Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](F)=[CH:6][C:5]=1[F:14].[CH3:16][NH2:17]>CN(C=O)C>[F:14][C:5]1[CH:6]=[C:7]([NH:17][CH3:16])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:3]([OH:2])=[O:15]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]

Procedure:
2-Fluoro-4-methylamino-5-nitro-benzoic acid (375 mg) was prepared by following General Procedure A starting from 2,4-difluoro-5-nitro-benzoic acid methyl ester (440 mg) and methylamine (2 M in THF, 1.01 mL) in DMF.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH3:15])[C:11]2=O)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[O:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.Cl>C1COCC1.O>[C:1]([C:5]1[CH:13]=[C:12]2[C:8](=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=1[O:22][CH3:23])[CH2:9][C:10]([CH3:15])=[CH:11]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(C)C2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(C)=C2
Temperature: 5 °C
Reaction time: 1 h
Yield: 99744.2 %

Procedure:
To a solution of 44.3 g (0.144 mmol) of 6-tert-butyl-5-methoxy-2-methyl-4-phenylindan-1-one in 150 ml of THF cooled to 5° C. 2.72 g (71.9 mmol) of NaBH4 was added. Further on, 75 ml of methanol was added dropwise to this mixture by vigorous stirring for 1 h at 5° C. The resulting mixture was stirred additionally 1 h at 5° C., then 0.5 h at room temperature, and then added to 1 liter of cold water and 30 ml of 12 M HCl in separating funnel. The crude product was extracted consequentially with 250, 100 and 50 ml of dichloromethane, and the combined organic extract was evaporated to dryness. To a solution of the residue in 500 ml of toluene 1.0 g of TsOH was added, this mixture was refluxed with Dean-Stark head for 10 min and then cooled to room temperature using water bath. The resulting solution was washed by aqueous K2CO3 (20 g K2CO3 in 200 ml of H2O), the organic layer was separated, the aqueous layer was extracted with 2×50 ml of dichloromethane. The combined organic solution was dried over K2CO3 and then passed through short layer of silica gel 60 (40-63 um, ca. 10 g). The silica gel layer was additionally washed by 50 ml of dichloromethane. The combined organic elute was evaporated to dryness. This procedure gave 42.0 g (˜100%) of yellowish oil which was further used without an additional purification.
Reaction SMILES: [C:1]([C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O)([CH3:4])([CH3:3])[CH3:2].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16].S(=O)(=O)(O)O>C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[N:16][NH:15][C:14]([O:18][CH2:19][CH3:20])=[O:17])[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:8][CH:9]=1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)C(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)NN=C(c1ccc(Cl)cc1)C(C)(C)C

Procedure:
A solution of 4.92 g (0.025 mol) 4-chlorphenyl tert.-butyl ketone and 8.05 g (0.075 mol) ethyl carbazate in 125 ml absolute ethanol was treated with ca. 0.3 g concentrated sulphuric acid and heated at reflux for 3 hours. The solution was then concentrated in vacuo and the residue added to water. It was then extracted with ethyl acetate, the organic phase dried with magnesium sulphate, concentrated and the residue recrystallised from diisopropyl ether.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]=[O:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C1COCC1.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:8]=[C:7]2[CH:13]=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)n1cc(C=O)c2cc(Cl)ccc21
Temperature: 25 °C
Yield: 58.5 %

Procedure:
NaH (0.36 gm, 12.6 mmol) was added to a solution of 2.26 gm (12.6 mmol) 5-chloro-1H-indole-3-carbaldehyde in THF cooled in an ice water bath After 20 m stirring, 1.4 g (12.6 mmol) methanesulfonyl chloride was added, and the solution was warmed to room temperature with stirring overnight. The mixture was diluted with EtOAc and washed with water and brine, dried (MgSO4) and concentrated. Normal phase chromatography (CH2Cl2 followed by gradient elution to 10% EtOAc in CH2Cl2) afforded 1.9 gm of the title compound as a white solid, 1H NMR (DMSO) δ 9.75 (s, 1H), 8.0 (s, 1H), 7.9 (s, 1H), 7.5 (d, 1H), 7.1 (d, 1H), 2.3 (s, 3H).
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][C@H:22]1[O:29][C@@H:26]([O:27][CH3:28])[C@H:25]([OH:30])[C@@H:24]([OH:31])[C@@H:23]1[OH:32])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Si:3]([O:20][CH2:21][C@H:22]1[O:29][C@@H:26]([O:27][CH3:28])[C@H:25]([O:30][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:24]([O:31][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:23]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.9 %

