Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na][Na].[O:3]1[CH2:8][CH2:7][CH2:6][CH:5]([O:9][C@H:10]2[CH2:45][CH2:44][C@@:43]3([CH3:46])[C:12](=[CH:13][CH:14]=[C:15]4[C@@H:42]3[CH2:41][CH2:40][C@@:39]3([CH3:47])[C@H:16]4[CH2:17][CH2:18][C@@H:19]3[C@H:20]([CH3:38])[CH:21](S(C3C=CC=CC=3)(=O)=O)[CH2:22][C@@H:23]([OH:28])[C:24]([OH:27])([CH3:26])[CH3:25])[CH2:11]2)[CH2:4]1>CO.[Na].[Hg]>[O:3]1[CH2:8][CH2:7][CH2:6][CH:5]([O:9][C@H:10]2[CH2:45][CH2:44][C@@:43]3([CH3:46])[C:12](=[CH:13][CH:14]=[C:15]4[C@@H:42]3[CH2:41][CH2:40][C@@:39]3([CH3:47])[C@H:16]4[CH2:17][CH2:18][C@@H:19]3[C@H:20]([CH3:38])[CH2:21][CH2:22][C@@H:23]([OH:28])[C:24]([OH:27])([CH3:26])[CH3:25])[CH2:11]2)[CH2:4]1
Reactant: C[C@H](C(C[C@@H](O)C(C)(C)O)S(=O)(=O)c1ccccc1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCOC5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Hg]
Agent: [Na]
Agent: [Na][Na]
Solvent: CO
Product: C[C@H](CC[C@@H](O)C(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCOC5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 9.3 %

Procedure:
A mixture of 1 g of anhydrous disodium hydrogenephosphate and 3.2 g of 5% sodium-amalgam was added to a solution of 160 mg of (24R)-22ξ-phenylsulfonyl-5,7-cholestadiene-3β,24,25-triol 3-tetrahydropyranyl ether in 5 ml of methanol in an argon stream under stirring, and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture 10 ml of methanol was added and the precipitate was filtered. The filtrate was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydous sodium sulfate. The solvent was evaporated under reduced pressure to give 11.6 mg (93%) of (24R)-5,7-cholestadiene-3β,24,25-triol 3-tetrahydropyranyl ether.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:12]=1)[NH:9][N:8]=[CH:7]2.I[CH2:20][CH:21]([CH3:23])[CH3:22]>>[CH3:16][O:15][C:13]([C:11]1[CH:12]=[C:4]([O:3][C:2]([F:1])([F:17])[F:18])[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:8]=[CH:7]2)=[O:14]
Reactant: CC(C)CI
Reactant: COC(=O)c1cc(OC(F)(F)F)cc2cn[nH]c12
Product: COC(=O)c1cc(OC(F)(F)F)cc2cnn(CC(C)C)c12
Yield: 56 %

Procedure:
Compound 13 was prepared following general method 1, using compound 8 as starting material and 1-iodo-2-methylpropane as alkylating agent. Yield: 56%.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[SH:13].[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([OH:23])[CH:22]=1)[CH:18]=O.C([O-])(=O)C.[Na+]>O.C(OCC)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]2[S:13][C:18]([C:17]3[CH:20]=[C:21]([OH:23])[CH:22]=[C:15]([OH:14])[CH:16]=3)=[N:5][C:6]=2[CH:11]=1
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: Nc1cc(Cl)ccc1S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1cc(O)cc(-c2nc3cc(Cl)ccc3s2)c1
Yield: 52.5 %

