Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 82 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 82%). 1H NMR (300 MHz, CDCl3): δ 3.18-3.21 (m, 4H), 3.74-3.78 (m, 4H), 4.14 (s, 3H), 6.88-6.92 (m, 4H), 7.25-7.42 (m, 3H), 7.76-7.81 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].[O:16]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17]1>>[O:16]1[CH:20]=[CH:19][C:18]([CH:21]=[C:10]2[CH2:9][CH2:8][C:7]3[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=[CH:13][C:12]=3[C:11]2=[O:15])=[CH:17]1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Reactant: O=Cc1ccoc1
Product: COC(=O)c1ccc2c(c1)CCC(=Cc1ccoc1)C2=O
Yield: 80 %

Procedure:
The title compound was prepared from 5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396 mg, 1.9 mmol) and 3-furaldehyde (192 mg, 2.0 mmol) according to Method A3 in 80% yield. ES-MS m/z 283 (M+H)
Reaction SMILES: Br.[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.N1CC[CH2:12][C@@H:9]1[CH2:10][OH:11]>>[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:12][CH2:9][CH2:10][OH:11]
Reactant: OC[C@H]1CCCN1
Reactant: C[C@H]1CCCN1
Agent: Br
Product: C[C@H]1CCCN1CCCO

Procedure:
(2S)-2-methylpyrrolidine hydrobromide (2.70 g, 16.3 mmol), 3-bromopropanol (2.49 g, 17.9 mmol) and potassium carbonate (6.75 g, 48.9 mmol) were mixed in tetrahydrofuran (20 mL), and stirred at 60° C. for 18 hours. The precipitate was filtered off, and the filtrate was concentrated. The residue was distilled under reduced pressure, and the target compound (1.88 g, 80%) was thus obtained as a colorless oily substance. (2S)-2-methyl-pyrrolidine hydrobromide was manufactured by the method described in the literature (J. Org. Chem., 1989, Vol. 54, p. 209) using D-prolinol as starting material.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[Br:17][C:18]1[C:19]([NH:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH2:30][CH2:29]3)=[N:20][C:21](Cl)=[N:22][CH:23]=1>CO.C(O)CCC>[Br:17][C:18]1[C:19]([NH:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH2:30][CH2:29]3)=[N:20][C:21]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([O:5][CH2:4][CH:3]([OH:2])[CH2:13][N:14]([CH3:16])[CH3:15])=[CH:7][CH:8]=2)=[N:22][CH:23]=1
Reactant: Clc1ncc(Br)c(Nc2ccc3c(c2)CCC3)n1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Solvent: CO
Solvent: CCCCO
Product: CN(C)CC(O)COc1ccc(Nc2ncc(Br)c(Nc3ccc4c(c3)CCC4)n2)cc1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
A hot solution of 4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]aniline hydrochloride (Method 89, 156 mg, 0.56 mmol) in methanol (2 ml) was added to a solution of 5-bromo-2-chloro-4-(indan-5-ylamino)pyrimidine (Method 15, 200 mg, 0.62 mmol) in n-butanol (20 ml). The mixture was heated at 100° C. for 18 hours and silica.(1 g) was added. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 0-10% 2.0M methanolic ammonia solution in DCM, to give the product as a colourless solid (117 mg, 42%). NMR: 2.03 (m, 2H), 2.18 (s, 6H), 2.32 (m, 2H), 2.83 (m, 4H), 3.80 (m, 3H), 4.76 (d, 1H), 6.70 (d, 2H), 7.17 (m, 1H), 7.23 (m, 1H), 7.41 (m, 3H), 8.10 (s, 1H), 8.35 (s, 1H), 9.03 (s, 1H); MS (MH+): 498.4, 500.4.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: COCCCCCC(=O)N1CCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COCCCCCCN1CCCc2ccccc21

Procedure:
A solution of the above 1-(6-methoxyhexanoyl)-1,2,3,4-tetrahydroquinoline (2.7 g) in ether (200 ml) containing lithium aluminium hydride (9.9 g) was refluxed for 6 hours, then cooled and diluted with water. The ethereal solution was dried and evaporated and the residue was chromatographed on silica gel, eluting with 99:1 methylene chloride:methanol, so as to obtain the title compound as an oil.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[CH:53]=[CH:52][CH:51]=[C:50]2[C:45]=1[CH:46]=[CH:47][C:48]([S:54]([N:57]([CH2:63][C:64]1[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][C:65]=1[O:72][CH3:73])[C:58]1[S:62][N:61]=[CH:60][N:59]=1)(=[O:56])=[O:55])=[CH:49]2.[C:74]([Zn]C#N)#[N:75]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:74]([C:44]1[CH:53]=[CH:52][CH:51]=[C:50]2[C:45]=1[CH:46]=[CH:47][C:48]([S:54]([N:57]([CH2:63][C:64]1[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][C:65]=1[O:72][CH3:73])[C:58]1[S:62][N:61]=[CH:60][N:59]=1)(=[O:56])=[O:55])=[CH:49]2)#[N:75]
Reactant: N#C[Zn]C#N
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(C#N)cccc3c2)c(OC)c1
Temperature: 120 °C

