Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>>[F:27][C:26]([F:29])([F:28])[CH2:25][O:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:38]4[CH:37]=[N:36][C:35]([NH2:34])=[CH:40][CH:39]=4)[CH:7]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1C(F)(F)F
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.56) (0.25 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a light brown solid (0.21 g, 77%). MS (ISP) 560.0 [(M+H)+]; mp 223° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:20])[C:3]([NH:5][C:6]1[N:7]=[CH:8][N:9]([C:11]([CH3:19])([CH3:18])[CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:10]=1)=[O:4].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:1][CH:2]([CH3:20])[C:3]([NH:5][C:6]2[N:7]=[CH:8][N:9]([C:11]([CH3:19])([CH3:18])[CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[CH:10]=2)=[O:4])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: CC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-N-[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-propionamide was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: 1H NMR (400 MHz) 1.41 (d, 3H), 1.51 (s, 6H), 1.48 (s, 4H), 2.32 (s, 4H), 2.7 (s, 2H), 3.5 (s, 2H), 4.88-4.83 (m, 1H), 7.44 (d, 1H, J=1.4 Hz), 6.63-6.68 (m, 1H), 6.71-6.90 (M, 2 h), 7.58 (d, 1H, J=1.7 Hz), 11.8 (brs, 1H) MS m/z 434.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=2)=[CH:8][CH:7]=1.Cl.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][NH2:35].Cl>C(O)C>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=3)=[CH:8][CH:7]=2)[CH2:4][C:3]([C:2]([F:25])([F:1])[C:21]([F:24])([F:23])[F:22])=[N:35]1
Reactant: NNc1ccccc1Cl
Reactant: CSc1cccc(-c2ccc(C=CC(=O)C(F)(F)C(F)(F)F)cc2)c1
Agent: Cl
Solvent: CCO
Product: CSc1cccc(-c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 57.4 %

Procedure:
4,4,5,5,5-Pentafluoro-1-(3′-methylsulfanyl-biphenyl-4-yl)-pent-1-en-3-one (200.0 mg, 0.54 mmol) prepared in Step 2 of Preparation 2, 2-chlorophenylhydrazine hydrochloride (115.0 mg, 0.64 mmol) and conc. hydrochloric acid (200.0 uL) were added to ethanol (5.0 mL). The reaction mixture was stirred at 100° C. for 18 hours, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 154.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:13]([CH3:15])=O)[C:8]([O:10]CC)=O.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[CH:25]=[C:24]([NH2:29])[N:23]=1.O>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:21][C:22]1[N:23]=[C:24]([NH2:29])[C:25]2[C:13]([CH3:15])=[C:7]([CH2:6][C:5]3[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:8](=[O:10])[NH:28][C:26]=2[N:27]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(OC)c1)C(C)=O
Reactant: Nc1cc(N)nc(N)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: COc1ccc(Cc2c(C)c3c(N)nc(N)nc3[nH]c2=O)cc1OC
Yield: 50.8 %

