Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([C:15](OCC)=[O:16])[C:12]([N+:20]([O-])=O)=[C:11]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[N:10]=2)[CH2:4][CH2:3]1.ClC1N=C([C:39](OCC)=[O:40])C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1.[NH2:56][C@H]1CC[C@H](O)CC1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:10]=[C:11]3[C:12]([NH:20][C:39](=[O:40])[N:23]3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[C:13]([C:15]([NH2:56])=[O:16])[N:14]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@H](O)CC2)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc(Cl)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CC[C@H](O)CC3)nc21

Procedure:
Ethyl 2-(trans-4-hydroxycyclohexylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate. Ethyl 2-chloro-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (See Example 30.A) (0.300 g, 0.852 mmol), trans-4-aminocyclohexanol (0.117 g, 1.022 mmol) and diisopropylethylamine were reacted according to General Procedure C, except at room temperature and in dimethylformamide (5 mL). The crude reaction mixture was condensed and purified using Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (0.303 g, 82%). MS (ESI) m/z 432.5 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@H:9]2[C:11](NC(C2C=CC=CC=2)CO)=[O:12])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:24]>O1CCOCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@H:9]2[C:11]([OH:12])=[O:24])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: O=C(NC(CO)c1ccccc1)[C@@H]1C[C@@H]1c1ccc(O)cc1
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@@H]1c1ccc(O)cc1
Temperature: 100 °C
Yield: 100 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with 22 mL of dioxan. To the stirred solvent were added (1R,2S)-2-(4-hydroxyphenyl)-N-(2-hydroxy-1-phenylethyl)cyclopropanecarboxamide (0.75 g, 2.52 mmol) and 3N sulfuric acid (22 mL). The reaction mixture was heated at 100° C. for 7 h. The reaction mixture was poured into ice and extracted with ethyl acetate (25 mL). The organic layer was washed with brine solution (25 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as pale yellow oil (0.51 g, yield: 100%). 1H NMR (300 MHz, DMSO-d6): δ 12.20 (s, 1H), 9.25 (s, 1H), 6.93-6.96 (d, 2H), 6.64-6.67 (d, 2H), 2.24-2.31 (m, 1H), 1.63-1.68 (m, 1H), 1.31-1.37 (m, 1H), 1.20-1.26 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:18][N:19]([CH3:21])[CH3:20])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Solvent: C1CCOC1
Product: CN(C)C=Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Yield: 58 %

Procedure:
2,5-Dichloro-4-methyl-nitrobenzene (50 g, 0.24 mol) was heated at reflux, in tetrahydrofuran (200 ml), with t-butoxy-bis(dimethylamino)methane (63.3 g, 0.364 mol) for 8 hours. The reaction mixture was cooled to room temperature and slowly poured into hexanes (3L) with stirring. The desired product was collected by filtration as a dark red solid, 36.9 g, 58% yield. mp 173°-5° C. NMR (CDCl3) δ 8.01 (s, 1), 7.32 (s, 1), 7.08 (d, 1), 5.27 (d, 1), 3.00 (s, 6). Analysis Calculated for C10H10N2O2Cl2 : C, 45.99; H, 3.86; N, 10.73, Found: C, 45.91; H, 3.72; N, 10.61.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:21])([F:20])[C-:5]([C:16]([F:19])([F:18])[F:17])[C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].CN([S+](N(C)C)N(C)C)C>C(#N)C1C=CC=CC=1>[Br:1][C:5]([C:16]([F:17])([F:18])[F:19])([C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C:4]([F:20])([F:21])[F:3]
Reactant: BrBr
Reactant: FC(F)(F)[C-](C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: N#Cc1ccccc1
Product: FC(F)(F)C(F)(F)C(F)(F)C(Br)(C(F)(F)F)C(F)(F)F
Yield: 75 %

