Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([CH2:10][OH:11])([CH2:8][OH:9])[CH:6]=[CH2:7])[CH3:2].[F:13][CH2:14][C:15]([CH2:17][F:18])=O>>[CH2:1]([O:3][C:4]([C:5]1([CH:6]=[CH2:7])[CH2:8][O:9][C:15]([CH2:17][F:18])([CH2:14][F:13])[O:11][CH2:10]1)=[O:12])[CH3:2]
Reactant: O=C(CF)CF
Reactant: C=CC(CO)(CO)C(=O)OCC
Product: C=CC1(C(=O)OCC)COC(CF)(CF)OC1
Temperature: 100 °C
Yield: 77.5 %

Procedure:
A vial was loaded with 2,2-bis-hydroxymethyl-but-3-enoic acid ethyl ester (0.88 g, 5.05 mmol), 1,3-difluoroacetone (0.95 g, 10.1 mmol) and para-toluene-4-sulfonic acid monohydrate (0.96 g, 5.05 mmol). The vial was sealed and heated in a microwave reactor at 100° C. for 15 min. The resultant brown oil was partitioned between dichloromethane and aqueous sodium bicarbonate solution. The organic layer was filtered through a hydrophobic frit and evaporated to give a brown oil (0.98 g). The oil was purified by silica gel chromatography using iso-hexanes/ethyl acetate 3:1 to yield the title compound (0.619 g, 74%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.31 (t, J=7.1 Hz, 3H), 3.96 (d, J=12.0 Hz, 2H), 4.27 (q, J=7.1 Hz, 2H), 4.34-4.69 (m, 6H), 5.22-5.35 (m, 2H), 5.67-5.79 (m, 1H).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[C:13]1([CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:22]1([CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:20][N:21]=[C:5]=[O:11])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C=NCC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A suspension of triphosgene (0.78 g, 2.6 mmol) in 15 ml of CH2Cl2 was treated in small portions with 2,2-diphenylethylamine (1.54 g, 7.8 mmol) at 0° C., under N2. The reaction mixture was stirred for 30 minutes and filtered. The filtrate was then concentrated in vacuo to provide a yellow oil.
Reaction SMILES: Cl[C:2]1[NH:7][CH:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:10]([CH3:16])=[C:11]([C:12](=[O:15])[CH2:13][Cl:14])[C:3]=12.[NH2:26][CH:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:30][CH2:29][CH2:28][CH:27]([NH:26][C:2]1[NH:7][CH:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:10]([CH3:16])=[C:11]([C:12](=[O:15])[CH2:13][Cl:14])[C:3]=12)[CH2:31][CH2:32][CH3:33]
Reactant: Cc1cc(C)c(-n2c(C)c(C(=O)CCl)c3c2=NC(C)NC=3Cl)c(C)c1
Reactant: CCCC(N)CCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC(CCC)NC1=c2c(C(=O)CCl)c(C)n(-c3c(C)cc(C)cc3C)c2=NC(C)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of compound (7) (730 mg, 2 mmol), 4-aminoheptane (250 mg, 2.2 mmol) and triethylamine (250 mg, 2.5 mmol) were stirred at ambient temperature for 16 hours. The solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate and evaporated to dryness to provide compound (8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[NH2:46][C:47]1[S:48][C:49]([CH2:52][CH3:53])=[N:50][N:51]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([NH:46][C:47]2[S:48][C:49]([CH2:52][CH3:53])=[N:50][N:51]=2)=[O:44])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CCc1nnc(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nnc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2C)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-ethyl-1,3,4-thiadiazole (44 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 53 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:36])=[CH:11][C:12]([NH:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:13]([CH:28]=1)[C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:38](OC1C=CC([N+]([O-])=O)=CC=1)=[O:39].CCN(C(C)C)C(C)C.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:28]=[C:13]2[C:12](=[CH:11][C:10]=1[F:36])[N:29]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:38](=[O:39])[N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[C:14]2=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CNC(=O)c2cc(OCc3ccccc3)c(F)cc2NC2CCOCC2)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)c(F)cc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A mixture of 1.0 g of the compound obtained in Step 4.5, 1.223 g of 4-nitrophenyl chloroformate and 0.915 g of DIEA in 15 ml of THF is irradiated in a microwave field for 15 minutes at 80° C. 0.616 g of DBU is then added and the mixture is stirred for 1 hour at room temperature. The reaction medium is evaporated under reduced pressure. The residue is taken up in EtOAc and washed twice with saturated aqueous NaHCO3 solution, then with aqueous 1M KHSO4 solution and then with water. The organic phase is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (60/40, v/v) to give 0.74 g of the expected product.
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1>ClCCCl>[Br:3][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cc(O)ncc1[N+](=O)[O-]
Solvent: ClCCCl
Product: Cc1cc(Br)ncc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
A solution of phosphorus oxybromide (14.4 g, 50 mmol) in 1,2-dichloroethane (50 mL) was added to a stirred suspension of 2-hydroxy-4-methyl-5-nitropyridine (5 g, 32.4 mmol) in 1,2-dichloroethane (50 mL) and the resulting mixture was heated to reflux. After 4 h, the reaction was cooled and quenched with water. The organic layer was dried (Na2SO4), filtered through a pad of silica eluting with chloroform and evaporated in vacuo to give the title compound as a yellow solid:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([SH:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].I[CH:13]([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3]([C:5]1[C:10]([S:11][CH:13]([CH3:15])[CH3:14])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccnc1S
Reactant: CC(C)I
Product: COC(=O)c1nccnc1SC(C)C
Yield: 61 %

Procedure:
3-Mercapto-pyrazine-2-carboxylic acid methyl ester (0.35 g, 2.0 mmol) obtained in Step A and 2-iodopropane were reacted in the same manner as in Step A of Preparation Example 5 to obtain the title compound (0.267 g, 61%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:15])([F:14])[F:1])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc(OC(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(CCCBr)cc1
Reaction time: 3 h
Yield: 32.5 %

Procedure:
Compound 52-2 (3.33 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (4.35 g) and N-bromosuccinimide (2.95 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.39 g) as a yellow oil.
Reaction SMILES: [H][H].[F:3][C:4]([F:31])([F:30])[O:5][C:6]1[CH:29]=[CH:28][C:9]2[NH:10][C:11]([C:13]3[C:25]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18](=[N:26]O)[C:17]=4[CH:16]=[CH:15][CH:14]=3)=[N:12][C:8]=2[CH:7]=1>C(O)C.O1CCCC1.[Ni]>[F:31][C:4]([F:3])([F:30])[O:5][C:6]1[CH:29]=[CH:28][C:9]2[NH:10][C:11]([C:13]3[C:25]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]([NH2:26])[C:17]=4[CH:16]=[CH:15][CH:14]=3)=[N:12][C:8]=2[CH:7]=1
Reactant: [H][H]
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cc(OC(F)(F)F)ccc2[nH]1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3nc4cc(OC(F)(F)F)ccc4[nH]3)cccc21
Yield: 90.9 %

Procedure:
The procedure used in Example 6 is followed. In a 111 ml autoclave, dissolve 730 mg of 4-(5-trifluoromethoxy-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 25 ml of ethanol and 25 ml of tetrahydrofuran, add a spatula of Raney activated nickel and then subject to an initial hydrogen pressure of 1 bar and heat the autoclave at 600 for 4 hours. After cooling, the volume of hydrogen absorbed is 122 ml. After filtration of the catalyst over Celite, the filtrate is concentrated under reduced pressure and then taken up in dichloromethane and dried over magnesium sulphate. In this way, we obtain 640 mg of 4-(5-trifluoromethoxy-1H-benzimidazol-2-yl)-9H-fluorene-9(R,S)amine, in the form of a beige foam, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[N:18][NH:19]4)=[CH:15][C:14]=3[CH3:22])[CH:8]=[C:9](F)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24].CCN(C(C)C)C(C)C.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CC(N(C)C)=O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[N:18][NH:19]4)=[CH:15][C:14]=3[CH3:22])[CH:8]=[C:9]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24]
Reactant: C1COCCN1
Reactant: Cc1cc2cn[nH]c2cc1-c1cc(F)cc2c(N)c(C(N)=O)nnc12
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2cn[nH]c2cc1-c1cc(N2CCOCC2)cc2c(N)c(C(N)=O)nnc12
Temperature: 140 °C
Yield: 25.2 %

Procedure:
A mixture of 4-amino-6-fluoro-8-(5-methyl-1H-indazol-6-yl)cinnoline-3-carboxamide (200 mg, 0.59 mmol), DIPEA (1000 mg), morpholine (500 mg,) and DMA (4 mL) was heated at 140° C. in a microwave under N2 for 3 hours. The mixture was cooled, concentrated, and purified via preparative HPLC to give the title compound (60 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.95 (1H, s), 8.93 (1H, br s), 8.30 (1H, d, J=2.4 Hz), 8.03 (1H, s), 7.81 (1H, br s), 7.60 (1H, s), 7.54-7.51 (3H, m), 7.35 (1H, s), 3.79 (4H, t, J=4.8 Hz), 3.42 (4H, t, J=4.8 Hz), 2.00 (3H, s); LC-MS (5-95% ACN in H2O gradient with 0.02% NH4OAc, tR 3.053 minutes); ESI+APCI m/z [M+H]+ 404.
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[CH:10]=[CH:9][N:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:3]1[OH:22].CS(O)(=O)=O.[CH3:28][O:29][CH2:30][CH2:31]O>>[OH:22][C@H:3]1[C@@H:2]([O:1][CH2:31][CH2:30][O:29][CH3:28])[C:11]2[CH:10]=[CH:9][N:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH:22][C@H:3]1[C@H:2]([O:1][CH2:31][CH2:30][O:29][CH3:28])[C:11]2[CH:10]=[CH:9][N:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCCO
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)[C@@H]3O
Agent: CS(=O)(=O)O
Product: COCCO[C@@H]1c2ccn3cc(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Product: COCCO[C@H]1c2ccn3cc(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 23 %
Yield: 13 %

Procedure:
6 g (20.3 mmol) of (7R,8R,9R)-7,8-dihydroxy-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]-naphthyridine are introduced into 75 ml of ethylene glycol monomethyl ether at 65° C., treated with 4.9 g (50.8 mmol) of methanesulfonic acid and the mixture is stirred at 65° C. for 1.5 h. The reaction solution is concentrated in a rotary evaporator and residue is treated with 50 ml of dichloromethane and 50 ml of water. The aqueous phase is adjusted to pH 8 by means of saturated sodium hydrogencarbonate solution, the organic phase is separated off and the aqueous phase is extracted twice using 20 ml of dichloromethane each time. The combined dichloromethane phases are concentrated and the residue is separated by chromatography on silica gel (ethyl acetate/2-propanol/conc. ammonia water 98:2:0.1). The individual product fractions are concentrated and the products are dried at 50° C. in a high vacuum. 1.7 g (23% of theory) of (7S,8R,9R)-8-hydroxy-2-methyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine (12a) of m.p. 149–152° C. and 0.9 g (13% of theory) of (7R,8R,9R)-8-hydroxy-2-methyl-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo-[1,2-h][1,7]-naphthyridine (12b) of m.p. 108–110° C. are obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C@H:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].O.Cl>ClCCl>[C:1]([NH:5][C@H:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C[C@H](N)c1cccc(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C[C@H](NC(C)=O)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Acetyl chloride (7.9 ml, 111 mmol) in dichloromethane (50 ml) was added dropwise to a cold (0° C.) solution of ethyl (3S)-3-amino-3-(3-fluorophenyl)propanoate (WO99/31099, Scheme 3 page 97) (25.2 g, 102 mmol) in dichloromethane (200 ml). The reaction was stirred for 2 hours at 0° C., then water (100 ml) was added. The reaction mixture was adjusted to pH1 with 2 N hydrochloric acid and the organic layer separated. The dichloromethane layer was washed with saturated sodium hydrogencarbonate solution (50 ml), water (50 ml) and then dried (MgSO4). Solvent was evaporated under reduced pressure to afford a thick oil which was purified by column chromatography (silica gel, eluting with diethyl ether) to give the title compound as a clear, colourless oil, 25.1 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6]([N:9]=[C:10]=[O:11])([CH3:8])[CH3:7].O.Cl>[OH-].[Na+].CC(C)=O>[CH:6]([NH:9][C:10](=[O:11])[NH:1][CH2:2][C:3]([OH:5])=[O:4])([CH3:8])[CH3:7]
Reactant: NCC(=O)O
Reactant: CC(C)N=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)NC(=O)NCC(=O)O
Temperature: 0 °C
Yield: 48.6 %

Procedure:
A solution of glycine (75.1 g.) in normal sodium hydroxide solution (one litre) is heated at 36° C. A solution of isopropyl isocyanate (76.5 g.) in acetone (100 cc.) is then added dropwise, whilst stirring. A rise in temperature from 36° to 50° C is observed in the course of the addition. The reaction mixture is stirred for a further 30 minutes after the end of the addition. Crushed ice (500 g.) and water (250 cc.) are then added and the mixture is acidified by adding 5 N hydrochloric acid (200 cc.), while stirring. The precipitate is then filtered off, and dried. 2-(3-Isopropylureido)-acetic acid (70 g.) melting at 178° C is thus obtained. A second crop (44 g.) of 2-(3-isopropylureido)-acetic acid, melting at 178° C, is obtained by concentrating the filtrate.
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:3]([N:6]1[CH2:11][CH2:10][N:9]([NH:12][S:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(=O)N1CCN(N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(NS(=O)(=O)c2ccc(F)cc2)CC1
Yield: 47.8 %

Procedure:
To a mixture of 1-acetyl-4-aminopiperazine dihydrochloride (540 mg) and 4-fluorobenzenesulfonyl chloride (535 mg) in dichloromethane (5 ml) was added triethylamine (1.2 ml) in a few minutes with stirring in an ice bath. After stirring for half an hour at the same temperature, the mixture was washed with brine, dried, and concentrated in vacuo. The residue was crystallized from ethanol and recrystallized from a mixture of ethanol and diethyl ether to Yield N-(4-acetyl-1-piperazinyl)-4-fluorobenzenesulfonamide (360 mg) as white crystals.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1([CH3:18])[CH2:12][CH:11]([NH:13][CH2:14][CH3:15])[CH2:10][C:9]([CH3:17])([CH3:16])[NH:8]1.[OH-].[Na+]>C(Cl)Cl.O>[Cl:1][CH2:2][C:3]([N:13]([CH2:14][CH3:15])[CH:11]1[CH2:12][C:7]([CH3:6])([CH3:18])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]1)=[O:4]
Reactant: CCNC1CC(C)(C)NC(C)(C)C1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCN(C(=O)CCl)C1CC(C)(C)NC(C)(C)C1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of 23.16 g (0.205 mol) of chloroacetyl chloride in 30 ml of methylene chloride is slowly added to a solution of 36.85 g (0.2 mol) of N-(2,2,6,6-tetramethyl-piperidin-4-yl)-ethylamine in 160 ml of methylene chloride cooled to -20° C., taking care that the temperature does not rise above -10° C. The mixture is stirred for one hour and then left to stand, allowing the temperature to rise to 0° C.; a solution of 8.4 g (0.21 mol) of sodium hydroxide in 35 ml of water is then added in the course of 1 hour.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:19]([C:20]([NH:22][NH2:23])=[S:21])[N:18]=[C:17]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[S:16]2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[C:45](OC)(OC)[CH3:46]>CC1C=CC(S(O)(=O)=O)=CC=1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:19]([C:20]3[S:21][C:45]([CH3:46])=[N:23][N:22]=3)[N:18]=[C:17]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[S:16]2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(C)(OC)OC
Reactant: CC(C)(C)OC(=O)NCCCC1(c2cccc(O[Si](C)(C)C(C)(C)C)c2)SC(c2cc(F)ccc2F)=NN1C(=S)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1nnc(N2N=C(c3cc(F)ccc3F)SC2(CCCNC(=O)OC(C)(C)C)c2cccc(O[Si](C)(C)C(C)(C)C)c2)s1
Temperature: 80 °C
Yield: 72.2 %

Procedure:
Tert-butyl 3-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-5-(2,5-difluorophenyl)-3-(hydrazinecarbonothioyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (100 mg, 0.157 mmol) was weighed into a 25 mL flask and suspended in 5.0 mL of 1,1,1-trimethoxyethane (5 mL, 0.157 mmol). 4-methylbenzenesulfonic acid (0.540 mg, 0.00314 mmol) was then added, and the reaction heated to 80° C. for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (20-50% ethyl acetate/hexanes), to afford 75 mg (72% yield) of the desired product as a yellow solid on standing.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][Si](C)(C)C)=[CH:16][N:15]=2)[CH2:10][CH2:9]1>CO>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([CH3:7])[CH2:9][CH2:10]2)=[N:15][CH:16]=1)#[CH:21]
Reactant: CN1CCN(c2ccc(C#C[Si](C)(C)C)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N2CCN(C)CC2)nc1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Potassium carbonate (1M aq., 1.5 mL, 1.5 mmol) was added in a drop-wise manner to a solution of 1-methyl-4-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)piperazine (325 mg, 1.19 mmol) in MeOH (5.0 mL) at room temperature, and the resulting mixture was stirred for 2 h. After removal of the solvent in vacuo, water (5 mL) and brine (10 mL) were added and the product was extracted with DCM (150 mL, then 3×10 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and filtered. Evaporation of the solvent gave 1-(5-ethynylpyridin-2-yl)-4-methylpiperazine (239 mg, quantitative yield), which was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 8.32 (s, 1 H), 7.55 (dd, J=8.9, 2.1 Hz, 1 H), 6.58 (d, J=8.8 Hz, 1 H), 3.54-3.67 (m, 4 H), 3.08 (s, 1 H), 2.46-2.58 (m, 4 H), 2.35 (s, 3 H); MS ESI [M+H]+ 201.9, calcd for [C12H15N3+H]+ 202.1.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[I-].[Na+]>>[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccccc1
Reactant: C#Cc1ccccc1
Agent: [I-]
Agent: [Na+]
Product: C(#Cc1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
Following General Procedure C (120° C., 30 hours), phenylacetylene (84 μL, 1.5 mmol) was coupled with bromobenzene (106 μL, 1.0 mmol), in the presence of sodium iodide (NaI; 0.5 eq.; 0.5 mmol). The crude brown oil was purified by flash chromatography on silica gel to provide 90% 1,1′-ethyne-1,2-diyldibenzene.
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][CH:6]([F:15])[O:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10].Cl.[CH3:17][O:18][CH2:19][C:20](=[O:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23].CC([O-])=O.[Na+]>O.CO>[F:5][CH:6]([F:15])[O:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][N:1]=[C:21]([C:20](=[O:26])[CH2:19][O:18][CH3:17])[C:22]([O:24][CH3:25])=[O:23]
Reactant: O=N[O-]
Reactant: COCC(=O)CC(=O)OC
Reactant: Nc1ccccc1OC(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC(=O)C(=NNc1ccccc1OC(F)F)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.9 %

Procedure:
A solution of NaNO2 (2.378 g, 34.5 mmol) in H2O (10 mL) was added dropwise at 0° C. to a solution of 2-(difluoromethoxy)aniline (3.59 mL, 28.7 mmol) in 6 M HCl aqueous solution (28.7 mL, 172 mmol). After stirring for 15 min, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (3.72 mL, 28.7 mmol) and NaOAc (14.14 g, 172 mmol) in MeOH (50 mL) pre-cooled at 0° C. The precipitate was collected by filtration, washed with water, and dissolved in AcOEt. The organic solution was washed with water, saturated NaHCO3 aqueous solution and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (3/1) to give the title compound (8.70 g, 96% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.51 (3H, s), 3.89 (3H×0.5, s), 3.94 (3H×0.5, s), 4.68 (1H×0.5, s), 4.70 (1H×0.5, s), 6.63 (1H×0.5, t, J=72.7 Hz), 6.66 (1H×0.5, t, J=72.3 Hz), 7.10-7.34 (4H, m), 7.67 (1H×0.5, dd, J=8.3, 1.5 Hz), 7.90 (1H×0.5, dd, J=8.3, 1.5 Hz), 13.14 (1H×0.5, s), 14.96 (1H×0.5, br s).