Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccncc1
Reactant: N#Cc1ccc2nccc(Cl)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1ccc2nccc(-c3ccncc3)c2c1
Yield: 95.8 %

Procedure:
A mixture of 4-chloro-6-quinolinecarbonitrile (8.7 g, 46.2 mmol), 4-pyridineboronic acid (8.52 g, 69.3 mmol), tetrakis(triphenylphosphine)palladium(0) (2.67 g, 2.31 mmol) and 2 M potassium carbonate (69.3 mL, 3 eq) in 1,4-dioxane (380 mL) is heated at reflux for 3.5 hours. The dioxane is evaporated and the crude product purified by silica gel chromatography eluting with methylene chloride/methanol 0-4%. A yield of 10.23 g (95%) of the title compounds was obtained.
Reaction SMILES: [NH2:1][CH:2]([OH:29])[C:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:14][C:15]3[N:16]=[C:17](Cl)[N:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:20]=3[N:21]=2)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[CH3:30][C:31]1[O:32][C:33]2[CH:48]=[CH:47][CH:46]=[CH:45][C:34]=2[C:35]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:4][C:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:14][C:15]3[N:16]=[C:17]([C:35]4[C:34]5[CH:45]=[CH:46][CH:47]=[CH:48][C:33]=5[O:32][C:31]=4[CH3:30])[N:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:20]=3[N:21]=2)[CH2:8][CH2:7]1)([CH3:5])[C:2]([NH2:1])=[O:29]
Reactant: Cc1oc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C(N)O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1oc2ccccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C(N)=O)CC3)sc2n1
Temperature: 140 °C
Yield: 60.9 %

Procedure:
A mixture of 1-amino-2-[4-(5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)piperazin-1-yl]-2-methylpropan-1-ol (100 mg, 0.23 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzofuran (88 mg, 0.34 mmol), tetrakis(triphenylphosphine) palladium (26 mg, 0.02 mmol) and Cs2CO3 (148 mg, 0.45 mmol) in dioxane (6 mL) and H2O (3 mL) was purged with argon then heated at 140° C. for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM/MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 50-100%) to afford 211 as a cream solid (75 mg, 61%). LCMS (Method G): RT 10.35 min, [M+H]+ 536.4. 1H NMR (CDCl3, 400 MHz): δ 8.40-8.37 (m, 1 H); 7.46-7.42 (m, 1 H); 7.32-7.23 (m, 2 H); 7.10 (d, J=5.3 Hz, 1 H); 5.22 (d, J=5.3 Hz, 1 H); 4.40 (m, 4 H); 3.93-3.87 (m, 6 H); 2.92 (s, 3 H); 2.69 (m, 4 H); 2.62 (m, 4 H) and 1.26 (s, 6 H)
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([CH2:22][C:23]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=O)[CH2:27][CH2:26]2)=[O:24])=[CH:14]1.CN>ClCCl.O>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([CH2:22][C:23]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]([NH:3][CH3:1])=[O:33])[CH2:27][CH2:26]2)=[O:24])=[CH:14]1
Reactant: O=C(O)C1CCN(C(=O)Cc2coc3ccccc23)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: O
Solvent: ClCCl
Product: CNC(=O)C1CCN(C(=O)Cc2coc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
19 g of carbonyldiimidazole are added in portions to 33 g of the product obtained in Step B in 350 ml of dichloromethane. When the evolution of gas has stopped, the reaction mixture is stirred for 1 hour at room temperature and then a stream of methylamine is circulated through it. After 12 hours' stirring, the mixture is diluted with water, decanted, washed with 1N sodium hydroxide solution and then with 1N hydrochloric acid, decanted, dried and evaporated, enabling the expected product to be isolated.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[O:15]=[C:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[NH4+].[Cl-]>[C:8]([C:7]1[C:6]([NH:10][CH3:11])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=[CH:3][C:2]=1[C:17]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH2:19][CH2:20][C:16]1=[O:15])#[N:9]
Reactant: CNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Reactant: CCOC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc([N+](=O)[O-])c(NC)c2C#N)CCCC1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 40.3 %

