Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:27])=[CH:24][CH:23]=1
Reactant: NCCCN1CCCCC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NCCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of N-3-aminopropylpiperidine (1.4 g, 10 mmol) in dichloromethane (20 mL) was added DIEA (1.9 mL, 11 mmol) followed by slow addition of 4-methoxy benzoyl chloride (1.9 g, 11 mmol). The reaction mixture was stirred at room temperature for 18 h. The solution was washed with 1 N KOH (aq.) (1×20 mL) and brine (1×20 mL). The organic phase was dried (K2CO3) and concentrated in vacuo to afford 4-methoxy-N-(3-piperidin-1-ylpropyl)benzamide (1.9 g, 6.9 mmol, 69%) as an oil.
Reaction SMILES: Cl.[CH2:2]([C:6]1[C:10]2[CH:11]=[C:12]([NH:15]N)[CH:13]=[CH:14][C:9]=2[S:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>C(O)CO>[CH2:2]([C:6]1[C:10]2=[C:11]3[C:12](=[CH:13][CH:14]=[C:9]2[S:8][CH:7]=1)[NH:15][C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][C:20]3=1)[CH2:3][CH2:4][CH3:5]
Reactant: CN1CCC(=O)CC1
Reactant: CCCCc1csc2ccc(NN)cc12
Agent: Cl
Solvent: OCCO
Product: CCCCc1csc2ccc3[nH]c4c(c3c12)CN(C)CC4
Temperature: 100 °C

Procedure:
The compound is formed analogously to that described in Example 5, from 25.6 g of 3-butyl-5-hydrazinobenzothiophene hydrochloride and 13.5 g of 1-methyl-4-piperidone in ethylene glycol, the mixture being heated to 100° C. for 30 minutes and then to 180° C. Melting point: 192°-193° C.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:30]=[O:31])[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:32])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][C:34](OC(C)=O)=[O:35].OS([O-])(=O)=O.[Na+]>N1C=CC=CC=1>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]3[CH2:26][C:27](=[O:29])[O:28][CH:30]3[O:31][C:34](=[O:35])[CH3:33])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:32])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=CC(CC(=O)O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OC1OC(=O)CC1NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Reaction time: 6 h
Yield: 37.6 %

Procedure:
A solution of 214e (287 mg, 0.65 mmol) in pyridine (5 mL) was treated with Ac2O (0.4 mL, 3.62 mmol). After 6 hours, the reaction mixture was poured into 5% NaHSO4 and extracted 3 times with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatography (SiO2, EtOAc) afforded 119 mg of 2100h, 1HNMR (CDCl3, mixture of four diastereoisomers) δ 1.80-2.05(m), 2.12(s), 2.13(s), 2.19(s), 2.22(d), 2.67-2.75(m), 2.80-2.95(m), 3.00-3.20(m), 3.21-3.33(m), 3.50-3.95(four discrete multiplets), 4.19(m), 4.55(m), 4.57-4.65(m), 4.69(m), 4.85-4.95(m), 5.04(m), 5.10(s), 5.10-5.22(m), 6.46(d), 6.03(s), 6.50(d), 6.58(d), 6.75(d), 6.95-7.05(m), 7.22(m), 7.30(m), 7.71(d), 7.75-7.83(m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26]CC)=[O:25])[CH:17]=[N:16]3)[N:10]=2)[C:5](F)=[N:6][CH:7]=1.[CH3:29][C:30]1[CH:31]=[C:32]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[CH:33]=[CH:34][C:35]=1[CH2:36][OH:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([OH:26])=[O:25])[CH:17]=[N:16]3)[N:10]=2)[C:5]([O:37][CH2:36][C:35]2[CH:34]=[CH:33][C:32]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=3)=[CH:31][C:30]=2[CH3:29])=[N:6][CH:7]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(Cl)cnc3F)n2)c1C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ncc(Cl)cc1-c1cccc(-n2ncc(C(=O)O)c2C(F)(F)F)n1

Procedure:
The title compound was prepared according to the procedure described in Example 237 Step B, by reaction of the title compound from Example 239 Step A with [3-methyl-4′-(trifluoromethyl)biphenyl-4-yl]methanol (PCT Publication WO2005118542): LCMS m/z 632.7 [M+H]+; 1H NMR (500 MHz, acetone-d6) δ 8.22 (m, 2H), 7.92 (d, J=8.2 Hz, 2H), 7.83 (m, 3H), 7.63 (m, 2H), 5.70 (s, 2H), 2.52 (s, 3H).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[C:14]([NH:21][OH:22])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(N(CC)CC)C>C1COCC1>[C:17]([O:16][C:14]([NH:21][O:22][S:9]([C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:13])(=[O:11])=[O:10])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC(C)(C)OC(=O)NO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-mesitylene sulphonyl chloride (2.0 g, 9.14 mmol) in dry THF (50 mL), is added N-Boc-hydroxylamine (1.21 g, 9.14 mmol) and cooled to 0° C. under N2 atmosphere. The reaction mixture is stirred for 5 minutes. To this mixture triethylamine (1.1 g, 11 mmol) is added slowly over 10 minutes. The reaction mixture is stirred for 1 hour at 0° C. and upon completion, the solvent removed in vacuo. The residue is redissolved in dichloromethane (50 mL) and washed with water (2×50 mL), 10% aqueous NaHCO3 (50 mL) and dried over MgSO4. It is then concentrated under reduced pressure at room temperature to get the product as an off white solid; (2.1 g, 73%). TLC: pet ether/ethyl acetate (8/2) Rf—0.4. 1H NMR (DMSO-d6; 400 MHz): δ 11.16 (s, 1H), 7.12 (s, 2H), 2.49 (s, 6H), 2.28 (s, 3H), 1.23 (s, 9H).
Reaction SMILES: C([O:4][C:5](=[O:36])[CH2:6][C@@H:7]([N:20]1[CH:24]=[CH:23][C:22]([C:25](=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)=[CH:21]1)[C:8]([NH:10][C@H:11]([C:16](=[O:19])[NH:17][CH3:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:9])C=C.N1CCOCC1>C(#N)C.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>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:25]([C:22]2[CH:23]=[CH:24][N:20]([C@@H:7]([C:8]([NH:10][C@H:11]([C:16](=[O:19])[NH:17][CH3:18])[C:12]([CH3:15])([CH3:13])[CH3:14])=[O:9])[CH2:6][C:5]([OH:36])=[O:4])[CH:21]=2)=[O:35])=[CH:28][CH:29]=1)#[N:34]
Reactant: C=CCOC(=O)C[C@H](C(=O)N[C@H](C(=O)NC)C(C)(C)C)n1ccc(C(=O)Cc2ccc(C#N)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1COCCN1
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)n1ccc(C(=O)Cc2ccc(C#N)cc2)c1)C(C)(C)C
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
Routine allyl ester cleavage conditions were previously described by Friedrich-Bochnitschek, S.; Waldmann, H.; Kunz, H. J. Org. Chem. 1989, 54, 751-756. To a solution of 3(R)-[3-[(4-cyanophenyl)acetyl]-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid allyl ester (247 mg, 0.501 mmol) in acetonitrile (2 mL) was added in succession Pd(PPh3)4 (29 mg, 0.026 mmol) and morpholine (226 μL, 2.60 mmol). The resultant mixture was carefully purged with argon. After 30 min, the resultant green mixture was stirred with 10% aqueous KHSO4 (20 mL) and extracted with CHCl3 (35 mL). The organic layer was washed with 10% aqueous KHSO4 (20 mL), dried over Na2SO4, and concentrated. Flash column chromatography with 1% HOAc/3% MeOH/CHCl3 and drying via azeotrope with n-heptane gave 243 mg (94%) of 3(R)-[3-[(4-cyanophenyl)acetyl]-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid as a yellow solid. 1H NMR (CD3OD): δ 8.09 (d, 1H, J=8.7 Hz), 8.05 (dd, 1H, J=2.8, 6.9 Hz), 7.78 (dd, 1H, J=1.9, 1.9 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.46 (d, 2H, J=8.4 Hz), 6.90 (dd, 1H, J=2.2, 2.2 Hz), 6.59 (dd, J=1.9, 3.1 Hz), 5.33 (t, 1H, J=7.5 Hz), 4.22-4.15 (m, 3H), 3.24 (t, 1H, J=8.7 Hz), 2.98 (dd, 1H, J=5.3, 17.4 Hz), 2.66 (d, 3H, J=4.7 Hz), 0.99 (s, 9H). IR (KBr): 3332, 2696, 2230, 1719, 1654, 1532, 1412, 1177 cm-1. HRFABMS: Calculated for C24H29N4O5 (M+H+): 453.2125. Found: 453.2125. Anal. Calculated for C24H28N4O5.0.5 HOAc.0.3 CHCl3 : C, 58.62; H, 5.89; N, 10.81. Found: C, 58.41; H, 5.72; N, 10.50.