Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH2:28])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH:28][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(Sc2ccc(F)cc2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Sc2ccc(F)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (167 mg, 0.94 mmol) was reacted with the product from Example 49b (218 mg, 0.94 mmol) for 48 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (224 mg, 49%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.37 (m, 3H) 2.77 (m, 3H) 6.29 (d, J=6.99 Hz, 1H) 7.10 (m, 2H) 7.32 (m, 5H) 7.80 (d, J=8.46 Hz, 1H) 8.41 (d, J=6.99 Hz, 1H) 8.95 (d, J=8.46 Hz, 1H) 11.04 (br. s., 1H) 14.43 (br. s., 1H); MS (ESI+) m/z 376 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:30])[C@@:14]([CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:29][C:26]([CH3:27])([CH3:28])[CH2:25][CH2:24][C@:14]1([CH3:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]([OH:22])=[C:12]([C:7]2[NH:6][C:5]3[CH:31]=[CH:32][C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:3][C:4]=3[S:9](=[O:11])(=[O:10])[N:8]=2)[C:13]1=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 87.2 %

Procedure:
To a solution of the product of Example 49-6 (235.0 g, 0.518 mol) and pyridine (123.0 g, 1.55 mol) in dichloromethane (1645 mL) at 18-20° C. was added methane sulfonyl chloride (89.0 g, 0.777 mol) over 45 minutes. The solution was mixed at RT for 3.5 h then quenched with 1 M HCl (1500 mL). The layers were separated and the organic layer was concentrated under vacuum. The product was crystallized from ethyl acetate/heptane (1/1, 8 volumes) to give the title compound (240.01 g, 87%).
Reaction SMILES: [CH3:1][C@H:2]1[NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][CH2:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].CCN(CC)CC>CN(C=O)C>[CH3:1][C@H:2]1[N:8]([C:13](=[O:15])[CH3:14])[CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][CH2:3]1
Reactant: C[C@@H]1CNc2ccccc2CN1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1Cc2ccccc2NC[C@H]1C
Yield: 34.5 %

Procedure:
(3R)-3-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (8.6 mmol) was allowed to react with 8.4 mmol acetic anhydride and 12.9 mmol Et3N in 20 mL DMF to give 2.9 mmol of 1-[(3R)-3-methyl-1,2,3,5-tetrahydro-4H-1,4-benzodiazepin4-yl]-1-ethanone.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].O[CH2:15][C:16]1[O:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1.N1CCCCC1>C(O)C>[OH:22][CH2:21][C:19]1[O:20][C:16]([CH:15]=[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([C:1](=[O:3])[CH3:2])[C:5]2=[O:13])=[CH:17][CH:18]=1
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Reactant: O=Cc1ccc(CO)o1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(=O)N1C(=O)C(=Cc2ccc(CO)o2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-acetyloxindole (1 equivalent), 5-hydroxymethyl-2-furaldehyde (0.5 equivalent) and piperidine (0.2 equivalent) were dissolved in ethanol such that 1 mL of ethanol was used per 1 μmol of the total amount of the compounds, and the resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the resulting precipitate was collected by filtration, washed with cooled ethanol several times and dried, whereby 3-((5-(hydroxymethyl)furan-2-yl) methylene)-N-acetyl-2-oxoindoline was obtained.
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]1([NH2:9])[CH2:8][CH2:7]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[C:17]([N:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]3([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[OH:35])[CH2:28][CH2:27]3)[C:20]2=[O:36])[C:16]([CH3:37])=[C:15]([F:38])[CH:14]=1.Cl>C1COCC1.O>[CH:6]1([NH:9][C:12](=[O:11])[C:13]2[CH:18]=[C:17]([N:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[OH:35])[CH2:28][CH2:27]4)[C:20]3=[O:36])[C:16]([CH3:37])=[C:15]([F:38])[CH:14]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc(F)c(C)c(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (30.1 ml of a 2M solution in THF) was added over 20 min to a solution of cyclopropylamine (10.61 mL) and 3-fluoro-5-[3-[[1-(2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid methyl ester (Example 259b, 6.16 g) in tetrahydrofuran (200 mL) and the reaction stirred at room temperature under nitrogen for 1 h. Water (100 mL) and 2M HCl (200 mL) were cautiously added and the aqueous layer extracted with dichloromethane (3×200 mL) and the combined organic extracts dried (MgSO4) and the solvent removed to give the subtitle compound (5.00 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8]>CCOCC>[Cl:3][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: CCCCc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: CCCCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.9 %

