Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].I[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=2[C:22]=1[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])[O:15][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=2[C:22]=1[CH2:35][CH2:36][CH3:37]
Reactant: CCCc1c(O)ccc(C(=O)NC)c1O
Reactant: CCCc1c(OCCCI)ccc2c1OC(C(=O)OC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(=O)NC)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 10 (200 mg, 0 96 mmol), the compound of Example 23 (400 mg, 0.96 mmol) and potassium carbonate (264 mg, 1.92 mmol) were added to about 20 ml of DMF. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and concentrated under vacuum. Chromatography of the crude material on silica gel with 30% ethyl acetate/hexane as eluant followed by rechromatography using the same solvent system gave the product.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)[CH:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]4)[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1cn(CC2CCCCC2)c2ccccc12
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cn(CC3CCCCC3)c3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(1-cyclohexylmethyl-1 H-indol-3-yl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(1-cyclohexylmethyl-1 H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)-benzamide.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1.N1C=CC=C[CH:25]=1.Cl.S(Cl)(Cl)=O>CO>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:25])=[O:12])=[CH:5][C:4]=1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1
Reactant: COc1ccc(CCC(=O)O)cc1-c1ccc2ccccc2c1
Reactant: c1ccncc1
Agent: Cl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(O)c(-c2ccc3ccccc3c2)c1

Procedure:
According to the procedure described in the synthesis method of Intermediate 20 in Reference Example 6 (Step f), Intermediate 35 (551 mg), pyridine and concentrated hydrochloric acid (5 ml each) were reacted and treated. According to the procedure described in the synthesis method of Intermediate 1 in Reference Example 1 (Step c), the obtained residue was reacted with thionyl chloride (0.33 ml) in methanol to obtain the title compound (Intermediate 36, 531 mg).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[N:10]([O-])=O.[Na+].[ClH:14]>O>[ClH:14].[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:10])=[C:4]([CH3:9])[CH:3]=1
Reactant: O=N[O-]
Reactant: Cc1cc(Br)ccc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)ccc1NN
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71 %

Procedure:
To a solution of 4-bromo-2-methylaniline (2.50 g, 13.44 mmol) in concentrated HCl (5.4 mL) at 0° C. was added a cold solution of sodium nitrite (1.02 g, 14.78 mmol) in water (5.1 mL). Stirring was continued at 0° C. for 45 min then the mixture was filtered. To the filtrate at 0° C. was added a solution of tin(II) chloride in concentrated HCl (9.5 mL). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was made basic at 0° C. with 40% NaOH solution and extracted three times with diethyl ether. The combined organic extracts was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting solid was treated with 1.25 M HCl in methanol (30 mL), stirred for 10 min at 0° C. then concentrated in vacuo to give a pale yellow solid. The solid was triturated with diethyl ether and dried in vacuo to give (4-bromo-2-methylphenyl)hydrazine hydrochloride (2.26 g, 71%) as an off-white solid: 1H NMR (DMSO-d6, 300 MHz): δ 10.27 (br s, 3H), 7.97 (br s, 1H), 7.35 (m, 2H), 6.89 (d, J=8.2 Hz, 1H), 2.18 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:18]1([NH2:22])[CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH:18]1([NH:22][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([N:7]3[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)=[CH:11][CH:12]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCC1
Reactant: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(=O)N1CCN(c2ccc(CNC3CCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.6 %

Procedure:
To a solution of 4-(4-acetylpiperazin-1-yl)benzaldehyde (150 mg, 0.64 mmol) and cyclobutylamine (75 mg, 0.77 mmol) in dichloroethane (1.5 mL) was added sodium triacetoxyborohydride (216 mg, 0.96 mmol), followed by acetic acid (0.055 mL, 0.96 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was then quenched with 1 N aqueous NaOH, diluted with dichloromethane and the dichloromethane layer was isolated with a phase-separator cartridge and concentrated to give 1-(4-(4-((cyclobutylamino)methyl)phenyl)piperazin-1-yl)ethanone (185 mg). The product was used without purification. LCMS (m/z) ES+ 288 [M+1]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:24]([CH:25]=O)=[CH:23][N:22]=[C:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1.[CH2:38](P(=O)(OCC)OCC)[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42].[H-].[Na+].Cl>O.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:24](/[CH:25]=[CH:38]\[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:23][N:22]=[C:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1
Reactant: COc1cc(COc2nc(-c3ccccc3)ncc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C\c1cnc(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.5 %

