Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]#[C:21][C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])[CH:18]=3)[N:6]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:5]=2[C:4](=[O:39])[N:3]1[CH2:40][CH2:41][CH3:42].C(=O)([O-])[O-].[NH4+].[NH4+].C1C=CC2N(O)N=[N:55]C=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]#[C:21][C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([NH2:55])=[O:26])[CH:18]=3)[N:6]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:5]=2[C:4](=[O:39])[N:3]1[CH2:40][CH2:41][CH3:42]
Reactant: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4cccc(C(=O)O)c4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4cccc(C(N)=O)c4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.9 %

Procedure:
A mixture of 3-(3-{4-[2,6-dioxo-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-pyrazol-1-yl}-prop-1-ynyl)-benzoic acid (100 mg, 0.17 mmol), ammonium carbonate (33 mg, 0.34 mmol), HOBT (36 mg, 0.24 mmol), N-methyl morpholine (34 mg, 0.34 mmol) were taken in DMF (2 ml), EDCI (130 mg, 0.68 mmol) was added at cold condition and stirred for 18 hrs at room temperature. The reaction mixture was diluted with water (10 ml) and extracted with DCM (3×5 ml), the organic layer was washed with brine (2×10 ml), dried over Na2SO4. The organic solvent was evaporated and the crude product was purified using HPLC to obtain 3-(3-{4-[2,6-Dioxo-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-pyrazol-1-yl}-prop-1-ynyl)-benzamide (33 mg, 18%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:31])(=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH2:32])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([C:36]1[C:37]([N:43]=[CH:44][N:45]([CH3:47])C)=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=1)#N>>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:30])(=[O:31])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH:32][C:47]2[C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[N:38][C:37]=3[N:43]=[CH:44][N:45]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(S(=O)(=O)Nc3ccc(Br)cc3)cc2N)cc1
Product: Cc1ccc2c(Nc3cc(S(=O)(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1

Procedure:
The product from Example 149D was reacted with the product from Example 10B using the procedure described in Example 149E substituting the product from Example 10B for the product from Example 36E to provide {4-[4-(4-Bromo-phenylsulfamoyl)-2-(7-methyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-phenyl}-carbamic acid tert-butyl ester which was deprotected according to the procedure described in Example 149F, followed by silica gel chromatography provided the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.74 (s, 3H), 6.64 (d, J=8.46 Hz, 2H), 6.89 (d, J=8.09 Hz, 1H), 7.05 (d, J=9.19 Hz, 2H), 7.12 (d, J=8.82 Hz, 2H), 7.44 (d, J=8.82 Hz, 2H), 7.63 (dd, J=7.72, 0.74 Hz, 1H), 7.74 (s, 1H), 7.79 (dd, J=7.72, 1.10 Hz, 1H), 8.70-8.83 (m, 1H), 8.88 (d, J=8.09 Hz, 1H), 10.55 (s, 1H); MS (ESI+) m/z 593/595 (M+H)+.
Reaction SMILES: [OH-:1].[Ca+2:2].[OH-:3].[S:4](=[O:6])=[O:5]>>[S:4]([O-:1])([O-:6])=[O:5].[Ca+2:2].[S:4]([O-:3])([O-:1])(=[O:6])=[O:5].[Ca+2:2]
Reactant: [OH-]
Reactant: O=S=O
Agent: [Ca+2]
Product: O=S(=O)([O-])[O-]
Product: O=S([O-])[O-]

Procedure:
injecting dry calcium hydroxide into said humidified gaseous stream such that said calcium hydroxide reacts with sulfur dioxide present therein to form calcium sulfite or calcium sulfate;
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:31](O)[C@@H:12]2[O:13][Si:14]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:15][Si:16]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:17][CH2:18][C@H:11]2[C:10]1=[CH2:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:40])CC)C.C(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:31]([F:40])[C@@H:12]2[O:13][Si:14]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:15][Si:16]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:17][CH2:18][C@H:11]2[C:10]1=[CH2:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: C=C1[C@@H]2CO[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)O[C@H]2[C@H](O)[C@H]1OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C=C1[C@@H]2CO[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)O[C@H]2[C@H](F)[C@H]1OCc1ccccc1

