Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:26]2[CH:31]=[CH:30][C:29](C3OCC(C)(C)N=3)=[CH:28][CH:27]=2)([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=1)(C)(C)C.C[C:41]([OH:43])=[O:42]>CO.C(Cl)(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:18]([OH:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:26]2[CH:31]=[CH:30][C:29]([C:41]([OH:43])=[O:42])=[CH:28][CH:27]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC1(C)COC(c2ccc(C(O)(c3ccccc3)c3cccc(OCCCNC(=O)OC(C)(C)C)c3)cc2)=N1
Reactant: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NCCCOc1cccc(C(O)(c2ccccc2)c2ccc(C(=O)O)cc2)c1
Temperature: 75 °C
Yield: 96 %

Procedure:
In a 50 mL round bottomed flask placed with [3-(3-{[4-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-phenyl]-hydroxy-phenyl-methyl}-phenoxy)-propyl]-carbamic acid tert-butyl ester (3, 220 mg) was added 3 mL of 80% aqueous AcOH and the reaction mixture was heated 75° C. for overnight. Then the reaction mixture was concentrated and dried and added 3 mL of 20% NaOH/EtOH (1:1, v/v) and refluxed for 3 h. Residue obtained on evaporation of the solvent was dissolved in CH3OH/CHCl3 mixture and adsorbed with silica gel and dried. The dried silica gel with compound was purified by silica gel column already flashed with 1% NH4OH in Et2O solution. Elution of the column at 50% CH3OH/CH2Cl2 gave 4-{[3-(3-Amino-propoxy)-phenyl]-hydroxy-phenyl-methyl}-benzoic acid, 4 as a colorless gelly solid. Yield: 96%. Mass: 378 (MH+), 376 (M-H), 360 (M-OH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][N:18]=3)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:27]1[C:28]2[CH:29]=[C:30]3[O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][C:31]3=[CH:32][C:33]=2[N:34]=[CH:35][N:36]=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:27]4[C:28]5[CH:29]=[C:30]6[O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][C:31]6=[CH:32][C:33]=5[N:34]=[CH:35][N:36]=4)=[CH:19][N:18]=3)=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: Clc1ncnc2cc3c(cc12)OCCOCCOCCO3
Reactant: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(O)cn2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(Oc3ncnc4cc5c(cc34)OCCOCCOCCO5)cn2)c1=O
Temperature: 25 °C
Yield: 93.6 %

Procedure:
2-(4-Fluoro-phenylamino)-5-(5-hydroxy-pyridin-2-yl)-3-methyl-3H-pyrimidin-4-one (2.18 g, 7 mmol) was dissolved in dry DMF (30 ml) to which was added 60% NaH (774 mg, 19.3 mmol). After the mixture was stirred at room temperature for several minutes, a suspension of 4-Chloro-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]-naphthalene (2.08 g, 6.7 mmol) in dry DMF (40 ml) was added. The reaction mixture was stirred at room temperature for 1-2 hrs, then diluted with EtOAc and washed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give crude title compound and further purification to yield product (3.68 g, 90%). 1HNMR (400 MHz, DMSO): 9.18 (s, 1H), 8.60 (m, 3H), 8.45 (d, 1H), 7.84 (s, 1H), 7.82 (m, 1H), 7.55 (m, 3H), 7.21 (m, 2H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+587.6. found 587.9.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([C:12]1[C:13](=[O:23])[O:14][C:15]([OH:22])=[C:16]([C:19](=O)[CH3:20])[C:17]=1[OH:18])(=[O:11])[CH3:10]>CO>[C:9]([C:12]1[C:13](=[O:23])[O:14][C:15](=[O:22])[C:16](=[C:19]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:20])[C:17]=1[OH:18])(=[O:11])[CH3:10]
Reactant: Nc1ccc(F)cc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(F)cc2)C(=O)OC1=O

Procedure:
p-Fluoroaniline (2.2 g., 0.02 m.) is added to a hot solution of 4.24 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of methanol. The mixture is refluxed overnight and filtered to give 5-acetyl-3-[1-(p-fluorophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6-(3H)-dione, m.p. 199°-201° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10]([NH:12][C:4]2=[CH:3][CH:2]=1)=O)=[O:8].C(Cl)(Cl)(Cl)Cl.CCN(C(C)C)C(C)C.P([O-])(OCC1C=CC=CC=1)OCC1C=CC=CC=1>CC#N.CN(C1C=CN=CC=1)C>[CH:1]1[CH:2]=[CH:3][C:4]2[N:12]=[CH:10][NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Agent: CN(C)c1ccncc1
Agent: [O-]P(OCc1ccccc1)OCc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]cnc2ccccc12
Reaction time: 0.17 h
Yield: 185.4 %

