Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.Cl.[C:5]([N:13](C)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:23])=[O:22])=[CH:17][CH:16]=1)(=O)C1C=CC=CC=1>O>[CH3:5][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CN(Cc1ccc(S(C)=O)cc1)C(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNCc1ccc(S(C)=O)cc1
Yield: 84.1 %

Procedure:
To a mixture of ethanol (40 ml), water (20 ml) and conc. hydrochloric acid (60 ml), N-benzoyl-N-methyl-N-(4-methylsulfinylbenzyl)amine (4.1 g) is added and the mixture is heated with refluxing for 12 hours. After the reaction, the solvent is distilled off under reduced pressure, and to the resulting residue is added 20% aqueous sodium hydroxide solution, and the mixture is extracted with diethyl ether. The extract is washed successively with water and aqueous sodium chloride solution, and dried over magnesium sulfate. Diethyl ether is distilled off to give N-methyl-N-(4-methylsulfinylbenzyl)amine (2.2 g).
Reaction SMILES: Br[CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1O.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1.CN(C)C=[O:27]>>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:21][CH:3]2[CH:2]([OH:27])[C:7]([CH3:9])([CH3:8])[O:6][C:5]3[CH:10]=[CH:11][S:12][C:4]2=3)=[O:20])=[CH:17][CH:16]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: CN(C)C=O
Reactant: CC1(C)Oc2ccsc2C(O)C1Br
Product: CC1(C)Oc2ccsc2C(NC(=O)c2ccc(Cl)cc2)C1O

Procedure:
The title compound was prepared as described in Example 3 starting with 6-bromo-7-hydroxy-5,6-dihydro-5,5-dimethyl-7H-thieno[3,2-b]pyran (4.75 g, 18.1 mmol) and 4-chlorobenzamide (7.0 g, 45 mmol) in N,N-dimethylformamide (125 mL) to give 1.41 (23%) as a yellow solid: mp 196°-197° C.; IR (KBr): 3483, 3317, 1632 and 1525 cm-1 ; MS: m/z 338 (MH+); 1H NMR (DMSO-d6): δ 1.20 (s, 3H), 1.39 (s, 3H), 3.79 (m, 1H, simplifies to d, J=8.8 Hz, with D2O), 4.98 (m, 1H, simplifies to d, J=8.8 Hz with D2O), 5.64 (d, J=6.0 Hz, 1H, exchanges with D2O), 6.58 (d, J=5.3 Hz, 1H), 7.29 (d, J=5.3 Hz, 1H), 7.56 (d, J=6.8 Hz, 2H), 7.93 (d, J=6.8 Hz, 2H) and 8.88 (d, J=8.3 Hz, 1H, exchanges with D2O).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.C[NH:20][OH:21].O.N1C=CC=C[CH:24]=1>>[CH3:24][O:21][N:20]=[CH:14][C:13]1[CH:16]=[CH:17][C:10]([CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=1
Reactant: CCCC(c1ccc(C=O)cc1)n1ccnc1
Reactant: CNO
Reactant: c1ccncc1
Agent: Cl
Solvent: O
Product: CCCC(c1ccc(C=NOC)cc1)n1ccnc1
Reaction time: 8 h

