Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.Br[C:18]1[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[N:21]=[C:22]([Cl:24])[CH:23]=1>CCO>[Cl:24][C:22]1[CH:23]=[C:18]([NH:1][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[N:21]=1
Reactant: Nc1ccc(N)cc1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
p-Aminoaniline (0.48 g, 4.4 mmol) and triethylamine (1.3 ml, 9.2 mmol) were added to 8-bromo-6-chloroimidazo[1,2-b]pyridazine HCl (1.0 g, 4.2 mmol) from Example I(1), step 1b in EtOH (20 mL). The mixture was heated to 90° C. and stirred for 1 hr. The solution was then concentrated in vacuo to give crude N1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine. Cold ethanol was then added and the crude solid rinsed 3×. Following filtration, collected 0.45 g of the desired material.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:17])=[N:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:5]1.[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)#[N:19]>CO>[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:17])=[N:11][CH2:12][C:13]([F:14])([F:16])[F:15])=[N:5]2)=[CH:22][CH:21]=1)#[N:19]
Reactant: NC(=NCC(F)(F)F)Nc1ccn(CCO)n1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CO
Product: N#Cc1ccc(COCCn2ccc(NC(N)=NCC(F)(F)F)n2)cc1
Yield: 55 %

Procedure:
A mixture of 1-(2-hydroxyethyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (2.5 g.) and 4-cyanobenzyl bromide (1.96 g.) was heated at 140° for 10 minutes. When cool, the residue was dissolved in a little MeOH and purified by medium pressure chromatography on silica gel using triethylamine/EtOH/EtOAc 1:10:95 v/v/v as eluant to give 1-[2-(4-cyanobenzyloxy)ethyl]-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (yield 55%) having the following n.m.r. spectrum in d6DMSO: 7.5 (br m, 5H); 5.85 (d, 1H); 5.1 (s, 2H); 4.05 (br m, 4H); 3.7 (br t, 2H).
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[CH:14][C:15](N)=[N:16][C:17]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.S(=O)(=O)(O)[OH:26].[OH-].[Na+]>O>[F:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[CH:14][C:15](=[O:26])[NH:16][C:17]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1cnc(-c2ccncc2F)c(-c2cccnc2)n1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1cnc(-c2ccncc2F)c(-c2cccnc2)[nH]1
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of sodium nitrite (0.248 g, 3.6 mmol) in water (2.5 mL) was added dropwise to a stirred, cooled (ice-bath) mixture of 5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) (0.80 g, 3.0 mmol) and 5% aqueous sulphuric acid (18 mL). After 1 hour, the mixture was taken to pH 5-6 with aqueous sodium hydroxide solution with external cooling. The mixture was concentrated to low bulk then extracted with chloroform. The organic layer was dried (MgSO4) and concentrated in vaccuo to give the title compound (0.793 g, 99%) as a white solid.
Reaction SMILES: C([CH:5]([C@H:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[C:41]4[C:36](=[N:37][CH:38]=[C:39]([Cl:42])[CH:40]=4)[CH:35]([OH:43])[C:34]([CH2:45][CH2:46][OH:47])([OH:44])[C:33]3=[O:48])[CH2:28][CH2:27]2)=[O:25])=[C:20]([F:49])[CH:19]=1)[CH3:10])[C:6]([OH:8])=[O:7])(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:42][C:39]1[CH:40]=[C:41]2[C:36]([CH:35]([OH:43])[C:34]([CH2:45][CH2:46][OH:47])([OH:44])[C:33](=[O:48])[N:32]2[CH:29]2[CH2:30][CH2:31][N:26]([C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][C@H:9]([CH3:10])[CH2:5][C:6]([OH:8])=[O:7])=[CH:19][C:20]=3[F:49])=[O:25])[CH2:27][CH2:28]2)=[N:37][CH:38]=1
Reactant: C[C@@H](Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(O)(CCO)C(O)c4ncc(Cl)cc43)CC2)c(F)c1)C(C(=O)O)C(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CC(=O)O)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(O)(CCO)C(O)c4ncc(Cl)cc43)CC2)c(F)c1
Reaction time: 6 h
Yield: 96.1 %