Procedure:
To a solution of alcohol 6 (6.5 g, 13.2 mmol) in anhydrous CH2Cl2, (diethylamino)sulfur trifluoride (DAST, 1.84 mL, 13.9 mmol) was added slowly at room temperature. The reaction mixture was quenched with iced H2O after 20 min. The organic layer was collected and the aqueous phase was extracted with dichloromethane. The organic layer was then combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was used immediately for the next deprotection step. The analytic sample of 8 was obtained by the purification using column chromatography on a silica gel (EtOAc:Hexanes=1:100 to 1:20).[α]24D −104.08° (c 0.51, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.39-7.26 (m, 5H), 5.36 (t, J=2.5 Hz, 1H), 5.20 (dd, J=2.5 and 5.0 Hz, 1H), 4.92 (ddd, J=6.0, 7.5 and 55.0 Hz, 1H), 4.78 (d, J=11.5 Hz, 1H), 4.65 (d, J=11.5 Hz, 1H), 4.31-4.26 (m, 1H), 4.23-4.16 (m, 1H), 4.01-3.92 (m, 1H), 1.08-0.94 (m, 27H); 13C NMR (100 MHz, CDCl3) δ 142.6 (d, J=9.2 Hz), 137.9, 128.4, 127.8, 127.7, 112.7, 103.4 (d, J=189.0 Hz), 80.4 (d, J=21.3 Hz), 73.8 (d, J=19.8 Hz), 71.3, 61.6, 48.8 (d, J=5.3 Hz), 17.5, 17.4, 17.1, 17.0, 16.9, 16.8, 13.4, 13.3, 12.7, 12.5. HR-MS Calcd. for (C26H43FO4Si2+H)+ 495.2762, found 495.2769.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[Cl:10]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[NH2:1][C:2]1[C:7]([Cl:10])=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(N)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(N)ncc1Cl
Product: N#Cc1ccnc(N)c1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 60 %
Yield: 2 %

Procedure:
2-Amino-4-cyanopyridine (8.00 g, 67.2 mmol) was dissolved in DMF (40 mL), and the solution was stirred at 50° C. for 1 hour after adding N-chlorosuccinimide (8.97 g, 67.2 mmol). After the reaction was completed, a sodium hydrogen carbonate aqueous solution was added under ice-cooled condition, and the precipitated solid was collected by filteration. The resulting solid was purified by silica gel column chromatography (chloroform/methanol=95/5→90/10, heptane/ethyl acetate=65/35→50/50) to give 2-amino-5-chloro-4-cyanopyridine (6.23 g, yield 60%) and 2-amino-3-chloro-4-cyanopyridine (0.254 g, yield 2%).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]12[CH2:12][CH:11]([C:13]([OH:15])=O)[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2.C1C=CC=CC=1>ClCCl>[C:5]12[CH2:12][CH:11]([C:13]([Cl:3])=[O:15])[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(O)C1Cc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccccc1
Product: O=C(Cl)C1Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (0.5 ml) was added to a solution of bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid [14381-41-0] (0.001 mol) in dichloromethane. The reaction mixture was refluxed for 1 hour. Then stirred overnight at room temperature. The solvents were co-evaporated 2 times with benzene to obtain bicyclo[4.2.0]octa-1,3,5-triene-7-carbonyl chloride [1473-47-8] which was dissolved in DIPE. The obtained solution was added dropwise to a cooled mixture (0° C.) of N-allyl-2-adamantanamine [24161-63-5] and sodium carbonate in DIPE. The reaction mixture was stirred for 30 minutes on ice and then for 2 hours at room temperature. The mixture was poured out into water and extracted with dichloromethane. The organic layer was filtered through Extrelut™ and the filtrate was evaporated. The residue was purified by flash column chromatography on TRIKONEX FlashTube™ (eluent: CH2Cl2/EtOAc 90/10). The product fractions were collected and the solvents were evaporated, yielding 0.13 g of intermediate 1.
Reaction SMILES: [C:1]([CH:4]([CH2:9][C:10]([N:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C@H:14]([O:29][CH3:30])[CH2:13]1)=O)[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:19]([NH:18][C@H:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:40][C:1]([CH3:2])=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=2)[CH2:13][C@H:14]1[O:29][CH3:30])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C(CC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](OC)C1)C(C)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)sc1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 7.3 %

