Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:32]=O.[OH-].[Na+]>C(O)=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH3:32])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CCCCc1ccc(C#Cc2ccc(CN(C)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Yield: 22.3 %

Procedure:
A solution of methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (305 mg; 0.73 mmol), formaldehyde (Aldrich, 50 μl; 1.84 mmol) and formic acid (2.5 mL) was stirred under microwaves at 100° C. for 5 min. The reaction mixture was then poured into an aqueous solution of NaOH 1M and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and concentrated. Purification of the crude (257 mg, yellow oil) by flash chromatography on silicagel afforded 70 mg of the title compound as a yellow powder. HPLC, Rt: 5.84. min (purity=100%). 1H NMR (CDCl3) δ: 7.4 (m, 4H), 7.3 (s, 1H), 7.2 (m, 4H), 6.9 (t, J=7.8 Hz, 1H), 6.75 (m, 1H), 4.4 (s, 2H), 2.92 (s, 3H), 2.5 (t, J=7.7 Hz, 2H), 1.5 (m, 2H), 1.25 (m, 2H), 0.8 (t, J=7.53 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12]Br)[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH2:34][OH:35])[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH2:12][O:35][CH2:34][C:21]1([C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=2)[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: FC(F)(F)c1cc(Br)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.2 g, 3.78 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.96 g, 3.2 mmol) were combined in dimethylformamide (10 mL) and cooled to 0° C. The reaction was treated with sodium hydride (151 mg, 6.3 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 1.1 g (61%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.61 (s, 1H), 7.35 (s, 1H), 7.30-7.31 (m, 2H), 7.26 (s, 1H), 7.03-7.07 (m, 2H), 4.36 (s, 2H), 3.72-3.75 (m, 2H), 3.38 (s, 2H), 3.01-3.06 (m, 2H), 2.13-2.16 (m, 2H), 1.81-1.87 (m, 2H), 1.43 (s, 9H). 13C-NMR (CDCl3, 126 MHz) δ 161.6 (d, J=245.7 Hz), 152.0, 141.9, 138.3, 133.3, 132.4 (q, J=32.6 Hz), 128.8, 127.5 123.2 (q, J=273.5 Hz), 122.8, 122.4, 115.5, 115.3, 79.7, 79.5, 71.7, 68.0, 41.4, 32.2, 28.5, 25.7. Mass spec.: 548.16 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.Cl.[CH2:22]([NH2:25])[C:23]#[CH:24].C(N)C#C>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:25][CH2:22][C:23]#[CH:24])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: C#CCN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 416.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (137.9 g, 0.624 mol) in anhydrous DMF (1.4 L) was cooled to 0° C., and anhydrous triethylamine (109 mL, 0.780 mol) was added. Propargyl amine hydrochloride (4.72 g, 51.6 mmol) and propargyl amine (38.4 g, 0.697 mol) were sequentially added dropwise, and the reaction was allowed to warm to room temperature and then heated at 40° C. for 22 hours. The volatiles were removed under reduced pressure, and water (1.5 L) and solid sodium carbonate (75 g) were added to the resulting oil. The mixture was then extracted with dichloromethane, and the combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting sequentially with 60:40 dichloromethane/hexane and dichloromethane) to provide 51.54 g of 2-chloro-5,6-dimethyl-3-nitro-N-prop-2-ynylpyridin-4-amine as a brown solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]([NH:11][C@H:12]([C:20]([NH:22][C@@H:23]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@H:24]([OH:43])[CH2:25][N:26]2[C@H:35]([C:36]([NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][C@H:33]3[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]3)[CH2:27]2)=[O:21])[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])([CH3:15])[CH3:14])[S:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:39]([NH:38][C:36]([C@@H:35]1[CH2:34][C@H:33]2[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27][N:26]1[CH2:25][C@@H:24]([OH:43])[C@@H:23]([NH:22][C:20](=[O:21])[C@H:12]([C:13]([S:16]([CH3:19])(=[O:18])=[O:17])([CH3:15])[CH3:14])[NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][OH:4])[N:7]=1)[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:37])([CH3:40])([CH3:41])[CH3:42]
Reactant: CC(=O)OCc1csc(N[C@H](C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CN2C[C@H]3CCCC[C@H]3C[C@H]2C(=O)NC(C)(C)C)C(C)(C)S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Nc1nc(CO)cs1)C(C)(C)S(C)(=O)=O
Yield: 46.2 %

