Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH:13]([OH:16])[CH2:14][OH:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[C:24](OC)([CH3:26])[CH3:25].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH:13]2[CH2:14][O:15][C:24]([CH3:26])([CH3:25])[O:16]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)nc1)N(CC(O)CO)C1CCCC1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OCC(CN(C2CCCC2)S(=O)(=O)c2ccc(Cl)nc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A mixture of 0.83 g (2.48 mmol) of 6-chloro-N-cyclopentyl-N-(2,3-dihydroxypropyl)pyridine-3-sulfonamide, 0.67 mL (5.45 mmol) of 2,2-dimethoxypropane and 47 mg of pTsOH in 5 mL of DMF is stirred for 3 hours at room temperature. The medium is taken up in 100 mL of EtOAc, washed with 50 mL of saturated NaHCO3 solution and 50 mL of water, and then dried over Na2SO4, filtered and concentrated under reduced pressure. 0.92 g 6-chloro-N-cyclopentyl-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]pyridine-3-sulfonamide is obtained in the form of a brown oil, which is used without further purification in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:11]([OH:16])[CH2:12][CH2:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:17]([O:19][CH2:20][CH3:21])=[O:18].F[C:23]1C(C)=C(C=C(N=[N+]=[N-])C(OCC)=O)C=CC=1.S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:11]([O:16][CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(=Cc1cccc(F)c1C)N=[N+]=[N-]
Reactant: CCOC(=O)c1cc2c(Cl)ccc3c2n1CCCCC3O
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCOC(=O)c1cc2c(Cl)ccc3c2n1CCCCC3OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The ethyl 5,6,7,8-tetrahydro-11-chloro-8-hydroxy-4H-azocino [3,2,1-hi]indole-2-carboxylate (1.90 g, 6.17 mmol) obtained in Example 23, (a) was added to a mixture of methanol (19 ml) and concentrated sulfuric acid (1.89 g) which had been cooled to 0° C. The reaction mixture was heated to 40° C. and stirred for 1 hour. The reaction mixture was poured into ice water and extracted twice with ethyl acetate, and the extract solution was washed twice with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent:ethyl acetate/n-hexane= 1/99) to obtain 1.96 g of ethyl 5,6,7,8-tetrahydro-11-chloro-8-methoxy-4H-azocino [3,2,1-hi]indole-2-carboxylate as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].[CH3:13][C:14]([C:16](Cl)=[O:17])=[CH2:15]>CN(C)C=O.CO>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:16](=[O:17])[C:14]([CH3:15])=[CH2:13]
Reactant: C=C(C)C(=O)Cl
Reactant: NCC(O)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: C=C(C)C(=O)NCC(O)CO
Temperature: 0 °C

Procedure:
4.56 g of 3-amino-1,2-propanediol (0.05 mol) were dissolved in 30 ml of dimethylformamide (anhydrous). This solution, and also 13.8 g of K2CO3, were transferred to a 100 ml three-necked flask fitted with dropping funnel and gas inlet and gas outlet pipe. The mixture was cooled to 0° C. in an ice bath. 6.18 ml of methacryl chloride (0.06 mol), dissolved in 30 ml of dimethylformamide, were added dropwise over 30 minutes with moderate stirring and gentle passage of nitrogen. After stirring for a further hour with ice cooling, the mixture was allowed to warm to room temperature and was stirred for a further 30 minutes. The reaction batch was filtered through a fluted filter, and the residue was discarded. The filtrate was concentrated in a rotary evaporator until a viscous oil was produced. This oil was dissolved in 30 ml of methanol and filtered a second time, and the filtrate was again concentrated in a rotary evaporator. The residual amounts of solvent were removed in a high vacuum. The yield was 8.52 g.
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH3:17])(=[O:3])[CH3:2].C(O)(=O)C.Br.C([O-])(O)=O.[Na+]>O>[C:1]([C:4]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH3:17])(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2nc(C)c(C(C)=O)[nH]2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1[nH]c(-c2ccc(O)cc2)nc1C
Yield: 98.3 %

