Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[N:23]O)[C:14]=2[CH:13]=[CH:12][CH:11]=1>[Ni].C(O)C.O1CCCC1>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([NH2:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2cccnc2[nH]1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3nc4cccnc4[nH]3)cccc21
Yield: 85.4 %

Procedure:
Carry out the procedure as in Example 6, starting from 1.30 g of 4-(3H-imidazo[4,5-b]pyridin-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the preceding stage, and 2.45 mg of Raney Nickel in 65 ml of ethanol and 65 ml of tetrahydrofuran for 5 hours at 60° C. under a hydrogen pressure of 1 bar. After purification by making a paste in diisopropyl ether, we obtain 1.06 g of 4-(3H-imidazo[4,5-b]pyridin-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a white powder, with the following characteristics:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:20]1[CH:25]([C:26]#[N:27])[CH2:24][CH2:23][CH2:22][CH:21]1[C:28]#[N:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)P(=O)(N(C)C)N(C)C.Br[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>O1CCCC1>[CH2:13]([N:20]1[CH:25]([C:26]#[N:27])[CH2:24][CH2:23][CH2:22][C:21]1([CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:28]#[N:29])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#CC1CCCC(C#N)N1Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC1(C#N)CCCC(C#N)N1Cc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 378.000 mmol of diisopropylamine in 180 ml of tetrahydrofuran is admixed dropwise at −78° C. with 179.000 mmol of n-butyllithium (1.6M in hexane). The yellowish solution is stirred at −20° C. for 30 minutes then cooled again to −78° C. This solution is admixed dropwise at −78° C. with a solution of 126.000 mmol of 1-benzylpiperidine-2,6-dicarbonitrile [98195-08-5] and 138.600 mmol of hexamethylphosphorictriamide in 50 ml of tetrahydrofuran. The mixture is subsequently stirred at this temperature for 30 minutes. Then a solution of 130.000 mmol of tert-butyl bromoacetate in 50 ml of tetrahydrofuran is added dropwise. The mixture is subsequently stirred at −78° C. for an hour, the cold bath is removed, and the temperature is allowed to increase slowly overnight to room temperature. The reaction mixture is admixed with aqueous saturated ammonium chloride solution, the organic phase is separated off and the aqueous phase is extracted repeatedly with diethyl ether. The combined organic phases are washed with water and brine, dried with sodium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60 F) and identified on the basis of the Rf value.
Reaction SMILES: [N:1]([C:4]1[N:11]=[CH:10][CH:9]=[C:8]([NH:12][C@H:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:14])[C:5]=1[C:6]#[N:7])=[N+]=[N-].O>C1COCC1.CP(C)C>[NH2:1][C:4]1[N:11]=[CH:10][CH:9]=[C:8]([NH:12][C@H:13]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:14])[C:5]=1[C:6]#[N:7]
Reactant: C[C@@H](CCc1ccccc1)Nc1ccnc(N=[N+]=[N-])c1C#N
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CCc1ccccc1)Nc1ccnc(N)c1C#N
Yield: 68.4 %