Procedure:
A stirred solution of 73 mg (0.1 mmol) of 2-[3(S)-[[N-[4-(acetoxymethyl)-2-thiazolyl]-3-(methanesulfonyl)-L-valyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-3(S)-isoquinolinecarboxamide (Example 141) in 7 ml of methanol/water (5:2) was treated with 700 mg of potassium carbonate. After 1.5 hours the volatiles were evaporated and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give a gum which was chromatographed on silica eluting with dichloromethane/methanol (40:3) to give 32 mg (48%) of N-tert-butyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-2-[2(R)-hydroxy-3(S)-[[N-[4-(hydroxymethyl)-2-thiazolyl]-3-(methanesulfonyl)-L-valyl]amino]-4-phenylbutyl]-3(S)-isoquinolinecarboxamide as a solid, mp 126° C., [M+H]+ 692.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])=[O:5])[CH3:2].[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([N+]([O-])=O)[C:16]=1[C:17]#[N:18])([O-:14])=[O:13]>>[C:17]([C:16]1[C:15]([N+:12]([O-:14])=[O:13])=[CH:22][CH:21]=[CH:20][C:19]=1[O:9][CH2:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])([CH3:10])[CH3:11])#[N:18]
Reactant: CCNC(=O)NC(C)(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CCNC(=O)NC(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 65 %

Procedure:
Prepared as in Example 197c from 1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)urea (Example 209d) and 2,6-dinitrobenzonitrile in 65% yield. MS 307 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12](C(OCC)=O)[N:11]([CH2:19][CH2:20][NH:21][C:22]([O:24]C(C)(C)C)=O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl.O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]2[C:22](=[O:24])[NH:21][CH2:20][CH2:19][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)nn1CCNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1NCCn2nc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Ethyl 3-(benzyloxy)-1-{2-[(tert-butoxycarbonyl)amino]ethyl}-1H-pyrazole-5-carboxylate (0.51 g, 1.31 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (6.53 mL). The mixture was stirred at room temperature for 1 hour and then basified with a saturated solution of Na2CO3. The mixture was stirred at room temperature for 1 hour, diluted with water and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7 M solution of ammonia in MeOH in DCM 0/100 to 10/90). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-(benzyloxy)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.31 g, 99% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:37](=[O:38])[CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Reactant: O=C(Cl)Cc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)Cc3ccccc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 100, Step 1, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and phenylacetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:31]([CH3:30])(=[O:33])=[O:32]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(C)(=O)=O)N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (1.0 g, 3.22 mmol, 1.0 eq.) in pyridine (5 mL, 0.0644 mL, 20.0 eq.) and dichloro methane (20 mL) at 0 C was added dropwise a solution of methanesulfonyl chloride in dichloromethane (30 mL). The mixture was stirred at room temperature for 4 h. Thin layer chromatography and LC-MS showed the reaction was complete. The mixture was quenched with 50 mL water and extracted with ethyl acetate (100 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to afford 1.475 g of methyl 3,3-dimethyl-2-(2-(methylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (pyridine included) as light yellow solid, which was used in next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.C([Li])(C)(C)C.[Br-].[Mg+2].[Br-].Br[C:25]1[CH2:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2>CCOCC>[C:12]([C:4]1[CH:3]=[C:2]([C:25]2[CH2:33][C:32]3[C:27]([CH:26]=2)=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Reactant: BrC1=Cc2ccccc2C1
Agent: [Br-]
Agent: [Li]C(C)(C)C
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(C)(C)c1cc(C2=Cc3ccccc3C2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
1-Bromo-3,5-di-t-butylbenzene (47.2 g, 0.175 mol) was dissolved in ether (500 mL) and cooled to −70° C. t-Butyllithium (200 mL of 1.7 M solution in pentane, 0.34 mol) was added at −70° C. over a two hour period. The solution was allowed to warm to room temperature slowly. Magnesium bromide etherate (46.5 g, 0.18 mol) was added and the slurry was stirred for one hour. The mixture was then cooled to 5° C. and 2-bromoindene (34.2 g, 0.18 mol) was added. The mixture was warmed to room temperature and then refluxed for three hours. The solution was cooled to room temperature and the reaction was quenched carefully with water. The layers were separated and the organics washed with salt brine and dried over magnesium sulfate. The solvents were evaporated and the product was distilled twice and recrystallized from hexane to give 37.1 g of product (70%).
Reaction SMILES: C(N)C1C=CC=CC=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1.[F:29][C:30]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:31]=1[CH2:32][Cl:33].Cl>O1CCOCC1>[ClH:33].[F:29][C:30]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:31]=1[CH2:32][N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[C:19]([NH2:28])=[N:20][C:21]([NH2:27])=[N:22]3)[CH2:11][CH2:10]1
Reactant: Fc1ccc(CCl)c(F)c1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Agent: Cl
Solvent: NCc1ccccc1
Solvent: C1COCCO1
Product: Nc1nc(N)c2c(OCC3CCN(Cc4ccc(F)cc4F)CC3)cccc2n1
Temperature: 25 °C
Yield: 78 %