Procedure:
Bromine, 7.99 g (0.05 mol), was added dropwise at 0° to a solution of 0.05 mol of tris(dimethylamino)sulfonium 1,1,1,3,3,4,4,5,5,5-decafluoro-2-(trifluoromethyl)-2-pentanide, prepared as in Example D (except for the amounts), in 40 mL of benzonitrile. The reaction mixture was warmed to 25°, and the volatile portion was distilled out under reduced pressure, and then redistilled at atmospheric pressure to give 12.8 g (75%) of 2-bromo-1,1,1,3,3,4,4,5,5,5-decafluoro-2-(trifluoromethyl)-pentane as a colorless liquid: b.p. 96.5°-97.2°; 19F NMR (CDCl3) δ -65.2 ppm (m, 6F), -81.1 ppm (t, 3F), -105.9 ppm (2F) and -122.6 ppm (2F). Anal. Calcd. for C6BrF13 : C, 18.06; F, 61.91. Found: C, 17.90; F, 61.55.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:17](=[O:18])[CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:6]1)([CH3:9])[CH3:8]
Reactant: CC(C)n1nnc(N)n1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)n1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 175-177° and MS: (neg. ions): m/e=320.2 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-isopropyl-2H-tetrazole and diphenylacetyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH:12]=[CH:11]N=C1.[C:13](#[N:15])C>>[C:2]1([N:8]2[CH:12]=[CH:11][CH:13]=[N:15]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: c1c[nH]cn1
Reactant: Brc1ccccc1
Product: c1ccc(-n2cccn2)cc1

Procedure:
Operating protocol A (82° C., 48 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 211 μl of bromobenzene (2 mmoles), 204 mg of imidazole (3 mmoles) and 1.2 ml of acetonitrile.
Reaction SMILES: [NH:1]([C:3]([O:5]C)=[O:4])[NH2:2].[CH3:7][N:8]=[C:9]=[S:10].[CH2:11](Cl)Cl>>[CH3:11][N:1]([C:3]([OH:5])=[O:4])[NH:2][C:9]([NH:8][CH3:7])=[S:10]
Reactant: CN=C=S
Reactant: ClCCl
Reactant: COC(=O)NN
Product: CNC(=S)NN(C)C(=O)O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 20 g (0.22, 0.2 mole) methyl hydrazinocarboxylate in 150 ml methylene chloride, 14.6 g (0.2 mole) methyl isothiocyanate in 50 ml methylene chloride was added dropwise. The reaction mixture was refluxed at about 40° C. for 0.5 hour, was allowed to stir overnight at ambient temperature, and was refluxed an additional 2 hours. The reaction mixture was cooled, vacuum filtered and the solids were dried to give 27.2 g of the above-identified product.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[CH2:8][CH2:9][C:10]([O:12]C)=O.[C:21]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1>>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:14]([CH2:27][C:23]2[CH:22]=[C:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:25][CH:24]=2)[C:10](=[O:12])[CH2:9][CH2:8]1
Reactant: COC(=O)CCC(N)c1ccccc1-c1ccccc1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Product: O=C1CCC(c2ccccc2-c2ccccc2)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-([1,1′-biphenyl]-2-yl)-4-aminobutanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.01 min.; [M+H]+: 403.91 g/mol.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[CH3:12][C:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:17])[C:14]([OH:16])=[O:15].[N:24]1([C:29]([NH2:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>C(Cl)(Cl)(Cl)Cl>[N:24]1([C:29]([NH2:31])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:21]1[CH:22]=[CH:23][C:18]([C:13]([CH3:17])([CH3:12])[C:14]([OH:16])=[O:15])=[CH:19][CH:20]=1)=[O:10]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(C(=O)O)c1ccccc1
Agent: NC(=O)N1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
Add AlCl3 (8.31 g, 62.3 mmol) to carbon tetrachloride (65 mL) under a nitrogen atmosphere at room temperature. Add 4-chlorobutyryl chloride (03.5 mL, 31.2 mmol), stir for 15 minutes and add, by dropwise addition over 15 minutes, a solution of 2-methyl-2-phenyl-propionic acid, pyrrolidineamide (5.64 g,. 26.0 mmol) in carbon tetrachloride (60 mL). Stir at room temperature for 17 hours, pour into ice water (100 mL) and separate the layers. Wash the aqueous layer with methylene chloride (2×70 mL), 5% aqueous sodium hydrogen carbonate, combine the organic layers and dry (Na2SO4). Filter, evaporate the filtrate in vacuo and purify by silica gel chromatography (5:2 hexane/ethyl acetate) to give the title compound (6.55 g, 78%) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].Cl.[NH2:14][OH:15].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5](=[N:14][OH:15])[NH2:6]
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C(N)=NO)ccc1[N+](=O)[O-]

