Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])=[CH:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.[CH:30](OCC)=[O:31]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])=[C:9]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:30]=[O:31])=[C:4]([CH3:24])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(=Cc1nnnn1C)c1ccc(F)cc1C
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C(=C(C=O)c1nnnn1C)c1ccc(F)cc1C
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
To a solution of 1,1-bis(4-fluoro-2-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethene (1.6 g, 5.0 mmoles) in tetrahydrofuran at -70° C. was added butyl lithium (2.3 mL of 2.2M solution, 5.0 mmoles). After stirring for 0.25 hour, ethyl formate (0.44 g, 6.0 mmoles) was added and the mixture stirred for 2 hours. The reaction was quenched with 1N hydrochloric acid and the mixture was extracted with methylene chloride. The extracts were dried and concentrated in vacuo to give 1.0 g of the title compound; m.p.=135°-136° C.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([C:6](C2C(NC(=O)C3C=CC=CC=3)=CC3CCCCC=3C=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.C(O)C.O>[C:2]1([CH3:1])[CH:28]=[CH:27][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2cc3c(cc2NC(=O)c2ccccc2)CCCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C=O)cc1

Procedure:
To a 50 mL flask containing a stirred solution of N-[3-(4-methyl-benzoyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-benzamide (191 mg, 517 μmol) in tetrahydrofuran (5 mL), ethanol (5 mL) and water (1 mL) under nitrogen was added sodium hydroxide (340 mg, 8.5 mmol) and heated at reflux overnight. Heating was discontinued and solvents removed in vacuo. Added water (20 mL) and extracted with ethyl acetate (3×20 mL). Combined organics were dried with magnesium sulphate and evaporated in vacuo to give 3-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-p-tolyl-methanone as a partially crystalline red oil 146 mg (107% Yield). LCMS (5 min acidic) 2.99 min 100% pure by ELSD and UV ES+ and AP+ 266. HNMR (CDCl3) >90% pure 7.57-7.55 (m, 2H), 7.27-7.24 (m, 2H), 7.16 (s, 1H), 6.46 (s, 1H), 5.63 (br-s, 2H), 2.72-2.69 (m, 2H), 2.59-2.56 (m, 2H), 2.43 (s, 3H), 1.77-1.73 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH2:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([NH:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH3:9])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccnc1Cl
Reactant: Cc1ccccc1CN
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1CNc1nccnc1N
Yield: 19.7 %

Procedure:
A mixture of 2-amino-3-chloropyrazine (4.3 g), 2-methylbenzylamine (4.6 g), potassium carbonate (5.5 g), and potassium iodide (0.4 g) in N,N-dimethylformamide (43 ml) was refluxed for 24 hours under a nitrogen atmosphere and allowed to stand at room temperature. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (110 g) with a mixture of chloroform and methanol (100:3) as an eluent to give 2-amino-3-(2-methylbenzylamino)pyrazine (1.4 g).
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[C:7]([C:12]#[C:13][Si](C)(C)C)=[N:8][CH:9]=[CH:10][CH:11]=1)C.[O-]CC.[Na+]>C(O)C.[Cl-].[Na+].O>[NH:5]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:12]=[CH:13]1
Reactant: CCOC(=O)Nc1cccnc1C#C[Si](C)(C)C
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1cnc2cc[nH]c2c1
Reaction time: 1 h
Yield: 63.5 %

