Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:26])[CH2:10][CH2:11][C:12]([N:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][O:16][C:15]1=[O:25])=[O:13].C(N(C(C)C)CC)(C)C.[O:36]1[CH2:41]CCOO1.[Cl-].[NH4+]>ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:26])[CH2:10][C@@H:11]([CH2:41][OH:36])[C:12]([N:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][O:16][C:15]1=[O:25])=[O:13]
Reactant: C1COOOC1
Reactant: C=C(CCC(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccc(F)cc1F
Agent: [Ti+4]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C[C@@H](CO)C(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccc(F)cc1F
Temperature: -15 °C
Reaction time: 0.67 h

Procedure:
Titanium chloride solution (prepared from 33.8 ml of titanium chloride and 50 ml of dichloromethane) was added to a pre-cooled solution of (R)-3-(4-(2,4-difluorophenyl)pent-4-enoyl)-4-phenyloxazolidin-2-one compound of formula-4 (100 g) in dichloro methane (1000 ml) at −20 to −10° C. under nitrogen atmosphere and diisopropyl ethylamine (45.61 μm) was added to the reaction mixture and stirred for 40 minutes at −20 to −10° C. A trioxane solution (prepared from 52.94 g of trioxane and 150 ml of dichloro methane) was added to the reaction mixture at −20 to −10° C. and followed by titanium chloride solution (prepared from 33.8 ml of titanium chloride and 50 ml of dichloro methane) at −20 to −10° C. Temperature of the reaction mixture was raised to −5 to 0° C. and stirred for 2 hours at −5 to 0° C. After completion of the reaction, the reaction mixture was added to 10% ammonium chloride at 10-15° C. Both organic and aqueous layers were separated and the aqueous layer was extracted with dichloro methane. Both the dichloro methane layers were combined and washed with water followed by 10% sodium chloride solution. The obtained dichloro methane layer was taken to the next step without isolating the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14](Br)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][N:15]=[C:16]([NH:18][CH3:19])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)ccn1
Yield: 56.5 %

Procedure:
0.5 g (0.0014 mol) of 4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide was dissolved in 25 ml of ethanol, treated with 0.05 g of Pd/C and hydrogenated with hydrogen gas under normal pressure for 1 hour. The catalyst was filtered off, the filtrate was concentrated and the residue was dissolved in 10 ml of 1N NaOH, filtered and the filtrate was then adjusted pH 8 by means of 1N HCl. The precipitate which separated slowly was filtered off under suction, rinsed and dried in a high vacuum. There was obtained 0.22 g (57%) of 4-amino-N-(2-methylamino-pyridin-4-yl)-benzenesulfonamide as white crystals; m.p.: >261° C. (dec).
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[OH:8][CH:9]([CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:10][N:11]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:37])[C@H:29]([C:31]2[N:32]=[C:33]([NH2:36])[S:34][CH:35]=2)[OH:30])=[CH:23][CH:22]=1)C(=O)OC(C)(C)C>>[ClH:7].[ClH:7].[OH:8][CH:9]([CH2:38][O:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:10][NH:11][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:37])[C@H:29]([C:31]2[N:32]=[C:33]([NH2:36])[S:34][CH:35]=2)[OH:30])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(NC(=O)[C@@H](O)c2csc(N)n2)cc1)CC(O)COc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1nc([C@H](O)C(=O)Nc2ccc(CCNCC(O)COc3ccccc3)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 ml of a 4N hydrogen chloride-ethyl acetate solution was added to 10 ml of a methanolic solution of 285 mg of t-butyl (S)-N-(2-hydroxy-3-phenoxypropyl)-N-[2-[4-[[2-(2-aminothiazol-4-yl)-2-hydroxyacetyl]amino]phenyl]ethyl]-carbamate at room temperature. The reaction mixture was stirred at room temperature for four hours. The solvent was evaporated off and the residue was purified by means of silica gel column chromatography (eluate: chloroform/methanol=7/1) to obtain 222 mg of (S)-4'-[2-[(2-hydroxy-3-phenoxypropyl)-amino]ethyl]-2-(2-aminothiazol-4-yl)-2-hydroxyacetanilide dihydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: O=c1[nH]cc(Br)cc1Br
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cn1cc(Br)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
A 1-L round-bottomed flask equipped with a magnetic stirrer was charged with 3,5-dibromo-1H-pyridin-2-one (7.0 g, 27.7 mmol), anhydrous DMF (280 mL) and powdered potassium carbonate (−350 mesh, 8.4 g, 61.1 mmol), and the suspension stirred for 15 min at ambient temperature. After this time, methyl iodide (4.3 g, 30.5 mmol) was added, and the mixture was stirred at room temperature under nitrogen for a further 18 h. The reaction mixture was then diluted with water (200 mL), extracted with ethyl acetate (3×250 mL), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica to give an 84% yield (6.2 g) of 3,5-dibromo-1-methyl-1H-pyridin-2-one (1) as an off-white solid: mp 87-88° C.; MS (ESI+) m/z 266 (M+H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:17](I)[CH2:18][CH3:19].Cl>>[CH2:17]([N:12]1[CH2:11][CH2:10][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:14][CH2:13]1)[CH2:18][CH3:19]
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Reactant: CCCI
Agent: Cl
Product: CCCN1CCC(c2cccc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 4-(3-Trifluoromethyl-phenyl)piperidine and n-Pr-I: m.p. 195° C. (HCl), MS m/z (rel. intensity, 70 eV) 271 (M+, 4), 243 (16), 242 (bp), 159 (13), 70 (49).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][N:6]([C:13]([C:15]1[CH:34]=[CH:33][C:18]2[N:19]([CH3:32])[C:20]([CH2:22][NH:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)=[N:21][C:17]=2[CH:16]=1)=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].CO>>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][CH2:22][C:20]2[N:19]([CH3:32])[C:18]3[CH:33]=[CH:34][C:15]([C:13]([N:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[O:14])=[CH:16][C:17]=3[N:21]=2)=[CH:25][CH:26]=1)#[N:31]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)ccc21
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
To a solution of the product of 1d (13.0 mmol) in 100 mL methanol sodium hydroxide (20.0 mmol) was added. The mixture was stirred for 2.5 hours at 40° C. and then evaporated to dryness. The remaining solid was stirred with 100 mL water and the pH was adjusted to about 6 with concentrated acetic acid. The precipitated product was isolated by filtration, washed with water and dried at 60° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>CCCCO>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: NCc1cccc(Cl)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1nc(NCc2cccc(Cl)c2)c2nc[nH]c2n1
Temperature: 100 °C

