Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[B:30](OC(C)C)([O:35]C(C)C)[O:31]C(C)C>C1COCC1>[C:26]([O:25][C:23]([N:18]1[C:19]2[C:15](=[C:14]([F:13])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:17]1[B:30]([OH:35])[OH:31])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2c(F)cccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2c(F)cccc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 66.6 %

Procedure:
To a solution of diisopropylamine (175 mL, 1.25 mol) in THF (800 mL) at 0° C. was added n-BuLi (500 mL, 1.25 mol) dropwise. The mixture was stirred at 0° C. for 40 min. Then the mixture was cooled to −78° C. Tert-butyl 4-fluoro-1H-indole-1-carboxylate (118 g, 0.50 mol) in THF (300 mL) was added dropwise slowly, followed by triisopropyl borate (231 mL, 1.00 mol). The mixture was stirred at −78° C. for another 40 min. The reaction was monitored by HPLC. When the reaction was completed, the reaction was quenched with NH4Cl (sat. 500 mL). Then the mixture was adjusted to pH=6 with 1 N HCl. Extracted with EtOAc (2000 mL) and the combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated. The obtained solid was recrystallized with EtOAc and PE to give (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (93 g, yield: 64%, store in fridge). 1H-NMR (CDCl3, 400 MHz) δ 7.77 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H)+: 280.
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19].OO.C(=O)([O-])[O-:23].[Na+].[Na+]>C(O)C>[Cl:1][C:2]12[C:14]([Cl:15])([Cl:16])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]1[O:23][CH:8]1[C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19]
Reactant: O=C([O-])[O-]
Reactant: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: O=C1C2OC2C(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
38 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared according to Example 1, were added slowly to a soluton of 200 ml. of ethanol containing 20 ml. of 30% hydrogen peroxide and 13 g. of sodium carbonate at such a rate that the temperature was maintained at 40°-50° C. The yellow color of the dione disappeared quickly. The solution was then cooled to 10°-13° C. and white precipitate formed. This solid was filtered and recrystallized from ethanol, m.p. 180°-181° C.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[F:5][C:6]([F:15])([F:14])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.N1C=CC=CC=1>ClCCl>[N:13]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([F:5])([F:14])[F:15])=[CH:8][CH:9]=1)=[C:1]=[S:2]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc(N=C=S)cc1

Procedure:
Thiophosgene (5 mL) was added portion wise to a stirred solution of 4-trifluoromethyl-phenylamine (10 grams) and pyridine (12.5 mL) in dichloromethane (2 Liters) at 0° C. The reaction was maintained at the same temperature for 30 minutes. The reaction mixture was then diluted with dichloromethane and washed several times with a saturated solution of copper sulfate, followed by water, drying over sodium sulfate and evaporating to give the crude product which was further purified by passing through a column of silica gel, to yield the pure product (11 grams).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[OH-].[K+].O.Cl.[C:10]([NH2:16])(=[NH:15])[CH2:11][CH:12]([CH3:14])[CH3:13]>C(Cl)Cl>[CH3:5][O:4][C:2]([NH:16][C:10](=[NH:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:3]
Reactant: COC(=O)Cl
Reactant: CC(C)CC(=N)N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)NC(=N)CC(C)C
Yield: 93.3 %