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)=[CH:5][CH:4]=[N:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:48][CH:49]([C:59]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=[CH:61][CH:60]=1)[CH2:50][NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([NH:48][CH:49]([C:59]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[CH:62]=[CH:61][CH:60]=3)[CH2:50][NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:55])[CH3:56])=[O:14])[CH:8]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1-c1cc(C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NCC(N)c1cccc2ccccc12
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)NC(CNC(=O)OC(C)(C)C)c2cccc3ccccc23)cs1
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxylic acid (104 mg, 0.5 mmol), PyBrOP (384 mg, 0.83 mmol) and diisopropylethyl amine (0.14 mL, 0.83 mmol) in DCM (8 mL) at 25° C. was added 1,1-dimethylethyl [2-amino-2-(1-naphthalenyl)ethyl]carbamate (144 mg, 0.5 mmol) [from Preparation 6]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (76 mg, 32%) as a white solid: LC-MS (ES) m/z=477 (M+H)+.
Reaction SMILES: CO[CH:3](OC)[CH2:4]Br.Br.O.[NH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1>CN(C)C=O>[N:12]1[CH:13]=[CH:14][N:10]2[CH:4]=[CH:3][N:15]=[CH:16][C:11]=12
Reactant: COC(CBr)OC
Reactant: Nc1cnccn1
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Product: c1cn2ccnc2cn1
Reaction time: 12 h

Procedure:
A mixture of 34 g (0.2 mol) of bromoacetaldehyde dimethyl acetal, 6,6 ml of concentrated aqueous HBr solution and 28 ml of distilled water is brought to reflux for one hour. After reaction, the mixture is alkalinized and extracted with ether. This organic phase is added to a solution of 19 g (0.2 mol) of aminopyrazine in 50 ml of dimethylformamide (DMF). The ether is removed by distillation and the mixture is maintained with stirring and under a stream of nitrogen for 12 hours. After reaction, the DMF is distilled off; the reaction medium is dissolved in 150 ml of anhydrous ethanol, and then brought to reflux for one hour. The alcohol is then removed by distillation; the residue is dissolved in water, alkalinized with Na2CO3 and extracted using dichloromethane. After chromatography on a neutral alumina column (eluant =anhydrous ether), 10.7 g (Yld=45%) of imidazo[1,2-a]pyrazine (m.p. 84° C.). are obtained.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]3[C:21]=2[CH:22]=[CH:23][NH:24]3)[C:11]1=[O:30])[CH2:7][CH2:8][CH3:9])C.[C:32]([O-])([O-])=O.[K+].[K+].CI>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:29][C:27]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][N:24]2[CH3:32])=[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:3])=[O:31])[C:11]2=[O:30])[CH:28]=1
Reactant: O=C([O-])[O-]
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(Cl)cc3[nH]ccc23)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Cl)cc3c2ccn3C)c2ccccc21
Temperature: 65 °C
Reaction time: 18 h
Yield: 9 %

Procedure:
3-[3-(6-Chloro-1H-indol-4-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (300 mg, 0.68 mmol), prepared as described in example 72 using the appropriate reagents, was dissolved in acetonitrile (5 mL) and treated with K2CO3 (700 mg, 5.1 mmol), methyl iodide (0.31 mL, 5 mmol) and tetrabutylammonium bromide (161 mg, 0.5 mmol). The resulting mixture was heated at 65° C. for 60 h, filtered, and the solution was treated directly with Amberlyst® A26 (OH— form) (1.5 g, 2 mmol). This mixture was agitated for 18 h, filtered and the resin was washed with several portions of methanol. The product was eluted from the resin with 20% formic acid in methanol (2×2 mL). The eluant was concentrated and the residue was purified by preparative HPLC to provide 26 mg (9%) of the title compound. LCMS (ESMS): m/z 426 (M+H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([OH:13])[C:9](=[CH:11][CH:12]=1)[OH:10])([O-:5])=[O:4].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>CN(C=O)C.O>[N+:3]([C:6]1[CH:12]=[CH:11][C:9]2[O:10][CH:16]([CH2:17][OH:18])[CH2:14][O:13][C:8]=2[CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)OCC(CO)O2
Yield: 32.8 %

Procedure:
1.93 g of 60% sodium hydride was suspended in 90 mL DMF. At 0° C. a solution of 5.15 g of 4-nitrocatechol was added dropwise over 15 min. Subsequently, 3.9 g of epichlorohydrin in 10 mL DMF were added over 15 min. Stirring was continued at room temperature, then at 80° C. overnight. The mixture was diluted with water and extracted three times with ethyl acetate, dried (Na2SO4), filtered and concentrated under vacuum to give a yellow oil. The oil was purified by column chromatography on silica gel using a EtOAc-hexanes (0-100% gradient) to give the product (2.3 g) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(C(c3ccccc3)c3ccccc3)C2)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a stirred solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (330 mg) in dimethylformamide (6 mL) was added potassium carbonate (158 mg) and 1,1′-(bromomethylene)dibenzene (225 mg), and the mixture was stirred at 60° C. for 2 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography (hexane:ethyl acetate=4:1 then chloroform:methanol=20:1) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (210 mg) as an oil.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([O:14]C(C2CC2)=O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:21])[C:9]=2[F:20])[N:4]=1)[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:3]1[C:12]([CH3:13])=[C:11]([OH:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:21])[C:9]=2[F:20])[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc2ccc(F)c(F)c2c(O)c1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
2-Ethyl-3-methyl-4-cyclopropanecarbonyloxy-5,6-difluoroquinoline (1 g) prepared as described in Example 1 was dissolved in 10 ml of methanol to prepare a solution. A solution of 0.5 g of sodium hydroxide in 10 ml of water was added to this solution, and the mixture was stirred at 50° C. for 3 hr. The reaction solution was allowed to stand for cooling and was then poured into 50 ml of water, and the mixture was neutralized with 1 N hydrochloric acid. The precipitate was then collected by filtration to give 700 mg of 2-ethyl-3-methyl-4-hydroxy-5,6-difluoroquinoline. In 20 ml of tetrahydrofuran was suspended in 96 mg of 60% sodium hydride. The 2-ethyl-3-methyl-4-hydroxy-5,6-difluoroquinoline (starting material 1) (446 mg) was suspended in 10 ml of tetrahydrofuran, and this suspension of starting material 1 was added dropwise to the above suspension under ice cooling. The mixture was stirred for one hr, 200 mg of acetyl chloride (starting material 2) was then added thereto, and the mixture was stirred at room temperature for 4.5 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 424 mg of 2-ethyl-3-methyl-4-acetyloxy-5,6-difluoroquinoline (compound 12). 1H-NMR data are shown in Table 3.