Procedure:
To a solution of 3-methyl-4-nitrobenzonitrile (5 g) in ethanol (100 ml) at room temperature was added hydroxylamine hydrochloride (2.25 g) followed by triethylamine (4.5 ml). The mixture was heated under reflux for 2.5 hours. On cooling the mixture was evaporated to a third of its original volume and poured on to water (200 ml). The mixture was filtered to give the title product as a solid, m.p. 127-9° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:17][C:18]1[C:26]([F:27])=[C:25]2[C:21]([C:22]([CH3:31])([CH3:30])[C:23](=[O:29])[N:24]2[CH3:28])=[CH:20][C:19]=1[F:32]>CN(C=O)C.C([O-])(O)=O.[Na+]>[F:32][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([F:27])[C:18]=1[NH:17][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1)[N:24]([CH3:28])[C:23](=[O:29])[C:22]2([CH3:31])[CH3:30]
Reactant: CN1C(=O)C(C)(C)c2cc(F)c(N)c(F)c21
Reactant: O=C(O)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C(=O)C(C)(C)c2cc(F)c(NC(=O)c3ccncc3)c(F)c21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of isonicotinic acid (70 mg, 0.569 mmol) in DMF (2 ml) were added triethylamine (0.24 ml, 1.7 mmol) and Mukaiyama reagent (312 mg, 1.13 mmol) followed by the addition of 6-amino-5,7-difluoro-1,3,3-trimethyl-1,3-dihydro-indol-2-one (154 mg, 0.682 mmol). The resultant reaction mixture was stirred at 25° C. for 12 hours. The mixture was diluted with saturated aqueous NaHCO3 solution (10 ml), and extracted with dichloromethane (2×20 ml). The combined organic layers were washed with brine (15 ml), dried over anhydrous Na2SO4 and the solvent was evaporated. The crude material was purified by column chromatography with amine functionalized silica gel using ethyl acetate/heptane as eluent, followed by purification by prep-HPLC. The title compound was obtained as off-white solid (45 mg).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:39])[NH:32][C:33]5[S:37][N:36]=[C:35]([CH3:38])[CH:34]=5)=[CH:27][C:26]=4[NH:40][C:41]4[C:42]5[CH:50]=[CH:49][C:48]([CH:51]([CH3:53])[CH3:52])=[N:47][C:43]=5[N:44]=[CH:45][N:46]=4)=[CH:20][CH:19]=3)C3C(=CC=CC=3)C=2C=CC=1.O.[OH-].[Li+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:32][C:33]3[S:37][N:36]=[C:35]([CH3:38])[CH:34]=3)=[O:39])=[CH:27][C:26]=2[NH:40][C:41]2[C:42]3[CH:50]=[CH:49][C:48]([CH:51]([CH3:53])[CH3:52])=[N:47][C:43]=3[N:44]=[CH:45][N:46]=2)=[CH:20][CH:19]=1
Reactant: Cc1cc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)sn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NC(=O)c2ccc(Sc3ccc(N)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)sn1
Temperature: 70 °C
Yield: 71.1 %

Procedure:
A solution of the product of Example 167C (117 mg, 0.156 mmol) in 1,4-dioxane (4 mL) was treated with a solution of lithium hydroxide monohydrate (13.1 mg, 0.312 mmol) in water (2 mL) at ambient temperature, then heated at 70° C. for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL) and water (25 mL), adjusted the aqueous pH to 5 with 1N aqueous hydrochloric acid, and separated the layers. The organic phase was washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Purification of the residue by silica gel chromatography eluting with 5% methanol/methylene chloride afforded the title compound as a light yellow solid (58.5 mg, 71%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 2.33 (s, 3 H) 3.14-3.30 (m, 1 H) 5.63 (s, 2 H) 6.65 (d, J=8.46 Hz, 2 H) 6.87 (s, 1 H) 6.91 (d, J=8.82 Hz, 1 H) 7.15 (d, J=8.46 Hz, 2 H) 7.65 (d, J=8.09 Hz, 1 H) 7.86 (d, J=7.72 Hz, 1 H) 8.03 (s, 1 H) 8.59 (s, 1 H) 8.89 (d, J=8.09 Hz, 1 H) 10.19 (s, 1 H) 12.17 (s, 1 H); MS (ESI+) m/z 528 (M+H)+, (ESI−) m/z 526 (M−H)−.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[OH-].[Na+].Br[CH2:16][CH2:17][CH2:18][OH:19].Cl>O.C(Cl)(Cl)Cl>[OH:19][CH2:18][CH2:17][CH2:16][O:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([OH:12])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6]
Reactant: OCCCBr
Reactant: COc1cc(C(=O)O)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)O)ccc1OCCCO