Procedure:
To a stirred suspension of sodium hydride (1.67 g, 41.6 mmol) in 100 mL of dry THF was added at 0° C. a solution of methyl 6-O-tert-butyldiphenylsilyl-β-D-glucopyranoside (4.0 g, 9.25 mmol) in 50 mL of dry THF. After 5 minutes, the suspension was warmed to room temperature and stirred for 1 hour. Benzyl bromide (5.50 mL, 46.2 mmol) was added at room temperature followed by tetrabutylammonium iodide (341 mg, 0.93 mmol). The suspension was warmed to 50° C. and stirred for 4 days. After quenching with 40 mL of saturated aqueous ammonium chloride, the resulting mixture was diluted with ether (600 mL) and washed with H2O (2×200 mL), saturated aqueous NaCl (1×200 mL), and dried over magnesium sulfate. Concentration and flash chromatography (silica, 10% ether in petroleum ether) provided pure target compound (4.48 g, 69%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[CH:5]=[CH:4][N:3]=1.[Br:10]Br>>[NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([Br:10])=[CH:4][N:3]=1
Reactant: Nc1nccc(F)c1O
Reactant: BrBr
Product: Nc1ncc(Br)c(F)c1O

Procedure:
The 2-amino-4-fluoro-3-pyridinol from Example 2 and bromine in a molar ratio of 1:1 are heated in the vapor phase at 300° according to the procedure of McElvain and Goese [J. Am. Chem. Soc., 65, 2227 (1943)] to give 2-amino-5-bromo-4-fluoro-3-pyridinol. The latter with an equivalent amount of cesium fluoride by the procedure of Example 2gives 2-amino-4,5-difluoro-3-pyridinol.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>>[CH2:27]([S:29]([N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1)(=[O:31])=[O:30])[CH3:28]
Reactant: CCS(=O)(=O)Cl
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Agent: Cl
Product: CCS(=O)(=O)N1CC=C(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1

Procedure:
(5R)-3-(4-(1,2,5,6-Tetrahydropyridin-4-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (380 mg, 1 mM) was), was treated with ethanesulfonyl chloride essentially as in Example 77 to give the desired product (21 mg) after chromatography. MS (ESP): 436 (MH+) for C19H22FN5O4S
Reaction SMILES: [F:1][C:2]1[CH:52]=[CH:51][C:5]([C:6]([N:8]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:49]=[CH:48][C:25]4[N:26]([C:29]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:27]=[N:28][C:24]=4[CH:23]=3)[CH:19]=[CH:18][C:17]=2[F:50])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[CH:53](I)([CH3:55])[CH3:54].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:49]=[CH:48][C:25]4[N:26]([C:29]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:27]=[N:28][C:24]=4[CH:23]=3)[CH:19]=[CH:18][C:17]=2[F:50])[CH:9]2[CH2:14][CH2:13][N:12]([CH:53]([CH3:55])[CH3:54])[CH2:11][CH2:10]2)=[O:7])=[CH:51][CH:52]=1
Reactant: CC(C)I
Reactant: O=C(c1ccc(F)cc1)N(Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CCC(N(Cc2cc(-c3ccc4c(c3)nnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)ccc2F)C(=O)c2ccc(F)cc2)CC1
Reaction time: 240 h
Yield: 61.5 %

Procedure:
A mixture of 4-Fluoro-N-[2-fluoro-5-(1-trityl-1H-benzotriazol-5-yl)-benzyl]-N-piperidin-4-yl-benzamide (25 mg, 0.04 mmol), isopropyl iodide (34 mg, 0.2 mmol) and potassium carbonate (28 mg, 0.2 mmol) in 2 mL of DMF was heated at 40° C. for 3 h when additional isopropyl iodide (34 mg, 0.2 mmol) was added. The mixture was heated for an additional 2 h and then left at ambient temperature for 10 days. The mixture was diluted with water and the product extracted into ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 18 mg of product.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:29]=[N:28][C:13]3[N:14]([CH2:26][CH3:27])[C:15]4[N:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:16]=4[N:17]([CH3:20])[C:18](=[O:19])[C:12]=3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[I-:30].[Na+]>>[Cl:25][C:23]1[CH:22]=[CH:21][C:16]2[N:17]([CH3:20])[C:18](=[O:19])[C:12]3[CH:11]=[C:10]([CH2:9][CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([I:30])[CH:3]=4)[CH:29]=[N:28][C:13]=3[N:14]([CH2:26][CH3:27])[C:15]=2[N:24]=1
Reactant: [I-]
Reactant: CCN1c2ncc(CCc3cccc(N)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: [Na+]
Product: CCN1c2ncc(CCc3cccc(I)c3)cc2C(=O)N(C)c2ccc(Cl)nc21

