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]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([S:23][C:24]2[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2cccc(O)c2)c(N)c1
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3cccc(O)c3)ccnc2n1

Procedure:
The product from Example 2g (275 mg, 1.33 mmol) was reacted with the product from Example 52b (307 mg, 1.33 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (305 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3 H) 1.75-1.94 (m, 2 H) 2.38 (s, 3 H) 2.98 (t, J=7.35 Hz, 2 H) 6.30 (d, J=6.99 Hz, 1 H) 6.49-6.66 (m, 3H) 6.91-7.04 (m, 1 H) 7.29-7.44 (m, 3 H) 7.79 (d, J=8.82 Hz, 1 H) 8.39 (d, J=7.35 Hz, 1 H) 8.96 (d, J=8.46 Hz, 1 H) 9.57 (s, 1 H) 10.95 (s, 1 H) 14.34 (s, 1 H); MS (ESI+) m/z 402 (M+H−TFA)+.
Reaction SMILES: [CH3:1][C:2]([CH3:59])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:56])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:55])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C:45]4([C:48]5[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[CH:49]=5)[CH2:47][CH2:46]4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:58])[CH3:57])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[Cl:54][C:50]1[CH:49]=[C:48]([C:45]2([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]34[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]3[C@@H:25]3[C@@:20]([CH3:55])([CH2:21][CH2:22]4)[C@@:19]4([CH3:56])[C@@H:28]([C@:29]5([CH3:32])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:58])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:59])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)[CH2:47][CH2:46]2)[CH:53]=[CH:52][CH:51]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3cccc(Cl)c3)CC2)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3cccc(Cl)c3)CC2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(3-chlorophenyl)cyclopropyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (200 mg, 0.241 mmol) in dichloromethane (5 mL) stirred at rt was added TFA (3 mL, 38.9 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was evaporated to get the crude product which was purified by preparative-HPLC to get the product (100 mg, 53%) as a light white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.18 (br. s., 1H), 8.78 (s, 1H), 7.38-7.18 (m, 2H), 7.13 (d, J=5.3 Hz, 1H), 7.08-6.96 (m, 1H), 6.65 (d, J=15.8 Hz, 1H), 5.92 (d, J=16.1 Hz, 1H), 4.39 (dd, J=4.8, 11.0 Hz, 1H), 3.31-3.08 (m, 1H), 2.85-2.72 (m, 1H), 2.63-0.58 (m, 53H); LC/MS: m/z calculated 773.4. Found 772.3 (M−1)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1
Reactant: Fc1ccccc1S
Reactant: O=C(O)c1coc(Br)c1
Product: O=C(O)c1coc(Sc2ccccc2F)c1