Procedure:
Vanillic acid (C1) (114.5 g, 0.68 mol) was dissolved in a solution of sodium hydroxide (54.5 g, 1.36 mol) in water (400 mL). 3-Bromopropan-1-ol (101.3 g, 0.73 mol, 1.07 eq) was added and the mixture was heated under reflux for 5 hours. The mixture was cooled and acidified with 2.5 M HCl. The resulting precipitate was filtered and dried under vacuum. Recrystallisation from butan-2-one gave the product as an off white solid. (110 g, 71%). mp: 162° C.; 1H NMR (DMSO-d6, 400 MHz) δ 7.56 (dd, 1H, J=1.98 Hz, J=8.39 Hz), 7.44 (d, 1H, J=1.96 Hz), 7.04 (d, 1H, J=8.50 Hz), 4.55 (bs, 1H), 4.09 (t, 2H, J=6.37 Hz), 3.80 (s, 3H, OMe), 3.57 (t, 2H, J=6.20 Hz), 1.88 (p, 2H, J=6.29 Hz); 13C NMR (100 MHz, DMSO-d6) δ167.1, 152.0, 123.1, 122.7, 112.0, 111.7, 65.3, 57.2, 55.4, 31.9; IR (CHCl3) 1673, 1596, 1585, 1517, 1425, 1271, 1227, 1188, 1134, 1051, 1026, 951, 876, 814, 758 cm−1; MS (ES−) m/z (relative intensity) 225.04 ([M−H]−, 100).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C-:9]#[N:10].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.[Cu]I>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: [C-]#N
Agent: [Cu]I
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cnc(N)cn1
Temperature: 155 °C
Reaction time: 0.67 h

Procedure:
5-Bromo-pyrazin-2-ylamine was combined with copper (I) iodide (1.3 g, 6.9 mmol), potassium cyanide (0.44 g, 6.8 mmol), tetrakis (triphenylphosphine)palladium(0) (0.95 g, 0.83 mmol), and 18-crown-6 (0.058 g, 0.22 mmol) in DMF (15 mL). The resulting mixture was stirred for 40 min, then heated at reflux (155° C.) for 2 h. The reaction was cooled to room temperature, then allowed to stand overnight. The precipitate was separated by filtration and the filtrate was concentrated to dryness in vacuo. The orange-colored residue was taken up in EtOAc and hexanes and an initial precipitate was formed, then separated by filtration. Upon standing, additional precipitate formed in the mother liquor and was collected by filtration. The solids were combined to yield 0.10 g of a bright orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)C>[ClH:1].[C:8]([C:7]1[C:2]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)[CH:6]=1)#[N:9]
Reactant: C1CNCCN1
Reactant: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1Cl
Solvent: CCO
Product: Cl
Product: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1N1CCNCC1

Procedure:
A mixture of 2 g 2-chloro-3-cyano-5,4'-bipyridine-1'-oxide, 0.8 g piperazine, 0.52 g of KHCO3 and 80 ml ethanol is refluxed for 3 hours and then evaporated to dryness under vacuum. The residue is dissolved in 10 ml 1N HCl and the solution is mixed with ethanol until crystallization occurs. After cooling overnight, the crystals that are formed are filtered off with suction and dried at 110° C. Yield: 2.23 g (81.2% of the theoretical yield), having a melting point of 255° C.-260° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=2[C:10]([CH3:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)C.N1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([Cl:20])[N:14]=[CH:15][C:16]([C:17]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:19])=[C:11]2[C:10]([CH3:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN1CCOCC1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCN1
Product: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-3-methyl-pyrrolo[2,3-c]pyridine-1,4-dicarboxylic acid 1-tert-butyl ester (80 mg) in dimethylformamide (2 ml) was added 4-ethylmorpholine (131 μl), morpholine (46 μl), 1-hydroxybenzotriazole hydrate (54 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg) and the solution stirred at room temperature overnight. The dimethylformamide was evaporated and the residue dissolved in ethyl acetate (20 ml). The organic layer was then washed with 5% sodium hydrogen carbonate solution (2×4 ml) and water (2×10 ml). The organic layer was dried (MgSO4) and evaporated to give a yellow oil (107 mg) which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]2[O:18][C:17](=S)[NH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:17]1[O:18][C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: S=c1[nH]cc(-c2ccccc2)o1
Solvent: CCN(CC)CC
Product: Clc1ncc(-c2ccccc2)o1
Temperature: 0 °C