Procedure:
Prepared according to the methods above using (S)-2-azido-4-((4-phenylbutan-2-yl)amino)nicotinonitrile (59.1 mg, 0.192 mmol) in THF (2.0 mL), trimethylphosphine 1.0 M in tetrahydrofuran (0.960 mL, 0.960 mmol) and water (0.017 mL, 0.960 mmol) at rt for 3.5 hours to give the desired product as a white solid (35 mg). LC/MS (267, [M+H]+); 1H NMR (400 MHz, CHLOROFORM-d) δ 7.78 (d, J=6.3 Hz, 1H), 7.35-7.26 (m, 2H), 7.26-7.19 (m, 1H), 7.19-7.11 (m, 2H), 5.83 (d, J=6.3 Hz, 1H), 5.13 (br. s., 2H), 4.70 (d, J=8.0 Hz, 1H), 3.65-3.51 (m, 1H), 2.71 (t, J=7.7 Hz, 2H), 1.98-1.80 (m, 2H), 1.32-1.23 (m, 3H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:59][C:60]([CH3:62])=O>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][N:27]([CH:60]([CH3:62])[CH3:59])[C@@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)=O
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN[C@@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)[C@@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To crude (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-((S)-3-methylpiperazin-1-yl)pyrimidin-4-yl)benzo[d]thiazol-6-yl)acetate (43.8 mg, 0.075 mmol) and sodium triacetoxyborohydride (80.1 mg, 0.377 mmol) in DMF (1 mL) was added acetic acid (22.7 mg, 21.6 μL, 0.377 mmol) and acetone (17.6 mg, 22.2 μL, 0.302 mmol). The reaction mixture was heated at 60° C. for 6.5 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent) and concentrated. Purification by flash column chromatography on silica gel using 100:5:1 EtOAc/MeOH/NH4OH (0 to 100%) in EtOAc provided the product. LCMS-ESI+ calc'd for C33H41ClN5O3S (M+H1): 622.3; Found: 622.2 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:17])[CH:13]([CH2:15][CH3:16])[CH3:14].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[CH3:14][CH:13]([CH2:15][CH3:16])[CH2:12][O:17][C:1]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:10]
Reactant: CCC(C)CO
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC(C)COC(=O)c1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
315 g of said terephthalaldehydic acid chloride dissolved in 400 ml of toluene was dropped into an ice-cooled mixed solution of commercially available S(-)-2-methylbutanol (optically active amyl alcohol) and 230 g of pyridine, and heated under reflux for 2 hours. The reaction solution was cooled to room temperature and further cooled with ice, and acidified by adding 6N hydrochloric acid thereto to remove pyridine in the organic layer. The organic layer was then washed successively with water, 2N aqueous sodium hydroxide solution, and again with water. Toluene as a solvent was distilled off in vacuum, and the remaining reaction product was distilled in vacuum to obtain p-(2-methylbutoxycarbonyl)benzaldehyde (b.p. 118°-124° C./3.5 Torr).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:24][C:25](=[O:35])[C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)=[CH:12][C:13]([O:16][Si](C(C)(C)C)(C)C)=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:24][C:25](=[O:35])[C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)=[O:8])=[CH:36][CH:37]=1
Reactant: CCCc1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2ccc(OC)cc2)cc1
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a solution of N1-(4-methoxybenzoyl)-N2-(4-propylbenzoyl)-4-(tert-butyldimethylsilyloxy)-1,2-benzenediamine (360 mg, 0.69 mmol) in tetrahydrofuran (20 mL) cooled to 0° C. was added a 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1.4 mL, 1.4 mmol). After 15 min, the reaction mixture was diluted with water and partitioned with ethyl acetate. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 10% ethyl acetate/90% methylene chloride to 40% ethyl acetate/60% methylene chloride) to give 239 mg (86%) of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[K+].Cl>O1CCCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:13][CH:14]=1
Reactant: CC(C(=O)O)c1ccc(CC2CCCCC2=O)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(C[C@@H]2CCCC[C@@H]2O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
10.0 g of (±)-2-[4-(2-oxocyclohexylmethyl)phenyl]-propionic acid were dissolved in 150 ml of tetrahydrofuran. The solution was cooled to -78° C. and, whilst maintaining the solution at this temperature and under a stream of nitrogen, 200 ml of K-Selectride (as a 0.5 molar tetrahydrofuran solution) were added dropwise. When the whole of the K-Selectride had been added, the reaction mixture was stirred for 1 hour at 0° C., after which it was cooled to -10° C. and 400 ml of a 0.5N solution of hydrochloric acid was added through a dropping funnel. The reaction mixture was stirred for 1 hour, after which it was extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulphate. The solvent was distilled off, giving 10.5 g of the title compound in the form of crystals. These were recrystallised from a mixture of diethyl ether and hexane, giving the title compound as pure crystals melting at 130°-133° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[CH:29]([CH2:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[O:28]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].B(F)(F)F.CCOCC>C1C=CC=CC=1.CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][C:29](=[O:28])[CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4OC4CCc4ccccc4)cc3)cc2)CC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)CCc4ccccc4)cc3)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-{4′-[3-methyl-4-(3-phenethyl-oxiranyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.421 g, 0.85 mmol) in benzene (4.2 mL) was added boron trifluoride diethyl etherate (1 M in Et2O, 0.94 mL, 0.94 mmol) and the reaction was stirred for 1 hour. The mixture was diluted with EtOAc and H2O, separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>C(OCC)(=O)C.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c2c(-c3cccc(Br)c3)coc2c1C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2c(c1C)OCC2c1cccc(Br)c1
Yield: 82 %

Procedure:
Using 3-(3-bromophenyl)-4,6,7-trimethyl-1-benzofuran obtained in Reference Example 186, the title compound was synthesized in the same manner as in Reference Example 199. Yield 82%. Melting point: 73-74° C. (ethyl acetate-hexane).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([NH:11][C:12](=[O:17])[C:13](Br)([CH3:15])[CH3:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH3:14][C:13]1([CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:11][C:12]1=[O:17]
Reactant: CC(C)(Br)C(=O)Nc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(C)C(=O)Nc2ccccc21
Temperature: 0 °C