Procedure:
78.8 parts of methyl chloroformate and a mixture of 46.8 parts of potassium hydroxide in 215 parts of water are added via two inlets to a mixture of 113.8 parts of isovaleramidine hydrochloride in 530 parts of methylene chloride, at from 0° to 10° C., in the course of 25 minutes, while stirring. The mixture is stirred at 25° C. for 30 minutes, the phases are separated and the aqueous phase is extracted once with methylene chloride. The solvent is removed from the organic extract to give 123 parts (93.3% of theory) of N-methoxycarbonylisovaleramidine of melting point 82°-86° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1[C:22]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][C:11]=1[C:23]([OH:25])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:69])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[O:51]=[C:50]([N:52]1[CH2:53][CH2:54][N:55]([C:58](=[O:69])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:56][CH2:57]1)[CH2:49][NH:48][C:23]([C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:21][C:22]=2[CH:10]=1)=[O:25]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc2c(c1)Cc1ccccc1-2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
DIPEA (184 mg, 0.24 mL, 1.42 mmol) was added to a stirred solution of 9H-fluorene-2-carboxylic acid (100 mg, 0.47 mmol) in DMF (2 mL). HOBT (64 mg, 0.47 mmol) and EDCI (109 mg, 0.57 mmol) were then added at room temperature. After 2 minutes 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (167 mg, 0.47 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, filtered the solid precipitated. The solid obtained was recrystallized from a mixture of ethyl acetate and hexane afford 105 mg (43.4%) of 9H-fluorene-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 98.25%. 1H NMR (DMSO-d6): δ 8.6 (m, 1H), 8.1 (s, 1H), 8.0-7.4 (m, 10H), 4.2 (bs, 2H), 4.0 (s, 2H), 3.8-3.4 (m, 6H), 3.2 (b, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][C:15]2[C:18]([I:27])=[N:19][N:20]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:14]=2[CH:13]=1.S(Cl)([Cl:31])(=O)=O>C(Cl)Cl>[Cl:31][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[C:12]1[N:17]=[CH:16][C:15]2[C:18]([I:27])=[N:19][N:20]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:14]=2[CH:13]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.1 %

Procedure:
At r.t. to a solution of 6-(2-fluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (35 mg, 0.072 mmol) (Example 52, Step 4) in methylene chloride (3 mL) was added sulfuryl chloride (7.0 μL, 0.087 mmol). The mixture was stirred at r.t. for 20 min then concentrated. The solid was filtered out and the crude material was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.025 g). LCMS (M+H)+=518.1.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:3][CH:2]=1.[OH:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.[CH:24](OC(C)C)(C)C>C1C=CC=CC=1>[CH:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][C:9](=[O:15])[C:10](=[CH:24][NH:21][C:20]2[CH:22]=[CH:23][C:17]([OH:16])=[CH:18][CH:19]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:3][CH:2]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)OC(C)C
Reactant: COC(=O)CC(=O)C=CC1CC=CCC1
Solvent: c1ccccc1
Product: COC(=O)C(=CNc1ccc(O)cc1)C(=O)C=CC1CC=CCC1
Temperature: 25 °C

Procedure:
In 20 ml benzene was dissolved 2.0 g of methyl 5-(cyclohexen-4-yl)-3-oxo-4-pentenoate, and 1.4 g of N,N-dimethylformamidodimethylacetal was added thereto. They were reacted at 70° C. for 1.5 hours. This reaction mixture was cooled to room temperature, and 1.2 g of p-hydroxyaniline was added thereto. They were reacted for 1.5 hours. After completion of the reaction, 50 ml of diisopropyl ether was added to the reaction mixture and the precipitated crystals were collected by filtration and washed with 20 ml of diisopropyl ether to obtain 2.1 g of methyl 5-(cyclohexen-4-yl)-2-(4-hydroxyphenylaminomethylene)-3-oxo-4-pentenoate having a melting point of 151°-153° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:25]=[CH:24][C:16]3[N:17]([CH2:20][CH:21]4[CH2:23][CH2:22]4)[N:18]=[N:19][C:15]=3[C:14]=2[C:26]([F:29])([F:28])[F:27])=[CH:9][CH:8]=1)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+].O>CS(C)=O>[N:30]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:25]=[CH:24][C:16]3[N:17]([CH2:20][CH:21]4[CH2:23][CH2:22]4)[N:18]=[N:19][C:15]=3[C:14]=2[C:26]([F:29])([F:28])[F:27])=[CH:9][CH:8]=1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazole-5-yl]benzyl methanesulfonate (185 mg, 0.435 mmol) was dissolved in dimethylsulfoxide, treated with sodium azide (141 mg, 2.17 mmol, 5 equiv) and placed into a preheated oil bath at 70° C. for 30 minutes. The mixture was cooled to ambient temperature, poured into water (150 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[S:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[S:8][CH2:9][C:10](=[O:12])[N:11]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1CSc2ccc([N+](=O)[O-])cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)N1C(=O)CSc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A mixture of 6-nitro-2H-benzo[b][1,4]thiazin-3(4H)-one (0.512 g, 2.436 mmol), ethyl 2-bromopropanoate (0.573 g, 3.17 mmol) and K2CO3 (1.01 g, 7.31 mmol) in acetone (40 mL) was heated at reflux for 16 h. After cooling to ambient temperature, the mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 9% EtOAc in petroleum ether) to give ethyl 2-(6-nitro-3-oxo-2H-benzo[b][1,4]thiazin-4(3H)-yl)propanoate (0.376 g, 50%). TLC (eluting with 20% EtOAc/PE) Rf=0.6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[N:5]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)C(OC(C)(C)C)=O.[ClH:27].CCOCC>C(Cl)Cl>[ClH:27].[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1
Reaction time: 8 h

