Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:12]([C:13](O)=[O:14])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].O1CCCC1>CCOCC>[OH:14][CH2:13][C@H:12]1[CH2:11][CH2:10][CH2:9][N:8]1[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CO

Procedure:
In accordance with Scheme I, N-α-t-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M borane-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)C(O)=O)[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2].C([N:37](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH2:1]([N:3]([CH2:33][CH3:34])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:24]3[CH:32]=[CH:31][CH:30]=[C:26]([NH2:37])[CH:25]=3)[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCCC(C)CN1CCC(c2cccc(C(=O)O)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CCCC(C)CN1CCC(c2cccc(N)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Temperature: 120 °C
Reaction time: 22 h
Yield: 63.5 %

Procedure:
To a stirring solution of 3-[4-(5-Diethylcarbamoyl-pyrimidin-2-yl)-1-(2-methyl-pentyl)-piperidin-4-yl]-benzoic acid (210 mg, 0.45 mmol) in 8 mL Toluene and 2 mL tert-butyl alcohol at room temperature was added triethylamine (0.066 mL, 0.48 mmol) and diphenylphosphoryl azide (0.07 mL, 0.45 mmol). The resulting mixture was heated at 120° C. for 20 hours, cooled to room temperature, washed with water, dried and concentrated. The resulting residue was taken up in EtOH/5N HCl (1:1) and stirred at room temperature for 22 hours. The resulting mixture was basified (pH=9) with NaOH and extracted with EtOAc (3×20 mL). The combined organic layers were dried and concentrated. Purification of the crude material was accomplished by flash chromatography with a solvent gradient of 5% and 10% MeOH/CH2Cl2 to yield 125 mg of the desired product. 1HNMR (400 MHz, CDCl3) δ 8.71 (s, 2H), 7.02 (t, 1H), 6.76 (d, 1H), 6.71 (s, 1H), 6.45 (d, 1H), 3.57-3.52 (comp, 4H), 3.28-3.26 (comp, 2H), 2.93-2.89 (comp, 2H), 2.71 (br s, 2H), 2.33 (br s, 2H), 2.15-1.96 (comp, 4H), 1.61 (br s, 1H), 1.38-1.17 (comp, 10H), 1.03-0.96 (comp, 1H), 0.86-0.83 (comp, 6H); MS (M+1) 438.6.
Reaction SMILES: C[Li].Br[C:4]1[CH:5]=[C:6]([N:10]([CH3:19])[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])[CH:7]=[CH:8][CH:9]=1.C([Li])(C)(C)C.[B:25](OC)([O:28]C)[O:26]C.Cl>C(OCC)C.CCCCC.O1CCCC1>[CH3:19][N:10]([C:6]1[CH:5]=[C:4]([B:25]([OH:28])[OH:26])[CH:9]=[CH:8][CH:7]=1)[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12]
Reactant: COB(OC)OC
Reactant: CCCCCNC(=O)N(C)c1cccc(Br)c1
Agent: Cl
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCOCC
Product: CCCCCNC(=O)N(C)c1cccc(B(O)O)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
150 mL (0.24 mol) of methyllithium at 1.6M in diethyl ether are added to a solution cooled to −70° C. of 123 g (0.41 mol) of 1-(3-bromophenyl)-1-methyl-3-pentylurea in 1.21 of tetrahydrofuran. The reaction medium is stirred at −70° C. for 1 hour and 530 mL (0.91 mol) of a 1.7M solution of tert-butyllithium in pentane are added. The reaction medium is stirred at −70° C. for 45 minutes and 115 mL (0.91 mol) of trimethyl borate are then added. The reaction medium is stirred at room temperature for 1 hour and then hydrolyzed by addition of ice, acidified with 1 l of 2 N hydrochloric acid and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and the residue is purified by chromatography on a column of silica eluted with a 1/1 heptane/ethyl acetate mixture and crystallization from a heptane/ethyl acetate mixture. 42 g (39%) of 3-(1-methyl-3-pentylureido)phenylboronic acid are obtained in the form of a pink solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[NH:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=O)(=[O:3])[CH3:2].CC([O-])(C)C.[K+].C1COCC1>C1COCC1>[CH3:11][O:10][C:7]1[CH:6]=[C:5]2[C:4]([C:1]([OH:3])=[CH:2][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:12]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2ccccn2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc2c(O)cc(-c3ccccn3)nc2c1
Temperature: 70 °C
Yield: 83.7 %