Reaction SMILES: [CH2:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17](Cl)=[O:18])[CH2:14][CH3:15].O1CCCC1>C(N(CC)CC)C>[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH2:14][CH3:15]
Reactant: CCCCS(=O)(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)c1ncn(C(=O)N(CCC)CCC)n1

Procedure:
A mixture of 5.7 g. 3-n-butylsulphonyl-1,2,4-triazole, 5.4 g. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The reaction mixture was worked up as described in Example 1 to produce a solid product which was recrystallized from petroleum ether (60° - 80°C.) to give 1-dipropylcarbamoyl-3-n-butylsulphonyl-1,2,4-triazole, m.p. 46° - 47°C. Elemental analysis satisfactory.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[C:16]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([C:2]([O:1][CH2:14][C:15]2[C:16]([C:21]3[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=3)=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:3][N:4]=1)[CH:8]=[O:9]
Reactant: COc1cc(C=O)c(O)cn1
Reactant: Cn1nccc1-c1ncccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccnn2C)cn1
Temperature: 70 °C
Yield: 74.7 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (147 mg, 0.96 mmol, 1 eq.), 3-(chloromethyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine hydrochloride (236 mg, 0.96 mmol, 1 eq.), and K2CO3 (532 mg, 3.85 mmol, 3 eq.) in DMF (3.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-methoxy-5-((2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (232.5 mg, 75%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.77 (dd, J=4.7, 1.7 Hz, 1H), 8.03 (dd, J=7.9, 1.7 Hz, 1H), 7.93 (s, 1H), 7.55 (d, J=1.9 Hz, 1H), 7.44 (dd, J=7.9, 4.8 Hz, 1H), 7.11 (d, J=0.4 Hz, 1H), 6.43 (d, J=1.9 Hz, 1H), 5.20 (s, 2H), 3.97 (s, 3H), 3.92 (s, 3H). LRMS (M+H+) m/z 325.1.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:29]1([CH2:35][CH2:36][C:37](O)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:37](=[O:38])[CH2:36][CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Dicyclohexylcarbodiimide (4.5 g) was added to a mixture of 3.52 g of 1-benzylpiperazine, 3.5 g of 3-phenylpropionic acid and 20 ml of tetrahydrofuran, and the mixture was stirred overnight at room temperature. The resultant dicyclohexylurea was filtered off, and the mother liquor was concentrated under reduced pressure. Ethyl acetate (100 ml) and 50 ml of water were added to the residue, and the mixture was made alkaline with potassium carbonate and then allowed to undergo phase separation. The ethyl acetate layer was washed in sequence with water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 6 g of 1-benzyl-4-(3-phenylpropionyl)piperazine.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][F:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:22]=1>N1CCCCC1.C(#N)C.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.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:29]#[C:28][C@:26]([C:23]4[N:22]=[C:21]([CH3:20])[O:25][N:24]=4)([OH:30])[CH3:27])[CH:10]=3)[C:6]([CH2:18][F:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccc(-n2nc(CF)c3ccc(Br)cc32)n1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CC#N
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(CF)nn(-c4ccnc(N)n4)c3c2)no1
Temperature: 66 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amine (70 mg, 0.21 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.02 mmol), copper(I) iodide (3 mg, 0.02 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (90 mg, 0.41 mmol). The reaction mixture was warmed to 66° C. for 2 hr, re-treated with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (45 mg, 0.20 mmol) and warming continued at 66° C. for a further 1 hr. Following cooling to RT, the reaction mixture was concentrated in vacuo, DCM (10 mL) was added and the solution re-evaporated to dryness in vacuo (re-evaporation process repeated twice). Purification of the residue by column chromatography (Biotage, DCM containing a 0-10% gradient of methanol) furnished a brown oil which was suspended in acetonitrile and concentrated in vacuo. The residue was slurried in diethyl ether (0.5 mL) to which was introduced acetonitrile until a fine cream precipitate resulted. Filtration furnished the title compound as a cream solid: 1H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 2.62 (3H, s), 5.85 (2H, d, J=47.45 Hz), 6.82 (1H, s), 6.95-7.23 (3H, m), 7.43 (1H, dd, J=8.28, 1.18 Hz), 7.98 (1H, d, J=8.20 Hz), 8.33 (1H, d, J=5.36 Hz), 8.94 (1H, s); LC-MS: m/z=+394.00 (M+H)+.