Procedure:
0.5 g of 4-[1-(1-imidazolyl)-butyl]-benzaldehyde (of example 6) is dissolved with 0.42 g of O- methylhydroxylamine hydrochloride in 20 ml of pyridine and stirred overnight. It is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is concentrated by evaporation in a vacuum and distilled on a bulb tube, boiling point 200° C./0.03 mbar. 0.39 g of 1-[1-(4-methoxyiminomethylphenyl)-butyl]imidazole is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][Cl:30]>CN(C=O)C>[ClH:30].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:17][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1
Reactant: COc1cccc(CCl)c1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(COc2ccc3c(N4CCCC4)cc(C)nc3c2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A mixture of 114 mg (0.5 mmol) of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example 2, 166 mg (0.6 mmol) of potassium carbonate and 84 μl (0.6 mmol) of 3-methoxybenzyl chloride was heated at 80° C. in 8 ml of DMF under an argon atmosphere for 23 h. The mixture was cooled to RT and partitioned between EtOAc and water. The organic layer was separated, washed with water then saturated NaCl solution, dried over magnesium sulphate and concentrated in vacuo. The residue was taken up in diethyl ether and some not dissolved material was removed by filtration. The filtrate was treated under stirring with 0.25 ml of 3N HCL in MeOH and stirring was continued for 1 h. The solid that precipitated was filtered off by suction and dried in a high vacuum to give 138 mg (69.7%) of 7-(3-methoxy-benzyloxy)-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochloride as an light-yellow solid. ISP mass spectrum, m/e: 349.4 (M+1 calculated for C22H24N2O2: 349).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[C:3]([C:10]([OH:12])=[O:11])[CH:2]=1.S(Cl)([Cl:15])=O.[CH3:17]O>>[ClH:15].[CH3:17][O:8][C:7]([C:5]1[CH:6]=[N:1][CH:2]=[C:3]([C:10]([OH:12])=[O:11])[CH:4]=1)=[O:9]
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: O=C(O)c1cncc(C(=O)O)c1
Product: COC(=O)c1cncc(C(=O)O)c1
Product: Cl
Reaction time: 0.5 h