Procedure:
To a suspension suspension of Pyridine-2-carboxylic acid (2-acetyl-5-methoxy-phenyl)-amide (2.90 g, 10.7 mmol) in THF (50 mL) was added t-BuOK/THF (1M, 24 mL, 24 mmol). The reaction mixture was heated at 70° C. for 3 h and stirred overnite. The solvent was removed the in vacuo. Cold water was added to the residue and adjusted pH to 4.6 with aqueous 1.0 N HCl, filtered. The solid residue was purified over a Biotage 65M column (MeOH/CH2Cl2: 0 to 15%) to provide the product (2.26 g, 84%): LC-MS (retention time: 1.19, Method D), MS m/z 253 (M++1).
Reaction SMILES: O1CCCC1.[Br-].[F:7][C:8]([F:13])([F:12])[C:9]([Zn+])=[CH2:10].Br[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][CH:23]([F:25])[F:24])=[C:17]([Cl:26])[CH:16]=1.O>CN(C)C=O>[Cl:26][C:17]1[CH:16]=[C:15]([C:9]([C:8]([F:13])([F:12])[F:7])=[CH2:10])[CH:20]=[C:19]([Cl:21])[C:18]=1[O:22][CH:23]([F:25])[F:24]
Reactant: C=C([Zn+])C(F)(F)F
Reactant: FC(F)Oc1c(Cl)cc(Br)cc1Cl
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)c(OC(F)F)c(Cl)c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To 21 mL of a 1M tetrahydrofuran solution of 1-trifluoromethylethenyl zinc bromide prepared according to a method described in the literatures, a solution of 2.4 g of 4-bromo-2,6-dichloro(difluoromethoxy)benzene in 12 mL of N,N-dimethylformamide was added, and tetrahydrofuran was distilled off under reduced pressure. To the remaining N,N-dimethylformamide solution, 0.23 g of dichlorobis(triphenylphosphine) palladium (II) was added and the resultant mixture was stirred at 100° C. for 3 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and charged into 100 mL of water and the resultant mixture was extracted with diethyl ether (100 mL×1). The organic phase was washed with water and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with hexane to obtain 1.8 g of the objective substance as a brown oily substance.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[V+3:4].[Cl-].[Al+3].[Cl-].[Cl-].[Al].[Mg].C[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>ClCCCl.O1CCCC1.C1C=CC=CC=1>[V:4].[CH:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1.[CH:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCCCCC
Reactant: [V+3]
Agent: [Al+3]
Agent: [Al]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: [V]
Temperature: 25 °C