Procedure:
Following the procedure of Example 13, o-fluorothiophenol (4.02 g., 31.4 mmoles) was reacted with 5-bromofuran-3-carboxylic acid. Isolation according to the procedure of Example 16 gave crude product as an oil. The product was chromatographed on silica gel with ethyl acetate-1/hexane-5/5% acetic acid as eluant. Combination of clean middle cuts, evaporation to dryness and recrystallization from methanol/water gave purified 5-(2-fluorophenylthio)furan-3-carboxylic acid (266 mg., m.p. 100°-103° C., m/e 238).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32]>N1C=CC=CC=1>[NH2:1][C:2]1[NH:3][C:4](=[S:32])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=S)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 135 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of 25 (1 g, 2.26 mmol) in pyridine (50 mL) was added at room temperature P2S5 (2.13 g, 4.79 mmol). The solution was refluxed gently (bath temperature 130-140° C.) for 29 h. The reaction mixture was evaporated to dryness in vacuo. The excess P2S5 was decomposed by the addition of H2O (40 mL) at 60° C. The mixture was stirred for 1 h at 60° C. and then cooled to room temperature. The mixture was extracted with CHCl3 (3×40 mL). The dried (MgSO4) organic layer was evaporated to yield a syrup, which was purified by flash column chromatography (silica, acetone/CHCl3=15%) to afford 0.93 g (90%) of 77 as a yellow solid: 1H (400 MHz, d6-DMSO) δ 12.50 (s, 1H), 7.35 (br s, 2H), 5.89 (m, 2H), 5.51 (t, J=6.4 Hz, 1H), 4.36 (dd, J=12.0, 4.0 Hz, 1H), 4.24 (m, 1H), 4.10 (q, J=6.0 Hz, 1H), 2.07 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H); MS (+)-ES [M+H]+ m/z 459.3.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl-:12].[NH2:13][N:14]1[CH:18]=[CH:17][N+:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)=[C:15]1[CH2:30][CH3:31]>C(O)(=O)C>[Cl-:12].[CH2:30]([C:15]1[N:14]([N:13]=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=2)[CH:18]=[CH:17][N+:16]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1)[CH3:31]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCc1n(N)cc[n+]1NCc1ccc(N(C)C)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1NCc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.5 g (3.38 mmol) of p-dimethylaminobenzaldehyde is added to a solution of 1.0 g (3.38 mmol) of 3-amino-1-[[p-(dimethylamino)benzyl]amino]-2-ethylimidazolium chloride in 15 ml of glacial acetic acid, the mixture is stirred at room temperature for 24 hours, the solution is evaporated and the crude product is chromatographed on 60 g of silica gel (particle size 0.063-0.200 mm) while eluting with methylene chloride/methanol (3:1 v/v). After recrystallizing the resulting material from ethanol/ether there is obtained 2-ethyl-1-[[p-(dimethylamino)benzyl]-amino]-3-[[p-(dimethylamino)benzylidene]amino]imidazolium chloride of melting point 201°-202°.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][C:7]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:5].[F:38][C:39]1[CH:44]=[CH:43][C:42]([C:45](=O)[CH2:46][N:47]2[C:51]([CH3:52])=[CH:50][N:49]=[CH:48]2)=[CH:41][CH:40]=1>>[F:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([CH2:46][N:47]2[C:51]([CH3:52])=[CH:50][N:49]=[CH:48]2)=[CH:10][C:9]2[CH:30]=[CH:31][C:6]([C:4]([O:3][CH3:2])=[O:5])=[C:7]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:8]=2)=[CH:41][CH:40]=1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccccc1
Reactant: Cc1cncn1CC(=O)c1ccc(F)cc1
Agent: [Br-]
Product: COC(=O)c1ccc(C=C(Cn2cncc2C)c2ccc(F)cc2)cc1-c1ccccc1
Yield: 76 %

Procedure:
Product from step E was reacted with 1-(4-fluorophenyl)-2-(5-methylimidazol-1-yl)-ethanone using methodology as described in Example 4, compound a), step B and purified by flash chromatography eluting with CH2Cl2/EtOH (93/7) to give methyl 4-[2-(4-fluorophenyl)-3-(5-methylimidazol-1-yl)-prop-1-enyl]-2-phenyl-benzoate as an oil. Yield=76%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].O.[F:14][C:15]([F:19])([F:18])[CH:16]=O.C(=O)CC>>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:16][C:15]([F:19])([F:18])[F:14]
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: O=CC(F)(F)F
Solvent: O
Solvent: CCC=O
Product: COc1cc([N+](=O)[O-])ccc1NCC(F)(F)F

Procedure:
This compound was prepared in a similar fashion as that described in Example 2, General Procedure IV but using 2-amino-5-nitroanisole and trifluoroacetaldehyde hydrate in place of Compound 200 and propionaldehyde. Compound 465 was isolated as a light brown crystalline solid after recrystallization (1:1 EtOAc:hexanes, 30 mL): Rf 0.52 (2:1 hexanes:EtOAc); 1H NMR (400 MHz, acetone-d6) 7.87 (dd, J=8.9, 2.4, 1H), 7.69 (d, J=2.4, 1H), 6.96 (d, J=8.9, 1H), 6.38 (broad s, 1H), 4.20 (qd, J=9.3, 7.1, 2H), 4.00 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:34]1(=[O:44])[N:38]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12
Reactant: OC#CCCCCc1cccc(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C#CCCCCc1cccc(Cl)c1
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A solution of 6-(3-chlorophenyl)hexyn-1-ol (11.5 g, 55 mmol), triphenylphosphine (14.5 g, 55 mol) and phthalimide (8.1 g, 55 mol) in dry THF (110 ml) was treated with a solution of DEAD (9.6 g, 55 mmol) in THF (20 ml) over several minutes. After 16 h, volatiles were removed in vacuo and the residue treated with ether. The precipitated solid was removed, the filtrate evaporated and the residue purified by flash chromatography on silica using dichloromethane as eluant. Evaporation of the appropriate fractions gave the product as a solid (16.5 g, 89%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[N:6]=[C:7]([NH2:10])[S:8][CH:9]=1.[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](O)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[N:6]=[C:7]([NH:10][C:19](=[O:20])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:8][CH:9]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1csc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1csc(NC(=O)C(c2ccccc2)c2ccccc2)n1
Reaction time: 16 h

