Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=[O:11].[Cl:13][C:14]1[C:19]([NH2:20])=[C:18]([Cl:21])[N:17]=[CH:16][N:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([NH:20][C:19]1[C:14]([Cl:13])=[N:15][CH:16]=[N:17][C:18]=1[Cl:21])=[O:11]
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Reactant: Nc1c(Cl)ncnc1Cl
Product: O=C(Cc1c(Cl)cccc1Cl)Nc1c(Cl)ncnc1Cl
Temperature: 130 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a mixture of 2,6-dichlorophenyl acetic acid (100 g, 487 mmol) and DMF (1.5 mL) in toluene (600 mL) was added thionyl chloride (116 g, 974 mmol). The resulting mixture was stirred at rt. After 12 h, the solution was concentrated to provide 2,6-dichloro-phenylacetyl chloride as colorless oil. MS (ESI): mass calcd. for C8H5Cl3O, 221.94; m/z found, 223.0 [M+H]+. 1H NMR (CDCl3): 7.33 (d, J=8.1 Hz, 2H), 7.29-7.24 (m, 1H), 4.56 (s, 2H). A suspension of the crude 2,6-dichloro-phenylacetyl chloride and 4,6-dichloro-pyrimidin-5-ylamine (76 g, 463 mmol) was heated neat to 130° C. After 1 h, the resulting solid was cooled, collected by filtration, and washed with cold MeOH (400 mL) to provide the title compound as a solid (135 g, 84%). MS (ESI): mass calcd. for C12H7Cl4N3O, 348.9; m/z found, 350.0 [M+H]+. 1H NMR ((CD3)2SO): 10.59 (s, 1H), 8.86 (s, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.37-7.33 (m, 1H), 4.13 (s, 2H).
Reaction SMILES: [CH3:1][S:2]([N:5]([S:7]([NH:10][C:11]([NH:13]N(S(C)(=O)=O)C)=[O:12])(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3].N[C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1>ClC1C=CC=CC=1>[CH3:1][S:2]([N:5]([S:7]([NH:10][C:11]([NH:13][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1)=[O:12])(=[O:8])=[O:9])[CH3:6])(=[O:3])=[O:4]
Reactant: COc1cc(OC)nc(N)n1
Reactant: CN(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)S(C)(=O)=O
Solvent: Clc1ccccc1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)n1
Temperature: 80 °C
Yield: 103.2 %

Procedure:
32.3 g of 1-[(N-methylsulfonyl-N-methylamino)-sulfonyl]-3-(N-methylsulfonyl-N-methylamino)urea are slurried in 500 ml of chlorobenzene, 15.5 g of 2-amino-4,6-di-methoxypyrimidine are added at 80° C. with stirring, and the mixture is heated for 3 hours at 80° C. After cooling to 20° C., the precipitate is filtered off and washed with 100 ml of chlorobenzene. 36.4 g of the desired product are obtained with a purity of 98.1%, corresponding to a yield of 96.8% of theory. The melting point for the product is 183°-185° C. 5.1 g of N-methylmethanesulfonamide are recovered from the filtrate by distillation, corresponding to a yield of 92.7% of theory.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:47])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:46])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:45])[NH:31][C@@H:32]4[CH2:35][C@H:34]([C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[C:33]4([CH3:44])[CH3:43])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:49])[CH3:48])(=O)C.[OH-].[Na+]>CO.C1COCC1>[CH3:43][C:33]1([CH3:44])[C@@H:34]([C:36]([N:38]2[CH2:39][CH2:40][CH2:41][CH2:42]2)=[O:37])[CH2:35][C@H:32]1[NH:31][C:30]([C@:14]12[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]1[C@@H:16]1[C@@:11]([CH3:46])([CH2:12][CH2:13]2)[C@@:10]2([CH3:47])[C@@H:19]([C@:20]3([CH3:23])[C@@H:7]([CH2:8][CH2:9]2)[C:6]([CH3:48])([CH3:49])[C@@H:5]([OH:4])[CH2:22][CH2:21]3)[CH2:18][CH2:17]1)=[O:45]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3S)-2,2-dimethyl-3-(pyrrolidine-1-carbonyl)cyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 43, 0.350 g, 0.517 mmol) in MeOH:THF (2:1) (30 ml) 2N NaOH (10 ml) was added at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the volatile was evaporated and the aqueous layer was extracted with ethyl acetate and the organic layer was washed with water, brine and dried over Na2SO4 then the solvent was evaporated and the resulting crude was stirred in hexane and the resulting solid was obtained which was filtered and dried under vacuum to afford the title compound. Wt: 0.220 g: Yield: 67%; 1H NMR (300 MHz, CDCl3): δ 6.27 (d, 1H, J=8.1 Hz), 4.72 (s, 1H), 4.57 (s, 1H), 4.17-4.07 (m, 1H), 3.56-3.11 (m, 4H), 3.19-3.09 (m, 2H), 2.82-2.76 (m, 1H), 2.57-2.43 (m, 1H), 2.39-2.18 (m, 2H), 2.01-1.72 (m, 7H), 1.67 (s, 3H), 1.61-1.11 (m, 22H), 0.96, 0.93, 0.87, 0.81, 0.74 (s, 18H); Mass: [M+1]+ 635 (5%), [M+Na]+ 657 (100%); IR (KBr, cm−1): 3390, 3071, 2947, 2869, 1617, 1455, 1369, 1341, 1250, 1194, 1168, 1108, 1034, 921, 880; M.R: 176.3° C.-180.9° C.; HPLC: 98.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].C1COCC1.Cl>CO.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.3 %

Procedure:
To a solution of Example 100 (1.00 g, 2.18 mmol) in methanol (5 ml), lithium hydroxide (0.856 g, 20.40 mmol) in water (5 ml) and THF (19 ml) were added and stirred at RT. After 12 h, pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as an off-white solid (0.900 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC.[Cl-].[Li+].O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([CH:13]=[CH2:14])=[CH:7][N:6]=1)=[O:4]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ncc(Cl)nc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1cnc(C(=O)OC)c(N)n1
Temperature: 85 °C

Procedure:
To a mixture of 3-amino-5-chloro-pyrazine-2-carboxylic acid methyl ester (GB 1248146, 161 mg 0.86 mmol), tributyl(vinyl)tin (0.352 ml, 1.204 mmol) and lithium chloride (102 mg, 2.498 mmol) in DMF (4 ml) was added PdCl2(PPh3)2 (30.2 mg, 0.043 mmol) and the mixture was heated to 85° C. for 2.5 h. After cooling to room temperature water was added and the mixture was extracted with EtOAc, the combined organic layers were washed with water and half saturated aq. NaCl, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:9) to provide the title compound as yellow solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1>CS(C)=O.ClCCl>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Temperature: 95 °C

Procedure:
5-Fluoro-2-nitrobenzotrifluoride (400 mg, 1.91 mmol) and trans-4-aminocyclohexanol (220 mg, 1.91 mmol) were dissolved in dimethylsulfoxide (10 mL). The resulting mixture was heated at 95° C. for 3.5 hr. After cooling at room temperature, the mixture was diluted with dichloromethane (15 mL) and washed with water (3×10 mL). The organic phase was collected and dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was re-crystallized from petrol ether. The desired product was then isolated as a yellow solid (490 mg, 84% yield).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.[Pd].C([O-])(=O)C>[CH:25]1[C:26]2[C:21](=[CH:20][C:19]([N:8]3[CH2:7][CH2:6][C:5]4([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]4)[CH2:10][CH2:9]3)=[CH:28][CH:27]=2)[CH:22]=[CH:23][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: Brc1ccc2cnccc2c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc4cnccc4c3)CC2)C1
Temperature: 120 °C
Yield: 52 %

Procedure:
Sodium t-butylate (6.24 mmol, 3.0 eq.) was added to a solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.08 mmol, 1.0 eq.) and 6-bromoisoquinoline (2.08 mmol, 1.0 eq.) in toluene (10 ml) and the reaction mixture was degassed with N2. BINAP (0.124 mmol, 0.06 eq.) and Pd acetate (0.04 mmol, 0.02 eq.) were added and the mixture was heated at 120° C. for 12 h. The reaction mixture was filtered over Celite and the filtrate was concentrated on a rotary evaporator. The crude product was purified by means of column chromatography (silica gel, 5% methanol in methylene chloride) in order to obtain the desired product. Yield: 52%
Reaction SMILES: [O:1]1CCC[CH2:2]1.[C:6]1([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([Li])CCC.C(OCC)=O.C(O)(=O)C>CCCCCC>[C:6]1([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH:2]=[O:1])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C1CCOC1
Reactant: c1ccc(-n2ccnc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOC=O
Product: O=Cc1nccn1-c1ccccc1
Reaction time: 1 h

Procedure:
To 50 ml of dry tetrahydrofuran containing 5.0 g (3.5 mmoles) of 1-phenylimidazole and cooled to -78° C. was added 13.8 ml (3.5 mmoles) of a 2.5M solution of n-butyllithium in hexane and the mixture stirred in the cold for one hour. Ethyl formate (2.8 ml, 3.5 mmoles) was then added and the mixture stirred for 80 minutes. Acetic acid (1.99 ml, 3.5 mmoles) was added and the cooling bath was removed. After stirring for 5 minutes the mixture was poured into water and the product extracted with ethyl acetate. The extracts were combined, dried over magnesium sulfate and concentrated to give 6.58 g of a pale yellow oil which solidified when triturated with a small amount of cold ether, 4.02 g.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:12](/[CH:13]=[CH:14]/[C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[CH:24][CH:23]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[F:31][CH:29]([F:30])[O:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:18]2[N:17]=[CH:16][C:15]([CH2:14][CH2:13][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:33][CH:32]=3)=[CH:20][N:19]=2)=[CH:23][CH:24]=1
Reactant: FC(F)Oc1ccc(Nc2ncc(/C=C/c3ccc(OCc4ccccc4)cc3)cn2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(CCc2cnc(Nc3ccc(OC(F)F)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
To a solution of (E)-5-(4-(benzyloxy)styryl)-N-(4-(difluoromethoxy)phenyl)pyrimidin-2-amine (0.04 g, 0.090 mmol) in methanol (5 mL) was added Pd/C (0.03 g, 0.282 mmol) and stirred at room temperature under H2 (1 atom) for 3 h. The reaction mass was filtered through Celite, concentrated and purified by preparative HPLC on a Waters Xbridge C18 column (19×150 mm, 5 μm) using 0-100% mobile phase B (95:5 Acetonitrile:water with 10 mM NH4OAc) in mobile phase A (5:95 Acetonitrile:water with 10 mM NH4OAc) to give 4-(2-(2-((4-(difluoromethoxy)phenyl)amino)pyrimidin-5-yl)ethyl)phenol (0.013 g, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.73 (s, 4H), 6.66 (d, J=8.40 Hz, 2H), 6.83-7.35 (m, 5H), 7.71-7.79 (m, 2H), 8.26 (s, 2H), 9.15 (br. s., 1H), 9.55 (s, 1H). LCMS: RT 2.14 min, (M+H)+358.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10]([O:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:25][CH2:26][C:27]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)=[O:28]>CN(C=O)C.C(#N)C>[Br-:25].[C:1]([O:5][C:6]([NH:8][CH:9]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:10]([O:12][C@@H:13]1[CH2:17][CH2:16][N+:15]([CH3:18])([CH2:26][C:27](=[O:28])[C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CC[C@@H](OC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1
Reactant: O=C(CBr)c1cccs1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@@H]1CC[N+](C)(CC(=O)c2cccs2)C1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 48 %

Procedure:
To a solution of (R)-1-methylpyrrolidin-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (C61) (170 mg, 0.51 mmol) in DMF (5 ml) and acetonitrile (3 ml), was added 2-bromo-1-(thiophen-2-yl)ethanone (115 mg, 0.56 mmol) and the reaction was stirred at RT for 15 hours. The solvent was evaporated, and the crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (3R)-3-(2-(tert-butoxycarbonylamino)-2-phenylacetoxy)-1-methyl-1-(2-oxo-2-(thiophen-2-yl)ethyl)pyrrolidinium bromide (132 mg; 48% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[Cl:37][CH2:38][C:39](O)=[O:40]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:37][CH2:38][C:39]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])=[O:40]
Reactant: O=C(O)CCl
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)=CCC(OC(=O)CCl)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3ml of dry dichloromethane. To the resulting solution was added 94.5 mg (1 mmole) of monochloroacetic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedure as described in Example 1 to obtain 218 mg (Yield: 60%) of the title compound having the following structure as a red oil.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[CH2:12]([N:14]([CH2:17][CH2:18][O:19][C:20]([N:22]1[N:27]=[C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[NH:34][CH2:33][CH2:32][CH2:31]3)[CH:25]([CH3:38])[S:24][C:23]1=[O:39])=[O:21])[CH2:15][CH3:16])[CH3:13].O>ClCCl>[CH2:12]([N:14]([CH2:17][CH2:18][O:19][C:20]([N:22]1[N:27]=[C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]([C:8](=[O:10])[CH3:9])[CH2:33][CH2:32][CH2:31]3)[CH:25]([CH3:38])[S:24][C:23]1=[O:39])=[O:21])[CH2:15][CH3:16])[CH3:13]
Reactant: CCN(CC)CCOC(=O)N1N=C(c2ccc3c(c2)CCCN3)C(C)SC1=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCOC(=O)N1N=C(c2ccc3c(c2)CCCN3C(C)=O)C(C)SC1=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
5 ml of triethylamine and then, dropwise with stirring, 4 ml of acetyl chloride are added to a solution of 12 g of 3-[2-(N,N-diethylamino)ethoxycarbonyl]-5-(1,2,3,4-tetrahydro-6-quinolyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one [obtainable in analogy to Example 1 by reacting 5-(1,2,3,4-tetrahydro-6-quinolyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one with 2-(N,N-diethylamino)ethyl chloroformate] in 100 ml of dichloromethane. The mixture is subsequently stirred at 20° C. for one hour and decomposed with water and the mixture is worked up in the conventional manner to give 3-[2-(N,N-diethylamino)ethoxycarbonyl]-5-(1-acetyl-1,2,3,4-tetrahydro-6-quinolyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][S:17][C:11]=2[NH:10][C:9]1=[O:18].[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1>CN(C)C=O.O>[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][S:17][C:11]=2[N:10]([CH2:22][CH:19]2[CH2:21][CH2:20]2)[C:9]1=[O:18]
Reactant: Cn1c(=O)[nH]c2sccc2c1=O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2ccsc2n(CC2CC2)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Potassium carbonate (1.0 g) was added to a mixture of 3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (400 mg; J. Chem. Soc. Perkin Trans.1; 1980; 1853) and cyclopropylmethyl bromide (1.0 ml) in dry dimethylformamide (15 ml). The solution was stirred at room temperature for 20 hours and was then diluted with water and extracted thrice with diethyl ether. The combined organic extracts were washed with brine, then dried, filtered and evaporated. The residue was purified by column chromatography over silica, eluting with ethyl acetate: isohexane (1:4) to give the subtitle compound (180 mg).
Reaction SMILES: [CH2:1]([NH:4][NH2:5])[CH:2]=[CH2:3].C(N(CC)CC)C.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>ClCCl.C(OCC)(=O)C>[CH2:1]([N:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH2:5])[CH:2]=[CH2:3]
Reactant: C=CCNN
Reactant: CCOC(=O)CBr
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(N)CC(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
To the solution of 70%-allylhydrazine 7.73 g (75 mmol) and triethylamine 8.38 ml (60 mmol), ethyl 2-bromoacetate in dichloromethane 25 ml was added and stirred at room temperature for 24 hours and reflux for additional 1 hour. The reaction mixture was diluted with ethyl acetate 150 ml and washed with brine 100 ml. The organic phase was dried with magnesium sulfate and filtered and the mother solution was concentrated in vacuo to obtain the title compound 6.90 g (87%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.O[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(Cl)ncnc32)CC1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
To a solution of 5-bromo-4-chloro-1H-pyrrolo[2,3-d]pyrimidine (214 mg, 0.921 mmol), 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate (556 mg, 2.76 mmol) and triphenylphosphine (483 mg, 1.841 mmol) in Tetrahydrofuran (THF) (10 mL) was added dropwise DEAD (0.291 mL, 1.841 mmol). The solution was stirred at room temperature. After 2 hr the reaction was concentrated then loaded on to a 25 g Biotage SNAP column to give 1,1-dimethylethyl 4-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (330 mg, 86% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.23 (s, 1H), 4.83-4.97 (m, 1H), 4.11 (br. s., 2H), 2.95 (br. s., 2H), 1.84-2.05 (m, 4H), 1.43 (s, 9H)
Reaction SMILES: C=O.[ClH:3].[C:4]1([SH:10])C=CC=CC=1.[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:10][CH2:4][Cl:3])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Sc1ccccc1
Reactant: Cl
Reactant: c1ccccc1
Agent: C=O
Product: ClCSc1ccccc1
Temperature: 31 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
With stirring, 37.5 grams (1.25 moles) of paraformaldehyde was added to 250 ml of benzene. To the benzene-paraformaldehyde mixture 500 ml of concentrated hydrochloric acid was added slowly at ambient temperature. The mixture was then heated at 31° C. for 30 minutes, and 110 grams of thiophenol was added. Upon complete addition the reaction mixture was heated at 50°-55° C. for 2 hours, then allowed to cool to ambient temperature where it stood for 18 hours. The reaction mixture was separated and the organic layer washed with 250 ml of water. The water wash was extracted with 250 ml of benzene and the two benzene layers were combined. The benzene combination was washed with 300 ml of aqueous saturated sodium chloride, dried with magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to a residue which was further evaporated under high vacuum and distilled to give 115.9 grams (73.2%) of phenylthiomethyl chloride; b.p. 80° C./3 mm. The nmr and the ir spectra were consistent with the assigned structure.
Reaction SMILES: C(N=C=S)C=C.[CH2:7]([N:10]1[C:14]([SH:15])=[N:13][N:12]=[C:11]1[OH:16])[CH:8]=[CH2:9].Br[C:18]1[S:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][N:22]=1>>[CH2:7]([N:10]1[C:14]([S:15][C:18]2[S:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][N:22]=2)=[N:13][N:12]=[C:11]1[OH:16])[CH:8]=[CH2:9]
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: C=CCn1c(O)nnc1S
Solvent: C=CCN=C=S
Product: C=CCn1c(O)nnc1Sc1ncc([N+](=O)[O-])s1