Procedure:
To a mixture of 4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidine-5-carbaldehyde (1.00 g), tetraethyl methylenediphosphonate (0.58 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.090 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, 2N hydrochloric acid was added to acidify the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (2:3, v/v) to give diethyl (Z)-2-(4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidin-5-yl)ethenylphosphonate as crystals (0.095 g, yield 7%). Recrystallization from acetone-hexane gave colorless needle crystals. melting point: 154-155° C.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[CH3:19][N:20]1[CH:24]=[C:23](I)[CH:22]=[C:21]1[C:26]([O:28][CH3:29])=[O:27]>>[CH3:19][N:20]1[CH:24]=[C:23]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:14]=[CH:13][C:12]3[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=3[CH:6]=2)[CH:22]=[C:21]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1cc(I)cn1C
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: COC(=O)c1cc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cn1C

Procedure:
Following the basic procedure of Example 11(d), by reacting 2.9 g (12 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 3.2 g (12.1 mmol) of methyl N-methyl-4-iodo-2-pyrrolecarboxylate, 2.8 g (61%) of the expected ester, with a melting point of 150°-152° C., were recovered by trituration in isopropyl ether.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([NH:24][CH2:25][C:26]([OH:28])=O)=[O:23])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[C:29]([NH:33][C:26](=[O:28])[CH2:25][NH:24][C:22]([N:19]1[CH2:18][CH2:17][C:16](=[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1)=[O:23])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N
Reactant: O=C(O)CNC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CNC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
300 mg (0.801 mmol) of ({[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]carbonyl}amino)acetic acid, 1.0 ml (0.961 mmol) of t-butylamine and 230 mg (1.20 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 10 ml of dichloromethane. The obtained solution was stirred at room temperature for 1 hour. Water was added to the reaction mixture. After extracting with dichloromethane, the dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue thus obtained was purified by the silica gel chromatography (dichloromethane: methanol=4:1 to 1:9) to obtain the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[CH2:10][CH2:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)=[O:2].[F:39][C:40]([Si](C)(C)C)([F:42])[F:41].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:24][C:17]([O:16][C:15]1[CH:25]=[CH:26][C:12]([CH2:11][CH2:10][N:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]([OH:2])[C:40]([F:42])([F:41])[F:39])=[CH:8][N:7]=2)[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[CH:13][CH:14]=1)([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C=O)cn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C(O)C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A solution of ethyl 2-[4-(2-{(5-formylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (400 mg; 0.75 mmol) in 5 ml of dry THF was treated in an ice bath, under nitrogen, with trifluoromethyltrimethylsilane (128 mg; 0.90 mmol), followed by tetrabutylammonium fluoride (0.075 ml of a 1M solution in THF; 0.075 mmol). The reaction mixture was allowed to warm to rt and stirred overnight. Additional trifluoromethyltrimethylsilane (128 mg; 0.90 mmol) and tetrabutylammonium fluoride (0.075 ml) were added. After 6 hours the previous reagents were added again in the same amounts. After stirring at rt overnight, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. Purification by radial chromatography using ethyl acetate-hexane mixtures (5–40% gradient) afforded ethyl 2-methyl-2-[4-(2-{[5-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoate (247 mg; 55% yield).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:38]=[C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH2:45][C:46]5[CH2:51][CH2:50][C:49]([CH3:53])([CH3:52])[CH2:48][C:47]=5[C:54]5[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=5)[CH2:41][CH2:40]4)[CH:36]=[CH:35][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:21]([N+:32]([O-:34])=[O:33])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:61][C:62]([CH3:64])=O.C([BH3-])#N>O1CCCC1.C(O)(=O)C>[Cl:60][C:57]1[CH:56]=[CH:55][C:54]([C:47]2[CH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][CH2:51][C:46]=2[CH2:45][N:42]2[CH2:41][CH2:40][N:39]([C:37]3[CH:36]=[CH:35][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH:26]5[CH2:31][CH2:30][N:29]([CH:62]([CH3:64])[CH3:61])[CH2:28][CH2:27]5)=[C:21]([N+:32]([O-:34])=[O:33])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:38]=3)[CH2:44][CH2:43]2)=[CH:59][CH:58]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCNCC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1CCC(Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCN(CC5=C(c6ccc(Cl)cc6)CC(C)(C)CC5)CC4)cc3Oc3cnc4[nH]ccc4c3)cc2[N+](=O)[O-])CC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 226B (79 mg) in tetrahydrofuran (3 mL) and acetic acid (1 mL) was added acetone (54 mg) and MP-cyanoborohydride (150 mg, 2.25 mmol/g). The mixture was stirred overnight. The mixture was filtered. The filtrate was concentrated and the residue was loaded on a silica gel cartridge and eluted with 5 to 10% 7N NH3 in methanol in dichloromethane to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 12.09 (s, 1H), 8.34 (m, 1H), 7.93 (m, 2H), 7.66 (m, 4H), 7.35 (d, 2H), 7.06 (d, 2H), 6.89 (m, 1H), 6.74 (dd, 1H), 6.59 (dd, 1H), 6.50 (d, 1H), 3.11 (m, 6H), 2.73 (m, 4H), 2.26 (m, 9H), 1.97 (s, 3H), 1.40 (t, 2H), 1.23 (s, 8H), 0.94 (s, 6H).
Reaction SMILES: C(O)C.[OH-].[Na+].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([O:18]CC)=[O:17].Cl>O>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)COc1cccc(-c2ccco2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1cccc(-c2ccco2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
10 mL of ethanol and 4.0 mL of 1N aqueous sodium hydroxide solution were added to 615 mg (2.50 mmol) of ethyl [3-(furan-2-yl)phenoxy]acetate, and the mixture was stirred at room temperature for 4 hours. 1N hydrochloric acid was added to acidify the reaction mixture, and water was added thereto. The precipitated solids were collected by filtration, washed with water, and air-dried, thereby giving 448 mg of [3-(furan-2-yl)phenoxy]acetic acid (yield: 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][N:14]([CH2:26][CH2:27][CH:28]=[C:29]4[C:35]5[CH:36]=[CH:37][CH:38]=[N:39][C:34]=5[CH2:33][O:32][C:31]5[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]4=5)[CH2:13]3)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: O=C1CN([C@@H]2CCNC2)Cc2ccc(Cl)cc2N1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CC[C@@H](N3CC(=O)Nc4cc(Cl)ccc4C3)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.7 %