Procedure:
Methyl cis(±)-2-acetyl-4-(4-{[benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-oxobutanoate obtained in Example (188b) (1.1 g) was dissolved in toluene. Lawesson's reagent (660 mg) was added, and the mixture was stirred at 110° C. for two hours. Further, Lawesson's reagent (330 mg) was added, and the mixture was stirred at 110° C. for two hours. The reaction solution was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10) and recrystallized from methylene chloride/hexane, to obtain 50 mg of the title compound as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH:27]=4)[N:20]=3)=[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:38]1([C:44]2([C:47](O)=[O:48])[CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:37][N:35]([CH3:36])[CH2:34][CH2:33][O:32][C:28]1[CH:27]=[C:26]([NH:25][C:21]2[N:20]=[C:19]([C:18]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:47]([C:44]5([C:38]6[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=6)[CH2:46][CH2:45]5)=[O:48])[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=34)[CH:24]=[CH:23][N:22]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc2c(-c3ccnc(Nc4cccc(OCCN(C)C)c4)n3)c(-c3cccc(N)c3)nn2c1
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(-c3ccnc(Nc4cccc(OCCN(C)C)c4)n3)c(-c3cccc(NC(=O)C4(c5ccccc5)CC4)c3)nn2c1
Reaction time: 16 h
Yield: 40.9 %

Procedure:
4-[2-(3-Aminophenyl)-6-(methyloxy)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine (100 mg, 0.21 mmol), 1-phenylcyclopropanecarboxylic acid (41 mg, 0.25 mmol), and diisopropylethylamine (0.10 mL, 1.0 mmol) were combined in DMF (1 mL) followed by the addition of HATU [O-(7-azabenzotriazole-1 yloxy)tripyrrolidinophosphonium hexafluorophosphate] (78 mg, 0.21 mmol). The mixture was stirred for 2 h at rt after which time additional HATU (80 mg, 0.21 mmol), 1-phenylcyclopropanecarboxylic acid (40 mg, 0.25 mmol), and diisopropylethylamine (0.10 mL, 1.0 mmol) were added. The mixture was stirred for 16 h after which time the mixture was poured into water, extracted with DCM, and the organic phase concentrated and purified by silica get chromatography to afford the title compound as a yellow solid (55 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.24 (s, 1H), 8.53 (d, J=2.1 Hz, 1H), 8.43 (d, J=10.4 Hz, 1H), 8.20 (d, J=5.2 Hz, 1H), 7.85 (br s, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.52 (br s, 1H), 7.39-7.31 (m, 5H), 7.28-7.20 (m, 4H), 7.13 (t, J=8.1 Hz, 1H), 6.51 (dd, J=7.9, 2.3 Hz, 1H), 6.43 (d, J=5.2 Hz, 1H), 3.97 (t, J=6.5 Hz, 2H), 3.86 (s, 3H), 2.65-2.60 (m, 2H), 2.20 (s, 6H), 1.42 (m, 2H), 1.09 (m, 2H). ES-LC/MS m/z=640 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18]>[Cu]>[CH:16]1[CH:15]=[C:14]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]([F:18])=[CH:12][CH:17]=1
Reactant: Fc1ccccc1Br
Reactant: Oc1ccc(F)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Product: Fc1ccc(Oc2ccccc2F)cc1
Reaction time: 0.17 h

Procedure:
4-Fluorophenol (1.12 g, 10 mmol) was heated to 50° C. KOH (0.56 g, 10 mmol) was added thereto, and the reaction mixture was stirred over 10 min. 2-Bromofluorobenzene (1.75 g, 10 mmol) and powdered copper (0.64 g) were added thereto. The reaction mixture was stirred at 110° C. over a further 2 hours. Unconverted 2-bromofluorobenzene was removed by means of vacuum distillation. The product was subsequently purified on a silica gel-packed column with n-hexane as the mobile phase. Yield: 1.0 g (4.8 mmol, 48%) of the product with a purity of 97.3%, determined by means GC. 1H NMR: δ 6.92-7.21 multiple peaks. 13C NMR: δ 158.0 (d, 1JC-F=341.2, C-4′), 154.8 (d, 1JC-F=348.5, C-2), 153.2 (d, 4JC-F=3.1, C-1′), 144.2 (d, 2JC-F=11.3, C-1), 124.7 (m, C-6, C-2′ and C-6′), 121.3 (d, 4JC-F=1.7, C-5), 118.9 (d, 3JC-F=8.3, C-4), 117.1 (d, 2JC-F=18.3, C-3), 116.2 (d, 2JC-F=23.8, C-3′ and C-5′).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([S:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][OH:16])[N:13]=1)([CH3:7])[CH3:6])[CH3:2].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([S:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([Br:18])=[CH:20][CH:21]=2)[N:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)(C)Sc1nc(CCO)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Sc1nc(CCOCc2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid ethyl ester (1.6 g) synthesized in Example 155-1 and 4-bromobenzylbromide (1.7 g) were dissolved in N,N-dimethylformamide (30 mL), potassium tert-butoxide (0.72 g) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 3:1) to give the title compound (1.3 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:3]=1.[OH:16]S(O)(=O)=O.[OH2:21]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([OH:16])=[O:21])=[C:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc(F)cc1-c1ncccn1
Reactant: O
Product: O=C(O)c1ccc(F)cc1-c1ncccn1
Temperature: 100 °C