Procedure:
A mixture of 6-chloro-2-methylamino-3-nitrobenzonitrile (200 mg, 0.95 mmol) (Example 4), ethyl 2-oxocyclopentanecarboxylate (177 mg, 1.13 mmol) and K2CO3 (287 mg, 2.07 mmol) in DMF (5 mL) was stirred at room temperature for 60 h. The mixture was diluted with sat. NH4Cl solution and extracted with ether. The ethereal layer was washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography on silica (hexanes: EtOAc=3:1) to give ethyl 1-(2-cyano-3-methylamino-4-nitrophenyl)-2-oxo-cyclopentanecarboxylate (127 mg, 40%) as a yellow solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH:23]([C:25]1[S:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH3:24])=[N+]=[N-].O.Cl>C1COCC1.C(OCC)(=O)C>[F:30][C:27]1[S:26][C:25]([CH:23]([NH2:20])[CH3:24])=[CH:29][CH:28]=1
Reactant: CC(N=[N+]=[N-])c1ccc(F)s1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(N)c1ccc(F)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
Triphenylphosphine (873 mg) was added to a solution of 2-(1-azidoethyl)-5-fluorothiophene (518 mg) in THF (10 mL), and the reaction solution was stirred at room temperature for 1 hour. Water (2 mL) was added to the reaction mixture, and the mixture was heated to reflux for 3 hours. After allowing the reaction mixture to be cooled, a 5 N aqueous solution of hydrochloric acid and ethyl acetate were added thereto to separate the aqueous layer. A 5 N aqueous solution of sodium hydroxide was added to the aqueous layer to make the layer basic, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 324 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([C:18]1[C:19](=[O:38])[N:20]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1O)[CH3:17].O>N1C=CC=CC=1>[CH2:16]([C:18]1[C:19](=[O:38])[N:20]([CH:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]2)[CH:21]=[CH:22][C:23]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH3:17]
Reactant: CCc1c(O)ccn(C2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: CCc1c(OS(=O)(=O)C(F)(F)F)ccn(C2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Reaction time: 0.5 h

Procedure:
Trifluoromethanesulfonic anhydride (1.76 mL) was added at 0 C to a mixture of tert-butyl 4-(3-ethyl-4-hydroxy-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate (1.12 g) in pyridine (17.4 mL), and the mixture was stirred at 0 C for 30 minutes in a nitrogen atmosphere. Water was added thereto, and then, the solvent was distilled off under reduced pressure. Water was added again to the residue, followed by extraction with ethyl acetate. The obtained organic layer was washed with 1 M hydrochloric acid and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.14 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[S:19]([CH3:22])(=[O:21])=[O:20])[N:8]([CH2:23][CH2:24][CH2:25]Cl)[C:7]=2[CH:6]=1)([CH3:3])[CH3:2].[OH:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:1]([O:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[S:19]([CH3:22])(=[O:21])=[O:20])[N:8]([CH2:23][CH2:24][CH2:25][N:33]3[CH2:34][CH2:35][CH:30]([CH2:29][CH2:28][OH:27])[CH2:31][CH2:32]3)[C:7]=2[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc2c(c1)N(CCCCl)c1cccc(S(C)(=O)=O)c1S2
Reactant: OCCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)N(CCCN1CCC(CCO)CC1)c1cccc(S(C)(=O)=O)c1S2
Temperature: 150 °C
Yield: 36.7 %