Procedure:
N-BOC-4-aminobenzoyl methionine methyl ester (3.53 g, 9.59 mmol) was placed into CH2Cl2 (30-35 ml) and to it was added 3M HCl/Et2O (38.4 ml). After standing a white precipitate formed. After 2 hours the solution was decanted, and the crystals were collected by centrifugation. The crystals were then washed several times with fresh ether and dried overnight on the vacuum pump. Meanwhile, the filtrate was left to stand overnight to allow additional product to precipitate. The second fraction was washed with ether and dried overnight on the vacuum pump. The total yield of pure fully deprotected material was 2.87 g (93.9%) yield. mp 158-164° C.; 1H NMR (CDCl3) 2.10 (3 H, s), 2.12-b 2.29 (1 H, m), 2.52-2.71 (1 H, m), 2.59 (2 H, t, J=7.6 Hz), 3.75 (3 H, s), 4.79 (1 H, m), 7.02 (2 H, d, J=8.6 Hz), 7.55 (2 H, d, J=8.6 Hz); 13C NMR (CDCl3) 15.23, 31.43, 31.53, 52.91, 52.43, 124.35, 130.56, 135.31, 135.76, 168.95, 173.87; HRMS calc. for C13H18N2O3 S, 282.1038, found 282.1009.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:15]([NH:22][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([Cl:5])=[N:7][CH:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Temperature: 80 °C
Yield: 78.4 %

Procedure:
3.5 ml (47.6 mMol) Thionylchloride and 50 μl DMF were added to a suspension of 5.0 g (31.7 mMol) 6-chloronicotinic acid in 50 ml toluene and the reaction mixture was heated at 80° C. for 2 hours. The solvent and excess thionyl chloride were removed under reduced pressure and the residue was dissolved in 50 ml dichloromethane. After cooling to 0° C., 10.4 ml (95.2 mMol) benzylamine were added over 20 minutes and after 30 minutes further stirring at room temperature, the reaction mixture was poured onto 50 ml aqueous saturated sodium bicarbonate solution. Extraction with dichloromethane, followed by crystallization from ethyl acetate/n-hexane 2:1 gave 6.13 g (78%) N-benzyl-6-chloro-nicotinamide as light brown crystals of m.p.=113-114° 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:11])=[O:8].Cl[CH2:14][CH2:15][CH2:16][S:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[N:21]1[CH:22]=[CH:23][C:18]([S:17][CH2:16][CH2:15][CH2:14][N:9]2[C:7](=[O:8])[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[NH:12][C:10]2=[O:11])=[CH:19][CH:20]=1
Reactant: ClCCCSc1ccncc1
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ccccc2c(=O)n1CCCSc1ccncc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 29.1 %

