Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20]([OH:22])=O)=[CH:5][N:4]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH2:30].ON1C2C=CC=CC=2N=N1.Cl.ClCCCl>CN(C)C=O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20](=[O:22])[NH:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[CH:5][N:4]=1
Reactant: NCc1ccccn1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)O)cc1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(SC)ncc2C(=O)NCc2ccccn2)cc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Methylthio-4-(3-chloro-4-methoxybenzylamino)-5-carboxypyrimidine (prepared in Example 79) 0.500 g, 2-pyridylmethylamine 0.1749 g, 1-hydroxybenzotriazole 0.1987 g, 1,2-dichloroethane hydrochloride 0.3102 g and anhydrous dimethylformamide 5 ml are mixed together and stirred at 0° C. overnight and triturated with ethyl acetate-isopropyl ether to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyridylmethyl)carbamoyl]pyrimidine as a colorless powder, 0.5966 g. mp 143-144.5° C.
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CCN(CC)CC.[C:22]1([C:28]#[C:29][C:30]2[O:34][C:33]([C:35](ON3C(=O)CCC3=O)=[O:36])=[CH:32][CH:31]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:8][N:5]1[CH2:4][CH2:3][C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([NH:1][C:35]([C:33]2[O:34][C:30]([C:29]#[C:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:31][CH:32]=2)=[O:36])[CH2:7][CH2:6]1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(C#Cc2ccccc2)o1
Reactant: CCOC(=O)CC1(N)CCN(C)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC1(NC(=O)c2ccc(C#Cc3ccccc3)o2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A stirred solution of ethyl 2-(4-amino-1-methylpiperidin-4-yl)acetate (53 mg, 0.263 mmol) in CH2Cl2 (2 mL) was treated with NEt3 (0.11 mL, 0.789 mmol), and 2,5-dioxopyrrolidin-1-yl 5-(phenylethynyl)furan-2-carboxylate, prepared as described in Preparation 5 (89 mg, 0.289 mmol). The reaction was stirred overnight, at room temperature, then the solvent removed in vacuo and the product purified by column chromatography to obtain the title compound (51 mg, 49%). 1H NMR (400 MHz, CD3OD) δ 7.57-7.53 (m, 2H), 7.44-7.40 (m, 3H), 7.16 (s, 1H), 6.84 (s, 1H), 4.08 (q, 2H, J=7.2 Hz), 2.89 (s, 2H), 2.70-2.65 (m, 2H), 2.54-2.47 (m, 2H), 2.39-2.25 (m, 5H), 1.85-1.80 (m, 2H), 1.17 (t, 3H, J=7.2 Hz); MS ESI 395.2 [M+H]+, calcd for [C23H26N2O4+H]+ 395.47.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][Cl:19])=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)nc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87 %

Procedure:
To a dichloromethane (4.00 mL) solution of (6-benzyloxy-pyridin-3-yl)-methanol (1.80 g, 8.36 mmol) described in Manufacturing Example 191-1-1 was added dropwise thionyl chloride (732 μL, 10.0 mmol) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 5 minutes at room temperature. Aqueous sodium bicarbonate was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (1.70 g, 87.0%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]([F:23])([F:22])[F:21])[N:8]=2)[N:5]=[C:4]([C:24]([O:26]CC)=O)[CH:3]=1.CO.[NH4+:31]>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]([F:23])([F:22])[F:21])[N:8]=2)[N:5]=[C:4]([C:24]([NH2:31])=[O:26])[CH:3]=1
Reactant: CCOC(=O)c1cc(C)n(-c2cccc(-c3ccccc3OC(F)(F)F)n2)n1
Reactant: [NH4+]
Solvent: CO
Product: Cc1cc(C(N)=O)nn1-c1cccc(-c2ccccc2OC(F)(F)F)n1

Procedure:
A solution of the ester from Step 2 of EXAMPLE 137 (0.025 g, 0.064 mmol) in ammonium-methanol solution (7.0M, 3 mL) (placed in a sealed tube) was stirred at 70° C. for 2 days. After cooling, the reaction was concentrated to give the titled compound as yellow powder (0.02 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12