Procedure:
A solution of 45 (1.0 g, 0.004 mol), glacial acetic acid (5.33 ml) and 48% HBr (22 ml) was heated at reflux for 3 hours with stirring. The reaction was cooled in an ice bath and the yellow precipitate was collected and combined with the residue resulting from concentration of the mother liquor. The solid was suspended in H2O (15 ml) and saturated NaHCO3 solution (41 ml) and stirred at ambient temperature overnight. The solids were collected, washed with H2O, and dried to yield 850 mg (98.4%) of 46; m.p. 300° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)[CH:3]=1.C(C1[S:32]C(N)=NC=1)C>>[CH2:2]([C:7]1[S:32][C:4]([NH:8][C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)=[N:5][CH:6]=1)[CH3:3]
Reactant: CC1(C)OB(c2ccc(C(=O)Nc3cc(F)ccn3)cc2)OC1(C)C
Reactant: CCc1cnc(N)s1
Product: CCc1cnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)s1
Yield: 34.2 %

Procedure:
This compound was prepared, in an analogous manner as described in Intermediate 4, starting from 5-ethylthiazol-2-amine, to afford the title compound (191 mg, 34.2%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH:12]=[C:11]([OH:16])[CH2:10]1.[C:17](OC(=O)C)(=[O:19])[CH3:18].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:10][C:11](=[O:16])[C:12](=[C:17]([OH:19])[CH3:18])[C:13](=[O:15])[CH2:14]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C=C(O)CC(c2ccc(F)cc2Br)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)=C1C(=O)CC(c2ccc(F)cc2Br)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 500 mL recovery flask was added 5-(2-bromo-4-fluorophenyl)-3-hydroxycyclohex-2-enone (1D) (14.3 g, 50.1 mmol, 1.0 eq.), CH2Cl2 (200 mL), acetic anhydride (6.65 g, 65.2 mmol, 1.3 eq.), Et3N (15.22 g, 150 mmol, 3.0 eq.), and DMAP (catalytic amount). The reaction mixture was stirred overnight at room temperature. Monitoring by LC/MS judged the reaction to be complete. The reaction mixture was concentrated and purified via column chromatography (gradient 70% CH2Cl2/Hex to 100% CH2Cl2) to yield the product as light yellow foam which later became an oil (3.55 g, 22%). The crude material was used in the next step without further purification. ESI-MS: m/z 327.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:10]=1)=[O:5])C.[OH-].[K+].Cl>CO.O>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:8]2[S:7][C:6]([C:4]([OH:5])=[O:3])=[N:10][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Yield: 67.8 %

Procedure:
40 Part A; Ethyl-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (4.10 gram, 9.93 mmol) is suspended in methanol (75 mL). A solution of KOH (1.98 gram, 30 mmol) in water (75 mL) is added and the resulting mixture is heated at reflux temperature for 2 hours. The resulting yellow solution is allowed to attain room temperature, poured into water and acidified with 1N aqueous HCl to give a white precipitate. This precipitate is collected by filtration and twice washed with water. Drying in vacuo gives 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylic acid as a white solid (2.59 gram, 68% yield). 1H-NMR (200 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.65-7.72 (m, 1H), 7.28-7.52 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:12][NH:13][O:14][CH3:15].CCN(CC)CC.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:7]
Reactant: COc1ncccc1C(=O)O
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncccc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a cooled mixture of 2-methoxy-nicotinic acid (2 g, 13.05 mmol), N,O-dimethylhydroxylamine (1.91 g, 19.59 mmol) in CH2Cl2 (20 mL) and Et3N (7.26 mL, 15.66 mmol) was added 1-propane phosphonic acid cyclic anhydride (9.96 mL, 15.66 mmol; 50 wt % solution in EtOAc) dropwise and stirred at room temperature for 2 h. The reaction mixture was filtered, washed with CH2Cl2 (10 mL), evaporated to dryness and subjected to column chromatography (SiO2, 50% EtOAc-hexanes) to obtain 2,N-dimethoxy-N-methyl-nicotinamide (2.33 g) in 91% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:28][C@@H:29]1[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[NH:30]1>>[F:1][C:2]1[CH:7]=[C:6]([N:30]2[C@H:29]([CH3:28])[CH2:33][CH2:32][S:31]2(=[O:35])=[O:34])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(I)cc2F)CC1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Product: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(N3[C@H](C)CCS3(=O)=O)cc2F)CC1
Yield: 5.6 %

Procedure:
Using (2-fluoro-4-iodophenyl)[4-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazin-1-yl]methanone (507 mg) described in Preparation Example 161 and (R)-3-methylisothiazolidine 1,1-dioxide (139 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (29 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]([F:42])([F:41])[O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH:18]([N:13]1[C:12]([C:35]2[CH:34]=[CH:33][C:32]([O:31][C:30]([F:29])([F:41])[F:42])=[CH:37][CH:36]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CC(C)n1nc2c(c1-c1ccc(OC(F)(F)F)cc1)CCNCC2
Yield: 88.8 %