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (1 g, 1 eq, 5.9 mmol) in n-BuOH (50 ml) under an argon atmosphere, was added DIEA (2.6 ml, 2.5 eq, 14.75 mmol) followed by 3-chloro-benzylamine (1.25 g 1.5 eq, 8.85 mmol). The reaction mixture was heated at 100° C. for 3 hours after which the reaction was complete. The solvent was evaporated in vacuo and the residue purified by gradient column chromatography on silica gel, eluted with DCM:ether:MeOH (55:45:0→55:43:2), to afford the title compound as a white solid; Yield: 1.15 g (70%). δH (250 MHz, d6-DMSO) 4.78-4.6 (2 H, m, NHCH2Ar), 7.41-7.28 (4 H, m, ArH), 7.57 (1 H, s, br, ArH), 8.15 (1 H, s, br, NH), 8.88 (1 H, s, br, NH); δC (250 MHz, d6-DMSO) 142.3 (C), 133.02 (C), 132.92 (C), 130.25 (CH), 130.17 (C), 127.82 (CH), 127.27 (CH), 127.03 (CH), 126.76 (C), 125.92 (CH), 116.4 (C), 115 (C), 42.67 (CH2); m/z 278 (M+H)
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[Cl:7][C:8]1[C:13]([NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=1>ClCCl>[Cl:7][C:8]1[C:13]([N:14]([S:15]([C:18]([F:21])([F:19])[F:20])(=[O:17])=[O:16])[C:2]([C:1]([N:14]([C:13]2[C:8]([Cl:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[S:15]([C:18]([F:19])([F:20])[F:21])(=[O:16])=[O:17])=[O:5])=[O:3])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=S(=O)(Nc1cccnc1Cl)C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(C(=O)N(c1cccnc1Cl)S(=O)(=O)C(F)(F)F)N(c1cccnc1Cl)S(=O)(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (0.762 gram; 0.006 mole) is added dropwise to a suspension of N-(2-chloro-3-pyridyl)-trifluoromethanesulfonamide (2.61 grams; 0.01 mole) and powdered Type 3A molecular sieves (5.0 grams) in dichloromethane (75 mls) at 0° C. under a nitrogen atmosphere. The mixture is then heated to 60° C., held thereat for 3 hours, and then stirred at room temperature for 60 hours. The reaction mixture is filtered and the filtrate is evaporated to dryness. The resulting residue is extracted with diethyl ether, and the combined ethereal extracts are dried over anhydrous sodium sulfate. The dried ethereal extract is then separated and evaporated to obtain 2.33 grams (81% of theoretical) of crude product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH:30]1([NH2:33])[CH2:32][CH2:31]1>>[CH:30]1([NH:33][C:6]2[C:5]3[C:10](=[CH:11][C:2]([F:1])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[CH:4]=3)[N:9]=[C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)[N:7]=2)[CH2:32][CH2:31]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: NC1CC1
Product: Cc1ccccc1-c1cc2c(NC3CC3)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropyl amine in step E. MS (ESI): predicted mass calcd. for C22H18FN5O2, 403.1
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:18](=[S:20])=[S:19]>O>[Na+:2].[CH2:11]([N:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:18](=[S:19])[S-:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C=S
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: S=C([S-])N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a solution of 8.0 g. (0.2 mole) of sodium hydroxide in 32 ml of water was added 39.4 g. (0.2 mole) of dibenzyl amine. The mixture was cooled to 0° and to it was added 25.3 g. (0.334 mole) of carbon disulfide. A solid separated spontaneously. The mixture was stirred at room temperature for 1 hour, and then filtered. The solid was triturated first with 100 ml of ether and then with 100 ml of benzene and dried to give 43.5 g. (74% yield) of N,N-dibenzyldithiocarbamic acid sodium salt, mp 260°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[NH:34]1[CH2:37][CH2:36][CH2:35]1>>[N:34]1([C:2]2[CH:3]=[C:4]([S:8]([N:11]3[CH2:20][CH2:19][C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]5[CH:23]=[N:22][N:21]([C:24]6[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=6)[C:16]=5[CH:17]=4)[CH2:12]3)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: C1CNC1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(Br)c1)C2
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(N3CCC3)c1)C2