Procedure:
{1-Benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl 2-{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}-2-oxoacetate (0.463 g, 0.991 mmol), potassium hydroxide (0.224 g, 3.99 mmol) in THF (5 mL) and water (5 mL) according to the procedure described in Step 4 of Example 5. The title compound was obtained as a light yellow solid (0.314 g, 78%), mp 169-171° C. Mass spectrum (+APCI, [M+H]+) m/z 440; 1HNMR (400 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.75 (s, 1H), 8.45 (d, 1H, J=1.5 Hz), 7.75-7.8 (m, 2H), 7.7 (d, 1H, J=8.5 Hz), 7.6 (dd, 1H, J=8.7 Hz), 7.45 (d, 2H, J=8.8 Hz), 7.25-7.35 (m, 5H), and 5.65 ppm (s, 2H). Elemental Analysis for C24H16F3NO4: Calculated: C, 65.61; H, 3.67; N, 3.19. Found: C, 65.59; H, 3.54; N, 3.17.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[F:28][C:29]1[CH:30]=[CH:31][C:32]([O:36][CH3:37])=[C:33]([NH2:35])[CH:34]=1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:35][C:33]2[CH:34]=[C:29]([F:28])[CH:30]=[CH:31][C:32]=2[O:36][CH3:37])=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(F)cc1N
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Product: COc1ccc(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 5-fluoro-2-methoxy-phenylamine (commercially available; CAS RN 1978-39-8). White solid (74%). MS (ESI): m/z=407.036 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](Cl)(=[O:23])[CH3:22]>>[CH2:1]([N:8]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:11]=1[Br:20])[C:21](=[O:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(Br)c(CNCc2ccccc2)c1
Reactant: CC(=O)Cl
Product: CC(=O)N(Cc1ccccc1)Cc1cc(C(F)(F)F)ccc1Br

Procedure:
Benzyl-(2-bromo-5-trifluoromethyl-benzyl)-amine and acetyl chloride were reacted as described in Example 11, Step 2 to provide N-benzyl-N-(2-bromo-5-trifluoromethyl-benzyl)-acetamide.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:18])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1c(Br)cc(C(=O)O)cc1C=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1c(Br)cc(C(=O)Cl)cc1C=O
Yield: 98.1 %

Procedure:
5-Bromo-3-formyl-4-methoxybenzoic acid (480 mg, 1.84 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and the solution was flushed with dry nitrogen for 5 minutes. Oxalyl chloride (1.2 mL, 2.4 mmol, 1.3 eq) was added slowly to the solution while vigorous stirring and then a catalytic amount of dry dimethylformamide was added. The mixture was stirred for 1 hour and then concentrated by rotary evaporation and dried on high vacuum to give 5-bromo-3-formyl-4-methoxybenzoyl chloride (501 mg) as yellow crystals.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:8]2[CH2:12][C@:11]3([CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)[O:10][C:9]2=[O:20])[S:5][C:6]=1Br.C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)CCC>>[N:29]1[CH:30]=[CH:31][C:26]([C:2]2[N:3]=[C:4]([N:8]3[CH2:12][C@:11]4([CH:17]5[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]5)[CH2:13]4)[O:10][C:9]3=[O:20])[S:5][CH:6]=2)=[CH:27][CH:28]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1nc(Br)c(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1nc(-c2ccncc2)cs1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from the reaction of the mixture of(R)-3′-(4-bromothiazol-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and (R)-3′-(4,5-dibromothiazol-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one with 4-(tri-n-butylstannyl)pyridine. Separation by reverse phase HPLC separation followed by conversion to the free base as described in Example 14 to give the title compound, m/z 343 (MH+); and (R)-3′-[4,5-di(4-pyridyl)thiazol-2-yl]spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one, m/z 420 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]=[O:12]>C(COC)OC>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:11](=[O:12])[NH:10][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOC(=O)CN=C=O
Solvent: COCCOC
Product: CCOC(=O)CNC(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
A solution of 2.74 g (23 mmol) of 4-aminobenzonitrile in 10 ml of dimethoxyethane is added dropwise to a cooled solution (0° C.) of 3 g (23 mmol) of ethyl isocyanatoacetate in 10 ml of dimethoxyethane and the mixture is stirred at room temperature. The product is filtered off and washed with dimethoxyethane.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]([OH:22])=[O:21].O[CH:24]([C@@H:26]1[C@@H:29]([S:30][CH3:31])[N:28]([C:32](=[C:37]([CH3:39])[CH3:38])[C:33]([O:35][CH3:36])=[O:34])[C:27]1=[O:40])[CH3:25].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:20]([O:22][CH:24]([C@@H:26]1[C@@H:29]([S:30][CH3:31])[N:28]([C:32](=[C:37]([CH3:39])[CH3:38])[C:33]([O:35][CH3:36])=[O:34])[C:27]1=[O:40])[CH3:25])=[O:21]
Reactant: O=CO
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)O)[C@H]1SC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)OC=O)[C@H]1SC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (1.647 g), formic acid (0.20 ml), and a mixture (1:3) of methyl 2-[(3S,4R)-3-{(1RS)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (1.145 g) in tetrahydrofuran (14 ml) was added dropwise diethyl azodicarboxylate (0.83 ml) at 0° C. under a nitrogen atmosphere. After keeping at the same temperature for 15 minutes, the solution was allowed to warm to room temperature and stirred for two hours. The mixture was cooled to 0° C. and additional fornic acid (24 μl) and diethyl azodicarboxylate (0.10 ml) were added. After stirring at room temperature for one hour, the solution was concentrated, taken up into ethyl acetate (60 ml) and washed with a chilled dilute aqueous sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, evaporated and re-dissolved in benzene (20 ml) to result in precipitation of crystals. These crystals were collected and washed with benzene. The combined filtrate and washings were evaporated and chromatographed on silica gel (60 g) eluting with 10-30% ethyl acetate in hexane to give a mixture (5:1) of methyl 2-[(3S,4R)-3-{(1RS)-1-formyloxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (889 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[C:7]1[CH:8]=[C:9](/[CH:12]=[CH:22]/[CH:23]=[O:24])[S:10][CH:11]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cc(-c2ncccn2)cs1
Product: O=C/C=C/c1cc(-c2ncccn2)cs1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-pyrimidinyl)-2-thiophenecarboxaldehyde (prepared as described in Reference Example 90) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])=[CH:8][CH:9]=1
Reactant: O=C1COCCN1c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2.6 g 4-(4-Nitro-phenyl)-morpholin-3-one in 350 ml ethyl acetate and 17 ml ethanol, 13.2 g SnCl2 dihydrate were added and the reaction mixture was heated to reflux for 2 h. Then after cooling to RT the mixture was stirred for 16 h. The precipitated product was collected by filtration and was pure enough for the next reaction step. Yield: 2.07 g.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].CCN(CC)CC.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:18]([O:10][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OCCOCCOCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a CH2Cl2 (300 mL) solution of triethylene glycol (21 g, 140 mmol) was added Et3N (20 mL, 140 mmol); then trityl chloride (19.5 g, 70 mmol) in CH2Cl2 (100 mL) was added dropwise at 0° C. The mixture was stirred overnight and quenched with H2O. The organic phase was washed with H2O and brine successively, concentrated through rotary evaporation, and subjected to silica gel chromatography using hexane/EtOAc as the eluent to afford compound 21 (21 g, 53.6 mmol, 77% yield) as a clear liquid: 1H NMR (500 MHz, CDCl3) δ 7.47-7.46 (m, 6H), 7.28 (t, J=7.0 Hz, 6H), 7.21 (t, J=7.0 Hz, 3H), 3.68 (s, 8H), 3.60 (br, 2H), 3.25 (br, 2H), 2.57 (br, 1H); 13C NMR (126 MHz, CDCl3) δ 144.2, 128.8, 127.9, 127.1, 86.8, 72.7, 71.0, 70.8, 70.7, 63.4, 61.9; MS (ESI) m/z 415 (M+Na)+.
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:24][C:25]([F:31])([F:30])[S:26](O)(=[O:28])=[O:27]>N1C=CC=CC=1>[O:23]([C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:16][CH:15]=2)=[CH:18][CH:19]=1)[S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCCCCCCCCCc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Product: CCCCCCCCCCc1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Temperature: 0 °C
Yield: 98.9 %