Procedure:
In an acetic acid (0.6 mL) solvent, a mixture including 2-amino-4-chlorobenzenethiol (100 mg, 0.44 mmol), 3,5-dihydroxybenzaldehyde (60 mg, 0.44 mmol), and sodium acetate (107 mg, 1.30 mmol) was refluxed for 7 hours. After cooling, the reaction mixture was distributed between ethyl acetate and water, and an organic layer was dried by using MgSO4, filtered, and evaporated under reduced pressure. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (2:1) as a developer to obtain a solid Compound 90 (64.2 mg, 34.7%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][OH:34])[N:18]=[C:17]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.[CH:63](O)=[O:64].Cl>CN(C)C=O.C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][OH:34])[N:18]=[C:17]([N:35]3[CH2:36][CH2:37][N:38]([CH:63]=[O:64])[CH2:39][CH2:40]3)[N:16]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCNCC2)nc1OCCCO
Reactant: O=CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(C=O)CC2)nc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
4-t-Butyl-N-[6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-2-piperazinyl-4-pyrimidinyl]-benzenesulfonamide (80 mg; 0.14 mmol), WSC·HCl (61.6 mg; 0.28 mmol), N-hydroxybenzotriazole (75.6 mg; 0.56 mmol), and formic acid (6.5 mg; 0.15 mmol) were dissolved in dimethylformamide-methylene chloride (1:1, 1 ml). The mixture was stirred overnight at room temperature. The reaction mixture was poured into water, made acidic with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1), to thereby obtain 20 mg (yield: 23.8%) of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]=[C:21]=[S:22]>C(O)C>[CH3:19][NH:20][C:21]([NH:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[S:22]
Reactant: CN=C=S
Reactant: NCCSCc1ncccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CNC(=S)NCCSCc1ncccc1N

Procedure:
3-Amino-2-[(2-aminoethyl)thiomethyl]pyridine (3.0 g,) prepared from an aqueous slurry of the dihydrobromide and potassium carbonate, by extraction with ethanol-ether (2:1) was dissolved in ethanol (25 ml.), methyl isothiocyanate (1.16 g.) added, and the solution then heated under reflux for 30 minutes. The residue was triturated with ether affording a solid (3.4 g.) m.p. 98°-100°. Recrystallisation from isopropyl acetate gave N-methyl-N'-[2-((3-amino-2-pyridyl)methylthio)ethyl]thiourea in 3 crops, m.p. 99.5°-100.5 (1.33 g.), m.p. 100°-101° (1.04 g.) and m.p. 99°-100° (1.0 g.).
Reaction SMILES: [CH3:1]N(C)C=O.S(OC)(OC)(=O)=O.C[O-].[Na+].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]1[N:38]=[C:37]([O:39][S:40]([C:43]2[C:48]([CH3:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=2[CH3:51])(=[O:42])=[O:41])[C:36]([F:52])=[CH:35][C:26]=1[C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:28].C(OC(=O)C)(=O)C.Cl.C(OC(C)C)(C)C>O.C(Cl)Cl.C(O)C>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N:24]1[C:25]2[C:26](=[CH:35][C:36]([F:52])=[C:37]([O:39][S:40]([C:43]3[C:48]([CH3:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=3[CH3:51])(=[O:41])=[O:42])[N:38]=2)[C:27](=[O:28])[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:1]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)CC(=O)c1cc(F)c(OS(=O)(=O)c2c(C)cc(C)cc2C)nc1Nc1ccc(F)cc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OS(=O)(=O)c3c(C)cc(C)cc3C)c(F)cc2c1=O
Yield: 80.2 %