Procedure:
A microwave vial was charged with Xantphos (44.5 mg, 0.077 mmol) and Pd2(dba)3 (35.2 mg, 0.038 mmol). The vessel was flushed with Ar (g), then DMF (3843 μl) was added. The vessel was sealed and heated in a microwave reactor at 120° C. for 10 min. The mixture was cooled, then a solid mixture of 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D; 200 mg, 0.384 mmol) and dicyanozinc (226 mg, 1.922 mmol) was added. The vial was re-sealed and heated in the microwave for 3 h at 120° C. The mixture was then diluted with water and extracted with EtOAc (3×). The combined organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography on a 40-g column with 50 to 100% EtOAc/Heptane to give 5-cyano-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide as an off-white solid. This material was dissolved in DCM (1 mL) and TFA (0.5 mL). The mixture was stirred for 4 h, then diluted with 2-propanol and concentrated. The residue was purified by silica gel chromatography (12-g, with 0 to 10% MeOH/DCM) to give 5-cyano-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (12.98 mg, 0.041 mmol, 67.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.70 (br. s., 1H), 8.60 (d, J=9.0 Hz, 1H), 8.48 (br. s., 1H), 8.34 (d, J=7.1 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.88-7.77 (m, 1H); m/z (ESI) 317.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:35]1[C:34]([CH2:33][NH:32][C:3](=[O:5])[CH:2]([OH:1])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:8][CH:7]=2)=[N:38][N:37]=[N:36]1
Reactant: NCc1nnn[nH]1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1nnn[nH]1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 50 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), 5-(aminomethyl)tetrazole (6.89 mg, 0.070 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (1 mL). This was stirred for 1 h and was then purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=29.2 min) to provide (R/S)-N-((1H-tetrazol-5-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12 mg, 0.023 mmol, 49.8% yield): LCMS=513.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.11-8.24 (2 H, m), 7.53-7.75 (7 H, m), 5.22 (1 H, s), 4.67-4.81 (2 H, m); HPLC peak RT=8.8 min (Method A).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.O>C1(C)C=CC=CC=1>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2([C:20]3[CH:21]=[CH:22][C:17]([OH:23])=[CH:18][CH:19]=3)[CH2:6][CH2:5][CH:4]([C@H:1]3[CH2:3][CH2:2][C@H:1]([CH2:4][CH2:5][CH3:6])[CH2:3][CH2:2]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: CCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Reactant: Oc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CC[C@H](C2CCC(c3ccc(O)cc3)(c3ccc(O)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
4-(Trans-4-n-propylcyclohexyl)cyclohexanone (449 g), phenol (756 g) and CaCl (446 g) were mixed, followed by gradually dropwise adding conc. hydrochloric acid (335 ml) with vigorous stirring at room temperature, further agitating the mixture for 30 minutes after completion of the dropwise addition, allowing the resulting material to stand at room temperature, further for 50 hours, adding hot water (2 l) and toluene (3 l), heating the mixture, cooling, filtering off crystals, washing the crystals with water and then with toluene, drying the crystals and recrystallizing from tetrahydrofuran solvent to obtain white crystals of 1,1-bis(4-hydroxyphenyl)-4-(trans-4-n-propylcyclohexyl)cyclohexane as a diol compound of the present invention (436 g). M.P.: 222.0°-222.8° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1B(O)O.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][CH:32]=[N:33]3)=[CH:28][CH:27]=2)[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][CH:32]=[N:33]3)=[CH:28][CH:27]=2)[CH:20]=1
Reactant: COCOc1cc(C(F)(F)F)ccc1B(O)O
Reactant: Clc1cc(Oc2ccc3cccnc3c2)ncn1
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: CCO
Solvent: Cc1ccccc1
Product: COCOc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Temperature: 140 °C