Procedure:
Thionyl chloride (2.5 ml, 34 mmol) was added to a solution of 4-n-butylbenzyl alcohol (2.0 g, 12 mmol) in ether (25 ml), and this mixture was stirred at room temperature for 3 hours. After concentration of the mixture, excess thionyl chloride was removed by azeotropic distillation with benzene to give the title compound (2.3 g). This compound was used in the following reaction without purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([N:13]1[C@H:17]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH2:16][S:15][CH2:14]1)=[O:12].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([N:13]1[C@H:17]([C:18]([N:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:19])[CH2:16][S:15](=[O:33])[CH2:14]1)=[O:12]
Reactant: O=C([C@@H]1CSCN1C(=O)CC1Cc2ccccc2C1)N1CCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C([C@@H]1CS(=O)CN1C(=O)CC1Cc2ccccc2C1)N1CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
Dissolved in 100 ml of chloroform were 5 g of 3-(2-indanacetyl)-4(R)-(1-pyrrolidinecarbonyl)thiazolidine (a compound according to Preparation Example 2 set forth in Japanese Patent Application Laid-Open No. 262557/1990). While chilling with ice water, 3.3 g of meta-chloro-perbenzoic acid were gradually added to the solution. After stirring the mixture for 3 hours, the resultant liquid reaction mixture was washed successively with a 5% solution of sodium thiosulfate and a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:chloroform=5:95), thereby obtaining 3.8 g of the title compound as a diastereomeric mixture. Yield: 73%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][C:39]#[N:40]>>[OH:22][C:19]([CH:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:2]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[C:30]4[CH2:38][C:39]#[N:40])[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]=3[N:11]=2)[CH2:14][CH2:15]1)([CH3:21])[CH3:20]
Reactant: N#CCc1nc2ccccc2[nH]1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-n4c(CC#N)nc5ccccc54)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure D, 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 was reacted with 2-(1H-benzo[d]imidazol-2-yl)acetonitrile to give 158. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=7.8 Hz, 1H), 8.21 (d, J=8.5 Hz, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.38 (overlapping m, 2H), 4.88 (s, 2H), 4.54 (s, 4H), 4.04 (s, 1H), 3.86 (s, 4H), 3.73 (s, 2H), 2.92 (d, J=10.5 Hz, 2H), 1.99 (t, J=11.5 Hz, 2H), 1.67 (d, J=11.7 Hz, 2H), 1.26 (overlapping m, 3H), 1.04 (s, 6H). LCMS: 527.3
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.C[O:16][B:17](OC)[O:18]C.Cl>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[B:17]([OH:18])[OH:16]
Reactant: COB(OC)OC
Reactant: Cc1ccc(Br)cc1I
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(Br)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 2-methyl-5-bromo-iodobenzene (12 g, 40.4 mmol) in tetrahydrofuran (75 ml), cooled to −78° C., was added a solution of isopropylmagnesium chloride (4.6 g, 44.5 mmol) in tetrahydrofuran (22.2 ml) dropwise over 20 minutes. After stirring at −78° C. for 30 minutes, the mixture was warmed slowly to −20° C. and stirred for 1 hour. After cooling again to −78° C., trimethylborate (8.4 g, 80.8 mmol) was added dropwise. After warming to 0° C., the mixture was stirred for 2 hours, treated with 1 M hydrochloric acid (35 ml), and extracted with ethyl acetate (2×50 ml). The combined extracts were washed with water (50 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residual solid was suspended in hexane (50 ml), filtered, washed with hexane (30 ml) and dried under reduced pressure to provide 2-methyl-5-bromo-phenylboronic acid (7.32 g, 84% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.92 (s, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 2.59 (s, 3H).
Reaction SMILES: C1COCC1.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[C:17]([F:25])[C:16]=2[F:26])=[C:11]([F:27])[C:10]=1[F:28])[CH3:7].C([Li])CCC.[CH2:34]([C@H:37]1[CH2:42][CH2:41][C@H:40]([CH:43]2[CH2:46][CH2:45]O2)[CH2:39][CH2:38]1)[CH2:35][CH3:36]>C(O)=O>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:36][CH2:35][CH:34]([CH:37]4[CH2:38][CH2:39][CH:40]([CH2:43][CH2:46][CH3:45])[CH2:41][CH2:42]4)[O:23][C:22]3=[O:24])=[C:17]([F:25])[C:16]=2[F:26])=[C:11]([F:27])[C:10]=1[F:28])[CH3:7]
Reactant: CCOc1ccc(-c2ccc(CC(=O)O)c(F)c2F)c(F)c1F
Reactant: CCC[C@H]1CC[C@H](C2CCO2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O=CO
Product: CCCC1CCC(C2CCC(c3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)C(=O)O2)CC1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
THF (50 ml) was added to 2-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)acetic acid (10) (2.0 g) prepared in the eighth step. The solution was cooled to −5° C., and n-butyllithium (1.59 M in n-hexane; 7.66 ml) was added dropwise. After the addition had been completed, the reaction mixture was returned to room temperature, and the stirring was continued for 30 minutes. The solution was then cooled to −65° C., and 2-(trans-4-propyl-cyclohexyl)-oxetane (5) (1.0 g) in a THF (5 ml) solution and a boron trifluoride-diethyl ether complex (0.86 g) were added dropwise. After the addition had been completed, the reaction mixture was returned to room temperature, and a 10% aqueous solution of formic acid (100 ml) was added to give two layers. The water layer was extracted with toluene (20 ml) three times and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 200 g, eluent: heptane/ethyl acetate=90/10 by volume) to give 3-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)-6-(4-propylcyclohexyl)tetrahydropyran-2-one (11) (2.35 g) in 86.1% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)c2ccc(OCc3ccccc3)cc2n1
Reactant: C1CCNC1
Product: Cc1cc(N2CCCC2)c2ccc(OCc3ccccc3)cc2n1
Temperature: 80 °C
Yield: 75 %