Procedure:
A mixture of 2-isopropoxy-6-methylsulphonyl-10-(3-chloropropyl)phenothiazine (20 g.), 4-hydroxyethylpiperidine (6.4 g.) and sodium bicarbonate (16.5 g.) in dimethylformamide (170 cc.) is heated at 150°C. for 7 hours 30 minutes with stirring. The reaction mixture is then treated under the conditions mentioned in Example 1. 2-Isopropoxy-6-methylsulphonyl-10-[3-(4-hydroxyethylpiperidino)propyl]phenothiazine (9.0 g.), melting at about 50°C., is thus obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1.[C:15]1([C@H:21]([NH:39][C:40]([O:42][C@@H:43]2[CH:48]3[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]3)[CH2:44]2)=[O:41])[C:22]2[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=2)[O:25][CH2:26][C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.C1([C@H](NC(O[C@@H]2C3CCN(CC3)C2)=O)C2C=C(C=CC=2)OCC2C=CC(C(OC)=O)=CC=2)C=CC=CC=1>>[C:15]1([C@H:21]([NH:39][C:40]([O:42][C@@H:43]2[CH:48]3[CH2:49][CH2:50][N:45]([CH2:46][CH2:47]3)[CH2:44]2)=[O:41])[C:22]2[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=2)[O:25][CH2:26][C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([O:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])=[CH:6][CH:7]=2)=[O:31])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2cccc(C(=O)O)c2)c1)O[C@H]1CN2CCC1CC2
Reactant: COC(Cc1ccc(CO)cc1)OC
Agent: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Agent: Cl
Product: COC(Cc1ccc(COC(=O)c2cccc(COc3cccc([C@@H](NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)c2)cc1)OC

Procedure:
The title compound was prepared as described in Example 1 Step 10 with (4-(2,2-dimethoxyethyl)phenyl)methanol and 3-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoic acid replacing 4-(2-hydroxyethoxy)-3-methylbenzaldehyde and methyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoate hydrochloride respectively.
Reaction SMILES: [Cl:1][C:2]([F:6])=[C:3]([F:5])[F:4].[OH:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]=[N:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][CH:2]([F:6])[C:3]([F:5])([F:4])[O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]=[N:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(O)cn2)cc1
Reactant: FC(F)=C(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N=Nc2ccc(OC(F)(F)C(F)Cl)cn2)cc1

Procedure:
26 liters of chlorotrifluoroethene were introduced from a gas burette into a gas-tight stirred apparatus containing a mixture of 244 g (1.0 mol) of 5-hydroxy-2-(4-nitrophenylazo)pyridine, 138 g (1.0 mol) of potassium carbonate and 2 liters of dry DMF. The mixture was filtered through Celite, and the solid was washed with 1 liter of acetone. The solvent was removed from the filtrate by evaporation on a rotary evaporator. The residue was taken up in 2.5 liters of ethyl acetate and washed four times with 500 ml of saturated sodium chloride solution in each case.
Reaction SMILES: OC1C(=O)NC=C(CCC2C=CC=CC=2C)C=1.C[O:19][C:20]1[C:25]([O:26]C)=[CH:24][C:23]([C:28]#[C:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)=[CH:22][N:21]=1>>[OH:26][C:25]1[C:20](=[O:19])[NH:21][CH:22]=[C:23]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[CH:24]=1
Reactant: COc1cc(C#Cc2cccc(C)c2)cnc1OC
Agent: Cc1ccccc1CCc1c[nH]c(=O)c(O)c1
Product: Cc1cccc(CCc2c[nH]c(=O)c(O)c2)c1

Procedure:
Prepared as described for 3-hydroxy-5-(2-methylphenethyl)pyridin-2(1H)-one (Example 27) from 2,3-dimethoxy-5-[(3-methyl-phenyl)ethynyl]pyridine (Intermediate 34).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][O:26]C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:25][O:26][C:5]1[CH:6]=[C:1]([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Product: CCOC(=O)c1c(NS(=O)(=O)c2cccc(OC)c2)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxlyate and 3-methoxybenzenesulphonyl chloride.
Reaction SMILES: [CH2:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:14]=1)[C:4]([O:6]C)=[O:5])[CH3:2].[OH-].[K+]>O.C(O)C>[CH2:1]([CH:3]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:14]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCC(CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1)C(=O)O