Procedure:
The quinazoline 1 (0.2 g, 0.62 mmol) was dissolved in CH3CN (5 mL). After cooling to −10° C. (ice/NaCl), CCl4, DIEA and DMAP were added. After stirring for 10 min, a solution of dibenzyl phosphite in CH3CN (2 mL) was slowly added over 10 min. Stirring was continued at −10° C. for 2 h, then at RT for 24 h. Quenched by addition of 0.5 M K2HPO4, diluted with water (15 mL), extracted with DCM (30 mL), dried, concentrated, purified by flash chromatography (100% DCM) to obtain 2 (168 mg, 47% yield) as a colorless oil. LC/MS (10-99%) M/Z 586.0 retention time 2.54 min.
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])C.C[C:7]([CH3:10])([O-])[CH3:8].[K+].[CH2:12]1[CH2:16]OC[CH2:13]1>O>[CH2:13]=[CH:12][CH:16]=[CH:8][CH2:7][CH2:10][CH2:3][CH2:1][CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: C=CC=CCCCCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The latter compound (5.4 g) was dissolved in 20 mL of 1:9 THF:tert-butanol and added dropwise to an ice cold solution of potassium tert-butoxide (6.75 g) in 100 mL of 1:9 THF:tert-butanol. The reaction mixture was stirred in ice for 1 hour and at room temperature for 0.5 hours. The reaction mixture was diluted with water (200 mL) and extracted with pentane (2×75 mL). The combined organic layer was washed with water (4×150 mL). The organic layer was separated, dried with anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to give an oil. Distillation gave 1.79 g (72% yield) of a 2:1 mixture of (Z)- and (E)-1,3-nonadiene as established by NMR, IR and capillary GC analysis.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=O.[CH3:22][C:23](=O)[CH2:24][C:25](=[O:27])[CH3:26]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:24]([C:25](=[O:27])[CH3:26])=[C:23]([CH3:22])[N:1]=[C:2]3[S:6][C:5]4[CH2:7][CH2:8][CH2:9][C:4]=4[C:3]=23)=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: CC(=O)CC(C)=O
Reactant: CS(=O)(=O)c1ccc(C(=O)c2c(N)sc3c2CCC3)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccc(S(C)(=O)=O)cc1)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 31.1 %

Procedure:
To a stirred solution of 50 mg (0.15 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-methanesulfonyl-phenyl)-methanone (described above) in 2 ml acetic acid was added 0.011 ml (0.15 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 18 mg (30%) 1-[4-(4-methanesulfonylphenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a light brown solid. ES-MS m/e (%): 386 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20]([OH:22])=O)=[CH:11]2)[C:4]=1[CH3:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:49][CH2:50][C@H:51]([OH:53])[CH3:52]>C(Cl)Cl>[OH:53][C@H:51]([CH3:52])[CH2:50][NH:49][C:20]([C:12]1[C:13]2=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:23])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:22]
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(C)cc32)c1C
Reactant: C[C@@H](O)CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncnc(Cn2cc(C(=O)NC[C@@H](C)O)c3ncc(C)cc32)c1C
Temperature: 25 °C
Yield: 39.5 %