Procedure:
(2-Amino-thiazol-4-yl)-acetic acid methyl ester (45 mg, 0.20 mmol) and diphenyl-acetic acid (37 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (29.4 mg, 0.0802 mmol, 40. %). ESI-MS m/z calc. 380.1. found 381.3 (M+1)+ Retention time 3.28 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O>[C:1]([O:5][C:6]([N:8]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1coc(-c2ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cc(-c2nc(C(=O)O)co2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
To a solution of ethyl 2-(2-((tert-butoxycarbonyl) (2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxylate (13 g) in ethanol (100 mL) was added 2M aqueous sodium hydroxide solution (30 mL). The reaction mixture was stirred at room temperature for 16 hr, diluted with water, acidified with 1M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether, and dried under reduced pressure to give the title compound (10 g).
Reaction SMILES: [CH2:1]([N:3]1C(C2SC3N=CN=C(SC)C=3C=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1)C.[CH3:25][S:26][C:27]1[C:28]2[O:35][C:34]([CH:36]=O)=[CH:33][C:29]=2[N:30]=[CH:31][N:32]=1.CSC1C2C=C(C=O)SC=2N=CN=1.CN>>[CH3:1][N:3]1[C:36]([C:34]2[O:35][C:28]3[C:27]([S:26][CH3:25])=[N:32][CH:31]=[N:30][C:29]=3[CH:33]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1
Reactant: CCn1cnc(-c2ccccc2)c1-c1cc2c(SC)ncnc2s1
Reactant: CSc1ncnc2cc(C=O)oc12
Agent: CN
Agent: CSc1ncnc2sc(C=O)cc12
Product: CSc1ncnc2cc(-c3c(-c4ccccc4)ncn3C)oc12

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 70 but using 4-(methylthio)furo[3,2-d]pyrimidine-6-carbaldehyde (Intermediate 86) in place of 4-(methylthio)thieno[2,3-d]pyrimidine-6-carbaldehyde (Intermediate 15) and methylamine in place of ethylamine. Pale yellow solid (105 mg, 54%);
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][N:13]([NH2:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(N(CC)CC)C>ClCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:21][N:13]([CH3:12])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(NC(=O)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A solution of 4-cyanobenzoyl chloride (2.5 g) in dichloromethane (50 ml) was added dropwise with stirring over 45 minutes to an ice-cold solution of t-butyl 2-methylcarbazate (2.0 g) in dichloromethane (50 ml) containing triethylamine (1.9 ml). The reaction mixture was stirred at ambient temperature for 2 hours and then washed with water, dilute aqueous sodium bicarbonate solution and brine, dried (MgSO4) and evaporated. The residue was crystallised from ethyl acetate to give t-butyl 3-(4-cyanobenzoyl)-2-methylcarbazate (2.5 g) as a white solid; m.p. 179°-181° C.; NMR Spectrum (DMSO-d6) 1.27-1.55 (9H, br s), 3.10 (3H, br s), 8.00 (4H, s), 10.90 (1H, s); Mass Spectrum m/Z 276 (M+H)+ ; Elemental Analysis: calculated for C14H17N3O3 : C, 61.1%; H, 6.2%; N, 15.3%; found: C, 61.6%; H, 6.2%; N, 15.5%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH2:15]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>C1C=CC=CC=1>[Cl:22][CH2:15][C:14]1[CH:13]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(OCCCCc2ccccc2)c1
Solvent: c1ccccc1
Product: ClCc1cccc(OCCCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
m-(4-Phenylbutoxy)benzyl alcohol (510 mg) was dissolved in 5 ml of benzene, 1.4 g of thionyl chloride was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give 520 mg of m-chloromethyl-(4-phenylbutoxy)benzene. This compound was then treated by the procedure of Reference Example 4 to give 470 mg of m-(4-phenylbutoxy)benzylamine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[CH:10][C:11]([OH:13])=O)[CH2:7][CH2:8][CH2:9][C:2]1=2.CN(C=O)C.[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH2:21]([N:20]([CH3:19])[C:11](=[O:13])/[CH:10]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:2]2[S:1][CH:5]=[CH:4][C:3]\1=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)C=C1CCCc2sccc21
Reactant: CNCc1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)/C=C1\CCCc2sccc21
Temperature: 25 °C
Yield: 59.7 %