Procedure:
A neat mixture of AlCl3 (8.28 g) and the amide obtained in Step 1. above (5 g) is heated slowly to about 135°-140° C. and maintained at this temperature for about 10-15 min. Ice water is added slowly to the reaction mixture and the residue is extracted with ether. The organic extract is washed with 1N HCl, 10% aqueous sodium carbonate, dried, filtered and evaporated affording a solid. The solid is purified by flash chromatography (silica gel; 2% methanol/methylene chloride) affording the desired product as a white crystalline solid, M.P.=151°-152° C.
Reaction SMILES: C1(CCOC2C=CC(C(NC(CC3C=CC(CCC)=CC=3)C(NCCO)=O)=O)=CC=2)CC1.[CH:33]1([CH2:36][CH2:37][O:38][C:39]2[CH:65]=[CH:64][C:42]([C:43]([NH:45]/[C:46](/[C:58]([NH:60][CH2:61][CH2:62][OH:63])=[O:59])=[CH:47]\[C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)=[O:44])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>>[CH:33]1([CH2:36][CH2:37][O:38][C:39]2[CH:65]=[CH:64][C:42]([C:43]([NH:45][CH:46]([CH2:47][C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:57])([F:55])[F:56])=[CH:52][CH:53]=3)[C:58]([NH:60][CH2:61][CH2:62][OH:63])=[O:59])=[O:44])=[CH:41][CH:40]=2)[CH2:34][CH2:35]1
Reactant: O=C(NCCO)/C(=C/c1ccc(C(F)(F)F)cc1)NC(=O)c1ccc(OCCC2CC2)cc1
Agent: CCCc1ccc(CC(NC(=O)c2ccc(OCCC3CC3)cc2)C(=O)NCCO)cc1
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(=O)NCCO)c1ccc(OCCC2CC2)cc1
Yield: 86.9 %

Procedure:
A reaction similar to that described in Example (1 (1e) was conducted using 4-(2-cyclopropylethoxy)-N-{(Z)-1-{[(2-hydroxyethyl)amino]carbonyl}-2-[4-(trifluoromethyl)phenyl]vinyl}benzamide (212 mg) to give 185 mg of the title compound (white powder).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.Br[C:54]1[S:55][CH:56]=[N:57][N:58]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:54]2[S:55][CH:56]=[N:57][N:58]=2)[CH2:25]1
Reactant: Brc1nncs1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CN(c2nncs2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 20 %

Procedure:
The desired compound was prepared according to the procedure of Example A157 using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 2-bromo-1,3,4-thiadiazole as the starting materials in 20% yield. LCMS for C24H23ClN9OS (M+H)+: m/z=520.0.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([CH3:18])=[C:13]([C:15]([NH2:17])=O)[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:15]([C:13]1[N:14]=[C:10]([CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[S:11][C:12]=1[CH3:18])#[N:17]
Reactant: Cc1sc(CNC(=O)OC(C)(C)C)nc1C(N)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1sc(CNC(=O)OC(C)(C)C)nc1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(N-Boc-Aminomethyl)-5-methylthiazole-4-carboxamide (6.8 g, 25 mmol) was introduced into dichloromethane (120 ml). After the mixture had cooled to 0° C. diisopropylethylamine (15.84 g, 122.8 mmol) was added dropwise. Then, a solution of trifluoroacetic anhydride (8.25 g, 39.3 mmol) in dichloromethane (20 ml) was added dropwise at −5° C. in the course of 30 minutes. After the mixture had been stirred for 30 minutes at 0° C., it was warmed to room temperature, and stirring was continued for another 12 hours. The mixture was diluted with dichloromethane (100 ml) and washed with 20% strength citric acid, saturated NaHCO3 [sic] solution and saturated NaCl solution. The organic phase was dried (MgSO4) and concentrated in vacuo. Yield: 6.3 g (25 mmol, quant.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[P:12](=[O:23])([N:20]=[C:21]=[O:22])([S:16][CH2:17][CH2:18][CH3:19])[O:13][CH2:14][CH3:15]>CCOCC>[CH2:14]([O:13][P:12]([NH:20][C:21]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)=[O:22])([S:16][CH2:17][CH2:18][CH3:19])=[O:23])[CH3:15]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCCSP(=O)(N=C=O)OCC
Solvent: CCOCC
Product: CCCSP(=O)(NC(=O)N1CCC(C(=O)OCC)CC1)OCC
Reaction time: 8 h