Procedure:
To a solution of (R)-8-chloro-4-pyrrolidin-3-yl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.198 g, 0.58 mmol) in acetonitrile/water (8:2) (5.8 mL) was added K2CO3 (0.655 g, 4.6 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.183 g, 0.48 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (5% methanol/95% methylene chloride to 10% methanol/90% methylene chloride to 15% methanol/85% methylene chloride) to yield the title compound (0.077 g, 28%). 1H-NMR (CDCl3): δ1.55 (s, 6H), 1.74 (septet, 1H), 2.01 (sextet, 1H), 2.32-2.60 (m, 6H), 2.76 (t, 1H), 3.26 (pentet, 1H), 3.43 (d, 1H), 3.46 (s, 2H), 3.74 (s, 2H), 5.27 (bs, 2H), 6.12 (t, 1H), 6.78 (d, 1H), 6.96 (s, 1H), 7.06 (dd, 1H), 7.13 (d, 1H), 7.19-7.27 (m, 2H), 7.44 (d, 1H), 7.55 (dd, 1H), 8.47 (dd, 1H), 8.49 (s, 1H). ESI-MS m/z: 559 (M+1), retention time 1.24.
Reaction SMILES: I.[PH2](O)=O.[C:5]([C:10]1[NH:11][C:12]([CH3:16])=[C:13]([CH3:15])[CH:14]=1)([O:7][CH2:8][CH3:9])=[O:6].[CH:17](=O)[CH2:18][CH3:19].N>O.C(O)(=O)C>[C:5]([C:10]1[NH:11][C:12]([CH3:16])=[C:13]([CH3:15])[C:14]=1[CH2:17][CH2:18][CH3:19])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(C)c(C)[nH]1
Reactant: CCC=O
Agent: I
Agent: N
Agent: O=[PH2]O
Solvent: O
Solvent: CC(=O)O
Product: CCCc1c(C(=O)OCC)[nH]c(C)c1C
Yield: 40 %

Procedure:
Hydriodic acid (d 1.95, 10 ml) was slowly added to 10 ml of stirred and cooled acetic acid; hypophosphorous acid (50%, 2 ml) was then added. 2-Carbethoxy-4,5-dimethylpyrrole (0.004 mol) was added to the mixture at room temperature followed by propionaldehyde (0.008 mol). The solution was stirred 21/2 h at ca. 25° C. then poured into 200 ml of water. This was made alkaline with ammonia, extracted with ether, and the ether was evaporated to leave the crude product. This was an oil which solidified after distillation (1 × 10-4 mm). It was recrystallized from aqueous ethanol, then from ethanol m.p. 101°-104° C. (lit. 102° C), yield 40%. ##STR68##
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11]N3CCN(S(C)(=O)=O)CC3)[S:8][C:6]=2[N:7]=1.ClC1N=C(N2CC[O:41]CC2)C2C=CSC=2N=1.[Li]CCCC.CN(C=O)C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH:11]=[O:41])[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2ccsc2n1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: -60 °C