Procedure:
To a dichloromethane solution (1 ml) of tert-butyl (3R)-3-{[4′-({4-[7-chloro-3-(2-hydroxyethyl)-2-oxo-3,4-dihydroxy-1,5-naphthyridin-1(2H)-yl]piperidin-1-yl}carbonyl)-3′-fluorobiphenyl-2-yl]oxy}butanoic acid (28.3 mg) were added at room temperature triethylsilane (20.2 mg) and trifluoroacetic acid (0.5 ml). The reaction solution was stirred for 6 hours, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography to afford (3R)-3-{[4′-({4-[7-chloro-3-(2-hydroxyethyl)-2-oxo-3,4-dihydroxy-1,5-naphthyridin-1(2H)-yl]piperidin-1-yl}carbonyl)-3′-fluorobiphenyl-2-yl]oxy}butanoic acid (25.0 mg).
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([C:17]([NH:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:18])[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)[C@@H](CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of (R)-tert-butyl 3-(biphenyl-4-ylmethyl)-4-(2-tert-butoxy-2-oxoethylamino)-4-oxobutanoate (Intermediate 6-1: 40 mg, 0.088 mmol) and TFA (0.5 mL, 6.49 mmol) in DCM (1.5 mL) is allowed to stir for 2 hours at room temperature. The reaction is concentrated under reduced pressure, and the obtained residue is suspended in DCM (0.5 mL) and heptane (2 mL), and collected on a funnel, giving (R)-3-biphenyl-4-ylmethyl-N-carboxymethyl-succinamic acid (9.6 mg). HPLC retention time=1.26 minutes (condition A); MS (m+1)=342.0; 1H NMR (400 MHz, CD3OD) δ ppm 2.39 (dd, J=16.67, 5.31 Hz, 1 H) 2.63-2.82 (m, 2 H) 2.98-3.14 (m, 2 H) 3.84 and 3.95 (AB, 2 H, J=17.8 Hz) 7.26-7.33 (m, 3 H) 7.40 (t, J=7.71 Hz, 2 H) 7.56 (dd, J=19.96, 8.08 Hz, 4 H).
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18]1>C(Cl)Cl.[Pd]>[C:25]([O:24][C:23](=[O:29])[NH:22][C@@H:19]1[CH2:20][CH2:21][N:17]([CH:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:9]3[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=3)[CH2:3][CH2:4]2)[CH2:18]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)c1ncc(C2(O)CCC(=O)CC2)s1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: [Pd]
Solvent: ClCCl
Product: CC(C)c1ncc(C2(O)CCC(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)s1
Reaction time: 24 h
Yield: 75.7 %

Procedure:
To a Parr hydrogenation bottle was added 4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexanone (0.50 g, 2.09 mmol) and tert-butyl (3R)-pyrrolidin-3-ylcarbamate (0.373 g, 2.0 mmol), dissolved in CH2Cl2 (20 mL), followed by the addition of 10% Pd/C (0.12 g). This mixture was hydrogenated at 35 psi for 24 hour. After the catalyst was filtered and washed with methanol, the filtrate was concentrated in vacuo and chromatographed using MeOH/EtOAc/Et3N (1:9:0.1) to give 0.62 g of title compound in 76% yield. MS (EI) calcd: (M+1)+=409.2; found: 410.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@@H:4]([CH:5]([OH:7])[OH:6])[C@H:3]1[C:8](O)=O.[CH2:12]([O:15][C:16]([CH2:18]P1(=O)OC(C)C(C)O1)=[O:17])[CH2:13][CH3:14]>>[CH3:11][C:2]1([CH3:1])[CH:3]([CH:8]=[CH:18][C:16](=[O:17])[O:15][CH2:12][CH2:13][CH3:14])[CH:4]1[C:5]([OH:7])=[O:6]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C(O)O
Reactant: CCCOC(=O)CP1(=O)OC(C)C(C)O1
Product: CCCOC(=O)C=CC1C(C(=O)O)C1(C)C