Procedure:
20 grams of vanadium trichloride, 32.8 grams anhydrous aluminum chloride, 3.2 grams of aluminum powder and 500 milliliters of benzene were added to a reaction vessel equipped with a stirrer, a reflux condenser and a thermometer. The reaction mixture was vigorously stirred and refluxed for about thirty hours in an inert atmosphere or argon, then cooled to room temperature. To the resulting mixture were then added, drop-wise, 30 milliliters of freshly-distilled tetrahydrofuran, followed by the addition of a slurry of activated magnesium prepared by reacting 45 grams of magnesium, 80 milliliters of tetrahydrofuran and 16 milliliters of 1,2-dichloroethane. The mixture was refluxed in an atmosphere of argon for about three days, cooled to room temperature, and the volume reduce to about 100 milliliters. Then, 200 milliliters of heptane were added, the mixture stirred, and the solvent removed until practically dry. An additional amount of heptane was then added, the mixture stirred and filtered. The residue was washed with benzene portions, the washings combined with the filtrate, and the solvent removed to yield zero valent dibenzene vanadium as a crystalline solid having infrared spectrum peaks at 988 cm-1, 957 cm-1, and 742 cm-1, which are consistent with those of the dibenzene vanadium compound obtained by the known process.
Reaction SMILES: [CH2:1](C(CC)(C([O-])=O)C([O-])=O)C.C(O)C.[Mg].[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=1)[C:22](Cl)=[O:23].S(=O)(=O)(O)O>CCOCC.C(Cl)(Cl)(Cl)Cl.O1CCCC1>[Br:16][C:17]1[CH:25]=[C:21]([C:22](=[O:23])[CH3:1])[CH:20]=[N:19][CH:18]=1
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cncc(Br)c1

Procedure:
44.2 g (0.276 mol) of diethylmalonate, 19.9 g (0.432 mol) of absolute ethanol and 7 g (0.288 mol) of magnesium chips are refluxed for 18 hours with stirring in 254 ml of ether and 1.27 ml of carbon tetrachloride. To this solution, 55.3 g (0.25 mol) of 5-bromonicotinic acid chloride in 170 ml of absolute tetrahydrofuran are slowly added dropwise and refluxed for a further hour. The reaction mixture is cooled in an ice bath and carefully mixed with 508 ml of 2N sulphuric acid. The organic phase is separated off, dried over sodium sulphate and concentrated by evaporation. The residue is taken up in 83 ml of water, 127 ml of glacial acetic acid and 16.6 ml of concentrated sulphuric acid and refluxed for 18 hours. The reaction solution is evaporated down, the residue is diluted with 200 ml of water and adjusted to pH 8 with sodium hydroxide solution. It is then extracted with chloroform, dried over sodium sulphate and evaporated down.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([C:9]([O:11]C)=O)=[CH:7][C:6]([C:13]([O:15][CH3:16])=[O:14])=[N:5]1.C(N(C(C)C)CC)(C)C.[C:26]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][NH2:41])[CH2:35][CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[I-].[K+]>CC#N>[CH3:16][O:15][C:13]([C:6]1[CH:7]=[C:8]2[C:9](=[O:11])[N:41]([CH2:40][CH2:39][CH:36]3[CH2:35][CH2:34][N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:38][CH2:37]3)[CH2:2][CH2:3][N:4]2[N:5]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: COC(=O)c1cc(C(=O)OC)n(CCBr)n1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2n(n1)CCN(CCC1CCN(C(=O)OC(C)(C)C)CC1)C2=O

Procedure:
A solution of 3-2 (14.0 g, 48.0 mmol), diisopropylethyl amine (25 ml, 144 mmol), Boc-4-aminoethylpiperidine (12.0 g, 52.6 mmol), and potassium iodide (2.39 g, 0.3 mmol) in 250 ml CH3CN was refluxed under N2 for 4.5 h then cooled, filtered and evaporated at reduced pressure. The resulting yellow residue was chromatographed on silica gel using EtOAc as eluent to give 3-3 as an off-white crystalline solid.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][C:23]1[S:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O.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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:26]3[S:27][C:23]([CH3:22])=[CH:24][CH:25]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
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: [K+]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3ccc(C)s3)CCC2)CCN(C)C1
Temperature: 90 °C

