Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:4]=O.O.[NH2:19][NH2:20]>CCO>[C:12]1([C:2]2[C:3]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][NH:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: O=CC(C(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCO
Product: c1ccc(-c2c[nH]nc2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 56 %

Procedure:
3-Oxo-2,3-diphenylpropanal (5.00 g, 22.3 mmol) was dissolved in EtOH (40 mL). Hydrazine monohydrate (2.0 mL, 38.7 mmol) was added slowly via syringe. The reaction was stirred at room temperature for an hour. The solvent was evaporated and the residue was purified by silica gel column chromatography to yield the title compound as a light purple solid (2.75 g). LCMS m/z=221.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.99-7.57 (m, 10H), 7.66-8.09 (bs, 1H), 13.15 (bs, 1H)
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:13]([NH:15][S:16](/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:18])=[O:17])=[O:14])[C:6](N(CC)CC)=[O:7])#[N:2].[F:27][C:28]1[CH:37]=[CH:36][C:31]([NH:32][CH:33]([CH3:35])[CH3:34])=[CH:30][CH:29]=1>>[C:1]([CH2:3][CH2:4][CH:5]([C:13]([NH:15][S:16](/[CH:19]=[CH:20]/[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:17])=[O:18])=[O:14])[C:6]([N:32]([C:31]1[CH:36]=[CH:37][C:28]([F:27])=[CH:29][CH:30]=1)[CH:33]([CH3:35])[CH3:34])=[O:7])#[N:2]
Reactant: CC(C)Nc1ccc(F)cc1
Reactant: CCN(CC)C(=O)C(CCC#N)C(=O)NS(=O)(=O)/C=C/c1ccccc1
Product: CC(C)N(C(=O)C(CCC#N)C(=O)NS(=O)(=O)/C=C/c1ccccc1)c1ccc(F)cc1
Yield: 41.9 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (657 mg) obtained in Example 216 (2) and 4-fluoro-N-isopropylaniline (306 mg). This was purified by silica gel column chromatography to give the title compound (334 mg) as a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:10][CH:9]=1
Reactant: c1cn[nH]c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.9 %

Procedure:
Copper (II) acetate (960 mg, 5.28 mmol) was added to a flame-dried flask charged with pyrazole (240 mg, 3.52 mmol), 4-methoxyphenylboronic acid (1.07 g, 7.04 mmol), 4 A molecular sieves (1.35 activated powder), and pyridine (570 μl, 7.04 mmol) in methylene chloride. The reaction was stirred for approximately two days at room temperature and then filtered through diatomaceous earth. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel; isocratic 8% ethyl acetate/hexanes) to yield 381 mg (2.18 mmol, 62% yield) of the title compound. LRMS ([M+H]+)=175.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16].CS(O)(=O)=O>>[OH:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:15]([C:14]1[CH:18]=[CH:19][CH:20]=[C:12]([O:11][CH3:10])[CH:13]=1)=[O:16]
Reactant: COc1cccc(O)c1
Reactant: COc1cccc(C(=O)O)c1
Agent: CS(=O)(=O)O
Product: COc1cccc(C(=O)c2ccc(OC)cc2O)c1