Procedure:
To a suspension of 2-methoxymethoxy-4-trifluoromethylphenyl-boronic acid, (Example 135(b)), (220 mg, 0.87 mmol) and 7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example 102(a)), (150 mg, 0.58 mmol) in toluene/EtOH (1:4, 3.8 mL) was added 2 M K2CO3 (1.2 mL, 2.3 mmol) and Pd(PPh3)4 (34 mg, 0.030 mmol, Strem). The reaction mixture was stirred and heated by microwave synthesizer at 140° C. for 10 min. The mixture was partitioned between CH2Cl2 and 1 N NaOH. The organic phase was separated, and the aqueous phase was extracted with CH2Cl2. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (MeOH/CH2Cl2 1:125 and then 1:100) afforded a light-yellow gum. The title compound was obtained as a white solid after recrystallization from MeOH. MP: 98.8-99.4° C. MS (ESI, pos. ion) m/z: 428 (M+1). Anal. Calcd for C22H16F3N3O3: C, 61.83; H, 3.77; N, 9.83. Found: C, 62.13; H, 3.87; N, 9.52.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:4]1.[H-].[Na+].[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:19]=1[C:20]#[N:21]>C1COCC1>[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([O:1][CH2:2][C@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:4]2)[C:19]=1[C:20]#[N:21]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)CC(=O)N1CCC[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
A solution of (S)-1-(3-(hydroxymethyl)piperidin-1-yl)-3-methylbutan-1-one (Example 5d) (42 g, 210.75 mmol, 1.2 eq.) in anhydrous THF (300 mL) was added dropwise at 0° C. to a suspension of NaH (60% in mineral oil, 8.43 g, 273.97 mmol, 1.63 eq.) in anhydrous THF (600 mL). The mixture was warmed up to about 25° C. and stirred for 1 h while keeping the temperature below 25° C. A solution of 2-amino-6-fluorobenzonitrile (22.95 g, 168.6 mmol, 1 eq.) in THF (300 mL) was added dropwise. The reaction was heated slowly to reflux and stirred overnight. The mixture was cooled down to room temperature, concentrated to about 400 mL of residual material. Saturated ammonium chloride (200 mL) was added. After stirring vigorously for 15 minutes, EtOAc (800 mL) was added and stirring continued for additional 30 minutes. The organic phase was washed subsequently with water, brine and dried over Na2SO4. The solvent was removed under vacuum and the residue was chromatographed on silica gel (Hex/EtOAc to provide the desired product (44.6 g, 141.40 mmol, 83.87%). 1H NMR (400 MHz, DMSO-d6, 20° C.) δ 0.79-0.92 (3×d, J=6.4 Hz/each, 6H), 1.19-1.46 (m, 2H), 1.51-2.01 (m, 4H), 2.03-2.25 (m, 2H), 2.57 (dd, J=10.4, 12.8 Hz, 0.3H), 2.75-2.88 (m, 0.6H), 2.92-3.10 (m, 1H), 3.65-4.08 (m, 3.6H), 4.27-4.40 (dm, 0.3H), 5.98 & 6.00 (s & s, 2H), 6.18 (pseudo t, J=8.4 & 9.2 Hz, 1H), 6.32 (pseudo d, J=8.4 Hz, 1H), 7.11-7.21 (m, 1H). MS 316 (MH+)
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].N1C=CC=CC=1>C(O)C>[C:1](=[N:16][OH:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C(c1ccccc1)c1ccccc1
Yield: 73 %

Procedure:
A solution of benzophenone (10.0 g), hydroxylamine hydrochloride (10.0 g), pyridine (50 ml), and absolute ethanol (50 ml) was pumped through the CMR (15 ml/min; 155°-60° C., 700 kPa). The effluent was cooled and the solvent removed by rotary evaporation, and the residue stirred with cold water (50 ml). The crued oxime was filtered off and recrystallised from ethanol to afford pure product (8.0 g; 73% yield), m.p. 140.5°-141° C., cf lit.5 for a batchwise preparation by microwave heating.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4](=[O:19])[CH:3]=1.[N:20]([O-])=[O:21].[Na+]>O>[CH2:8]([N:7]1[C:2]([NH2:1])=[C:3]([N:20]=[O:21])[C:4](=[O:19])[N:5]([CH2:16][CH2:17][CH3:18])[C:6]1=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCn1c(=O)cc(N)n(Cc2ccccc2)c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCCn1c(=O)c(N=O)c(N)n(Cc2ccccc2)c1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
2.0 g (7.7 mmol) of 6-amino-1-benzyl-3-propyluracil are heated to B0° C. in 15 ml of water and mixed with a solution of 0.55 g of sodium nitrite in 3 ml of water. After the addition of 1 ml of glacial acetic acid-a red solid is precipitated. The pH is adjusted to 4 and the suspension is stirred for a further 30 minutes at 80° C. After cooling, the crystals are filtered under suction and washed with water. 1.9 g of the title compound are obtained in the form of reddish-violet crystals (86% of theory), m.p. 208°-212° C./decomposition.
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=O)[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[C:22]1([CH3:28])C=CC=CC=1>CN(C)C1C=CC=CC=1>[CH3:2][N:1]1[CH2:28][CH2:22][N:11]([C:10]2[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:11]=2)[CH2:5][CH2:6]1
Reactant: Cc1ccccc1
Reactant: O=C1Nc2cccnc2Sc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CN1CCN(C2=Nc3cccnc3Sc3ccccc32)CC1