Procedure:
The title compound was prepared by the method of Preparation 12c using (R)-6-(5-bromopyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and azetidine. LCMS (Method C): 510 (M+H)+, Retention time 11.3 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:43][CH2:42][NH:41][C:40]1=[O:44].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17]([N:41]3[CH2:42][CH2:43][N:39]([CH3:38])[C:40]3=[O:44])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNC1=O
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C)C3=O)cn2)CN1C(=O)OC(C)(C)C
Temperature: 180 °C
Yield: 60.8 %

Procedure:
In a 2 mL glass microwave reaction vessel are placed in (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.32 mmol), 1-Methyl-imidazolidin-2-one (35 mg, 0.35 mmol), CuI (123.4 mg, 0.35 mmol), trans-1,2-cyclohexane (0.005 mL, 0.35 mmol), K2CO3 (88 mg, 0.64 mmol) in dry dioxane (2 mL). The reaction vessel is sealed and heated under microwave irradiation at 180° C. for 20 min. After completion of the reaction, the solvent is diluted with EtOAc and washed with sat. NH3 (aq.), water, dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel to give (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(3-methyl-2-oxo-imidazolidin-1-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=NC=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.BrC1C=C[N:28]=[C:27]([Cl:31])C=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[CH:21][N:28]=[C:27]([Cl:31])[CH:18]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Reactant: Clc1cc(Br)ccn1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2ccnc(Cl)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 4-Bromo-2-chloropyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=360.1, 362.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:37][C:38]4[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: ClCc1ccncc1
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccncc4)c(OC)cc23)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl) oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine hydrochloride (41 mg) were dissolved in N,N-hr dimethylformamide (1 ml), and the solution was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC to give 71 mg (yield 71%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[C:5]([C:18]1[C:23](N)=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:2].N([O-])=O.[Na+]>CC(C)=O.O>[CH:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[CH2:2]
Reactant: C=Cc1ccccc1C(c1ccccc1)(c1ccccc1)c1c(N)cccc1O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=Cc1ccccc1C(c1ccccc1)(c1ccccc1)c1ccccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
The 2-(vinyltrityl)-3-aminophenol is dissolved in a 50/50 solution of acetone and 50% H2PO3. The solution is chilled to 0° C. NaNO2 (1.0 g, 2.0 equiv.) is dissolved in water (10 mL) and added at a rate to keep the temperature of the reaction mixture below 5° C. The mixture is stirred for an additional 30 minutes. The product 2-(vinyltrityl)phenol is obtained by filtration and dried under vacuum (yield 35-45%). Product is recrystallized from hot acetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([F:43])[C:29]=1[Sn](CCCC)(CCCC)CCCC>>[F:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([F:43])[C:29]=1[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cncc1F
Product: Fc1ccc(-c2nncc(-c3ccc(F)c(-c4c(F)cncc4F)c3)n2)c(F)c1