Procedure:
Substituted 2-hydroxybenzophenones may be prepared as illustrated by exemplary reaction in Scheme 8. Reaction of 3-methoxyphenol with 3-methoxybenzoic acid in the presence of Al2O3 and CH3SO3H produces 2-hydroxy-4-methoxy-3′-methoxy-benzophenone.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([C:27]#[N:28])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.O.[OH-].[Li+].CO>O.O1CCCC1>[C:27]([CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:11][CH:12]=1)[C:4]([OH:29])=[O:3])#[N:28]
Reactant: CCOC(=O)C(C#N)Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(CC(C#N)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
A mixture of 2-cyano-3-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 7) (0.9 g; 2.16 mmole), lithium hydroxide hydrate (0.12 g; 2.86 mmole), methanol (5 ml), water (5 ml) and tetrahydrofuran (10 ml) was stirred for 30 minutes at room temperature. Water was added and the mixture was washed with diethyl ether. The water phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and evaporated in vacuo. The crude product was purified by crystallization in diisopropyl ether to give 0.56 g (yield 67%) of 2-cyano-3-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid.
Reaction SMILES: O1C=CC([C:6]2[CH:7]=[C:8]3[CH2:14][C@:13]4([CH:19]5[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]5)[CH2:15]4)[O:12][C:9]3=[N:10][CH:11]=2)=C1.BrC1C=C2C[C@]3(C4CCN(CC4)C3)OC2=NC=1.[O:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:41]=[C:40]1B(O)O>>[O:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:41]=[C:40]1[C:6]1[CH:7]=[C:8]2[CH2:14][C@:13]3([CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)[O:12][C:9]2=[N:10][CH:11]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: c1cc(-c2cnc3c(c2)C[C@@]2(CN4CCC2CC4)O3)co1
Agent: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Product: c1ccc2oc(-c3cnc4c(c3)C[C@@]3(CN5CCC3CC5)O4)cc2c1

Procedure:
Prepared by a method analogous to that described for the preparation of (2′R)-5′-(furan-3-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] in Preparation 1 from (2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] and benzofuran-2-boronic acid. The compound was purified by flash chromatography using a gradient of ammoniated methanol in chloroform and obtained as a pale solid; m/z 333 (100%, MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Br[C:23]1[CH:28]=[CH:27][C:26]([CH:29]([OH:31])[CH3:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([OH:31])[CH3:30])=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: CC(O)c1ccc(Br)cc1
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Product: CC(O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 1-(4-bromo-phenyl)-ethanol. White solid. MS (ESI): 449.1 MH+).
Reaction SMILES: [C:1]1([CH:7]([OH:13])[CH2:8][CH2:9][C:10]#[C:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])(C)C.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)C>[F:23][C:22]([F:25])([F:24])[S:19]([O:18]/[C:11](=[C:10]1/[CH:2]([CH:1]([CH3:7])[CH3:6])[O:13][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]/1)/[CH3:12])(=[O:20])=[O:21]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC#CCCC(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C/C(OS(=O)(=O)C(F)(F)F)=C1/CCC(c2ccccc2)OC1C(C)C
Reaction time: 1 h
Yield: 75 %

Procedure:
In dichloromethane (3.0 mL) were dissolved 1-phenylhex-4-yn-1-ol (0.28 mmol) and isobudylaldehyde (0.34 mmol) and the solution was cooled to −78° C. before the addition of trimethylsilyltriflate (TMSOTf) (0.86 mmol) thereto. At the same temperature, the reaction solution was stirred for 1 hour, followed by slow temperature elevation to room temperature over 3 hours. Stirring was further conducted at room temperature for an additional one to two hours in the reaction solution. After the addition of an aqueous NaHCO3 solution, the reaction solution was diluted with diethylether. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The purification of the concentrate through column chromatography afforded the title compound (Yield 75%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[CH2:14]([C:16]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH:31]=O)[CH:17]=1)[CH3:15]>C1COCC1.O>[CH2:14]([C:16]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18](/[CH:31]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])[CH:17]=1)[CH3:15]
Reactant: CCOC(=O)c1c(C=O)cc(CC)cc1C(F)(F)F
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(/C=C/C(=O)OC)cc(CC)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a solution of trimethyl phosphonoacetate (1.60 mL, 9.90 mmol) in 100 mL of THF was added sodium hydride (0.24 g of 60% dispersion in mineral oil, 9.90 mmol) portionwise. The mixture was stirred at ambient temperature for 30 min and then ethyl 4-ethyl-2-formyl-6-(trifluoromethyl)benzoate (1.81 g, 6.60 mmol) as a solution in THF. The reaction mixture was allowed to stir at ambient temperature for 30 min and then was diluted with water. The mixture was extracted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 15% EtOAc/hexane) to afford 2.1 g (96%) of the title compound as an off-white solid. 1H NMR (CDCl3): δ 7.72 (d, 1H, J=15.9 Hz), 7.62 (s, 1H), 7.53 (s, 1H), 6.44 (d, 1H, J=15.9 Hz), 4.45 (q, 2H, J=7.2 Hz), 3.81 (s, 3H), 2.75 (q, 2H, J=7.6 Hz), 1.40 (t, 3H, J=7.2 Hz), 1.28 (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:27][N:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:34]/[OH:35])/[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:27][N:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CN(S(C)(=O)=O)C3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CN(S(C)(=O)=O)C3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, from (R)-1-(2-methylpyridin-4-yl)-3-(4-(1-(methyl-sulfonyl)azetidin-3-yl)phenyl)-3-o-tolylpropan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless oil, MS (ESI+): m/z=464.1 ([M+H]+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13].O>C(O)(=O)C.[Cl-].[Na+].O>[OH:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13]
Reactant: CN(C)S(=O)(=O)c1ccccc1O
Reactant: O=[N+]([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Yield: 22 %