Procedure:
1.00 g (3.22 mM) of 4-(4-decylphenyl)phenol, 1.6 ml of pyridine were mixed and stirred on a common salt-ice bath. To the mixture, 0.60 ml (3.57 mM) of anhydrous trifluoromethanesulfonic acid was added dropwise and stirred for 18 minutes, followed by further stirring for 70 minutes at room temperature. After the reaction, the reaction mixture was poured into ice water, followed by extraction with isopropyl ether. The isopropyl ether layer was successively washed with a common salt aqueous solution, 12%-HCl and a common salt aqueous solution, followed by drying with anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated into a solid product, whereby 1.41 g of 4-(4-decylphenyl)phenyl triflate (Yield: 98.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][CH:13]([CH2:16][N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[O:12][C:8]3=2)[N:3]=1.[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29](Cl)[CH:28]=[CH:27]2.C(=O)(O)[O-].[Na+]>>[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([N:20]1[CH2:21][CH2:22][N:17]([CH2:16][C@@H:13]3[O:12][C:8]4=[C:9]5[C:4](=[CH:5][CH:6]=[C:7]4[O:15][CH2:14]3)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]5)[CH2:18][CH2:19]1)[CH:28]=[CH:27]2
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: Cc1ccc2c3c(ccc2n1)OCC(CN1CCNCC1)O3
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2ccc4cc(Br)ccc4n2)CC1)O3
Temperature: 95 °C