Procedure:
A mixture of 534 mg (1.8 mmol) of 7-benzyloxy-4-chloro-2-methyl-quinoline and 3.77 ml (45 mmol) pyrrolidine was heated at 80° C. (oil bath temperature) under an argon atmosphere for 23 h after which time the reaction was completed according to HPLC analysis. The reaction was partitioned between EtOAc and water, the aqueous layer was extracted once with EtOAc, the combined organic layers were washed with water then saturated NaCl solution, dried over magnesium sulphate and concentrated in vacuo. The residue was applied to silica gel column with CH2Cl2/MeOH/NH4OH (19:1:0.05) as eluent. Combination of the purified fractions and concentration in vacuo gave 430 mg (74.5%) of the 7-benzyloxy-2-methyl-4-pyrrolidin-1-yl-quinoline as a brown solid. ISP mass spectrum, m/e: 319.4 (M+1 calculated for C21H22N2O: 319).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][CH:23]([S:25]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)(=[O:27])=[O:26])[CH3:24]>CS(C)=O.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>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[NH:28][S:25]([CH:23]([CH3:24])[CH3:22])(=[O:27])=[O:26])=[CH:3][C:4]=2[F:15])=[N:9][CH:10]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: CC(C)S(=O)(=O)Nc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)S(=O)(=O)Nc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Temperature: 80 °C
Yield: 9 %

Procedure:
To a solution of 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine (309 mg, 1.15 mmol) in DMSO (5 mL) was added K2CO3 (317 mg, 2.3 mmol). The mixture was sparged with N2 several times. Pd(PPh3)4 (66 mg, 0.058 mmol) and (2-(1-methylethylsulfonamido)-phenyl)boronic acid (280 mg, 1.15 mmol) were added and the resultant mixture sparged with N2. The mixture was heated at 80° Celsius for 14 hours before cooling to rt and diluting with water (70 mL). The precipitate was collected, rinsed with water, air dried, and then purified by HPLC to give the title compound (40 mg, 9%). MS (ESI): mass calcd. for C19H19FN4O2S, 386.12; m/z found, 387.1 [M+H]+. 1H NMR (300 MHz, CD3OD) δ 8.72 (s, 1H), 8.25 (d, J=1.2, 1H), 8.16 (m, 1H), 7.50 (d, J=7.8, 1H), 7.47-7.34 (m, 5H), 3.15-3.03 (m, 1H), 1.23 (d, J=6.8, 6H).
Reaction SMILES: [CH3:1][C:2]1O[C:5]([C:7]2[CH:12]=[CH:11][N:10]3[C:13]([C:16]4[CH:17]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:19]=[CH:20][CH:21]=4)=[CH:14][N:15]=[C:9]3[CH:8]=2)=[N:4][N:3]=1.[CH3:31][NH2:32]>>[CH3:31][N:32]1[C:2]([CH3:1])=[N:3][N:4]=[C:5]1[C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:16]3[CH:17]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:19]=[CH:20][CH:21]=3)=[CH:14][N:15]=[C:9]2[CH:8]=1
Reactant: CN
Reactant: Cc1nnc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)o1
Product: Cc1nnc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)n1C