Procedure:
The benzylamine was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (75 mg; 0.27 mmol) and 2,4-difluorobenzyl chloride (69 mg; 0.35 mmol) via Method BB. Solids were suspended in 2 mL dioxane and 0.5 mL 4M HCl in dioxane was added and after 2 hours stirring at room temperature solids were collected by filtration to yield 92 mg. (78% yield). 1HNMR (400 MHz, DMSO-d6) δ 12.8 (s, 1H), 11.2 (s, 1H), 8.84 (s, 1H), 8.23 (s, 1H), 7.88 (q, J=8.8, 6.4 Hz, 1H), 7.7 (m, 2H), 7.4 (m, 1H), 7.23 (m, 1H), 7.02 (m, 2H), 4.28 (d, J=4.4 Hz, 2H), 4.17 (d, J=6.4 Hz, 2H), 3.4 (br d, J=11.6 Hz, 2H), 2.95 (m, 2H), 2.23 (m, 1H), 1.81 (d, J=13.2 Hz, 2H), 1.73 (m, 2H). MS m/z (ESI) 400 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:21])[N:9]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:8]2=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N(CC(OCC)=O)=C=O.C1(N2C(=O)CC(=O)N(C3CCCC3)C2=O)CCCCC1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:10]([OH:21])[N:9]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[C:8]2=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(C2CCCC2)c1=O
Agent: CCOC(=O)CN=C=O
Agent: O=C1CC(=O)N(C2CCCC2)C(=O)N1C1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCC2)c(=O)n(C2CCCCC2)c1=O
Reaction time: 2 h
Yield: 49 %

Procedure:
N-[(1-Cyclohexyl-3-cyclopentyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycine. Ethyl isocyanatoacetate (8.33 mL, 74.3 mmoles) was added to a mixture of 1-cyclohexyl-3-cyclopentyl-2,4,6(1H,3H,5H)-pyrimidinetrione (18.8 g, 67.54 mmoles) and diisopropylethylamine (23.53 mL, 135.08 mmoles) in dichloromethane (800 mL) and stirred for 2 hours. Reaction mixture from a prior run (approx 25% scale) was added. The combined reaction mixture was washed with 2 molar hydrochloric acid (2×1.0 L) and evaporated. The residue was dissolved in ethanol (200 mL) and treated with 3.0 molar sodium hydroxide (100 mL). The mixture was stirred for 2 hours. Ethyl acetate (500 mL) was added and the mixture acidified with 6 molar hydrochloric acid (200 mL), water (500 mL) was added and the layers separated. The aqueous layer was extracted with ethyl acetate (500 mL) and the organic solution was washed with 1 molar hydrochloric acid. The organic solution was dried and evaporated to a solid residue which recrystallized from acetic acid (300 mL) to afford the title compound (15.5 g, 49%). Mp 222-224° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.08 (s, 1H), 10.17 (t, J=5.43 Hz, 1 H), 5.08-5.33 (m, 1 H), 4.63 (t, J=12.25 Hz, 1 H), 4.12 (d, J=5.81 Hz, 2 H), 2.18-2.36 (m, 2 H), 1.93-2.06 (m, 2 H), 1.69-1.91 (m, 6 H), 1.46-1.68 (m, 5 H), 1.28 (q, J=12.88 Hz, 2 H), 1.12 (q, J=13.05 Hz, 1 H).
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[S:6](=[O:10])(=[O:9])([OH:8])[OH:7].[Cl:11][CH2:12][CH2:13][C:14]#[N:15]>C(Cl)Cl.CC(C)=O>[S:6](=[O:8])(=[O:7])([OH:10])[OH:9].[S:1]([NH:5][C:14](=[NH:15])[CH2:13][CH2:12][Cl:11])(=[O:3])(=[O:2])[NH2:4]
Reactant: N#CCCCl
Reactant: NS(N)(=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: ClCCl
Product: N=C(CCCl)NS(N)(=O)=O
Temperature: 57.5 °C

Procedure:
Sulfamide (9.6 g, 0.1 mole) was added to a solution of conc. sulfuric acid (98%, 9.8 g, 0.1 mole) in 3-chloropropionitrile (51.3 g, 0.6 mole). The suspension was heated at 55-60° C., for 18 hours. At the end of the heating period, the mixture was cooled to room temperature, diluted with methylene chloride (150 ml), and filtered. The solid, thus obtained, was suspended in acetone (50 ml), and the suspension filtered and the product dried.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[C:10]([NH2:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:32])[C:30]=1Cl>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:32])[C:30]=1[NH:12][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: COc1ccc(C(N)=O)cc1OC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1