Procedure:
2.24 ml (47.4 mmol, 1.3 eq) of fuming nitric acid at 90% were added, over the course of 15 minutes, to a mixture of 7.17 g (35.6 mmol, 1 eq) of 2-hydroxy-N,N-dimethylbenzenesulfonamide in 35.5 ml of acetic acid in a bath at 5° C. The reaction medium was then stirred at ambient temperature. After one and a half hours, the reaction medium was hydrolyzed with water and brine. The reaction medium was then extracted with a 4/1 ethyl acetate/heptane mixture (2×100 ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The solid obtained (8.66 g) was combined with GUL1537-178 and was chromatographed on silica gel (prepacked column, eluent heptane/(ethyl acetate+1% methanol), from 20% to 65% of (ethyl acetate+1% methanol)). A fraction enriched in ortho isomer was isolated, that is to say 3.7 g of a yellow solid. This solid was recrystallized from 40 ml of ethanol. 1.93 g of product were obtained in the form of a pale yellow solid. Yield=20%.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[C@@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CO[C:18](C)([CH3:20])[CH3:19].COC(OC)(C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O.C1COCC1>[C:4]([O:3][C:1]([N:8]1[C@H:9]([C:13]([OH:15])=[O:14])[C@@H:10]([CH3:12])[O:11][C:18]1([CH3:20])[CH3:19])=[O:2])([CH3:6])([CH3:5])[CH3:7]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)OC
Product: C[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)O

Procedure:
Boc-L-threonine (600 g, 2.74 mol) was added to methyl-tert-butyl ether (3.6 L) and THF (1.2 L) followed by 2,2-dimethoxypropane (1710 g, 16.42 mol) and pyridinium p-toluenesulfonate (171.9 g, 684 mmol) and the suspension heated to reflux for 20 hours. The reaction was cooled and diluted with water (3 L) and stirred to achieve a solution. The organic layer was collected, washed with water (1.8 L), and diluted with methyl-tert-butyl ether (4.2 L). A solution of NaOH in water (109 g in 120 mL) was added and the mixture stirred for 20 minutes. The mixture was concentrated to low volume to effect precipitation. The resulting solid was filtered and collected as the sodium salt of the title compound.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:7]=[CH:6][NH:5][N:4]=1.[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>CO.CN(C=O)C.ClCCl.CO>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:5]2[CH:6]=[N:7][C:3]([NH2:2])=[N:4]2)=[CH:11][CH:10]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1nc[nH]n1
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ncn(Cc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
Sodium metal (460 mg, 20 mmol) was dissolved in 30 ml of methanol and 3-amino-1,2,4-triazole (1.682 g, 20 mmol) added. The resulting clear solution was stirred for 1 hour at room temperature, evaporated to dryness and the sodium salt suspended in 45 ml DMF. A solution of 4-chlorobenzyl chloride (3.221 g, 20 mmol) in 5 ml DMF was slowly added to the heavily stirred suspension obtained previously. After 3 hours at room temperature, a cloudy solution was obtained, which was stirred overnight at 20° C. The resulting mixture was concentrated in the rotatory evaporator and the oily residue treated with 100 ml of dichloromethane. Insoluble material was filtered off and the filtrate concentrated to give a brownish oil which solidified on standing. Chromatography on silica gel using dichloromethane/methanol 98:2 v/v as an eluent gave a poor separation of the two regioisomers. However, a pure fraction (215 mg, 5%) of the title compound could be obtained as a colorless solid after trituration with diethyl ether. MS ISP (m/e): 209.0 & 211.0 (100 & 43) [(M+H)+].
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[Cu][C:13]#[N:14]>CC(C)=O>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:13]#[N:14])=[N:3][CH:4]=1
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Solvent: CC(C)=O
Product: N#Cc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 60 %