Procedure:
See FIG. 23(c). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (75 mg, 0.24 mmol) was taken in a thermal reactor. DCM (5 mL) was added to get a suspension. Added triethyl amine (0.067 mL, 0.48 mmol) followed by the addition of 1-Propanephosphonic acid cyclic anhydride (0.286 mL, 0.48 mmol). (R)-1-aminopropan-2-ol (36.1 mg, 0.48 mmol) was added and stirred at RT for ON. After completion of the reaction, reaction mixture was concentrated and dissolved in DCM:MeOH. This crude compound was subjected for reverse phase purification to obtain (R)—N-(2-hydroxypropyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (35.0 mg, 39.5%) as a off-white solid. ES+MS m/z: 370 (M+I). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10 (d, J=5.84 Hz, 3 H ) 2.24 (s, 3 H ) 2.39 (s, 3 H ) 3.16-3.29 (m, 1 H ) 3.37-3.48 (m, 1 H ) 3.77 (br. s., 1H ) 3.93 (s, 3 H ) 4.85 (d, J=4.33 Hz, 1 H ) 5.63 (s, 2 H ) 7.74 (s, 1 H ) 8.12 (s, 1 H ) 8.33 (s, 1 H ) 8.41 (s, 1 H ) 8.82 (br. s., 1 H ).
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][N:19]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:20]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]4[CH:33]=[CH:34][C:35]([CH:37]([OH:40])[CH2:38][CH3:39])=[CH:36][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.OI1(=O)C2C=CC=CC=2C(=O)O1.C(OCC)(=O)C>CS(C)=O>[C:1]1([CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][N:19]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:46])([CH3:47])[CH3:48])[C:20]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:31])[CH3:32])[C:23]4[CH:33]=[CH:34][C:35]([C:37](=[O:40])[CH2:38][CH3:39])=[CH:36][C:22]=4[N:21]=3)[CH2:16][CH2:17]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)c1ccc2c(c1)nc(N(COCC[Si](C)(C)C)CC1CCN(Cc3cccc4ccccc34)CC1)n2COCC[Si](C)(C)C
Agent: O=C1OI(=O)(O)c2ccccc21
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC(=O)c1ccc2c(c1)nc(N(COCC[Si](C)(C)C)CC1CCN(Cc3cccc4ccccc34)CC1)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-ol (72 mg, 0.10 mmol) in dimethylsulfoxide (1 ml) was added to a solution of 1-hydroxy-1-oxo-1H-1λ5-benzo[d][1,2]iodoxol-3-one (44 mg, 0.157 mmol) in dimethylsulfoxide (1 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice water (50 ml) and stirred at room temperature for 30 minutes, after which ethyl acetate was added and stirring was continued vigorously for 10 minutes for extraction. After washing with saturated aqueous sodium bicarbonate and then with saturated brine, the mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1-[2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazol-5-yl]-propan-1-one.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>C(Cl)Cl>[CH3:17][S:18]([O:9][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:20])=[O:19]
Reactant: OCc1cccnc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCc1cccnc1F
Reaction time: 0.5 h

Procedure:
To a solution of (2-fluoropyridin-3-yl)methanol (200 mg, 1.57 mmol) and triethylamine (658 μL, 4.72 mmol) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (269 mg, 2.36 mmol). The reaction mixture was kept at 0° C. for 30 min., poured into water, and the mixture was extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH2:12])=[O:11])[N:5]=[CH:4][C:3]=1[NH:13][C@@H:14]1[CH2:19][C@@H:18]2[CH2:20][C@@H:16]([C:17]2([CH3:22])[CH3:21])[C@H:15]1[CH3:23].CO[CH:26](OC)[N:27](C)C.[O:32]1[CH2:36]CCC1.O.Cl.CON>O1CCCC1.CN(C)C=O.O>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12]/[CH:26]=[N:27]\[O:32][CH3:36])=[O:11])[N:5]=[CH:4][C:3]=1[NH:13][C@@H:14]1[CH2:19][C@@H:18]2[CH2:20][C@@H:16]([C:17]2([CH3:22])[CH3:21])[C@H:15]1[CH3:23]
Reactant: C1CCOC1
Reactant: COC(OC)N(C)C
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(N)=O)c(=O)c1Cl)C2(C)C
Agent: CON
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CO/N=C\NC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O
Yield: 78 %