Procedure:
(2-Trimethylsilanylethynyl-pyridin-3-yl)carbamic acid ethyl ester described in Preparation Example S-3 (0.42 g, 1.6 mmol) was dissolved in ethanol (8 mL), sodium ethoxide (204 mg, 3 mmol) was added thereto, followed by stirring for 1 hour under reflux. After the reaction was completed, the reaction mixture was poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then evaporated, the resulting solid was washed with solvent (diethylether:hexane=1:2), and the title compound (0.12 g, 1 mmol, 63.5%) was obtained.
Reaction SMILES: ClC(OCC(C)C)=O.C[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[NH2:16][C:17]1[N:26]=[C:25]([C:27]([OH:29])=O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.OC1CCNC1>CN(C=O)C>[NH2:16][C:17]1[N:26]=[C:25]([C:27]([N:10]2[CH2:15][CH2:14][CH:12]([OH:13])[CH2:11]2)=[O:29])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: CN1CCOCC1
Reactant: Nc1nc(C(=O)O)c2ccccc2n1
Agent: CC(C)COC(=O)Cl
Agent: OC1CCNC1
Solvent: CN(C)C=O
Product: Nc1nc(C(=O)N2CCC(O)C2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
68.76 μl of isobutyl chloroformate and 63.93 μl of 4-methylmorpholine are added to a solution of 100 mg of 2-amino-4-carboxyquinazoline in 2 ml of DMF. The mixture is stirred at room temperature for 30 minutes, 50.66 mg of 3-hydroxypyrrolidine are added, and the mixture is stirred for a further 30 minutes. Conventional work-up gives 55.7 mg of “A17”; Rt 0.797; M+H+ 259.28.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:17]C)(OC)[CH3:14])=[CH:9][CH:8]=1.[CH3:19][C:20]1([CH3:29])[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22](=[O:28])[CH2:21]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[OH:28][C:22]1([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:17])[CH3:14])=[CH:11][CH:12]=2)[CH2:23][C:24]([CH3:27])([CH3:26])[CH2:25][C:20]([CH3:29])([CH3:19])[CH2:21]1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: COC(C)(OC)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C2(O)CC(C)(C)CC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
27.5 ml of a 1.6 M solution of n-butyllithium in hexane are added dropwise at −78° C. to a solution of 10 g of 1-bromo-4-(1,1-dimethoxyethyl)benzene (compound Vp) in 100 ml of tetrahydrofuran. The reaction mixture is stirred for 2 hours at this temperature. A solution of 6.92 ml of 3,3,5,5-tetramethylcyclohexanone in 20 ml of tetrahydrofuran is added over 20 minutes and the reaction mixture is stirred at −78° C. for 1 hour. After warming to room temperature, 140 ml of saturated aqueous ammonium chloride solution are added. The phases are separated after settling has taken place, the aqueous phase is extracted with diethyl ether, the organic phases are combined and dried over magnesium sulphate, and the solvents are evaporated off under reduced pressure. The oil obtained is purified by chromatography on a column of silica gel, eluting with a 95/5 (v/v) cyclohexane/ethyl acetate mixture; yield=88%; m.p.=135° C. The following compounds are prepared in the same way:
Reaction SMILES: C([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:14])(=O)C.C(NC1C=CC([N+]([O-])=O)=CC=1C)(=O)C>>[NH2:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:14]
Reactant: CC(=O)Nc1c(C)cccc1[N+](=O)[O-]
Agent: CC(=O)Nc1ccc([N+](=O)[O-])cc1C
Product: Cc1cccc([N+](=O)[O-])c1N
Yield: 46 %

Procedure:
The wet mixture of 2-acetylamino-3-nitrotoluene (4) and 2-acetylamino-5-nitrotoluene as obtained in Preparation Example 1 was placed in a steam distillation apparatus, and 300 ml of concentrated hydrochloric acid was added thereto. Immediately on heating and boiling, the mixture was hydrolyzed. The boiling was continued until 36 l of a distillate was collected. On cooling the distillate, there was obtained 2-amino-3-nitrotoluene (5) as an orange needle-like crystal having a melting point of 92.8° to 93.2° C. and a 46% yield.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15].C([BH3-])#N.[Na+]>CO.O>[C:9]([CH:8]([NH:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:11])=[O:10]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H](NC(Cc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A mixture of phenylpyruvic acid (753 mg) and L-alanyl-L-proline (171 mg) in methanol-water are adjusted to pH 6.8 and treated with sodium cyanoborohydride (173 mg) at room temperature until reaction is complete. The product is absorbed on strong cation exchange resin and eluted with 2% pyridine in water to give 294 mg of crude diastereomeric product, N-(1-carboxy-2-phenylethyl)-L-alanyl-L-proline. A portion is purified by gel filtration (LH-20) for spectrographic analysis. The nmr spectrum shows a broad singlet at 7.2, complex absorption from 3.0 to 4.6, a multiplet at 2.1 and a pair of doublets at 1.5 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=2)[N:26]=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:23]4[C:32]5[C:27](=[CH:28][C:29]([C:33]([F:36])([F:34])[F:35])=[CH:30][CH:31]=5)[N:26]=[CH:25][CH:24]=4)=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(CN2CCN(c3ccc(Br)cc3)CC2)cc1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Product: FC(F)(F)c1ccc2c(Nc3ccc(CN4CCN(c5ccc(Br)cc5)CC4)cc3)ccnc2c1