Procedure:
A mixture of 8-methyl-2-piperazin-1-ylmethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline of Step B′ (0.493 g, 1.64 mmol) and 6-bromo-2-chloroquinoline of Example 1, Step A (0.507 g) is heated at 95° C. under nitrogen for 6 hours, followed by heating at 105° C. for 4 hours. The mixture is cooled, poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is flash chromatographed on silica Merck-60 using a gradient of methanol (0.5–2%) in dichloromethane-hexane (45:55), to provide the title compound (0.147 g) identical to the compound of Example 27, Step C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH2:23])[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)=[CH:29][C:28]=1[C:47](O)=[O:48])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:47]([C:28]3[CH:29]=[C:30]([C:33]4[CH:34]=[C:35]([C:43]([F:44])([F:45])[F:46])[CH:36]=[C:37]([C:39]([F:40])([F:42])[F:41])[CH:38]=4)[CH:31]=[CH:32][C:27]=3[O:26][CH2:24][CH3:25])=[O:48])[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Reactant: CCOc1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C(=O)O
Product: CCOc1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1
Yield: 82.4 %

Procedure:
4-Ethoxy-3′,5′-bis-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 (57 mg) was prepared from 2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (33 mg, 0.10 mmol) and 4-Ethoxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid (37 mg, 0.1 mmol) following the general procedure A.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH:13]([CH:15]=O)=O.O>C1(C)C=CC=CC=1>[CH2:11]1[N:12]2[C@@H:7]([C@@H:6]3[N:1]([CH2:13][CH2:15]2)[CH2:2][CH2:3][CH2:4][NH:5]3)[NH:8][CH2:9][CH2:10]1
Reactant: O=CC=O
Reactant: NCCCNCCNCCCN
Solvent: O
Solvent: Cc1ccccc1
Product: C1CN[C@@H]2[C@H]3NCCCN3CCN2C1

Procedure:
A solution of 87.2 g of 1,10-diamino-4,7-diazadecane in 500 ml of toluene was admixed with 72.3 g of a 40% aqueous glyoxal solution, and the mixture was refluxed, with a water separator fitted, for 3 hours. When the solution was cooled, a solid precipitated out which was filtered off with suction, washed three times with 50 ml of toluene each time and dried under reduced pressure. This gave 34.9 g of pale yellow needles.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[C:12]=2[CH2:11][CH2:10]1
Reactant: Cc1cccc(N2CCc3c(Cl)nc4c(OC(F)(F)F)cccc4c32)c1C
Reactant: NCCCO
Product: Cc1cccc(N2CCc3c(NCCCO)nc4c(OC(F)(F)F)cccc4c32)c1C

Procedure:
1-(2,3-Dimethylphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(500 mg, 1.3 mmol) was dissolved in 3-amino-1-propanol(6 ml) in the pressure tube, then reacted at the same condition of Step 3 in the Example 14 to obtain 300 mg of desired compound as solid in 56% of yield.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:13](=O)[C:12]2[C:7](=[C:8]([CH3:15])[CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:1][CH2:2][CH2:3][C:4]1[N:5]=[N:6][C:7]2[C:12]([C:13]=1[Cl:18])=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc2c(=O)c(CCCl)n[nH]c12
Product: Cc1cccc2c(Cl)c(CCCl)nnc12

Procedure:
3-(2-Chloroethyl)-8-methyl-4-oxo-(1H)-cinnoline (9 g, 0.04 mol) and phosphorus oxychloride (100 ml) were heated under reflux for 2 hours. The excess phosphorus oxychloride was evaporated under reduced pressure and the residue was poured onto ice, basified with concentrated ammonia solution and extracted with chloroform (3×200 ml). The chloroform extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a dark brown solid. Recrystallization from diethyl ether/petroleum ether (b.p. 40-60°) gave an analytically pure sample, m.p. 102-104°
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:13][CH:14]([CH2:17][CH2:18][CH3:19])[CH2:15][OH:16]>>[OH:16][CH2:15][CH:14]([NH:13][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:12])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(N)CO
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: CCCC(CO)NC(=O)c1ccc2c(c1)OCO2
Yield: 76 %

Procedure:
N-(1-hydroxypentan-2-yl)benzo[d][1,3]dioxole-5-carboxamide was prepared in a similar manner to example 4 using benzo[d][1,3]dioxole-5-carboxylic acid and 2-aminopentan-1-ol. Yield: 76%. MS (M+H, 252).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[C:13]=1[NH:20][CH:21]1[CH2:23][CH2:22]1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([C:10]1[N:20]([CH:21]2[CH2:23][CH2:22]2)[C:13]2[C:14]([Br:19])=[C:15]([F:18])[CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c(Br)c1NC1CC1
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(Br)c2n1C1CC1
Temperature: 70 °C
Yield: 76.8 %

Procedure:
[(S)-1-(3-Bromo-2-cyclopropylamino-4-fluoro-phenylcarbamoyl)ethyl]carbamic acid tert-butyl ester (1.05 g, 2.52 mmol) was taken up in AcOH (12 mL) and heated at 70° C. for 16 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue was partitioned between EtOAc and a saturated solution of NaHCO3. The aqueous phase was further extracted with EtOAc and the combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound (771 mg, 77%) as a yellow oil. LCMS (Method C): RT 3.65 min [M+H]+ 398.09.