Procedure:
0.29 g (2.8 mmol) of triethylamine is added to a mixture of 0.5 g (2.8 mmol) of 5-phenyl-3H-oxazole-2-thione (FR 1,450,443) and 2.3 mL of phosphoryl chloride cooled to 0° C. The mixture is heated to 120° C. for 3 hours.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH:4]([CH3:16])[C:5]([NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CC(C)([O-])C.[K+].O.C1(C)C=CC=CC=1>O1CCCC1>[F:1][C:2]([F:17])([F:18])[CH2:3][C@@H:4]([CH3:16])[C:5]([NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6]
Reactant: CC(CC(F)(F)F)C(=O)N[C@@H](C)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](CC(F)(F)F)C(=O)N[C@@H](C)c1ccccc1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
10 g of 4,4,4-trifluoro-2-methyl-N-[(S)-1-phenylethyl]butyramide (diastereomer ratio 2(S):1(R), prepared by a method similar to that described in step c)above) was dissolved in tetrahydrofuran (25 ml) with stirring. Potassium t-butoxide (2.02 g) was then added, together with tetrahydrofuran (5 ml). The resultant solution was then stirred for one hour, by which time complete equilibration of the diastereomers had occured, as monitored by HPLC analysis. Water was then added with cooling to maintain the temperature at 20°-25° C. The solution was then stirred for 10 minutes, and then toluene (25 ml) was added, and the stirring was continued for a further 15 minutes. The organic layer was then separated, washed with water (12.5 ml) and concentrated by distillation at atmospheric pressure to a temperature of 110° C. The volume was adjusted to 80 ml by adding toluene, and the mixture heated under reflux. Petroleum ether (b.p. 100°-120° C.) (80 ml) was then added. The solution was then allowed to cool to 40° C., seeded with (R)-4,4,4-trifluoro-2-methyl-N-[(S)-1-phenylethyl]butyramide and held at 40° C. for 2 hours. The mixture was then allowed to cool to 30° C., and was stirred overnight. The crystalline product was then filtered off, washed with petroleum ether (b.p. 100°-120° C.) and dried at 65° C. to afford 3.20 g (32%) of (R)-4,4,4-trifluoro-2-methyl-N-[(S)-1-phenylethyl]butyramide contaminated with about 6% of the undesired (S) diastereomer. ##STR2##
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=O)[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N)CCCC>ClCCl>[CH2:33]([NH:32][C:15](=[O:17])[C@H:12]([CH2:13][OH:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: c1ccncc1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCN
Product: CCCCCNC(=O)[C@H](CO)NC(=O)OCc1ccccc1

Procedure:
A 5-L, 3-necked flask was charged with N-CBZ-L-serine (110 g, 0.46 mole) (CBZ =carbobenzyloxy) followed by dichloromethane (2.1 L). The resulting slurry was stirred under argon and treated with triethylamine (61.7 mL, 0.443 mole) over several minutes. The resulting hazy solution was cooled to an internal temperature of -35° and treated over 10 minutes with trimethylacetylchloride (51.06 mL, 0.415 mole) such that the internal temperature did not rise above -30°. The reaction was stirred an additional 40 minutes at -25° to -30°, treated with pyridine (35.2 mL, 0.435 mole) over 5 minutes and stirred an additional 10 minutes. Amylamine (51 mL, 0.44 mole) was added over 10 minutes while maintaining the internal temperature at -25° to -29°. The reaction was stirred for 30 minutes while warming to -25°. A precipitate formed during this warming. The reaction was further warmed to -10° over 40 minutes during which time the precipitate redissolved. After stirring an additional 20 minutes at -10°, the reaction was quenched by the addition of 500 mL of 1N HCl. The biphasic mixture was stirred for 20 minutes and transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (2×75 mL). The combined dichloromethane solutions were concentrated in vacuo to a weight of 500 g. Ethyl acetate (EtOAc) (2.25 L) was added and the organic solution was washed with 1N HCl (2×400 mL) and 1N K2CO3 (1×700 mL and 2×500 mL). The organic solution was dried (magnesium sulfate), filtered and concentrated in vacuo to the title compound which was used in the next step without purification.