Procedure:
In a manner analogous to the procedure described for Example 23, 8-[2-(3-aminophenyl)ethyl]-2-chloro-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.15 g, 0.37 mmol) was diazotized and treated with sodium iodide to provide 9 mg of the pure product, m.p. 143°-145° C. (petroleum ether).
Reaction SMILES: [CH2:1]([C:3]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=O)[CH3:2].[C:14](Br)(Br)([Br:16])[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:15][C:14]([Br:16])=[CH:5][C:4]1[C:3]([CH2:1][CH3:2])=[C:10]([F:11])[CH:9]=[CH:8][C:7]=1[CH2:12][CH3:13]
Reactant: CCc1ccc(F)c(CC)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1ccc(F)c(CC)c1C=C(Br)Br

Procedure:
2-(2,2-Dibromo-vinyl)-1,3-diethyl-4-fluoro-benzene was prepared from 2,6-diethyl-3-fluoro-benzaldehyde, carbon tetrabromide and triphenylphosphine in analogy to Example 1d): colourless oil; 1H-NMR (CDCl3): 1.15 (3H, t, CH3), 1.18 (3H, t, CH3), 2.58 (4H, m, 2×CH2), 6.97 (1H, dd, ArH), 7.04 (1H, dd, ArH), 7.42 (1H, s, CH═CBr2).
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:7]=2[C:6]([O:18]C)=[C:5]([O:20][CH3:21])[C:4]=1[O:22][CH3:23].N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[CH3:23][O:22][C:4]1[C:3](=[O:2])[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:7]=2[C:6](=[O:18])[C:5]=1[O:20][CH3:21]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CC(=O)O)CC2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: C1CCOC1
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CCC(CC(=O)O)CC2)C1=O
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a mixture of 2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)acetic acid (800 mg), 2,6-pyridinedicarboxylic acid (1.24 g), THF (16 ml), and water (8 ml) was dropwise added a solution of CAN (5.42 g) in water (8 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with, 1N hydrochloric acid, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo. The residue was recrystallized from ethyl acetate to yield the entitled compound (450 mg) as crystals.
Reaction SMILES: C[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1(CBr)CC1.C(OC(=O)C(SC1SC(N)=NC=1)C)C>>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[CH:2][CH:10]=2)[CH:6]=[CH:7]1
Reactant: Cc1ccc2cc[nH]c2c1
Agent: BrCC1CC1
Agent: CCOC(=O)C(C)Sc1cnc(N)s1
Product: c1ccc2[nH]ccc2c1

Procedure:
6-methylindole, R5X=cyclopropyl-methylbromide; NH2A=(2-amino-thiazole-5-ylsulfanyl)-propionic acid ethyl ester
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[CH2:26][N:27]([C:30](=[O:32])[CH3:31])[CH2:28][CH3:29])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH3:2].I[CH3:35]>>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][C:17]=2[CH2:26][N:27]([C:30](=[O:32])[CH3:31])[CH2:28][CH3:29])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH3:35])[CH3:2]
Reactant: CCOC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)cc(C(F)(F)F)c1
Reactant: CI
Product: CCOC(=O)C(C)c1cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 213, Step 5, using the following starting materials: {2′-[(acetyl-ethyl-amino)-methyl]-5,4′-bis-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester and iodomethane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([OH:26])[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:38]4[CH:39]=[CH:40][C:35]([O:34][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:36][CH:37]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(O)ccc(F)c32)cc1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(OCc5ccccc5)cc4)ccc(F)c32)cc1
Yield: 83 %

Procedure:
(1S,2S)-2-[4-((R)-7-Fluoro-4-hydroxy-indan-1-yloxy)-phenyl]-cyclopropanecarboxylic acid ethyl ester (Intermediate 5, 0.6 g, 1.7 mmol), 4-benzyloxyphenylboronic acid (1.53 g, 6.7 mmol), copper (II) acetate (306 mg, 1.7 mmol), triethylamine (1.83 mL, 13.1 mmol), 4-dimethylaminopyridine (21 mg, 0.17 mmol) and 4 Å molecular sieves (3 g) are suspended in dichloromethane and stirred under an oxygen atmosphere over a weekend. The mixture is filtered through a plug of CELITE filter aid, washing the filter cake with dichloromethane. The organic phases are washed with 1 M aqueous HCl solution, dried and the solvent removed. The residue is purified by flash chromatography (0-40% ethyl acetate in cyclohexane) to give the title compound (Yield 0.76 g). LC (METHOD 6): tR=1.04 min; Mass spectrum (ES+): m/z=539 [M+H]+.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C1COCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH2:12][C:13](=[O:15])[NH:34][CH:31]([CH3:33])[CH3:32])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)N
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)NC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of N-Cbz-glycine (20.9 g, 100 mmol) in THF (400 mL) at 0° C. was added N-methylmorpholine (NMM) (12.1 mL, 110 mmol) and i-butylchloroformate (13 mL, 100 mmol). The resultant mixture was stirred at 0° C. for 2 min and then i-propylamine (9.4 mL, 110 mmol) was added. The reaction mixture was warmed to room temperature and stirred at this temperature for 16 h. The mixture was filtered through a pad of CELITE™ and concentrated in vacuo. The crude residue was dissolved in ethyl acetate (500 mL) and washed with 1N HCl (aq.) (1×100 mL), sat. NaHCO3 (aq.) (1×100 mL) and brine (1×100 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford (isopropylcarbamoylmethyl)carbamic acid benzyl ester as a white solid (24.5 g, 98 mmol, 98%) which was used without further purification.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[C:27]([O:31][C:32](=[O:42])[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40]O)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32](=[O:42])[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][I:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1CI
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of imidazole (404 mg, 5.94 mmol) and triphenylphosphine (1.56 g, 5.94 mmol) in methylene chloride (50 mL) is added iodine (1.51 g, 5.94 mmol) in portions. When the reaction is complete, a solution of (2-hydroxymethylphenyl)-carbamic acid tert-butyl ester (1.2 g, 5.4 mmol) in methylene chloride (20 mL) is added dropwise and the mixture is stirred at RT for 75 min. The mixture is concentrated and the insoluble material is filtered. The filtrate is evaporated and the residue is purified by column chromatography using a gradient of 25-50% MTBE/methylene chloride as eluent to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:33].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:33].[ClH:33].[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1
Reactant: CC1CCCCN1CCCNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1CCCCN1CCCNc1ccc(N)cc1

Procedure:
The N-[3-(2-methylpiperidin-1-yl)propyl]-4-nitro-1-aminobenzene (17) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C(N)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: NCc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Yield: 80.1 %

Procedure:
53.0 g of ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0161 mol), 15.4 ml of benzyl amine, and 37.0 g of anhydrous K2CO3 in 220 ml of acetonitrile were stirred at 100-110° C. for 1 hour. The reaction was monitored by TLC. After the solvent was evaporated, the residue was re-crystallized from ethanol to give 53.7 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.129 mol) in 80.0% yield, mp 133-135° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15]CC3C=CC=CC=3)=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O>O1CCOCC1.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[NH:8][CH:7]=1
Reactant: COC(=O)C(=O)c1c[nH]c2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: C1COCCO1
Product: COC(=O)Cc1c[nH]c2cc(O)ccc12
Yield: 62.2 %

Procedure:
A mixture of (6-benzyloxy-1H-indol-3-yl)-oxo-acetic acid methyl ester (1.45 g, 4.7 mmol) and Pd/C (10%, 0.9 g) in dioxane (38 mL) is degassed and filled with nitrogen for three times, then a solution of NaH2PO2 (6 g) in water (5 mL) is added dropwise at 100° C. The reaction mixture is heated overnight, filtered through celite and concentrated. The residue is taken into ethyl acetate, washed with water and brine, dried over sodium sulfate. Concentration and column chromatography on silica gel yields the title compound (600 mg).
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(Cl)Cl.C(#N)C>[Cl:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:25]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: Nc1cc(Cl)ccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1cc(Cl)ccn1)c1ccn2c1CSC2c1cccnc1
Temperature: 67 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature in the vicinity of 67° C., to a solution of 2-amino-4-chloropyridine (2.6 g) and triethylamine (4.05 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 67° C., in the course of 15 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 7 hours and 30 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue obtained is dissolved in methylene chloride (350 cc). The solution obtained is washed twice with distilled water (200 cc in total), twice with an aqueous 1N sodium hydroxide solution (200 cc in total) and 3 times with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolorizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (5 g) is thereby obtained, which is dissolved in boiling acetonitrile (200 cc). Decolorizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 2 hours. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (10 cc in total) and twice with diethyl ether (20 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(4-chloro-2-pyridyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (2.6 g) in the form of cream-coloured cyrstals, m.p. 190° C., is thereby obtained.