Procedure:
To a degassed solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 5-methylthiophene-2-boronic acid pinacol ester (100 mg, 0.575 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-DME (4 mL) and water (2 mL) was added Pd(PPh3)4 (17 mg, 0.0147 mmol). The reaction mixture was heated at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure and the residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(5-methylthiophen-2-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR, (CD3OD, TFA salt) δ (ppm): 7.3 (s, 1H), 7.0 (m, 2H), 6.71 (d, 1H), 6.58 (d, 1H), 4.72 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.51 (m, 1H), 3.12 (s, 3H), 3.03 (m, 4H), 2.8 (m, 2H), 2.4 (s, 3H), 2.2-2.3 (m, 5H).
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:14])[C@@H:5]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]([CH3:8])[CH3:7].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:45])=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:36][C:37]([C:39]3[N:40]=[N:41][N:42]([OH:44])[CH:43]=3)=[O:38])[CH2:30][C@@H:31]([OH:35])[C:32]([OH:34])=[O:33])=[CH:24][CH:23]=2)[CH:21]=1.CC(C)=O.CCN(CC)CC>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:45])=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C@@H:29]([NH:36][C:37]([C:39]3[N:40]=[N:41][N:42]([O:44][CH2:2][O:3][C:4](=[O:14])[C@@H:5]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]([CH3:8])[CH3:7])[CH:43]=3)=[O:38])[CH2:30][C@@H:31]([OH:35])[C:32]([OH:34])=[O:33])=[CH:24][CH:23]=2)[CH:21]=1
Reactant: O=C(N[C@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Reactant: COC(=O)N[C@H](C(=O)OCCl)C(C)C
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)OCOn1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)nn1)C(C)C
Temperature: 65 °C
Reaction time: 2 h
Yield: 7.7 %

Procedure:
(S)-2-Methoxycarbonylamino-3-methylbutyric acid chloromethyl ester (37.4 mg, 167 μmol) was added to a solution of (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (30.0 mg, 66.8 mol) in acetone (0.5 mL, 6.8 mmol). Et3N (18.6 μL, 134 μmol) was added and the resulting mixture was stirred at 65° C. for 2 hours. The mixture was then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (8.2 mg). MS m/z [M+H]+ calc'd for C28H31ClFN5O9, 636.18. found 636.1.
Reaction SMILES: C(OC([N:8]([CH:19]([C:24]1[CH:25]=[N:26][C:27]([N:30]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[N:31]2)=[CH:28][CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:22][CH:21]([CH3:23])[CH2:20][CH:19]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=1)[C:24]1[CH:25]=[N:26][C:27]([N:30]2[CH:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=[N:31]2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(N(C(=O)OC(C)(C)C)C(CC(C)C)c2ccc(-n3cc(C(F)(F)F)cn3)nc2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(CC(C)C)c2ccc(-n3cc(C(F)(F)F)cn3)nc2)nc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
To a 0° C. solution of (+\−)-methyl 6-(tert-butoxycarbonyl(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butyl)amino)nicotinate (110 mg, 4.7 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10 mL). The solution was stirred at 20° C. for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and washed with water (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give (+\−)-methyl 6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinate (800 mg) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 11.11 (d, J=4.0 Hz, 1H), 8.76 (s, 1H), 8.45 (d, J=1.6 Hz, 1H), 8.36 (d, J=1.6 Hz, 1H), 8.17 (d, J=9.2 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.86-7.82 (m, 2H), 6.59 (d, J=9.6 Hz, 1H), 4.54-4.49 (m, 1H), 3.83 (s, 3H), 2.06-1.97 (m, 1H), 1.72-1.58 (m, 2H), 0.96 (d, J=6.4 Hz, 3H), 0.89 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([NH:8][C:9](=[S:11])[NH2:10])=[N:6][CH:7]=1.Br[CH2:20][C:21](=O)[CH2:22][CH:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C:24]1=[O:29]>>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]([NH:8][C:9]2[S:11][CH:20]=[C:21]([CH2:22][CH:23]3[CH2:27][CH2:26][N:25]([CH3:28])[C:24]3=[O:29])[N:10]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Reactant: CN1CCC(CC(=O)CBr)C1=O
Product: CN1CCC(Cc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)C1=O