Procedure:
A mixture of ethyl α-(3,4-dimethoxybenzyl)acetoacetate (42 g) and 2,4,6-triaminopyrimidine (21 g) in diphenyl ether (120 ml) was heated at 190°-230° C. for 2 hours during which time the ethanol and water formed were azeotropically removed. The reaction was cooled, and methanol (250 ml) and ethanol (50 ml) were added. The resulting solid was collected by filtration and treated with boiling water (1) to give 2,4-diamino-5-methyl-6-(3,4-dimethoxybenzyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine (26 g), m.p. 346°-348° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.[Cl:21][C:22]1[C:27](B(O)O)=[CH:26][CH:25]=[CH:24][N:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:21][C:22]1[C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:13])[CH3:14])[CH:9]=[CH:10][C:3]=23)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(-c3cccnc3Cl)ccnc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.03 g, 16.3 mmol, 1 equiv), 2-chlorpyridine-3-boronic acid (4.36 g, 27.7 mmol, 1.7 equiv), palladium acetate (183 mg, 0.815 mmol, 5 mol %), 2-(dicyclohexylphosphino)biphenyl (571 mg, 1.63 mmol, 10 mol %), and finely ground anhydrous K3PO4 (10.4 g, 48.9 mmol, 3 equiv) were added into a sealed tube. The tube was purged with argon for 5 minutes. Dioxane (30 mL) was added via syringe under a positive argon flow. The tube was sealed and the reaction was stirred at RT for 5 minutes. Then the tube was placed in a preheated oil bath at 110° C. for 2 h. The reaction was cooled down to room temperature. The content was filtered through a plug of celite with an aid of diethyl ether. The filtrated was concentrated under reduced pressure. The product was purified by column chromatography using a mixture of 95:5 Hex:Et2O as eluent. The product, 4-(2-chloropyridine-3-yl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3,b]pyridine was obtained as a light yellow solid. 1H NMR (Varian, 300 MHz, CDCl3) ppm: 8.35 (d, J=4.7 Hz, 1H), 8.30-8.28 (m, 1H), 8.10-8.03 (m, 1H), 7.40-7.30 (m, 2H), 7.15 (dd, J=4.3, 1.7 Hz, 1H), 6.54 (dd, J=3.6, 1.9 Hz, 1H), 1.89 (sept, J=7.4 Hz, 3H), 1.15 (d, J=7.4 Hz, 18H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:20])[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:18]=[O:19])[CH:4]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>CS(C)=O>[CH2:22]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([CH3:20])[CH:8]=[CH:7][CH:6]=3)=[CH:17][CH:16]=2)[C:12]([CH:18]=[O:19])=[CH:13]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Cc1cccc(-c2ccc3[nH]cc(C=O)c3c2)c1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCn1cc(C=O)c2cc(-c3cccc(C)c3)ccc21
Reaction time: 3 h
Yield: 62 %

Procedure:
NaH (60% in mineral oil dispersion, 6 mmol, 1.2 equiv.) was added to a stirred solution of aldehyde 8 (5 mmol, 1 equiv.) in anhydrous dimethylsulfoxide (DMSO) at room temperature. After 1 h of stirring at the same temperature, 1-bromooctane was added and the mixture stirred for another 3 h. Distilled water was added to the reaction mixture which was then extracted with CH2Cl2. The organic layer was washed with brine, dried (anhydrous Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography with EtOAc/hexane as eluting solvents as described in Section 5.4.1. Yield: 62%; 1 H NMR (300 MHz, CDCl3): δ 9.98 (s, 1 H), 8.53 (s, 1 H), 7.66 (s, 1 H), 7.57-7.46 (m, 3 H), 7.39-7.29 (m, 2 H), 7.13 (d, J=7.2H, 1 H), 4.1 (t, J=8.7 Hz, 2 H), 2.42 (s, 3 H), 1.86 (t, J=3 H), 1.29-1.24 (m, 10 H), 0.86 (t, J=6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3): δ 184.8, 143.7, 141.6, 138.9, 135.4, 135.1, 129.1, 128.9, 127.1, 119.3, 119.2, 118.5, 116.8, 111.6, 47.4, 32.7, 31.6, 29.6, 29.0, 26.7, 22.5, 14.0.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:24]CCC.CI.O>C1COCC1>[CH3:24][C:11]1[N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[C:18]2[C:13]([CH:12]=1)=[C:14]([C:19]([F:21])([F:22])[F:20])[CH:15]=[CH:16][CH:17]=2
Reactant: [Li]CCCC
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(C(F)(F)F)cccc21
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cc1cc2c(C(F)(F)F)cccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(phenylsulfonyl)-4-(trifluoromethyl)-1H-indole (60.0 g, 184.6 mmol) in THF (300 mL) at 0° C. was added n-BuLi (88.6 mL of a 2.50 M solution in hexanes), dropwise over 5 min. The mixture was stirred 1 h and methyl iodide (23.0 mL, 369.2 mmol) was added dropwise over 5 min. The mixture was stirred at 0° C. for 2.5 h and then overnight, slowly warming to rt, poured into water and extracted with Et2O (×3). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 26.0 g of the title compound as a colorless oil: MS (ES) m/z 338 (M−1).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([O:14][C:15]3[CH:45]=[CH:44][C:18]([CH2:19][CH:20]([N:29]([CH3:43])[S:30]([C:33]4[C:34]5[CH:35]=[CH:36][N:37]=[CH:38][C:39]=5[CH:40]=[CH:41][CH:42]=4)(=[O:32])=[O:31])[CH2:21][N:22]4[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]4)=[CH:17][CH:16]=3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[BH4-].[Na+]>CO>[OH:28][CH:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH:20]([N:29]([CH3:43])[S:30]([C:33]2[C:34]3[CH:35]=[CH:36][N:37]=[CH:38][C:39]=3[CH:40]=[CH:41][CH:42]=2)(=[O:32])=[O:31])[CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][S:11]([C:6]3[C:5]4[CH:4]=[CH:3][N:2]=[CH:1][C:10]=4[CH:9]=[CH:8][CH:7]=3)(=[O:12])=[O:13])=[CH:45][CH:44]=2)[CH2:23][CH2:24]1
Reactant: CN(C(Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)CN1CCC(=O)CC1)S(=O)(=O)c1cccc2cnccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C(Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)CN1CCC(O)CC1)S(=O)(=O)c1cccc2cnccc12
Yield: 57.8 %