Procedure:
Scheme 7 shows the synthesis of 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine 20 by formylation of 4-(2-chlorothieno[2,3-d]pyrimidin-4-yl)morpholine 18 in THF at −78° C. with n-BuLi in hexanes (1.2 equiv.). The resulting slurry was allowed to warm up to −60° C., cooled to −78° C. and DMF (1.5 equiv.) was added slowly to afford 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde 19. To a suspension of 19, 4-(methylsulfonyl)piperazin-1-ium chloride 8 (alternatively named as 1-(methylsulfonyl)piperazine hydrochloride, 1.45 equiv.) and anhydrous sodium acetate in 1,2-dichloroethane was added trimethyl orthoformate (10 equiv.). The slurry was stirred at ambient temperature for at least 6 hours, then sodium triacetoxyborohydride was added and the reaction was stirred for 24 hours to give 20.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]([CH:13]=[CH:14][N:15]=2)[N:9]=[C:10]([Cl:12])[CH:11]=1)=O)C.O.[NH2:17][NH2:18]>C(O)C>[Cl:12][C:10]1[CH:11]=[C:6]([C:4]([NH:17][NH2:18])=[O:3])[C:7]2[N:8]([CH:13]=[CH:14][N:15]=2)[N:9]=1
Reactant: CCOC(=O)c1cc(Cl)nn2ccnc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc(Cl)nn2ccnc12
Reaction time: 0.25 h
Yield: 57 %

Procedure:
To a solution of crude 6-chloro-imidazo[1,2-b]pyridazine-8-carboxylic acid ethyl ester (5.00 g, “22 mmol”) in 40 mL of ethanol at 0-5° C. was added 10 mL of hydrazine hydrate. Yellow solid immediately precipitated. After 15 min. at 0-5° C., the solid was isolated by Buchner filtration, rinsing well with ice-cold ethanol (250 mL total) and dried by sucking air through then in vacuo. A small amount of additional solid precipated from the filtrate and was isolated and dried similarly to the first crop. A total of 2.38 g (57% over three steps) of 6-chloro-imidazo[1,2-b]pyridazine-8-carboxylic acid hydrazide was isolated as a yellow solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20](O)[C:21]#[CH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>C1COCC1>[Br:50][C@H:20]([C:21]#[CH:22])[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@H](O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C#C[C@@H](Br)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.75 h
Yield: 96.8 %

Procedure:
A flask was charged with (S)-1-[(tert-Butyldiphenylsilyl)oxy]-3-butyn-2-ol (1) (1.30 g, 4 mmol), triphenylphosphine (2.52 g, 9.60 mmol), THF (30 mL), pyridine (360 mg, 4.56 mmol). To this mixture was added carbon tetrabromide (1.53 g, 4.60 mmol) in THF (10 ml) over a 5 minute period. The resulting reaction mixture was stirred for 45 minutes. Hexanes (50 mL) was added, and the mixture was filtered and concentrated in vacuo. The residue was taken up into hexanes (50 mL), washed with 1 M HCl (40 mL), saturated NaCl (40 mL). The organic extracts were dried (MgSO4) and concentrated by rotary evaporation to yield a yellow oil. Purification by flash silica gel chromatography (98:02 hexane/EtOAc) afforded (R)-2-bromo-1-[tert-butyldiphenylsilyloxy]-3-butyne (4) (1.50 g, 97%) as a colorless oil (Note: this material is unstable and should be used immediately): Rf 0.74 (90:10 hexane/EtOAc); IR (neat) 3308, 1437, 1112, 701 cm-1 ; 1H NMR (CDCl3) δ 7.70 (m, 4 H), 7.42 (m, 6 H), 4.46 (dt, J1 =6.66 Hz, J2 =2.36 Hz, 1 H), 3.91 (ddd, J1 =10.7 Hz, J2 =6.32, Hz, J3 =3.78 Hz, 2H), 2.59 (d, J=2.4 Hz, 2 H), 1.08 (m, 9H); 13C NMR (CDCl3); δ 135.8, 132.8, 129.6, 127.6, 80.3, 75.6, 67.5, 36.2, 26.8, 19.3. ##STR19##