Procedure:
4-Fluoro-2-(pyrimidin-2-yl)benzonitrile (85 mg, 0.4 mmol) was hydrolyzed to the acid in water (1 mL) by addition of 18 M H2SO4 (1 mL). The reaction was heated at 100° C. for 10 min, then cooled to 23° C., and extracted with EtOAc (3×5 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. This material was used crude in subsequent reactions.
Reaction SMILES: [K].[O-:2][CH2:3][CH2:4]CC.[Br:7][C:8]1[NH:9][C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14].[O:17]1CC[CH2:19][CH2:18]1>>[Br:7][C:8]1[N:9]([CH2:19][C:18]([O:2][CH2:3][CH3:4])=[O:17])[C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14]
Reactant: CCCC[O-]
Reactant: C1CCOC1
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Agent: [K]
Product: CCOC(=O)Cn1c(Br)c(Br)c(C#N)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium! -butoxide (0.75 g, 6.7 mmol) is added in portions at room temperature to a solution of 2,4,5-tribromopyrrole-3-carbonitrile (2.0 g, 6.1 mmol) in anhydrous tetrahydrofuran (20 mL). After 30 minutes, ethyl bromoauetate (1.12 g, 6.7 mmol) is added dropwise and the mixture stirred for 4-5 hours at room temperature. Work-up as described in Example 15 gives the product as white solid (0.42 g); mp 140°-143° C.
Reaction SMILES: C(OC([NH:11][C:12]1([C:18]([O:20][CH2:21][CH:22]([O:44][CH2:45][N:46]2[CH:54]=[N:53][C:52]3[C:51](=[O:55])[NH:50][C:49]([NH2:56])=[N:48][C:47]2=3)[CH2:23][O:24][C:25]([C:27]2([NH:33]C(OCC3C=CC=CC=3)=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[NH2:33][C:27]1([C:25]([O:24][CH2:23][CH:22]([O:44][CH2:45][N:46]2[CH:54]=[N:53][C:52]3[C:51](=[O:55])[NH:50][C:49]([NH2:56])=[N:48][C:47]2=3)[CH2:21][O:20][C:18]([C:12]2([NH2:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:19])=[O:26])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1.[C:18]([O-:20])(=[O:19])[CH3:12]
Reactant: [H][H]
Reactant: Nc1nc2c(ncn2COC(COC(=O)C2(NC(=O)OCc3ccccc3)CCCCC2)COC(=O)C2(NC(=O)OCc3ccccc3)CCCCC2)c(=O)[nH]1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)[O-]
Product: Nc1nc2c(ncn2COC(COC(=O)C2(N)CCCCC2)COC(=O)C2(N)CCCCC2)c(=O)[nH]1

Procedure:
To a solution of 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediyl bis (N-benzyloxycarbonyl-1-amino-cyclohexanecarboxylate), 2.0 g (2.58 mmol) in glacial acetic acid (30 mL) was added palladium on carbon (10%, 0.5 g) and the mixture was hydrogenated under 1 atmosphere hydrogen overnight at room temperature. The mixture was filtered through Celite and the filtrate concentrated under reduced pressure to a thick oil. Water was added to the residue and the mixture was lyophilized to give 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediyl bis (1-amino-cyclohexanecarboxylate) as an acetate as a white solid. Mass spectrum: MA+ 506; Mw 505. Elemental Analysis: C29H47O12N7.1HOAc.1H2O. Calc.: C 49.49; H 7.02; N 13.93. Found: C 49.32; H 6.97; N 13.89.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([N:18]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23](F)[CH:24]=2)[C:19]1=[O:38])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O>[CH2:11]([N:18]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:24]=2)[C:19]1=[O:38])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(F)ccc2c(=O)n1Cc1ccccc1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil, 400 mg) was added to benzyl alcohol (6 ml) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 30 min. To the reaction mixture was added 2-benzyl-6-fluoro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (310 mg) and the mixture was stirred at 120° C. for 6 hrs. To the reaction mixture were added water and 10% hydrochloric acid to acidify the aqueous layer of the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diisopropyl ether-hexane and the crystals were collected by filtration. Recrystallization (ethyl acetate-hexane) gave the title compound (250 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N(CC)CC)C.[C:23](=[S:25])=[S:24].[CH2:26](I)[CH2:27][CH2:28][CH3:29]>O.CO>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:23]([S:25][CH2:26][CH2:27][CH2:28][CH3:29])=[S:24]
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Reactant: CCCCI
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCSC(=S)N1Cc2[nH]c3ccccc3c2C[C@H]1CO