Procedure:
Using the procedure of Example 6, 1.26 g of the lactone of (1R,cis) 2,2-dimethyl-3-dihydroxymethyl-cyclopropane-carboxylic acid and 3.13 g of the product of Step A were reacted to obtain after crystallization from hexane 0.89 g of (1R,cis,ΔZ) 2,2-dimethyl-3-[3-oxo-3-propoxy-1-propenyl]-cyclopropane-carboxylic acid melting at 59° C. and having a specific rotation of [α]D20 =+77°±1.5° (c=1% in chloroform).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[C:7]([C:20]#[N:21])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)[Cl:25]>Cl.C(O)C>[ClH:25].[C:1]([C:5]1[S:9][C:8]2[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=[C:20]([NH2:21])[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cl[Sn]Cl
Reactant: CC(C)(C)c1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc2c(s1)Nc1ccccc1N=C2N
Yield: 90 %

Procedure:
Add 5-tert-butyl-2-(2-nitro-phenylamino)-thiophene-3-carbonitrile (21.2 g, 70 mmol) to a solution of tin(II)chloride dihydrate (46.1 g, 209 mmol) in conc. HCl (200 mL) and ethanol (600 mL). Reflux the mixture for 2 hours. Concentrate the solution to 200 mL and add to water (1 L). Filter and wash with water then hexanes to obtain the title compound as an orange powder (19.4 g): 1H NMR (DMSO-d6) δ 1.27 (s, 9H), 6.86 (d, 1H), 6.89 (s, 1H), 6.95 (d, 1H), 7.03 (t, 1H), 7.11 (t, 1H), 8.69 (s, 1H), 9.11 (s, 1H), 9.52 (s, 1H), 10.88 (s, 1H); MS (APCI) m/z (rel intensity) 272 (100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH2:26][CH3:27])[CH:24]=[C:19]3[N:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:37]=1[OH:43]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH2:26][CH3:27])[CH:24]=[C:19]3[N:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]=2[O:43][C:37]2[C:38]([CH3:42])=[CH:39][CH:40]=[CH:41][C:36]=2[CH3:35])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C)c1O
Reactant: CCOc1cnc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)n(-c3ccccc3)c2c1
Product: CCOc1cnc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3c(C)cccc3C)n(-c3ccccc3)c2c1

Procedure:
The title compound was prepared from the compound of example 54, step 7, (290 mg, 598 μmol) and 2,6-dimethylphenol analogously as described in example 1, step 6.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
2-Thiophenecarbonylchloride (2.04 g, 1.49 mL) was added to a solution of tert-butyl-1-piperazinecarboxylate (2.5 g, 13.4 mmol) and DMAP (20 mg) in pyridine (15 mL) at 0° C. under N2 atmosphere and stirred at room temperature for overnight. The mixture was poured into ice water, the precipitate was filtered, washed several times with water, and dried to yield white solids (3.5 g, 88%). Mp 76° C. 1H NMR (DMSO-d6): δ 1.42 (s, 12H), 3.40 (m, 4H), 3.61 (m, 4H), 7.12 (m, 1H), 7.43 (d, J=4.1 Hz, 1H), 7.77 (d, J=4.8 Hz, 1H). EIMS m/z 297 (M+1), 319 (M+23). Anal. (C14H20N2O3S)C, H, N.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15]2[CH:21]=[CH:20][NH:19][C:16]2=[N:17][CH:18]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[C:15]2[CH:21]=[CH:20][NH:19][C:16]2=[N+:17]([O-:9])[CH:18]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: [O-][n+]1cc(Br)cc2cc[nH]c21
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.4 %