Procedure:
The procedure in Example 6 is followed but using methyl 2-ethyl-6-[(4,6-diphenyl-2-pyridyl)oxy]hexanoate (3.15 g), potassium hydroxide pellets (0.9 g) dissolved in distilled water (20 cc) and ethanol (100 cc). The reaction mixture is refluxed for 8 hours. The product is purified by recrystallisation in an n-hexane-ethyl acetate (2-1) mixture (40 cc), white crystals (m.p.=115° C.)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:20])[C@@H:5]([NH2:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[Br:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26]([CH:30]=1)[C:27](O)=[O:28].Cl>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:20])[C@@H:5]([NH:19][C:27](=[O:28])[C:26]1[CH:30]=[C:22]([Br:21])[CH:23]=[CH:24][C:25]=1[OH:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1O
Yield: 35.2 %

Procedure:
3-Biphenyl-4-yl-(2S)-(5-bromo-2-hydroxy-benzoylamino)-propionic acid methyl ester (2.75 g, 35%) was prepared from (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester-hydrochloride (5.0 g, 17.2 mmol), 5-bromo-2-hydroxy-benzoic acid (3.7 g, 17.2 mmol) as described in general procedure A except for an adapted work-up. After reaction completion, the reaction mixture was poured onto 150 mL of 1N HCl and 150 mL of EtOAc. The organic layer was washed with 1N HCl, saturated sodium bicarbonate, dried over sodium sulfate and evaporated. The crude material was purified over silica gel (7:3, DCM-hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:13])[C:11]=1[N:26]1[CH2:25][CH2:24][NH:23][CH:22]([CH3:21])[CH2:27]1)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(Cl)cc2c1=O
Reactant: CC1CNCCN1
Product: CC1CN(c2c(Cl)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CCN1

Procedure:
The product from Example C is reacted with 2-methyl-piperazine analogously to Example B1 to give 6,8-dichloro-1cyclopropyl-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid of melting point 288°-291° C. (with decomposition).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([O:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)=[O:7])(C)(C)C.[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]=[CH:39][C:38](C(O)=O)=[CH:37][CH:36]=1.C(P(=O)(OCC)OCC)#N>C(N(CC)CC)C>[C:35]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:40]=[CH:39][C:38]([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([O:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=3)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=2)=[O:7])=[CH:37][CH:36]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(C(C)C)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)Oc1ccc(C(C)C)cc1
Yield: 74.7 %

Procedure:
In a similar manner to that described in Example 73, a reaction was carried out using ethyl 3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-(4-isopropylphenoxy)propionate (723 mg), which is the product of Reference example 25, biphenyl-4-carboxylic acid (303 mg), diethyl cyanophosphonate (0.25 ml) and triethylamine (0.47 ml) and the reaction mixture was treated to give the title compound (630 mg) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[C:7]([C:9]1[C:14]([CH:15]2[O:19][CH2:18][CH2:17][O:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1)=O.Cl.[C:24]([O:28][NH2:29])([CH3:27])([CH3:26])[CH3:25].N1CCCC1>C(O)CC>[C:24]([O:28]/[N:29]=[C:7](\[C:9]1[C:14]([CH:15]2[O:19][CH2:18][CH2:17][O:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1)/[C:6]1[CH:20]=[C:2]([Cl:1])[C:3]([F:22])=[CH:4][C:5]=1[OH:21])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)ON
Reactant: O=C(c1cc(Cl)c(F)cc1O)c1ncccc1C1OCCO1
Agent: Cl
Solvent: CCCO
Solvent: C1CCNC1
Product: CC(C)(C)O/N=C(/c1cc(Cl)c(F)cc1O)c1ncccc1C1OCCO1
Yield: 30.5 %