Procedure:
The title compound (196 mg) was prepared according to Example 189 using 278 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 402 mg of 4-trifluoromethoxyphenylboronic acid. MS (ESI): exact mass calculated for C17H20F3N3O, 339.36; found, m/z 340.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.53-7.45 (m, 4H), 4.66 (br s, 1H), 4.40 (J=6.68 Hz, 1H), 3.45-3.43 (m, 1H), 3.23-3.21 (m, 1H), 2.88-2.79 (m, 2H), 1.42 (d, J=6.7 Hz, 6H).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][CH2:11]/[C:12](=[CH:14]/[CH2:15][CH2:16]/[CH:17]=[C:18](/[CH2:20][CH2:21]/[CH:22]=[C:23](/[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])\[CH3:24])\[CH3:19])/[CH3:13])/[CH3:8])[CH3:3].[H][H]>[Ni].CCCCCC>[CH3:30][CH:28]([CH2:27][CH2:26][CH2:25][CH:23]([CH2:22][CH2:21][CH2:20][CH:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH:12]([CH2:11][CH2:10][CH2:9][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:8])[CH3:13])[CH3:19])[CH3:24])[CH3:29]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Reactant: [H][H]
Agent: [Ni]
Solvent: CCCCCC
Product: CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C

Procedure:
A tubular reactor of 1.2 cm in inner diameter and 10 cm in length was packed with 10 g of carrier-supported nickel catalyst. Hydrogenation was carried out by feeding into the reactor the n-hexane solution of squalene and hydrogen gas to obtain a squalane solution in n-hexane. Samples were taken out for 30 hours after the temperature was stabilized at 200° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C@H:14]([C:19]([O:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:17][CH:16]([CH3:18])[CH2:15][C@H:14]([NH:13][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:19]([O:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:20]
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
4-Nitrobenzoyl chloride (0.60 g, 3.9 mmol) in DCM (2 ml) was added dropwise over 10 min to a solution of cyclopentyl L-leucinate (0.70 g, 3.5 mmol) and diisopropylethylamine (0.94 ml, 5.3 mmol) in DCM (10 ml) at −5° C. under an atmosphere of nitrogen. On completion of the addition, the reaction mixture was allowed to warm to RT and stirred for a further 30 min. The reaction mixture was poured on to sat. aq. NaHCO3 and the aqueous layer was extracted with DCM. The organic extracts were combined, washed with brine, dried over MgSO4 and evaporated under reduced pressure afford the title compound as an oily solid (1.2 g, 87%). m/z 347.1 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:9][C:10]([C:12]2[N:13]=[CH:14][C:15]3[C:16](=[O:30])[N:17]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]=[CH:19][C:20]=3[C:21]=2[OH:22])=[O:11])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:23]([N:17]1[C:16](=[O:30])[C:15]2[CH:14]=[N:13][C:12]([C:10]([NH:9][C:6]3([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)=[O:11])=[C:21]([OH:22])[C:20]=2[CH:19]=[CH:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1(NC(=O)c2ncc3c(=O)n(Cc4ccccc4)ccc3c2O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NC1(C(=O)O)CC1)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
A mixture of 1-[(7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-cyclopropanecarboxylic acid ethyl ester (23 mg, 0.057 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture to pH about 2, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 9 mg of the title compound as a yellow solid. MS: (+) m/z 380.27 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH2:22][N:23]1[C:27](=[O:28])[CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[S:25][CH:24]1[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.C(Cl)(Cl)(Cl)[Cl:45]>>[Cl:45][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[S:25][CH:24]1[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCCCCCCCCC1SC(c2cccnc2)N(CCO)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCCC1SC(c2cccnc2)N(CCCl)C1=O
Temperature: 25 °C
Yield: 80 %

Procedure:
Triphenylphosphine (3.44 g, 13 mmol) was added to a mixture of 3-(2-hydroxyethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (3.49 g, 10 mmol) and carbon tetrachloride (20 ml) with stirring at room temperature. Then the mixture was refluxed with stirring for 2.5 hours. The product mixture was cooled and filtered to remove the formed crystals. The filtrate was concentrated and chromatographed, giving the cis-isomer (0.55 g) and trans-isomer (1.46 g) of the title compound and a mixture of two isomers (0.94 g) (total 2.95 g, 80% yield).
Reaction SMILES: N.[N+:2]([C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([N+:20]([O-])=O)[CH:13]=[CH:14][CH:15]=3)[C:10](=[O:23])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:3].[Br-].[NH4+]>C(O)COCCO>[NH2:20][C:12]1[C:11]2[C:10](=[O:23])[C:9]3[C:18](=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=[CH:7][CH:8]=3)[C:17](=[O:19])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Agent: N
Agent: [Br-]
Agent: [NH4+]
Solvent: OCCOCCO
Product: Nc1cccc2c1C(=O)c1cccc([N+](=O)[O-])c1C2=O
Yield: 86.2 %