Procedure:
2-Bromo-5-chloro-3-nitropyridine (103) (6.0 g, 25 mmol) was mixed with copper (I) cyanide (4.6 g, 51 mmol) in a 100 mL round-bottom flask having a condensor loosely plugged with cotton was attached. The flask was slowly heated in an oil bath. When the temperature reaches approximately 150° C. (takes 2 h), the reaction mass begins to turn black. When the reaction mass turned completely black, the pressure was reduced to approximately 1 mm Hg by vacuum and the oil bath removed after 30 sec. (If the reaction goes too long, a vigorous reaction ensues, leaving little recoverable product.) The mixture was cooled to room temperature, and the sublimed solid (on the cotton) and reaction mass were treated with hot acetone (100 mL). The resulting mixture was gravity filtered, and the mother liquor rota-evaporated to dryness to yield the crude title compound as a dark brown solid. This solid can be purified by column chromatography using 4:1 hexane-EtOAc (Rf =0.13). Purified 104 was obtained in 60% yield overall, mp 93°-5° C. (Lit., 75° C., Berrie, et al., J. Amer. Chem. Soc.:2042 (1952)); 1H NMR (CDCl3): δ8.62 (d, J=1.5 Hz, 1H), 8.95 (d, J=1.5 Hz, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([Cl:14])[CH:9]=[C:8](Cl)[N:7]=1)(=[O:3])[CH3:2].[C:16]1([C@H:22]([NH:24][C:25]([NH2:27])=[O:26])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(N(CC)CC)C>C1COCC1>[C:1]([O:4][CH2:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([Cl:14])[CH:9]=[C:8]([NH:27][C:25]([NH:24][C@@H:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:23])=[O:26])[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc(Cl)cc(Cl)c1C#N
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc(Cl)c1C#N
Temperature: 50 °C

Procedure:
A mixture of (4,6-dichloro-3-cyanopyridin-2-yl)methyl acetate (366.3 mg, 1.495 mmol), (R)-1-(1-phenylethyl)urea (443 mg, 2.70 mmol) and Xantphos G2 precatalyst (130 mg, 0.146 mmol) in THF (2 ml) was sealed, sparged with argon, charged with triethylamine (0.73 ml, 5.24 mmol) and heated to 50° C. for 17 hr. The mixture was filtered through celite, eluted with EtOAc, concentrated in vacuo and purified via flash chromatography (25-100% Et2O/Hex) to provide (R)-(4-chloro-3-cyano-6-(3-(1-phenylethyl)ureido)pyridin-2-yl)methyl acetate. MS ESI calc'd. For C18H18ClN4O3 [M+H]+ 373. found 373.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]2[N:24]=[C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[C:13]([C:14]4[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=4)[C:17]#[N:18])[N:8]3[N:7]=2)[CH2:5][CH2:4]1.[H-].[Na+].[N:27]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[C:17]([C:16]1[CH:15]=[C:14]([C:13]2[N:8]3[N:7]=[C:6]([C:3]4([CH2:2][O:1][C:32]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[O:33])[CH2:5][CH2:4]4)[N:24]=[C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=2)[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: O=C(Cl)N1CCCC1
Reactant: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(CO)CC3)nc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(COC(=O)N4CCCC4)CC3)nc12
Reaction time: 1 h