Procedure:
200 mg of the amorphous compound obtained in Example 95 was dissolved in 5 ml of methanol, to the solution was added in portions 35.2 mg of sodium borohydride at a room temperature with stirring, and the mixture was stirred for 2 hours and evaporated to remove the solvent. Resulting residue was applied to a silica gel column and eluted with chloroform/methanol (100:4), to obtain 116 mg of the title compound as pale yellow oil.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH2:30][OH:31])[N:17]=2)[CH2:9]1.[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([CH:42]3[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]3)=[CH:41][C:36]=2[O:35][CH2:34]1>>[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([CH:42]3[CH2:47][CH2:46][CH:45]([N:8]4[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]5[C:24]6[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=6)[N:18]([CH2:29][CH2:30][OH:31])[N:17]=5)[CH2:9]4)[CH2:44][CH2:43]3)=[CH:41][C:36]=2[O:35][CH2:34]1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Reactant: O=C(CNc1nn(CCO)c2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nn(CCO)c2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(c3ccc4c(c3)OCO4)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-(2-hydroxy-ethyl)-5-trifluoromethyl-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 74, Step A) and 4-benzo[1,3]dioxol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1
Reactant: [H][H]
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(=O)O)n[nH]1

Procedure:
5-Nitro-1H-pyrazole-3-carboxylic acid 1 is reduced under standard conditions, such as treatment with hydrogen in the presence of palladium(0) on carbon in a solvent such as methanol, to yield 5-amino-1H-pyrazole-3-carboxylic acid 2. Compound 2 is reacted with di-aldehyde 3, carrying a bromo or chloro substituent at the R1 position, under acid conditions, such as acetic acid, at elevated temperatures to give 6-bromo- or 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (4). A compound of Formula I is prepared from 4 via reaction with an appropriate secondary amine 5 in the presence of a condensation agent, including, for example, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (“TBTU”) or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC).
Reaction SMILES: C([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:37]([NH:39][C@H:40]([C:45]([N:47]1[CH2:65][CH2:64][CH2:63][C@H:48]1[C:49]([NH:51][C@H:52]([C:60]([OH:62])=[O:61])[CH2:53][CH2:54][CH2:55][NH:56][C:57](=[NH:59])[NH2:58])=[O:50])=[O:46])[CH2:41][C:42](=[O:44])[OH:43])=[O:38])[CH2:28][O:29]CC1C=CC=CC=1)=[O:25])[CH2:13][C:14](=[O:23])[O:15]CC1C=CC=CC=1)(OCC1C=CC=CC=1)=O>C([O-])(=O)C.[NH4+].[Pd]>[NH2:11][C@H:12]([C:24]([NH:26][C@H:27]([C:37]([NH:39][C@H:40]([C:45]([N:47]1[CH2:65][CH2:64][CH2:63][C@H:48]1[C:49]([NH:51][C@H:52]([C:60]([OH:62])=[O:61])[CH2:53][CH2:54][CH2:55][NH:56][C:57](=[NH:58])[NH2:59])=[O:50])=[O:46])[CH2:41][C:42](=[O:43])[OH:44])=[O:38])[CH2:28][OH:29])=[O:25])[CH2:13][C:14](=[O:15])[OH:23]
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(=O)O)C(=O)O

