmol). The mixture was stirred at about 0° C. for about 2 hours, then it was warmed to room temperature and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (2:1) as eluent to provide the desired product. MS (DCI-NH3): m/z 259, 261 (M+NH4)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.C(N(CC)CC)C.[CH3:41][S:42][CH2:43][CH2:44][C:45](Cl)=[O:46].O>O1CCCC1>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:45](=[O:46])[CH2:44][CH2:43][S:42][CH3:41])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: CSCCC(=O)Cl
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CSCCC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (230 mg) and triethylamine (0.61 mL) in tetrahydrofuran (8.0 mL) was added 3-(methylthio)propionyl chloride (0.15 mL) under ice-cooling. After stirring at room temperature for 20 hrs, water was added, and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=9:1) to give the title compound (133 mg) as colorless crystals.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].N([O-])=O.[Na+].[OH-].[K+].[C:20](Cl)(=[O:23])[CH:21]=[CH2:22].C(N[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)CO)(=O)C=C>O.C(Cl)Cl>[C:20]([N:2]([CH3:1])[CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5])(=[O:23])[CH:21]=[CH2:22]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C=CC(=O)Cl
Agent: C=CC(=O)N[C@@H](CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 41 %

Procedure:
N-methyl-1-amino-1-deoxy-D-glucitol (0.5 mol, 97.6 g) was dissolved in about 300 ml of water. Then 1-2 g of sodium nitrite was added and the solution was cooled in an ice bath. Potassium hydroxide (0.6 mole) was dissolved in water and cooled. Acryloyl chloride (0.55 mole) was mixed with an equal volume of methylene chloride. The reaction was done in the same way as described in step 3 for the synthesis of N-acryloyl-2-amino-2-deoxy-D-glucitol. The salts were also removed as described above. However, even after several weeks long evaporation from a crystallization dish, the product was not dry. After addition of more polymerization inhibitor, drying was continued in a desiccator. The semi-dry mass (yield 41-60%) was dissolved in warm dioxane which contained p-methoxy phenol. The warm solution was filtered through Celite and upon cooling the crystals were formed. They were collected and recrystallized from dioxane. The title compound is very hygroscopic.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:33]=[CH:32][C:11]([CH2:12][NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:31]=[CH:30][C:29]4[O:28][CH2:27][O:26][C:25]=4[CH:24]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][C:8]1[CH:33]=[CH:32][C:11]([CH2:12][NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:31]=[CH:30][C:29]4[O:28][CH2:27][O:26][C:25]=4[CH:24]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1
Reactant: O=C(NCc1ccc(OC2CCCCO2)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C(NCc1ccc(O)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-piperonylpiperazine-1-carboxylic acid 4-(tetrahydropyran-2-yloxy)benzylamide (1.1 g, 2.43 mmol) in methanol (50 mL) was added p-toluenesulfonic acid monohydrate (1.0 g, 5.26 mmol), and the resulting solution was stirred for 1 hour at room temperature. The resulting reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield 330 mg of the title compound.