Procedure:
A solution of 2-(5-chloro-4-fluoro-2-hydroxybenzoyl)-3-(1,3-dioxolan-2-yl)pyridine (1.45 g), O-t-butylhydroxylamine hydrochloride (1.69 g) and pyrrolidine (9.56 g) in n-propanol (20 ml) was heated for 1.5 hour under reflux. The reaction mixture was concentrated, to which was added water, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give a mixture (540 mg) of (Z)-2-(5-chloro-4-fluoro-2-hydroxybenzoyl)-3-(1,3-dioxolan-2-yl)pyridine O-t-butyloxime and (Z)-2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-yl)benzoyl]-3-(1,3-dioxolan-2-yl)pyridine O-t-butyloxime (about 2:1). A mixture of this mixture (470 mg), p-toluenesulfonic acid monohydrate (162 mg), acetone (9.0 ml) and water (3.5 ml) was heated for 14 hours under reflux. The reaction mixture was concentrated, to which was added water, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated to leave an oily substance. This oily substance was dissolved in chloroform (2.0 ml), to which was added, at room temperature, 50% m-chloroperbenzoic acid (75 mg). The mixture was stirred for 8 minutes at the same temperature, which was then poured into an aqueous solution of sodium sulfite, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give (Z)-2-(5-chloro-4-fluoro-2-hydroxybenzoyl)-3-formylpyridine O-t-butyloxime (230 mg) (Compound 155).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH:15][C:16](OCC)=O)=[CH:10][CH:9]=1.CCOC(C)=O>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][NH:15][CH3:16])=[CH:10][CH:9]=1
Reactant: CCOC(=O)NNc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNNc1ccc(F)cc1
Temperature: 60 °C
Yield: 74.4 %

Procedure:
To a mixture of LiAlH4 (1.1 g) in THF (15 mL) is added a solution of ethyl 2-(4-fluorophenyl)hydrazinecarboxylate (1.9 g, 9.59 mmol) in THF (10 mL) dropwise under nitrogen in an ice-salt bath. After the addition, the ice bath is removed and the mixture is heated to 60° C. overnight. The reaction is cooled and quenched with water. The precipitate is filtered and washed with EtOAc. The organic phase is separated, dried over Na2SO4, and concentrated. The residue is purified by flash chromatography, eluting with PE:EtOAc (80:1 to 60:1) to afford the title compound (1 g, 74% yield). MS (m/z): 141 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[C:15]([C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[CH:21][N:22]=[C:23]([O:26]C)[C:24]=4[N:25]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]>CCO>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[C:15]([C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[CH:21][NH:22][C:23](=[O:26])[C:24]=4[N:25]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: COc1ncnc2ccc(-c3cccnc3-c3ccc(F)c(Cl)c3)nc12
Agent: Cl
Solvent: CCO
Product: O=c1[nH]cnc2ccc(-c3cccnc3-c3ccc(F)c(Cl)c3)nc12
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
Conc. HCl (0.2 ml) was added to a stirring heterogeneous slurry of 6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)-4-methoxypyrido[3,2-d]pyrimidine (2.2 g) in EtOH (25 mL) at room temperature and heated the slurry gradually to 60° C. The pale yellow heterogeneous slurry transformed to homogeneous solution in 15 min and turned to heterogeneous slurry back again after 2 h of heating. Heating and stirring was continued for 4 h and cooled the reaction mixture to room temperature. The solid was collected by filtration and concentrated the filtrate. The solid was neutralized with aq.NaHCO3, filtered and dried to obtain title compound as a white solid (1.3 g).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].Cl.[S:7]1[CH:11]=[CH:10][C:9]2[CH:12]([NH2:16])[CH2:13][CH2:14][CH2:15][C:8]1=2>>[CH2:1]([NH:3][C:4]([NH:16][CH:12]1[C:9]2[CH:10]=[CH:11][S:7][C:8]=2[CH2:15][CH2:14][CH2:13]1)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: NC1CCCc2sccc21
Agent: Cl
Product: CCNC(=O)NC1CCCc2sccc21

Procedure:
In the manner described in Example 1, ethyl isocyanate is allowed to react with 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride to afford 10.1 grams of 1-ethyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea. Recrystallization of the crude product from 2-propanol-water (9/1) affords crystals which are dissolved in chloroform and washed successively with 1 N sulfuric acid, water and saturated sodium bicarbonate solution. This gives the desired product, melting point 184° C. to 188.5° C. after evaporation of the chloroform.