Procedure:
To 6 ml of methylene chloride was added 335 mg of (N,N-dimethylformamide-dimethyl sulfate) complex compound, and 65 mg of sodium methoxide was added thereto at 0° C., after which the resulting mixture was subjected to reaction at 0° to 10° C. for 1 hour. Subsequently, 300 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinoyl]acetate and 115 mg of acetic anhydride were added thereto. The resulting mixture was subjected to reaction at room temperature for 2 hours, and 0.31 ml of 2N hydrochloric acid and 3 ml of ethanol were added to the reaction mixture, after which the resulting mixture was subjected to reaction at room temperature for 1.5 hours. The reaction mixture was added to a mixture of 6 ml of methylene chloride and 6 ml of water, and the organic layer was separated, washed with 6 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 2 ml of diisopropyl ether, after which crystals were collected by filtration to obtain 245 mg (yield 80.2%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(2,4,6-trimethylbenzenesulfonyloxy)-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 41.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=O)=[CH:24][C:23]=1[F:31]>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)=[CH:24][C:23]=1[F:31]
Reactant: O=C(O)c1ccc(Cl)c(F)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(Cl)c(F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 4-chloro-3-fluorobenzoic acid: MS (ES) m/z 421 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:16]=[C:15]([N:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH3:18])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Na+].Cl>C1COCC1.C(OCC)(=O)C>[CH3:22][S:19]([N:17]([CH3:18])[C:15]1[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=[C:4]([CH:16]=1)[C:3]([OH:23])=[O:2])(=[O:21])=[O:20]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 5-(methanesulfonyl-methylamino)-N-methyl-N-propyl-isophthalamic acid methyl ester (1.09 g, 3.18 mmol) in THF (80 mL) and add 1 N NaOH (16 mL, 16 mmol). Stir at room temperature for 16 h and add 5 N HCl (5 mL). Dilute with ethyl acetate, wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: CN([C:5](=[O:18])[CH:6]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17])[CH2:7][CH2:8][CH3:9])OC.O1CCC[CH2:20]1.C[Mg]Br.Cl>CCOCC>[Br:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH:6]([CH2:7][CH2:8][CH3:9])[C:5](=[O:18])[CH3:20]
Reactant: CCCC(Oc1ccccc1Br)C(=O)N(C)OC
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CCCC(Oc1ccccc1Br)C(C)=O
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
6 g of N-methyl-O-methyl-2-(2-bromophenoxy)pentanohydroxamic acid and 190 ml of anhydrous tetrahydrofuran are placed in a 500 ml round-bottomed flask. The solution is cooled to -10° C. and 19 ml of a 3M solution of methylmagnesium bromide in ether are slowly added. The mixture is stirred for 45 minutes and 60 ml of a molar hydrochloric acid solution are slowly added. The mixture is extracted with 3×100 ml of ethyl ether. The combined organic phases are dried over magnesium sulphate, filtered and concentrated under vacuum to provide 5.13 g of 3-(2-bromophenoxy)-2-hexanone in the form of a colourless oil. Quantitative yield.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:21]([CH:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[CH2:27][CH2:26][NH:25]1)([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:25]1[CH2:26][CH2:27][C:28]2[C:33](=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)[CH:24]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OC)C(C(C)C)NCC2
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(C(C)C)N(CCCCCCCC(=O)NOCc1ccccc1)CC2

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.3 g, 1.1 mmol) was reacted with 1-isopropyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.3 g, 1.1 mmol) in the presence of potassium carbonate (0.15 g, 1.1 mmol) and DMF as solvent to give 8-(1-isopropyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-octanoic acid benzyloxyamide as an almost colorless wax (yield 0.1 g, 20%; purified by column chromatography using silica gel and ethyl acetate as eluent). MS (M+H+)=483.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[O:19][CH:18]=[N:17][CH:16]=3)[N:10]=2)[CH:3]=1.Br[C:21]#[C:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC(P(C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.O(C(C)(C)C)[Li]>O1CCOCC1.C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni].O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[O:19][C:18]([C:21]#[C:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:17][CH:16]=3)[N:10]=2)[CH:3]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnco3)n2)c1
Reactant: BrC#Cc1ccccc1
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Agent: [Li]OC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: C1=CCCC=CCC1
Product: Cc1ccnc(Nc2cccc(-c3cnc(C#Cc4ccccc4)o3)n2)c1
Temperature: 100 °C
Reaction time: 36 h
Yield: 12.5 %