Procedure:
To a solution of 1.62 g (10 mmol) of benzoylene urea and 1.88 g (10 mmol) of 4-(3-chloropropylthio)pyridine in 50 ml of dimethylformamide, 1.65 ml (11 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate/ethanol=25:1 to 10:1 to 2:1). First, 0.913 g of 3-[3-(4pyridylthio)propyl]quinazoline-2,4-(1H,3H)-dione (31.1% yield, pale yellow crystals) was obtained, and then, 0.487 g of the desired product was obtained (10.4% yield, yellow oil).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[F:13][C:14]([F:19])([F:18])[CH2:15]CO.CCN(C(C)C)C(C)C.[O:29]=[C:30]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)[CH2:31][NH:32][C:33]([C:35]1[CH:39]=[C:38]([O:40][CH2:41][C:42]([N:44]2[CH2:48][CH2:47][CH2:46][C@H:45]2[C:49](=[O:55])[NH:50][CH:51]2[CH2:54][CH2:53][CH2:52]2)=[O:43])[N:37]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[N:36]=1)=[O:34]>ClCCl>[F:19][C:14]([F:13])([F:18])[CH2:15][CH2:7][O:6][C:5]([N:65]1[CH2:64][CH2:63][N:62]([C:30](=[O:29])[CH2:31][NH:32][C:33]([C:35]2[CH:39]=[C:38]([O:40][CH2:41][C:42]([N:44]3[CH2:48][CH2:47][CH2:46][C@H:45]3[C:49](=[O:55])[NH:50][CH:51]3[CH2:54][CH2:53][CH2:52]3)=[O:43])[N:37]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:36]=2)=[O:34])[CH2:67][CH2:66]1)=[O:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCC(F)(F)F
Reactant: O=C(NCC(=O)N1CCNCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCN(C(=O)OCCC(F)(F)F)CC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 22 mg triphosgene and 31 l 3,3,3-trifluoropropan-1-ol in 3 ml dichloromethane were added 37 l DIPEA dropwise at 0° C. After 2 h a solution of 93 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide and 37 l DIPEA in 1 ml dichloromethane were added at 0° C. The reaction mixture was allowed to warm to RT overnight. Excess triphosgene was destroyed by adding a solution of 140 mg NaOH in 5 ml water and stirring for 2 h. The layers were separated, the organic layer washed with 1 M HCl and dried over MgSO4 and concentrated. The crude product was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 25 mg MS (ES+): m/e=678.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.Cl.[NH:26]([C:28]([NH2:30])=[O:29])[NH2:27]>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2=[N:20][C:19](/[C:22](=[N:27]/[NH:26][C:28]([NH2:30])=[O:29])/[CH3:23])=[CH:18][N:17]=[C:16]2[N:15]=[N:14]1
Reactant: NNC(N)=O
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Agent: Cl
Solvent: CO
Product: C/C(=N\NC(N)=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Temperature: 45 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (30.0 mg, 0.09 mmol) in MeOH (10 mL), was added hydrazinecarboxamide hydrochloride (31.0 mg, 0.28 mmol). The mixture was heated at 45° C. and stirred overnight. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography with gradient (DCM:MeOH=10:1) to give the title compound as a white solid (25.0 mg, 67%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.91 (s, 1H), 9.85 (s, 1H), 8.93 (dd, 1H), 8.42 (d, 1H), 8.185 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 6.20 (s, 2H), 2.28 (s, 3H). LCMS (method A): [MH]+=380, tR=1.98 min.
Reaction SMILES: C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Al+3:13].C(OCCOCCO)CCC.COC1C=CC(O)=CC=1.[C:34]([OH:38])(=[O:37])[CH:35]=[CH2:36]>C(O)(C)C>[C:34]([O-:38])(=[O:37])[CH:35]=[CH2:36].[C:34]([O-:38])(=[O:37])[CH:35]=[CH2:36].[C:34]([O-:38])(=[O:37])[CH:35]=[CH2:36].[Al+3:13]
Reactant: C=CC(=O)O
Agent: CC(C)[O-]
Agent: COc1ccc(O)cc1
Agent: [Al+3]
Solvent: CC(C)O
Solvent: CCCCOCCOCCO
Product: C=CC(=O)[O-]
Temperature: 53 °C