Procedure:
3 g 5H, 6H-pyrido(2,3-b)benzo-1,4-thiazepine-6-one are refluxed with an excess of phosphorous oxychloride and 5 drops of N,N-dimethylaniline for 20 hours. The solution is taken up with anhydrous toluene and evaporated to dryness. The residue is taken up with 5 ml anhydrous toluene and an excess of N-methylpiperazine is added. This mixture is then refluxed for 2-4 hours. Once the reaction is terminated, the solvent is eliminated. The colored mass is taken up with chloroform and washed two times with water. The chloroformic phase is decolored with carbon and dried. After concentration into a small volume, the mixture is passed through a silica column (Woelm act III). The eluent phase is acetone. Once separated, the different phases containing the above mentioned product are evaporated to dryness. The residue is recrystallized in petrolein 100/140. The melting point is 134° C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:33])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:33])[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2cc(C)ccc2n(Cc2ccc(F)cc2)c1=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2Cc1ccc(F)cc1
Yield: 92.2 %

Procedure:
Cyclohexylamine (3.22 mL, 28.14 mmol) was added to a solution of Compound 16 (5.0 g, 14.07 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 5.3 g (93%) of yellow solids. M.P. 156° C. 1H NMR (DMSO-d6): δ 1.24 (m, 1H), 1.37 (m, 4H), 1.57 (m, 1H), 1.68 (m, 2H), 1.88 (m, 2H), 2.36 (s, 3H), 3.87 (m, 1H), 5.49 (s, 2H), 7.11 (m, 2H), 7.22 (m, 2H), 7.36 (d, J=8.7 Hz, 1H), 7.51 (dd, J=1.6, 8.7 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 10.39 (s, 1H). EIMS m/z 409 (M+1), 431 (M+23).
Reaction SMILES: [ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.[CH2:37]([NH:44][C:45](=[O:53])[C:46]1[CH:51]=[CH:50][CH:49]=[N:48][C:47]=1[Cl:52])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[ClH:52].[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:47]4[N:48]=[CH:49][CH:50]=[CH:51][C:46]=4[C:45]([NH:44][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:53])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: O=C(NCc1ccccc1)c1cccnc1Cl
Agent: Cl
Product: O=C(NCc1ccccc1)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Yield: 15.8 %

Procedure:
4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.043 g, 0.18 mmol, Compound C of Example 1) was converted to the title compound (0.015 g, 17%) in a manner similar to the preparation of 4-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide hydrochloride salt (Compound D of Example 1), except that N-benzyl-2-chloronicotinamide (Maybridge, 0.043 g, 0.18 mmol) was used instead of 4-chloro-N-(2,4-difluorophenyl)nicotinamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH2:21](Br)[CH:22]=[CH2:23]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH2:23][CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Product: C=CCN1C(=Nc2ccc([N+](=O)[O-])cc2C)SCC12CCCC2

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with allyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-(prop-1-en-3-yl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:6]1[O:7][C:8]([CH3:11])=[N:9][N:10]=1.[Cl-].[C:16]([O:20][C:21](=[O:24])[CH2:22][Zn+])([CH3:19])([CH3:18])[CH3:17]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:11][C:8]1[O:7][C:6]([CH2:5][C:4]2[CH:3]=[C:2]([CH2:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:24])[CH:14]=[CH:13][CH:12]=2)=[N:10][N:9]=1
Reactant: Cc1nnc(Cc2cccc(Br)c2)o1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cc1nnc(Cc2cccc(CC(=O)OC(C)(C)C)c2)o1
Reaction time: 20 h
Yield: 59.5 %

Procedure:
To a solution of 2-(3-bromobenzyl)-5-methyl-1,3,4-oxadiazole 1105 (0.50 g, 1.97 mmol) in dioxane (1 mL), under an atmosphere of Argon, was added Bis(tri-t-butylphosphine)palladium(0) (0.15 g, 0.295 mmol) followed by the addition of 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in diethyl ether, 4.92 mmol, 9.84 mL). The mixture was allowed to stir under Argon for 20 hours and the volatiles were removed under reduced pressure. The residue was taken up in EtOAc (10 mL) and washed with water (2×5 mL), brine (2×5 mL) and dried over Na2SO4. The Na2SO4 was removed by filtration and the volatiles removed under reduced pressure. The crude material was purified by normal phase chromatography 0-50% EtOAc/Hexanes to give 0.338 g of tert-butyl 2-(3-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)acetate 1106. 1H NMR 300 MHz CDCl3: δ 7.24 (m, 4H), 4.12 (s, 2H), 3.51 (s, 2H), 2.46 (s, 3H), 1.43 (s, 9H).