Procedure:
2-[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetamide (32 mg, 0.0944 mmol) in tetrahydrofuran/N,N-dimethylformamide (1/0.1 mL) was stirred with 1,1-dimethoxy-N,N-dimethylmethanamine (25 μL, 0.188 mmol) at room temperature for 3 hours. The reaction solution was concentrated and stirred with tetrahydrofuran/water (1/2 mL) and methoxyamine hydrochloride (12 mg, 0.143 mmol) at room temperature for 2 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (29 mg, 78% yield).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([C:15]([O-:17])=[O:16])[CH2:10][CH2:11][C:12](=O)[CH:13]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CCO[C:27]([CH3:29])=O>C1(C)C=CC=CC=1>[Cl:21][C:12]1[CH:13]=[C:8]([C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=2)[CH:9]([C:15]([O:17][CH2:27][CH3:29])=[O:16])[CH2:10][CH:11]=1
Reactant: Cc1ccc(C2=CC(=O)CCC2C(=O)[O-])cc1
Reactant: CCOC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC=C(Cl)C=C1c1ccccc1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(4-methylphenyl)-4-oxocyclohex-2-enecarboxylate(1.24 g, 5.1 mmol) in toluene(10 ml) was added oxalyl chloride(2.58 g, 20.4 mmol). After stirring for 2 hr. at 70-75° C., AcOEt was added to the reaction mixture and washed with water, sat.NaHCO3 and brine, dried over MgSO4. Concentration afford 1.24 g of ethyl 4-chloro-2-phenylcyclohexa-2,4-dienecarboxylate and ethyl 4-chloro-2-phenylcyclohexa-1,3-dienecarboxylate(y=93.0%) as a pale yellow oil. This product was used at next step without purification. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.25-7.45(8H), 7.13-7.16(2H), 6.35(1H, s), 6.19(1H, s), 5.87(1H, brs), 4.09(2H, q, J=7.3 Hz), 3.93(2H, q, J=7.3 Hz), 3.64(1H, dd, J=3.8 and 8.6 Hz), 2.90-3.05(1H, m), 2.60-2.85(5H), 1.34(3H, t, J=7.3 Hz), 0.89(3H, t, J=7.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]3[CH2:17][CH3:18])=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=[N:6][N:5]2[CH:22]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][N:14]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:13][C@H:12]3[CH2:17][CH3:18])=[C:8]([C:19]([NH2:21])=[O:20])[CH:7]=[N:6][N:5]2[CH:22]=1
Reactant: CC[C@@H]1CNCC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H]1CN(S(C)(=O)=O)CC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a solution of 6-bromo-4-(((3R,4R)-3-ethylpiperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 2 of Example 125 (150 mg, 0.410 mmol) and DIEA (429 μl, 2.457 mmol) in DMF (2.7 ml) was added methanesulfonyl chloride (47.5 μl, 0.614 mmol). The reaction was stirred at room temperature for 2 hrs. After removal of the solvent, the residue was dissolved in ethyl acetate, washed successively with saturated ammonium chloride, water, and brine; dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via medium pressure chromatography (silica gel column, EtOAc/hexanes eluent, 0-100% gradient elution) to yield 6-bromo-4-(((3R,4R)-3-ethyl-1-(methylsulfonyl)piperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (95 mg, 0.214 mmol, 52.2% yield) as a yellow solid. LCMS (Method K) m/z 446.0 ([M+H]+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:8][Si:9]([CH3:11])([CH3:10])[C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of iodobenzene (1 mmole) in DMF (5 mL) was treated with trimethylsilylacetylene (2 mmole), Pd(PPh3)2Cl2 (0.035 mmole), CuI (0.08 mmole) and triethylamine (4 mmole), and the resulting reaction mixture was stirred under nitrogen at room temperature for 5 h. Evaporation followed by chromatography gave 1-trimethylsilyl-2-phenylacetylene as a solid.
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl.[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:14]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCO
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Agent: Cl
Product: CCCCCCCCOC(=O)C(N)/C=C/CP(=O)(O)O

Procedure:
2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of n-octanol and the suspension is saturated with hydrogen chloride gas for 4 hours at 70°. The mixture is concentrated in vacuo at 70° to half its volume, 50 ml of diethyl ether and 15 ml of propylene oxide are added and the whole is filtered. Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphono-3-pentenoic acid octyl ester, m.p. 161°-162°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]1([O:30][C:31](Cl)=[O:32])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:31](=[O:32])[O:30][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)Oc1cccc2ccccc12
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)Oc1cccc2ccccc12

Procedure:
According to the general method of Example 7, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and chloroformic acid 1-naphthyl ester were combined to provide 1-naphthyl N-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a tan powder, m.p. 89.0-92.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.10 (d, J=7.4 Hz, 1H), 8.05 (t, J=5.8 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.66-7.45 (m, 6H), 7.30 (m, 1H), 7.19 (d, J=7.5 Hz, 1H), 6.72 (broad s, 2H), 4.67 (t, J=6.9 Hz, 2H), 3.17 (q, J=6.3 Hz, 2H), 1.96 (m, 2H), 1.59 (m, 2H); MS (EI) m/e 426.1929 (426.1930 calcd for C25H23N5O2).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]=[O:8].CC1N=C(C2C=NC([C:33]([F:36])([F:35])[F:34])=CC=2)SC=1CO.FC([Si](C)(C)C)(F)F.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:34][C:33]([F:36])([F:35])[CH:7]([C:6]1[S:5][C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)=[N:3][C:2]=1[CH3:1])[OH:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1CO
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(F)(F)F
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1C(O)C(F)(F)F
Temperature: 25 °C