Procedure:
A solution of a mixture E/Z of 2-(6,7-dihydrobenzo[b]thiophen-4(5H)-ylidene)acetic acid (0.38 g, 1.96 mmol) in thionyl chloride (3 mL) and a catalytic amount of DMF is refluxed for 5 min. The solvent is evaporated at reduced pressure and the residue is slowly added to a solution of N-methyl-N-benzylamine (0.24 g, 1.96 mmol) and triethylamine (0.5 mL) in dry CH2Cl2 (15 mL) cooled in an ice bath and stirred at room temperature monitoring the reaction by TLC. The solution is washed with water and the organic phase is dried and evaporated under reduced pressure, and the resulting crude is purified by column chromatography, giving (E)-N-benzyl-2-(6,7-dihydrobenzo[b]thien-4(5H)-ylidene)-N-methylacetamide (0.35 g, 1.17 mmol, 60%, viscous oil). 1H NMR (300 MHz, CDCl3): δ 1.95 (m, 2H), 2.87 (m, 4H), 3.00 (s, 3H), 4.65 (s, 2H), 6.34 (s, 1H), 7.04 (d, J=5.3 Hz, 1H), 7.09 (d, J=5.3 Hz, 1H), 7.23-7.38 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([OH:15])=O)=[N:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl.Cl.[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[F:29])[N:25]=[C:24]([NH:30][CH2:31][CH2:32][NH:33][CH3:34])[CH:23]=[N:22]2>>[F:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[F:29])[N:25]=[C:24]([NH:30][CH2:31][CH2:32][N:33]([CH3:34])[C:13]([C:9]1[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:12][NH:11][N:10]=1)=[O:15])[CH:23]=[N:22]2
Reactant: CNCCNc1cnc2cc(F)c(F)cc2n1
Reactant: O=C(O)c1n[nH]cc1-c1ccc(F)cc1
Agent: Cl
Product: CN(CCNc1cnc2cc(F)c(F)cc2n1)C(=O)c1n[nH]cc1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 4-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (43 mg, 0.21 mmol) and N-(6,7-difluoro-quinoxalin-2-yl)-N′-methyl-ethane-1,2-diamine.dihydrochloride, D2 (65 mg, 0.21 mmol) according to the procedure described for Example 1, as a yellow solid (65 mg, 71%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[CH:2]([CH3:4])[CH3:3].[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[C:13]([C:14](=[O:18])[CH:15]([CH3:16])[CH3:17])=[C:5]1[CH2:1][CH:2]([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc2c(C(=O)C(C)C)c(CC(C)C)[nH]c2c1
Reactant: Clc1ccccc1CBr
Product: COC(=O)c1ccc2c(C(=O)C(C)C)c(CC(C)C)n(Cc3ccccc3Cl)c2c1
Yield: 86.9 %