Procedure:
In the manner given in Example 1C, 1-(4-bromophenyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(4-bromophenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][C@H:17]3[C@H:21]([OH:22])[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][C@H:17]3[C@H:21]([OH:22])[CH2:20][NH:19][CH2:18]3)=[O:15])=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NC(=O)c2ccc(-c3cccc(F)c3)nc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(N[C@@H]1CNC[C@H]1O)c1ccc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.4 %

Procedure:
To a solution of trans-tert-butyl 3-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)-4-hydroxypyrrolidine-1-carboxylate (500 mg, 1.24 mmol) in dioxane was added 4N HCl in dioxane (10 mL). The reaction was stirred at room temperature for ˜4 hrs and then diluted with ether to give a white solid, which was filtered and collected to give the desired product as the hydrochloride salt, trans-6-(3-fluorophenyl)-N-[4-hydroxypyrrolidin-3-yl]nicotinamide (390 mg, 92% ). LC/MS (M+H)=301.9 observed, 302.13 expected.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:44][C:45]([CH3:65])=[CH:46][CH2:47][CH2:48]/[C:49](/[CH3:64])=[CH:50]/[CH2:51][CH2:52]/[C:53](/[CH3:63])=[CH:54]/[CH2:55][S:56][CH2:57][C@H:58]([NH2:62])[C:59]([OH:61])=[O:60]>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1([C:8](=[O:10])[NH:62][CH:58]([C:59]([OH:61])=[O:60])[CH2:57][S:56][CH2:55][CH:54]=[C:53]([CH3:63])[CH2:52][CH2:51][CH:50]=[C:49]([CH3:64])[CH2:48][CH2:47][CH:46]=[C:45]([CH3:65])[CH3:44])[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
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: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1(C(=O)NC(CSCC=C(C)CCC=C(C)CCC=C(C)C)C(=O)O)CC1
Temperature: 25 °C

Procedure:
In a 100 mL round bottom flask, 1,1-Cyclopropanedicarboxylic acid monomethyl ester (158 mg, 1.1 mmol), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.1 mg, 1.1 mmol) and N,N-diisopropyl-ethyl-amine (0.52 mL, 3 mmol) were mixed in THF (5 mL). The reaction solution was stirred at room temperature for ten minutes. S-trans, trans-Farnesyl-L-cysteine (325 mg, 1 mmol) was added to reaction mixture. The reaction solution was stirred at room temperature overnight. Ethyl acetate (50 mL) was added and then washed with saturated ammonium chloride aqueous solution (20 mL×2), DI water (20 mL×2) and brine (20 mL×2) sequentially. The ethyl acetate solution was dried by Na2SO4 and concentrated in vacuo to afford crude Compound N-52. The crude Compound N-52 was purified by HPLC (120 mg, 27%) to yield Compound N-52. 1H-NMR (500 MHz, MeOH-d4): δ 1.45-1.48 (m, 4H), 1.50 (s, 6H), 1.57 (s, 3H), 1.58 (s, 3H), 1.85-1.89 (m, 2H), 1.93-1.98 (m, 4H), 2.01-2.05 (m, 2H), 2.78-2.91 (m, 2H), 3.06-3.15 (m, 2H), 3.62 (s, 3H), 4.56 (t, J=5.0 Hz, 1H), 4.97-5.02 (m, 2H), 5.12 (t, J=7.5 Hz, 1H). 13C-NMR (125 MHz, MeOH-d4): δ 9.2, 16.14, 16.20, 17.80, 20.05, 25.95, 27.31, 27.37, 27.78, 30.61, 33.62, 40.74, 40.88, 52.96, 53.97, 121.61, 125.11, 125.45, 132.11, 136.28, 140.59, 170.81, 173.75, 174.39; ES-MS: mass calcd for Chemical Formula: C24H37NO5S 451.2. Found (M+Na) m/z 474.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:5]([NH2:17])=[C:4]([Cl:18])[N:3]=1.C(O)(=O)C.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>CO>[NH2:1][C:2]1[N:7]=[C:6]2[C:5]([N:17]=[C:27]([C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([F:23])[CH:25]=3)[N:8]2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[C:4]([Cl:18])[N:3]=1
Reactant: O=Cc1cccc(F)c1
Reactant: N#Cc1cccc(Nc2nc(N)nc(Cl)c2N)c1
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1cccc(-n2c(-c3cccc(F)c3)nc3c(Cl)nc(N)nc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude crystals (3.2 g) of 3-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]benzonitrile were dissolved in 64 ml of methanol, then 3.2 ml of acetic acid and 1.7 ml of 3-fluorobenzaldehyde were added thereto and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and was subjected to an azeotropy with toluene for two times. The resulting residue after concentration was dissolved in ethanol, a solution of 1.72 g of ferric chloride in 10 ml of ethanol was added and the mixture was heated under reflux for 1 hour. The reaction solution was returned to room temperature, concentrated to dryness and added to ice-water and the resulting crystals were collected by filtration to give 2.6 g of the title compound, i.e. 3-[2-amino-6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]benzonitrile.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5](OB(O)O)=[CH:4][CH:3]=1.Br[C:13]1[CH:27]=[CH:26][C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(OC)(C)C>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[N:7]=[CH:6][C:5]([C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: OB(O)Oc1ccc(F)nc1
Reactant: Brc1ccc(OCCN2CCOCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: COC(C)(C)C
Product: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Temperature: 80 °C
Reaction time: 17 h
Yield: 101 %