Procedure:
To an ice cooled solution of 2.0 g 4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazole-5-carbaldehyde (derived from [4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-methanol according to the method described for 4-Methyl-2-(trans-1,4-trifluoromethyl-cyclohexyl)-thiazole-5-carbaldehyde) and 1.09 ml (trifluoromethyl)trimethylsilane in 10 ml tetrahydrofuran were added 100 mg tetrabutylammoniumfluoride. The reaction mixture was stirred at room temperature for thirty minutes. Then 20 ml 2N HCL were added and the mixture stirred at room temperature for thirty minutes. The mixture was extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo to obtain 1.5 g 2,2,2-Trifluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-ethanol as a solid.
Reaction SMILES: O=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]#[N:13])[CH:9]=2)[N:4]=[CH:3]1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]#[N:13])=[CH:7][CH:6]=2
Reactant: N#Cc1ccc2ncc(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2ncc(Cl)nc2c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A solution of 3-oxo-3,4-dihydro-quinoxaline-6-carbonitrile (5.99 g, 35 mmol, 1.0 eq) in phosphorus oxychloride (26 mL, 280 mmol, 8.0 eq) is heated under reflux for 1 hour. Then the reaction mixture is cooled down to room temperature and the solvent is evaporated. The residue is poured into ice water, the resulting mixture is neutralized with sodium carbonate and extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: dichloromethane 100%) to afford 3-chloro-quinoxaline-6-carbonitrile as a white solid (5.27 g, 79% yield).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:11])[CH:3]=1.Cl.[CH:13]([O:16][NH2:17])([CH3:15])[CH3:14]>CO>[CH:13]([O:16][N:17]=[CH:6][C:5]1[C:4]([CH3:11])=[CH:3][C:2]([NH2:1])=[C:9]([CH3:10])[CH:8]=1)([CH3:15])[CH3:14]
Reactant: CC(C)ON
Reactant: Cc1cc(C=O)c(C)cc1N
Agent: Cl
Solvent: CO
Product: Cc1cc(C=NOC(C)C)c(C)cc1N
Yield: 80.8 %

Procedure:
0.32 g (2.10 mmol) of 4-amino-2,5-dimethylbenzaldehyde is initially charged in 10 ml of methanol, 0.31 g (2.73 mmol) of O-isopropyl hydroxylamine hydrochloride is added at room temperature and the reaction mixture is heated under reflux for 6 h. The mixture is then concentrated using a rotary evaporator, the residue is taken up in dichloromethane, extracted twice with water, dried over Na2SO4 and freed from the solvent under reduced pressure. This gives 0.35 g of product (purity 98.0%, yield 79.1%, log P (pH 2.3)=2.77).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[N:7][C:8]#[N:9])OCC.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].[O-:18]CC.[Na+]>C(O)C>[Cl:1][CH2:2]/[C:3](/[NH:7][C:8]([NH2:9])=[O:18])=[C:12](\[C:10]#[N:11])/[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC[O-]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(CCl)=NC#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)/C(C#N)=C(/CCl)NC(N)=O
Reaction time: 1 h
Yield: 17.9 %

Procedure:
A solution of 20 g of ethyl 2-chloro-N-cyanoacetoimidate (20), 16.6 g of ethyl cyanoacetate (21) and 9.28 g of sodium ethoxide in ethanol (350 ml) was stirred at room temperature for 3 hours. After the reaction mixture was distilled, 140 ml of 2 N hydrochloric acid were added, followed by stirring under ice cooling for 1 hour. After the reaction mixture was neutralized with a 2 N aqueous solution of sodium hydroxide, the resultant mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue so obtained was purified by chromatography on a silica gel column while using gradient elution with hexane-ethyl acetate, whereby 5.66 g of the title compound were obtained (yield: 18%).