Procedure:
Alternatively the title compound could be prepared through reaction of 1-{3-[7-(5-methyl-[1,3,4]oxadiazol-2-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea with methylamine.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.[CH2:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][CH2:21][C:22]#[CH:23]>CCCCCCC.CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:23]#[C:22][CH2:21][CH2:20][CH2:19][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:5]=[CH:6][N:7]=1
Reactant: C#CCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C)ncn2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1cc(C#CCCCc2ccccc2)ncn1

Procedure:
This product was prepared from toluene-4-sulfonic acid 6-methyl-pyrimidin-4-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (36.6 mg, 31%); 1H NMR δ (CDCl3): 9.01 (s, 1H), 7.31-7.25 (m, 2H), 7.22-7.16 (m, 4H), 2.78 (t, J=7.18 Hz, 2H), 2.51 (s, 3H), 2.41 (t, J=7.17 Hz, 2H), 1.93 (p, J=7.22 Hz, 2H); LCMS m/z: 236.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[NH2:33][CH2:34][CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:36][CH2:35][CH2:34][NH:33][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCNCCO
Temperature: 80 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (compound 123) (50 mg), 2-aminoethanol (20 mg), and potassium carbonate (76 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (23 mg, yield 44%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:11](Br)[CH:12]=[CH2:13].[BH4-].[Na+]>CC(C)=O.CO>[CH2:13]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: c1cnc2ccncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: C=CCN1CCc2ncccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,6-naphthyridine (6.5 g, 0.05 mol) and allyl bromide (9.1 g, 0.075 mol) in acetone (50 ml) was refluxed for 8 hours. The precipitated quatenary salt was separated by filtration, dissolved in technical grade methanol (300 ml) and sodium borohydride (18.9 g, 0.5 mol) was added portionwise under ice cooling. After stirring overnight at room temperature, the reaction mixture was evaporated in vacuo, water added and extracted with benzene. The benzene layer was dried over anhydrous potassium carbonate and evaporated in vacuo. The residue was purified by alumina column chromatography (eluted successively with n-hexane and benzene-chloroform (3:1)) and distilled, bp 98° C./1.0 mmHg, to afford the Compound No. 12 (5.70 g, 65.5%) as a colorless oil.
Reaction SMILES: [BH4-].[Na+].[C:3]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O)(OCC1C=CC=CC=1)=O.OS(O)(=O)=O>C1COCC1.CCOCC>[CH3:18][C:14]1[CH:15]=[C:15]([C@@H:14]2[CH2:18][CH2:19][CH2:20][N:13]2[CH3:3])[O:17][N:13]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc([C@@H]2CCCN2C)on1
Temperature: 0 °C
Yield: 88 %

Procedure:
To a stirred suspension of sodium borohydride (7.59 g, 200 mmol) in 100 mL of THF cooled to 0° C. was added a solution of 20 g (80.28 mmol) of N-Cbz-L-proline, from step 24a above, in 50 mL of ether. To this solution was added dropwise a solution of 5 mL of H2SO4 in 20 mL of ether, with stirring and while maintaining the temperature below 20° C. The reaction mixture was warmed to room temperature and stirred for 16 hr. The reaction was quenched by the addition of 100 mL of methanol dropwise. The solvents were removed, 30 mL of 4N NaOH was added, and the mixture was extracted with ethyl acetate. The organic extract was dried over Na2SO4 and concentrated to afford the title product; 16.61 g (88% yield).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([OH:27])=O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][CH2:33][OH:34]>>[CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([NH:30][CH2:31][CH2:32][CH2:33][OH:34])=[O:27])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F
Reactant: NCCCO
Product: O=C(NCCCO)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F

Procedure:
Prepared by a similar procedure as described for the preparation of Example 499, starting from 5-[(2-benzyloxycarbamoyl-phenylamino)methyl]-2-fluoro-benzoic acid (Example 498) and 3-amino-propan-1-ol.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=4)[C:32]#[N:33])[CH2:23][C:22](=[O:34])[NH:21][C:9]=3[CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4cccc(F)c4)cc3NC(=O)C2)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-3′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K65) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (57 mg).