Procedure:
Under an argon atmosphere 3-[2-(1-Hydroxymethyl-cyclopropyl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzonitrile (compound 150) (0.03 g, 0.08 mmol) was dissolved in DMF (0.5 mL). NaH (0.02 g, 0.48 mmol) was added and the suspension was heated at 65° C. for 1 h after which 1-pyrrolidine carbonylchloride (0.088 mL, 0.8 mmol) was added. Stirring was performed at 65° C. for 1 h. The reaction mixture was cooled and aq. NaHCO3 and H2O was added. The aqueous phase was extracted with EtOAc (×2). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica using DCM:MeOH 99:1 as eluent to afford the title compound as a solid.
Reaction SMILES: ClC1C=C(F)C=CC=1[C@H:9]1[C:14]([C:15]([O-:17])=[O:16])=[C:13]([CH2:18][Br:19])[NH:12][C:11]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[N:10]1.[C:25](OCC)(=O)[CH2:26]C(C)=O.[F:34][C:35]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:36]=1C=O.ClC1C=C(F)C=CC=1C=O>>[Br:19][CH2:18][C:13]1[NH:12][C:11]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[N:10][C@@H:9]([C:36]2[CH:39]=[CH:40][CH:41]=[C:42]([F:43])[C:35]=2[F:34])[C:14]=1[C:15]([O:17][CH2:25][CH3:26])=[O:16]
Reactant: O=C([O-])C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1cccc(F)c1F
Agent: O=Cc1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1cccc(F)c1F

Procedure:
Ethyl (4R)-6-(bromomethyl)-4-(2,3-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 140a was prepared in analogy to compound C in Example 1 by using ethyl acetoacetate and 2,3-difluorobenzaldehyde instead of methyl acetoacetate and 2-chloro-4-fluoro-benzaldehyde, respectively.
Reaction SMILES: C([O:8][C:9](=[O:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:19]2(=[O:34])=[O:33])[CH:13]=1)C1C=CC=CC=1.CCO.[H][H]>CCOC(C)=O.[Pd]>[C:39]([O:38][C:36]([NH:35][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH2:22][C:21](=[O:23])[N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[S:19]2(=[O:33])=[O:34])[CH:13]=1)[C:9]([OH:43])=[O:8])=[O:37])([CH3:40])([CH3:42])[CH3:41]
Reactant: COc1ccc(CN2C(=O)CN(c3cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc4ccccc4)c3)S2(=O)=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CN2C(=O)CN(c3cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c3)S2(=O)=O)cc1

Procedure:
The title D compound, (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester (187 mg, 0.307 mmol) is dissolved in a 1:1 mixture of EtOAc:EtOH (50 mL) in a 200 mL Parr bottle. 10% Palladium on carbon (52 mg) is added as a solid and the reaction mixture is hydrogenated on a Parr Shaker Apparatus at 47 psi of hydrogen for 1.33 h. The reaction mixture is filtered through celite and concentrated in vacuo to give (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid as a white foam: [M−1]−=518.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:14](=[O:15])[N:13]([CH3:21])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a solution of 5.0 g (18 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 80 ml of tetrahydrofuran at −75° C. 18 ml (18 mmol) of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofurane) was added. After stirring for 30 min at −75° C. the mixture was allowed to reach room temperature and 3.07 g (21.6 mmol) of methyl iodide was added. The mixture was stirred for 2.5 hours at room temperature and concentrated in vacuo. The residue was distributed between 1M NaHSO4 solution and ethyl acetate. The combined organic layers were reextracted with water and dried (MgSO4) to yield 4.95 g (94%) of (1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[N:4]1[C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]2[C:10]1=[O:15]
Reactant: Nc1ccc(I)cc1Cl
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1c1ccc(I)cc1Cl

Procedure:
2-Chloro-4-iodoaniline (12.65 g) and phthalic anhydride (7.4 g) are dissolved in 30 mL of dimethylformamide. The solution is heated to reflux for 16 hours. The reaction mixture is diluted with diethyl ether and washed with brine to yield a precipitate which is filtered off and washed with water and diethyl ether to yield N-(2-chloro-4-iodophenyl)phthalimide as a white solid.