Procedure:
Prepared according to the method of Example 391, Step C, from 1-(5-bromo-3-(phenoxypyridin-2-yl)thiourea and 3-(3-bromo-2-oxopropyl)-1-methylpyrrolidin-2-one. 1H NMR (DMSO-d6 δ 1.60-1.72 (m, 1H), 2.08-2.14 (m, 1H), 2.51-2.58 (m, 1H), 2.68-2.78 (m, 5H), 3.02 (d, 1H), 3.21-3.29 (m, 2H), 6.80 (s, 1H), 7.13-7.47 (m, 6H), 8.25 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)(=[O:15])=[O:14])=[O:11])[N:3]=1.[H][H]>[Pd].C(O)C>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:10]([NH:9][C:4]1[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)=[O:11])(=[O:14])=[O:15]
Reactant: [H][H]
Reactant: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2N)n1
Reaction time: 1 h

Procedure:
A suspension containing 1 g of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-nitrobenzenesulfonamide, 0.2 g of 5% palladium on carbon and 50 ml of ethanol was shaken in a Paar apparatus under 40 p.s.i.g. hydrogen at ambient temperature. After one hour, the reaction mixture was filtered and the solids thereby recovered, which contained catalyst and desired product, was stirred with 10% aqueous sodium hydroxide. Filtration of that mixture and acidification of the filtrate with hydrochloric acid to pH 3 caused the desired product to precipitate. After removal by filtration and drying, the desired product melted at 212°-216° and showed infrared absorption peaks at 3200 and 3300 cm-1, consistent for the desired amino-containing compound. Mass spectrometry showed two particles of mass 198 and 123 units, equivalent to aminobenzenesulfonyl isocyanate and 2-amino-4,6-dimethylpyrimidine respectively, as expected for the desired compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(Cc1ccc(Cl)cc1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
256 mg (0.441 mmol) of (2R*,4S*)-2-benzyl-1-(4-chlorophenylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 66 mg (1.76 mmol) of sodium borohydride in analogoy to Example 2. The title compound ##STR35## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.48, FD-MS: M+ =484.
Reaction SMILES: [C:1]([O:13]C)(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.CO.[C:17]([O-:26])(=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23]>C(O)CO>[C:1]([O-:13])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[C:17]([O-:26])(=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: O=C([O-])CCCCC(=O)[O-]
Solvent: CO
Solvent: OCCO
Product: O=C([O-])c1ccc(C(=O)[O-])cc1
Reaction time: 2 h

Procedure:
In a stainless steel distilling pot having a drain valve in the bottom is placed 11 lbs. (5.0 kilograms) of dimethyl terephthalate, 7 lbs. 6 oz. (3.35 kilograms) of ethylene glycol and 120 milliliters glycol solution of 2.45 grams Mn(C2H3O2)2 . 4H2O and 1.69 grams of Sb2O3. The mixture is heated to 240°C. over a 3 hour period during which time 1,650 grams of methyl alcohol and 750 grams of ethylene glycol are removed sequentially. The resulting monomer is drained to a stainless steel autoclave fitted with stirrer, charging port, vacuum distillation system, and extrusion valve. To the autoclave is added 285 grams of a glycol solution of di(2-hydroxyethyl) adipate (equal to 163.6 grams of adipic acid), 24 milliliters of an ethylene glycol solution of phosphoric acid containing 1.79 grams of phosphoric acid (as 100% H3PO4), and 27 milliliters of 20% TiO2 in ethylene glycol. The pressure is reduced slowly over a period of about 2.5 hours to about 5 torr, then the autoclave is pressurized with inert gas (Kemp gas) and 317 grams of PHP-20EO diluted with 200 milliliters of ethylene glycol is added. The pressure is gradually reduced over a period of 0.5-hour and polymerization is then continued for about 2 hours at 225°C. at 1.3 torr. The melt is extruded, cooled, and cut to 0.25-inch (0.64-centimeter) flake. The flake has a relative viscosity of 11.1 and contains 0.077% nitrogen and 4.5 mole % adipate units.