Procedure:
N-carbobenzoxy-O-benzyl-L-aspartyl-O-benzyl-L-seryl-L-aspartyl-L-prolyl-L-arginine (2.7 Kg) is dissolved in 19 L of aqueous 2.3M ammonium acetate. Palladium on charcoal (5-20%) is added. The mixture is purged with nitrogen and then contacted with hydrogen flowing at a rate of 50-100 L/hr for three to sixteen hours at 15°-25° C. and from atmospheric pressure to 50 psig.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14](O)=[O:15])=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.[OH:35][C@H:36]([CH3:50])[C@H:37]([NH:42][C:43]([C@@H:45]1[CH2:49][CH2:48][CH2:47][NH:46]1)=[O:44])[C:38]([O:40][CH3:41])=[O:39]>C(Cl)Cl.CN(C=O)C>[C:1]([O:4][CH2:5][C@@H:6]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([N:46]1[CH2:47][CH2:48][CH2:49][C@H:45]1[C:43]([NH:42][C@@H:37]([C@H:36]([OH:35])[CH3:50])[C:38]([O:40][CH3:41])=[O:39])=[O:44])=[O:15])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1)[C@@H](C)O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](COC(C)=O)NC(=O)OCc1ccccc1)[C@@H](C)O
Reaction time: 3 h
Yield: 18.6 %

Procedure:
Compound 3 (1.0 g, 2.64 mmol) was dissolved in CH2Cl2 (10 mL), NMM (0.32 g, 3.17 mmol) and IBCF (0.41 g, 3.04 mmol) were added to the reaction mixture at −15° C. and stirred for minutes under inert atmosphere. A mixture of (2S,3R)-methyl 3-hydroxy-2-((S)-pyrrolidine-2-carboxamido)-butanoate (4) (0.73 g, 3.17 mmol) and NMM (0.35 mL) in DMF (3 mL) were added drop wise to the reaction mixture at −15° C. and stirring was continued for another 3 h at RT. The reaction mixture was diluted with DCM (200 mL), washed with water (20 mL), citric acid solution (2×20 mL) and brine (2×50 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue obtained was purified by silica gel column chromatography eluting with 5% CH3OH/EtOAc to afford compound (5) (0.29 g, 19%).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[N:13]=[CH:12][N:11]=1)=[O:8])C.[Li+].[OH-]>C1COCC1.O>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:13]=[CH:12][N:11]=[C:10]([NH:9][C:7](=[O:8])[NH:6][CH2:5][C:4]([OH:24])=[O:3])[CH:15]=1
Reactant: CCOC(=O)CNC(=O)Nc1cc(-c2ccccc2OC)ncn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(NC(=O)NCC(=O)O)ncn1
Reaction time: 2 h

Procedure:
To a solution of {3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-acetic acid ethyl ester (LII) (190 mg, 0.57 mmol) in a mixture of THF and water (1:1) was added LiOH (50.0 mg, 1.12 mmol) solution in water at ice bath temperature over 10 min and the mixture was then allowed to stir for 2 hours. THF was evaporated and the aqueous solution was acidified with 2N HCl. This aqueous phase was then extracted with ethyl acetate (2×100 ml). The organic phases were separated, combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in a vacuum rotavapor to afford {3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-acetic acid as a white solid. Yield: 184 mg, ˜quantitative.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][CH2:17][C:18]#[N:19])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), 3-bromopropionitrile (23 uL, 0.28 mmol, Aldrich, Cat. No. 109231) and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling, it was diluted with ethyl acetate, washed with water twice and brine once, dried over Na2SO4. After filtration the filtrate was concentrated to yield 55 mg of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>O.C(Cl)(Cl)(Cl)Cl>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(C)C(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 57.9 %

Procedure:
4.2 g (0.03 mole) of 3-amino-5-t-butylpyrazole as prepared in Example 1 was dissolved in 50 ml of water, and 3.2 g of sodium carbonate was added thereto. To the resulting aqueous solution was added dropwise 3.2 g of methacryloyl chloride dissolved in 20 ml of carbon tetrachloride at 0° C. while cooling with ice for one hour. The reaction mixture was placed at room temperature (i.e., about 20° to 30° C.), followed by filtration and washing with water to obtain 3.6 g of 5-t-butyl-3-methacryloylaminopyrazole. The mass analysis showed the presence of a molecular ion peak at 207.
Reaction SMILES: O[CH2:2][CH2:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2.P(Br)(Br)(Br)(Br)[Br:15]>C(OCC)C>[Br:15][CH2:2][CH2:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2
Reactant: BrP(Br)(Br)(Br)Br
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Solvent: CCOCC
Product: BrCCC12CC3CC(CC(C3)C1)C2