Procedure:
To a solution of 2.36 g of ethyl 4-piperidine-carboxylate in 50 ml of ether at ambient temperature was added dropwise with stirring 3.14 g of O-ethyl S-n-propyl phosphoroisocyanatidothioate. The mixture was allowed to stir overnight and was then concentrated by evaporation under reduced pressure using a rotary evaporator and then a Kugelrohr apparatus at 55° C. and 13 Pascals pressure. The residue, which was the title compound, amounted to 5.2 g (94 percent of theory) and was an amber colored viscous oil having a refractive index at 25° C. of 1.5083.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:18][C:7]1[C:6]([Cl:8])=[N:5][C:4]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:3][C:2]=1[Cl:1]
Reactant: N#Cc1ccc(Nc2nc(Cl)cc(Cl)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(Nc2nc(Cl)c(Br)c(Cl)n2)cc1
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To 2.11 g of 4-[(4,6-dichloro-2-pyrimidinyl)amino]benzonitrile (0.00796 mol) was added 500 ml of CHCl3 and the mixture was stirred for 30 minutes to allow the dissolution of almost all of starting compound. 1-bromo-2,5-pyrrolidinedione (0.0397 mol) was added in one portion and the reaction mixture was stirred at room temperature. After about 30 minutes, the mixture became a clear orange solution and the reaction became increasingly reddish with time. After 40 hours, TLC and HPLC/MS showed the reaction was complete. The reaction mixture was purified by flash silica gel column chromatography using CH2Cl2 as eluent. The fractions containing the desired product were isolated and the solvent evaporated. The residue was recrystallized from acetonitrile to afford 1.51 g of 4-[(5-bromo-4,6-dichloro-2-pyrimidinyl)amino]benzonitrile, yield 55% (intermediate 1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].[CH3:18][N:19]=[C:20]=[O:21]>CO.O>[CH3:18][NH:19][C:20](=[O:21])[NH:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17]
Reactant: CN=C=O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Solvent: O
Solvent: CO
Product: CNC(=O)NC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of 5'-amino-5'-deoxythymidine (2, 2.40 g, 9.95 mmol) in methanol-water (2.5:1, v/v) at 0° was added methyl isocyanate (0.63 g, 10.95 mmol). The reaction mixture was kept at 0° with stirring for 1 h, allowed to warm up to room temperature, and then clarified by filtration. The filtrate was evaporated to dryness under reduced pressure at a temperature not exceeding 35°, and the residue was then crystallized from methanol at 3° overnight to give 2.14 g (72%) of white fine needles: mp 238-239°. Anal. (C12H18N4O5) C, H, N.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:3]=1.[CH3:27][NH2:28]>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:4]2[N:3]=[C:2]([NH:28][CH3:27])[C:7]([C:8]#[N:9])=[CH:6][C:5]=2[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:21][CH:22]=1
Reactant: CN
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(Cl)nc2-c2ccc(F)cc2)cc1
Product: CNc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C#N
Temperature: 70 °C
Reaction time: 24 h

Procedure:
2-Chloro-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile (Example 7) (200 mg, 0.52 mMol) was charged with methylamine. The solution was shaken for 24 hours at 70° C. and 74 psi by a Parr Shaker. The vessel was cooled to room temperature and vented to allow excess methylamine to evaporate leaving a yellow solid. The solid was washed with methyl alcohol and recrystallized from chloroform: m.p. (DSC): 295.63° C. Anal. Calc'd. for C20H16N3O2SF (381.43): C, 62.98; H, 4.23; N, 11.02. Found: C, 62.59; H, 4.15; N. 10.77.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=1)C1C=CC=CC=1>Br>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=1
Reactant: O=C1C=C(c2ccccc2OCc2ccccc2)CC1
Agent: Br
Product: O=C1C=C(c2ccccc2O)CC1

Procedure:
8.0 g 3-(2-benzyloxy-phenyl)-2-cyclopenten-1-one are stirred in 80 ml of 20% HBr/glacial acetic acid for 1 hour at room temperature. After evaporation of the glacial acetic acid, the residue is dissolved in methylene chloride and neutralized by shaking with a sodium-hydrogen-carbonate solution. After recrystallization from diisopropyl ether/diethyl ether, 3.7 g of 3-(2-hydroxyphenol)-2-cyclopenten-1-one are obtained with a melting point of 162°-165° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[CH:17][C:16]=2[N+:32]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>[Fe]>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)=[CH:17][C:16]=2[NH2:32])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2N)cc1
Yield: 58.5 %

Procedure:
The product from Example 254b (1.1 g, 2.1 mmol) was reacted with Fe and NH4Cl as described for Example 9E to give the desired product (0.6 g, 58.8%).