Procedure:
A sealed tube with a teflon screw cap was charged with a mixture of (4-methyl-pyridin-2-yl)-(6-oxazol-5-yl-pyridin-2-yl)-amine (200 mg, 0.793 mmol), bromoethynylbenzene (172 mg, 0.951 mmol) Ni(cod)2 (11 mg, 0.040 mmol), dppbz (18 mg, 0.040 mmol) and LiOtBu (127 mg, 1.59 mmol) in dry dioxane (5 ml) and heated to 100° C. for 2 h. Further bromoethynylbenzene (172 mg), Ni(cod)2 (11 mg), dppbz (18 mg) LiOtBu (127 mg, 1.59 mmol) and dry dioxane (2 ml) were added and heating continued for 36 h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2 eluting with 30% EtOAc in cyclohexane to afford the title compound as an off-white solid (35 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.11 (d, J=5.1 Hz, 1H), 7.87 (s, J=26.8 Hz, 1H), 7.80-7.69 (m, 5H), 7.60-7.49 (m, 3H), 7.33 (d, J=7.2 Hz, 1H), 6.77 (d, J=5.1 Hz, 1H), 2.33 (s, 3H). (ESI+) m/z 353 (M+H)+. Retention time=3.24 mins (method 1).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](Cl)=[O:36]>C(Cl)Cl>[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[CH2:21][N:20]([C:35]([C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)=[O:36])[CH2:19][CH2:18]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(Cl)c1cccs1
Reactant: c1cc2c(c(OCCCN3CCCCC3)c1)CNCC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccs1)N1CCc2cccc(OCCCN3CCCCC3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a mixture of 8-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride salt (300 mg, 0.86 mmol) and NEt3 (0.36 mL, 2.6 mmol) in CH2Cl2 (10 mL) is added 2-thiophene carbonyl chloride (0.10 mL, 0.95 mmol). After stirring at room temperature overnight, the mixture is partitioned between EtOAc and water. The organic phase is washed with brine, dried (MgSO4), and concentrated. The residue is purified by flash chromatography [Biotage 40S SiO2, elute 20% (90/10/1 CH2Cl2/MeOH/NH4OH)/80% CH2Cl2 to 100% (90/10/1 CH2Cl2/MeOH/NH4OH)] to yield the title compound as a yellow oil (0.181 g, 55%). MS (ES+) 385.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=CC=CC=1.CC1N=C(N2CCN(CCC)C2=O)SC=1C(O)=O.[NH2:41][CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1>>[CH3:18][C:16]1[N:17]=[C:13]([N:10]2[CH2:11][CH2:12][N:8]([CH2:1][CH2:2][CH3:7])[C:9]2=[O:22])[S:14][C:15]=1[C:19]([NH:41][CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)=[O:21]
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: CCCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Product: CCCN1CCN(c2nc(C)c(C(=O)NCc3cccnc3)s2)C1=O
Yield: 46 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-propylimidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 46% yield: mp 109-111° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.52-8.42 (m, 2H), 7.63 (d, J=7.8 Hz, 1H), 7.24-7.17 (m, 1H), 6.54 (t, J=6.0 Hz, 1H), 4.52 (d, J=6.0 Hz, 2H), 4.05-4.00 (m, 2H), 3.55-3.49 (m, 2H), 3.20 (t, J=7.5 Hz, 2H), 2.60 (s, 3H), 1.59-1.49 (m, 2H), 0.85 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.8, 157.5, 155.4, 153.5, 149.1, 148.6, 135.6, 134.1, 123.6, 116.7, 45.4, 42.1, 42.0, 41.2, 20.5, 17.2, 11.1; MS (ES+) m/z 360.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-:3])=[O:2].[OH-].[K+].[CH2:13]1[CH:15]([CH:16]([OH:19])C#N)[CH2:14]1>CN(C=O)C>[CH:15]1([CH:16]([OH:19])[CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:13][CH2:14]1
Reactant: N#CC(O)C1CC1
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1CC(O)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To 4.9 g (35.7 mmol) of 2-nitrotoluene in 30 ml of DMF are added, within one hour, 0.168 g (2.55 mmol; 85% purity) of KOH and simultaneously 5 g (71.34 mmol) of cyclopropylcarboxaldehyde. The mixture is stirred at room temperature (RT) for 0.5 h, then 0.5 equivalent of cyclopropylcarboxaldehyde is added and the mixture is stirred at RT for a further hour. Subsequently, a majority of the DMF is distilled off under reduced pressure, and the residue is admixed with water and extracted with ethyl acetate. After the evaporation of the solvent and chromatography using silica gel (elution with toluene/ethyl acetate mixtures), 4.2 g (yield 55% of theory, purity (GC-MS 95.9%) of 1-cyclopropyl-2-(2-nitrophenyl)ethanol were obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]([OH:20])=[O:19])=[CH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.[N+:24]([O-])([O-:26])=[O:25].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][C:13]([N+:24]([O-:26])=[O:25])=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]([OH:20])=[O:19])=[CH:9][C:8]2=[O:21])=[CH:22][CH:23]=1
Reactant: O=C(O)Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)Cc1cc(=O)n(Cc2ccc(Cl)cc2)c2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
1-(4-Chlorobenzyl)-1,2-dihydro-2-oxoquinol-4-ylacetic acid (33 g.) was added to concentrated sulphuric acid (210 ml.) at 0° C. The mixture was stirred at 0° C. and potassium nitrate (11g.) was added in small portions over 8 minutes. The mixture was then stirred at 0° C. for a further 10 minutes and then for 2 hours at room temperature. The mixture was poured into an ice-water mixture (2.5 l.), and the precipitated solid was filtered off. The dried solid was crystallised from 3/1 v/v dimethylformamide-ethanol to give 1-(4-chlorobenzyl)-1,2-dihydro-6-nitro-2-oxoquinol-4-ylacetic acid, m.p. 217°-9° C., in 85% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5](I)=[CH:6][CH:7]=1.CN(C)[CH:11]=[O:12]>>[OH:1][CH2:2][C:3]1([C:3]2[S:4][CH:5]=[CH:6][CH:7]=2)[CH2:7][CH:6]=[C:5]([CH2:11][OH:12])[S:4]1
Reactant: CN(C)C=O
Reactant: OCc1ccc(I)s1
Product: OCC1=CCC(CO)(c2cccs2)S1

Procedure:
2-hydroxymethyl-5-iodothiophene was refluxed with Cu powder in dimethyl formamide ("DMF"). This Ullmann condensation also yielded a very low amount of 2,5-dihydroxymethyl bithiophene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([C:22]([OH:24])=O)=[CH:8][CH:9]=1.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CO.CN(C=O)C>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH:29][C:22]([C:7]1[CH:6]=[C:5]2[C:10]([S:11](=[O:21])(=[O:20])[NH:12][C:13]3[C:4]2=[CH:3][C:2]([Cl:1])=[C:19]2[C:14]=3[N:15]=[CH:16][CH:17]=[CH:18]2)=[CH:9][CH:8]=1)=[O:24]
Reactant: O=C(O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)CCNC(=O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 51.6 %

Procedure:
In a similar fashion using route 54 general procedure 123, 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid 524 (100 mg, 0.27 mmol), N,N dimethylethylenediamine (0.06 ml, 0.55 mmol), EDC.HCl (80 mg, 0.41 mmol), HOBt (56 mg, 0.41 mmol), TEA (0.12 ml, 0.83 mmol) and DMF (1 ml) gave the title compound (60 mg, 50%) after trituration from MeOH.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[C:12]([C:16]4([CH3:23])[NH:21][C:20](=O)[CH2:19][O:18][CH2:17]4)[CH:13]=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH:24]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[C:12]([C:16]4([CH3:23])[NH:21][C:20](=[S:34])[CH2:19][O:18][CH2:17]4)[CH:13]=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(c2cccc(-c3nc4cc(Cl)ccc4o3)c2)COCC(=O)N1
Product: CC1(c2cccc(-c3nc4cc(Cl)ccc4o3)c2)COCC(=S)N1
Yield: 57 %

Procedure:
In close analogy to the procedure described for the preparation of Intermediate XVIII-1, the reaction of (RS)-5-[3-(5-chloro-benzooxazol-2-yl)-phenyl]-5-methyl-morpholin-3-one with Lawesson's reagent yielded the title compound (57% of theory). MS (ISP): m/z=359.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:9])[C:6]=1[CH:7]=[O:8].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:9])[C:6]=1[CH2:7][OH:8]
Reactant: Cn1ncc(Br)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1ncc(Br)c1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (677 mg, 3.58 mmol) in MeOH (8 mL) at 0° C., NaBH4 (136 mg, 0.86 mmol) was added. The solution was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo and diluted with water. The solution was extracted with EtOAc, the organic layer collected, dried over sodium sulphate and concentrated in vacuo to afford the title compound as a white solid (614 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=5)[CH2:22][CH2:21]4)[C:15](=[O:33])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:34]=1.[CH2:35]([CH2:37][NH2:38])[OH:36]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([C:26]5[CH:31]=[CH:30][N:29]=[C:28]([NH:38][CH2:37][CH2:35][OH:36])[N:27]=5)[CH2:24][CH2:25]4)[C:15](=[O:33])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:34]=1
Reactant: NCCO
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCN(c2ccnc(Cl)n2)CC1
Solvent: CCO
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCN(c2ccnc(NCCO)n2)CC1

Procedure:
To a solution of 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-ylmethyl]-piperazin-2-one (0.40 g, 0.74 mmol) in EtOH is added ethanolamine (0.089 mL, 1.5 mmol). The solution is heated to reflux for 18 h and evaporated to dryness. The residue is chromatographed eluting successively with 1%, 2% and 4% MeOH in CH2Cl2. Fractions containing only product are combined and the solvent evaporated. Trituration with ether afforded the title compound as a yellow solid: MS (ESI): m/z 565 (M++H).