Procedure:
A 72 L reactor equipped with reflux condenser, sparging tube, bubbler, and temperature probe was charged with 6-fluoropyridin-3-ylboric acid (2.84 kg, 1.24 equiv.), 4-(2-(4-bromophenoxy)ethyl)morpholine (4.27 kg, 1.0 equiv.), and DME (27 L). Agitation was started and sodium carbonate (4.74 kg, 3.0 equiv.) as a solution in DI water (17.1 L) was then charged to the reaction mixture. Argon was bubbled through the reaction mixture for 50 minutes. Under an argon atmosphere, tetrakis(triphenylphosphine)palladium (750 g, 0.04 equiv.) was added to the reaction mixture as a slurry in DME (1.0 L). The reaction mixture was heated to 75-85° C. and stirred overnight (17 h). The reaction mixture was cooled to between 18-22° C. DI water (26.681 kg) and MTBE (26.681 L) were charged to the reactor and stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with MTBE (2×26.7 L). The combined organics were extracted with 2M HCl (1×15.0 L, 3×21.8 L). The aqueous phase was then charged back to the reactor and ethyl acetate was added (26.7 L). The pH was adjusted to 6.2 using 6 M sodium hydroxide (26.7 L) while maintaining a temperature between 15-25° C. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×26.7 L). The combined organics were dried with magnesium sulfate and concentrated to give 4555 g of a residue (101% crude yield, 67.1% AUC by HPLC).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl:24][C:25]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]([C:32]([F:35])([F:34])[F:33])[N:26]=1.C(N(CC)CC)C>C1COCC1.CN(C=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:31][C:30]1[C:25]([Cl:24])=[N:26][C:27]([C:32]([F:34])([F:33])[F:35])=[CH:28][CH:29]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)nc1Cl
Reactant: O=C(O)c1ccccc1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)nc1Cl)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.4 %

Procedure:
To a stirring solution of 2-(benzyloxy)benzoic acid (2.55 g, 11.19 mmol) and oxalyl chloride (2.84 g, 22.39 mmol) in THF (20 mL) was added a few drops of DMF (0.012 mL, 0.153 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and further stirred 30 minutes, diluted with toluene and then solvent evaporated. The residue was taken up in THF (20 mL) and to this solution was added 2-chloro-6-(trifluoromethyl)pyridin-3-amine (2.0 g, 10.18 mmol) at 0° C. followed by the addition of triethylamine (4.68 mL, 33.6 mmol). The reaction mixture was allowed to stir 3 days at room temperature then quenched with saturated bicarbonate solution, extracted with EtOAc and solvent evaporated to afford title compound 72 (3.0 g, 73% yield) after purification by flash chromatography (0 to 100% ethyl acetate in hexane). LRMS (ESI): (calc) 406.07. (found) 407.4 (MH)+.
Reaction SMILES: [C:1](Cl)(=[O:17])[O:2][CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15].[CH2:19]([S:21][S:22][CH2:23][C@H:24]([NH:28][CH3:29])[C:25]([OH:27])=[O:26])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>O1CCOCC1.O>[CH3:13][O:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:4]([CH2:3][O:2][C:1]([N:28]([CH3:29])[C@@H:24]([CH2:23][S:22][S:21][CH2:19][CH3:20])[C:25]([OH:27])=[O:26])=[O:17])=[C:5]([N+:14]([O-:16])=[O:15])[CH:6]=1
Reactant: COc1cc(COC(=O)Cl)c([N+](=O)[O-])cc1OC
Reactant: CCSSC[C@H](NC)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: CCSSC[C@@H](C(=O)O)N(C)C(=O)OCc1cc(OC)c(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
4,5-Dimethoxy-2-nitrobenzyl carbonochloridate (394 mg, 1.43 mmol) was added to a solution of (R)-3-(ethyldisulfanyl)-2-(methylamino)propanoic acid (Compound 2f-F) (232 mg, 1.19 mmol) and sodium carbonate (252 mg, 2.38 mmol) in dioxane (3 ml) and water (3 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (3 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→0/100) to afford (R)-2-((((4,5-dimethoxy-2-nitrobenzyl)oxy)carbonyl)(methyl)amino)-3-(ethyldisulfanyl)propanoic acid (Compound 2k-F) (483 mg, 93%).
Reaction SMILES: [CH3:1][N:2]1[C:11](O)([C:12]([NH:14][C:15]([NH2:17])=[O:16])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:19]>ClC1C=CC=CC=1Cl>[CH3:1][N:2]1[C:11]2([C:12](=[O:13])[NH:14][C:15](=[O:16])[NH:17]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:19]
Reactant: CN1C(=O)Nc2ccccc2C1(O)C(=O)NC(N)=O
Solvent: Clc1ccccc1Cl
Product: CN1C(=O)Nc2ccccc2C12NC(=O)NC2=O
Reaction time: 1.5 h
Yield: 57.2 %