Procedure:
Pyridine-3,5-dicarboxylic acid (5.00 g, 29.9 mmol) was stirred in CH3OH (100 mL), cooled in an ice bath, and treated dropwise with thionyl chloride (17.45 mL, 239.2 mmol). After 0.5 hr, the reaction mixture was refluxed for 48 hrs. Concentration to dryness gave the title compound as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[C:27]([O:29][CH3:30])=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:30][O:29][C:27]([CH:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])=[O:28]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: COC(=O)C1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with methyl pyrrolidine-2-carboxylate hydrochloride (79397-50-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=396.5 [MH+].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9](=[S:11])[NH2:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([C:39](=O)[CH2:40]Br)[CH:25]=[C:26]([N+:36]([O-:38])=[O:37])[C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([C:39]2[N:10]=[C:9]([C:8]3[C:3]([C:2]([F:1])([F:12])[F:13])=[N:4][CH:5]=[CH:6][CH:7]=3)[S:11][CH:40]=2)[CH:25]=[C:26]([N+:36]([O-:38])=[O:37])[C:27]=1[O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NC(=S)c1cccnc1C(F)(F)F
Reactant: O=C(CBr)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Solvent: CCO
Product: O=[N+]([O-])c1cc(-c2csc(-c3cccnc3C(F)(F)F)n2)cc(OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 2-(trifluoromethyl)pyridine-3-carbothioamide (0.227 g, 1.10 mmol) and 1-[3,4-bis(benzyloxy)-5-nitrophenyl]-2-bromoethanone (0.50 g, 1.10 mmol) were refluxed overnight in absolute ethanol (5 mL). After cooling to room temperature, the reaction mixture was poured onto water (50 mL). The resulting precipitate was filtered off, washed with water (25 mL) and dried. Recrystallisation from dichloromethane/isopropanol afforded 4-(3,4-bis(benzyloxy)-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)thiazole, 0.539 g (87%).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1.[CH3:37]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>C(Cl)Cl.CO>[C:2]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)#[CH:37]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CO)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound 21a (195 mg, 0.393 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (2 mL) was added. The Dess-Martin periodinane (184 mg, 0.433 mmol) was added and then the reaction was stirred at rt for 20 min. The reaction was diluted with DCM (20 mL) and washed with saturated NaHCO3 solution (2×20 mL). The organic phase was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was placed in a 20 mL vial equipped with a stir bar and then MeOH (5 mL) was added. K2CO3 (163 mg, 1.18 mmol) was added and then dimethyl (1-diazo-2-oxopropyl)phosphonate (113 mg, 0.590 mmol) dissolved in MeOH (2 mL) was added. The reaction was stirred at reflux for 3 h. Additional K2CO3 (163 mg, 1.18 mmol)) and diazophosphonate (113 mg, 0.590 mmol) were added and the reaction was refluxed for 6 h. The reaction was cooled to rt and then the solvent was removed under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with water (20 mL). The aqueous layer was extracted with DCM (3×10 mL) and then the combined organic extracts were washed with brine (20 mL), dried over MgSO4, and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 40 g SiO2 pre-packed column eluting with 0-60% ACN/DCM to afford compound 26a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.85 (d, J=2.2 Hz, 1H), 8.16 (dd, J=8.8, 2.4 Hz, 1H), 8.03 (d, J=5.6 Hz, 1H), 6.77 (d, J=9.0 Hz, 1H), 6.08 (d, J=5.6 Hz, 1H), 3.95-4.03 (m, 4H), 3.88-3.95 (m, 4H), 3.60-3.68 (m, 4H), 3.50-3.60 (m, 4H), 3.28 (s, 1H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H31N7O3: 490.3 (M+H). Found: 490.3.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:9]2[C:10]([CH2:17][N:18]3[C@@H:22]([CH3:23])[C@@H:21]([C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=4)[O:20][C:19]3=[O:38])=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].N(OCCCCC)=O.[I:47]I>C(Cl)(Cl)Cl.C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:26]1[CH:25]=[C:24]([C@H:21]2[O:20][C:19](=[O:38])[N:18]([CH2:17][C:10]3[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([I:47])[CH:3]=4)=[CH:14][N:13]=[C:12]([S:15][CH3:16])[N:11]=3)[C@H:22]2[CH3:23])[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=1
Reactant: CSc1ncc(-c2ccc(F)c(N)c2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reactant: II
Agent: CCCCCON=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CSc1ncc(-c2ccc(F)c(I)c2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of the title compound from Step A (2.1 g, 3.75 mmol), n-pentyl nitrite (0.66 g, 5.62 mmol) and I2 (1.24 g, 4.87 mmol) in chloroform (20 mL) was stirred at 80° C. for 1 h. The mixture was cooled, and the solvent was diluted with CH2Cl2. The mixture was washed with Na2S2O3 (5 mL), and with brine (5 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/hexane (10/90) to give the title compound as a yellow gum. 1H NMR (CDCl3, 500 MHz) δ 8.41 (s, 1H), 7.92 (s, 1H), 7.78 (s, 2H), 7.77 (m, 1H), 7.35 (m, 1H), 7.22 (m, 1H), 5.76 (d, J=8.5 Hz, 1H), 4.91 (d, J=17 Hz, 1H), 4.45 (m, 1H), 4.06 (d, J=17.5 Hz, 1H), 2.64 (s, 3H), 0.76 (d, J=7 Hz, 3H). LCMS=672.1 (M+H)+.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:17]=[C:16]([Br:18])[C:15]([Br:19])=[CH:14][C:13]=1[NH2:20]>>[Br:18][C:16]1[C:15]([Br:19])=[CH:14][C:13]2[NH:20][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[NH:11][C:12]=2[CH:17]=1
Reactant: O=C(O)c1cccnc1Br
Reactant: Nc1cc(Br)c(Br)cc1N
Product: O=C1Nc2cc(Br)c(Br)cc2Nc2ncccc21
Temperature: 150 °C

Procedure:
A mixture of 0.1 mole of 2-bromonicotinic acid and 0.1 mole of 1,2-diamino-4,5-dibromobenzene is heated in an open vessel to 150° C. with vigorous stirring. After 3 minutes the source of heat is removed, and the reaction mixture is allowed to cool to room temperature and to crystallizes to give a solid. The solid is removed from the vessel, powdered, washed with dilute sodium hydroxide, and then with boiling water, and finally recrystallized from dioxane to give 6,11-dihydro-8,9-dibromo-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:8]([NH:10][NH2:11])=[O:9])=[CH:5][S:6][CH:7]=1.[N:12]([O-])=O.[Na+]>Cl.C(O)(=O)C.C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4]([C:8]([N:10]=[N+:11]=[N-:12])=[O:9])=[CH:5][S:6][CH:7]=1
Reactant: O=N[O-]
Reactant: COc1cscc1C(=O)NN
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cscc1C(=O)N=[N+]=[N-]
Temperature: 25 °C

Procedure:
4-Methoxy-3-thiophenecarboxylic acid hydrazide (20 g, 0.116 mol) in 3N hydrochloric acid (200 ml), acetic acid (200 ml) and chloroform (300 ml) was cooled to 0°. Sodium nitrite (8 g, 0.116 mol) in water (25 ml) was added dropwise whilst maintaining the temperature at 0°. On completion of the addition the reaction mixture was allowed to warm up to room temperature. The organic layer was separated, washed with sodium bicarbonate solution (3 times), dried over sodium sulphate and the solvent evaporated without heat to give the title compound as a buff-coloured solid, 21.2 g.
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][N:8]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])(O)=[O:2].C(N(CC)CC)C.ClC(OCC(C)C)=O>O1CCCC1>[OH:2][CH2:1][CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][N:8]1[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)=[O:18]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCCO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of (2S,4R)-2-(carboxymethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.4 g) in tetrahydrofuran (50 ml) was added triethyamine (1.6 ml). Isobutyl chloroformate (1.1 ml) was dropwise added to the mixture at -5° to -10° C. under nitrogen, followed by stirring for 30 minutes at the same temperature. The insoluble material was filtered off and the filtrate was added to a solution of sodium borohydride (0.70 g) in water (20 ml) at 0° C. After stirring for 2 hours at the same temperature, acetic acid (3 ml) was added thereto. The reaction mixture was evaporated, diluted with ethyl acetate and washed successively with water, saturated sodium bicarbonate and brine. The dried organic layer was concentrated under reduced pressure, and the obtained syrup was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and acetone (4:1 v/v) to give (2S,4R)-2-(2-hydroxyethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.1 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][OH:12].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[C:59]([C:63]1[CH:67]=[C:66]([CH2:68][NH2:69])[N:65]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([Cl:76])[CH:71]=2)[N:64]=1)([CH3:62])([CH3:61])[CH3:60]>C1COCC1.CN(C=O)C>[C:59]([C:63]1[CH:67]=[C:66]([CH2:68][NH:69][C:14](=[O:16])[CH:13]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][O:9][CH2:10][CH2:11][OH:12])=[C:2]([F:1])[CH:3]=2)[CH3:17])[N:65]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([Cl:76])[CH:71]=2)[N:64]=1)([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C(=O)O)c1ccc(COCCO)c(F)c1
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C(=O)NCc1cc(C(C)(C)C)nn1-c1cccc(Cl)c1)c1ccc(COCCO)c(F)c1
Reaction time: 36 h
Yield: 86.9 %

Procedure:
To a stirred THF/DMF (2.0 mL/0.1 mL) solution of 2-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)propanoic acid (synthesis described for example A118) (60.0 mg, 0.25 mmol, 1.0 eq) DIPEA (0.169 mL, 0.13 mmol, 4.0 eq), TBTU (81 mg, 0.25 mmol, leg) and HOBt (33 mg, 0.25 mmol, leg) were sequentially added at RT and the mixture stirred for 15 min. (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (65 mg, 0.25 mmol, 1 eq) was then added and the mixture stirred for 36 h. After completion of the reaction the solvent was evaporated. The crude product was purified by CC using EtOAc/cyclohexane (1:1) to get N-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)-propanamide (106 mg; 87%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][S:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](O)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:1][CH:2]2[CH2:6][S:5][CH2:4][CH:3]2[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C(=O)O)c1ccc(CC2CSCC2O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OC2CSCC2Cc2ccc(C(C)C(=O)O)cc2)cc1
Yield: 44.3 %

Procedure:
2-[4-(4-Hydroxythiolan-3-ylmethyl)phenyl]propionic acid (1.0 g) obtained in Example 9 was dissolved in toluene (30 ml), and p-toluenesulfonic acid (710 mg) was added to the solution and refluxed by heating for 5 hours. After completion of the reaction, the reaction mixture was quenched with water, and the organic layer was separated, and washed with water and saturated brine. Then, the solvent was evaporated under reduced pressure to give a crude product of 2-{4-[4-(4-toluenesulfonyloxy)thiolan-3-ylmethyl]phenyl}propionic acid (700 mg). A part of the product (474 mg) was dissolved in tetrahydrofuran (4.0 ml), and potassium tert-butoxide (506 mg) was added to the solution, and refluxed by heating for 5 hours. After completion of the reaction, the reaction mixture was acidified with 2.0 M aqueous hydrochloric acid under ice cooling, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (90 mg, 14.4% for 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[NH2:22][C@@H:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:22][C@@H:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)[CH:6]=1
Reactant: N[C@H]1CCc2ccccc21
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN[C@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester and (S)-(+)-1-aminoindan.
Reaction SMILES: C([N+](CC)(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C)C=O.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1.[C:36](Cl)([Cl:39])([Cl:38])[Cl:37]>C(Cl)(Cl)Cl>[Cl:37][C:36]([CH:32]([C:31]1[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)[OH:33])([Cl:39])[Cl:38]
Reactant: COc1ccc(C=O)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(O)C(Cl)(Cl)Cl)cc1
Yield: 94.5 %

Procedure:
A 10 g quantity of tetraethyl ammonium salt of p-toluenesulfonic acid was dissolved in 60 ml of dimethylformamide containing 0.1 mole of chloroform. The solution was placed in a cathode chamber and in an anode chamber. Further 13.6 g (0.1 mole) of p-methoxybenzaldehyde and 0.01 mole of carbon tetrachloride was introduced into the cathode chamber. A glass filter was used as a diaphragm. Electrolysis was conducted at a constant current of 0.1 A. After current (2 F/mole) was passed, the reaction liquid was withdrawn from the cathode chamber. The carbon tetrachloride and chloroform were distilled off and the residue was extracted with methylene chloride. The methylene chloride was distilled off from the extract and the residue was distilled in a vacuum, giving trichloromethyl-4-methoxyphenyl carbinol. Yield 94.5%, b.p. 122°-124° C./1 mmHg.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([F:13])=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH3:14][CH:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[C:5]([F:13])=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH2:14][CH:15]([OH:16])[CH3:17])[CH:10]=[CH:9]2
Reactant: Fc1ccc2cc[nH]c2c1Cl
Reactant: CC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)Cn1ccc2ccc(F)c(Cl)c21
Reaction time: 1 h
Yield: 77.8 %

Procedure:
A suspension of 45 mg of sodium hydride dispersion in 10 ml of tetrahydrofuran was treated with 0.2 g of 7-chloro-6-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.17 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 4 days and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 15 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.21 g (77.8%) of (RS)-1-(7-chloro-6-fluoro-indol-1-yl)-propan-2-ol as white crystals with m.p. 85°-87°.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:22])=[CH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:12]=[C:9]32)=[CH:4][CH:3]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[C:23]1([NH:29][C:30](=[O:31])[NH:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([CH3:22])=[CH:7][N:8]4[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:12]=[C:9]43)=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cnc2c3cc(N)ccc3c(C)cn2c1=O
Reactant: O=C=Nc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc2c3cc(NC(=O)Nc4ccccc4)ccc3c(C)cn2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 10-amino-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (600 mg) in pyridine (60 ml) was added phenyl isocyanate (0.22 ml) at ice bath temperature. The reaction mixture was allowed to stir overnight at room temperature. The precipitate was collected, washed with methanol and dried. Recrystallization from dimethyl sulfoxide gave ethyl 10-(3-phenylureido)-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (0.58 g).