Procedure:
m-Chloroperbenzoic acid (25 wt % water content, 322 mg, 1.40 mmol) in ethyl acetate (5 mL) was gradually added dropwise to 5-bromo-1H-pyrrolo[2,3-b]pyridine (184 mg, 0.934 mmol) in ethyl acetate (10 mL), and the reaction mixture was stirred at room temperature for 6 hours. After addition of saturated aqueous sodium hydrogen carbonate, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was mixed with a mixture of ethyl acetate/hexane=1/1 (v/v), and the solid was collected by filtration, washed with hexane and dried under reduced pressure to give the title compound as a light brown solid (150 mg, yield 75%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH2:45][CH3:46])=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH2:45][CH3:46])=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cc(C)c(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnc(CC)cc3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(6-ethyl-4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K35) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous red substance (184 mg, 42%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:25])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37]Cl.O>CN(C)C=O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:37][CH2:36][CH2:35][N:34]([CH3:39])[CH3:33])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)CCCCl
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(=O)c1cnc2c(OCCCN(C)C)cccc2c1Nc1ccc(F)cc1C
Reaction time: 1 h
Yield: 10.9 %

Procedure:
3-Butyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (3.38 g, 10 mmol) and potassium t-butoxide (3.05 g, 25 mmol) were dissolved in dimethyl formamide (30 ml), warmed to 70° and 3-dimethylaminopropyl chloride hydrochloride (1.90 g, 12 mmol) added. The mixture was stirred for 1 hour at 80° then a further portion of potassium t-butoxide (2.44 g, 20 mmol) and 3-dimethylaminopropyl chloride hydrochloride (1.58 g, 10 mmol) added, and stirring continued overnight. A third portion of potassium t-butoxide (2.44 g, 20 mmol) and 3-dimethylaminopropyl chloride hydrochloride (1.58 g, 10 mmol) was added and the temperature raised to 85° . After a further 5 hours the mixture was poured into water, extracted with ether and the ether extracts dried and evaporated. Chromatography (silica gel, 4-6% methanolic ammmonia in dichloromethane) and recrystallisation from ethyl acetate gave 3-butyryl-4-(4-fluoro-2-methylphenyl-amino)-8-(3-dimethylaminopropoxy)quinoline (0.46 g, 11%), m.p. 99°-100°.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27](C3CCCCO3)[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:34])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:16][C:15]1[CH:14]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[CH:12]=[C:11]([F:34])[C:10]=1[S:7]([NH:6][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CCC[C@@H]3c3ccnn3C3CCCCO3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncn1)c1c(F)cc(O[C@H]2CCC[C@@H]2c2ccn[nH]2)cc1F
Yield: 85.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)-4-({(1S*,2R*)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide (121 mg, 0.185 mmol) prepared in Example 139a, triethylsilane (0.30 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (3.0 mL), to yield the title compound (67 mg, 86%) as a colorless solid.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[CH3:13][CH:14]([NH2:23])[CH:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:23][CH:14]([CH3:13])[CH:15]([OH:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)#[N:2]
Reactant: COC(=NC#N)c1ccccn1
Reactant: CC(N)C(O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(N=C(NC#N)c1ccccn1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.24 g, 1.5 mmol) was dissolved in methanol (5 ml), DL-phenylpropanolamine hydrochloride (0.31 g, 1.7 mmol, supplied by Tokyo Chemical Industry Co. Ltd.) and triethylamine (0.17 g, 1.7 mmol) were added, and the resulting mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was extracted with ethyl acetate (30 ml×3). The ethyl acetate layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue thus obtained was crystallized from diethyl ether to give the title compound (0.23 g, 0.8 mmol, yield: 54%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:10]=[C:11]([CH:13]=O)[N:12]=2)=[CH:4][CH:3]=1.[N:25]1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:10]=[C:11]([C:13]#[N:25])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-n2cc(C=O)nc2-c2ccc(Cl)cc2)cc1
Reactant: c1ccncc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-n2cc(C#N)nc2-c2ccc(Cl)cc2)cc1