Procedure:
3-Methyl-4-hydroxy-4-ureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline (1.5 g) is added to 1,2-dichlorobenzene (30 ml), and the mixture is refluxed with stirring for 1.5 hour. After cooling, the precipitates are taken by filtration and recrystallized from dimethylsulfoxide to give 3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (0.8 g).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([NH2:10])=[O:9])[C:3]1=[O:11].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[C:37]1([CH2:43][O:44][C:45]2[C:50]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[CH:49][N:48]=[C:47]([C:59](O)=[O:60])[CH:46]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O>[C:37]1([CH2:43][O:44][C:45]2[C:50]([O:51][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[CH:49][N:48]=[C:47]([C:59]([NH:1][N:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]([NH2:10])=[O:9])[C:3]3=[O:11])=[O:60])[CH:46]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)cn1
Reactant: NC(=O)N1CCCN(N)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)N1CCCN(NC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)cn2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of 3-aminotetrahydro-2-oxo-1(2H)-pyrimidinecarboxamide (10 g, 63.2 mmol) in 350 ml N,N-dimethylformamide were added dicyclohexylcarbodiimide (15.7 g, 75.9 mmol), N-hydroxybenzotriazole (0.97 g, 6.32 mmol) and 4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid (21.2 g, 63.2 mmol) and the mixture was stirred overnight at room temperature. Dicyclohexylurea (13.6 g) was filtered off and the solvent was removed in vacuo. Trituration of the residue with ether gave 27.5 g of the desired product, melting point 192°-195° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH3:17])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:21][CH2:22][C:23]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:24]=1[N:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:44]=2)[C:39]1=[O:51])(=O)C>>[C:47]([C:43]1[CH:44]=[C:45]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:51])[N:38]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([C:2]3[N:3]=[C:4]([NH:10][C:11]4[CH:12]=[N:13][N:14]([CH2:16][CH3:17])[CH:15]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:23]=1[CH2:22][OH:21])[CH2:46]2)([CH3:50])([CH3:48])[CH3:49]
Reactant: CCn1cc(Nc2nc(Br)cn(C)c2=O)cn1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Product: CCn1cc(Nc2nc(-c3cccc(N4Cc5cc(C(C)(C)C)ccc5C4=O)c3CO)cn(C)c2=O)cn1
Yield: 48.2 %

Procedure:
Using the same general procedure as Example 105, reaction of 111c (253 mg, 0.85 mmol) and 103f (473 mg, 1.02 mmol) afforded a 48% yield (210 mg) of 111 as an off-white solid: mp 138-140° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.17 (s, 1H), 7.72 (m, 3H), 7.61 (m, 2H), 7.51 (t, 1H, J=7.6 Hz), 7.43 (m, 1H), 7.31 (s, 1H), 4.94 (s, 2H), 4.88 (t, 1H, J=5.0 Hz), 4.49 (d, 2H, J=5.0 Hz), 4.06 (q, 2H, J=7.1 Hz), 3.52 (s, 3H), 1.37 (s, 9H), 1.33 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 513.2 (M+H).