Procedure:
The title compound was prepared in a similar manner described in Example 6 starting with allyl isothiocyanate. 4-Allyl-3-hydroxy-5-mercapto-1,2,4-triazole was reacted with 2-bromo-5-nitrothiazole as in Example 6. Crystallization from ethanol and water gave 4-allyl-3-hydroxy-5-[(5-nitrothiazol-2-yl)mercapto]-1,2,4-triazole as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].O[CH2:17][CH:18]([CH2:20]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O>>[N+:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:13])([F:14])[F:15])[CH:8]=[C:7]2[C:5]=1[N:6]=[CH:20][CH:18]=[CH:17]2)([O-:3])=[O:2]
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reactant: OCC(O)CO
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Product: O=[N+]([O-])c1cc(OC(F)(F)F)cc2cccnc12
Yield: 94.7 %

Procedure:
In a similar fashion using route 10 general procedure 20, 2-nitro-4-(trifluoromethoxy)aniline (1.0 g, 4.50 mmol), glycerol (1.3 g, 13.96 mmol) and 3-nitrobenzenesulfonic acid sodium salt (1.32 g, 5.85 mmol), gave the title compound (1.1 g, 95%) which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH3:13])[NH:8][C:7](=[O:14])[C:6](=[O:15])[NH:5]2.[N+:16]([O-:19])([OH:18])=[O:17]>>[Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][CH3:13])[NH:8][C:7](=[O:14])[C:6](=[O:15])[NH:5]2.[Cl:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:8][C:7](=[O:14])[C:6](=[O:15])[NH:5]2)=[C:10]([N+:16]([O-:19])=[O:17])[C:11]=1[CH2:12][CH3:13]
Reactant: CCc1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Reactant: O=[N+]([O-])O
Product: CCc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]
Product: CCc1cc2[nH]c(=O)c(=O)[nH]c2c([N+](=O)[O-])c1Cl
Temperature: 0 °C
Yield: 91 %

Procedure:
1,4-Dihydro-6-chloro-7-ethylquinoxalin-2,3-dione (2.34 g, 10.4 mmol) was added in small portions over 10 minutes to vigorously stirred concentrated nitric acid (20 ml) at room temperature. The mixture was then heated at 40° C. for 12h, cooled, and poured into ice water. The yellow solid which formed was filtered off, washed with water, and dried to give 1,4-dihydro-6-chloro-7-ethyl-5-nitroquinoxalin-2,3-dione and 1,4-dihydro-7-chloro-6-ethyl-5-nitroquinoxalin-2,3-dione (2.55 g, 91%), as a mixture (1.7:1 ratio).