Procedure:
A solution of 82 mg (0.23 mmole) of 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-carboxaldehyde (Example 163) and 51 mg (0.45 mmole) of hydroxylamine O-sulfonic acid in 10 ml of absolute ethanol and 1 ml of pyridine was stirred at reflux overnight. After cooling, the mixture was evaporated, and the residue was taken up in dichloromethane. The solution was washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using 50% ethyl acetate in hexane as the eluent gave the title compound; 71 mg, as a pure white crystalline solid: mp (DSC) 205° C. Anal. Calc'd. for C17H12ClN3O2S.¼H2O (MW 362.32): C, 56.36; H, 3.34; N, 11.60. Found: C, 56.49; H, 3.27; N, 11.45.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][C@H:27]2[C@H:32]([CH:33]([F:35])[F:34])[CH2:31][CH2:30][NH:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].Cl.[CH2:37](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][C@H:27]2[C@H:32]([CH:33]([F:35])[F:34])[CH2:31][CH2:30][N:29]([CH3:37])[CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCOCC
Reactant: CCCCc1nnc(O[C@@H]2CNCC[C@H]2C(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(O[C@@H]2CN(C)CC[C@H]2C(F)F)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
To a solution of (±)-trans-3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-difluoromethyl-piperidin-3-yloxy)-pyridazine dihydrochloride (0.18 mmol, 0.095 g) and aqueous formaldehyde (37%, 0.89 mmol, 0.075 mL) in dry DCM (2.0 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 1.07 mmol, 0.45 g). The mixture was shaken for 4 hours. The reaction was filtered and the resin was washed with DCM (10 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give (±)-3-butyl-4-(4-cyclohexyloxy-phenyl)-6-((trans-3,4)-4-difluoromethyl-1-methyl-piperidin-3-yloxy)-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.05 g). LCMS: m/z 475 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.30-7.58 (3H, m), 7.08 (2H, d), 6.02-6.42 (1H, m), 5.54-5.94 (1H, m), 4.36-4.50 (1H, m), 3.83-4.19 (1H, m), 3.45-3.78 (1H, m), 2.89-3.35 (6H, m), 2.11-2.87 (3H, m), 1.92-2.08 (3H, m), 1.74-1.89 (2H, m), 1.18-1.67 (10H, m), 0.81 (3H, t).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[N:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1>>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[N:11]1[C:18]1[N:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:30][CH2:31]2)=[O:25])=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](COCc5ccccc5)CCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 61.4 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (536 mg) described in Preparation Example 1 and (6-bromopyridin-3-yl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (831 mg) described in Preparation Example 115 and by the reaction and treatment in the same manner as in Example 4, the title compound (729 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:25](O)=[O:26])=[C:11]([OH:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N=C=N.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][C@@H:47]([NH2:54])[C:48]3[O:52][N:51]=[C:50]([CH3:53])[N:49]=3)=[CH:42][CH:41]=2)[CH:36]=[CH:37][C:38]=1[F:39]>C1COCC1.ClCCCl>[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][C@@H:47]([NH:54][C:25]([C:12]3[CH:13]=[C:14]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][C:11]=3[OH:28])=[O:26])[C:48]3[O:52][N:51]=[C:50]([CH3:53])[N:49]=3)=[CH:42][CH:41]=2)[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)c(OCc2ccccc2)cc1O
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Agent: N=C=N
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1noc([C@@H](Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)NC(=O)c2cc(-c3ccc(C(F)(F)F)cc3)c(OCc3ccccc3)cc2O)n1
Reaction time: 12 h
Yield: 20.6 %

Procedure:
To a solution of 6-Benzyloxy-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (52 mg, 0.13 mmol) in THF:DCE (1:1, 2 mL) was added PS-Carbodiimide resin (0.14 g, 1.3 mmol/g) and 2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (0.03 g, 0.09 mmol) and stirred for 12 h, resin was filtered and washed with EtOAc (5 mL), filtrate was concentrated and silicagel chromatography of the residue gave pure 6-Benzyloxy-4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (0.013 g).