Procedure:
1-Hydroxy-2-(adamant-1-yl)ethane (901.0 mg, 5.0 mmol) was treated with phosphorus pentabromide(3.0 gm, 7.0 mmol) in diethyl ether and warmed slightly until a noticeable exotherm was observed. The resulting red solution was washed with aqueous sodium bicarbonate solution and dried (Na2SO4). Solvent removal gave crude 1-Bromo-2-(adamant-1-yl)ethane. The material was used as is without further purification.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1>C1COCC1.O>[CH3:1][S:2][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of sodium thiomethoxide in THF (53 mL) and H2O (20 mL) cooled to 0° C. was added 2-chloro-5-nitropyridine (LXV) (5.09 g, 32.09 mmol). The reaction was warmed to room temperature and stirred for 2 hrs. The reaction was poured into ice water and stirred for 10 minutes, filtered, washed with water, dried under vacuum to yield 2-(methylthio)-5-nitropyridine (CVII) as a yellow solid (5.14 g, 30.20 mmol, 94.1%). 1H NMR (DMSO-d6) δ ppm 2.62 (s, 3H), 7.57 (d, J=8.9 Hz, 1H), 8.38 (d, J=8.9 Hz, 1H), 9.22 (d, J=2.7 Hz, 1H); ESIMS found for C6H6N2O2S m/z 171.1 (M+H).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][C:9](=O)[N:8]([CH3:20])[C:7]1=O)=O)C.C1(C)C=CC=CC=1.O.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1.C1COCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:11]2[CH2:10][CH2:9][N:8]([CH3:20])[CH2:7][C@H:6]2[CH2:4][OH:3])=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@@H]1C(=O)N(C)C(=O)C[C@H]1c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CC[C@@H](c2ccc(F)cc2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of NaAlH4 (0.22 mol) in toluene/THF under argon was added (+/−) trans-3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) in THF holding the temperature below 15° C. After addition was complete, reaction was allowed to warm to room temperature. After 30 minutes at room temperature, the reaction was heated to >40° C. for 2 hr. The reaction was then cooled to <5° C. and toluene (50 ml) was added. Water (9 ml) was then added slowly holding the temperature below 15° C. Additional H2O or aqueous NaOH were used as necessary. The solid inorganic salts were removed by filtration. These solids were washed with additional THF or toluene. The filtered solution was then concentrated to give (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in lower yield (but similar impurity profile as with LiAlH4) as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvents.
Reaction SMILES: CS(O)(=O)=O.[CH2:6]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[NH:13])[CH2:7][CH3:8].S(O)(O)(=O)=O.N[C:25]1[C:29]([C:30](N)=[O:31])=[CH:28][NH:27][N:26]=1.C([O-])(=O)C.[Na+].C>[OH-].[Na+].C(O)(=O)C>[CH2:6]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH:12]1[N:14]=[C:28]2[N:27]=[N:26][CH:25]=[C:29]2[C:30](=[O:31])[NH:13]1)[CH2:7][CH3:8]
Reactant: CCCOc1ccccc1C(=N)N
Reactant: NC(=O)c1c[nH]nc1N
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCCOc1ccccc1C1N=C2N=NC=C2C(=O)N1
Temperature: 180 °C

Procedure:
A stirred mixture of 2-propoxybenzamidine methane-sulphonate (1.0 g), 3-amino-4-pyrazole-carboxamide sulphate (0.5 g) and sodium acetate (0.82 g) was heated in an oil bath (180° C.) for one hour. The reaction mixture was dissolved in hot 2 Normal sodium hydroxide (10 ml) and the solution was treated with charcoal and neutralised with glacial acetic acid. A precipitate was collected, washed with water and eluted from a silica column with chloroform. The combined fractions containing product were evaporated to dryness to afford the title compound, 148 mg, m.p. 182-183.5° C.