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine was coupled to 3,5-difluoro-4-tributylstannylpyridine using the method of Example 6 to give 5-[3-(3,5-difluoropyridin-4-yl)-4-fluorophenyl]-3-(2,4-difluorophenyl)-[1,2,4]triazine, crystallised from hot 2-propanol as a pale yellow solid: δH (500 MHz, d6-DMSO) 7.35 (1H, m), 7.52 (1H, m), 7.79 (1H, t, J 8.9 Hz), 8.34 (1H, m), 8.71 (2H, m), 8.79 (2H, s), 10.13 (1H, s); m/z (ES+) 401.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[I-].[OH:9][C:10]1[C:11]([CH2:16][N+](C)(C)C)=[N:12][CH:13]=[CH:14][CH:15]=1>CS(C)=O.O>[O:9]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:16][CH2:4]1
Reactant: C[N+](C)(C)Cc1ncccc1O
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1cnc2c(c1)OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
To a suspension of 60% sodium hydride (11.4 g, 286 mmol) in DMSO (170 mL) was added trimethylsulfonium iodide (29.9 g, 136 mmol), and the mixture was stirred at room temperature for 30 min. A solution of (3-hydroxypyridin-2-yl)-N,N,N-trimethylmethanaminium iodide (40.0 g, 136 mmol) in DMSO (130 mL) was added dropwise thereto, and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. 1M Hydrochloric acid was added to the extract, and the mixture was extracted with water. The extract was basified with 1M aqueous sodium hydroxide solution and extracted again with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→50/50) to give the title compound (7.77 g, yield 47%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@@H:14]([O:17][C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[CH:23]=2)[C@H:13]([F:41])[CH2:12]1)=O)C1C=CC=CC=1>[Pd].CO>[CH2:37]([C:21]1[N:20]=[N:19][C:18]([O:17][C@@H:14]2[CH2:15][CH2:16][NH:11][CH2:12][C@H:13]2[F:41])=[CH:23][C:22]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCc1nnc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1nnc(O[C@@H]2CCNC[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 1.5 h
Yield: 78 %

Procedure:
A mixture of (±)-trans-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-3-fluoro-piperidine-1-carboxylic acid benzyl ester (65 mg, 0.12 mmol) and 10% palladium on carbon (10 mg) in MeOH (5 mL) was stirred under an atmosphere of H2 for 1.5 hrs, filtered through celite and concentrated to provide (±)-trans-3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(3-fluoro-piperidin-4-yloxy)-pyridazine (40 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C1[C:21](=O)[N:20](Br)[C:18](=O)C1.CNC>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH2:13][N:20]([CH3:21])[CH3:18])[S:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc2nc(C)sc2c1
Agent: CNC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2nc(CN(C)C)sc2c1
Yield: 32 %

Procedure:
6-ethoxycarbonyl-2-methylbenzothiazole (2.09 g) prepared according to the method described in J. Gen. Chem. vol. 5, pp. 260-266 (1945) was subjected to bromination with NBS (1.78 g) in carbon tetrachloride (30 mg). Then, the product was caused to react with dimethylamine to yield a new compound of 6-ethoxycarbonyl-2-dimethylaminomethylbenzothiazole (0.8 g). Then, the compound was provided with the same treatment as that described in Examples 49-51 to yield 6-[(2-aminoethyl)thiomethyl]-2-(dimethylaminomethyl)benzothiazole.2hydrobromide (1.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C2(O)CCN(C)CC2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[ClH:38].C([O:42][CH2:43][CH3:44])(=O)C>CO>[ClH:38].[ClH:38].[ClH:38].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]2[CH2:44][CH:43]([OH:42])[CH2:8][CH2:9][N:10]2[CH3:15])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CN1CCC(O)(C(CN2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Agent: Cl
Solvent: CO
Product: CN1CCC(O)CC1C(CN1CCN(CCCCc2cccc3ccccc23)CC1)c1ccc(F)cc1

Procedure:
33 mg of 4-{1-(4-Fluorophenyl)-2-[4-(naphthalen-1-yl-butyl)piperazin-1-yl]ethyl}-1-methylpiperidin-4-ol was dissolved in 4 ml of methanol, and 1 ml of 4M hydrogen chloride/ethyl acetate solution was added. The solution was concentrated under reduced pressure, and the resulting solid was washed with ethyl acetate to give 35 mg of 4-{(1-(4-fluorophenyl)-2-[4-(naphthalen-1-yl-butyl)piperazin-1-yl]ethyl}-1-methylpiperidin-4-ol trihydrochloride.