Procedure:
17.5 liters (STP)/hour of ammonia are passed, under normal pressure, for 40 minutes into a solution of 60 g of 1,5-dinitro-anthraquinone (97% pure) and 5 g of ammonium bromide in 450 g of diethylene glycol, at 220° C, while stirring vigorously. After cooling, the product is filtered off and washed with water. After drying, 46.5 g of 80.5% pure 1-amino-5-nitroanthraquinone (71.5% of theory) are obtained. The product contains 19.0% (19.0% of theory) of 1,5-diaminoanthraquinone.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH2:11]([O:10][P:9]([CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4])([O:13][CH2:14][CH3:15])=[O:16])[CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: NC(=O)NC(=O)CCl
Product: CCOP(=O)(CC(=O)NC(N)=O)OCC

Procedure:
While stirring, 682 gm (5 mol) of chloroacetylurea were added portionwise to 831 gm (5 mol) of triethyl phosphite at a temperature of 135°C to 150°C. Each time, the addition of the next portion was delayed until the violent gas evolution had abated. After the last portion of chloracetylurea had been added, the stirring was continued at 150°C until the evolution of gas was terminated. Small quantities of a volatile substance distilled off when the reaction mixture was heated on the water bath under the vacuum generated by an oil pump. The reaction mixture solidified upon cooling. The pure diethylphosphonoacetylurea was obtained from the crude product by recrystallization from isopropanol or acetone and proved to be a water-soluble product having a melting point of 120°C. The yield of crude product was 1120 gm (94% of the theory).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([OH:35])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:38]([O:45][C:46](=[O:49])[CH2:47]Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([O:35][CH2:47][C:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:49])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3 g of 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester and 1.5 g of Bromo-acetic acid benzyl ester in 38 ml of DMF, 2 g of cesium carbonate was added. The reaction mixture was stirred for 4 h at RT, diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 2.8 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@H:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.Cl.N>O>[CH3:15][C@H:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]3)=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: O=c1ccocc1
Reactant: C[C@@H]1CC(=O)NN=C1c1ccc(N)cc1
Agent: Cl
Agent: N
Solvent: O
Product: C[C@@H]1CC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A mixture of (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (100 mg), 4H-pyran-4-one (52 mg) and hydrochloric acid (0.1N, 1 ml) in water (1.3 ml) was stirred under reflux under nitrogen for 3 hours. Aqueous ammonia (880, 0.01 ml) was added to the cooled reaction mixture to afford the title compound which was collected, washed with water and dried, 91 mg, m.p. 257°-8° C. (softens 120° C.), [α]D25 =-369.5° (1.07% in dimethylformamide).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]#[N:14].O.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18]>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]([CH2:18][CH2:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])[N:5]=[C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]#[N:14]
Reactant: N#Cc1c(-c2cccnc2)n[nH]c1N
Reactant: C=CC(=O)OCC
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)CCn1nc(-c2cccnc2)c(C#N)c1N
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of 5-amino-3-(pyridine-3-yl)-1H-pyrazole-4-carbonitrile (300 mg, 1.62 mmol) in pyridine (4 mL)/H2O (1 mL) was added ethyl acrylate (325 mg, 3.24 mmol). The resulting mixture was stirred at 100° C. for 5 hours. After cooling to rt, the mixture was concentrated in vacuo. The residue was purified by preparative-TLC to afford the desired product: MS (m/z): 286.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Temperature: -5 °C

Procedure:
3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester is dissolved in dry pyridine (20 ml) and cooled to −5° C. Methanesulphonyl chloride is added over a period of 10 minutes keeping the temperature between −5° C. and 0° C. after which the yellow solution is allowed to warm up to room temperature over a period of 30 minutes. Water (20 ml) is added and the mixture is then extracted using DCM (2×30 ml), the organic washings being combined and washed with 2N potassium hydrogen sulphate solution (2×30 ml). The organic phase is dried (using MgSO4), filtered and evaporated to give the title compound as a colourless oil.