Procedure:
Alternatively, a suspension of 3-cyclopentyloxy-4-methoxybenzamide (2.58 g; that is prepared as described in Reference Example 73) in dry toluene (40 mL) is heated at reflux and treated with potassium t-butoxide (1.4 g), followed by 3,4,5-trichloro-pyridine (1.82 g). The mixture is then heated at reflux for 3 hours and 45 minutes, and is then treated with a further quantity of potassium t-butoxide (1.4 g) and heated at reflux for a further period of 7 hours. The mixture is allowed to cool and is then filtered. The filtrate is evaporated and the resulting residue is extracted with aqueous sodium hydroxide solution (2 M). The alkaline solution is then acidified by treatment with acetic acid, and the solid which separates is collected by filtration, washed with water and dried, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxy-benzamide (2.09 g) in the form of a buff solid, m.p. 153°-155° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[F:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:35]([O:37][CH3:38])=[O:36]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:26][C:20]1[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=1[C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:35]([O:37][CH3:38])=[O:36])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(F)c2F)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCO[C@@H](c1cccc(F)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(2,3-difluorophenyl)methyl)piperidine-1-carboxylate (195 mg, 0.402 mmol), DMAP (25.8 mg, 0.201 mmol) and Et3N (0.18 mL) in dry CH2Cl2 at 0° C. was added methyl chloroformate (189 mg, 2.013 mmol), the mixture was allowed to warm to rt and stirred overnight. The mixture was concentrated in vacuo to give the crude product (R)-tert-butyl 3-((R)-(2,3-difluorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (168 mg, 98%), which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.21 (m, 3H), 4.57 (m, 1H), 4.44 (d, 1H), 4.08 (m, 1H), 3.82 (m, 1H), 3.53 (s, 3H), 3.29 (d, 2H), 2.93 (m, 2H), 1.79 (m, 1H), 1.63 (m, 1H), 1.43 (s, 9H), 1.34 (m, 3H).
Reaction SMILES: O.[N+:2]([C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3].[Br:15]Br.N>C(O)(=O)C>[Br:15][C:8]1[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=1[NH2:7]
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of H2O (3.75 L) and acetic acid (375 mL) at RT was added 2,4-dinitroaniline (500 g, 2.73 mol) followed by drop wise addition of bromine (210 mL, 4.09 mol) over 30 min. The reaction mixture was stirred at RT for 15 min and then heated to 100° C. for 2 h. The reaction was cooled to RT and poured onto ice-cold H2O (5-6 L) and basified (pH 8-10) with aqueous ammonia. The solid was filtered, washed with cold H2O and dried under vacuum. This solid was washed with n-pentane to obtain i (600 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: CC(C)COC(=O)C(C)N
Agent: Cl
Product: Cc1ccc(CC(=O)NC(C)C(=O)OCC(C)C)cc1

Procedure:
Following General Procedure B′ and using 4-methylphenylacetic acid (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared as a solid having a melting point of 102°-104° C. The reaction was monitored by tlc on silica gel (Rf=0.6 in 33% ethyl acetate/hexanes) and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: C1(S(O[C@H:11]2[CH2:14][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)(=O)=O)C=CC=CC=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)P(N(C)C)(N(C)C)=O.O>[N:19]([C@@H:11]1[CH2:14][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H]1C[C@H](OS(=O)(=O)c2ccccc2)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)[C@H]1C[C@@H](N=[N+]=[N-])C1
Temperature: 105 °C
Reaction time: 2.75 h

Procedure:
A solution of trans 3-carbomethoxycyclobutyl benzenesulfonate* (6.1 g, 22.6 mmol) in hexamethylphosphoramide (35 ml) was treated with sodium azide (289 g, 44.5 mmol) and stirred at 105° C. for 2.75 h. The reaction mixture was cooled to 23° C., diluted with water (350 ml) and extracted with ether (4×125 ml). The organic extracts were combined, washed with water (2×15 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo to a slightly yellow liquid which was distilled under high vacuum; bp 66°-7° C. (0.6 mm); 2.8 g; 80%; ir (neat) νmax : 2100 (N3) and 1735 cm-1 (C=O); Hmr (CDCl3) δ: 40.34 (m, H-1), 3.7 (s, methyl) and 2.9-2.1 ppm (5H, 2H-2, H-3 and 2H-4).