Procedure:
In the same manner as described in Example 2 by using (3S)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (2.02 g), triethylamine (1.52 g), CS2 (1.14 g), n-butyl iodide (2.97 g), methanol (25 ml) and water (5 ml), there is prepared the title compound (2.0 g, 60%) as colorless needles, m.p. 60°-63° C. (recrystallized from ethanol), [α]D20 +133.6° (c=1.0, methanol). NMR (CDCl3, δ): 0.93 (m, 3H, CSS(CH2)3CH3), Mass m/e: 334 (M+), 244 (M+ -n-thiobutanol).
Reaction SMILES: Cl.C1(NC2C(C)=C(C)N=C(NCC3C=CC=CN=3)N=2)CCCCC1.[CH2:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1)[CH3:26].Cl[C:36]1[N:41]=[C:40]([NH:42][CH:43]2[CH2:48][CH2:47][C:46]([F:50])([F:49])[CH2:45][CH2:44]2)[C:39]([CH3:51])=[C:38]([CH3:52])[N:37]=1>>[F:50][C:46]1([F:49])[CH2:47][CH2:48][CH:43]([NH:42][C:40]2[C:39]([CH3:51])=[C:38]([CH3:52])[N:37]=[C:36]([NH:34][CH2:33][C:29]3[CH:28]=[C:27]([CH2:25][CH3:26])[CH:32]=[CH:31][N:30]=3)[N:41]=2)[CH2:44][CH2:45]1
Reactant: Cc1nc(Cl)nc(NC2CCC(F)(F)CC2)c1C
Reactant: CCc1ccnc(CN)c1
Agent: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: CCc1ccnc(CNc2nc(C)c(C)c(NC3CCC(F)(F)CC3)n2)c1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(4-ethylpyridin-2-yl)methyl]amine instead of (pyridin-2-ylmethyl)amine and 2-chloro-N-(4,4-difluorocyclohexyl)-5,6-dimethylpyrimidin-4-amine (Step A) instead of 2-chloro-N-cyclohexyl-5,6-dimethylpyrimidin-4-amine. The product was purified by crystallization from ethanol to afford the titled compound as the hydrochloride salt as a light-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.59 Hz, 3H), 1.57-1.1.89 (m, 11H) 2.25 (s, 3H) 2.62 (m, 2H) 3.95 (s, 1H) 4.64 (d, J=5.12 Hz, 2H) 7.17 (d, J=5.12 Hz, 1H) 7.24 (s, 1H) 7.64 (d, J=6.40 Hz, 1H) 8.31 (s, 1H) 8.40 (d, J=4.94 Hz, 1H) 12.58 (bs, 1H); MS (ESI) m/z 375.9 (M+1)+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[C:29]([OH:31])=O)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[NH2:32][NH:33][C:34]([NH2:36])=[S:35]>O1CCCC1.O1CCOCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[C:29]([NH:32][NH:33][C:34](=[S:35])[NH2:36])=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: NNC(N)=S
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC(=S)NNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Yield: 49.4 %

Procedure:
1,1′-Carbonyidimidazole (195 mg) was added to a solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid (287 mg) [see Preparation 38] in tetrahydrofuran (5 ml). The reaction mixture was stirred and heated under reflux for 1 hour and then evaporated under reduced pressure to afford a yellow gum. The gum was dissolved in 1,4-dioxane (5 ml) and thiosemicarbazide (182 mg) was added. The reaction mixture was heated under reflux for 1.25 hour. After this time the cooled mixture was purified by column chromatography on MCI (trade mark) reverse phase gel eluting with a solvent gradient of 30:70 changing to 70:30, by volume, methanol:water to afford 2-((2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidylcarbonyl)-1-hydrazinecarbothioamide (178 mg) as a white foam.