Procedure:
Into the flask described hereinabove there were placed 102.1 g of aluminium triisopropanolate, 120.1 g of diethylene glycol monobutyl ether, and 0.7 g of 4-methoxyphenol. To this mixture there were added in drops using a dropping funnel 108 grams of acrylic acid. The acid was added during 15 minutes at room temperature (25° C.). Owing to the reaction heat, the temperature increased to 53° C. The mixture was cooled to 39° C. using a water bath. The product remained liquid and stable so that it could be further treated as follows, namely it was heated to 60° C. during 30 minutes and the co-product isopropanol was expelled during 2 hours using a continuous vacuum up to 243 mbar.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:12]([O:8][C:6]1[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(I)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(I)cc1OCc1ccccc1
Temperature: 65 °C

Procedure:
To a solution of 5-iodo-2-nitrophenol (2.65 g, 10 mmol) [J Org Chem, Vol. 63, pp. 4199-4208 (1998)] in DMF (10 mL) is added benzyl bromide (1.71 g, 10 mmol) and K2CO3 (2.07 g, 15 mmol) and the mixture is heated at 65° C. for 30 min. Then water is added (400 mL) and it is extracted by EtOAc (2×200 mL). The water layer is then acidified and extracted with EtOAc (100 mL). The combined EtOAc layer is then washed with 1N HCl and brine, dried with NaSO4 and concentrated to give the title compound as a yellow solid.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][O:29][CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:35]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[O:29][CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC1COCCC1=O
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[5-(trifluoromethyl)-3′,6′-dihydro-3,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentanamine (9.0 mg, 0.024 mmol), 3-methoxytetrahydro-4H-pyran-4-one (12.3 mg, 0.0709 mmol) and triethylamine (6.58 μL, 0.0472 mmol) in dry methylene chloride (2.0 mL) was added sodium triacetoxyborohydride (15.0 mg, 0.0708 mmol). After being stirred at room temperature overnight, the reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The organic layers were combined, dried over MgSO4, filtered and evaporated under reduced pressure. The crude product (45 mg) was purified by silica gel column (30:70 MeOH/EtOAc) to provide 1.6 mg (14%) of pure product. LC-MS calculated for C26H36F3N3O3: (M+H) 496; found 496.1.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([OH:13])=[C:6]([O:14][CH2:15][CH2:16][OH:17])[CH:5]=1)([O-:3])=[O:2].[CH3:18]N>C(O)C.C(N)=O>[CH3:18][NH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:14][CH2:15][CH2:16][OH:17])=[C:7]([OH:13])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(O)c(OCCO)cc1[N+](=O)[O-]
Reactant: CN
Solvent: CCO
Solvent: NC=O
Product: CNc1cc(O)c(OCCO)cc1[N+](=O)[O-]
Temperature: 95 °C

Procedure:
A mixture consisting of 0.115 mol (28.2 g) of 4,5-dinitro-2-(β-hydroxyethoxy)phenol, prepared in Example 3, in 300 ml of a 33% strength solution of methylamine in absolute ethanol and 100 ml of formamide is heated to 95° C. for 6 hours in an autoclave (pressure 5-6 kg/cm2) After the reaction medium has been cooled, the expected product crystallizes. It is recrystalized from formamide. It melts at 210° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[N:10](C)[CH:9]1[C:15]([CH3:18])(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[C@H]1CNCCN1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:18][C@@H:15]1[NH:10][CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: CN1C(=O)CN(C(=O)OC(C)(C)C)C1C(C)(C)C
Agent: C[C@H]1CNCCN1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-2-tert-butyl-3-methyl-4-imidazolidinone (2 g, 8.3 mmol) (BOC-ON) in chloroform (15 ml) was added (2S)-2-methylpiperazine (5 g, 50 mmol), a compound of formula (6), and triethylamine (1.25 g, 12.5 mmol) in chloroform. The mixture was stirred for about 15 hours at room temperature, and then washed with water, the solvent removed from the organic layer under reduced pressure, and the residue purified using column chromatography, to give tert-butyl (3S)-3-methylpiperazinecarboxylate, a compound of formula (7).