Procedure:
Methyl 1-(2-chlorobenzyl)-2-isobutyl-3-isobutyrylindole -6-carboxylate (258 mg) was prepared from methyl 2-isobutyl-3-isobutyrylindole-6-carboxylate (210 mg) and 2-chlorobenzyl bromide (157 mg) in a similar manner to that of Example 1.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].[CH2:18]([CH:23]1[CH2:29][CH:28]2[NH:30][CH:25]([CH2:26][CH2:27]2)[CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]>CCN(CC)CC>[CH2:18]([CH:23]1[CH2:24][CH:25]2[N:30]([CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]3[C:10]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:16])[CH:28]([CH2:27][CH2:26]2)[CH2:29]1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Cc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Reactant: CCCCCC1CC2CCC(C1)N2
Solvent: CCN(CC)CC
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(C)cc21
Yield: 69.3 %

Procedure:
Crude (S)-4-(3-Iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one (0.15 g), Et3N (0.5 mL) and 3-pentyl-8-azabicyclo[3.2.1]octane (95 mg, 5.2 mmol) were reacted according to GP17. Flash CC (SiO2; CH2Cl2/I-PrOH 92:8) gave the title compound (0.12 g, 68%). 1H NMR (CD3OD) δ 7.06 (s, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.81 (brd, J=8.0 Hz, 1H), 4.52 (ABq, J=14.8, 27.2 Hz, 2H), 4.06 (dd, J=5.6, 14.2 Hz, 1H), 4.96 (dd, J=8.8, 14.2 Hz, 1H), 3.16-3.02 (m, 2H), 2.34-2.07 (m, 7H), 2.31(s, 3H), 2.04-1.81 (m, 3H), 1.70-1.55 (m, 3H), 1.46-1.21 (m, 10H), 0.92-0.85 (m, 6H); 13C NMR (CD3OD) δ 167.2, 145.1, 133.6, 129.4, 125.5, 117.7, 117.5, 68.7, 61.6, 60.2, 58.6, 46.1, 39.6, 37.2, 36.9, 33.1, 32.4, 29.6, 29.5, 28.5, 27.8, 23.7, 21.18, 17.0, 14.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:13][CH:14]([O:24]C1CCCCO1)[CH2:15][P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[O:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5])[CH3:2].Cl>C(O)C>[CH2:1]([O:3][C:4]([N:6]([CH2:13][CH:14]([OH:24])[CH2:15][P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[O:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)ON(CC(CP(=O)(OCC)OCC)OC1CCCCO1)C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)ON(CC(O)CP(=O)(OCC)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A mixture of diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2-(tetrahydro-2H-pyran-2-yloxy)propylphosphonate (54.0 g.), ethanol (100 ml.) and 0.1 N hydrochloric acid (100 ml.) was stirred for 4 hours at ambient temperature. After the reaction was completed, the ethanol was distilled off from the reaction mixture under reduced pressure to give an aqueous solution, which was extracted three times with ethyl acetate (200 ml. once and 50 ml. twice). The combined extracts were washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated to dryness under reduced pressure to give oily diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2-hydroxypropylphosphonate (39.25 g.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[CH:14]=[N:15][CH:16]=3)=[N:9][N:8]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C:5]2=[CH:6][N:7]=1.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](B(O)O)[CH:38]=1.C(#N)C.C([O-])(=O)C.[K+]>O.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[C:13]([N:17]5[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:19][CH2:18]5)[CH:14]=[N:15][CH:16]=4)=[N:9][N:8]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)[C:5]3=[CH:6][N:7]=2)[CH:38]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4cnc(Br)cc34)c2)CC1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)c2)CC1

Procedure:
To a mixture of tert-butyl 1-(5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (45.0 mg, 0.0807 mmol), 3-Pyridylboronic acid (29.8 mg, 0.242 mmol) and 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (9.888 mg, 0.01211 mmol) in Acetonitrile (1.01 mL, 19.4 mmol) was added 1.0 M of Potassium acetate in Water (0.121 mL) and 1.0 M of Sodium carbonate in Water (0.121 mL). The reaction mixture was irradiated in microwave at 125° C. for 20 min. The reaction was filtered thru celite. The filtrate was washed H2O and brine. The organic layer was dried with Na2SO4, filtered, and concentrated to give tert-butyl 1-(5-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate.